R3 Consumer Guide for Stem Cell and Exosome Therapy

R3
Consumer Guide
for Stem Cell and
Exosome Therapy

Brought to you by
the Regenerative Genius Team at

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Table of Contents

Introduction 3 Inflammatory Bowel Diseases 140

The Skinny on Stem Cells 5 Kidney/Renal 152
The Exosome Revolution 11 Liver Failure 159
What You Need to Know About PRP Therapy 15 Systemic Lupus Erythematosus 168
FAQ’s on Regenerative Medicine and Lyme Disease 177
Stem Cell and Exosome Therapy 18
Migraines and Chronic Headaches 185
CONSUMER GUIDE TO STEM CELL TREATMENT FOR:
Multiple Sclerosis 192
Amyotrophic Lateral Sclerosis 23
Osteoarthritis 206
Ankylosing Spondylitis 30
Parkinson’s Disease 216
Anti-Aging 38
Peripheral Neuropathy 223
Ataxia 51
Premature Ovarian Failure 233
Autism 60
Psoriasis 242
Back Pain 69
Rheumatoid Arthritis 250
Cerebral Palsy 80
Rotator Cuff Disease 259
COPD 90
Spinal Cord Injury 266
Diabetes 98
Stroke 277
Erectile Dysfunction 107
Systemic Sclerosis (Scleroderma 287
Duchenne Muscular Dystrophy 115
Traumatic Brain Injury 294
Hair Regeneration 124
Trigeminal Neuralgia 302
Heart Disease 133

No portion of this Document may be reproduced without the

Express Written Consent of R3 Stem Cell.

Disclaimer: This guide’s education does not constitute medical advice.

The USA FDA considers stem cell therapy experimental. Any claims made in
the Guide refer to procedures performed outside the USA.

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Introduction

I used to hear it all the time. “Stem cells are would be a shame, as there are millions
a fad. Stem cells don’t work. There’s of individuals globally who can,
not enough evidence yet. You and should, benefit. That’s why
shouldn’t offer something R3 has over 45 Centers in
that’s not FDA Approved.” 7 Countries offering stem
And so on. You know what cell biologics that are top
though? After thirteen quality, very safe and highly
years and 25,000 stem cell affordable!”
procedures around the world
He added, “The only way for
at R3’s Centers, I don’t hear
R3 to combine quality, safety
those thoughts anymore.
and affordability was to complete
Now, I often hear, “You changed my the regenerative treatment vertical
life!”“This is incredible.”“I don’t have to think and build state-of-the-art labs to process tissue
about the pain anymore.”“My child spoke for the first and create first rate biologics. That way, R3 maintains
time ever!”“I’m off the transplant list!” the strictest quality control from start to finish, with
The reality is that when performed properly, stem cell substantial global volume that has reduced our costs
treatment works extremely well for many conditions. so those savings are passed on to patients!”
There are now tens of thousands of peer-reviewed Patient satisfaction year over year at R3 has exceeded
publications showcasing statistically significant 85%. Over 85 out of 100 patients say they would “do
results along with established safety, and I’m happy it again” and “recommend it to friends or family”. The
to debate ANYONE who desires a robust discussion goal is to contribute extensively towards pushing
on the merits. the field of regenerative medicine forward. The R3
R3 Stem Cell is the world’s largest regenerative Stem Cell Masterclass has
therapy provider. R3 offers cutting edge regenerative been downloaded
medicine therapies with the potential to harness over 10,000
the body’s ability to repair, regenerate and restore times (stemcell
damaged tissue. This may allow individuals to masterclass.org),
decrease pain and increase functional ability in a cost and R3’s YouTube
effective manner with a low risk profile. channel contains
over 800 educational
R3’s mission is to offer therapies that are: videos and success
• Available Globally stories.

• Safe For Patients

• Effective Clinically
• Affordable To All
According to Founder/CEO David Greene, MD, PhD,
MBA, “Developing first rate stem cell therapies and
offering them in one location to only the top 1%

David Greene, MD, PhD, MBA,

Founder/CEO

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With a research team consisting of four This book contains over 30 Chapters on
PhD’s, R3 continues to publish stem cell and exosome therapy
extensively on regenerative for specific medical conditions,
topics in peer-reviewed along with three chapters
journals (over 8 papers in the on stem cells, exosomes
past year alone). and PRP therapy. It is
important for you to be
At the end of the day,
knowledgeable about your
R3’s success comes down
options so that there is a
to patient outcomes and
comfort level when making
satisfaction. If regenerative
decisions on what’s best for your
therapies didn’t work, then how is
(or a loved one’s) health.
it that R3 performs over 150 procedures
per month globally? Over a third of those Investing in your health with regenerative therapies
procedures are word-of-mouth referrals from happy provides an excellent return on your investment. R3’s
patients! track record of incredible patient outcomes, safety,
customer service and affordability make it an easy
With clinics in 7 countries, there is bound to be
choice.
one that is convenient for you. R3’s protocols
are consistent globally, and the value offered is You don’t want to second guess yourself when it
substantial. For example, R3 knows that multivitamin comes to investing in a potentially life-changing,
infusions boost outcomes with the stem cells. So we revolutionary new technology such as stem
include it at no cost for all patients. We know that PRP cell therapy. Globally, R3 Stem Cell offers free
boosts success for stem cell joint injections. Yes, that’s consultations to see if you or a loved one is a
included free as well! candidate. Contact us today!

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The Skinny
on Stem Cells
Well, it’s official. The future of medicine is here! After replacement, and the pain relief lasts for two years.
a century of medicine consisting of mostly band- That’s the reality of regenerative medicine.
aid options that suppress symptoms, regenerative
So let’s delve into what stem cells are. Stem cells exist
medicine is now a reality.
in all tissues throughout the body and their primary
Well, part of it is a reality. I’ll explain the “fictional” role is to repair and maintain the tissue where they
part in a bit. Let’s start with defining regenerative reside.
medicine. Regenerative medicine may be defined
There are three main characteristics of stem cells:
as the process of replacing or “regenerating” human
cells, tissues or organs to restore or establish – Copy: They are able to make exact copies of
normal function. This field holds the promise of themselves and are capable of dividing and
regenerating damaged tissues and organs in the renewing themselves for long periods of time.
body by replacing damaged tissue or by stimulating These cells can proliferate or replicate in culture
the body’s own repair mechanisms to heal tissues or for months or even years depending on the cell
organs. type.
Here’s an example that will explain – Unspecialized: They are
the old practice of medicine unspecialized cells. Stem cells do
versus the new. Tom comes not have any specific function
in with knee arthritis that and are not necessarily
bothers him every day. committed to one specific
His orthopedic doctor type of tissue.
performs a steroid injection, – Differentiation: They can
prescribes NSAIDS and puts give rise to a specialized cell
him in a brace. Tom gets 3 in the human body. The process
weeks of relief, while the NSAIDS of the cells converting into a specific
lead to an ulcer and it’s too hot outside to type of tissue or specialized cell is called
wear the brace. Then the pain is worse than ever. differentiation
Does any of that treatment actually work to repair Ok so they can replicate, they are unspecialized,
his arthritis issue? Does any of it actually promote and at some point they turn into a specialty cell by
new cartilage formation? It’s a rhetorical question, differentiating. So let’s define the “Action Potential”.
the answer is NO! And he’s worse off than when he Depending on the type of stem cell, they have
started. different Action Potential of what they can become:
Now, picture this. Tom visits R3 Stem Cell. The R3 • Totipotent – these stem cells are capable of
provider performs the same exam, evaluates the turning into ANY cell type in the body, and they
same x-rays. Instead of the steroids, NSAIDS and can also become the embryo or placenta. It would
brace, the doctor performs a platelet rich plasma truly be awesome if these really existed, were safe,
therapy along with an injection of mesenchymal and we could control them.
stem cells derived from umbilical cord Wharton’s Jelly • Pluripotent – these stem cells are capable of
tissue. Within 3 weeks, Tom’s knee is feeling 20 years turning into ANY cell type in the body, but
younger and he begins the recreational activities he’s they cannot become the embryo or placenta.
been missing. Unfortunately they are mostly fictional for human
He’s able to play with his grandkids, avoid a knee use, as described below.

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• Multipotent– these stem cells are capable of stem cells (iPSC’s) is that iPSCs retain some degree
turning into multiple cell types in the body, but of residual epigenetic memory from the somatic cell
not all. These stem cells are not only a reality, but source from which they are derived, and this can lead
helping patients globally with many medical to their biased differential potential.
conditions. These are the stem cells R3 uses, and
are described more below. So what is being used successfully? Well, it’s the
multipotent stem cells, which have the following
• Unipotent – these unfortunate stem cells are only sources:
capable of turning into one cell type. That’s great
if it’s the type of stem cell you want, but not very 1.Birth tissue – amniotic fluid, placenta, umbilical
practical. cord tissue/blood

Now that we’ve described the Action Potential 2. Menstrual blood – not actually performed yet,
categories, let’s describe where these cells actually but it’s been shown as a great source.
come from. Pluripotent stem cells are known to come 3. Wisdom teeth– as close to pluripotent activity as
from three sources: you can get.
1. Embryos left over after an in vitro 4. Autologous source (the patient him/
fertilization. (Embryonic) herself).
2. Fetal Tissue obtained from a. Bone marrow
an abortion. (Embryonic)
b. Adipose (fat)
3. Induced Pluripotent Stem
Cells – taking a specialty Ok so when you start
cell, and inducing it back to delving into multipotent
being a pluripotent stem cell. stem cells, there are 3
predominant sub-types, Most
Discussing these sources in depth is adult stem cells are multipotent. Here
not necessary. Why? Because notwithstanding are the most common:
the ethical issues to ponder over sourcing, none of
the 3 sources producing pluripotent stem cells are o HSC– hematopoietic stem cell – give rise to all
safe to use in humans. After literally billions of dollars blood cell types
being pumped into pluripotent stem cell research
over the past few decades, NONE of them are o MSC – mesenchymal stem cell – bone, muscle,
acceptable to use in humans! cartilage, fat, etc.

It’s very sad, yes, and what happens is one of two o NSC - Neural Stem Cells – can give rise to glial
things. Either the pluripotent stem cells are either and neuronal cells
immediately rejected, which can be serious. Or they Bone marrow tissue contains both MSCs and HSCs.
can form tumors, which leaves the patient worse off If you undergo a bone marrow stem cell procedure,
than before. you will need to use your own bone marrow.
Induced pluripotent stem cells are looked at as the Bone marrow contains MHC-2 markers, which will
potential holy grail of regenerative medicine, as you cause a rejection reaction unless matched to that
can achieve pluripotency without an ethical issue. individual.
One of the additional issues with induced pluripotent While bone marrow is still used around the world,

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R3 Stem Cell does not use

it. Why? If you look at the
table below, you can see that
Stem Cell Fitness MSCS
the amount of stem cells in Newborn: 1/10,000

one’s bone marrow drops

MSCs Per Marrow Cells

precipitously as we age. So Mesenchymal stem cells (MSCs) are ADULT STEM CELLS traditionally found in the bone
there are better options! marrow. However, MSCs can also be isolated from other tissues including discarded cord blood
and umbilical cord tissue from donors following normal C section births. Multipotent stem
cells, MSCs differentiate to form adipocytes, cartilage, bone, tendons, muscle, and skin.
If a patient is going to have
an autologous stem cell
procedure, the best option is Teen: 1/100,000
with adipose (fat) tissue. As 30 YRS: 1/250,000 50 YRS: 1/400,000 60+ YRS: 1/1,000,00,000

a person ages, the amount Newborn Teen

Age
30 YRS 50 YRS 60+ YRS
of mesenchymal stem cells
in the adipose remains very
high. While they are not as active as a “youngster”, the global procedures with umbilical cord stem cells in
numbers are still there. Unfortunately, the quality of the past decade, R3 has not experienced a rejection
those stem cells is diminished as a lot of them are just reaction!
older and not very active. But once again, they can be
very effective nevertheless. Umbilical cord Wharton’s Jelly tissue has a
considerable amount of mesenchymal stem cells per
R3 Stem Cell has some centers that perform centimeter. Research from over 20 years ago showed
autologous adipose stem cell therapy. Even though that there are close to 5 million live mesenchymal
the capacity of the adipose stem cells to promote stem cells per cm of cord. So even if an umbilical
regeneration is diminished, good results can still be cord’s stem cells are not expanded, there are over 150
seen! million stem cells per cord available!
Over 99% of individuals calling in Umbilical cord stem cells have
globally to R3 Stem Cell seeking been shown to proliferate faster
a regenerative procedure are than either bone marrow
interested in the stem cells or adipose sources, be
obtained from birth tissue. more active with colony
Options include amniotic forming units, and have the
fluid, amniotic membrane, highest amount of anti-
placenta or umbilical inflammatory qualities.
cord tissue/blood. R3 Stem
Cell uses predominantly Studies have shown that not
mesenchymal stem cells obtained only do umbilical cord stem cells
from the umbilical cord tissue, which is NOT promote tumor formation, but
known as Wharton’s Jelly. These stem cells are very they actually have the opposite effect. We get this
active, powerful and pure. question a lot, “Will I get cancer from my stem cell
procedure?” The answer is no.
Interestingly, stem cells obtained from umbilical
cord tissue do not get rejected. Why? They do not When it comes to treating various diseases with
contain MHC-2 markers (HLA-2), so they are not stem cells, it’s important to know up front that only
recognized as foreign in the recipient. After 25,000 multipotent stem cells should be used. Those are

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the only ones that have been shown to be safe. The o Angiogenesis = new blood flow
chapters in this book showcase just how well stem
cells work for the 30 conditions discussed. But in o Inflammation Reduction
reality, there are at least 30 more conditions that also o Immune Modulation = e.g. inhibits cytokine
benefit, including these categories: ”storm” that can lead to ARDS in the lungs.
1. Arthritis – all types o Anti-apoptosis = prevents cell death
2. Autoimmune conditions – lupus, psoriasis, o Cell to Cell signaling = new cell proliferation,
RA, etc. chemotaxis.
3. Diabetes o Direct Mechanisms = unknown.
4. Neurologic – neuropathy, spinal So does the DNA from the donor stem
cord injury, ALS, MS, cells become part of the recipient
Parkinsons, Alzheimers, DNA? The answer is no. The
Stroke, TBI term “engraftment” means
5. Autism and CP that the cells would engraft
and become part of the
6. Inflammatory Bowel recipient’s DNA. It also means
Disease the administered stem cells
would be the ones turning
7. Muscular Dystrophy into a patient’s specialty cell (i.e.
8. Hair Loss cartilage, liver, lung, etc).

9. Erectile Dysfunction All evidence points to NO, unless the

recipient undergoes a myeloablation first (such as
10. Premature Ovarian Failure with a bone marrow transplant). So in effect, the
recipient of adult stem cells from peri-natal tissue
11. Neuralgias and Neuropathy
does not become a chimera (have 2 DNA profiles).
12. Multiple Sclerosis From donor to treatment
13. Lyme Disease Here is a summary of how the stem cells are
obtained. In the USA, tissue acquisition companies
The list goes on and on actually, as more research
obtain consent from mothers undergoing a
continually comes out showing benefits. How do
scheduled c-section. Ethicists have determined the
stem cells work in one’s body? Over the past decade,
donors are not allowed to be paid.
scientists have learned a lot more about how
mesenchymal stem cells work in one’s body. The mothers complete a 210 question packet,
which eliminates over half of the potential donors.
Interestingly, we now know that when you receive
Questions about risk factors, recent travel, smoking,
mesenchymal stem cells, from your own body or
medical conditions, etc are asked.
a donor tissue, it’s typically NOT those stem cells
turning into your specialty cells. If the mother is accepted, the birth tissue is collected
into a sterile container in the operating room.
The power revolves mostly around PARACRINE (Cell
Remember, if the tissue isn’t donated, it’s typically
to Cell) signaling for:

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discarded so there are no ethical issues for

donation. Here’s an example. Julie has chronic
back and leg pain along with
The tissue is then transported inflammatory bowel disease
directly to the GMP tissue (IBD). R3’s consultant decided
processing lab. The to perform direct injections
processing of the tissue is in and around arthritic facet
performed in clean rooms joints in the back, along
that are ISO Certified. Once with an epidural procedure
completed, several samples to repair and regenerate the
are sent to a third party for pinched nerve root. Also, an IV
disease and sterility testing. drip procedure was performed to
assist with the IBD.
The biologics are kept in quarantine freezer
until all the quality control testing returns negative. If Basically, R3’s consultants perform a free consultation.
anything is positive, ALL the biologics are discarded Then they will make the recommendation that will
to ensure patient safety. The biologics are kept at -80 address the patient’s issues uniquely as opposed to a
degrees Celsius until just prior to administration. “one size fits all” approach.
R3’s biologics maintain viability over 90% after How many cells are recommended?
thawing, and the cells are extremely active. Testing of R3 Stem Cell uses evidence based medicine for its cell
R3’s batches continually shows purity, potency and count recommendations. Certain conditions have
effectiveness. This is of utmost importance to ensure been shown to have great results with one million
patient outcomes, trust and integrity. stem cells per kilogram, while others necessitate 2 to
How are they administered? 4 million cells per kilogram.
Not all stem cell treatments are performed the same. A lot of patients who come to R3 after failing
Options for application include: treatment at other centers received way too few
cells, and paid way too much for their treatment.
• Intravenous Drip That’s a huge disservice to a patient. Numbers of cells
• Direct Injection – joint, soft tissue. matter! More is better up to a point, and for certain
conditions a series of treatments has been shown to
• Epidural be best for optimal results.
• Nebulizer For joint injections, studies have shown that 25
million stem cells are just as effective as 100 million.
• Intra-nasal So R3 uses the evidence based numbers so patients
• Intrathecal (spinal cord) receive cost effective treatments.

• Subcutaneous In summary, here are the key points to

understand.
• Intralympatic
• Stem cells are integral to regenerative
R3’s providers make application decisions based on medicine, which is the process of replacing or
factors such as condition type, severity, age, and “regenerating” human cells, tissues or organs to
weight. Often times a combination treatment is the restore or establish normal function.
best approach.

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• The 3 main features of a stem cell are the ability • Stem cell survival once administered depends on
to replicate, being undifferentiated, and the the method of application.
ability to give rise to a specialized cell.
One of the biggest points to understand is that stem
• Action potential of stem cells include totipotent, cell therapy, in its current form is not a cure. I refer to
pluripotent, multipotent and unipotent. it as a mitigating procedure, that helps the root cause
• Embryonic stem cells and iPSC’s show huge of a disease but not in a permanent way. We know
potential in research studies for clinical use, but that patients want to be “one and done” forever by
neither have reached that point due to safety just receiving one procedure and be good for life. But
concerns. that is not reality!

• Adult stem cells are multipotent and obtained Because of that, R3 Stem Cell’s Mission Statement is to
from either bone marrow, adipose tissue, keep regenerative therapies very safe, effective and
menstrual blood, teeth or other body tissues. affordable. Since patients will need a repeat procedure,
Donor adult stem cells predominantly come from it is important to keep the procedures as affordable as
peri-natal birth tissues (amniotic, umbilical). possible. And that’s exactly what we do!
• The amount of stem cells in bone marrow Over the past 10 years, R3 Stem Cell’s centers have
dramatically decreases with increasing age. performed more stem cell procedures than anyone.
• Adipose stem cells are predominantly These procedures have been effective in over 85%
mesenchymal stem cells, high in number of patients, and adverse events have been mild to
throughout life, and remain somewhat active. moderate and temporary in over 99.9%.

• Adult stem cells from an older individual Based on existing research regarding what type of
(autograft) are lower in number and less active stem cells are safe and effective to use, R3 Stem Cell
than from a younger individual. has developed over 25 customized protocols for
patients so that the best results can be achieved.
• Stem cells from peri-natal donor tissue (allograft)
are immunologically privileged, robust and If you or a loved one would like to see if stem cell
plentiful. therapy is indicated for your condition, call R3 Stem
Cell today to set up a free consultation at +1 (844)
• Stem cells administered to a patient do not
GET-STEM or email [email protected].
appear to engraft into recipient DNA. They
exhibit their effects mostly through Paracrine
signaling.

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The Exosome Revolution

Exosomes have seen exponential interest over the do have VERY important functions. They participate
past decade in regenerative medicine. What’s their in cell to cell communication, which can promote
deal?? Why are they so popular and how did all the cellular repair, initiate new blood flow and provoke
interest begin? trophic activities.
Let’s start with a bit of basic science as to what The word “trophic” means growth, and an example
exosomes actually are. Exosomes are actually of an exosome function is to promote formation of
particles that are 30-150 nanometers in size. That myelin sheath around a neuron. In a patient with
means they are actually nano-technology. multiple sclerosis whose own immune system is
To put that size into perspective, a typical stem attacking and destroying myelin sheath, having
cell is 12,000 nanometers. That makes exosomes exosomes to initiate new myelin sheath formation
approximately 100 times smaller than a stem cell! may lead to improved function and a better quality of
Exosomes are not cells, in fact they do not have a life. Much better than the “garbage truck” theory!
nucleus, and they do not replicate like a cell can. Exosomes are formed inside cells (endosomal), and
Exosomes are actually part of a sub-group of what’s include a LARGE amount of proteins, RNA, DNA,
called Extracellular Vesicles. Extracellular vesicles (EVs) Amino Acids and metabolites. Picture below.
have three main types, which are: Cells release exosomes through a poorly
1. microvesicles (MVs) understood process where the vesicle fuses to the
plasma membrane and are then released into the
2. exosomes, and extracellular space. Exosomes are secreted by all cell
3. apoptotic bodies types and have been found in plasma, urine, semen,

Apoptotic bodies are actually dead

cells, so let’s immediately get those
out of the discussion. Microvesicles
(MVs) are protein containing vesicles
formed by an outward budding of
the cell membrane. They are larger
than exosomes, between 100 to 1000
nanometers. The protein composition
in MVs depends on which type of
cell they originate from, and The
applications of and uses of MVs in the
clinical setting are similar to those of
exosomes.
Originally, exosomes and MV’s were
thought to be a source of cellular
dumping. A way for cells to get rid
of unwanted material, sort of like a
biological garbage truck. Over the last
few decades, scientists have come to
understand that exosomes and MV’s

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saliva, bronchial fluid, cerebral spinal angiogenesis, stress response, and

fluid (CSF), breast milk, serum, immune signaling.
amniotic fluid, synovial fluid,
So to summarize, there are
tears, lymph, bile, and gastric
three potential uses for
acid.
exosomes:
It's important to note that
• Exosomes are the drug
the contents of exosomes
– regenerative medicine
are highly dependent on
applications.
the cell types from which
they originate. For regenerative • Exosomes carry the drug –
medicine treatment, we are cancer, vaccines, etc.
not using exosomes from the sources
• Exosome markers for diagnostic.
mentioned above. Rather, they are obtained by
culturing mesenchymal stem cells from umbilical Over the past decade there has been an explosion
cord tissue, bone marrow or adipose tissue. The of peer-reviewed research studies evaluating the
exosomes are contained in the conditioned media benefits of mesenchymal stem cell exosomes. In fact,
byproduct of the cell culturing process, and then a PubMed search for the term “mesenchymal stem
separated out with special filtering. cell exosomes” displayed over 2500 results for studies
over the past decade.
Once exosomes are released into the extracellular
space, exosomes have a long circulating half-life, are When did the interest in exosomes really explode?
well tolerated by the human body, and capable of To understand how exosomes became so popular,
not only penetrating cellular membranes but also you only have to look at Stanford University’s mice
potentially targeting specific cell types. This may studies from 2005 by Dr. Tom Rando’s group. The
make them a great candidate as a drug delivery initial study involved connecting mice blood flow
system, where the exosome can be loaded with together through a technique called parabiosis.
specific anti-cancer drug and targeted to a tumor cell.
An old mouse blood supply was connected to a
It has been demonstrated that the mesenchymal young mouse, so they shared one circulation. They
stem cell exosomes themselves can act as a gave the old mouse a skeletal muscle injury, and it
therapeutic entity to help reduce tissue injury healed amazingly well. Much better than it normally
and promote repair and regeneration. That is the would.
type of exosomes used at R3 Stem Cell, where the
exosome manufactured is the actual biologic and The researchers wanted to understand what was
already has the desired components (no need in the young mouse blood promoting the healing
to inject any additional proteins). This ability to qualities. But when they repeated the study and
contribute to several distinct processes is due to the radio-labeled stem cells from the young mouse,
complexity of exosomes, as they carry a multitude NONE of them showed up in the muscle repair! So
of signaling moieties, including proteins, lipids, cell the theory of what was helping the repair turned out
surface receptors, enzymes, cytokines, transcription to be exosomes, and that is the theory to this day.
factors, and nucleic acids. These vesicles aid in a vast In fact, the same study has been repeated in mice
array of cellular functions, including intercellular over the past two decades for Alzheimer’s, cardiac
communication, cell differentiation and proliferation,

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hypertrophy, memory and aging. All of the results from mesenchymal stem cells, have been found to
have been impressive! While several companies have enormous benefits in a variety of diseases and
are trying to move through regulatory hurdles to injuries through the proteins and RNAs that they
incorporate “young blood” as a treatment, exosomes contain.
are now being used for treatment globally.
One of the amazing potential options for exosome
Note: Mesenchymal stem cell exosomes have not therapy involves brain injury (stroke, TBI, etc).
been approved by the USA FDA. Successful treatment of brain injuries is limited
due to the neuronal tissue and function. Successful
With regards to what exosomes are being used for, treatment of brain injuries is limited due to the
I’ll keep it to uses outside the USA. R3 Stem Cell need for swift diagnosis and difficulties in delivering
International uses exosomes for the following: therapeutics past the blood-brain barrier for swift
1. Aesthetic – hair regeneration, facial diagnosis and difficulties in delivering therapeutics
rejuvenation and erectile dysfunction. past the blood-brain barrier (BBB). Additional
complications arise due to the myriad of changes that
2. Musculoskeletal – soft tissue overuse take place (BBB). Additional complications arise due
conditions (plantar fasciitis, tennis elbow) and to the myriad of changes that take place following
arthritis in joints/spine. brain damages. MSC-Exos are not only capable
of crossing the BBB (Blood Brain Barrier) through
3. Systemic – Exosomes have been shown to
intravenous or intranasal delivery, but also have
reduce inflammation, promote tissue repair/
beneficial effects in treating chronic inflammation
regeneration, reduce oxidative stress, promote
in and promoting healthy healing, making them a
new blood flow and more. Systemically, they
potential therapeutic for complex brain injuries.
are showing effectiveness for autoimmune
disorders, wound healing, and in the past few When exosomes are placed into a person for
decades, studies have demonstrated that MSC- treatment through either an IV, intranasal, injection,
Exos can have advantageous effects in various nebulizer, etc they are taken up by recipient cells
contexts including neurological, respiratory, (i.e. ingested) through a poorly understood process.
cartilage, kidney, cardiac, and liver diseases Most likely, cells with inflammation ingest exosomes,
which then release their contents
Exosomes, and specifically
(payload) into the cell. As
exosomes derived
seen above, this

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includes a considerable amount of proteins which depending on their presentation.

then initiate a substantial intracellular response.
Typically, R3 Stem Cell’s clinics incorporate both
While it is beyond the scope of this chapter to mesenchymal stem cells and exosomes together
elucidate all of these intracellular responses, the to benefit from the “1-2 punch” aspect. Exosomes
end result is a substantial amount of inflammation typically show clinical response faster than the stem
reduction, immune system modulation and cells, and often don’t last as long. So the combination
trophic processes. This may include tissue repair, maximizes the response!
regeneration, new blood flow and resulting cell
to cell communication that promotes a regional With over 40 Centers of Excellence in 7 countries, R3
response. An example would be protection of the Stem Cell is the world’s largest regenerative therapies
myelin sheath from damage due to Multiple Sclerosis provider. Over 25,000 procedures in the past decade,
or peripheral neuropathy. and for the third year in a row R3 Stem Cell has been
named the World’s Best Regenerative Therapies
R3 Stem Cell’s labs have developed innovative Provider by Corporate Vision!
processes to produce highly concentrated exosome
products for patient treatments internationally. Over Call R3 today to set up your free consultation by
20 customized protocols exist to maximize patient calling +1 (844) GET-STEM or email us at info@
outcomes, so patients are often treated differently r3stemcell.com.

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 W H A T YO U N E E D T O K N O W A B O U T P R P T H E R A P Y

What You Need to Know

About PRP Therapy
Platelet Rich Plasma Therapy, known as Before discussing how PRP works, let’s
PRP, is a treatment that uses your talk platelets for a second. Platelets
own blood. This makes it an are produced in one’s bone
“autologous” procedure, where marrow from cells called
“auto-“ refers to self. By using megakaryocytes. While
your own blood, the procedure platelets possess almost every
is inherently very safe. characteristic of a cell, they
don’t actually have a nucleus.
Disclaimer: The procedures
Therefore they cannot replicate
mentioned below are not FDA
and not truly cells.
approved.
Interestingly, platelets are shaped like
PRP has turned out to be a fantastic procedure
plates initially. That’s how they got their name. When
either by itself, or used in conjunction with exosomes
they are activated, though, they begin to display
or mesenchymal stem cells for:
tentacles and look very different.
1. Injections for painful joints, spine and soft tissue
A normal platelet count in an individual is between
overuse conditions.
150,000 and 450,000 per microliter of blood. If one’s
2. Aesthetic procedures for hair regeneration, ED platelet count falls below 10,000 to 20,000, the risk of
and facial rejuvenation. bleeding develops. Platelets are instrumental in the
clotting process.
3. Neuropathy and neuralgia procedures.
However, they do a LOT more than just help with
4. Nebulizer for lung conditions. clotting! The functions of platelets include:
5. Epidural procedures for nerve damage/ • Hemostatic Sealant – they stop bleeding
compression.
• Scaffold for tissue regeneration
6. Intranasal procedures for CNS repair.
• Growth factor concentrator
But what happens to your blood?? • Stem Cell Binding
PRP starts very simply with a blood draw, as if you
were at a lab. Depending on the procedure being • Resting State – plate appearance
performed, anywhere from 10cc to 60cc may be
• Active State – octopus like
withdrawn. The whole blood is mixed with a blood
thinner such as Heparin to prevent clotting. • Growth factors
The blood is then spun at three to four thousand • Chemotaxis – attracts cells
RPM’s for 5 to 10 minutes, which separates your
blood into a top layer of plasma and a bottom layer • Stem cell attractant
of red blood cells (dark). The top part above the red • Proliferation
blood cell portion is used for the treatment, with the
plasma just above the RBC’s containing the largest • Promote Cell Division
percentage of platelets and growth factors.

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Platelets contain over 30 bioactive Notice the amazing functions that

proteins, many of which have a these growth factors perform!
fundamental role in tissue
healing. The goal with PRP, at times, is used by
PRP is to concentrate itself for regenerative
the platelets from procedures. It may
one’s blood work very well.
significantly more However, there are
than it contains a few key points
normally. Preferably that need to be
three to five times mentioned:
more. 1. We call PRP a minor
Numerous proteins are league regenerative
contained in the alpha- procedure. One reason is
granules of platelets: that PRP has about 12 growth
factors, whereas, mesenchymal
• platelet-derived growth factor (PDGF) stem cells have over 80.

• transforming growth factor (TGF) 2. For most applications, using PRP by itself means
a series of treatments will be necessary. More
• platelet factor interleukin (IL) studies are showing that multiple PRP treatments
• platelet-derived angiogenesis factor (PDAF) are necessary to get best benefit.
• vascular endothelial growth factor (VEGF) 3. PRP therapy is NOT a stem cell procedure. While
• epidermal growth factor (EGF) there are some stem cells in whole blood, there
are just not enough to refer to PRP as a stem cell
• insulin-like growth factor IGF treatment. Beware of this with clinics trying to
• fibronectin. call it that.

• They act as
transmitters in Platelet Growth Factor Type Growth Factor Source Biological Actions
most processes in Platelet derived growth Platelets, osteoblasts, endothelial cells, Mitogenic for mesenchymal celss and osteoblasts, stimulates
factor (a-b ) macrophages, monocytes, smooth muscle cells chemotaxis and mitogenesis in fibroblasVglial/smooth muscle cells,
tissues, particularly in regulates collagenase secretion and collagen synthesis, stimulate
healing where they Transforming growth factor Platelets, extracellular matrix of bone, cartilage macrophage and neutrophil chemotaxis
are responsible for TGF(alpha -beta) matrix, activated THl cells and na ural killer cells, Stimulates undifferented mesenchymaI cell proliferation regulates
endothelial, fibroblastic and osteoblastic mitogenesis; regulates
macrophages/monocytes and neutrophils
cellular proliferation, collagen synthesis and collagenase secretion, regulates mitogenic
differentiation, Vascular endothelial growth Platelets, endothelial cells effects of growth factors, stimulate endothelial chemotaxix and
factor, VEGF anglogenesis, inhibits macrophage and lymphocyte proliferation
chemotaxis (calling in Epidermal growth factor, Platelets, macrophages, monocytes increases angiogenesis and vessel permeability, stimulates
stem cells) and tissue EGF mitogenesis for endothelial cells
Stimulates endothelial chemotaxis / angiogenesis, regulates
repair. Fibroblast growth factor, Platelets, macrophages, mesenchymal cells,
collagenase secretion, stimulates epithelial /mesenchymal mitogenesis
FGF chondrocytes, osteoblasts
Connective tissue growth Platelets through endocytosis from Promotes growth and differentiation chondrocytes and osteoblasts,
factor CTGF extracellular environment in bone marrow mitogenlc for mesencymal cells, chondrocytes and osteoblasts
Insulin like growth factor - Plasma, epithelial cells, endothelial cells, Promotes angiogenesis cartilage regeneratlon, fibrosis and platelet
1 IGF -1 fibroblasts, smooth muscle cells, osteoblasts, adhesion, Chemotaxis for fibroblasts and stimulates protein synthesis,
bone matrix enchances bone formation by proliferation and differentiation of
osteoblasts

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R3 Stem Cell typically combines • Spine arthritis and

PRP with either stem cells degenerative disc disease
and/or exosomes
• TMJ
to turn it into a
major league There have also
regenerative been papers
treatment. detailing PRP
The PRP acts utility for
as a great lung disease,
scaffold for neuropathy,
new tissue neuralgias,
repair and nerve repair
regeneration, and all types
and also R3 of inflammatory
feels like the PRP issues.
activates the stem cells
In the realm of aesthetics,
faster too.
PRP therapy has been fantastic
Numerous studies have shown that for hair regeneration (we combine with
increasing age only mildly affects PRP quality. So exosomes), ED (we combine with exosomes) and
we use PRP still in older patients, and also there is facial rejuvenation (also combine with exosomes).
no discernible difference between PRP quality in
R3 Stem Cell’s centers utilize a novel method of
males versus females.
activation for PRP known as photo-activation. This
There are several hundred studies detailing the activates what’s called very small embryonic like
benefits of PRP therapy for soft tissue conditions stem cells in the blood (VSELS), and also increases the
such as: growth factor secretion from platelets over 4 weeks
instead of the usual 4 days.
• Achilles tendonitis (should use stem cells
concomitantly) When patients come into an R3 Stem Cell Center
globally, PRP is included in most treatments for free.
• Plantar Fasciitis
With intravenous procedures, PRP treatment is not
• Rotator Cuff tendonitis (should use stem cells offered as putting the PRP IV would simply dilute it
concomitantly) back in with whole blood.
• Elbow tendonitis However, whenever injections, nebulizer, epidural,
• Greater Trochanteric Bursitis intranasal are performed, then PRP is often included
to boost patient outcomes.
When it comes to joint and spine pain, there are also
many peer-reviewed papers detailing PRP benefits If you or a loved one would like to find out if PRP
for: treatment may help your condition, call R3 today at
+1 (844) GET-STEM or email us at info@r3stemcell.
• Hip and knee arthritis
com for a free consultation!

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 FAQ’S ON REGENERATIVE MEDICINE AND STEM CELL AND EXOSOME THERAPY

FAQ’s on Regenerative Medicine and Stem Cell

and Exosome Therapy
What is Regenerative Medicine? embryonic stem cells). These can turn into
Regenerative Medicine is therapy any kind of cell in the body. Embryonic
designed to repair and regenerate stem cells are derived currently
damaged body tissues such as from either an aborted fetus, or
tendon, ligament, cartilage, bone, a left-over embryo after an IVF
organ, nerves. It’s a different procedure. Currently, embryonic
approach than the way medicine stem cells are not safe to offer
has been offered for centuries, to patients, as they commonly
where treatments and medications are result in rejection, or possibly tumor
typically a “band-aid” approach. formation.

The concept of Regenerative Medicine is to shift The second type is termed limited stem cells (also known
the paradigm of patient therapy into something as adult stem cells). These stem cells come from either:
that can assist with tissue repair, rather than just 1. Autologous source – the patient’s own bone
suppressing symptoms (like a narcotic). Traditional marrow or fat tissue.
therapies such as cortisone injections simply do not
offer healing potential, and actually make patients 2. Birth tissue – placenta, amniotic fluid, umbilical
worse. So Regenerative Medicine uses substances cord tissue or blood.
that provide potential to work on the healing process 3. Menstrual blood
for these injuries by providing building blocks known 4. Wisdom teeth
as stem cells along with exosomes, growth factors
and platelets that spur the body’s natural healing Of note, R3 stem cell clinics do not work with
processes to ramp up. embryonic stem cells, only adult stem cells. There are
about ten different kinds of adult stem cells. At R3
What are Stem Cells? Stem Cell Clinics, two separate kinds are utilized:
Stem cells are made by the body’s bone marrow and
are able to differentiate into several different cell types. 1. Hematopoietic Stem Cells – these are found in
They are a veritable “blank slate”. They can replicate human bone marrow, and umbilical cord blood and
into more unspecialized stem cells, or they may react are able to differentiate into several cell types.
to the environment in which they are placed by 2. Mesenchymal Stem Cells (MSC’s) – MSCs have
receiving signals from that environment telling them been isolated from placenta, adipose tissue,
which differentiation “pathway” to go down. lung, bone marrow and blood. They are able
This may be to turn into a skin cell or muscle, to differentiate into many different cell types
cartilage, tendon, bone, red blood cell and many while also assisting with the human immune
others depending on the type of stem cell. By response.
ramping up production of the cells needed to
stimulate repair, having extra supply in the area can
Does Insurance cover regenerative
provide the difference between an inadequate result
procedures?
and one that regenerates perfectly. Insurance does not currently cover regenerative
medicine procedures for the most part in any country.
What are the types of Stem Cells? There are certain instances in surgery where there are
There are two basic types of stem cells. The first codes for the various procedures. But by and large, the
is known as pluripotent stem cells (also known as procedures are considered a fee for service.

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 FAQ’S ON REGENERATIVE MEDICINE AND STEM CELL AND EXOSOME THERAPY

What are the types of Stem Cells? typically publish our pricing on social
The umbilical cord mesenchymal media and our websites for each
stem cells used by R3 Stem Cell location.
do not get rejected. We get For instance, currently in Mexico
frequently asked if there needs R3 Stem Cell offers 50 million stem
to be a related donor or whether cells, 25 billion exosomes, PRP and
a patient needs to have an a multivitamin IV for only $4,950
autologous umbilical cord blood USD. Not only is that pricing fantastic,
sample. but R3 will Price Match ANY comparable
The answer is no. The donor stem cells from the quote!
umbilical cord tissue are called “immunologically Also in Mexico, R3 Stem Cell’s pricing for 100
privileged” by scientists. They do not have MHC-2 million stem cells, 50 billion exosomes, PRP and
Markers, so the recipient does not recognize them as IV multivitamin is only $8,850 USD. Our reputable
foreign. Therefore, no rejection occurs. competitors charge two to three times that!
Now, please understand that if you consider Is there research showing stem cell
treatment at a clinic offering pluripotent stem cells therapy works?
(e.g. embryonic stem cells or induced pluripotent
stem cells), you are seriously putting yourself at risk. Absolutely! In this book, you will see that for each
Pluripotent stem cells from those sources are NOT condition discussed, we have summarized available
ready for clinical use and typically get rejected, which global research studies that have been published.
can be very serious. Overall, the amount of published studies evaluating
Are any babies harmed during the mesenchymal stem cells and exosomes for human
use exceeds 30,000 results. On clinicaltrials.gov, the
acquisition of stem cells that R3 uses?
amount of studies evaluating mesenchymal stem cells
No! No baby or mother are harmed at all, as the and exosomes exceeds 2,000!
umbilical cord tissue used is normally discarded
anyway. Where does R3 get its cells from?
Can the stem cells cause a tumor? R3 Stem Cell obtains its stem cells and exosomes from
umbilical cord tissue/blood that has been donated
The mesenchymal stem cells used at R3 Stem Cell do by a consenting mother undergoing a c-section
not cause or exacerbate tumors. There are over 10 procedure. There is no harm to baby or mother.
research studies that have been performed on MSCs
to see if they have tumor forming capacity, and the What kind of testing is performed on the
answer throughout has been NO. cells for safety?
So umbilical cord MSCs do not cause or exacerbate a R3 Stem Cell’s quality control on its biologics exceeds
tumor/cancer. that required by the USA FDA for safety.

How much do the procedures cost? Along with the extensive donor questionnaire, disease
testing of the tissue looks for HIV, Hepatitis, Syphilis,
As the world’s largest stem cell provider, R3 Stem Cell West Nile Virus, Chagas, Zika and more. The sterility
has used its volume to keep pricing as low as possible. testing looks for bacteria, virus, fungus and endotoxin.
While there are slight differences in the pricing in Only if all tests are passed are the stem cells and
each of the seven countries where R3 has clinics, we exosomes allowed to be used.

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 FAQ’S ON REGENERATIVE MEDICINE AND STEM CELL AND EXOSOME THERAPY

How long before I see benefits? them in conjunction to provide a“1-2 punch”for patient
This will vary between patients. Most individuals with outcomes.
musculoskeletal pain will start to realize benefits within How do stem cells work in one’s body?
2 to 4 weeks. It may be sooner or longer though. Stem cells and exosomes act in the body through several
For those with a systemic issue, Autism, autoimmune, mechanisms. They do NOT become part of a patient’s DNA,
kidney failure, it may take 6-12 weeks to see results. which means they do not engraft into the person’s existing
Neurologic issues such as stroke, CPI, spinal cord injury cells. The predominant method of action is thought to be
may take 6 months to see improvements. through paracrine mechanisms, which means“cell to cell”
interaction.
What are the risks of treatment?
After a decade of performing over 25,000 stem cell They act through:
procedures worldwide, R3 knows that the regenerative 1. Angiogenesis – provokes formation of new
procedures are safe. The quality control employed during blood vessels.
the stem cell production is second to none, and the
side effects R3 sees are usually mild to moderate and 2. Reduce inflammation –Cerebral Palsy is
temporary. associated with significant acute and chronic
inflammation, and the regenerative biologics
They may include itching, dizziness, lightheadedness, low
reduce it nicely.
grade fever, chills, nausea. These are typically temporary.
If a patient has an allergic reaction to the multivitamin or 3. Immune system modulation – the stem
a preservative, all of R3’s Centers have the medications to cells and exosomes modulate the immune
resolve it quickly. system very differently than steroids. Instead of
blanketly suppressing the immune system, the
While we have rarely seen an infection, it is possible for it to
occur as with anytime a medical procedure is performed. regenerative biologics tamp down the harmful
processes while amping up the beneficial ones.
What is an exosome? This includes ramping up production of several
R3 Stem Cell’s Centers of Excellence globally include helpful growth factors and cytokines, while
umbilical cord stem cell derived exosomes with umbilical tamping down harmful ones.
cord stem cells to provide enhanced results. Exosomes are 4. Cellular signaling – the biologics are able
lipid bound vesicles (acellular) produced by cells which to perform “cell to cell” communication. This
contain a plethora of growth factors, cytokines, mRNA and promotes recipient cells to proliferate their
other proteins.
growth factor production, protein production
They are exceptionally helpful in cell to cell and regenerate tissues that are damaged.
communication, and very effective for reducing
5. Prevent cell death – most cells have a timed
inflammation when they become ingested by their
death, where they are only allowed to live a
recipient cell. They act as shuttles to send nucleic acids
certain length of time. This is called apoptosis.
and proteins to other cells, in this way, allowing cell-to-cell
communication and transporting molecules among both The regenerative biologics allow normally
close and distant cells. In general, these released proteins functioning cells to live longer, and spare them
are important regulators of intracellular information. from the pre-programmed death.
Exosomes could be the mediators of many stem cell- 6. Preventing scar tissue – Scar tissue resulting
associated therapeutic activities. We have seen them to from Cerebral Palsy is known to occur, it is. Once
be“faster acting”than stem cells, so R3 frequently uses that scar tissue forms, it becomes nonfunctional.
Stem Cells and exosomes are great at preventing
scar tissue (anti-fibrosis).

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 FAQ’S ON REGENERATIVE MEDICINE AND STEM CELL AND EXOSOME THERAPY

Why does R3 use stem cells and Is cheaper stem cell treatment
exosomes together? better?
Both stem cells and exosomes No it’s not. Remember – a
are wonderful regenerative regenerative therapy involves
medicine biologics. R3 has seen a biologic being introduced
that exosomes tend to work a into your body. Not only do
bit quicker than mesenchymal you want it to be safe, but also
stem cells, but don’t last quite effective!
as long. So we typically combine
A lot of our competitors cut corners
them for optimal outcomes.
during stem cell processing. This may
Why is umbilical cord stem cell be with quality control testing for safety, or in
treatment better than autologous properly expanding (culturing) the stem cells to make
procedures? sure they are viable and functional. After 12 years
and 25,000 stem cell procedures with an unparalleled
R3 used to perform autologous therapies, where a patient satisfaction rate, R3 is at the forefront of
patient’s own bone marrow or adipose stem cells regenerative medicine globally and the most trusted
were used. However, a lot of stem cells in one’s body provider.
are as old as that person is, and hence not very active.
Their ability to successfully increase sufficient blood Are “hypoxic” stem cells better than
flow and allow for tissue regeneration is inferior to those produced under normal oxygen
umbilical cord stem cells, which are young, potent and conditions?
extremely active.
We get this question a lot. The answer is MAYBE. The
Specifically, the therapeutic potential of autologous only data to show that hypoxic stem cells live longer
bone marrow or adipose stem cells in the treatment of and proliferate better than those produced under
older patients is impaired by a number of age-related normal oxygen conditions is from the lab. Not in
factors such as oxidative stress, telomere length, animals or humans, just from petri dish studies.
DNA damage, disease, and long-term use of some
From R3’s perspective, this isn’t good enough. Our
medications.
stem cell biologics and treatment protocols are
This is in stark contrast to the youthful genotype based on actual evidence published in peer-reviewed
and phenotype of neonatal tissue-derived stem journals. The results are fantastic, and they mirror those
cells, such as from the umbilical cord. They are better seen in high level research publications.
at facilitating repair and regeneration of tissue
damage, creating new blood flow with superior
What’s the deal with sheep stem cells?
anti-inflammatory and immunomodulatory efficacy Believe it or not, there are actually clinics in the world
compared to mature stem cells from one’s adipose or offering stem cells for humans that are derived from
bone marrow. sheep. In short, this is absolutely ridiculous. Allow me
to explain.
As a result of the inferiority of autologous stem cells
due to the reasons above and better results being First of all, there are NO research studies that have
seen with umbilical cord stem cells, R3 mostly uses the been published on the effectiveness of sheep stem
donor stem cells today. cells in humans. Second, in order to harvest sheep
stem cells, the initial step is to slaughter a pregnant

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 FAQ’S ON REGENERATIVE MEDICINE AND STEM CELL AND EXOSOME THERAPY

sheep. Then the fetus is removed and then ground up Internationally, it’s allowed. If mesenchymal stem cells
to obtain live cells. are expanded under GMP conditions, they are pure,
potent and highly effective.
So in order to treat a patient they are murdering 2
sheep? Ethically, that’s despicable. But the bigger issue There is no evidence that non-cultured stem cells
is safety concerns. are more active than cultured. Unless the cells are
“over-cultured”. If the cells are expanded past the
There is no true quality control in place to test the 6th passage, the incidence of senescence (non-
sheep tissue for diseases, bacteria, virus or fungus. functional) stem cells starts to increase dramatically.
There are several reports online about deaths So it’s important for a lab to minimize the amount of
occurring and occult infections due to treatment with passages.
sheep stem cells, also called Live Cell Therapy (LCT).
R3 Stem Cell’s labs are very careful to minimize
These clinics exist, and they are expensive without passages. We don’t allow cells past the 4th passage. So
any evidence to back up effectiveness or safety. STAY they are VERY powerful!
AWAY.
How many procedures has R3 Stem Cell
Are expanded stem cells (cultured) less performed?
effective than non-cultured ones?
R3 Stem Cell’s Centers of Excellence have performed
It depends. First of all, in the USA stem cells are over 25,000 stem cell and exosome procedures in 7
not allowed to be expanded per regulations. countries over the past decade.

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 R3 Consumer Guide for Stem Cell and Exosome Therapy

Consumer Guide
to Stem Cell
Treatment for
Amyotrophic
Lateral Sclerosis

Brought to you by

* No portion of this Document may be reproduced without the Express Written Consent of R3 Stem Cell.
Disclaimer: This guide’s education does not constitute medical advice. The USA FDA considers stem cell
therapy experimental. Any claims made in the Guide refer to procedures performed outside the USA.

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR ATAXIA

Consumer Guide to Stem Cell Treatment for

Amyotrophic Lateral Sclerosis
Every day, R3 Stem Cell receives inquiries worldwide The origins of ALS, particularly in the more common
from individuals asking if stem cell therapy can help sporadic cases, continue to be a medical mystery.
with Amyotrophic Lateral Sclerosis (ALS). Spoiler Hypoxia may induce an inflammatory response in
alert: It can help a lot! In this guide, we’ll go through the brain, diminishing the motor neurons’ viability.
the basics of how stem cells work for ALS, the latest The specific molecular mechanisms underlying the
research, and what to expect with a regenerative disease pathology are not fully understood and
procedure. neuroprotective treatment options are minimally
effective.
A Significant Global Issue
Amyotrophic lateral sclerosis (ALS), Stem cells enter this scene armed with
also known as Lou Gehrig’s the full armamentarium of cellular
disease, is a rapidly progressive processes (neurotransmitter
neurodegenerative condition uptake, synapse formation,
characterized by selective inflammatory signaling,
degeneration of both upper neurotrophic factor signaling,
motor neurons (MNs) in the etc.) that can ameliorate toxic
motor cortex, and lower motor environments in a multifactorial
neurons in the brainstem and fashion.
ventral horn of the spinal cord.
Traditional Treatments for ALS
The incidence of ALS ranges from 1 to 4 cases per To date, only 3 drugs have been approved by the
100,000, although some subpopulations exhibit US Food and Drug Administration (FDA): riluzole,
above average incidence. The majority of ALS cases edaravone, and AMX0035 (Relyvrio). However,
are of unknown etiology and sporadic in nature they have modest therapeutic effects. For instance,
(90–95%) with no genetic association. riluzole only extends the lifespan of an ALS patient by
three months!
The disease typically manifests during the sixth to
seventh decade of life leading to progressive muscle Truly, additional treatments are needed to help
atrophy, weakness and paralysis. Affected individuals improve patient quality of life and also lifespan.
usually die within 2 to 5 years after diagnosis Stem Cell Therapy for Amyotrophic Lateral
due to respiratory failure. ALS manifests as an
Sclerosis
insidious, inexorable decline in motor function, with
progressively compromised strength, coordination, If a new technology such as mesenchymal stem
gait, and respiratory function, leading to death within cell and exosome therapy could provide significant
an average of 3–5 years from diagnosis. improvement for those with for ALS, it would and
should become first line therapy. A regenerative
How does Amyotrophic Lateral Sclerosis therapy that can reduce motor neuron death,
develop? improve quality of life and significantly enhance
ALS is mainly sporadic in origin (SALS) but a family lifespan should be tried.
history of the disorder can be found in ~10% of cases. Given the multifaceted nature of ALS, stem cell-
Hereditary forms of the disease (familial ALS or FALS), based therapy has recently become an attractive
are predominantly autosomal dominant and rarely option. Initially proposed as a means for motor
X-linked or recessive.

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neuron replacement, stem cells may mesenchymal stem cells. Patients were
actually provide a number of assessed using the ALSFRS-R
benefits by modulating the scale.
local microenvironment to
facilitate native motor The median survival time
neuron survival. increased two-fold in
all groups. No serious
There have been adverse drug reactions
several advancements were observed. In
using mesenchymal the entire study
stem cells (MSCs), all of population, the risk of
which rely on using the death was decreased
stem cells to stimulate in patients treated with
the survival of existing MSCs versus the paired
motor neurons rather than control group by 70%, p =
motor neuron replacement itself. 0.0004). Median overall survival
Cell therapy focused on replacing was almost twice longer in MSC
injured cells and differentiation into motor patients than in the reference group (1183 days
neurons is challenging. Therefore, a therapeutic vs. 640 days, p = 0.002).
strategy using MSCs should be focused away from
neuronal replacement or reconstruction and toward This study yielded highly encouraging results
creating an anti-inflammatory microenvironment. when it comes to WJ-MSC administration in all ALS
subgroups distinguished based on demographical
Mesenchymal stem cells have been used to and clinical factors. This ground-breaking research
generate immunomodulatory cells, growth factor- indicated that the female sex and a positive clinical
releasing cells, functional support cells such as response (decreased progression rate) to the first
glia, or GABAergic interneurons to modify motor MSC administration when compared to the strictly
neuron survival and activity. Besides direct effects, matched reference patient is a significant predictor
such as the release of neurotrophic factors and the for overall efficacy of the treatment.
stimulation of intrinsic neurogenesis, intrathecally
administered MSCs have diverse immune In 2010, a Phase I/II open-safety clinical trial by
inflammatory modulatory efficacy that can regulate Karussis and colleagues at the Hadassah Medical
the onset and progression of ALS by potentiating Center in Jerusalem, Israel showed that intrathecal
regulatory T cells and anti-inflammatory microglia in and intravenous administration of autologous bone
the CNS environment. marrow- derived MSCs into ALS patients was feasible
and safe. In this study, patients with ALS or multiple
A recent 2020 case-control study involved 67 sclerosis were treated either via a standard lumbar
patients treated with Wharton’s jelly mesenchymal puncture 60 million MSCs) or intravenously (24
stem cells (WJ-MSC). The treated patients were paired million MSCs for both ALS and MS patients).
with 67 reference patients and were fully matched in
terms of race, sex, onset of symptoms (bulbar/spinal), While the definitive survival of injected cells was
disease stage at the beginning of therapy and ALS not shown, this treatment induced immediate
medications. immunomodulatory effects and was deemed safe.
Although this study was not designed to detect
All patients received three intrathecal injections therapeutic efficacy of this treatment, encouragingly,
of Wharton’s jelly-derived mesenchymal stem ALS patient ALSFRS scores remained stable for up to
cells every two months at a dose of 30 million 6 months following treatment.

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In a 2021 case report published in European Review method of action is thought to be through paracrine
for Medical and Pharmacological Sciences, a 46-year- mechanisms, which means “cell to cell” interaction
old man noticed weakness of his legs, difficulties on
going down the stairs and coughing during eating. They act through:
After a complete workup, a diagnosis of ALS was
confirmed. 1. Angiogenesis – provokes formation of new
blood vessels.
His ALS Functional Rating Scale-R (ALSFS-R) was
43. Symptoms rapidly progressed and he coughed 2. Reduce inflammation –ALS is associated
and choked during eating. Starting in 2013, the with significant neuro inflammation, and the
patient received a total of six intravenous infusions regenerative biologics reduce it nicely. This can
of mesenchymal stem cells. The number of preserve or repair neuron function..
mesenchymal stem cell administrations in each time
3. Immune system modulation – the stem cells
were 38 million, 42 million, 17 million, 59 million, 43
and exosomes modulate the immune system
million and 52 million.
very differently than steroids. Instead of
Soon after administration, he noticed that he did not blanketly suppressing the immune system, the
cough during conversation or eating food. Although regenerative biologics tamp down the harmful
he had difficulty in walking down the stairs, he processes while amping up the beneficial ones.
remained well without coughing, trouble speaking or This includes ramping up production of several
swallowing. His ALSFS-R increased up to 45. helpful growth factors and cytokines, while
tamping down harmful ones.
The patient was well for 7 years after mesenchymal
stem cell therapy by the time of this report and more 4. Cellular signaling – the biologics are able
than 10 years from the time of onset. The authors to perform “cell to cell” communication. This
noted that the case suggested that mesenchymal promotes recipient cells to proliferate their
stem cells can be administered safely and may be growth factor production, protein production
potentially useful in patients with ALS. and regenerate tissues that are damaged.
The significance of this case is huge, because ALS is 5. Prevent cell death – most cells have a timed
an incurable disease that usually leads to death in death, where they are only allowed to live a
about 3 to 5 years. However, the case study patient certain length of time. This is called apoptosis. The
remained well for more than 10 years from the first regenerative biologics allow normally functioning
diagnosis. cells (i.e. chondrocytes) to live longer, and spare
In R3’s experience, 75% of patients with ALS achieve them from the pre-programmed death. This can
success with stem cell and exosome therapy. It’s an reduce the rate of cartilage loss in a joint!
exciting option for patients!
6. Preventing scar tissue –ALS patients may
Why doesn’t R3 Stem Cell use a person’s own experience significant scarring throughout the
Stem Cells? brain due to the chronic neuro inflammation.
Once that scar tissue forms, it becomes
Stem cells and exosomes act in the body through
nonfunctional. Stem Cells and exosomes are
several mechanisms. They do NOT become part of
great at preventing scar tissue (anti-fibrosis).
a patient’s DNA, which means they do not engraft
into the person’s existing cells. The predominant

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Stem Cells can also release a huge variety of

molecules into the extracellular environment. These
molecules, which include extracellular vesicles, lipids,
free nucleic acids, and soluble proteins, exert crucial
roles in repairing damaged tissue.
Along with offering MSCs for treatment of
Amyotrophic Lateral Sclerosis, R3 Stem Cell includes
stem cell exosomes, which are a type of extracellular
vesicle participating in extensive cell to cell
communication for new blood flow creation.

Where do the stem cells and exosomes come

from?
R3 Stem Cell’s regenerative biologics originate from
umbilical cord tissue that has been donated after a Stem Cell Derived Exosomes
scheduled c-section. No baby (or mother) is harmed R3 Stem Cell’s Centers of Excellence globally include
during the c-section procedure. The umbilical cord umbilical cord stem cell derived exosomes with
tissue is normally discarded, but if the mother umbilical cord stem cells to provide enhanced
passes screening tests then the umbilical cord is results. Exosomes are lipid bound vesicles (acellular)
immediately sent to the lab. The screening tests are produced by cells which contain a plethora of growth
extremely rigorous, and mandated by the USA FDA. factors, cytokines, mRNA and other proteins.
The lab carefully processes the umbilical cord to They are exceptionally helpful in cell to cell
generate large amounts of stem cells and exosomes communication, and very effective for reducing
that are of the highest quality possible. The lab team inflammation when they become ingested by their
consists of multiple PhD’s working in ISO Certified, recipient cell. They act as shuttles to send nucleic
cGMP compliant clean rooms to ensure quality acids and proteins to other cells, in this way, allowing
assurance that exceeds USA FDA standards. The cell-to-cell communication and transporting
proprietary production process combines the highest molecules among both close and distant cells. In
potency, safety and affordability for providers to general, these released proteins are important
confidently offer exosome procedures. regulators of intracellular information.
Millions of dollars have been invested into the Exosomes could be the mediators of many stem cell-
pharmaceutical grade production of the biologics associated therapeutic activities. We have seen them
including first rate clean rooms, bioreactors, to be “faster acting” than stem cells, so R3 frequently
nano-particle tracking analyzers, cytometers, uses them in conjunction to provide a “1-2 punch” for
PCR, tangential flow machines and real time patient outcomes.
environmental monitoring. The quality assurance
testing complies with screening and testing Is stem cell therapy safe?
stan¬dards consistent with the American Association After a decade of performing over 24,000 stem
of Tissue Banks, cGMP standards, FDA regulations cell procedures worldwide, R3 knows that the
and the highest level of any regulatory agency regenerative procedures are safe. The quality control
globally

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR ATAXIA

employed during the stem cell production is second Therefore, MSCs generally have low immunogenicity
to none, and the side effects R3 sees are usually mild and can avoid immune rejection by the recipient,
to moderate and temporary. which serves as the foundation for their successful
application without needing to match the
They may include itching, dizziness, lightheadedness, donor to the recipient. Scientists call this being
low grade fever, chills, headache, nausea. These “immunologically privileged”.
are typically temporary. If a patient has an allergic
reaction to the multivitamin or a preservative, all Another question often asked is “Is there a chance of
of R3’s Centers have the medications to resolve it a tumor forming?” Current research has concluded
quickly. that the answer is NO. The mesenchymal stem cells
and exosomes used during treatment have never
One of the questions we get asked a lot is, “Will the been shown to have tumor forming potentials. In
stem cells get rejected?” The answer is NO. fact, they have been shown to be anti-tumor forming.
MSCs do not express major histocompatibility
complex (MHC) antigens of the class II subtype and
Protocol
contain low levels of MHC molecules of the class I For the past decade, R3 has been
subtype. MSCs also lack the co-stimulatory molecules successfully treating Amyotrophic
essential for immune detection, including CD40, Lateral Sclerosis with stem cell and
CD80, and CD86. exosome procedures. The procedure

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR ATAXIA

is performed as a combination of intravenous R3 Stem Cell offers free consultations for individuals to
stem cells and exosomes along with intrathecal discuss whether regenerative therapy is indicated for
application. their ALS. Simply call +1 (844) GET-STEM to schedule
yours!
R3’s providers use approximately two to three million
stem cells per kilogram and 100 billion exosomes for References:
the procedure.
1. Chen et al, Intraspinal Stem Cell Transplantation for
Amyotrophic Lateral Sclerosis, Ann Neurol. Author
Outcomes manuscript; available in PMC 2017 March 01.
Similar to the research mentioned above, R3 Stem 2. SHIGEMATSU et al, Long-term survival of a patient
Cell’s outcomes for ALS have been very good! The with amyotrophic lateral sclerosis (ALS) who received
patient satisfaction rate for ALS is 75%, with patients autologous adipose-derived mesenchymal stem cells,
typically experiencing stoppage of the disease European Review for Medical and Pharmacological
Sciences, 2021; 25: 4086-4090
progression for a period of time. Keep in mind
3. Barczewska et al, Umbilical Cord Mesenchymal Stem Cells
results cannot be guaranteed and will vary between
in Amyotrophic Lateral Sclerosis: an Original Study, Stem
individuals. Cell Reviews and Reports (2020) 16:922–932
It may take a few months to see improvements, as 4. Goutman et al, Stem cell treatments for amyotrophic
it can take that long to build up new blood flow. It lateral sclerosis (ALS): A critical overview of early phase
trials, Expert Opin Investig Drugs. 2019 June;_ 28(6):
should be noted, again, that stem cell therapy is not a 525–543.
cure for ALS, and will need to be repeated every 6-12
5. Ciervo et al. Advances, challenges and future directions
months or so for continued benefit. for stem cell therapy in amyotrophic lateral sclerosis,
Molecular Neurodegeneration (2017) 12:85, DOI 10.1186/
Affordability s13024-017-0227-3
Because stem cell therapy for and the Prospects of Mesenchymal Stem Cell Therapy. Front.
ALS is not a permanent cure, it’s Immunol. 13:835005.doi: 10.3389/fimmu.2022.835005
important to make it affordable. 10. Zhang et al, Umbilical Cord Mesenchymal Stem Cell
Repeat therapies can help Treatment for Crohn’s Disease: A Randomized Controlled
maintenance and/or achieve additional improvements Clinical Trial, Gut and Liver, Vol. 12, No. 1, January 2018, pp.
73-78
for ALS. So a lot of patients seek additional treatments
at R3 Stem Cell every six to twelve months.
R3 Stem Cell’s fees are less than half what comparable
(and reputable) regenerative clinics charge.

R3’s Experience
For the past decade, R3 Stem Cell’s Centers globally
have performed over 24,000 regenerative procedures
in six countries. Several hundred have been for ALS

R3 combines safety, effectiveness and affordability

for the therapies. Internationally, the Intellicell is used,
which is culturing the most active mesenchymal stem
cells to create the “smartest” stem cell in the world!

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 R3 Consumer Guide for Stem Cell and Exosome Therapy

Consumer Guide
to Stem Cell
Treatment for
Ankylosing
Spondylitis

Brought to you by

* No portion of this Document may be reproduced without the Express Written Consent of R3 Stem Cell.
Disclaimer: This guide’s education does not constitute medical advice. The USA FDA considers stem cell
therapy experimental. Any claims made in the Guide refer to procedures performed outside the USA.
30
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 CONSUMER GUIDE TO STEM CELL TREATMENT FOR ANKYLOSING SPONDYLITIS

Consumer Guide to Stem Cell Treatment

for Ankylosing Spondylitis
Every day, R3 Stem Cell receives inquiries worldwide arthritis, since rheumatoid factor antibodies are not
from individuals asking if stem cell therapy can help present.
with Ankylosing Spondylitis (AS). Spoiler alert: It can
help a lot! In this guide, we’ll go through the basics of Symptoms and signs generally begin in young
how stem cells work for AS, the latest research, and adulthood. Pain and stiffness awaken the patients in
what to expect with a regenerative procedure. the early morning hours. As the disease progresses,
spinal mobility and chest expansion become
A Significant Global Issue increasingly impaired. AS can occur in
Ankylosing spondylitis (AS) is a any part of the spine or the entire
chronic rheumatic bone and joint spine, often with pain referred
disease that affects 1%–2% of to one or the other buttock or
the world’s population and is the back of the thigh from the
2.5 times more common in men sacroiliac joint. About half of
as in women. Inflamma-tion is AS patients will also develop
accompanied by bone erosion and inflammation of the eye’s anterior
new bone formation, often resulting in chamber, causing eye pain, redness,
severe structural deformities of the bone floaters, and sensitivity to light.
and joints and functional impairment. This state-of-affair is believed to be due to the
The disease primarily affects the sacroiliac joints and association that both AS and uveitis have with the
the axial skeleton (spine) and less frequently, the HLA-B27 antigen inheritance. Prostatitis occurs
peripheral joints and other extra articular organs with increased frequency in men. Cardiovascular
including the eyes, skin and cardiovascular system. involvement may include inflammation of the aorta,
This leads to severe pain, a reduction in spinal aortic valvular regurgitation, or disturbances of the
mobility and stiffness. cardiac electrical conduction system.

By region, the average prevalence of ankylosing Pulmonary involvement is characterized by

spondylitis per 10,000 individuals has been reported progressive fibrosis of the upper lobes. In advanced
as 16.7 in Asia, 23.8 in Europe, 31.9 in North America, stages of AS, a “bamboo spine” develops when the
and 10.2 in Latin America [6]. Also, there is some outer fibers of the intervertebral disks’ fibrous rings
gender difference in AS patients between continents ossify. About 90% of patients express the HLA-B27
and countries. genotype, indicating a strong genetic association,
and individuals with the HLA-B27 genotype contract
How does Ankylosing Spondylitis the disease more commonly than noncarriers.
develop?
Traditional Treatments for AS
Ankylosing spondylitis (AS), also known as
Bechterew’s disease or Marie–Strümpell disease, The major purpose of therapy in patients affected
is an inflammatory disease primarily involving the with AS is to attenuate inflammation and relieve
joints of the spine and pelvis. The cause is unknown; progressive back pain, morning stiffness, fatigue,
however, genetic factors, environmental triggers, and movement disabilities and as a result, improve
and autoimmunity are all strongly implicated. The quality of life. Current AS treatments are widely
condition belongs to the “seronegative” forms of pharmacological interventions.

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NSAIDs are still the first line of drugs that (SSZ), a highly effective type of DMARDs, is
alleviate preliminary clinical symptoms helpful for dampening symptomatic
of this ailment and dramatically
diminish pain and stiffness of arthritis in patients with the
active AS patients. Although more active disease but have
long-term consumption no significant impact on the
of NSAIDs, particularly axial skeleton. Methotrexate
in symptomatic active (MTX), another conventional
patients, results in promising DMARD, seem to be less
effects in slowing spinal effective in AS in contrast
radiographic progression, with rheumatoid arthritis.
some patients have In some patients with
experienced gastrointestinal persistent joint involvement,
and cardiovascular difficulties combination DMARDs therapy
. Continuous consumption of may be beneficial to manage
NSAIDs induce upper gastrointestinal arthritis. The recent emerging line of
ulcers in about one-third of patients, which therapies is comprised of biologic agents
is diagnosed by endoscopy. with beneficial outcomes, particularly anti-TNF-α.
Cardiovascular disease is stated as the most TNF-α is a pro-inflammatory cytokine that is
common cause of mortality in AS patients. The rate predominantly generated by activated macrophages
of cardiovascular dysfunction in AS patients range and lymphocytes during immune responses.
from 2 to 10%. In at-risk patients with long-term The use of TNF-α inhibitors is the best choice for
AS, increased heart morbidity rates are reported. patients who poorly respond to former treatments.
Cardiovascular events comprising of conduction and Four synthetic anti-TNF-α agents, including infliximab
rhythm disturbances, valve ischemic heart failure, (Remicade®), adalimumab (Humira®), golimumab
and acute coronary syndrome, are related to the (Simponi®) and the recombinant receptor etanercept
chronic inflammatory pathology of AS. (Enbrel®) [64] are currently used in order to
Glucocorticoids are the subsequent suggested dramatically decrease signs of spinal inflammation
medication to suppress inflammation and reduce and seem to improve imaging outcomes. In addition
spinal pain in some subjects with a flareup of AS to axial manifestations, TNF-α inhibitors could
symptoms. Glucocorticoids can be taken orally or improve uveitis, peripheral arthritis and bowel
injected into affected joints locally. AS patients with inflammation.
concurrent acute anterior uveitis (AAU) show a good The most important obstacle is that almost 40%
response to this treatment. However, the long-term of AS patients are unable to tolerate or respond to
use of glucocorticoids can lead to serious adverse conditional medications. Despite switching TNF-
effects, including osteoporosis and increased risk of blocking agent, there is still a chance of failure
bone fractures, the occurrence of new infections and because of drug inefficacy or possible side effects.
weight gain. Another substantial risk of the anti-TNF-α appliance
DMARDs are the next group of drugs that have is the recurrence of bacterial and fungal infections,
proven to be efficacious for only peripheral joint especially tuberculosis (TB) and candidiasis, as
involvement and some extra-articular manifestations, a result of suppressing immune responses. The
like uveitis and bowel inflammation. Sulphasalazine incidence rate of these serious infections are low but
are severe, or even fatal, in some cases

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Stem Cell Therapy for Ankylosing

Spondylitis
If a new technology such as
mesenchymal stem cell and exosome
therapy could provide a long term
solution for AS, it would and
should become first line therapy.
A regenerative therapy that can
initiate spontaneous erections,
negate the need for medications or
injections and is a safe option should
receive consideration.
In a landmark study by Wang et al, thirty-one
males with AS, 20 to 30 years of age, were enrolled
from Sun Yat-sen University. Of the 31 patients, 22
patients had a suboptimal response to NSAIDs, and However, there were no marked improvements in
9 could not tolerate the side effects. the symptoms of patients during this period. All
patients experienced pain relief and the scores
AS patients enrolled in this study received four assessing AS activity and severity were decreased
IV infusions of mesenchymal stem cells on days following umbilical cord mesenchymal stem cell
0, 7, 14, and 21. Patients received one million infusion.
mesenchymal stem cells per kilogram for each
infusion. A number of patients were able to perform
certain exercises following treatment, whereas
The percentage of responders at the fourth week these activities had been limited prior to MSC
was 77.4% (24/31). The results showed that MSC transfusion. Physical examinations demonstrated
infusion resulted in an improvement of ASAS scores that the majority of patients exhibited less marked
and symptoms and that the results lasted for up symptoms of AS. ESR and CRP levels returned to and
to five months post treatment. During the study, remained within normal ranges, suggesting that AS
no clinically significant deteriorations were found activity was reduced, inflam¬mation was inhibited
in all of the preestablished laboratory tests and and the disease was not progressing.
radiological examinations in all patients, indicating
that MSC infusion is safe for the treatment of AS In R3’s experience, 90% of patients with AS achieve
treatment over a 20-week period. success with stem cell and exosome therapy. It’s an
exciting option for patients!
The authors theorized they could have obtained
better results with a higher dose of MSCs. Why doesn’t R3 Stem Cell use a person’s
own stem cells for AS?
From July 2009 to October 2012, Li et al enrolled
5 AS patients (4 males and 1 female) aged 17 44 R3 used to perform autologous therapies, where a
years to receive mesenchymal stem cell therapy. patient’s own bone marrow or adipose stem cells
These patients were treated with SSZ and NSAIDs were used. However, a lot of stem cells in one’s body
for at least 4 weeks prior to MSC transfusion. are as old as that person is, and hence not very active.

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a patient’s DNA, which means they do not engraft

into the person’s existing cells. The predominant
method of action is thought to be through paracrine
mechanisms, which means “cell to cell” interaction.
They act through:
1. Angiogenesis – provokes formation of new blood
vessels.
2. Reduce inflammation – AS is associated with
significant inflammation, and the regenerative
biologics reduce it nicely.
3. Immune system modulation – the stem cells
and exosomes modulate the immune system
Their ability to successfully increase sufficient blood very differently than steroids. Instead of
flow and allow for spontaneous erections is inferior blanketly suppressing the immune system, the
to umbilical cord stem cells. regenerative biologics tamp down the harmful
Specifically, the therapeutic potential of autologous processes while amping up the beneficial ones.
bone marrow or adipose stem cells in the treatment This includes ramping up production of several
of older patients is impaired by a number of age- helpful growth factors and cytokines, while
related factors such as oxidative stress, telomere tamping down harmful ones.
length, DNA damage, disease, and long-term use of 4. Cellular signaling – the biologics are able
some medications. to perform “cell to cell” communication. This
This is in stark contrast to the youthful genotype promotes recipient cells to proliferate their
and phenotype of neonatal tissue-derived stem growth factor production, protein production
cells, such as from the umbilical cord. They are better and regenerate tissues that are damaged.
at facilitating repair and regeneration of tissue 5. Prevent cell death – most cells have a timed death,
damage, creating new blood flow with superior where they are only allowed to live a certain length
anti-inflammatory and immunomodulatory efficacy of time. This is called apoptosis. The regenerative
compared to mature stem cells from one’s adipose or biologics allow normally functioning cells (i.e.
bone marrow. chondrocytes) to live longer, and spare them from
As a result of the inferiority of autologous stem cells the pre-programmed death. This can reduce the
due to the reasons above and better results being rate of cartilage loss in a joint!
seen with umbilical cord stem cells, R3 only uses the 6. Preventing scar tissue –Once that scar tissue
donor stem cells today. forms, it becomes nonfunctional. Stem Cells and
exosomes are great at preventing scar tissue
How do the Stem Cells and Exosomes
(anti-fibrosis).
work for AS?
Stem Cells can also release a huge variety of
Stem cells and exosomes act in the body through molecules into the extracellular environment. These
several mechanisms. They do NOT become part of molecules, which include extracellular vesicles, lipids,

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free nucleic acids, and soluble proteins, exert crucial The lab carefully processes the umbilical cord to
roles in repairing damaged tissue. generate large amounts of stem cells and exosomes
that are of the highest quality possible. The lab team
Along with offering MSCs for treatment of Ankylosing consists of multiple PhD’s working in ISO Certified,
Spondylitis, R3 Stem Cell includes stem cell cGMP compliant clean rooms to ensure quality
exosomes, which are a type of extracellular vesicle assurance that exceeds USA FDA standards. The
participating in extensive cell to cell communication proprietary production process combines the highest
for new blood flow creation. potency, safety and affordability for providers to
confidently offer exosome procedures.
Where do the stem cells and exosomes
come from? Millions of dollars have been invested into the
R3 Stem Cell’s regenerative biologics originate from pharmaceutical grade production of the biologics
umbilical cord tissue that has been donated after a including first rate clean rooms, bioreactors,
scheduled c-section. No baby (or mother) is harmed nano-particle tracking analyzers, cytometers,
during the c-section procedure. The umbilical cord PCR, tangential flow machines and real time
tissue is normally discarded, but if the mother environmental monitoring. The quality assurance
passes screening tests then the umbilical cord is testing complies with screening and testing
immediately sent to the lab. The screening tests are stan¬dards consistent with the American Association
extremely rigorous, and mandated by the USA FDA. of Tissue Banks, cGMP standards, FDA regulations

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and the highest level of any regulatory agency typically temporary. If a patient has an allergic reaction
globally. to the multivitamin or a preservative, all of R3’s Centers
have the medications to resolve it quickly.
Stem Cell Derived Exosomes
One of the questions we get asked a lot is, “Will the
R3 Stem Cell’s Centers of Excellence globally include stem cells get rejected?” The answer is NO.
umbilical cord stem cell derived
exosomes with umbilical cord MSCs do not express major
stem cells to provide enhanced histocompatibility complex
results. Exosomes are lipid (MHC) antigens of the class
bound vesicles (acellular) II subtype and contain low
produced by cells which levels of MHC molecules of
contain a plethora of the class I subtype. MSCs
growth factors, cytokines, also lack the co-stimulatory
mRNA and other proteins. molecules essential
for immune detection,
They are exceptionally including CD40, CD80, and
helpful in cell to cell CD86.
communication, and very
effective for reducing inflammation Therefore, MSCs generally have low
when they become ingested by their immunogenicity and can avoid immune
recipient cell. They act as shuttles to send nucleic rejection by the recipient, which serves as the
acids and proteins to other cells, in this way, allowing foundation for their successful application without
cell-to-cell communication and transporting needing to match the donor to the recipient. Scientists
molecules among both close and distant cells. In call this being “immunologically privileged”.
general, these released proteins are important
regulators of intracellular information. Another question often asked is “Is there a chance of a
tumor forming?” Current research has concluded that
Exosomes could be the mediators of many stem cell- the answer is NO. The mesenchymal stem cells and
associated therapeutic activities. We have seen them exosomes used during treatment have never been
to be “faster acting” than stem cells, so R3 frequently shown to have tumor forming potentials. In fact, they
uses them in conjunction to provide a “1-2 punch” for have been shown to be anti-tumor forming.
patient outcomes.
Protocol
Is stem cell therapy safe? For the past decade, R3 has been
After a decade of performing over 24,000 stem cell successfully treating Ankylosing
procedures worldwide, R3 knows that the regenerative Spondylitis with stem cell and
procedures are safe. The quality control employed exosome infusions. The regenerative
during the stem cell production is second to none, and biologics are infused through an IV,
the side effects R3 sees are usually mild to moderate and will travel to the inflamed areas
and temporary. for substantial pain relief. In addition, if a patient has
significant low back pain, R3 has an effective injection
They may include itching, dizziness, lightheadedness, protocol that also includes platelet rich plasma
low grade fever, chills, headache, nausea. These are therapy.

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R3’s providers use one to two million R3’s Experience

stem cells per kilogram, to make For the past decade, R3 Stem Cell’s
sure that patients achieve Centers globally have performed
the absolute best outcome over 24,000 regenerative
possible. Between 50 and procedures in six countries.
150 billion exosomes Several hundred have been
are included with each for AS. Patient satisfaction
procedure. PRP, short for across all conditions treated is
platelet rich plasma therapy, 85%!
is also included at no additional
charge. The procedure takes less R3 combines safety, effectiveness
than an hour! and affordability for the therapies.
Internationally, the Intellicell is used, which is
Outcomes culturing the most active mesenchymal stem cells to
Similar to the research mentioned above, R3 Stem create the “smartest” stem cell in the world!
Cell’s outcomes for AS have been exceptional! The
patient satisfaction rate is 85% year over year. Keep R3 Stem Cell offers free consultations for individuals
in mind results cannot be guaranteed and will vary to discuss whether regenerative therapy is indicated
between individuals. for their AS. Simply call +1 (844) GET-STEM or +1 (480)
808-7057 to schedule yours!
It may take a couple months to see all the
improvements, as it can take that long to build up References:
new blood flow. It should be noted, again, that stem
1. Feng et al, Impact of immune regulation and
cell therapy is not a cure for AS, and will need to be differentiation dysfunction of mesenchymal stem cells
repeated every 12 months or so for continued benefit. on the disease process in ankylosing spondylitis and
prospective analysis of stem cell transplantation therapy,
Affordability Postgraduate Medical Journal, 2023, 99, 1_1_3_8_–
1_1_4_7.
Because stem cell therapy for AS is
not a permanent cure, it’s important 2. Li et al, Infusion of umbilical cord mesenchymal stem
cells alleviates symptoms of ankylosing spondylitis,
to make it affordable. Repeat
EXPERIMENTAL AND THERAPEUTIC MEDICINE 14: 1538-
therapies can help maintenance 1546, 2017
and/or achieve additional 3. Zeng et al, Efficacy and Safety of Mesenchymal Stem Cell
improvements for pain relief. So a lot of patients seek Transplantation in the Treatment of Autoimmune Diseases
additional treatments at R3 Stem Cell every twelve to (Rheumatoid Arthritis, Systemic Lupus Erythematosus,
eighteen months. Inflammatory Bowel Disease, Multiple Sclerosis, and
Ankylosing Spondylitis): A Systematic Review and Meta-
R3 Stem Cell’s fees are less than half what comparable Analysis of Randomized Controlled Trial, Stem Cells
(and reputable) regenerative clinics charge. Be wary International, Volume 2022, Article ID 9463314, 20 pages
of clinics trying to pass off PRP as a stem cell therapy. 4. Wang et al, Effects and Safety of Allogenic Mesenchymal
If they mention only taking your blood for the Stem Cell Intravenous Infusion in Active Ankylosing
Spondylitis Patients Who Failed NSAIDs: A 20-Week
treatment, it is NOT a stem cell treatment!
Clinical Trial, Cell Transplantation, Vol. 23, pp. 1293–1303,
2014

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 R3 Consumer Guide for Stem Cell and Exosome Therapy

Guide to
Stem Cell and
Exosome Therapy
for Anti-Aging

Brought to you by

* No portion of this Document may be reproduced without the Express Written Consent of R3 Stem Cell.
Disclaimer: This guide’s education does not constitute medical advice. The USA FDA considers stem cell
therapy experimental. Any claims made in the Guide refer to procedures performed outside the USA.
38
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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR ANTI-AGING

Guide to Stem Cell and Exosome Therapy for Anti-Aging

Every day, R3 Stem Cell receives inquiries worldwide

from individuals asking if stem cell therapy can
help for anti-aging. Spoiler alert: It can help a lot!
In this guide, we’ll go through the basics of how
stem cells and exosomes work for turning back the
clock, the latest research, and what to expect with a
regenerative procedure.
Aging has always been a fascinating topic for
scientists, trying to understand how and why our cell
and tissue function decline over time. The decline
leads to a plethora of diseases such as cancer, 50, the amount of stem cells in one’s bone
diabetes, osteoporosis, sarcopenia, marrow have dropped by a factor of
cardiovascular diseases, arthritis, 40. By the age of 60 it’s dropped by
and neurodegenerative a whopping 200 fold!
diseases.
Stem cell therapy for anti-
When looking at aging, one aging is turning out to be
of the biggest problems is an excellent opportunity for
the building blocks of tissue individuals to turn back the
repair, stem cells, diminish clock, resulting in decreased
progressively in numbers over inflammation, a reduction in the
time. It becomes a supply and markers of aging, more energy, better
demand phenomenon. sleep and an increased quality of life. Read on
to learn more.

A Growing Global Concern

Aging is an unavoidable phenomenon characterized
by the appearance of flabby skin, sparse and gray
hair, memory decline, and various degenerative
diseases. Furthermore, aging results in susceptibility
to various chronic diseases, which make the healthy
life span expectancy less than the actual life span.
This phenomenon will increasingly threaten
The human body needs more stem cells to fulfill socioeconomic growth and sustainable
the demands of tissue repair and regeneration development. The World Health Organization states
with aging, but either they don’t exist or they don’t that population aging is accelerating around the
function well enough! world, and the number of people over the age of 60
Here is another graph showing exactly the drop off worldwide is expected to reach 2 billion by 2050.
in human bone marrow with aging. By the age of Therefore, addressing global aging has become a
clinical necessity and an ongoing research focus.

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR ANTI-AGING

Aging is a biological phenomenon in which the are reduced, and there is defective mitochondrial
structures and functions of organisms decline over function, all of which generate additional oxidative
time. Senescent (nonfunctional) cells were once stress. So oxidative stress leads to MORE oxidative
considered to be potential contributors to the age- stress, which further increases overall body
associated loss of regenerative potential, but there inflammation.
is increasing evidence of the detrimental role of
senescent cells in aging. The main characteristics An imbalance occurs between the increased oxidant
of senescent cell damage include mitochondrial load (oxidative stress) versus the anti-oxidants
dysfunction; impaired immune function or available. This induces DNA damage, limited free
immunosenescence; accumulation of damaged radical scavenging, and inhibition of stem cell
proteins (impaired proteostasis) and somatic and function. The theory of oxidation-inflammaging
mitochondrial DNA mutations; aberrant intracellular and the theory of stem cell aging are particularly
communication; telomere shortening; and alteration important. Based on the close association between
of autophagy, epigenetics, and nutrient sensing. oxidative stress, inflammation, and aging, De la
Fuente M et al. proposed the oxidation-
Senescence reduces the regenerative inflammation theory of aging. The
potential of stem cells pools theory holds that oxidative
and leads to endogenous stress leads to inflammaging.
stem cells exhaustion. Glucocorticoid resistance,
The resident stem cells, sympathetic nervous
including mesenchymal system function changes,
stem cells, hematopoietic and parasympathetic
stem cells, neural stem cells nervous system function
and satellite cells undergo changes during chronic
senescence during aging stress may be the mechanism
process, showing age-related of stress-induced inflammation.
decline in repopulation capacity Inflammaging is closely related to
and differentiation potential with reduced stem cell aging. Chronic inflammation
lifespan. induces stem cell senescence during pathological
processes of inflammaging.
Previous studies have shown that the number and
function of stem cells decline with age, potentially How can Stem Cell Therapy Help
leading to destructive diseases such as dementia, Inflammaging?
autoimmunity, arthritis, cardiovascular disease, Regenerative medicine can reverse or inhibit
cancer, tissue degeneration, neuropathy, stroke, many of these health problems through the use of
obesity, and depression. endogenous stem cells or exogenous replacement
During aging, chronic, sterile, low-grade cells derived from stem or progenitor cells to restore
inflammation, called inflammaging, develops and or rejuvenate tissue and maintain homeostasis.
this contributes to the chronic disease exacerbation. As stem cells age, their renewal ability deteriorates,
Recent studies show oxidative stress accelerates and their ability to differentiate into various cell
aging, and a consequence is that stem cell types is depleted. This is one of the main reasons
populations are depleted, antioxidant defenses R3 Stem Cell rarely uses a patient’s own tissue for
a regenerative therapy. Not only are the stem cell
counts continually decreasing, but their function

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR ANTI-AGING

continues to diminish as well! Umbilical cord stem

cells do NOT have these problems.
Aging frailty has been recognized
as a disease by the World Health
Organization. In Western countries,
the prevalence of physical frailty
is around 15% in adults ≥65 years
and increases to more than 25% in
adults >85 years. Locomotion frailty
increases the risk of falls, disability and
hospitalization.
Since lack of stem cells is the main
cause for aging and frailty, cell replacement
therapy provides an exciting avenue for the
treatment of degenerative age-related diseases. The
regenerative potential of these cells is due to their rationale. A large amount of evidence suggests that
high proliferation and differentiation capabilities, SC exhaustion is associated with the progression
paracrine activity, and immune privilege (no of aging frailty. In addition, human studies showed
rejection). that MSCs possess therapeutic potential for
musculoskeletal regeneration.
Stem cells play a key role in organogenesis and
maintaining homeostasis throughout life, possess Neuroprotective Effects of MSCs
the ability to migrate long distances and target TIn aging process, almost all the brains undergo
pathological conditions, express therapeutic genes, characteristic changes, including brain atrophy,
and respond to cues that redirect their differentiation loss of neurons and synapse connections. These
into defective lineages. This means that stem cells age-related changes are responsible for the decline
can be used for cell replacement as a therapeutic in neuronal activity and synaptic dysfunction
intervention aimed at mitigating the effects of aging. that linked to neurodegeneration. The effects of
MSCs secrete a range of paracrine factors, collectively transplanted MSCs have been documented in vivo
referred to as secreted proteomes, which perform and vitro experiments in several studies, which have
a variety of biological functions, including immune shown that MSCs could promote neurogenesis and
regulation, angiogenesis, anti-apoptosis, anti- improve neurological state. Intravenous infused MSCs
oxidation, cell homing, and the promotion of cell can cross the blood-brain barrier (BBB), which is an
differentiation. essential prerequisite for proper efficacy.
Then intravenous injected MSCs can migrate to
Reducing physical frailty with intravenous the injured regions and facilitate formation of
mesenchymal stem cell administration neuron-like-cells via secreting various neurotrophic
can increase healthy life expectancy factors, such as nerve growth factor (NGF), vascular
and decrease costs to the public health endothelial growth factor (VEGF) and fibroblast
system! growth factor 2 (FGF2). These secretomes are
The clinical development of MSCs preparations released from non-genetically modified MSCs,
for physical frailty in older persons has a strong playing a significant role in inducing neuronal

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR ANTI-AGING

differentiation and increasing survival rates after

injury.
MSCs possess anti-inflammatory properties adding
to their neuroprotective effects. A great number
of studies have showed that transplanted MSCs
could reduce the levels of pro-inflammatory
cytokines, or promote macrophages to polarize
into the anti-inflammatory M2 phenotype. The
anti-inflammatory effects are conducted through
secreting multiple cytokines, including IL-10 and
transforming growth factor-β (TGF-β). At such, the
anti-inflammatory microenvironments induced by
transplanted MSCs help promote neurogenesis and
prevent neural degeneration. Ameliorating cognitive
decline may be a promising approach to prevent
brain frailty

Liver Disease
Renal Disease
Increased oxidant stress is recognized as a key
factor in most chronic liver diseases, such as viral Similar to how Mesenchymal Stem Cells work for
hepatitis, liver fibrosis, nonalcoholic fatty liver liver disease, they work fantastic for renal disease
disease, and alcoholic liver disease. The progression as well. The MSCs reduce inflammation, facilitate
of hepatocarcinogenesis is often accompanied by the formation of new renal cells, and can prevent diabetic
imbalance of intracellular oxidative stress. induced kidney failure. The mechanisms include anti-
oxidation along with promoting cellular proliferation,
More and more researchers currently use anti-apoptosis, and typically a significant increase in a
antioxidants as therapeutic agents. Indeed, there is person’s eGFR.
increasing evidence showing that the therapeutic
effects of MSCs are driven by the release of exosomes Lung Disease
which reduce the oxidative stress substantially. Chronic obstructive pulmonary disease (COPD) is
a prevalent and debilitating respiratory condition
Digestive Disease with limited treatment options. Stem cell therapy
Exosomes have been shown to attenuate the severity has emerged as a promising approach for
of colitis. The therapeutic effect of exosomes in colitis COPD management due to its regenerative and
is related to the suppression of oxidative disturbance, immunomodulatory properties.
which is manifested by decreased activities of
myeloperoxidase and malondialdehyde (MDA), as Stem Cells secrete various factors, including anti-
well as increased levels of SOD and glutathione. anti- inflammatory cytokines, growth factors, and
inflammatory factors and other bioactive molecules, extracellular vesicles, inhibiting pro-inflammatory
thereby gradually becoming the simplest and easiest responses and promoting tissue repair processes.
method to treat OA. Stem cells also exhibit anti-fibrotic effects, which are

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR ANTI-AGING

apoptosis, interstitial fibrosis [89],

comprehensively account for the
decreased cardiac function,
which may eventually
lead to the progression
of cardiovascular
diseases in the
aging populations.
MSCs have shown
potential to
migrate to the
injured zones and
facilitate cellular
differentiation into
endothelial cells and
cardiomyocyte-like cells to
promote neovascularization
and cardiac functions, which can
effectively offer repair in the sites of
crucial in COPD management as fibrosis is a damaged myocardium. It has been found that
characteristic feature of the disease. MSCs exert many therapeutic functions through
Stem cells can inhibit the activation of fibroblasts and paracrine effects (cell to cell messaging). MSCs can
myofibroblasts, thereby reducing excessive collagen produce multiple cytokines and angiogenic factors
deposition and preventing the progression of fibrotic released directly in soluble form or in extracellular
remodeling in the lungs. vesicles and exosomes, playing a role in improving
cardiac functions after damage.
Additionally, stem cells can promote angiogenesis,
and the formation of new blood vessels. This Hormones
enhanced vascularization improves blood supply to Researchers have documented that MSCs
the damaged lung tissue, enhancing oxygenation transplantation could recover the levels of
and supporting tissue repair processes. By harnessing testosterone back to normal through paracrine
these mechanisms, stem cell therapy offers a functions. Notably, growth hormone and IGF1 also
potential strategy to modify the course of COPD, decrease with aging, the insufficient hormones result
mitigate disease progression, and improve patients’ in body composition parameters with elevated fat
lung function and quality of life. mass and reduced lean mass. MSCs are capable of
secreting multiple growth factors and cytokines,
Cardiovascular promoting of the diminishing growth hormone and
The cardiac senescence is reflected by decreased IGF1 along with Leydig cells in the adult testis.
cardiac performance and progressive cardiac
structural remodeling. The various phenotypic The chronic inflammation is an important determiner
changes in functions and structures of heart, of insulin resistance, so the protective role of MSCs in
including cardiomyocyte hypertrophy and improving insulin sensitivity via suppressing the

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR ANTI-AGING

inflammatory activity has been focused. A number This effect can go so far as to allow joints to create
of research studies have reported that MSC-based new cartilage, which can greatly improve a person’s
therapy can attenuate insulin resistance and improve function and pain relief.
beta cell function via inhibiting the production of
inflammatory cytokines. In the renowned CRATUS study where mesenchymal
stem cells were infused in several doses in aging
Musculoskeletal System patients, all patients in the treatment groups had
increased 6-minute walk distance at 3 months and
Degenerative diseases of the musculoskeletal system, 6 months. The levels of inflammatory cytokine,
such disc disease, arthritis, and osteoporosis, have TNF-α decreased at 6 months. Among the three
had a huge impact on society, and the quality of life groups, 100-millon cell-dose group showed the best
of middle-aged and elderly people suffering from performance in the improvement of 6-minute walk
these diseases is significantly decreased. distance, cognitive status and physical function.
With regard to the safety of MSCs administration,
Osteoarthritis is the most common joint disease
no treatment-emergent serious adverse events
worldwide. Arthritis inflammation is associated with
occurred. The results showed that immunologic
oxidative stress damage in arthritic chondrocytes
improvement was seen in both the treatment groups.
which produce iNOS (inducible nitric oxide synthase)
and NO (nitric oxide). Exosomes and mesenchymal Notably, patients in the 100-million mesenchymal
stem cells can reduce the structural abnormalities of stem cell group performed better than that in the
mitochondria and the intracellular oxidative stress 200 million with improved 6-minute walk distance,
production, thereby having a therapeutic effect on short physical performance, forced expiratory
cartilage degeneration. volume in 1 second and decreased serum TNF-α
levels from baseline to 6 months. More importantly,

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR ANTI-AGING

this study documented that intravenous

administration of MSCs was safe, which did not incur 1. Angiogenesis – provokes formation of new
any treatment-related serious adverse events for 12 blood vessels.
months post infusion. 2. Reduce inflammation – chronic disease is
associated with significant inflammation, and the
MSCs are emerging as the ideal sources regenerative biologics reduce it nicely.
of cells to solve the multi-organ
problems. MSCs have potent 3. Immune system modulation
self-renewal and differentiation – the stem cells and exosomes
capability. They are easy to modulate the immune
be harvested from umbilical system very differently than
cord tissues and can migrate steroids. Instead of blanketly
to injured sites. In addition, suppressing the immune
the immune privileged system, the regenerative
state and anti-inflammatory biologics tamp down the
property make MSC-based harmful processes while
therapy as a promising tool to be amping up the beneficial ones.
given intravenously for anti aging This includes ramping up production
improvements. of several helpful growth factors and
cytokines, while tamping down harmful ones.
How Does Stem Cell Therapy Work? 4. Cellular signaling – the biologics are able
If a new technology such as mesenchymal stem cell to perform “cell to cell” communication. This
and exosome therapy could provide excellent anti- promotes recipient cells to proliferate their
aging benefits and lower overall healthcare costs for growth factor production, protein production
an individual, it would and should become a pre- and regenerate tissues that are damaged.
emptive therapy. Aging gracefully and continuing to
stay active are highly desired traits, with the adage 5. Prevent cell death – most cells have a timed death,
being, “Health is Wealth”. where they are only allowed to live a certain length
of time. This is called apoptosis. The regenerative
MSC-based therapy reduces inflammation, biologics allow normally functioning cells (i.e.
modulates the immune system and involves chondrocytes) to live longer, and spare them from
improving local microenvironmental, immune- the pre-programmed death. This can promote
regulation and anti-inflammatory biological activities healthy, new tissue growth!
through the secretion of exosomes, growth factors,
cytokines, anti-inflammatory factors and other 6. Preventing scar tissue –Once that scar tissue
bioactive molecules. forms, it becomes nonfunctional. Stem Cells and
exosomes are great at preventing scar tissue
Stem cells and exosomes act in the body through (anti-fibrosis).
several mechanisms. They do NOT become part of a
patient’s DNA, which means they do not engraft into
the person’s existing cells.
They act through:

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR ANTI-AGING

Stem Cells can also release a huge variety of cells “themselves”, but rather coordinate and enhance
molecules into the extracellular environment. These this repair response by one’s own mechanisms.
molecules, which include extracellular vesicles
(exosomes), lipids, free nucleic acids, and soluble Where do the stem cells and exosomes
proteins, exert crucial roles in repairing damaged come from?
tissue. Along with offering stem cells for anti-aging, R3 Stem Cell’s regenerative biologics originate from
R3 Stem Cell includes stem cell exosomes, which umbilical cord tissue that has been donated after a
are a type of extracellular vesicle participating in scheduled c-section. No baby (or mother) is harmed
extensive cell to cell communication for tissue repair during the c-section procedure. The umbilical cord
and regeneration. tissue is normally discarded, but if the mother passes
screening test then the umbilical cord is immediately
The stem cells administered by R3 are not the
sent to the lab.
ones that become a patient’s new specialty cells.
The administered mesenchymal stem cells are not The lab carefully processes the umbilical cord to
specifically designed to replace damaged and lost generate large amounts of stem cells and exosomes
that are of the highest quality possible. The lab team

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR ANTI-AGING

consists of multiple PhD’s working in ISO Certified, in reducing oxidative and

cGMP compliant clean rooms to ensure quality nitrosation damage has
assurance that exceeds USA FDA standards. The attracted a lot of attention.
proprietary production process combines the highest
potency, safety and affordability for providers to Numerous studies have
confidently offer exosome procedures. evaluated the antioxidant
effects of exosomes in
Millions of dollars have been invested into the different disease models, such as
pharmaceutical grade production of the biologics the damage caused by hyperglycemia and obesity,
including first rate clean rooms, bioreactors, alcohol-related brain damage, Parkinson’s disease,
nano-particle tracking analyzers, cytometers, PCR, musculoskeletal diseases (e.g., intervertebral disc
tangential flow machines and real time environmental degeneration (IVDD), radiation-induced bone loss,
monitoring. The quality assurance testing complies osteoarthritis (OA)), liver injury, ischemia injuries,
with screening and testing stan¬dards consistent colitis and skin wounds. Further, exosomes can
with the American Association of Tissue Banks, cGMP directly alleviate oxidative stress in various types
standards, FDA regulations and the highest level of of cells such as glial cells, neurons, cardiomyocytes,
any regulatory agency globally. endothelial cells, immune cells, hepatocytes, and
Stem Cell Derived Exosomes nucleus pulposus cells in vitro.
R3 Stem Cell’s Centers of Excellence globally include Oxidative stress plays a key role in the
umbilical cord stem cell derived exosomes with pathophysiology of many diseases, by causing cell
umbilical cord stem cells to provide enhanced damage, inflammation, and metabolic disorders. In
results. Exosomes are lipid bound vesicles (acellular) all living cells, similar components are responsible for
produced by cells which contain a plethora of growth mediating excessive oxidative stress and unbalanced
factors, cytokines, mRNA and other proteins. reduction. Therefore, exosomes can regulate these
They are exceptionally helpful in cell to cell molecular components which can be used to treat
communication, and very effective for reducing different diseases.
inflammation when they become ingested by their As life expectancy increases, aging related diseases,
recipient cell. They act as shuttles to send nucleic such as neurodegenerative diseases have further
acids and proteins to other cells, in this way, allowing increased. Parkinson’s is one of the fastest-growing
cell-to-cell communication and transporting aging related neurological diseases in developed
molecules among both close and distant cells. In countries. Exosomes are thought to have the
general, these released proteins are important ability to cross the blood-brain barrier and can
regulators of intracellular information. avoid clearance by the immune system due to the
Exosomes could be the mediators of many stem membrane layer.
cell-associated therapeutic activities. Considering
they are 100 times smaller than stem cells, they do Exosomes can play an anti-oxidative stress role
not have any issues passing through the blood-brain- by themselves in neurodegenerative diseases.
barrier to reach the brain from the bloodstream Ezquer et al. used ethanol to induce excessive
oxidative stress and neuro inflammation in rats.
What is the role of exosomes in anti aging? Intranasal administration of MSC-derived exosomes
Previous reports have confirmed the cell-protective significantly increased the expression of GLT1 and
effects of exosomes in the heart, skin, and skeletal rescued the brain oxidative stress damage caused by
muscle diseases. Recently, the role of exosomes alcohol.

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR ANTI-AGING

So what are the anti-aging benefits with • Better sleep patterns

stem cell therapy? • Reduced appearance of wrinkles and age spots
While it’s great to know that the stem cells and • Increased libido (sex drive)
exosomes work hard to reduce overall inflammation • Decreased blood sugar levels
in the body and prevent chronic disease from often
getting worse, what are the actual benefits that • Improved Hgb-A1C
patients experience? • Improved lipid profile
• Improved liver function tests
Here are the benefits we see frequently:
• Decreased creatinine
• Increased energy levels
• Decreased C reactive protein (marker of
• Increase in walking ability
inflammation)
• Easier breathing
• Anecdotal – patients say they can “see better”.
• Improved memory
• Less aches and pains.
• Better concentration and focus

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR ANTI-AGING

Is stem cell therapy safe? large component of all types of chronic disease.
After a decade of performing over 24,000 stem R3’s providers use between one million stem cells
cell procedures worldwide, R3 knows that the per kilogram up to three million stem cells per
regenerative procedures are safe. The quality control kilogram. Why such a variable amount? The reason is
employed during the stem cell production is second patients are different! Some are very healthy, take no
to none, and the side effects R3 sees are usually mild medications and are lean.
to moderate and temporary. Others have multiple chronic diseases, drink alcohol,
They may include itching, dizziness, lightheadedness, smoke cigarettes, etc. We’re not here to judge, just
low grade fever, chills, headache, nausea. These want to make sure enough cells are provided to
are typically temporary. If a patient has an obtain the desired effects. So our providers use
allergic reaction to the multivitamin or judgment on the cell quantity needed.
a preservative, all of R3’s Centers have Safety is paramount with the biologics
the medications to resolve it quickly. products being rigorously tested prior
One of the questions we get asked a to use, and expert providers managing
lot is, “Will the stem cells get rejected?” each treatment as if you are a family
The answer is NO. member!
MSCs do not express major histocompatibility Why does R3 Stem Cell use donor tissue
complex (MHC) antigens of the class II subtype and
contain low levels of MHC molecules of the class I
for its stem cells?
subtype. MSCs also lack the co-stimulatory molecules Although autologous (your own) stem cells provide
essential for immune detection, including CD40, significant advantages, allogeneic (donor) stem cells
CD80, and CD86. have more advantages. First of all, autologous MSCs
need a long time to culture and expand, which limits
Therefore, MSCs generally have low immunogenicity
its application in treatment, while allogeneic stem
and can avoid immune rejection by the recipient,
cells can be obtained and expanded more quickly,
which serves as the foundation for their successful
thus avoiding the delay of time window.
application without needing to match the
donor to the recipient. Scientists call this being Second, age is a factor that affects the physiological
“immunologically privileged”. characteristics of MSCs. Studies have shown that
stem cells from elderly donors have decreased
Another question often asked is “Is there a chance of
proliferation and differentiation ability. This means
a tumor forming?” Once again the answer is NO. The
they are less in number and less effective!
mesenchymal stem cells and exosomes used during
treatment have never been shown to have tumor What are the Outcomes?
forming potentials. In fact, they have been shown to
be anti-tumor forming. Similar to the research mentioned above, R3 Stem
Cell’s outcomes for anti-aging patients have been
Treatment Protocol exceptional! The patient satisfaction rate is 85% year
over year. Patients typically see exceptional pain
For the past decade, R3 has been
relief, increased range of motion, improved function
successfully offering stem cell and
and mobility, and all of the benefits mentioned
exosome therapy intravenous for anti-
above.
aging. The cells and exosomes are
attracted to inflammation, which is a It may take four to six weeks for the results to kick

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR ANTI-AGING

in, although we have had patients symptomatically R3 Stem Cell offers free consultations for individuals
feel much better within the first couple of weeks. It to discuss whether regenerative therapy is indicated
should be noted, again, that stem cell therapy is not for you. Simply call +1 (844) GET-STEM to schedule
a “one and done” procedure, and may need to be yours!
repeated every one to two years.
References:
Affordability 1. Yeh, D.-C. and Chan, T.-M. (2018) Therapeutics of Stem
Because stem cell therapy is not a Cell Treatment in Anti-Aging and Rejuvenation. Stem Cell
Discovery, 8, 13-31.
“one and done” cure, it’s important
to make it affordable. Repeat 2. Garay RP (2023), Recent clinical trials withstem cells to
slow or reverse normalaging processes. Front. Aging
therapies every 1-2 years can
4:1148926. doi: 10.3389/fragi.2023.1148926
help people achieve continued
3. Xia C, Dai Z, Jin Y and Chen P (2021) Emerging
improvements. So a lot of patients
Antioxidant Paradigm of Mesenchymal Stem Cell-Derived
seek additional anti-aging treatments at R3 Stem Cell Exosome Therapy. Front. Endocrinol. 12:727272. doi:
repetitively. 10.3389/fendo.2021.727272
Unfortunately, stem cell clinics in Colombia, China 4. Xia et al, Combined Antioxidant, Anti-inflammaging
and Panama charge over $15,000 USD for anti-aging and Mesenchymal Stem Cell Treatment: A Possible
Therapeutic Direction in Elderly Patients with Chronic
treatment. Because the one treatment cost so much,
Obstructive Pulmonary Disease, Aging and Disease,
how are individuals supposed to budget for that Volume 11, Number 1: 129-140, Feb 2020.
every few years?? R3 Stem Cell’s fees are less than half 5. Zhu et al, Application of mesenchymal stem cell therapy
that for full treatment, which also includes free PRP for aging frailty: from mechanisms to therapeutics, 2021;
and a multivitamin infusion! 11(12): 5675-5685. doi: 10.7150/thno.46436.

R3’s Experience
For the past decade, R3 Stem Cell’s Centers globally
have performed over 24,000 regenerative procedures
in six countries. Thousands have been for anti-aging.
Patient satisfaction across all conditions treated is 85%!
R3 combines safety, effectiveness and affordability
for the therapies. Internationally, the Intellicell is used,
which is culturing the most active mesenchymal stem
cells to create the “smartest” stem cell in the world!
Our experience with all types of patients has been
extensive, and our Success Stories on R3’s YouTube
Channel are impressive. You can visit the channel
Success Story Playlist HERE.

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 R3 Consumer Guide for Stem Cell and Exosome Therapy

Guide to
Stem Cell and
Exosome Therapy
for Ataxia

Brought to you by

* No portion of this Document may be reproduced without the Express Written Consent of R3 Stem Cell.
Disclaimer: This guide’s education does not constitute medical advice. The USA FDA considers stem cell therapy experimental. Any claims
made in the Guide refer to procedures performed outside the USA.
51
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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR ATAXIA

Guide to Stem Cell and Exosome Therapy

for Ataxia
Every day, R3 Stem Cell receives inquiries worldwide The overall prevalence of ataxia is 26 cases per
from individuals asking if stem cell therapy can help 100,000 in children. The overall prevalence rate of
for Ataxia. Spoiler alert: It can help a lot! In this guide, hereditary ataxias is 10 cases per 100,000 individuals.
we’ll go through the basics of how stem cells and Dominant cerebellar ataxia is present in 2.7 cases
exosomes work for Ataxia, the latest research, and per 100,000 individuals, and recessive hereditary
what to expect with a regenerative procedure. cerebellar ataxia in 3.3 per 100,000 individuals. An
increased prevalence occurs in countries where
Conventional treatments for Ataxia are often not
able to stop the disease progression and control the consanguinity is a common practice. The worldwide
movement disorder. For those who desire prevalence of spinocerebellar ataxias is 3 to 5.6
continued ability for self care and cases per 100,000 individuals. The most
improved motor activities, failure common spinocerebellar ataxia is
with conventional treatments is spinocerebellar ataxia type 3.
disappointing and occurs all too Spinocerebellar ataxia (SCA)
often. and multiple system atrophy-
Stem cell therapy for Ataxia is cerebellar type (MSA-C) are
turning out to be an excellent both neurodegenerative
opportunity for individuals to disorders with cerebellar
achieve meaningful long term ataxia as the main clinical
results. Let’s dig in! manifestation. Spinocerebellar ataxia
is characterized by cerebellar ataxia
A Significant Global Issue movement disorder as the main symptom.
Ataxia is a neurological sign that manifests in a lack of A genetic degenerative disease with clinical
coordination in the movement of different muscles manifestations, involving the cerebellum, brainstem
in the body. It is a clinical finding and not a disease, and spinal cord. Symptoms include unsteady walking
which mainly presents abnormalities in gait, changes and standing, poor stability of fine movements of the
in speech such as scanning speech, and abnormal upper limbs, dysarthria, and consciousness.
eye movements such as nystagmus. It results from
The disease progresses to tremor, etc., and finally
dysfunction of the brain areas, responsible for the
loses the ability to live independently. It causes
coordination of movements, and, most commonly,
a huge burden on the family and society, and
the cerebellum. The three types of ataxia, according
drug treatment is not effective. Other clinical
to the location, are cerebellar, sensory, and vestibular.
manifestations include impaired fine motor activities,
Ataxia can also subdivide into sporadic (patients difficulty speaking and intention tremor. Until now,
have no family history of ataxia and manifest in no effective modalities have been available to control
adulthood), hereditary (caused by a defect in a the disease progression and, as a result, the majority
gene and manifesting in childhood), and acquired of patients may lose their self-care ability
(due to structural or demyelinating conditions,
toxicity, paraneoplastic, inflammatory or infections, Traditional Treatments
and autoimmune conditions). Friedreich ataxia Currently, there is no curative treatment available
is an autosomal recessive form of ataxia and the for hereditary ataxia. Depending on the causes, if
commonest among the hereditary forms. the ataxia results from a stroke, toxic substances,
hypothyroidism, or any modifiable risk factors,

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treatment is targeted at the specific condition standing, slow movement, upper limb fine motor
causing ataxia. Some treatable causes are reversible disorder, writing difficulties, dysarthria, eye movement
by medication such as vitamin E, coenzyme Q10 disorders were improved.
deficiencies, and episodic ataxia type two. After treatment, common adverse effects were
Patients may use devices to reduce dizziness (1 case), low back pain (2
functional disability, such as cases), headache (1 case), and fever
walking aids, canes, wheelchairs, (2 cases). All these symptoms
and walkers. Patients can disappeared within 1-3 days.
receive physical, speech No treatment-related adverse
therapy, and symptomatic events happened in the median
treatment. Medications can follow-up of 39 months (11-59
reduce tremors, muscle months). The illness of effective
stiffness, and sleeping patients had been stable for
disorders. There is evidence 1-19 months,
that physical and mental average (5.95±4.84) months.
exercises can improve the lives of The authors noted in conclusion that
patients with ataxia. Intrathecal injection of umbilical cord
mesenchymal stem cells is safe to ameliorate clinical
Stem Cell Therapy for Ataxia
symptoms to some extent within a certain time. It
Over the past decade there have been several peer- may delay the progression of spinocerebellar ataxia.
reviewed studies published evaluating stem cell Multiple courses of treatment can help to further
therapy for ataxia. Mostly, the results have been improve neurological function in most patients.
positive. Here are summaries of the published studies.
In a 2021 systematic review and meta-analysis titled,
In 2014, a Chinese study evaluated Intrathecal “Effect of stem cell treatment on functional recovery of
injection of umbilical cord mesenchymal stem cells spinocerebellar ataxia”, authors evaluated the clinical
for spinocerebellar ataxia . Thirty-eight cases of efficacy and safety of treatments involving individuals
spinocerebellar ataxia were given umbilical cord with spinocerebellar ataxia who have undergone stem
mesenchymal stem cells by intrathecal injection, one cell treatments, as well as other types of ataxia, such as
million stem cells per kilogram, once a week, four multiple systems atrophy-cerebellar type.
times as a course. These 38 cases received 52 courses In all studies, research participants had no major
of treatment overall. side effects. They looked at a study by Dongmei et al.
International Cooperative Ataxia Rating Scale (ICARS) (2011), which noted a significant improvement in the
and Activity of Daily Living Scale (ADL) were used to ICARS and ADL (Activity of Daily Living Scale) scales, in
evaluate patients neural functions (the greater scores, addition to no adverse effects.
the more severe damage) and ability of daily living There was an observed delay in the degenerative
(the lower score, the stronger the ability of daily living). process, in addition to an increase in the time of
After treatment, all patients were subjected to follow- stabilization of the disease. Jin et al. (2013), also
up visit. showed improvement in the ICARS and Berg
The total effective rate of 52 courses of treatment Balance Scale, mainly from 3 to 6 months after
was 84.62%. ICARS and ADL scores were significantly application of stem cells from the umbilical cord.
decreased at 1 month after treatment (P < 0.01). In Tsai et al. (2017) showed that applications with cells
most of effective patients, unstable walking and from adipose tissue, show little significant results

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR ATAXIA

as to their effectiveness, but they were shown to According to the ICARS score, of 27 courses of
be safe, evaluating individuals with the SARA scale, treatment in 24 patients, posture and gait disorder
posturography and magnetic resonance imaging. were improved in 25 cases, coordination and mapping
THIS IS JUST ONE REASON WE USE UMBILICAL were improved in 21 cases, language disorder was
CORD STEM CELLS, AS THEY SHOW CONSISTENT improved in nine cases, and ocular motility disorder
EFFECTIVENESS IN STUDIES FOR ATAXIA. WHEREAS, was improved in two cases. According to the ADL
ADIPOSE AND BONE MARROW STEM CELLS ARE score, of 27 courses of treatment in 24 patients, self-
INCONSISTENT! care ability was improved in 19 cases.
Umbilical cord mesenchymal stem cells at passage
One of the best studies to date evaluating umbilical 3 were used in this study and no overt clinical signs
cord mesenchymal stem cells for ataxia was published of immunologic reaction and other serious adverse
in 2011 titled, “Clinical analysis of the treatment of reactions were found.
spinocerebellar ataxia and multiple system atrophy-
cerebellar type with umbilical cord mesenchymal Of 24 patients with SCA or MSA-C treated with
stromal cells”. intrathecal injection of UC-MSC, 23 showed obvious
improvement by ICARS and ADL. Although effective
Lumbar punctures were performed after patients were for the majority of the patients in this report, the
admitted to hospital. Umbilical cord mesenchymal disease still progressed in some patients.
stem cells (one million stem cells per kilogram) with 5
mg dexamethasone was injected intrathecally weekly Note the impressive improvements in function in the
for 4 weeks, which means 4 injections for 4 weeks. tables below.

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In a 2021 Case Report titled, “Human Allogeneic The product was administered at one million stem
Bone Marrow-Derived Mesenchymal Stem Cell cells per kilogram through an intrathecal route twice
Therapy for Cerebellar Ataxia: A Case Report”, a 64 four weeks apart. The degenerative nature of this
year old ataxia patient was treated with allogeneic disease dictates that the patient’s symptoms would
bone marrow derived Mesenchymal stem cell gradually deteriorate. However, the patient’s symptoms
therapy via the intrathecal route twice every four confirmed a trend of steady improvement following 10
weeks using his 36-year-old son as a donor. He had months of allogeneic MSC therapy.
visited the researcher’s clinic due to his progressive
gait disturbance that started two years ago. He also The K-SARA scores at the beginning of the stem cell
presented non-motor symptoms such as constipation administration had gradually deteriorated since the
and sleep apnea. The patient had no history of previous initial diagnosis. However, the subsequent scores
neurological disorders and relevant family history. revealed a gentle curve up to three months following
He showed cerebellar speech and an ataxic gait. The the completion of the second stem cell administration.
tandem gait was also impaired. From then, the results demonstrated a significant
improvement up to 10 months post administration.

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR ATAXIA

How do Stem Cells and Exosomes Act patient’s DNA, which means
patient’s DNA, which means
in the Body? they do not engraft into the
Stem cells and exosomes act in the body through person’s existing cells
several mechanisms. They do NOT become part of a

They act through: 4. Cellular signaling – the biologics are able

to perform “cell to cell” communication. This
1. Angiogenesis – provokes formation of new promotes recipient cells to proliferate their
blood vessels. growth factor production, protein production
and regenerate nerve tissues that are damaged.
2. Reduce inflammation – Ataxia is associated with
significant inflammation, and the regenerative 5. Prevent cell death – most cells have a timed
biologics reduce it nicely. death, where they are only allowed to live a
certain length of time. This is called apoptosis.
3. Immune system modulation – the stem cells
The regenerative biologics allow normally
and exosomes modulate the immune system
functioning cells (i.e. neuron cells) to live longer,
very differently than steroids. Instead of
and spare them from the pre-programmed
blanketly suppressing the immune system, the
death.
regenerative biologics tamp down the harmful
processes while amping up the beneficial ones. 6. Preventing scar tissue –Once that scar tissue
This includes ramping up production of several forms, it becomes nonfunctional. Stem Cells and
helpful growth factors and cytokines, while exosomes are great at preventing scar tissue
tamping down harmful ones. (anti-fibrosis).

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR ATAXIA

Stem Cells can also release a huge variety of molecules tangential flow machines and real time environmental
into the extracellular environment. These molecules, monitoring. The quality assurance testing complies
which include extracellular vesicles (exosomes), with screening and testing stan¬dards consistent
lipids, free nucleic acids, and soluble proteins, exert with the American Association of Tissue Banks, cGMP
crucial roles in repairing damaged tissue. Along with standards, FDA regulations and the highest level of any
offering stem cells for treatment of Ataxia, R3 Stem regulatory agency globally.
Cell includes stem cell exosomes, which are a type
of extracellular vesicle participating in extensive cell Stem Cell Derived Exosomes
to cell communication for ovarian tissue repair and R3 Stem Cell’s Centers of Excellence globally include
regeneration. umbilical cord stem cell derived exosomes with
The stem cells administered by R3 are not the umbilical cord stem cells to provide enhanced
ones that become part of a patient’s results. Exosomes are lipid bound vesicles
DNA. The administered mesenchymal (acellular) produced by cells which
stem cells are not specifically contain a plethora of growth factors,
designed to replace damaged cytokines, mRNA and other proteins.
and lost epithelial cells, but rather They are exceptionally helpful
coordinate immune system in cell to cell communication,
modulation. and very effective for reducing
Where do the stem cells and inflammation when they become
ingested by their recipient cell.
exosomes come from?
They act as shuttles to send nucleic
R3 Stem Cell’s regenerative biologics acids and proteins to other cells, in this
originate from umbilical cord tissue that has way, allowing cell-to-cell communication and
been donated after a scheduled c-section. No baby (or transporting molecules among both close and distant
mother) is harmed during the c-section procedure. The cells. In general, these released proteins are important
umbilical cord tissue is normally discarded, but if the regulators of intracellular information.
mother passes screening test then the umbilical cord is
immediately sent to the lab. Exosomes could be the mediators of many stem cell-
associated therapeutic activities. Considering they are
The lab carefully processes the umbilical cord to 100 times smaller than stem cells, they do not have any
generate large amounts of stem cells and exosomes issues passing through the blood-brain-barrier to reach
that are of the highest quality possible. The lab team the brain from the bloodstream.
consists of multiple PhD’s working in ISO Certified,
cGMP compliant clean rooms to ensure quality Is stem cell therapy safe?
assurance that exceeds USA FDA standards. The After a decade of performing over 24,000 stem cell
proprietary production process combines the highest procedures worldwide, R3 knows that the regenerative
potency, safety and affordability for providers to procedures are safe. The quality control employed
confidently offer exosome procedures. during the stem cell production is second to none, and
the side effects R3 sees are usually mild to moderate
Millions of dollars have been invested into the
and temporary.
pharmaceutical grade production of the biologics
including first rate clean rooms, bioreactors, They may include itching, dizziness, lightheadedness,
nano-particle tracking analyzers, cytometers, PCR, low grade fever, chills, headache, nausea. These are
typically temporary. If a patient has an allergic reaction

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR ATAXIA

to the multivitamin or a preservative, all of R3’s Centers IV therapy combining mesenchymal stem cells and
have the medications to resolve it quickly. exosomes, along with a multivitamin IV as well. R3 also
performs an intrathecal injection, which is essentially
One of the questions we get asked a lot is, “Will the a “reverse” spinal tap. Safety is paramount with the
stem cells get rejected?” The answer is NO. biologics products being rigorously tested prior to use,
MSCs do not express major histocompatibility complex and expert providers managing each treatment as if
(MHC) antigens of the class II subtype and contain low you are a family member!
levels of MHC molecules of the class I subtype. MSCs
also lack the co-stimulatory molecules essential for
Why does R3 Stem Cell use donor tissue for
immune detection, including CD40, CD80, its stem cells?
and CD86. Although autologous (your own)
stem cells provide significant
Therefore, MSCs generally have
advantages, allogeneic
low immunogenicity and can
(donor) stem cells have more
avoid immune rejection by
advantages. First of all,
the recipient, which serves
autologous MSCs need a
as the foundation for their
long time to culture and
successful application
expand, which limits its
without needing to match
application in treatment,
the donor to the recipient.
while allogeneic stem cells
Scientists call this being
can be obtained and expanded
“immunologically privileged”.
more quickly, thus avoiding the
Another question often asked delay of time window.
is “Is there a chance of a tumor
forming?” Once again the answer is NO. The Second, age is a factor that affects the
mesenchymal stem cells and exosomes used during physiological characteristics of MSCs. Studies have
treatment have never been shown to have tumor shown that stem cells from elderly donors have
forming potentials. In fact, they have been shown to be decreased proliferation and differentiation ability. This
anti-tumor forming. means they are less in number and less effective!

Treatment Protocol Affordability

For the past decade, R3 has been Stem cell therapy for Ataxia may be
successfully treating patients with the key step to completely changing a
stem cell and exosome therapies with person’s quality of life, and we want to
injection, infusion, intranasal, intrathecal make it affordable for as many individuals as possible.
and nebulizer procedures. Our global volume has allowed us to keep our patient
cost as low as possible.
For Ataxia, R3’s providers use between one and two
million stem cells per kilogram (depends on patient Unfortunately, stem cell clinics in Colombia, China and
weight). In addition, billions of stem cell exosomes and Panama charge over $20,000 USD for Ataxia treatment.
platelet rich plasma therapy (PRP) are included at no How are individuals supposed to budget for that?? R3
cost. Stem Cell’s fees are typically less than half that for full
treatment, which also includes free exosomes, PRP and
R3 Stem Cell’s Ataxia treatment protocol includes an a multivitamin infusion!

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR ATAXIA

R3’s Experience References:

1. Jing et al, Intrathecal injection of umbilical cord mesenchymal
For the past decade, R3 Stem Cell’s Centers globally stem cells for spinocerebellar ataxia, Chinese Journal of Tissue
have performed over 24,000 regenerative procedures Engineering Research October 1, 2014 Vol.18, No.41
in six countries. Patient satisfaction across all conditions 2. Dongmei et al, Clinical analysis of the treatment of spinocerebellar
treated is very high, at 85%. R3 has treated many ataxia and multiple system atrophy-cerebellar type with umbilical
cord mesenchymal stromal cells, Cytotherapy, 2011; 13: 913–917
patients with varying types of heart disease.
3. Appelt et al, Effect of stem cell treatment on functional recovery
R3 combines safety, effectiveness and affordability of spinocerebellar ataxia: systematic review and meta-analysis,
Appelt et al. Cerebellum & Ataxias (2021) 8:8
for the therapies. Internationally, the Intellicell is used,
which is culturing the most active mesenchymal stem 4. Ko, P.-W.; Park, S.; Kang, K.; Lim, Y.-H.; Kim, S.R.; Suk, K.; Kim, K.S.; Lee,
H.-W. Human Allogeneic Bone Marrow-Derived Mesenchymal
cells to create the “smartest” stem cell in the world! Stem Cell Therapy for Cerebellar Ataxia: A Case Report. Medicina
2021, 57, 334. https://doi.org/10.3390/ medicina57040334
R3 Stem Cell offers free consultations for individuals to
discuss whether regenerative therapy is indicated for 5. Tsai et al, Treatment of Spinocerebellar Ataxia With Mesenchymal
Stem Cells: A Phase I/IIa Clinical Study Cell Transplantation, Vol. 26,
your heart disease. Simply call +1 (844) GET-STEM to pp. 503–512, 2017
schedule yours!
6. Ko, P.-W.; Park, S.; Kang, K.; Lim, Y.-H.; Kim, S.R.; Suk, K.; Kim, K.S.; Lee,
H.-W. Human Allogeneic Bone Marrow-Derived Mesenchymal
Stem Cell Therapy for Cerebellar Ataxia: A Case Report. Medicina
2021, 57, 334. https://doi.org/10.3390/ medicina57040334

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 R3 Consumer Guide for Stem Cell and Exosome Therapy

Guide to
Stem Cell Therapy
for Autism
60
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 GUIDE TO STEM CELL THERAPY FOR AUTISM

Guide to Stem Cell Therapy for Autism

Autism Spectrum Disorder (ASD)

includes several conditions that were
previously considered separately. These
include Autism, Asperger’s Syndrome,
Childhood Disintegrative Disorder,
and an unspecified form of Pervasive
Developmental Disorder.

Patients with ASD show a wide range of

variations in symptoms, condition severity,
and functional disability (Geschwind, 2009).
Although scientists have not yet been able Existing Treatments
to determine the exact cause leading to ASD,
it has been theorized that the disturbances Traditional treatments for autism patients
caused during the embryonic stages may be include speech therapies, social interaction
responsible (Courchesne et al., 2019). training, applied behavioral analysis and use
of psychotropic drugs (Thibaut, 2017). While
ASD may be divided into two main symptom early behavioral interventions often improve
categories: The first one is reduced social functioning and outcome, there are currently
interaction and the second one is repetitive NO medications specifically approved
behaviors, curiosities, and aggressive for the core symptoms of
actions. ASD can sometimes ASD. They are usually
be detected at eighteen prescribed “off label”
months or younger. for the associated
The recent figures symptoms of
estimate ASD global irritability or
prevalence to be hyperactivity.
approximately one
in 100 children Alternative
(World Health therapies include
Organization). hyperbaric oxygen
management
(Oberman, Rotenberg, &
Pascual-Leone, 2015) music
therapy, cognitive behavioral
therapy, and fast learning therapies (S. R.
Sharma, Gonda, & Tarazi, 2018).

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The use of complementary and
alternative medicine (CAM) is common
in kids with ASD, despite the lack of
research and potential side effects. Some
regularly used CAM therapies, such as methyl
B12, oxytocin, ginkgo biloba, secretin, and
chelation therapy, have been found to be ineffective.
Hence, it is imperative that safer alternative
therapies such stem cell therapy be investigated and Autologous Stem Cell Procedures
promulgated further (Shuai et al., 2020). Autologous stem cell procedures involve
harvesting tissue from the patient to use, which is
The key point here is that to date, the conventional either bone marrow or adipose. That tissue is then
and alternative therapies that exist are typically just processed either immediately or over a period of
not satisfactory to parents. R3 receives many calls a weeks to administer back to the patient.
day from parents around the world who have tried
traditional therapies with unsatisfactory results. In a review of published clinical trials looking at
stem cell therapies for ASD, R3 Stem Cell noted that
Let’s discuss stem cell therapy for ASD and the risk/ Sharma et al performed several studies utilizing
benefits associated. First of all, researchers have not bone marrow mononuclear cells for ASD (Shamim
been able to pinpoint an exact cause for ASD. There et al, 2023, Regenerative Medicine). The cells were
are quite a few theories, but nothing has been delivered intrathecally (into the
universally agreed upon. Secondly, no spinal cord), with no significant
cure for ASD currently exists. So the adverse events being seen
focus has been on mitigation. (temporary nausea/
vomiting were reported).

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After six months of follow up, there
was improved concentration, stable
sleep patterns, proper eye contact,
great social interaction and improved
memory were recorded. There have not
been published clinical trials on adipose
stem cells for ASD to date.

There have been a few well documented clinical

trials evaluating autologous umbilical cord blood
treatment for ASD. In 2018 a phase I/II clinical to the study, none of the participants experienced
trial was conducted using autologous umbilical serious adverse events, nor did they have to be
cord blood (UCB) in patients with ASD by Sutter hospitalized as a consequence of cellular therapy
Pediatric Neurology (Sacramento, CA, USA). A total during the period of the study [44]. The researchers
of 30 patients were enrolled for the randomized, noted positive results, especially in the outcome
triple-blinded (participant, care provider and measures for social activities; however, when
investigator), placebo-controlled and crossover statistically analyzed, no significant changes were
study. An age range of 2–7 years was maintained. obtained in the outcomes. Nevertheless, it may be
The subjects were infused with autologous UCB inferred from the study results that autologous UCB
and placebo (saline). The dosage used was a infusions may be safely used in ASD subjects.
minimum of 10 million total nucleated cells/kg in
one infusion of 60 ml of study product. Twenty-nine A safety study with 25 autistic children
patients completed the post-treatment between the ages of 2 and 6
follow-up. years for phase I clinical
trials was conducted by
The outcome measures used Duke University. The
included CGI, expressive participants selected had
and receptive one-word their own autologous
picture vocabulary UCB unit, and no
tests, Stanford– Binet masking was done. The
Fluid Reasoning researchers discussed
and Knowledge the therapeutic utility of
and Vineland UCB by-products for the
Adaptive Behavior and treatment of children with
Socialization. According ASD. In this study, the intravenous
mode of delivery for treatment was
chosen. A dose of 1–5 × 107 cells/kg was given
to the participants.

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own autologous UCB unit, and no masking was
done. The researchers discussed the therapeutic
utility of UCB by-products for the treatment of
children with ASD. In this study, the intravenous
mode of delivery for treatment was chosen. A dose
of 1–5 × 107 cells/kg was given to the participants.

After the evaluation of the adverse and serious UCB on 180 participants. A minimum banked
adverse events for a whole year, the researchers total nucleated cell dose of ≥2.5 × 107 cells/
found this treatment to be safe for usage for kg or ≥4/6 HLA-matched allogeneic, unrelated
ASD patients. The results indicated a general UCB was used. Once again, the researchers
improvement in the symptoms specific to autistic noted UCB to be safe for administration, either
children. These also included speech and verbal/ autologous or allogenic. Significant improvement
nonverbal socialization skills. was observed in the communication activities
involving toys and employing focus. The
A phase II study was completed in 2019 by researchers observed insufficiency of the single
researchers at Duke University, using single dose of UCB toward alleviating symptoms of
intravenous autologous or allogeneic, unrelated autism or improving social skills.

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Donor Stem Cell Procedures
The 2019 study mentioned in the
previous paragraph included both
autologous and allogeneic umbilical cord
tissue, so it spans into this section.

Researchers from Shandong Jiaotong

Hospital Jinan, Shandong (China)
conducted a phase I/II clinical trial
to measure the safety, feasibility and
efficacy of UCMSCs and CBMNCs in
autistic children. It was an open-label and parallel Periodic psychiatric evaluations showed that the
intervention in which 37 autistic subjects were group of children who presented improvements
enrolled. Patients received both cord blood cells in efficacy variables also manifested increased
and umbilical cord mesenchymal stem cells. At awareness, and noticeable improvements in social
the time of cell therapy, no adverse event was communication (both verbal and expressive)
measured except for low grade fever. and motor ability, despite causing an increase in
anxiety and emotional liability in some of them.
The significant changes observed included
According to the researchers, “From our previous
improved social and behavioral withdrawals,
clinical observations, the therapeutic effect of MSC
enhanced eye contact, less emotional and
infusions often declines between 3 and 6 months
aggressive response, adaptability, and less
after administration, likely due to the immune”
hyperactivation and unstable speech patterns.
evasive properties of MSCs that allow them to
At 24-week follow-up, the results were compared
persist in the body before being eliminated.”
with the control group, and considerably higher
improvements were seen in the combination Stem Cell Derived Exosomes
group.
R3 Stem Cell’s Centers of Excellence globally
A very well done study by Riordan et al (2019, Stem include umbilical cord stem cell derived exosomes
Cells Transl Med) included 20 participants receiving with umbilical cord stem cells to provide enhanced
a total of 144 million umbilical cord mesenchymal results. Exosomes are lipid bound vesicles (acellular)
stem cells over 4 treatments. While the study produced by cells which contain a plethora of
has been retracted (due to patients paying for growth factors,
treatment), adverse events included fatigue,
headache, fever, hyperactivity, anxiety and swelling.
All of these were temporary.

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cytokines, mRNA and other proteins.

They are exceptionally helpful in

cell to cell communication, and very
effective for reducing inflammation
when they become ingested by their
recipient cell. They act as shuttles to
send nucleic acids and proteins to
other cells, in this way, allowing cell-to-
cell communication and transporting
molecules among both close and
distant cells. In general, these released
proteins are important regulators of intracellular The biologics utilized undergo rigorous screening
information. processes for all types of contaminants and
communicable diseases. Only if all the testing is
Exosomes could be the mediators of many stem negative, are the biologics able to be used.
cell-associated therapeutic activities. Considering
they are 100 times smaller than stem cells, they Results
do not have any issues crossing the blood brain Secondly, effectiveness is critical. One of the main
barrier to reach the central nervous system from reasons R3’s Centers have become so popular for
the bloodstream. (Alessio et al, Int Jour Env Res Pub autism therapy is the success rates. Over 85% of
Health, 2020). families are exceptionally happy with their child’s
results. The results seen span the categories of
R3 Stem Cell’s Experience behavior and communication. Whether it’s verbal
R3 Stem Cell has over 45 Centers of Excellence or non-verbal improvements, the results are
globally with a presence in six countries. Autism is typically obvious.
one of the top conditions for which therapy with
stem cells and exosomes is performed. There are A lot of children with ASD are hyperactive and/
several factors R3 has taken into consideration or aggressive with their family or friends. In line
when optimizing these therapies for children. with the results Duke University saw, R3’s patients
typically see a significant reduction in these
First of all, safety with these treatments is behaviors.
paramount. In line with ALL of the studies
mentioned in this guide, R3 Stem Cell has not Affordable
seen significant adverse events. Temporary issues And third, affordability is key. Because stem cell
such as low grade fever, nausea, headaches, therapy for Autism is not a ure, it’s important to
dizziness are frequently seen. make it affordable. Repeat therapies can help gain
additional improvements for ASD children.

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So a lot of families seek additional treatments at
R3 Stem Cell every six to eighteen months. It’s
not mandatory, but something we see a lot.

Unfortunately, stem cell clinics in Colombia,

China and Panama charge over $20,000 USD for
autism treatment. Because the one treatment
cost so much, how are families supposed to
budget for that every year?? R3 Stem Cell’s
fees are less than half that for 100 million high
quality stem cells! Conscious sedation may be administered,
which allows the child to be awake but not
Protocol aware of the procedure. It is not general
When it comes to stem cell and exosome anesthesia, it’s simply a fast acting medication
therapy for autism, R3’s protocol is safe and like Versed.
effective. The anesthesiologists at R3’s Centers
are experts in the intrathecal application. R3 Stem Cell administers a multivitamin
It’s basically a “reverse” spinal tap procedure infusion along with the stem cells,
and allows millions of stem cells to safely be
administered into the central nervous system.

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which helps to activate the cells for best results.
The umbilical cord stem cells are administered IV
as well as intrathecal.

R3’s experienced providers use clinical judgment and

best practice protocols to decide on the amount of
stem cells necessary for best results. This may include
from 3 to 6 million stem cells per kilogram, and from
30 billion to 180 billion exosomes as well.

Treatments may occur on one day, or be separated

into two days for patient safety. A family member is
typically allowed in the room. R3’s procedure rooms
have intensive monitoring equipment.

Bottom Line
R3’s Experience
There are plenty of naysayers who say the
For the past decade, R3 Stem Cell’s Centers
following:
globally have performed over 23,000
1. It’s not safe: There are no well performed regenerative procedures in six countries.
studies showing significant adverse events to date, Hundreds have been for ASD. Patient satisfaction
and R3 hasn’t seen any either. across all conditions treated is 85%!

2. Effectiveness isn’t proven: In R3’s experience, R3 combines safety, effectiveness and

the results are excellent and noticeable by the affordability for the autism therapies.
family 85% of the time. Numerous studies, some of Internationally, the Intellicell is used, which is
which are reported in this Guide, show the clinical culturing the most active mesenchymal stem
effectiveness. cells to create the “smartest” stem cell in the
world!
3. More research is needed: R3 hears this
frequently from providers who are offering only R3 Stem Cell offers free consultations for families to
conventional therapies. The families who have their discuss whether regenerative therapy is indicated
child being treated with those providers are not for their children. Simply call +1 (844) GET-STEM or
satisfied with the results. At what point does stem +1 (480) 808-7057 to schedule yours!
cell therapy become “acceptable” to these laggard
providers??

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 R3 Consumer Guide for Stem Cell and Exosome Therapy

Guide to
Stem Cell and
Exosome Therapy
for Back Pain

Brought to you by

* No portion of this Document may be reproduced without the Express Written Consent of R3 Stem Cell.
Disclaimer: This guide’s education does not constitute medical advice. The USA FDA considers stem cell
therapy experimental. Any claims made in the Guide refer to procedures performed outside the USA.
69
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Guide to Stem Cell and Exosome Therapy for Back Pain

Every day, R3 Stem Cell receives inquiries worldwide instability). We will use the term Low Back Pain moving
from individuals asking if stem cell therapy can help forward to include the combined sources.
for back pain. Spoiler alert: It can help a lot! In this
guide, we’ll go through the basics of how stem cells The tremendous impact of low back pain was
and exosomes work for relieving back pain long portrayed in a prospective multicenter study including
term, the latest research, and what to expect with a 8 industrialized countries which found that patients
regenerative procedure. with chronic spinal conditions have lower quality of
life scores when compared with patients with other
Back Pain is Everywhere chronic conditions such as arthritis, chronic lung
Chronic low back pain, defined as pain symptoms disease, congestive heart failure, and diabetes.
persisting beyond 3 months, affects an estimated Stem cell therapy for low back pain is turning
15–45% of the population. Back pain has out to be an excellent opportunity for
been termed as “an illness in search individuals to regain a pain free life,
of a disease.” For the minority improve function, avoid surgery,
who suffer from intractable avoid pain medications, and
symptoms, quality of life may get back to a quality of life
suffer tremendously. During you deserve. Read on to learn
life, over 80% of individuals more.
will experience low back pain,
and for an unfortunate few it Current Non-Surgical
becomes chronic. Options
In 2020, low back pain (LBP) affected Current non-surgical options to
619 million people globally and it is estimated that manage low back pain include exercise and
the number of cases will increase to 843 million cases physical therapy, weight loss, NSAIDS, TENS Units,
by 2050, driven largely by population expansion and bracing, traction, manipulation, massage, opioids,
aging (World Health Organization). LBP is the single antidepressants, topical medications and muscle
leading cause of disability worldwide. relaxants. Various types of injections for the low
back have been employed, including epidural
Chronic LBP is a major cause of work loss and steroid injections, facet or medial branch blocks, and
participation restriction and reduced quality of life radiofrequency ablation.
around the world. Considering the high prevalence,
LBP contributes to a huge economic burden on Steroids, although they present a good anti-
societies. It should be considered a global public inflammatory action, tend to destroy Facet cartilage
health problem, virtually an epidemic. at the same time. That is why when their action has
stopped, the pain gets worse than before. Opioids are
Close to 90% of those suffering from back pain do not not a great option for chronic back pain. They have
have a definitive anatomical correlation, and the pain significant side effects such as constipation, tolerance
remains nonspecific. In essence the following sources and possibly addiction.
of back pain are combined as “one” to define lumbar
spondylosis: (i.e. symptomatic disc degeneration, These injections and medications are not meant to
symptomatic facet joint osteoarthritis and segmental repair or regenerate degenerative spinal tissues, but
rather to mask pain for a period of time. In order

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to potentially change the narrative for nonsurgical The study showed that there was no clear evidence
treatment approach for lumbar spondylosis, that primary spinal fusion surgery was any more
umbilical cord allograft tissue may represent a safe beneficial than intensive rehabilitation in patients
and clinically effective option for achieving pain relief. with chronic low back pain. Surgery while not having
any superiority over conservative management was
Researchers have evaluated perinatal allogenic
associated with potential risk and increased cost.
tissues including clinical-grade minimally
manipulated umbilical cord tissue-derived allograft, In a study by Fritzell et al (2001) comparing surgical
and reported on the significant presence of growth with non-surgical treatment for low back pain 18%
factors, cytokines, hyaluronic acid and exosomes. of the patients in the fusion group developed early
(within 2 weeks) complications and 6% had late
Spinal Fusion for Low Back Pain complications. Complications included, bleeding,
Despite the existence of sophisticated imaging neural injury, heart failure, major GI bleeding,
techniques and a plethora of diagnostic testing, pulmonary oedema, aspiration sepsis, pulmonary
the source of pain in patients with embolism, dural tears, haematomas,
nonspecific back pain cannot be pseudoarthrosis and even wrong
established. There exists no causal level surgery. In patients who
relationship between imaging had complex fusion the
findings of degenerated complication rate was 31%.
disc, lumbar facet arthritis, The reoperation rate in the
spondylosis, spondylolysis surgical group was 6%.
and spondylolisthesis, to the
pain in these patients. Despite a lack of superiority
of spinal fusion over non-
Spinal fusion is a major operative treatment of patients
surgery which can be associated with chronic non-specific low
with significant morbidity and back pain, there has been a steep
occasionally with mortality. Is there rise in the rates of spinal fusion over the
justification for spinal fusion in the treatment of last two decades.
patients with non-specific low back pain?
Since having a spinal fusion is an elective procedure,
Fairbank et al, in 2005, published the results of a patients should truly try all beneficial conservative
randomised controlled trial which assessed the options prior to making the surgical decision.
clinical effectiveness of spinal stabilization or fusion
compared to intensive rehabilitation for patients with Is There Research on Stem Cell Therapy for
chronic low back pain. Their cohort included 349 Low Back Pain?
patients between the ages of 18 to 55 years with at In 2024, Wilson et al evaluated exosome injections
least one year of low back pain who were considered for low back pain. Twenty adult subjects with
by an experienced surgeon that they were candidates lumbar facet joint pain received a single injection
for spinal fusion. of mesenchymal stem cell derived extracellular
vesicles in the lumbar facet joint space. By the
There were surgical complications in 19 patients.
3-month end point, follow-up was successful, and
Eleven patients in the surgical group had
no complications or adverse events were noted.
reoperations. Complications included dural tears,
Significant improvements in all assessments of pain
excessive bleeding, implant problems, fractures and
and disability occurred throughout the study.
vascular injury.

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In 2023, Sharan et al published the first human

case report of umbilical cord mesenchymal
stem cell injections for both cervical and
lumbar being injected into the epidural
and facet joint spaces. A 47-year-old
male presented with complaints of
13-year-long chronic lower back pain
resistant to conservative treatment.
The decision was made to treat the
patient with umbilical cord-derived
mesenchymal stem cells (MSCs).
Eighty seven million MSCs were infused
intravenously.
Simultaneously, 1 million cells were injected
into each of the 8 lumbar epidural facet joints and
5 million cells into the lumbar epidural space. The significant difference in pain scores from baseline to
patient had no adverse events or complications all follow up periods.
related to the treatment. Five days after treatment,
most of his lumbar pain was gone, and his back At the end of the study period (12 months), among
spasms stopped. He no longer needed to take 22 patients in the treatment group, 8 patients did not
acetaminophen or ibuprofen and had no difficulty require opioids and 9 patients decreased opioid use.
sleeping without medications. The patient also An amazing 77% of patients in the investigational
reported his residual cervical radicular pain to be 98% group either stopped or decreased opioids compared
resolved due to the injection. The authors noted the to none in the control group. In contrast, all patients
exceptional pain relief achieved with “discogenic” in the control group remained on opioid therapy
back pain, but without injecting intradiscal. throughout the study period.

In a prospective study evaluating bone marrow The results of this study showed significant
stem cell injections for low back pain versus steroid improvement in function and pain relief in 67% of
injections, Atluri et al evaluated 44 patients, half of the study group. The authors concluded, “It appears
whom received the stem cells. that stem cell therapy could be a reasonable option
to treat chronic low back refractory to conventional
The treatment group patients received a one-time treatment, especially if performed by qualified
bone marrow concentrate injection into spinal physicians following the proper guidelines”.
structures (i.e., discs, facets, spinal nerves, and
sacroiliac joints), along with conventional treatment, Adipose stem cells were used by Rothoerl et al in
whereas, the control group received conventional Thirty-seven presenting with low back pain between
treatment with nonsteroid anti-inflammatory the ages of 31 and 78. After one week, patients
drugs, over-the-counter drugs, structured exercise already reported an improvement reflected by a
programs, physical therapy, spinal injections and decreased Visual Analog Scale pain level. At the
opioids, etc., as indicated. one-year follow-up the mean VAS level was 1.5, and
the mean ODI was 17.5%. At the five-year follow-
Typically, the stem cells were injected in each disc up, the mean VAS level was 1.4, and the mean ODI
(2 mL), epidural space (2 mL), facet joints (0.5 mL), was 18.7%. Every patient reported improved VAS
and sacroiliac joint (1 mL). Significant improvement pain after treatment with ADRCs compared to the
in mean pain scores from 7.1 ± 2.2 to 4.2 ± 2.8 with baseline.

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This result was observed in the short term (one week

and one month) and in the longer term after five years
of follow-up.
In one prospective study, 33 patients with lower
back pain and disc degeneration were treated with
culture-expanded, autologous, mesenchymal
stem cells with follow-up period up to 6 years. The
study of intradiscal injections has proven safety
with only minor adverse events and significant
improvements in pain, function, and overall
subjective improvement as evidenced by numeric
pain score (NPS), modified single assessment numeric
evaluation (SANE) rating and functional rating index
(FRI). Measurement of the intervertebral disc posterior
dimension has shown that 85% of the patients who
were evaluated by MRI demonstrated a reduction in a combination therapy. Stem cells travel through
disc bulge size, with an average reduction size of 23% the bloodstream and are attracted to areas of
post treatment. inflammation. All arthritis, stenosis, disc disease and
nerve root compression includes inflammation. So
A Chinese study in 2014 evaluated two patients the stem cells applied intravenously will also reach
receiving umbilical cord stem cell injections intra- the area and provide repair, regeneration and relief!
discal for chronic low back pain. After transplantation,
the pain and function improved immediately in How Does Stem Cell Therapy Work?
the 2 patients. The VAS and ODI scores decreased
If a new technology such as mesenchymal stem cell
significantly during a 2-year follow-up period.
and exosome therapy could provide excellent back
It has become apparent from the numerous studies pain relief and lower overall healthcare costs for an
reported on intra-discal stem cells that pain relief individual, it would and should become a first line
occurs, but rehydration of the disc does not. Many therapy.
studies have concluded that transplanted cells could MSC-based therapy reduces inflammation,
not survive in the hypoxic environment of the disc. modulates the immune system and involves
Likewise, various inflammatory mediators, the low improving local microenvironmental, immune-
pH, low glucose levels, and hyperosmolarity present
regulation and anti-inflammatory biological activities
in the degenerated disc may disturb the function of
through the secretion of exosomes, growth factors,
transplanted MSCs.
cytokines, anti-inflammatory factors and other
For the most part, R3 Stem Cell performs stem cell bioactive molecules. This can result in tissue repair,
injections into the epidural space, facet joints and in increased cartilage, nerve regeneration and a
the paraspinal musculature for patients with chronic significant reduction in the chronic back pain.
low back pain. This has worked unbelievably well for
those dealing with spinal stenosis, discogenic pain, Stem cells and exosomes act in the body through
arthritis or scoliosis pain. several mechanisms. They do NOT become part of a
patient’s DNA, which means they do not engraft into
In addition, an IV stem cell therapy works the person’s existing cells.
exceptionally well for helping with back pain as

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They act through: 4. Cellular signaling – the biologics are able

to perform “cell to cell” communication. This
1. Angiogenesis – provokes formation of new promotes recipient cells to proliferate their
blood vessels. growth factor production, protein production
2. Reduce inflammation – chronic disease is and regenerate tissues that are damaged.
associated with significant inflammation, and the 5. Prevent cell death – most cells have a timed death,
regenerative biologics reduce it nicely. where they are only allowed to live a certain length
3. Immune system modulation – the stem cells of time. This is called apoptosis. The regenerative
and exosomes modulate the immune system biologics allow normally functioning cells (i.e.
very differently than steroids. Instead of chondrocytes) to live longer, and spare them from
blanketly suppressing the immune system, the the pre-programmed death. This can promote
regenerative biologics tamp down the harmful healthy, new tissue growth!
processes while amping up the beneficial ones. 6. Preventing scar tissue –Once that scar tissue
This includes ramping up production of several forms, it becomes nonfunctional. Stem Cells and
helpful growth factors and cytokines, while exosomes are great at preventing scar tissue
tamping down harmful ones. (anti-fibrosis).

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Stem Cells can also release a huge variety of Where do the stem cells and exosomes
molecules into the extracellular environment. These come from?
molecules, which include extracellular vesicles
R3 Stem Cell’s regenerative biologics originate from
(exosomes), lipids, free nucleic acids, and soluble
umbilical cord tissue that has been donated after a
proteins, exert crucial roles in repairing damaged
scheduled c-section. No baby (or mother) is harmed
tissue. Along with offering stem cells for back pain
during the c-section procedure. The umbilical cord
relief, R3 Stem Cell includes stem cell exosomes,
tissue is normally discarded, but if the mother passes
which are a type of extracellular vesicle participating
screening test then the umbilical cord is immediately
in extensive cell to cell communication for tissue
sent to the lab.
repair and regeneration.
The lab carefully processes the umbilical cord to
The stem cells administered by R3 are not the generate large amounts of stem cells and exosomes
ones that become a patient’s new specialty cells. that are of the highest quality possible. The lab team
The administered mesenchymal stem cells are not consists of multiple PhD’s working in ISO Certified,
specifically designed to replace damaged and lost cGMP compliant clean rooms to ensure quality
cells “themselves”, but rather coordinate and enhance assurance that exceeds USA FDA standards. The
this repair response by one’s own mechanisms. proprietary production process combines the highest

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potency, safety and affordability for providers to distant cells. In general, these released proteins are
confidently offer exosome procedures. important regulators of intracellular information.
Millions of dollars have been invested into the Exosomes could be the mediators of many stem
pharmaceutical grade production of the biologics cell-associated therapeutic activities. Considering
including first rate clean rooms, bioreactors, nano- they are 100 times smaller than stem cells, they do
particle tracking analyzers, cytometers, not have any issues passing through the
PCR, tangential flow machines blood-brain-barrier to reach the brain
and real time environmental from the bloodstream
monitoring. The quality
assurance testing complies
What is the role of
with screening and testing exosomes in back pain?
standards consistent with Previous reports have
the American Association of confirmed the cell-protective
Tissue Banks, cGMP standards, effects of exosomes in the
FDA regulations and the heart, skin, and skeletal muscle
highest level of any regulatory diseases. Recently, the role of
agency globally. exosomes in reducing oxidative and
nitrosation damage has attracted a lot of
Stem Cell Derived Exosomes
attention.
R3 Stem Cell’s Centers of Excellence globally include
Numerous studies have evaluated the antioxidant
umbilical cord stem cell derived exosomes with
effects of exosomes in different disease models, such
umbilical cord stem cells to provide enhanced
as the damage caused by hyperglycemia and obesity,
results. Exosomes are lipid bound vesicles (acellular)
alcohol-related brain damage, Parkinson’s disease,
produced by cells which contain a plethora of growth
musculoskeletal diseases (e.g., intervertebral disc
factors, cytokines, mRNA and other proteins.
degeneration (IVDD), radiation-induced bone loss,
They are exceptionally helpful in cell to cell osteoarthritis (OA)), liver injury, ischemia injuries,
communication, and very effective for reducing colitis and skin wounds. Further, exosomes can
inflammation when they become ingested by their directly alleviate
recipient cell. oxidative stress in
They act as various types of
shuttles to send cells such as glial
nucleic acids cells, neurons,
and proteins to cardiomyocytes,
other cells, in this endothelial cells,
way, allowing immune cells,
cell-to-cell hepatocytes, and
communication nucleus pulposus
and transporting cells in vitro.
molecules among
both close and

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Oxidative stress plays a key role in the Is stem cell therapy safe?
pathophysiology of many diseases, by causing cell After a decade of performing over 24,000 stem
damage, inflammation, and metabolic disorders. In cell procedures worldwide, R3 knows that the
all living cells, similar components are responsible for regenerative procedures are safe. The quality control
mediating excessive oxidative stress and unbalanced employed during the stem cell production is second
reduction. Therefore, exosomes can regulate these to none, and the side effects R3 sees are usually mild
molecular components which can be used to treat to moderate and temporary.
different diseases.
They may include itching, dizziness, lightheadedness,
So what back pain disorders does R3 Stem low grade fever, chills, headache, nausea. These
Cell treat? are typically temporary. If a patient has an allergic
reaction to the multivitamin or a
• Herniated Disc (slipped disc) preservative, all of R3’s Centers
• Degenerative Disc Disease have the medications to
• Spinal Stenosis resolve it quickly.
• Degenerative One of the questions
Scoliosis we get asked a lot is,
“Will the stem cells get
• Facet Syndrome
rejected?” The answer is
• Ankylosing NO.
Spondylitis
MSCs do not express
• Failed Back Surgery major histocompatibility
Syndrome complex (MHC) antigens
• Arachnoiditis of the class II subtype and
contain low levels of MHC
• Sciatica and Radiculopathy
molecules of the class I subtype. MSCs
• Lumbago, Lumbar Spondylosis also lack the co-stimulatory molecules essential for
immune detection, including CD40, CD80, and CD86.
Here are the benefits we see frequently:
Therefore, MSCs generally have low immunogenicity
• Increased energy levels and can avoid immune rejection by the recipient,
• Increase in walking ability which serves as the foundation for their successful
• Decreased pain application without needing to match the
donor to the recipient. Scientists call this being
• Reduction of leg pains
“immunologically privileged”.
• Reduced spasms
Another question often asked is “Is there a chance of
• Better sleep patterns. a tumor forming?” Once again the answer is NO. The
• Less need for opioids and other pain mesenchymal stem cells and exosomes used during
medications. treatment have never been shown to have tumor
forming potentials. In fact, they have been shown to
• Avoiding surgery!
be anti-tumor forming.

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Treatment Protocol have shown that stem cells from elderly

For the past decade, R3 has been donors have decreased proliferation
successfully offering stem cell and and differentiation ability. This
exosome therapy intravenous for means they are less in number
all types of back pain. The cells and less effective!
and exosomes are attracted to What are the Outcomes?
inflammation, which is a large Similar to the research mentioned
component of all types of back pain above, R3 Stem Cell’s outcomes
conditions such as disc disease, spinal for all types of back pain have been
arthritis, stenosis, sciatica. exceptional! The patient satisfaction rate is
R3’s providers use between one million stem cells 85% year over year. Patients typically see exceptional
per kilogram up to three million stem pain relief, increased range of motion, improved
cells per kilogram. Why such a variable function and mobility, and all of the benefits
amount? The reason is patients are mentioned above. Wouldn’t it be fantastic to get off
different! Some are very healthy, take opioids? Avoid the need for a back surgery or obtain
no medications and are lean. relief after a failed back surgery?
It may take four to six weeks for the results to kick
Others have multiple chronic diseases,
in, although we have had patients symptomatically
drink alcohol, smoke cigarettes, etc.
feel much better within the first couple of weeks. It
We’re not here to judge, just want to make sure
should be noted, again, that stem cell therapy is not
enough cells are provided to obtain the desired
a “one and done” procedure, and may need to be
effects. So our providers use judgment on the cell
repeated every one to three years.
quantity needed.
Safety is paramount with the biologics products Affordability
being rigorously tested prior to use, and expert Because stem cell therapy is not a
providers managing each treatment as if you are a “one and done” cure, it’s important
family member! to make it affordable. Repeat
therapies every 1-3years can
Why does R3 Stem Cell use donor tissue for help people achieve continued
its stem cells? improvements. So a lot of patients seek additional
Although autologous (your own) stem cells provide back pain treatments at R3 Stem Cell repetitively.
significant advantages, allogeneic (donor) stem cells
have more advantages. First of all, autologous MSCs Unfortunately, stem cell clinics in Colombia, China
need a long time to culture and expand, which limits and Panama charge over $15,000 USD for back pain
its application in treatment, while allogeneic stem treatment. Because the one treatment cost so much,
cells can be obtained and expanded more quickly, how are individuals supposed to budget for that every
thus avoiding the delay of time window. few years?? R3 Stem Cell’s fees are less than half that
for full treatment, which also includes free PRP and a
Second, age is a factor that affects the physiological multivitamin infusion!
characteristics of MSCs. Studies

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R3’s Experience References:

For the past decade, R3 Stem Cell’s Centers globally 1. Dhillon KS, Spinal Fusion for Chronic Low Back Pain: A
‘Magic Bullet’ or Wishful Thinking?, Malays Orthop J. 2016
have performed over 24,000 regenerative procedures Mar; 10(1): 61–68.
in six countries. Thousands have been for back pain.
2. Wilson et al, Safety of bone marrow derived mesenchymal
Patient satisfaction across all conditions treated is 85%! stem cell extracellular vesicle injection for lumbar facet
joint pain, REGENERATIVE MEDICINE VOL. 19, NO. 1 Feb
R3 combines safety, effectiveness and affordability 2024.
for the therapies. Internationally, the Intellicell is used, 3. Atluri et al, Evaluation of the Effectiveness of Autologous
which is culturing the most active mesenchymal stem Bone Marrow Mesenchymal Stem Cells in the Treatment
cells to create the “smartest” stem cell in the world! of Chronic Low Back Pain Due to Severe Lumbar Spinal
Degeneration: A 12-Month, Open-Label, Prospective
Controlled Trial, Pain Physician: March/April 2022 25:193-207.
Our experience with all types of patients has been
extensive, and our Success Stories on R3’s YouTube 4. Rothoerl, R.; Tomelden, J.; Alt, E.U. Safety and Efficacy
of Autologous Stem Cell Treatment for Facetogenic
Channel are impressive. You can visit the channel
Chronic Back Pain. J. Pers. Med. 2023, 13, 436. https://doi.
Success Story Playlist HERE. org/10.3390/jpm13030436.
5. Barakat et al, Stem cell therapy in discogenic back pain, J
R3 Stem Cell offers free consultations for individuals to Spine Surg 2019;5(4):561-583 | http://dx.doi.org/10.21037/
discuss whether regenerative therapy is indicated for jss.2019.09.22
you. Simply call +1 (844) GET-STEM to schedule yours! 6. Pang, X.; Yang, H.; Peng, B. Human umbilical cord
mesenchymal stem cell transplantation for the treatment
of chronic discogenic low back pain. Pain Physician 2014,
17, E525–E530.
.

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 R3 Consumer Guide for Stem Cell and Exosome Therapy

Consumer Guide
to Stem Cell
Treatment for
Cerebral Palsy

Brought to you by

* No portion of this Document may be reproduced without the Express Written Consent of R3 Stem Cell.
Disclaimer: This guide’s education does not constitute medical advice. The USA FDA considers stem cell therapy experimental. Any claims
made in the Guide refer to procedures performed outside the USA.
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Consumer Guide to Stem Cell Treatment

for Cerebral Palsy
Every day, R3 Stem Cell receives inquiries worldwide Stem Cell Therapy for Cerebral Palsy
from individuals asking if stem cell therapy can help
UIn recent years, stem cell transplantation was
with Cerebral Palsy. Spoiler alert: It can help a lot! In
considered as a promising treatment strategy
this guide, we’ll go through the basics of how stem
in clinical practices and various clinical trials.
cells and exosomes work, the latest research, and
what to expect with a regenerative procedure. Therefore, studies on stem cell therapy for cerebral
palsy provide a new treatment strategy, and have
A Significant Global Issue displayed EXCEPTIONAL results as you will see below.
Cerebral palsy (CP), the most prevalent motor disorder Compared with other types of stem cells,
of childhood, affects two to three per 1,000 live births. human mesenchymal stem cells (hMSCs) have
CP typically results from in utero or perinatal brain the potential advantages of easy accessibility,
injury such as hypoxic insult, hemorrhage, or stroke. immunosuppression, and low immunogenicity, so
they are attractive and promising in treating various
Affected children have varying degrees of functional diseases.
impairments from mild limitations in
advanced motor skills to severely A meta-analysis published in
limited self-mobility despite 2020 evaluated four studies
use of assistive technology totaling 189 participants
resulting in a lifelong in the analysis. A meta-
inability to function analysis is a study that
independently. pools together results
from other studies to
Current Treatment potentially achieve
Options for statistical significance.
Cerebral Palsy GMFM scores (Gross
Despite extensive Motor Function
treatment, neurological Measure) are useful and
impairments still important as outcome
eventually lead CP patients evaluation results to evaluate
to lifelong disability. Furthermore, changes in gross motor function
while traditional treatment can only bring for CP after interventions. This is crucial to
improvement for sufferers of mild to moderate CP, determine effectiveness and benefit of interventional
severe CP lacks effective intervention options. therapy by measuring the change of gross motor skill
acquisition in children with CP.
To date, no disease-modifying treatments have been
found in CP and the current therapies are focused on Children’s gross motor function is commonly
treating disabilities and managing associated co- evaluated by rehabilitation specialists using GMFM
morbidities. The integral treatments of this condition scores. GMFM scored items consist of 5 parts: lying
includes physical therapy and rehabilitations but and rolling (17 items); walking, running, and jumping
have limited effectiveness in most cases. (24 items); sitting (20 items); climbing and kneeling
(14 items); and standing (13 items). The items are

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scored in a four-point order (cannot initiate item, severity and frequency scale in CP. No significance
0; initiates item, 1; partially completes item, 2; and in other adverse events, such as fever, vomiting,
completes item independently,3). Higher scores in anorexia, and urticaria in the studies. Serious adverse
GMFM scores indicate better capacity and favorable events were not observed in the included studies.
prognosis in children with CP.
In a 2018 study out of China, “A Randomized,
To further provide reliable evidence and high-quality Placebo-Controlled Trial of Human Umbilical Cord
evidence, the meta-analysis authors included three Blood Mesenchymal Stem Cell Infusion for Children
randomized controlled trials of mesenchymal stem With Cerebral Palsy”, 54 patients were randomized
cell (MSC) therapy in CP. The pooled results showed to either stem cell treatment or simply saline.
that MSC therapy significantly increased GMFM All participants received basic rehabilitation as a
scores in children with CP, compared with the control background treatment.
group.
The infusion group comprising 27 patients
Moreover, the authors performed received 4 infusions of human
a subgroup analysis of GMFM umbilical cord blood
scores of 3, 6, and 12 mesenchymal stem cells
months. The result of (hUCB-MSC ) (intravenous
subgroup analysis infusions at a fixed dose
showed that MSC of 50 million) and
therapy significantly basic rehabilitation
increased GMFM treatment, whereas
scores in 3, 6, and 12 27 patients in the
months. control group
received 0.9% normal
CFA (Comprehensive
saline and basic
Functional Assessment)
rehabilitation treatment.
is mainly used to evaluate
function improvement The changes in the total
and therapeutic effect of proportion of Gross Motor
patients with CP. Pooled analysis Function Measure and total scores of
indicated that MSC therapy significantly Comprehensive Functional Assessment in the
improved CFA scores, compared with the control hUCB-MSC infusion group were significantly higher
group. Furthermore, they conducted a subgroup than that in control group at 3, 6, 12, 24 months post-
analysis on CFA scores. Subgroup analysis showed treatment. In particular, significant improvement
that MSC therapy significantly increased CFA scores in gross movement was shown after hUCB-MSC
in 3 months (P = 0:0008) and 6 months (P = 0:005), infusion. The beneficial effects observed in the
compared with the control group in children with CP. hUCB-MSC infusion group was superior to the control
They concluded that MSC therapy for CP improved group with basic rehabilitation therapy only.
the comprehensive function of patients with high-
Duke University conducted a single-center, phase
quality evidence.
II, prospective, randomized, double-blind, placebo-
Salivation is a common symptom of patients with controlled, crossover study of a single IV autologous
cerebral palsy, which seriously affects the health cord blood (ACB) infusion in children ages 1 to 6
status of patients. The study found that UCMSC years with CP.
transplantation could significantly improve drooling

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Between September 27, 2010 and

February 14, 2014, 63 patients were
enrolled and randomized to
receive an initial infusion
of ACB or placebo with
a crossover to the
alternateinfusion
1 year later. Post-
thaw, a median
of 23 million total
nucleated cells/
kilogram were
administered. Infusions
of thawed ACB and
placebo products, both
containing DMSO, were well
tolerated, and there were no
serious adverse events.
However, subjects randomized to ACB who were
Therapy in Patients with Severe Cerebral Palsy: A
treated with total nucleated cell doses above the
Retrospective Study”. This study included 47 patients
median infused doses demonstrated statistically
with severe CP who received allogeneic umbilical
significant, clinically meaningful improvement in
cord blood stem cells treatment from August 2009 to
GMFM change scores, compared with subjects who
December 2012 in China.
received lower cell doses.
With doses of 20 to 30 million cells per injection, 4–8
The authors observed that children who received
injections that depended on health conditions were
higher cell doses demonstrated superior gains in
performed for each patient. In detail, they performed
both whole brain connectivity and motor function
cell injection 4 times for a single patient.
1 year after infusion of ACB. The observation that
children receiving cell doses higher than the mean The first injection was intravenous infusion and
having a better response was important. As a the rest were intrathecal injections. The intervals
therapeutic dose had not been established in this between injections were 3–5 days. Fever and
setting, we targeted a TNCC 1–5 3 107/kg based on vomiting were the most common adverse events,
safety data for this range in children undergoing with incidences of 42.6% and 21.2%, respectively.
allogeneic cord blood transplantation. There were 3 (6.4%) cases of seizures and 3 (6.4%)
cases of headaches for each. Two (4.3%) upper
However, in additional analyses, the authoris
respiratory tract infections and 2 (4.3%) episodes of
observed that children with CP demonstrated
dermatitis occurred in the group. Only 1 (2.1%) case
statistically significant improvement in gross motor
of waist pain and constipation occurred. No diarrhea,
function on two well validated measures (GMFM-66,
insomnia, pneumonia, or anorexia occurred in this
PDMS) when ACB was administered at doses higher
group of patients. All adverse events disappeared
than the mean.
after symptomatic treatment, with the remission time
Feng et al performed a safety study in 2015, “Safety ranging from 8 to 72 hours.
of Allogeneic Umbilical Cord Blood Stem Cells

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Duke University subsequently performed a follow points) and (3) post hoc analyses of the GMFM-66
up study using allogeneic cord blood for CP in 91 exploratory outcome suggested that participants
children age 2 to 5 years. treated with cord blood had greater improvement in
motor function than children who did not receive cell
The children had CP due to hypoxic–ischemic
therapy.
encephalopathy, stroke, or periventricular
leukomalacia and were randomized to three arms: (1) On the basis of Duke’s previous work, one hypothesis
the allogeneic cord blood group about the mechanism of umbilical cord blood cells
in the treatment of brain injuries was that they may
received 100 million cord blood total nucleated cells
improve myelination, whole brain connectivity,
(TNC) per kilogram at baseline
and connectivity between relevant motor areas
(n = 31); (2) the hCT-MSC group received 2 million of the brain through paracrine effects (cell to cell
human cord tissue mesenchymal stem cells per communication).
kilogram (hCT-MSC) at baseline, 3 months, and 6
In a 2020 study by Gu et al, “Therapeutic evidence
months (n = 28); (3) the natural history control group
of umbilical cord derived mesenchymal stem cell
received 100 million cord blood TNC per kilogram at
transplantation for cerebral palsy: a randomized,
12 months (n = 31).
controlled trial”, 39 patients were randomized to
Three important observations emerged in the study receiving either human umbilical cord mesenchymal
results: (1) there was no evidence of safety concerns stem cells (hUC-MSC) versus a control group.
related to administration of high-dose AlloCB or
Significant improvements in activities of daily living,
repeated doses of hCT-MSC in these children; (2) the
CFA, and GMFM were observed in the hUC-MSC
primary endpoint, the mean difference between
group compared with the control group. The clinical
a child’s actual and expected changes in GMFM-
data showed that hUC-MSC transplantation was
66 score at 12 months, was highest in the cord
safe and effective at improving the gross motor and
blood (5.8 points) followed by hCT-MSC groups (4.3
comprehensive function of children
points) and lowest in the natural history group (3.1

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with CP when combined with rehabilitation. The The authors also noted that increasing injection
authors hypothesized that recovery of cerebral frequency may improve the efficacy in longer
metabolic activity might play an essential role in the periods.
improvements in brain function in patients with CP.
A 2015 Russian study comprised 80 pediatric patients
Participants in the stem cell group received an with an average age of 12 years and a clinically
average of 50 million stem cells intravenously with confirmed diagnosis of CP, including 40 with spastic
each treatment. In total, four doses were given with quadriplegia, 24 with spastic di- or hemiplegia and
an interval of 7 days. 16 with other forms of CP. In most patients, CP was
associated with other pathological conditions, such
The clinical findings indicated that hUC-MSC
as epilepsy (n . 20), congenital hydrocephalus (n . 7),
transplantation significantly enhanced gross motor
partial atrophy of the optic nerve (n . 10) and other
and cognitive functions on the basis of rehabilitation
injuries (n . 5). Most children (n . 55) had a delay in
in children with CP.
physical and mental development.
In a 2021 study by Amanat et
Each treatment dose averaged
al, “Clinical and imaging
250 million total nucleated
outcomes after
cells per infusion.
intrathecal injection of
umbilical cord tissue Cell administration was
mesenchymal stem well tolerated, and
cells in cerebral no acute or delayed
palsy: a randomized adverse reactions
double-blind sham- (allergic reactions,
controlled clinical headache, waist pain,
trial”, the safety and fever, vomiting, etc.)
efficacy of intrathecal were registered.
administration of a single The results showed
dose of the umbilical cord positive dynamics observed
mesenchymal stem cells in in 38 patients (69.1%) receiving
children with CP was evaluated. cell therapy.
The data from all included outcome scales showed The improvement in neurological status was
that cell therapy was clinically effective. The imaging characterized by a decrease in the pathological
data also showed significant improvements in white muscular tone in one or more affected limbs, an
matter structural integrity of cases treated with stem increase in muscular strength, and a reduction in
cells. The intrathecal injection of the cells was safe in epileptic paroxysms.
participants, and
Amelioration in the mental sphere (speech, memory,
there was no difference in serious adverse events attention, intellectual and emotional development)
compared to the control group. was noted in 29 (52.7%) cases. Twenty-three children
(41.8%) demonstrated progress in both the physical
The study showed that intrathecal injection of the
and mental arenas. Seventeen patients (30.9%)
umbilical cord MSCs (20 million) improved motor
did not change their neurological and/or mental
function significantly after 6 months of cell injection
state during posttreatment observation. Negative
compared to the control group.
dynamics were not revealed in any of the children
receiving cell therapy.

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These findings indicated that repeated intravenous used. However, a lot of stem cells in one’s body are as
infusions of allogeneic HLA-unmatched umbilical old as that person is, and hence not very active. Their
cord blood cells to pediatric patients with CP is safe ability to successfully increase sufficient blood flow
and is an effective intervention in most cases. At and allow for tissue regeneration is inferior to umbilical
least partial improvement in neurological status, cord stem cells, which are young, potent and extremely
physical activity and/or intellectual development active.
was achieved in approximately 70% of cell therapy
Specifically, the therapeutic potential of autologous
patients.
bone marrow or adipose stem cells in the treatment of
The group of “non-responders” consisted older patients is impaired by a number of age-related
predominantly of patients suffering from the most factors such as oxidative stress, telomere length,
severe forms of CP complicated by other brain DNA damage, disease, and long-term use of some
damage and patients receiving no more medications.
than two UCB cell infusions (i.e.,
This is in stark contrast to the
completed only the initial
youthful genotype and
stage of cell therapy). After
phenotype of neonatal
two UCB cell infusions,
tissue-derived stem
neurological
cells, such as from
improvement was
the umbilical cord.
recorded in 8 of 19
They are better at
patients (42.1%).
facilitating repair
In children who and regeneration
received three cell of tissue damage,
infusions (n . 15), creating new blood
positive dynamics flow with superior
were achieved in anti-inflammatory and
40% (physical sphere) immunomodulatory
and 47% (mental sphere). efficacy compared to
mature stem cells from one’s
The best results were obtained
adipose or bone marrow.
in response to five and more
treatments; improvements in neurological/ As a result of the inferiority of autologous stem cells
physical and mental statuses were noted in 85.7% due to the reasons above and better results being seen
and 100% of patients, respectively. The effectiveness with umbilical cord stem cells, R3 only uses the donor
of the therapy was positively correlated with the stem cells today.
number of UCB cell infusions and was statistically
significant. The last observation indicates that How do the Stem Cells and Exosomes Work
combined severe brain injuries are less sensitive to for Cerebral Palsy?
this type of treatment. Stem cells and exosomes act in the body through
Why Doesn’t R3 Stem Cell Use A Person’s several mechanisms. They do NOT become part of
a patient’s DNA, which means they do not engraft
Own Stem Cells for Treatment? into the person’s existing cells. The predominant
R3 used to perform autologous therapies, where a method of action is thought to be through paracrine
patient’s own bone marrow or adipose stem cells were mechanisms, which means “cell to cell” interaction.

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They act through: acids, and soluble proteins, exert crucial roles in
1. .Angiogenesis – provokes formation of new repairing damaged tissue.
blood vessels. Along with offering MSCs for treatment of Cerebral
2. Reduce inflammation – Chronic Lyme Disease Palsy, R3 Stem Cell includes stem cell exosomes,
is associated with significant acute and chronic which are a type of extracellular vesicle participating
inflammation, and the regenerative biologics in extensive cell to cell communication for new blood
reduce it nicely. flow creation.
3. Immune system modulation – the stem cells
and exosomes modulate the immune system
Where do the stem cells and exosomes
very differently than steroids. Instead of blanketly come from?
suppressing the immune system, the regenerative R3 Stem Cell’s regenerative biologics originate from
biologics tamp down the harmful processes while umbilical cord tissue that has been donated after a
amping up the beneficial ones. This includes scheduled c-section. No baby (or mother) is harmed
ramping up production of several helpful growth during the c-section procedure. The umbilical cord
factors and cytokines, while tamping down tissue is normally discarded, but if the mother passes
harmful ones. screening tests then the umbilical cord is immediately
4. Cellular signaling – the biologics are able sent to the lab. The screening tests are extremely
to perform “cell to cell” communication. This rigorous, and mandated by the USA FDA.
promotes recipient cells to proliferate their The lab carefully processes the umbilical cord to
growth factor production, protein production generate large amounts of stem cells and exosomes
and regenerate tissues that are damaged. that are of the highest quality possible. The lab team
5. Prevent cell death – most cells have a timed consists of multiple PhD’s working in ISO Certified,
death, where they are only allowed to live a cGMP compliant clean rooms to ensure quality
certain length of time. This is called apoptosis. assurance that exceeds USA FDA standards. The
The regenerative biologics allow normally proprietary production process combines the highest
functioning cells to live longer, and spare them potency, safety and affordability for providers to
from the pre-programmed death. confidently offer exosome procedures.
6. Preventing scar tissue – While scar tissue resulting
Millions of dollars have been invested into the
from Lyme Diseases is not known to occur, it is a
pharmaceutical grade production of the biologics
problematic issue in many conditions. Once that
including first rate clean rooms, bioreactors,
scar tissue forms, it becomes nonfunctional. Stem
nano-particle tracking analyzers, cytometers, PCR,
Cells and exosomes are great at preventing scar
tangential flow machines and real time environmental
tissue (anti-fibrosis).Stem Cells can also release
monitoring. The quality assurance testing complies
a Stem Cells can also release a huge variety of
with screening and testing stan¬dards consistent
molecules into the extracellular environment. These
with the American Association of Tissue Banks, cGMP
molecules, which include extracellular vesicles,
standards, FDA regulations and the highest level of any
lipids, free nucleic acids, and soluble proteins, exert
regulatory agency globally.
crucial roles in repairing damaged tissue.
Stem Cell Derived Exosomes
Stem Cells can also release a huge variety of molecules R3 Stem Cell’s Centers of Excellence globally include
into the extracellular environment. These molecules, umbilical cord stem cell derived exosomes with
which include extracellular vesicles, lipids, free nucleic umbilical cord stem cells to provide enhanced results.

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Exosomes are lipid bound vesicles (acellular) produced recipient. Scientists call this being “immunologically
by cells which contain a plethora of growth factors, privileged”.
cytokines, mRNA and other proteins.
Another question often asked is “Is there a chance of a
They are exceptionally helpful in cell to cell tumor forming?” Current research has concluded that
communication, and very effective for reducing the answer is NO. The mesenchymal stem cells and
inflammation when they become ingested by their exosomes used during treatment have never been
recipient cell. They act as shuttles to send nucleic acids shown to have tumor forming potentials. In fact, they
and proteins to other cells, in this way, allowing cell-to- have been shown to be anti-tumor forming.
cell communication and transporting molecules among
both close and distant cells. In general, these released Protocol
proteins are important regulators of intracellular For the past decade, R3 has been
information. successfully treating Cerebral Palsy with
stem cell and exosome procedures. The
Exosomes could be the mediators of many stem cell-
regenerative biologics are applied with a
associated therapeutic activities. We have seen them to
combination of intravenous drip therapy
be “faster acting” than stem cells, so R3 frequently uses
along with intrathecal procedure. This way,
them in conjunction to provide a “1-2 punch” for patient
many millions of stem cells will easily reach the brain.
outcomes.
R3’s providers use one to four million stem cells per
Is stem cell therapy safe? kilogram, to make sure that patients achieve the
After a decade of performing over 25,000 stem cell absolute best outcome possible. Between 50 and 100
procedures worldwide, R3 knows that the regenerative billion exosomes are included with each procedure.
procedures are safe. The quality control employed
Outcomes
during the stem cell production is second to none, and
the side effects R3 sees are usually mild to moderate Similar to the research mentioned above, R3 Stem
and temporary. Cell’s outcomes for Cerebral Palsy have been
exceptional! The patient/family satisfaction rate is 85%
They may include itching, dizziness, lightheadedness,
year over year. Patients typically experience improved,
low grade fever, chills, nausea. These are typically
along with improved mental clarity and less brain fog.
temporary. If a patient has an allergic reaction to the
Keep in mind results cannot be guaranteed and will
multivitamin or a preservative, all of R3’s Centers have
vary between individuals.
the medications to resolve it quickly.
One of the questions we get asked a lot is, “Will the Affordability
stem cells get rejected?” The answer is NO.
Because stem cell therapy for Cerebral
MSCs do not express major histocompatibility complex Palsy is not typically a permanent cure,
(MHC) antigens of the class II subtype and contain low it’s important to make it affordable.
levels of MHC molecules of the class I subtype. MSCs Repeat therapies can help maintenance and/or
also lack the co-stimulatory molecules essential for achieve additional improvements for pain relief. So a
immune detection, including CD40, CD80, and CD86. lot of patients seek additional treatments at R3 Stem
Cell every twelve to eighteen months.
Therefore, MSCs generally have low immunogenicity
and can avoid immune rejection by the recipient, R3 Stem Cell’s fees are less than half what comparable
which serves as the foundation for their successful (and reputable) regenerative clinics charge. Be wary of
application without needing to match the donor to the clinics trying to pass off PRP as a stem cell therapy.

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If they mention only taking your blood for the References:

treatment, it is NOT a stem cell treatment!
1. Sun et al, Effect of Autologous Cord Blood Infusion on Motor
R3’s Experience Function and Brain Connectivity in Young Children with
Cerebral Palsy: A Randomized, Placebo-Controlled Trial, STEM
For the past decade, R3 Stem Cell’s Centers globally have performed CELLS TRANSLATIONAL MEDICINE 2017;6:2071–2078.
over 25,000 regenerative procedures in six countries. Patient
satisfaction across all conditions treated is 85%! 2. Feng et al, Safety of Allogeneic Umbilical Cord Blood Stem Cells
Therapy in Patients with Severe Cerebral Palsy: A Retrospective
R3 combines safety, effectiveness and affordability for the therapies. Study, Stem Cells International, Volume 2015, Article ID
Internationally, the Intellicell is used, which is culturing the most active 325652, 7 pages.
mesenchymal stem cells to create the “smartest” stem cell in the world!
3. Zarrabi et al. The safety and efficacy of umbilical cord blood
R3 Stem Cell offers free consultations for individuals to discuss mononuclear cells in individuals with spastic cerebral palsy: a
whether regenerative therapy is indicated for their Cerebral Palsy. randomized double‑blind sham‑controlled clinical trialBMC
Simply call +1 (844) GET-STEM or +1 (888) 988-0515 to schedule yours! Neurology (2022) 22:123
4. Sun et al, Motor function and safety after allogeneic cord blood
Disclaimer: This guide’s education does not constitute medical advice. The USA FDA
and cord tissue-derived mesenchymal stromal cells in cerebral
considers stem cell therapy experimental. Any claims made in this Guide refer to
procedures performed outside of the USA. palsy: An open-label, randomized trial, Dev Med Child Neurol.
2022;64:1477–1486.
5. Xie et al, Therapeutic Evidence of Human Mesenchymal Stem
Cell Transplantation for Cerebral Palsy: A Meta-Analysis of
Randomized Controlled Trials, Stem Cells International Volume
2020, Article ID 5701920, 10 pages
6. Huang et al, A Randomized, Placebo-Controlled Trial of Human
Umbilical Cord Blood Mesenchymal Stem Cell Infusion for
Children With Cerebral Palsy, Cell Transplantation 2018, Vol.
27(2) 325–334
7. Gu et al, Therapeutic evidence of umbilical cord derived
mesenchymal stem cell transplantation for cerebral palsy: a
randomized, controlled trial, Gu et al. Stem Cell Research &
Therapy (2020) 11:43.
8. Amanat et al, Clinical and imaging outcomes after intrathecal
injection of umbilical cord tissue mesenchymal stem cells in
cerebral palsy: a randomized double-blind sham-controlled
clinical trial, Stem Cell Research & Therapy (2021) 12:439
9. Romanov et al, Human allogeneic AB0/Rh-identical umbilical
cord blood cells in the treatment of juvenile patients with
cerebral palsy, Cytotherapy, 2015; 17: 969e978.

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Guide to
Stem Cell Therapy
for COPD

Brought to you by

* No portion of this Document may be reproduced without the Express Written Consent of R3 Stem Cell.

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Guide to Stem Cell Therapy for COPD

Every day, R3 Stem Cell receives inquiries worldwide deaths. However, as many as 1 out of 4 Americans
from individuals asking if stem cell therapy can help with COPD never smoked cigarettes.
with COPD. Spoiler alert: It can help a lot! In this There is mounting evidence that the rate of
guide, we’ll go through the basics of how stem cells progression of COPD can be reduced when
work for the lungs, the latest research, and what to
patients at risk of developing the disease stop
expect with a regenerative procedure..
smoking, while lifelong smokers have a 50%
A Significant Global Issue probability of developing COPD during
their lifetime. More significantly,
Chronic obstructive pulmonary
disease (COPD) is a there is also evidence that the
worldwide epidemic risk of developing COPD
affecting over 200 million falls by about half with
people and accounting smoking cessation.
for more than three The exact mechanisms
million deaths by which emphysema
annually. According and airway remodeling
to the World Health occur in COPD remain
Organization, COPD is largely a mystery. One of
now the third cause of the leading theories is the
global death, behind only “inflammatory hypothesis”.
heart disease and cancer. Over Proponents argue that in certain
the next twenty years, the WHO (genetically) susceptible individuals,
expects mortality to more than double!
lung inflammation, which occurs in response
The disease is characterized by chronic inflammation to environmental triggers such as air pollution and
of the airways and progressive destruction of lung cigarette smoke, changes from a “normal” response to
tissue, a process that in most cases is initiated by an abnormal one.
cigarette smoking.
Structural and functional changes caused by
Unfortunately, aside from supplemental oxygen chronic inflammation include narrowing or loss of
and smoking cessation for continued smokers, there small airways, mucus hypersecretion, mucociliary
are no interventions that have been unequivocally dysfunction, and destruction of the lung parenchyma
shown to prolong survival in patients with COPD, that leads to the loss of alveolar attachments to
and no therapies that can fully restore the lost lung the small airways and decreases lung elastic recoil.
function associated with COPD In turn, these changes diminish the ability of the
airways to remain open during expiration.
Why does COPD develop?
Smoking is by FAR the most common reason Interestingly, once the inflammatory changes are
individuals develops COPD. A condition that runs in firmly established in the lungs, the removal of the
families, called alpha-1 antitrypsin (AAT) deficiency, environmental trigger such as cigarette smoke
may also lead to lung damage and COPD. does not fully abrogate the abnormal inflammatory
response observed in the airways. Indeed, smokers
COPD is usually caused by smoking. Smoking who discontinue smoking continue to demonstrate
accounts for as many as 8 out of 10 COPD-related airway inflammation.

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Traditional Treatments for COPD One of the larger clinic trial studies performed to
The management of COPD actually includes date included 62 patients with COPD (Weiss et al).
primary and secondary prevention, early detection, They were randomized to four intravenous monthly
staging of severity, assessment of reversibility with infusions of either umbilical cord mesenchymal stem
bronchodilators and inhaled corticosteroids, chronic cells (MSC) or placebo control and were followed
pharmacotherapy, pulmonary rehabilitation, and for 2 years. Results showed that MSC infusions were
treatment of comorbidities. well tolerated with no serious or clinically significant
adverse effects.
When respiratory failure is detected, long-term
oxygen therapy is typically prescribed, and in In addition, a statistically significant decrease in
some cases (characterized by emphysema), lung circulating C-reactive protein at 1 month after the
surgery, including lung volume reduction, should be first infusion and for the entire duration of the study
considered. was reported in patients receiving MSCs, although
there were no significant differences in lung function
Medications for COPD therapy may include tests or quality-of-life indicators.
bronchodilators (anticholinergic, beta-2 agonist
and xanthine), anti-inflammation of Stessuk et al did a study in 2009 by
corticosteroid, antioxidant, mucolytic administering intravenous stem cells to
(ambroxol, edosteine and COPD patients. The study displayed
carbocisteine), antitussive increased lung function, slowing
and phosphodiesterase-4 of tissue degeneration process,
inhibitor (PD4 inhibitor). improvement of clinical
Those drugs can lessen condition and enhanced
airflow obstruction, patient quality of life. No side
decrease the frequency of effects were seen.
exacerbation and improve The intravenous MSC
patient quality of life, but none administration increased levels
can prevent progressivity and of Cluster of Differentiation 31
reduce the number of deaths. (CD31) markers. Increased levels
of CD31 in the study subjects indicate
Stem Cell Therapy for COPD protective effect and healing response towards tissue
If a new technology such as mesenchymal stem cell damage.
and exosome therapy could either reverse COPD or
stop the progression, it would and should become A 2020 study performed by Le Thi Bich et al in
first line therapy. A regenerative therapy that can Vietnam used umbilical cord-derived mesenchymal
initiate restoration of lung function and is a safe stem cells (UC-MSCs) in 20 COPD patients. Each
option should receive consideration. patient received one intravenous infusion of 1.5
million stem cells per kilogram.
Currently available therapeutic strategies aim to ease
COPD symptoms but cannot prevent its progress or Most clinical outcomes remain reduced after 6
regenerate physiological lung structure or function. months follow up including CRP, Modified Medical
Current research is showing that stem cells can Research Council Score, COPD assessment test and
perform these functions. number of exacerbations, while the 6MWT score was
slightly increased in stage D COPD patients.

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The researchers noted in their conclusion, “Systemic

UC-MSC administration appears to be safe in
patients with moderate-to-severe COPD,
and can significantly improve their
quality of life.”
A 2021 case report, also from
Vietnam, evaluated Autologous
adipose-derived stem cells in a 57
year old male with longstanding
COPD. The person had quit smoking
after 15 pack-years and received one IV
infusion at baseline and then a repeat at 6
months.
Interestingly, dyspnea and quality of life improved
at six and 12 months after the stem cell treatment.
The 6MWT increased at six- and 12-month follow- tissue damage, with superior anti-inflammatory and
up. Meanwhile, the CRP was almost unchanged. immunomodulatory efficacy compared to mature
Pulmonary function slightly improved at the stem cells from one’s adipose or bone marrow.
12-month follow-up. This patient did not have any
acute exacerbation in one-year follow-up. As a result of the inferiority of autologous stem cells
due to the reasons above and better results being
At 12-month follow-up, a slight increase was seen with umbilical cord stem cells, R3 only uses the
found in the patient’s inhaled total lung volume in donor stem cells today.
quantitative chest CT. The index of emphysema did
not show any difference How do the Stem Cells and Exosomes Work
for the Lungs?
Why Doesn’t R3 Stem Cell Use A Person’s Stem cells and exosomes act in the body through
Own Stem Cells for COPD? several mechanisms. They do NOT become part of a
R3 used to perform autologous therapies, where a patient’s DNA, which means they do not engraft into
patient’s own bone marrow or adipose stem cells the person’s existing cells
were used. However, a lot of stem cells in one’s body
are as old as that person is, and hence not very active. They act through:

Specifically, the therapeutic potential of autologous 1. Angiogenesis – provokes formation of new

bone marrow or adipose stem cells in the treatment blood vessels.
of older patients (such as COPD patients) is impaired 2. Reduce inflammation – chronic lung disease is
by a number of age-related factors such as oxidative associated with significant inflammation, and the
stress, telomere length, DNA damage, disease, and regenerative biologics reduce it nicely.
long-term use of some medications. 3. Immune system modulation – the stem cells
This is in stark contrast to the youthful genotype and exosomes modulate the immune system
and phenotype of neonatal tissue-derived stem very differently than steroids. Instead of blanketly
cells, such as from the umbilical cord. They are suppressing the immune system, the
better at facilitating repair and regeneration of

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mother passes screening tests then the umbilical

regenerative biologics tamp down the harmful
cord is immediately sent to the lab. The screening
processes while amping up the beneficial ones.
tests are extremely
This includes ramping up production of several
rigorous, and mandated by
helpful growth factors and cytokines, while
the USA FDA.
tamping down harmful ones.
The lab carefully processes
4. Cellular signaling – the biologics are able
the umbilical cord to
to perform “cell to cell” communication. This
generate large amounts of
promotes recipient cells to proliferate their
stem cells and exosomes
growth factor production, protein production
that are of the highest
and regenerate tissues that are damaged.
quality possible. The lab team consists of multiple
5. Prevent cell death – most cells have a timed PhD’s working in ISO Certified, cGMP compliant clean
death, where they are only allowed to live a rooms to ensure quality assurance that exceeds
certain length of time. This is called apoptosis. USA FDA standards. The proprietary production
The regenerative biologics allow normally process combines the highest potency, safety
functioning cells (i.e. hepatocytes) to live longer, and affordability for providers to confidently offer
and spare them from the pre-programmed exosome procedures.
death.
Millions of dollars have been invested into the
6. Preventing scar tissue – Lung disease patients pharmaceutical grade production of the biologics
may experience significant scarring throughout including first rate clean rooms, bioreactors,
the lung parenchyma. Once that scar tissue nano-particle tracking analyzers, cytometers,
forms, it becomes nonfunctional. Stem Cells and PCR, tangential flow machines and real time
exosomes are great at preventing scar tissue environmental monitoring. The quality assurance
(anti-fibrosis). testing complies with screening and testing
standards consistent with the American Association
Stem Cells can also release a huge variety of of Tissue Banks, cGMP standards, FDA regulations and
molecules into the extracellular environment. These the highest level of any regulatory agency globally.
molecules, which include extracellular vesicles,
lipids, free nucleic acids, and soluble proteins, exert
crucial roles in repairing damaged tissue. Along with
offering MSCs for treatment of lung disease, R3 Stem
Cell includes stem cell exosomes, which are a type
of extracellular vesicle participating in extensive
cell to cell communication for lung tissue
repair and regeneration.

Where do the stem cells and

exosomes come from?
R3 Stem Cell’s regenerative biologics originate
from umbilical cord tissue that has been donated
after a scheduled c-section. No baby (or mother)
is harmed during the c-section procedure. The
umbilical cord tissue is normally discarded, but if the

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patient outcomes.

Is stem cell therapy safe?

After a decade of
performing over 23,000
stem cell procedures
worldwide, R3
knows that the
regenerative
procedures are
safe. The quality
control employed
during the stem
cell production
is second to none,
and the side effects R3
sees are usually mild to
moderate and temporary.
They may include itching, dizziness,
lightheadedness, low grade fever, chills,
headache, nausea. These are typically temporary. If
Stem Cell Derived Exosomes a patient has an allergic reaction to the multivitamin
R3 Stem Cell’s Centers of Excellence globally include or a preservative, all of R3’s Centers have the
umbilical cord stem cell derived exosomes with medications to resolve it quickly.
umbilical cord stem cells to provide enhanced
results. Exosomes are lipid bound vesicles (acellular) One of the questions we get asked a lot is, “Will the
produced by cells which contain a plethora of growth stem cells get rejected?” The answer is NO.
factors, cytokines, mRNA and other proteins. MSCs do not express major histocompatibility
They are exceptionally helpful in cell to cell complex (MHC) antigens of the class II subtype and
communication, and very effective for reducing contain low levels of MHC molecules of the class I
inflammation when they become ingested by their subtype. MSCs also lack the co-stimulatory molecules
recipient cell. They act as shuttles to send nucleic essential for immune detection, including CD40,
acids and proteins to other cells, in this way, allowing CD80, and CD86.
cell-to-cell communication and transporting Therefore, MSCs generally have low immunogenicity
molecules among both close and distant cells. In and can avoid immune rejection by the recipient,
general, these released proteins are important which serves as the foundation for their successful
regulators of intracellular information. application without needing to match the donor to
Exosomes could be the mediators of many stem cell- the recipient. Scientists call this being
associated therapeutic activities. We have seen them
to be “faster acting” than stem cells, so R3 frequently
uses them in conjunction to provide a “1-2 punch” for

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“immunologically privileged”. R3’s providers will calculate the amount of stem cells
based on patient weight and COPD severity. It will
Another question often asked is “Is there a chance of range from 1 to 3 million stem cells/kg. Depending
a tumor forming?” Current research has concluded on the total amount, treatment may need to be
that the answer is NO. The mesenchymal stem cells broken up into two sessions, three at the most for
and exosomes used during treatment have never optimal safety.
been shown to have tumor forming potentials. In
fact, they have been shown to be anti-tumor forming. R3 Stem Cell’s lung disease protocols are based
on the latest research along with Best Practice
Protocol Protocols developed over the past decade to help
For the past decade, R3 has been patients achieve the best outcomes possible. Safety
successfully treating lung disease is paramount with the biologics products being
patients with IV and nebulizer stem cell rigorously tested prior to use, and expert providers
and exosome therapy. The cells and managing each treatment as if you are a family
exosomes are attracted to inflammation, which is a member!
large component of lung diseases. So they will go
predominantly to the lung, but also, to areas that are Outcomes
experiencing disease as well. Similar to the research mentioned above, R3 Stem
Cell’s outcomes for COPD have been exceptional! The
So, for example, if a person has COPD along with patient satisfaction rate is 85% year over year. Patients
diabetes, the cells and exosomes will also go to the typically experience better breathing, less need for
pancreas to assist with function there too. There is supplemental oxygen and improved mobility. Keep
no need to inject directly into the trachea. This is not in mind results cannot be guaranteed and will vary
necessary and entails additional risk! between individuals.

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In addition, just like the research studies R3 sees R3 Stem Cell offers free consultations for individuals to
improvements in the vast majority of patients with discuss whether regenerative therapy is indicated for
regards to pulmonary function tests and their COPD. Simply call +1 (844) GET-STEM or
other laboratory studies. +1 (480) 808-7057 to schedule yours!
It may take several months to Disclaimer: R3 Stem Cell is offering
see all of the improvements, stem cell therapy for COPD and other
although we have had lung diseases outside of the USA.
This guide’s education does not
patients symptomatically feel
constitute medical advice. The USA
much better within the first FDA considers stem cell therapy
couple of weeks. It should be experimental
noted, again, that stem cell
therapy is not a cure for COPD,
and will need to be repeated
every 6 to 12 months for continued
benefit.

Affordability References:
Because stem cell therapy for COPD is 1. Potential role of stem cells in management of COPD,
not a permanent cure, it’s important Hacket et al, International Journal of COPD 2010:5 81–88.
to make it affordable. Repeat therapies 2. Mesenchymal stromal cells: a novel therapy for the
can help maintenance and/or achieve treatment of chronic obstructive pulmonary disease?
additional improvements for the lungs. So a lot of Broekman W, et al. Thorax 2018;73:565–574. doi:10.1136/
patients seek additional treatments at R3 Stem Cell thoraxjnl-2017-210672 565.
every six to eighteen months. 3. Can Youthful Mesenchymal Stem Cells from Wharton’s
Jelly Bring a Breath of Fresh Air for COPD?, Janczewski
Unfortunately, stem cell clinics in Colombia, China et al, Int. J. Mol. Sci. 2017, 18, 2449; doi:10.3390/
and Panama charge over $20,000 USD for lung ijms18112449
disease treatment. Because the one treatment cost 4. The clinical use of regenerative therapy in COPD,
so much, how are individuals supposed to budget for International Journal of Chronic Obstructive Pulmonary
that every year?? R3 Stem Cell’s fees are less than half Disease, Roberto Lipsi, Paola Rogliani, Luigino Calzetta,
that for 100 million high quality stem cells! Andrea Segreti & Mario Cazzola (2014), 1389-1396, DOI:
10.2147/COPD.S49519.
R3’s Experience 5. Role of Mesenchymal Stem Cells In Chronic Obstructive
For the past decade, R3 Stem Cell’s Centers globally Lung Disease, Andari et al, Respir Sci, 2021: 1(3): 202-212.
have performed over 23,000 regenerative procedures 6. Autologous adipose-derived stem cells therapy in COPD
in six countries. Several hundred have been for COPD, treatment: a case report, Nguyen et al, Respirology Case
Reports, 2021 | Vol. 9 | Iss. 5 | e00748
and other lung diseases such as pulmonary fibrosis.
Patient satisfaction across all conditions treated is 85%! 7. Smoking and Chronic Obstructive Pulmonary Disease
(COPD). Parallel Epidemics of the 21st Century, Rafael
R3 combines safety, effectiveness and affordability Laniado-Laborín, Int J Environ Res Public Health. 2009
Jan; 6(1): 209–224.
for the therapies. Internationally, the Intellicell is used,
which is culturing the most active mesenchymal stem 8. Allogeneic umbilical cord-derived mesenchymal stem
cell transplantation for treating chronic obstructive
cells to create the “smartest” stem cell in the world!
pulmonary disease: a pilot clinical study, Bich et al, Stem
Cell Res Ther. 2020; 11: 60.

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Guide to
Stem Cell and
Exosome Therapy
for Diabetes

Brought to you by

* No portion of this Document may be reproduced without the Express Written Consent of R3 Stem Cell.

98
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Guide to Stem Cell and Exosome Therapy for Diabetes

Every day, R3 Stem Cell receives inquiries worldwide had diabetes. This number is expected to increase to
from individuals asking if stem cell therapy can help 578 million by 2030 and 700 million by 2045.
with diabetes. Spoiler alert: It can help a lot! In this
guide, we’ll go through the basics of how stem cells Due to one’s blood glucose levels being chronically
work for diabetes, the latest research, and what to abnormal, secondary complications may occur
expect with a regenerative procedure. such as neuropathy, kidney failure, skin ulcers,
cardiovascular disease and more.
Conventional therapies for diabetes,
such as with insulin, are not What happens in
able to effectively prevent diabetes?
long-term complications
Diabetes type 1 and type
that often include
2 come from different
vascular degeneration,
causes: In diabetes type 1,
blindness, and kidney
failure. The search for the pancreas does not
alternative approaches make insulin, because
such as with stem the body’s immune
cells is therefore of system attacks the islet
paramount clinical cells in the pancreas that
interest. make insulin.
In diabetes type 2, the pancreas
Stem cell therapy for diabetes
makes less insulin than used to, and
is turning out to be an excellent
your body becomes resistant to insulin. This
opportunity for individuals to control blood
means your body has insulin, but stops being able to
sugars, reduce Hb-A1C and prevent the secondary
use it.
complications that are simply NOT possible with
traditional therapies. Let’s dig in! Diabetes Type 1: An Autoimmune Disease
A Significant Global Issue We don’t know why the immune system attacks the
pancreatic islet cells.
Diabetes is a very common disease that affects over
450 million people around the world. Diabetes occurs Possible factors that might trigger this autoimmune
as two types. Type 1 is an autoimmune condition reaction include:
where one’s immune system attacks and destroys u Genes
your insulin producing cells in the pancreas. Type 2,
which is much more common, is an acquired variety u Viruses
often due to correctible lifestyle issues (overweight, u Foods
high blood pressure or cholesterol). u Chemicals
The International Diabetes Federation (IDF) And sometimes, people can lose the ability to make
introduces diabetes as one of the fastest-growing insulin altogether because of:
global health emergencies of this century and u Chronic type 2 diabetes
estimates that in 2019, 463 million people worldwide
u Chronic pancreatitis
u Pancreatic surgery

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Diabetes Type 2: A Common Disease hypoglycemia, gastrointestinal intolerance, heart

While both types of diabetes have inherited or failure, and atypical fractures.
genetic aspects, the insulin resistance that causes DM is the ninth most common cause of death
type 2 is related to having too much body fat. globally, and most diabetic patients have at least
Unlike type 1, type 2 diabetes: one complication. A large observational study
showed that 50% of patients with type 2 diabetes
u Is not an autoimmune disorder had microvascular complications, and 27% were
u Occurs mostly in people over 45, or in associated with macrovascular complications.
younger people with obesity or genetic The development of common DM complications,
reasons including diabetic kidney injury, diabetic
encephalopathy, and diabetic chronic ulcers,
What are the symptoms of diabetes? determines the quality of life of patients.

Damage to any part of the process that moves Traditional Treatments

glucose from your blood to your cells results in Depending on what type of diabetes you have, blood
diabetes. sugar monitoring, insulin and oral drugs
Signs of both type 1 and type 2 may be part of your treatment. Eating
diabetes include: a healthy diet, staying at a healthy
weight and getting regular
u Extreme thirst physical activity also are
u Hunger important parts of managing
diabetes.
u Fatigue
Treatment for type 1
u Blurry vision diabetes involves insulin
u Irritability injections or the use of an
u Increased urination insulin pump, frequent blood
sugar checks, and carbohydrate
u Headaches counting. For some people with type
1 diabetes, pancreas transplant or islet cell
People with type 2 diabetes may also experience: transplant may be an option.
u Frequent or recurring infections Treatment of type 2 diabetes mostly involves
u Poor wound healing lifestyle changes, monitoring of your blood sugar,
along with oral diabetes drugs, insulin or both.
u Numbness or tingling in the hands or feet
Stem Cell Therapy for Diabetes
u Problems with gums
Stem cell therapy for diabetes represents a new
u Itching paradigm, where the treatment can actually facilitate
u problems having and erection repair and regeneration of the pancreas while
preventing some of the secondary complications.
At present, neither oral hypoglycemic drugs nor While not a cure for diabetes, it can truly provide
insulin is a cure for diabetes; these treatments patients with better blood sugar control along with
increase the risk of complications, such as improvements in kidney and heart function,

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neuropathy pain relief and better skin healing.

A 2016 review of 22 studies on stem cell therapy for
diabetes showed that infusion of umbilical cord stem
cells for Type 1 diabetes worked exceptionally better
than traditional treatment alone. The authors
noted that the stem cell treatments were very
safe, and that earlier treatment produced better
results.
A study performed that same year looked
at umbilical cord stem cell infusions for over
50 patients with Type 2 diabetes. Postprandial
glucose and HbA1c measurements were lower in the
experimental group for up to 2 years. Insulin usage
and fasting C-peptide were significantly improved in
the stem cell treatment group. The conclusion was
that transplant of umbilical cord MSCs is feasible and
safe for Type 2 diabetes. In a meta-analysis titled, “Clinical Efficacy of Stem Cell
Therapy for Diabetes Mellitus “, 22 eligible clinical
To determine the efficacy and safety of umbilical
trials reporting stem cell-based therapy for DM with a
cord-derived mesenchymal stem cells (UC-MSCs)
total of 524 patients were evaluated. Both Type 1 and
with type 2 diabetes mellitus (T2DM), a Chinese study
Type 2 DM were evaluated.
evaluated 91 patients who were randomly assigned
to receive intravenous infusion of UC-MSCs (n = 45) The authors concluded the following: (1) remission
or placebo (n = 46) three times with 4-week intervals of DM is possible following stem cell therapy; (2)
and followed up for 48 week. At 48 weeks, 20% of stem cell transplantation can be a safe and effective
the patients in the UC-MSCs group and only 4.55% approach for therapy of DM; (3) available data from
in the placebo group achieved a 50% reduction in these clinical trials indicate that the most promising
insulin needs and HbA1C <7%. No major UC-MSCs therapeutic outcome was shown in mobilized
transplantation-related adverse events occurred. marrow CD34+ HSCs; (4)
patients with previously
Overall, 13.5% (5/37) patients became insulin-free
diagnosed diabetic
at 8–24 weeks after UC-MSCs transplantation and
ketoacidosis are not
remained insulin-free without re-use for 37.2 Å} 15.2
good candidates for the
weeks. No patient in the placebo group became
applied approaches stem
insulin-free. UC-MSCs treatment reduced daily insulin
cell therapy; (5) stem cell
requirement, decreased HbA1c levels, and ameliorated
therapy at early stages after DM diagnosis is more
insulin resistance in a time-dependent manner.
effective than intervention at later stages.

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Another meta-analysis titled, “Efficacy of

mesenchymal stem cell transplantation therapy for They act through:
type 1 and type 2 diabetes mellitus” of ten studies 1. Angiogenesis – provokes formation of new
with 239 patients showed that compared with blood vessels.
baseline levels, significant changes were found in the
2. Reduce inflammation – diabetes is associated
HbA1c, FBG, PBG, F-CP, and insulin requirements of
with significant pancreatic inflammation along
patients with DM after they received MSC therapy.
with the areas that deal with the secondary
It was clear that MSCs had a therapeutic effect on
complications, and the regenerative biologics
blood glucose regulation in patients with DM, and
reduce it nicely.
the benefits for patients with T1DM were more
pronounced. 3. Immune system modulation – the stem cells
and exosomes modulate the immune system
Mesenchymal stem cell derived exosomes have a
very differently than steroids. Instead of
repair function similar to MSCs, but do not have
blanketly suppressing the immune system, the
the shortcomings of MSCs in terms of difficulties
regenerative biologics tamp down the harmful
associated with storage. MSC-Exos are rich in a variety
processes while amping up the beneficial ones.
of growth cytokines, repair proteins, and therapeutic
This includes ramping up production of several
noncoding RNAs, which can promote the repair of
helpful growth factors and cytokines, while
organs damaged by DM and its complications by
tamping down harmful ones.
regulating inflammation, vascularization, and anti-
apoptotic mechanisms. The use of MSC-Exos may 4. Cellular signaling – the biologics are able
be an effective treatment strategy for DM and its to perform “cell to cell” communication. This
complications. promotes recipient cells to proliferate their
growth factor production, protein production
Exosomes have been shown to have a significant
and regenerate tissues that are damaged.
mitigatory effect on Type 1 Diabetes by increasing
the expression of anti-inflammatory factors (e.g., IL- 5. Prevent cell death – most cells have a timed
10), and the population of Tregs that are equipped to death, where they are only allowed to live a
suppress the immune response, preventing immune certain length of time. This is called apoptosis.
overactivation and autoimmune damage (101). In The regenerative biologics allow normally
addition, the results of the study by Shigemoto- functioning cells (i.e. islet cells) to live longer,
kuroda et al. also confirmed that MSC-EVs could and spare them from the pre-programmed
inhibit islet inflammation, significantly increasing the death.
plasma insulin levels, and effectively delaying the
occurrence of T1DM. These results suggested that 6. Preventing scar tissue – Diabetes patients
MSC-EVs have great potential as a cellular therapy for experience significant scarring throughout
the prevention of T1DM. the pancreas. Once that scar tissue forms,
it becomes nonfunctional. Stem Cells and
Stem cells and exosomes act in the body through exosomes are great at preventing scar tissue.
several mechanisms. They do NOT become part of a
patient’s DNA, which means they do not engraft into
the person’s existing cells.

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assurance that exceeds USA FDA standards. The

proprietary production process combines the
highest potency, safety and affordability for
providers to confidently offer exosome
procedures.
Millions of dollars have been
invested into the pharmaceutical
grade production of the biologics
including first rate clean rooms,
bioreactors, nano-particle tracking
analyzers, cytometers, PCR,
tangential flow machines and real
time environmental monitoring. The
quality assurance testing complies with
screening and testing standards consistent
with the American Association of Tissue Banks,
cGMP standards, FDA regulations and the highest
Stem Cells can also release a huge variety of level of any regulatory agency globally.
molecules into the extracellular environment. These
Stem Cell Derived Exosomes
molecules, which include extracellular vesicles
(exosomes), lipids, free nucleic acids, and soluble R3 Stem Cell’s Centers of Excellence globally include
proteins, exert crucial roles in repairing damaged umbilical cord stem cell derived exosomes with
tissue. Along with offering stem cells for treatment of umbilical cord stem cells to provide enhanced results.
diabetes, R3 Stem Cell includes stem cell exosomes, Exosomes are lipid bound extracellular vesicles
which are a type of extracellular vesicle participating (acellular) produced by cells which contain a plethora
in extensive cell to cell communication for brain of growth factors, cytokines, mRNA and other
tissue repair and regeneration. proteins.

Where do the stem cells and exosomes They are exceptionally helpful in cell to cell
come from? communication, and very effective for reducing
inflammation when they become ingested by their
R3 Stem Cell’s regenerative biologics originate from
recipient cell. They act as shuttles to send nucleic
umbilical cord tissue that has been donated after a
acids and proteins to other cells, in this way, allowing
scheduled c-section. No baby (or mother) is harmed
cell-to-cell communication and transporting
during the c-section procedure. The umbilical cord
molecules among both close and distant cells. In
tissue is normally discarded, but if the mother passes
general, these released proteins are important
screening test then the umbilical cord is immediately
regulators of intracellular information.
sent to the lab.
Exosomes could be the mediators of many stem
The lab carefully processes the umbilical cord to
cell-associated therapeutic activities. Considering
generate large amounts of stem cells and exosomes
they are 100 times smaller than stem cells, they do
that are of the highest quality possible. The lab team
not have any issues passing through the blood-brain-
consists of multiple PhD’s working in ISO Certified,
barrier to reach the brain from the bloodstream.
cGMP compliant clean rooms to ensure quality

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Is stem cell therapy safe? Therefore, MSCs generally have low immunogenicity
and can avoid immune rejection by the recipient,
After a decade of performing over 24,000 stem
cell procedures worldwide, R3 knows that the which serves as the foundation for their successful
application without needing to match the
regenerative procedures are safe. The quality control
employed during the stem cell production is second donor to the recipient. Scientists call this being
“immunologically privileged”.
to none, and the side effects R3 sees are usually mild
to moderate and temporary. Another question often asked is “Is there a chance of
They may include itching, dizziness, lightheadedness, a tumor forming?” Once again the answer is NO. The
mesenchymal stem cells and exosomes used during
low grade fever, chills, headache, nausea. These
are typically temporary. If a patient has an allergic treatment have never been shown to have tumor
forming potentials. In fact, they have been shown to
reaction to the multivitamin or a preservative, all
be anti-tumor forming.
of R3’s Centers have the medications to resolve it
quickly. Treatment Protocol
One of the questions we get asked a lot is, “Will the For the past decade, R3 has been
stem cells get rejected?” The answer is NO. successfully treating diabetes patients
with IV stem cell and exosome therapy.
MSCs do not express major histocompatibility
The cells and exosomes are attracted
complex (MHC) antigens of the class II subtype and
to inflammation, which is a large component of
contain low levels of MHC molecules of the class I
diabetes effects either on the pancreas, kidneys, eyes,
subtype. MSCs also lack the co-stimulatory molecules
or other areas.
essential for immune detection, including CD40,
CD80, and CD86. R3’s providers will calculate the amount of stem cells
based on patient weight and diabetes severity.

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It will range from 1 to 4 million stem cells/kg. What are the Outcomes
Depending on the total amount, treatment may need Similar to the research mentioned above, R3 Stem
to be broken up into two sessions, three at the most Cell’s outcomes for diabetic patients have been
for optimal safety. exceptional! The patient satisfaction rate is 85% year
R3 Stem Cell’s diabetes treatment over year. Patients typically see increased
protocols are based on the latest energy, function, better glucose
research along with Best Practice management, reduced Hb-A1C
Protocols developed over and less need for traditional
the past decade to help medications.
patients achieve the best It may take several months to
outcomes possible. Safety see all of the improvements,
is paramount with the although we have had patients
biologics products being symptomatically feel much
rigorously tested prior to use, better within the first couple of
and expert providers managing weeks. It should be noted, again,
each treatment as if it was a family that stem cell therapy does not cure
member! diabetes, and will need to be repeated every
Why does R3 Stem Cell use donor tissue for 12-24 months for additional benefits.
its stem cells? Affordability
Although autologous (your own) stem cells provide Because stem cell therapy for
significant advantages, allogeneic (donor) stem cells diabetes does benefit from repeat
have more advantages. First of all, autologous MSCs treatments, it’s important to make
need a long time to culture and expand, which limits it affordable. Repeat therapies can
its application in diabetes treatment, while allogeneic help people achieve additional
stem cells can be obtained and expanded from the improvements. So a lot of patients seek additional
freezer more quickly, thus avoiding the delay of time treatments at R3 Stem Cell every twelve to twenty
window. four months.
Diabetes patients need a LOT of stem cells for Unfortunately, stem cell clinics in Colombia, China
the outcome to be satisfactory, which is just not and Panama charge over $20,000 USD for diabetes
obtainable from one’s own stem cell harvesting. treatment. Because the one treatment cost so much,
Considering that the viability of donor stem cells how are individuals supposed to budget for that
after cryopreservation averages 87%, patients are every year?? R3 Stem Cell’s fees are less than half that
able to achieve the amount of cells needed without for 100 million high quality stem cells!
the harvesting procedure.
R3’s Experience
Second, age is a factor that affects the physiological For the past decade, R3 Stem Cell’s Centers globally
characteristics of MSCs. Studies have shown that have performed over 24,000 regenerative procedures
stem cells from elderly donors have decreased in six countries. Over a thousand have been for either
proliferation and differentiation ability. This means diabetes or secondary complications of the disease.
they are less effective! Patient satisfaction across all conditions treated is 85%!

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R3 combines safety, effectiveness and affordability References:

for the therapies. Internationally, the Intellicell is used, 1. Efficacy of mesenchymal stem cell transplantation therapy
which is culturing the most active mesenchymal stem for type 1 and type 2 diabetes mellitus: a meta-analysis, Li
cells to create the “smartest” stem cell in the world! et al. Stem Cell Research & Therapy (2021) 12:273
2. Efficacy and safety of umbilical cord‑derived
Our experience with diabetes patients has been mesenchymal stem cells in Chinese adults with type 2
extensive, and our Success Stories on R3’s YouTube diabetes: a single‑center, double‑blinded, randomized,
Channel are impressive. You can visit the channel placebo‑controlled phase II trial, Zang et al. Stem Cell
Research & Therapy (2022) 13:180.
Success Story Playlist HERE.
3. Mesenchymal stem cell transplantation in newly
R3 Stem Cell offers free consultations for individuals diagnosed type‑1 diabetes patients: a phase I/II
to discuss whether regenerative therapy is indicated randomized placebo‑controlled clinical trial, Izadi et al.
Stem Cell Research & Therapy (2022) 13:264
for their diabetes. Simply call +1 (844) GET-STEM or +1
(480) 808-7057 to schedule yours! 4. Concise Review: Mesenchymal Stem Cells for Diabetes,
Bendala et al, Stem Cells Transl Med. 2012 Jan; 1(1): 59–63.
Disclaimer: Any claims made in this guide refer to 5. Human umbilical cord mesenchymal stem cells in diabetes
procedures performed outside the USA. mellitus and its complications: applications and research
advances, Li et al, Int. J. Med. Sci. 2023, Vol. 20.
6. Clinical Efficacy of Stem Cell Therapy for Diabetes Mellitus:
A Meta-Analysis, El-Badawy et al, PLOS ONE | DOI:10.1371/
journal.pone.0151938 April 13, 2016
7. Efficacy of mesenchymal stem cell therapy on glucose
levels in type 2 diabetes mellitus: A systematic review and
meta-analysis, Ranjbaran et al, J Diabetes Investig Vol. 12
No. 5 May 2021.
8. Therapeutic Potential of Mesenchymal Stem Cells for
Diabetes , Moreira et al, J, Mol Endocrinol. 2017 October,
doi:10.1530/JME-17-0117

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 R3 Consumer Guide for Stem Cell and Exosome Therapy

Consumer Guide to
Stem Cell Therapy
for Erectile
Dysfunction

Brought to you by

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 CONSUMER GUIDE TO STEM CELL THERAPY FOR ERECTILE DYSFUNCTION

Consumer Guide to Stem Cell Therapy for Erectile Dysfunction

Every day, R3 Stem Cell receives inquiries worldwide obvious preference for men is to maintain the ability
from individuals asking if stem cell therapy can help for spontaneous erections.
with erectile dysfunction. Spoiler alert: It can help a
lot! In this guide, we’ll go through the basics of how Stem cell therapy for ED has been shown in numerous
stem cells work for ED, the latest research, and what to studies to display beneficial effects.
expect with a regenerative procedure. Why does Erectile Dysfunction develop?
A Significant Global Issue Erectile function involves a complex relationship
Male sexual arousal is actually a complicated process between neurologic, vascular, hormonal and
that involves the brain, nerves, muscles, blood vessels, psychological components. A person may suffer from
and emotions. Erectile Dysfunction (ED) is defined as a combination of reasons that together lead to ED.
the inability to get or keep an erection. Here are the most common issues:
Around age 40, about 40% of men say they have some Reasons men experience chronic ED
sexual dysfunction. This percentage increases by 10% • PHYSICAL
with each decade of life, meaning 50% by age 50, 60% • Hypertension
by age 60, 70% by age 70. That’s crazy right?? By 2025,
approximately 322 million men worldwide will be • Diabetes
diagnosed with ED. • Kidney
Disease
90 • Prostate
Cancer
67.5
• Low
Testosterone
Prevalence (%)

45 • Thyroid
• Post- Injury
22.5
• PSYCHOLOGICAL

0
• Stress
Overall 40-49 50-59 60-69 >_ 70
• Depression
Age group of the study population (years)
• Anxiety
• Low Self Esteem
ED is associated with many risk factors including
diabetes mellitus (DM), obesity, cardiovascular disease, Incidence
hypertension, increasing age, alcohol, smoking, According to the National Institute of Health,
depression, previous pelvic surgery and spinal cord between fifteen and twenty five percent of 65 year
injuries, among other psychological variables. These old men suffer from ED. That number continues to
typically lead to a blood flow problem to the penis. increase with age!
A Significant Global Issue Before letting the problem turn into the proverbial
elephant in the bedroom, you should consider what
While there are several oral medications available that the latest in modern medicine has to offer for a long
may facilitate the ability to achieve an erection, the term solution.

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Evaluating a Person for ED

Initially, a person should be
evaluated with Blood and Urine
tests to rule out abnormalities
such as infection, elevated
PSA, diabetes, etc.
An overnight erection
test is actually a pretty
straight forward test.
Usually men have 3 to 5
erections during the night
as they sleep. If the test
shows normal erections,
the underlying issue may be
mental.
An injection test involves placing
medication directly intracavernosal
to the penis. The medicine acts through
vasodilation, increasing blood flow to the penis.
If an erection occurs, then most likely the problem A person may benefit from counseling to improve
involves a blood flow issue. mental health, and possibly medications as well.
An ulltrasound looks at blood flow to the penis. At Short term medications may include:
present, penile Doppler US is principally used to
evaluate the integrity of the vascular mechanism and u Cialis/Viagra – works for 80%.
exclude underlying arterial or venous insufficiency. u Injections/Suppositories – alprostadil, MUSE
Traditional Treatments for ED Blood flow to the penis may be increased with a
Treating ED may be as simple as implementing vacuum device (penis pump) and/or shockwave
lifestyle changes. This would be “low hanging fruit therapy. While they may take months to work, these
option: options are effective in over 2/3 of patients. Through
different mechanisms, they induce new blood flow
u Losing Weight to form.
u Drinking Less Alcohol As a last resort, a penile implant may provide a
u Quitting Smoking permanent option for patients. If widespread
vascular blockage is seen on ultrasound, a vascular
Possibly, these changes reconstruction surgery may help.
alone may allow a person
to overcome ED. Mental Stem Cell Therapy for ED
health, though, can be a If a new technology such as mesenchymal stem
concomitant factor such as cell and exosome therapy could provide a long
high levels of stress and/or term solution for ED, it would and should become
anxiety. first line therapy. A regenerative therapy that can

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initiate spontaneous erections, negate the need for A 2021 study out of Jordan evaluated umbilical cord
medications or injections and is a safe option should stem cell injections for twenty two diabetic patients
receive consideration. with refractory ED. There were no patient reported
serious adverse effects. There were significant
The first clinical study was published in 2010 by a improvements in IIEF-5, EHS, peak systolic velocity
Korean team. Umbilical cord stem cells (15 million) (PSV) basal, and 20-min PSV, all over the follow-
were injected in seven men aged 57–83 years with up time points in comparison to the baseline.
diabetes-related ED. The results revealed that the Conclusion: This study showed proven tolerability,
majority of their participants regained their morning safety, and efficacy of penile injections of allogeneic
erections within one month and maintained this for Wharton’s Jelly mesenchymal stem cells for the
more than six months. treatment of diabetic patients with ED.
Moreover, their blood glucose levels decreased after In 2024, the European Society for Sexual Medicine
two weeks, highlighting that human umbilical cord performed a comprehensive review
blood stem cell therapy provided of available literature on Cell
positive outcomes in both ED Therapy for Erectile
and diabetes conditions. Dysfunction. They
Another significant looked at 19 studies
study from 2016 totaling over 400
evaluated for the patients. Their
first time the use conclusion
of various stem stated: In
cell numbers conclusion,
per injection. preliminary
Yiou et al. in findings are
a Phase I pilot available in
study reported favor of efficacy
the effects of a and safety of
stem cell Cellular Therapy in
patients with erectile
injection in patients with dysfunction or Peyronie’s
vasculogenic ED who had disease, suggesting a
undergone a radical prostatectomy. potential application of cell therapy
in these patients.
Specifically, they divided their participants in
four groups and administered escalating doses of In R3’s experience, 90% of patients with ED achieve
stem cells. Their results revealed that a significant success with stem cell and exosome therapy. It’s an
improvement without serious side effects was exciting option for patients!
observed in the patients who received the highest
dose of stem cells at six months post-treatment. Why Doesn’t R3 Stem Cell Use A Person’s
Blood flow was best and the erectile dysfunction Own Stem Cells for ED
outcomes were most improved with the higher R3 used to perform autologous therapies, where a
doses. patient’s own bone marrow or adipose stem cells

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were used. However, a lot of stem cells in one’s body They act through:
are as old as that person is, and hence not very active.
Their ability to successfully increase sufficient blood 1. Angiogenesis – provokes formation of new
flow and allow for spontaneous erections is inferior to blood vessels.
umbilical cord stem cells. 2. Reduce inflammation – lack of blood flow to the
Specifically, the therapeutic potential of autologous penis is associated with significant inflammation,
bone marrow or adipose stem cells in the treatment and the regenerative biologics reduce it nicely.
of older patients (such as ED patients) is impaired by 3. Immune system modulation – the stem cells
a number of age-related factors such as oxidative and exosomes modulate the immune system
stress, telomere length, DNA damage, disease, and very differently than steroids. Instead of blanketly
long-term use of some medications. suppressing the immune system, the
This is in stark contrast to the regenerative biologics tamp down
youthful genotype and the harmful processes while
phenotype of neonatal amping up the beneficial
tissue-derived stem cells, ones. This includes ramping
such as from the umbilical up production of several
cord. They are better helpful growth factors
at facilitating repair and cytokines, while
and regeneration tamping down harmful
of tissue damage, ones.
creating new blood 4. Cellular signaling
flow with superior – the biologics are able
anti-inflammatory and to perform “cell to cell”
immunomodulatory communication. This
efficacy compared to promotes recipient cells
mature stem cells from to proliferate their growth
one’s adipose or bone factor production, protein
marrow. production and regenerate
As a result of the inferiority of tissues that are damaged.
autologous stem cells due to the 5. Prevent cell death – most cells have
reasons above and better results being seen a timed death, where they are only allowed to
with umbilical cord stem cells, R3 only uses the donor live a certain length of time. This is called apoptosis.
stem cells today. The regenerative biologics allow normally
functioning cells to live longer, and spare them
How do the Stem Cells and Exosomes Work from the pre-programmed death.
for ED? 6. Preventing scar tissue – Peyronie’s disease
Stem cells and exosomes act in the body through patients may experience significant scarring
several mechanisms. They do NOT become part of throughout the penis. Once that scar tissue
a patient’s DNA, which means they do not engraft forms, it becomes nonfunctional. Stem Cells and
into the person’s existing cells. The predominant exosomes are great at preventing scar tissue
method of action is thought to be through paracrine (anti-fibrosis).
mechanisms, which means “cell to cell” interaction

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Stem Cells can also release a huge variety of molecules Millions of dollars have been invested into the
into the extracellular environment. These molecules, pharmaceutical grade production of the biologics
which include extracellular vesicles, lipids, free nucleic including first rate clean rooms, bioreactors,
acids, and soluble proteins, exert crucial roles in nano-particle tracking analyzers, cytometers, PCR,
repairing damaged tissue. tangential flow machines and real time environmental
monitoring. The quality assurance testing complies
Along with offering MSCs for treatment of erectile
with screening and testing standards consistent with
dysfunction, R3 Stem Cell includes stem cell exosomes,
the American Association of Tissue Banks, cGMP
which are a type of extracellular vesicle participating
standards, FDA regulations and the highest level of any
in extensive cell to cell communication for new blood
regulatory agency globally.
flow creation.

Where do the stem cells and exosomes Stem Cell Derived Exosomes
come from? R3 Stem Cell’s Centers of Excellence globally
include umbilical cord stem cell
R3 Stem Cell’s regenerative derived exosomes with
biologics originate from umbilical cord stem
umbilical cord tissue cells to provide
that has been enhanced results.
donated after Exosomes are lipid
a scheduled bound vesicles
c-section. (acellular)
No baby (or produced by
mother) is cells which
harmed during contain a
the c-section plethora of
procedure. The growth factors,
umbilical cord cytokines,
tissue is normally mRNA and other
discarded, but if the proteins.
mother passes screening
tests then the umbilical They are exceptionally
cord is immediately sent to the helpful in cell to cell
lab. The screening tests are extremely communication, and very effective for
rigorous, and mandated by the USA FDA. reducing inflammation when they become ingested
by their recipient cell. They act as shuttles to send
The lab carefully processes the umbilical cord to nucleic acids and proteins to other cells, in this way,
generate large amounts of stem cells and exosomes allowing cell-to-cell communication and transporting
that are of the highest quality possible. The lab team molecules among both close and distant cells. In
consists of multiple PhD’s working in ISO Certified, general, these released proteins are important
cGMP compliant clean rooms to ensure quality regulators of intracellular information.
assurance that exceeds USA FDA standards. The
proprietary production process combines the highest Exosomes could be the mediators of many stem cell-
potency, safety and affordability for providers to associated therapeutic activities. We have seen them
confidently offer exosome procedures. to be “faster acting” than stem cells, so R3 frequently

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uses them in conjunction to provide a “1-2 punch” for Protocol

patient outcomes. For the past decade, R3 has been successfully treating
erectile dysfunction with stem cell and exosome
Is stem cell therapy safe?
injections. The penis is numbed, so the procedure is
After a decade of performing over 23,000 stem cell virtually painless and tolerated well.
procedures worldwide, R3 knows that the regenerative
procedures are safe. The quality control employed A temporary tourniquet is placed at the base of the
during the stem cell production is second to none, penis so that the biologics will stay in the penis.
and the side effects R3 sees are usually mild to Otherwise, the biologics may simply shift to the
moderate and temporary. systemic circulation.

They may include itching, dizziness, R3’s providers use approximately 20 million stem
lightheadedness, low grade fever, chills, cells and 50 billion exosomes for the procedure.
headache, nausea. These are typically PRP, short for platelet rich plasma therapy, is also
temporary. If a patient has an allergic reaction included at no additional charge. The procedure
to the multivitamin or a preservative, all of R3’s takes less than an hour!
Centers have the medications to resolve it quickly.
Outcomes
One of the questions we get asked a lot is, Similar to the research mentioned above, R3
“Will the stem cells get rejected?” The Stem Cell’s outcomes for ED have been
answer is NO. exceptional! The patient satisfaction
MSCs do not express major rate is 85% year over year. Patients
histocompatibility complex typically experience spontaneous
(MHC) antigens of the class erections that are maintained
II subtype and contain low through penetration and
levels of MHC molecules of the intercourse. Keep in mind
class I subtype. MSCs also lack results cannot be guaranteed
the co-stimulatory molecules and will vary between
essential for immune detection, individuals.
including CD40, CD80, and It may take a couple months to
CD86. see all the improvements, as it can
Therefore, MSCs generally have low take that long to build up new blood
immunogenicity and can avoid immune flow. It should be noted, again, that stem
rejection by the recipient, which serves as the cell therapy is not a cure for ED, and will need
foundation for their successful application without to be repeated every 12 months or so for continued
needing to match the donor to the recipient. Scientists benefit.
call this being “immunologically privileged”.
Affordability
Another question often asked is “Is there a chance of a Because stem cell therapy for ED is
tumor forming?” Current research has concluded that not a permanent cure, it’s important
the answer is NO. The mesenchymal stem cells and to make it affordable. Repeat
exosomes used during treatment have never been therapies can help maintenance and/
shown to have tumor forming potentials. In fact, they or achieve additional improvements
have been shown to be anti-tumor forming. for sexual health. So a lot of patients

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seek additional treatments at R3 Stem Cell every References:

twelve to eighteen months. 1. Bahk, J.Y.; Jung, J.H.; Han, H.;Min, S.K.; Lee, Y.S. Treatment
of diabetic impotence with umbilical cord blood stemcell
R3 Stem Cell’s fees are less than half what comparable intracavernosal transplant: Preliminary report of 7 cases. Exp.
(and reputable) regenerative clinics charge. Be wary of Clin. Transplant. Off. J.Middle East Soc. Organ Transplant. 2010,
clinics trying to pass off PRP as a stem cell therapy. If 8, 150–160.
they mention only taking your blood for the treatment, 2. Protogerou et al, Erectile Dysfunction Treatment Using Stem
it is NOT a stem cell treatment! Cells: A Review, Medicines 2021, 8, 2. https://doi.org/10.3390/
medicines8010002
R3’s Experience 3. Yiou, R.; Hamidou, L.; Birebent, B.; Bitari, D.; Lecorvoisier, P.;
Contremoulins, I.; Khodari, M.; Rodriguez, A.-M.; Augustin,
For the past decade, R3 Stem Cell’s Centers globally D.; Roudot-Thoraval, F.; et al. Safety of Intracavernous Bone
have performed over 23,000 regenerative procedures Marrow-Mononuclear Cells for Postradical Prostatectomy
in six countries. Several hundred have been for ED, Erectile Dysfunction: An Open Dose-Escalation Pilot Study. Eur.
along with Peyronie’s disease. Patient satisfaction Urol. 2016, 69, 988–991.
across all conditions treated is 85%! 4. Manfredi et al, Cell therapy for male sexual dysfunctions:
systematic review and position statements from the European
R3 combines safety, Society for Sexual Medicine, Sexual Medicine, 2024, 12, 1–16.
effectiveness and 5. Demour et al, Safety and Efficacy of 2 Intracavernous Injections
affordability for the therapies. of Allogeneic Wharton’s Jelly-Derived Mesenchymal Stem Cells
Internationally, the Intellicell in Diabetic Patients with Erectile Dysfunction: Phase 1/2 Clinical
Trial, Urol Int 2021;105:935–943
is used, which is culturing the
most active mesenchymal stem
cells to create the “smartest” stem cell in the world! R3 Stem Cell offers free consultations
Disclaimer: This guide’s education does not constitute for individuals to discuss whether regenerative
medical advice. The USA FDA considers stem cell therapy is indicated for their ED.
therapy experimental. Simply call +1 (844) GET-STEM or
+1 (480) 808-7057 to schedule yours!

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 R3 Consumer Guide for Stem Cell and Exosome Therapy

Consumer Guide
to Stem Cell
Treatment for
Duchenne
Muscular Dystrophy

Brought to you by

* No portion of this Document may be reproduced without the Express Written Consent of R3 Stem Cell.
Disclaimer: This guide’s education does not constitute medical advice. The USA FDA considers stem cell therapy experimental. Any claims
made in the Guide refer to procedures performed outside the USA.
115
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 CONSUMER GUIDE TO STEM CELL TREATMENT FOR DUCHENNE MUSCULAR DYSTROPHY

Consumer Guide to Stem Cell Treatment

for Duchenne Muscular Dystrophy
Every day, R3 Stem Cell receives inquiries worldwide Traditional Treatments for Duchenne’s
from individuals asking if stem cell therapy can help Muscular Dystrophy
with Duchenne’s Muscular Dystrophy (DMD). Spoiler
alert: It can help a lot! In this guide, we’ll go through DMD remains an incurable disease, although several
the basics of how stem cells work for DMD, the latest medicines including corticosteroids are used to delay
research, and what to expect with a regenerative the process of muscle degeneration. Glucocorticoids
procedure. are widely used for its anti-inflammatory property,
however there are significant side effects including
A Significant Global Issue weight gain, diabetes, fragile bones, increased
Duchenne muscular dystrophy (DMD) is risk of fractures, reduced growth and
a progressive degeneration of the suppressed immune system.
striated muscles of the body, and Physiotherapy for DMD patients
has a fatal prognosis. It primarily such as stretching and mobility
affects the skeletal and cardiac exercises can aid in temporary
muscles of male children with muscle flexibility. However,
the occurrence of 1 in 3500. It these treatments loose
is one of the deadliest muscular effectiveness in later stages of
disorders with no definite cure the disease. Therefore, there is
available currently. Since 90% of great need to develop an effective
the male sufferers die by the age of clinical intervention that is capable of
21 years due to cardio respiratory failure, arresting the disease progression.
it has become a global cause of concern. The age of
onset of DMD is early childhood but most children Stem Cell Therapy for Duchenne’s
become wheelchair bound by the age of 10-12 years. Muscular Dystrophy
The disease is caused by mutation, deletion, or If a new technology such as mesenchymal stem cell
duplication of the dystrophin gene, leading to and exosome therapy could provide a long term
synthesis of functionally impotent dystrophin. solution for Duchenne’s Muscular Dystrophy, it would
Dystrophin is a protein essential to maintaining and should become first line therapy. A regenerative
the integrity of the exoskeleton of the muscle cells. therapy that can relieve pain and improve shoulder
Dystrophin is also a structural component of neurons, function that is a safe, nonsurgical option should
glial cells, and Schwann cells. receive consideration.
The disease manifests as progressive weakness of the In a 2014 Case Report, researchers treated A 9-year-
muscles, leading to loss of function. Children typically old boy who had a history of difficulty in getting up
exhibit loss of ambulation in the second decade of life, from the floor, climbing stairs, and frequent falls since
followed by premature death. Treatment of muscular the age of 4 years. The increasing weakness in the
dystrophy consists of medical, rehabilitation, and lower limbs led to toe walking and loss of ambulation
surgical management aiming to preserve the function by the age of 8 years. The weakness then progressed
of the individual and prolonging their independence. to the upper extremities and performing overhead
These treatments contribute very little towards activities was difficult. Diagnosis of DMD was
altering the pathology of the disease. confirmed based on the clinical features, elevated
serum creatinine phosphokinase (CPK) levels (5460

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IU/L), and genetic analysis with multiplex polymerase In our patient we used BMMNC transplantation
chain reaction for dystrophin gene showing deletion followed by rigorous rehabilitation. It has been
of exons 51 and 52. observed that physical activity facilitates the
effectiveness of the stem cell transplantation in
The boy was treated with serial autologous bone muscular dystrophy
marrow mononuclear cell transplantations
followed by multidisciplinary A 2015 study from India evaluated
rehabilitation. Brooke-Vignos 14 participants with DMD.
score was 10 and he was Nine received umbilical
wheelchair bound. cord mesenchymal stem
Over 36 months, cells (UC-MSCs), with
gradual progressive five control patients
improvement not receiving cells.
was noticed in The participants in
muscle strength, Group A (Control)
ambulation were not treated
with assistive with UC-MSCs and
devices, fine motor were monitored over
movements, Brooke- a period of 3 years
Vignos score, and while the participants in
functional independence Group B were injected with
measure score. Nine MSCs monthly for 4 months.
months after the transplantation,
electromyography findings showed For each monthly SCT (Stem cell therapy),
development of new normal motor unit potentials of approximately 2 millions UC-MSCs/kg body weight
the vastus medialis muscle. dissolved in normal saline were prepared for each
patient. 1 million UC-MSC/kg bodyweight were
A total of 33 million bone marrow mononuclear cells injected slowly intravenously into the circulatory
were administered both intrathecal (spinal cord) system of the patient, while 1 million UCMSC/ kg
along with intra-muscular at various points. The were injected intramuscularly keeping a watch
patient underwent serial cellular transplantations at on vital parameters of the patient. The UCMSCs
9, 21, and 31 months after the first transplantation for intramuscular injection was divided into equal
with the same regimen. aliquots to be injected into the major muscles such as
quadriceps, hamstring muscles, calf muscles, deltoid
Repair and regeneration of these cells is engineered muscle, gluteus major and minor, paraspinal group of
by local stem cells and infiltrating inflammatory cells. muscles.
These local stem cells are termed “satellite” cells.
There is, however, only a limited pool of satellite cells There was stability in muscle strength in DMD
in the muscles; therefore, in DMD it cannot meet patients after MSCs transplantation. After 1 year
the increasing demands of accelerated cell necrosis. (N=9), 4/9 subjects had a 1 unit increase in strength
In the presence of increased necrotic tissue, the (mean=3.11 (0.78)). In comparison, control patients
extracellular environment also becomes conducive to had shown progressive decline in muscle strength
necrosis.

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(3.2 ± 0.4472), after 1 year 3/5 subjects had 1 unit left leg significantly increased.
decrease in strength, (mean=2.6 (0.54)).
The patient tolerated the infusions well with no
Overall the researchers noted stability in the strength adverse reactions. Both the patient and his parents
measurements in the treatment groups versus the reported positive improvement in his overall
control group, who experience declines. Overall this balance and dexterity from their daily observations
study establishes the clinical safety for allogenic UC throughout the entire protocol.
-MSCs transplants in DMD patients. Combined case
studies on all the DMD patients in this study clearly A compassionate use study out of Poland was
establish a beneficial role of MSCs in the treatment of published in 2021 evaluating Wharton’s Jelly
DMD patients. Umbilical Cord mesenchymal stem cells for muscular
dystrophy. Treatment consisted of one to
UC-MSCs administration to the five intravenous injections per one
DMD patients did not result treatment course of advanced
into any deleterious effects therapy medicinal product
on such patients and thus containing WJ-MSCs.
considered to be a safe and The first administration
effective cellular therapy was always intravenous
for DMD patients in age for safety reasons; the
group 5 to 18 years. This following injections were
can be used as alternative administered intravenously
to glucocorticoid therapy to or intrathecally. The study
control decline in muscle power group included 22 patients: 11
in DMD patients. However, patients men and 11 women.
need repeated booster sessions of SCT to
maintain muscle power. In general, patients tolerated administrations well.
Only one patient experienced transient headache
A USA Case Report from 2021 evaluated treatment and lower back pain after the last administration.
of an 11 year old male with DMD. The treatment Overall, the individual response to treatment was
protocol was administered over a 90- day period. heterogenous.
Three consecutive treatments were performed. The
first infusion was given on day 0, the second on day In the most successful case, the patient began
30, and the third on day 60. MSCs and exosomes were moving without a crutch, stopped rehabilitation, and
mixed with processed platelet-rich plasma (PRP), rejoined a full-time job.
then infused via peripheral IV over a 60-120 minute
The genetic component of muscular dystrophies
interval. Pretreatment with IV diphenhydramine
cannot be resolved, but the consequences of
(Benadryl), methylprednisolone, and cephalexin were
the involved mutation may be ameliorated. A
infused 20-60 minutes before the infusion of MSCs/
potential mode of action may be related to the
exosomes.
antiinflammatory properties of these cells57-60
The patient showed promising improvement in because inflammatory. processes are involved in the
several of the evaluated categories. As demonstrated pathogenesis of muscular dystrophies.
in Table 1, the distance patient was able to walk in
61,62 For instance, the tumor necrosis factor-α serum
15 seconds increased, the number of claps patient
concentration in patients with DMD was increased
was able to make in 15 seconds increased, and the
eight times compared with healthy boys of the same
distance for standing long jump of both the right and
age,63 and interleukin-6 was increased twice..

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Our study showed objective and significant The patients suffered no adverse reactions in
improvement in muscle strength in 12 patients response to the transplantation of the hUC MSCs.
(54.5%). This amelioration resulted in improved gait At 1 week following transplantation all 3 patients
in three patients and improved results in a motor showed improvement in the muscle force of the
scale in another three patients; altogether, in 6 of limbs, muscle size and daily activity. The walking
22 (27.3%) patients the benefit from the therapy gait had improved by 1 week post-transplantation
was significant enough to ameliorate their clinical and reached a normal status by 12 weeks. Serum
parameters. CK and LDH levels were decreased relative to the
baseline levels. A histological examination of muscle
In 2015, Rajput et al described the administration biopsies displayed no obvious tissue regeneration. In
of WJ-MSCs in 11 children with DMD and reported conclusion, the treatment of patients with BMD using
stabilization compared with a small (n = 5) control hUC-MSCs was safe and of therapeutic benefit that
group. In 2018, Dai et al described an improvement lasted for up to 12 weeks. hUC-MSCs are, therefore,
in electromyography in nine patients with DMD after a potential cell therapy-based treatment option for
intra-arterial administration of UC-MSCs. patients with muscular dystrophies.
A 2015 Chinese study evaluated human umbilical A 2018 study out of India was published that
cord mesenchymal stem cell (hUC-MSCs) therapy on evaluated 150 patients diagnosed with muscular
3 patients. The transplantation of the hUC MSCs was dystrophy. These included Duchenne muscular
performed by infusion with an intravenous drip over dystrophy, limb-girdle muscular dystrophy, and
a 30 min period, and the patients were evaluated at 1, Becker muscular dystrophy variants. They were
3, 4 and 12 weeks following the procedure. administered autologous bone marrow-derived
The evaluation was based on physical characteristics, mononuclear cells intrathecally and intramuscularly
as well as on molecular testing for serum creatine at the motor points of the antigravity weak muscles
kinase (CK) and lactate dehydrogenase (LDH) levels followed by vigorous rehabilitation therapy. No
and a histological examination of muscle biopsies. significant adverse events were noted.

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Assessment after transplantation showed

neurological improvements in trunk
muscle strength, limb strength
on manual muscle testing, gait
improvements, and a favorable
shift on assessment scales
such as the Functional
Independence Measure and
the Brooke and Vignos Scales.
Furthermore, imaging and
electrophysiological studies also
showed significantchanges in
selective cases.
On a mean follow-up of 12 ± 1 months, overall
86.67% cases showed symptomatic and functional
improvements, with six patients showing changes
with respect to muscle regeneration and a decrease
in fatty infiltration on musculoskeletal magnetic allow for shoulder repair is inferior to umbilical cord
resonance imaging and nine showing improved stem cells.
muscle electrical activity on electromyography. Specifically, the therapeutic potential of autologous
Fifty-three percent of the cases showed an increase bone marrow or adipose stem cells in the treatment of
in trunk muscle strength, 48% showed an increase older patients is impaired by a number of age-related
in upper limb strength, 59% showed an increase factors such as oxidative stress, telomere length,
in lower limb strength, and approximately 10% DNA damage, disease, and long-term use of some
showed improved gait. These data were statistically medications.
analyzed using Student’s paired t test and found to This is in stark contrast to the youthful genotype and
be significant. The results show that this treatment is phenotype of neonatal tissue-derived stem cells, such
safe and efficacious and also improves the quality of as from the umbilical cord. They are better at facilitating
life of patients having muscular dystrophy. repair and regeneration of tissue damage, creating
new blood flow with superior anti-inflammatory and
In R3’s experience, 75% of patients with Duchenne’s
immunomodulatory efficacy compared to mature
Muscular Dystrophy achieve success with stem cell
stem cells from one’s adipose or bone marrow.
and exosome therapy. It’s an exciting option for
patients! As a result of the inferiority of autologous stem cells
due to the reasons above and better results being seen
Why Doesn’t R3 Stem Cell Use A Person’s with umbilical cord stem cells, R3 only uses the donor
Own Stem Cells for Duchenne’s Muscular stem cells today
Dystrophy? How do the Stem Cells and Exosomes Work
R3 used to perform autologous therapies, where a for Duchenne’s Muscular Dystrophy?
patient’s own bone marrow or adipose stem cells were
Stem cells and exosomes act in the body through
used. However, a lot of stem cells in one’s body are as
several mechanisms. They do NOT become part of a
old as that person is, and hence not very active. Their
patient’s DNA, which means they do not engraft into
ability to successfully increase sufficient blood flow and

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the person’s existing cells. The predominant method of Stem Cells can also release a huge variety of molecules
action is thought to be through paracrine mechanisms, into the extracellular environment. These molecules,
which means “cell to cell” interaction. which include extracellular vesicles, lipids, free nucleic
acids, and soluble proteins, exert crucial roles in
They act through:
repairing damaged tissue.
1. Angiogenesis – provokes formation of new Along with offering MSCs for treatment of Duchenne’s
blood vessels. Muscular Dystrophy, R3 Stem Cell often includes stem
2. Reduce inflammation – Duchenne’s Muscular cell exosomes, which are a type of extracellular vesicle
Dystrophy is associated with significant participating in extensive cell to cell communication for
inflammation, and the regenerative biologics new blood flow creation.
reduce it nicely Where do the stem cells and exosomes
3. Immune system modulation – the stem cells come from?
and exosomes modulate the immune system R3 Stem Cell’s regenerative biologics originate from
very differently than steroids. Instead of umbilical cord tissue that has been donated after a
blanketly suppressing the immune system, the scheduled c-section. No baby (or mother) is harmed
regenerative biologics tamp down the harmful during the c-section procedure. The umbilical cord
processes while amping up the beneficial ones. tissue is normally discarded, but if the mother passes
This includes ramping up production of several screening tests then the umbilical cord is immediately
helpful growth factors and cytokines, while sent to the lab. The screening tests are extremely
tamping down harmful ones. rigorous, and mandated by the USA FDA.
4. Cellular signaling – the biologics are able The lab carefully processes the umbilical cord to
to perform “cell to cell” communication. This generate large amounts of stem cells and exosomes
promotes recipient cells to proliferate their that are of the highest quality possible. The lab team
growth factor production, protein production consists of multiple PhD’s working in ISO Certified,
and regenerate nerve tissues that are damaged. cGMP compliant clean rooms to ensure quality
5. Prevent cell death – most cells have a timed assurance that exceeds USA FDA standards. The
death, where they are only allowed to live a proprietary production process combines the highest
certain length of time. This is called apoptosis. potency, safety and affordability for providers to
The regenerative biologics allow normally confidently offer exosome procedures.
functioning cells (i.e. neuron cells) to live longer, Millions of dollars have been invested into the
and spare them from the pre-programmed pharmaceutical grade production of the biologics
death. including first rate clean rooms, bioreactors,
6. Preventing scar tissue –Duchenne’s Muscular nano-particle tracking analyzers, cytometers, PCR,
Dystrophy patients may experience significant tangential flow machines and real time environmental
scarring throughout the shoulder. Once that scar monitoring. The quality assurance testing complies
tissue forms, it becomes nonfunctional. Stem with screening and testing stan¬dards consistent
Cells and exosomes are great at preventing scar with the American Association of Tissue Banks, cGMP
tissue (anti-fibrosis). standards, FDA regulations and the highest level of any
regulatory agency globally.

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Stem Cell Derived Exosomes MSCs do not express major histocompatibility complex
(MHC) antigens of the class II subtype and contain low
R3 Stem Cell’s Centers of Excellence globally include
umbilical cord stem cell derived exosomes with levels of MHC molecules of the class I subtype. MSCs
also lack the co-stimulatory molecules essential for
umbilical cord stem cells to provide enhanced results.
immune detection, including CD40, CD80, and CD86.
Exosomes are lipid bound vesicles (acellular) produced
by cells which contain a plethora of growth factors, Therefore, MSCs generally have low immunogenicity
cytokines, mRNA and other proteins. and can avoid immune rejection by the recipient,
which serves as the foundation for their successful
They are exceptionally helpful in cell to cell
application without needing to match the donor to the
communication, and very effective for reducing
recipient. Scientists call this being “immunologically
inflammation when they become ingested by their
privileged”.
recipient cell. They act as shuttles to send
nucleic acids and proteins to other Another question often asked is
cells, in this way, allowing cell- “Is there a chance of a tumor
to-cell communication and forming?” Current research has
transporting molecules among concluded that the answer is
both close and distant cells. In NO. The mesenchymal stem
general, these released proteins cells and exosomes used during
are important regulators of treatment have never been
intracellular information. shown to have tumor forming
potentials. In fact, they have been
Exosomes could be the mediators of
shown to be anti-tumor forming.
many stem cell-associated therapeutic
activities. We have seen them to be “faster Protocol
acting” than stem cells, so R3 frequently uses them
For the past decade, R3 has been
in conjunction to provide a “1-2 punch” for patient
successfully treating Duchenne’s Muscular
outcomes.
Dystrophy with stem cell and exosome
Is stem cell therapy safe? injections. The procedures are performed
both intravenous and intrathecal.
After a decade of performing over 24,000 stem cell
procedures worldwide, R3 knows that the regenerative Each patient receives a combination of the
procedures are safe. The quality control employed mesenchymal stem cells along with exosomes, and
during the stem cell production is second to none, and patients are given a multivitamin IV drip too. R3’s
the side effects R3 sees are usually mild to moderate providers use approximately two million stem cells
and temporary. per kilogram for the procedure. As you can see in the
research described above, typically treatments are
They may include itching, dizziness, lightheadedness,
necessary twice a year.
low grade fever, chills, headache, nausea. These are
typically temporary. If a patient has an allergic reaction Outcomes
to the multivitamin or a preservative, all of R3’s Centers
have the medications to resolve it quickly. Similar to the research mentioned above, R3 Stem
Cell’s outcomes for Duchenne’s Muscular Dystrophy
One of the questions we get asked a lot is, “Will the have been exceptional! The patient satisfaction rate is
stem cells get rejected?” The answer is NO. 85% year over year. Patients typically experience

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improved muscle function and improved quality of life. R3 Stem Cell offers free consultations for individuals to
Keep in mind results cannot be guaranteed and will discuss whether regenerative therapy is indicated for
vary between individuals. their Duchenne’s Muscular Dystrophy. Simply call +1
(844) GET-STEM to schedule yours!
It may take a couple months to see all the
improvements, as it can take that long to build up Disclaimer: This guide’s education does not constitute medical
advice. The USA FDA considers stem cell therapy experimental. Any
new muscle. It should be noted, again, that stem cell
claims made in this Guide refer to procedures performed outside of
therapy is not a cure, and may need to be repeated
the USA.
every six months or so for continued benefit with
DMD. References:

Affordability 1. Sharma et al, Autologous bone marrow mononuclear cell

transplantation in Duchenne muscular dystrophy – a case
report, Am J Case Rep, 2014; 15: 128-134
Because stem cell therapy for
Duchenne’s Muscular Dystrophy is 2. Rajput et al, Human umbilical cord mesenchymal stem cells
not a permanent cure, it’s important in the treatment of Duchenne muscular dystrophy: Safety
and feasibility study in India, Journal of Stem Cells, Volume 10,
to make it affordable. Repeat therapies can help
Number 2, 2015 Nova Science Publishers, Inc.
maintenance and/or achieve additional improvements
for musculoskeletal health. So a lot of patients seek 3. Pourakbar et al, Case Report: Treatment of Duchenne Muscular
Dystrophy with Intravenous Infusion of Mesenchymal Stem
additional treatments at R3 Stem Cell every six
Cells and Exosome Therapies Journal of American Physicians
months. and Surgeons Volume 26 Number 4 Winter 2021

R3 Stem Cell’s fees are less than half what comparable 4. Beata Świątkowska-Flis et al, The use of umbilical cord-derived
(and reputable) regenerative clinics charge. Be wary mesenchymal stem cells in patients with muscular dystrophies:
Results from compassionate use in real-life settings, STEM
of clinics trying to pass off PRP as a stem cell therapy. CELLS Transl Med. 2021;10:1372–1383.
If they mention only taking your blood for the
treatment, it is NOT a stem cell treatment! 5. Patel et al, Allogeneic transplantation of human umbilical
cord mesenchymal stem cells for a single male patients with
Duchenne muscular dystrophy (DMD), Cytotherapy poster
R3’s Experience abstract, Volume 17, Issue 6, Supplement, 2015.
For the past decade, R3 Stem Cell’s Centers globally
6. Li et al, Transplantation of human umbilical cord-derived
have performed over 24,000 regenerative procedures mesenchymalstems cells for the treatment of Becker muscular
in seven countries. Over fifty have been for Duchenne’s dystrophy in affected pedigree members, INTERNATIONAL
Muscular Dystrophy. Patient satisfaction across all JOURNAL OF MOLECULAR MEDICINE 35: 1051-1057, 2015.
conditions treated is 85%! 7. Sharma et al, A Clinical Study Shows Safety and Efficacy
of Autologous Bone Marrow Mononuclear Cell Therapy to
R3 combines safety, effectiveness and affordability Improve Quality of Life in Muscular Dystrophy Patients, Cell
for the therapies. Internationally, the Intellicell is used, Transplantation, Vol. 22, Supplement 1, pp. S127–S138, 2013
which is culturing the most active mesenchymal stem
cells to create the “smartest” stem cell in the world!

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 R3 Consumer Guide for Stem Cell and Exosome Therapy

Consumer Guide
to Stem Cell
Treatment for
Hair Regeneration

Brought to you by

* No portion of this Document may be reproduced without the Express Written Consent of R3 Stem Cell.
Disclaimer: This guide’s education does not constitute medical advice. The USA FDA considers stem cell therapy experimental. Any claims
made in the Guide refer to procedures performed outside the USA.
124
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Consumer Guide to Stem Cell Treatment

for Hair Regeneration
Every day, R3 Stem Cell receives inquiries worldwide Alopecia is broadly categorized into two subtypes:
from individuals asking if stem cell therapy can help scarring or non-scarring. The scarring type comprises
with hair loss. Spoiler alert: It can help a lot! In this approximately 5% of all cases of alopecia and
guide, we’ll go through the basics of how stem describes multiple subtypes of hair loss caused
cells work for regenerating hair, the latest by unknown inflammatory mechanisms.
research, and what to expect with a
regenerative procedure. Androgenic Alopecia (AGA) is the
most common cause of non-scarring
Why does hair loss occur? hair loss, affecting 30-50% of men
The science of hair loss has been (male-pattern hair loss [MPHL])
investigated for decades. It is and approximately 30% of middle-
understood that losing up to 100 hairs aged women (female-pattern hair
per day day is perfectly normal.Any loss loss [FPHL]). The disease manifests by
above this number with no replenishment progressive hair loss, usually in a pattern
however leads to eventual thinning of the hair. distribution. It can begin at any age after
Male and female hair loss has multiple causes. puberty, but the incidence increases with age.

The hair follicle (HF) grows following a cycle of The mechanisms of AGA are multiple, interlinked, and
dynamic and complex processes, which mainly common to both MPHL and FPHL. Among them is
alternate in three phases: rapid growth (anagen), the hypothesis of oxidative stress (OS) and it has been
regression (catagen), and quiescence (telogen). demonstrated that AA is associated with systemic
autoimmune activation in isolation as an acquired
Although hair follicles are protected and maintained autoimmune disorder (AD) or as a comorbidity with
through their association with immune responses diseases such as systemic lupus erythematosus (SLE).
against pathogens and different tissue regeneration The miniaturization of hair follicles and decreased
and healing processes, hair abnormalities or hair density occur in the affected scalp area of
loss (alopecia) commonly occurs in both males patients with AGA. Terminal hair growth length is
and females of all ages, affecting quality of life, gradually reduced in this disease entity. Although
attractiveness, and self-esteem. Reportedly, alopecia the causes of miniaturization are unknown, genetic
can lead to psychiatric disorders and increased risks tendencies and androgen effects are thought to be
of diseases, such associated with
as myocardial other factors that
infarction and have not yet been
metabolic
clarified
syndrome.

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Alopecia areata (AA) is a common autoimmune

disease characterized by hair loss. It affects more
than 6.5 million people in the United States, has
a worldwide prevalence of 0.1%-0.2%, and a
lifetime risk of 2% in the general population.
AA appears in extensive forms, such
as progressive and diffusing hair loss
(diffuse AA), a total loss of scalp hair
(alopecia totalis), and complete loss
of hair over the entire body (alopecia
universalis). Patients with AA suffer
from extensive hair loss that can have a
devastating impact on their quality of life.
Hair follicles contain a variety of cell resources,
such as melanocytic cells, epithelial cells, and stem
cells from different developmental origins, which are
capable of constantly renewing and regulating hair the only treatment option with strong evidence, for
growth. The subjects of the greatest interest are the both males and females with androgenic alopecia is
stem cells in the hair follicle. They can be stimulated
5% minoxidil.
to promote hair growth!
Traditional Treatments for Hair Loss Stem Cell Therapy for Hair Regeneration
Only a few pharmacological treatment options If a new technology such as mesenchymal stem cell
have been approved for clinical use by regulatory and exosome therapy could provide a long term
bodies, such as the United States Food and Drug solution for hair fall, it would and should become
Administration (FDA) and the European Medicines first line therapy. A regenerative therapy that can
Agency (EMA). Moreover, these conventional initiate spontaneous hair growth, negate the need for
therapies which mainly include corticosteroids, medications or injections and is a safe option should
minoxidil, and 5a-reductase inhibitors such receive consideration.
as finasteride and dutasteride, face significant Stem cell-based therapies have recently gained
challenges. considerable attention as potential novel treatments,
Nonetheless, the treatment options for androgenic focusing on the reactivation of hair follicle stem cells
alopecia are limited, with a poor prognosis. Therapy and thus improving the growth, regeneration, and
for hair loss includes the use of glucocorticoids, development of hair follicles.
minoxidil-based drugs, or hair transplantation, all of A recent reports indicated that mesenchymal stem
which present varying side effects. Therefore, these cells were safe and effective for treating AA. In the
options are not usually recommended for patients report, 19 of 20 patients exhibited an increased hair
with diffuse AA, AT, or AU. diameter and significantly increased hair density
Low level laser light therapy (LLLLT) is the only within 3 to 6 months of treatment.
approved device by the FDA to treat androgenetic In 2018, Elmaadawi et al. reported findings from a
alopecia. Gupta et al, in a systematic review with study on the safety and efficacy of mesenchymal
meta-analysis from 2022, came to the conclusion that

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stem cells in 20 patients with New treatment strategies for

AA and 20 patients with AA and related diseases are
AGA. In this study, each needed. Various studies
patient received one have been attempted
intradermal dose for the treatment
of stem cells, and of AA. Among
the impact was them is the use of
evaluated via mesenchymal stem
immunostaining cells (MSCs), which
and digital has had remarkable
dermoscopy after success. MSCs are
6 months. No study efficacious in the
patients experienced treatment of autoimmune
any side effects, and all diseases because they
subjects displayed significantly have anti-inflammatory and
improved hair growth with no immunomodulatory properties.
significant difference between the groups.
In addition, MSC treatment is suitable as a new
Human umbilical cord mesenchymal stem cells alternative treatment method for AA because MSCs
(MSCs) have proven useful in tissue repair and promote hair growth and strengthen the hair. Based
regeneration. Moreover, a study that utilized on these results, Ahn et al transplanted umbilical
allogenic, minimally manipulated umbilical cord cord mesenchymal stem cells to treat androgenic
MSCs reported for the first time the successful alopecia in 2 patients and alopecia universalis (AU) in
treatment of AA and alopecia universalis. 1 patient.

Umbilical Cord-MSCs were isolated from the umbilical The therapeutic effect of MSCs on AA and related
cord, immediately frozen, and stored at -197 C diseases is very high as shown in the patients
without any other manipulations including cell presented here. Recurrence of AA and AU and side
culture. Minimal manipulation of SCs reportedly effects did not occur during the treatment and
results in safer follow-up duration of at least 1 year.
and better Based on these results, we expect
proliferation that umbilical cord mesenchymal
and transplantation will be a safe and
differentiation efficient alternative for the treatment of
capacities than AA, AT, and AU.
long-term
cultured MSCs.

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Gentile et al. used mesenchymal micrografts which contain mesenchymal

stem cells in 11 patients (38 to 61 stem cells. Efficacy was evaluated
years old) affected by AGA in 1–6 months after treatment
stages 3–5, as determined by analyzing the change of
by the Norwood-Hamilton trichometry parameters, which
classification scale. In showed that depending on
patients with hair loss in the the scalp region there was
frontal and parietal areas, an increase in the mean hair
the stem cell injections were density by 4.5–7.12 hair/cm2. No
administered exclusively to the side effects were reported.
front scalp, and placebo injections
(i.e., normal saline) were administered to Kim et al. reported nine patients who were
the parietal areas. suffering from AGA with single transplantation of
autologous SVF in the upper scalp. Hair density of the
Similarly, in patients with hair loss limited to the ADSCs-treated side was significantly increased after 3
parietal and vertex regions, stem cells were injected and 6 months of transplantation compared to the non-
into the parietal region and placebos were injected treated side (p = 0.01 and p = 0.009 per each). There
into the scalp vertex. The hair density after 23 weeks was no mention of the occurrence of any side effects.
increased by 29% for a treated area and by less than
1% for the placebo area. They hypothesized that El-Khwalawany et al. analyzed the efficacy of the
stem cells can improve the formation of new follicles. mesenchymal stem cells in 30 patients with AGA.
No major side effects were reported. Patients received one stem cell injection and a single
6-month follow-up session. The number of hairs
Another study conducted by Gentile et al. in 2019 with increased from 130.87/cm2 to 151.93/cm2. Patients
21 participants demonstrated that the average hair were asked about experienced pain during and
density among patients from the treatment group after the procedure and 21 reported mild pain and
with mesenchymal stem cells increased by more than 9 reported moderate pain. Other than that, no other
30%, and from the placebo group it increased by less side effects were reported.
than 1% at 12
weeks after the According to the results of
treatment. There this review, the use of stem
was no mention of cell injections in female and
the occurrence of male AGA appears to be a
any side effects. promising treatment option.

The study carried In R3’s experience,

out by Zari et al. 90% of patients
in a group of 140 with hair loss
consecutive adults achieve success
with confirmed with stem cell
AGA sought and exosome
to examine therapy. It’s an
the efficacy exciting option for
of autologous patients!
cellular

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How is the Stem Cell This is in stark contrast to the youthful

and Exosome Hair genotype and phenotype of
neonatal tissue-derived stem
Regeneration
cells, such as from the
Procedure umbilical cord. They are
Performed? better at facilitating repair
Initially, some blood will and regeneration of
be taken from your arm tissue damage, creating
and then spun in a high new blood flow with
speed centrifuge machine to superior anti-inflammatory
make platelet rich plasma (PRP). and immunomodulatory
After that, a numbing procedure is efficacy compared to mature stem
performed which takes a few minutes. The cells from one’s adipose or bone marrow.
scalp is then numb and the procedure is painless. As a result of the inferiority of autologous stem cells
A combination of the PRP, stem cells and exosomes due to the reasons above and better results being
are then injected throughout the areas of the scalp seen with umbilical cord stem cells, R3 only uses the
where the hair follicles need to be activated. This is donor stem cells today.
done in a systematic fashion to make sure all areas How do the Stem Cells and Exosomes Work
are covered. for Hair Regeneration?
At that point, the second phase of the procedure Stem cells and exosomes act in the body through
occurs where more PRP is spread over the scalp. A several mechanisms. They do NOT become part of
microneedling procedure is performed to open up a patient’s DNA, which means they do not engraft
microchannels and allow the growth factors and into the person’s existing cells. The predominant
platelets to penetrate subdermal. The entire process method of action is thought to be through paracrine
takes approximately one hour. mechanisms, which means “cell to cell” interaction.

Why Doesn’t R3 Stem Cell Use A Person’s They act through:

Own Stem Cells for Hair Regeneration? 1. Angiogenesis – provokes formation of new
R3 used to perform autologous therapies, where a blood vessels.
patient’s own bone marrow or adipose stem cells 2. Reduce inflammation– Hair loss is associated
were used. However, a lot of stem cells in one’s body with significant inflammation, and the regenerative
are as old as that person is, and hence not very active. biologics reduce it nicely.
Their ability to successfully increase sufficient blood
flow and allow for shair growth is inferior to umbilical 3. Immune system modulation – the stem cells
cord stem cells. and exosomes modulate the immune system
very differently than steroids. Instead of blanketly
Specifically, the therapeutic potential of autologous suppressing the immune system, the regenerative
bone marrow or adipose stem cells in the treatment biologics tamp down the harmful processes while
of older patients is impaired by a number of age- amping up the beneficial ones. This includes
related factors such as oxidative stress, telomere ramping up production of several helpful growth
length, DNA damage, disease, and long-term use of factors and cytokines, while tamping down
some medications. harmful ones.

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4. Cellular signaling – the biologics that are of the highest quality possible.
are able to perform “cell to cell” The lab team consists of multiple PhD’s
communication. This promotes working in ISO Certified, cGMP
recipient cells to proliferate compliant clean rooms to ensure
their growth factor production, quality assurance that exceeds USA
protein production and FDA standards. The proprietary
regenerate tissues that are production process combines
damaged. the highest potency, safety
and affordability for providers to
5. Prevent cell death – most cells have confidently offer exosome procedures.
a timed death, where they are only
allowed to live a certain length of time. This Millions of dollars have been invested
is called apoptosis. The regenerative biologics allow into the pharmaceutical grade production of the
normally functioning cells to live longer, and spare biologics including first rate clean rooms, bioreactors,
them from the pre-programmed death. nano-particle tracking analyzers, cytometers, PCR,
tangential flow machines and real time environmental
6. Preventing scar tissue – Hair loss patients may monitoring. The quality assurance testing complies
experience significant scarring throughout the with screening and testing stan¬dards consistent
scalp. Once that scar tissue forms, it becomes with the American Association of Tissue Banks, cGMP
nonfunctional. Stem Cells and exosomes are great standards, FDA regulations and the highest level of any
at preventing scar tissue (anti-fibrosis). regulatory agency globally
Stem Cells can also release a huge variety of molecules Stem Cell Derived Exosomes
into the extracellular environment. These molecules,
which include extracellular vesicles, lipids, free nucleic R3 Stem Cell’s Centers of Excellence globally include
acids, and soluble proteins, exert crucial roles in umbilical cord stem cell derived exosomes with
repairing damaged tissue. umbilical cord stem cells to provide enhanced results.
Exosomes are lipid bound vesicles (acellular) produced
Along with offering MSCs for treatment of hair loss, by cells which contain a plethora of growth factors,
R3 Stem Cell includes stem cell exosomes, which are a cytokines, mRNA and other proteins.
type of extracellular vesicle participating in extensive
cell to cell communication for new blood flow creation. They are exceptionally helpful in cell to cell
communication, and very effective for reducing
Where do the stem cells and exosomes come inflammation when they become ingested by their
from? recipient cell. They act as shuttles to send nucleic acids
and proteins to other cells, in this way, allowing cell-
R3 Stem Cell’s regenerative biologics originate from
to-cell communication and transporting molecules
umbilical cord tissue that has been donated after a
among both close and distant cells. In general,
scheduled c-section. No baby (or mother) is harmed
these released proteins are important regulators of
during the c-section procedure. The umbilical cord
intracellular information.
tissue is normally discarded, but if the mother passes
screening tests then the umbilical cord is immediately Exosomes could be the mediators of many stem cell-
sent to the lab. The screening tests are extremely associated therapeutic activities. We have seen them
rigorous, and mandated by the USA FDA. to be “faster acting” than stem cells, so R3 frequently
The lab carefully processes the umbilical cord to uses them in conjunction to provide a “1-2 punch” for
generate large amounts of stem cells and exosomes patient outcomes.

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Is stem cell therapy safe? mesenchymal stem cells and exosomes used during
treatment have never been shown to have tumor
After a decade of performing over 24,000 stem cell
forming potentials. In fact, they have been shown to
procedures worldwide, R3 knows that the regenerative
procedures are safe. The quality control employed be anti-tumor forming.
during the stem cell production is second to none, and Protocol
the side effects R3 sees are usually mild to moderate
and temporary. For the past decade, R3 has been
successfully treating hair loss with stem
They may include itching, dizziness, lightheadedness, cell and exosome injections. The scalp
low grade fever, chills, headache, nausea. These are is numbed, so the procedure is virtually
typically temporary. If a patient has an allergic reaction painless and tolerated well.
to the multivitamin or a preservative, all of R3’s Centers
have the medications to resolve it quickly. After numbing, R3’s providers use approximately 20
million stem cells and 50 billion exosomes for the
One of the questions we get asked a lot is, “Will the procedure. PRP, short for platelet rich plasma therapy,
stem cells get rejected?” The answer is NO. is also included at no additional charge. The procedure
takes less than an hour!
MSCs do not express major histocompatibility
complex (MHC) antigens of the class II subtype and Outcomes
contain low levels of MHC molecules of the class I
Similar to the research mentioned above, R3 Stem
subtype. MSCs also lack the co-stimulatory molecules
Cell’s outcomes for hair loss have been exceptional! The
essential for immune detection, including CD40, CD80,
patient satisfaction rate is 85% year over year. Patients
and CD86.
typically experience significant hair growth that is
Therefore, MSCs generally have low immunogenicity maintained for a long time. Keep in mind results cannot
and can avoid immune rejection by the recipient, be guaranteed and will vary between individuals.
which serves as the foundation for
It may take several months to see
their successful application
all the improvements, as it can
without needing to match
take that long to build up
the donor to the recipient.
new blood flow and
Scientists call this being
hair growth. It should
“immunologically
be noted, again, that
privileged”.
stem cell therapy is
Another question not a cure for hair
often asked is “Is there loss, and will need
a chance of a tumor to be repeated every
forming?” Current 12-24 months or so for
research has concluded continued benefit.
that the answer is NO. The

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 CONSUMER GUIDE TO STEM CELL TREATMENT FOR HAIR REGENERATION

Affordability R3 combines safety, effectiveness and affordability

for the therapies. Internationally, the Intellicell is used,
Because stem cell therapy for hair
which is culturing the most active mesenchymal stem
loss is not a permanent cure, it’s
cells to create the “smartest” stem cell in the world!
important to make it affordable.
Repeat therapies can help R3 Stem Cell offers free consultations for individuals to
maintenance and/or achieve additional improvements discuss whether regenerative therapy is indicated for
for hair loss. So a lot of patients seek additional their hair loss. Simply call +1 (844) GET-STEM or +1 (480)
treatments at R3 Stem Cell every twelve to eighteen 808-7057 to schedule yours!
months.
Disclaimer: This guide’s education does not constitute medical
R3 Stem Cell’s fees are less than half what comparable advice. The USA FDA considers stem cell therapy experimental.
(and reputable) regenerative clinics
charge. Be wary of clinics trying References:
to pass off PRP as a stem cell 1. Ahn et al, Alopecia treatment
using minimally manipulated
therapy. If they mention only human umbilical cord-derived
taking your blood for the mesenchymal stem cells: Three
treatment, it is NOT a case reports and review of
stem cell treatment! literature,World J Clin Cases
2021 May 26; 9(15): 3741-
3751.
R3’s Experience
2. Shimizu et al, Regenerative
For the past decade, medicine strategies for hair
R3 Stem Cell’s growth and regeneration: A
Centers globally have narrative review of literature,
performed over 23,000 Regenerative Therapy 21
(2022) 527e539.
regenerative procedures
in six countries. Several 3. Gentile et al, Human Stem Cell
hundred have been for hair Use in Androgenetic Alopecia: A
Systematic Review
loss, along with various types
of alopecia Patient satisfaction
across all conditions treated is 85%!

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 R3 Consumer Guide for Stem Cell and Exosome Therapy

Guide to
Stem Cell and
Exosome Therapy
for Heart Disease

Brought to you by

* No portion of this Document may be reproduced without the Express Written Consent of R3 Stem Cell.
Disclaimer: This guide’s education does not constitute medical advice. The USA FDA considers stem cell therapy experimental. Any claims
made in the Guide refer to procedures performed outside the USA.
133
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 G U I D E TO S T E M C E L L A N D E XO S O M E T H E R A P Y F O R H E A R T D I S E A S E

Guide to Stem Cell and Exosome Therapy

for Heart Disease
Every day, R3 Stem Cell receives inquiries worldwide frequent hospitalizations.
from individuals asking if stem cell therapy can help
for heart failure. Spoiler alert: It can help a lot! In Heart diseases are the major cause of mortality
this guide, we’ll go through the basics of how stem worldwide, with approximately 20 million people
cells and exosomes work for heart disease, the latest aged 30–70 years dying from the disease every
research, and what to expect with a regenerative year. At present, the disease tends to affect younger
procedure. individuals. The available treatments include
heart transplantation, surgical interventions, and
Conventional treatments for heart disease are often pharmaceutical therapies. Surgical treatment is
not able to stop disease progression. For typically associated
those who desire improved heart
function along with enhanced with complications and generally
quality of life, failure with is not recommended unless
conventional treatments is the condition is severe. Even if
disappointing and occurs all too the patients survive and the
often. condition improves, a long-
term maintenance treatment is
Stem cell therapy for heart disease
necessary.
is turning out to be an excellent
opportunity for individuals to achieve Therefore, there is an ultimate need
meaningful long-term results. Let’s dig in! for a treatment to improve the clinical
conditions by either replacing the damaged heart
A Significant Global Issue cells and/or improving cardiac performance. Thus,
Heart failure (HF) is a common, expensive, lethal, and the cardiac tissue regeneration with the application
disabling condition. Its prevalence in industrialized of stem cells, or their exosomes, may be an effective
nations has reached epidemic proportions (e.g. therapeutic option.
6.5 million in the USA), and continues to rise as the
population ages. Stem Cell Therapy for Heart Disease
Human umbilical cord mesenchymal stem cells (HUC-
Despite significant advances over the last three
MSCs) offer a relatively safe and effective alternative
decades, the prognosis of patients hospitalized with
therapy for heart diseases. HUC-MSCs have been
heart failure remains poor, and the 5-year mortality
shown to treat and relieve various cardiovascular
approaches 50%. Therefore, heart failure constitutes
diseases, including myocardial infarction, heart failure,
a major public health problem worldwide, a leading
myocardial ischemia, and myocarditis.
cause of morbidity and mortality, and an increasing
burden on healthcare systems around the globe. Mesenchymal stem cells promote cardiac tissue
regeneration and angiogenesis, inhibit inflammation,
Traditional Treatments and significantly reduce infarct size and mortality. Also,
While the existing therapies for ischemic heart transplantation of HUC-MSCs improves the New York
disease lower the early mortality rates, prevent Heart Association functional class and the results of
additional damage to the heart muscle, and reduce the Minnesota Living with Heart Failure Questionnaire
the risk of further heart attacks, most of the patients and 6-min walk test, significantly improving patients’
are likely to have worse quality of life including quality of life.

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In 2012, Duckers and co-workers were the first in ejection fraction, starting at 3 months, and
reporting the feasibility, safety and beneficial effects, persisting through 12 months. The patients treated
including reduced myocardial scar formation and with placebo did not improve in either left ventricular
improved perfusion, of intracoronary ejection fraction or clinical functional class. As
indicated by the authors, it is tempting to
infused adipose tissue-derived speculate that the robust paracrine
mesenchymal stem cells in a secretion of various factors,
randomized, placebo-controlled including hepatocyte growth
clinical trial. factor, might play an important
The transplanted stem cells role in mediating the therapeutic
enhanced the local contractile effects of the UC-MSCs
function of the myocardium, The RIMECARD trial (Randomized
reduced the necrotic infarcted area, Clinical Trial of Intravenous Infusion
and increased ejection fraction. The Umbilical Cord Mesenchymal Stem Cells on
long-term follow-up found that the induction of Cardiopathy) was a phase 1/2, randomized, double-
blood vessel formation was also an essential part of blind, placebo-controlled clinical trial. The study was
heart repair after injury. Importantly, mesenchymal conducted in Chile and participants were enrolled in a
stem cells exert anti-inflammatory effects. In summary, 1:1 randomization to intravenous infusion of umbilical
mesenchymal stem cells perform a therapeutic cord mesenchymal stem cells or placebo.
function in heart-related diseases by the following
mechanisms: There were no acute adverse events associated
with the infusion and the intervention resulted in a
(1) enhancing the proliferation of cardiomyocytes to significant improvement in left ventricular function
improve heart function, (18%), functional status, and quality of life.
(2) enhancing angiogenesis and blood supply, Lunde et al. studied the activity capacity and quality of
(3) improvement of cardiac performance by life in 50 patients with myocardial infection following
inhibiting myocardial cell death, stem cell injection in 2007; activity capacity and
oxygen consumption were significantly higher in the
(4) anti-inflammatory and anti-fibrotic activity stem cell group compared to the control group.
through paracrine effects, and
A study called the POSEIDON trial, published in
(5) regulating the expression levels of miRNAs, 2012, was the first study to compare autologous and
lncRNAs, and circRNAs involved in cardiac repair. allogeneic MSCs in patients with ischaemic HF. In this
randomized Phase I/II study, three doses of autologous
Recent results of the RIMECARD study by Bartolucci
or allogeneic BM-MSCs (20, 100, and 200 million stem
et al. in human subjects using umbilical cord-derived
cells) were given transendocardially in 30 subjects.
MSCs as potential heart failure therapy are quite
At 12 months, both allogeneic and autologous MSCs
encouraging. The patients had stable heart failure (HF),
reduced scar size by 33%.
with a reduced ejection fraction of less than 40.
Allogeneic cells (donor), however, appeared to be
Although the sample size was small (15 controls and
more effective in that they significantly reduced
15 HF patients treated with UC-MSCs) to establish
left ventricle end-diastolic volume (LVEDV) whereas
either safety or efficacy, the echocardiographic and
autologous cells did not. POSEIDON was important
cardiac MRI evaluations demonstrated improvements
because it was the first trial to support the concept

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that allogeneic MSCs may be superior to autologous They act through:

MSCs.
1. Angiogenesis – provokes formation of new
Compared with bone marrow mesenchymal stem blood vessels.
cells, however, umbilical cord mesenchymal stem cells
offer several advantages, including wide availability, 2. Reduce inflammation – Heart disease is
easier isolation, higher proliferative capacity and less associated with significant inflammation, and the
cellular aging. Importantly, there is evidence that UC- regenerative biologics reduce it nicely.
MSCs are more potent than BM-MSCs (since they are
3. Immune system modulation – the stem cells
derived from a much younger organism).
and exosomes modulate the immune system
Another study conducted in chronic systolic heart very differently than steroids. Instead of
failure by Zhao et al. evaluated the effectiveness blanketly suppressing the immune system, the
of Umbilical cord-MSCs through intracoronary regenerative biologics tamp down the harmful
transplantation. Among the 30 recipients, 29 patients processes while amping up the beneficial ones.
had no adverse reactions, heart palpitations, chest This includes ramping up production of several
pain, chest tightness, dyspnoea or other symptoms, helpful growth factors and cytokines, while
while one experienced chest discomfort. The cardiac tamping down harmful ones.
left ventricle ejection fraction and 6-min walking
4. Cellular signaling – the biologics are able
distance were significantly improved at the six month
to perform “cell to cell” communication. This
follow up.
promotes recipient cells to proliferate their
The TRIDENT study adds to a growing body of growth factor production, protein production
research on the safety of allogeneic hMSCs in ICM and and regenerate nerve tissues that are damaged.
addresses the issue of dosage in cell-based therapies,
5. Prevent cell death – most cells have a timed
providing additional evidence of a direct relationship
death, where they are only allowed to live a
between cell dose and clinical efficacy.
certain length of time. This is called apoptosis.
The TRIDENT study was a randomized, double-blinded The regenerative biologics allow normally
comparison of two doses of allogeneic mesenchymal functioning cells (i.e. neuron cells) to live longer,
stem cells delivered to patients with ischemic and spare them from the pre-programmed
cardiomyopathy. The TRIDENT study demonstrated death.
that mesenchymal stem cells are clinically effective in
6. Preventing scar tissue –Once that scar tissue
reducing scar size and improving cardiac function. An
forms, it becomes nonfunctional. Stem Cells and
intriguing finding of this study was that ejection fraction
exosomes are great at preventing scar tissue
was improved only in the 100 million stem cell group,
(anti-fibrosis).
suggesting that the higher dose provides a greater
benefit to cardiac function than the lower dose. Stem Cells can also release a huge variety of molecules
into the extracellular environment. These molecules,
How do Stem Cells and Exosomes Act which include extracellular vesicles (exosomes),
in the Body? lipids, free nucleic acids, and soluble proteins, exert
crucial roles in repairing damaged tissue. Along with
Stem cells and exosomes act in the body through
offering stem cells for treatment of psoriasis, R3 Stem
several mechanisms. They do NOT become part of a
Cell includes stem cell exosomes, which are a type of
patient’s DNA, which means they do not engraft into
extracellular vesicle participating in extensive cell
the person’s existing cells

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to cell communication for ovarian tissue repair and proprietary production process combines the highest
regeneration. potency, safety and affordability for providers to
confidently offer exosome procedures.
The stem cells administered by R3 are not the ones
that become part of a patient’s DNA. The administered Millions of dollars have been invested into the
mesenchymal stem cells are not specifically designed pharmaceutical grade production of the biologics
to replace damaged and lost epithelial cells, but rather including first rate clean rooms, bioreactors,
coordinate immune system modulation. nano-particle tracking analyzers, cytometers, PCR,
tangential flow machines and real time environmental
Where do the stem cells and exosomes come
monitoring. The quality assurance testing complies
from? with screening and testing stan¬dards consistent
R3 Stem Cell’s regenerative biologics originate from with the American Association of Tissue Banks, cGMP
umbilical cord tissue that has been donated after a standards, FDA regulations and the highest level of any
scheduled c-section. No baby (or mother) is harmed regulatory agency globally.
during the c-section procedure. The umbilical cord
tissue is normally discarded, but if the mother passes Stem Cell Derived Exosomes
screening test then the umbilical cord is immediately R3 Stem Cell’s Centers of Excellence globally include
sent to the lab. umbilical cord stem cell derived exosomes with
umbilical cord stem cells to provide enhanced results.
The lab carefully processes the umbilical cord to
Exosomes are lipid bound vesicles (acellular) produced
generate large amounts of stem cells and exosomes
by cells which contain a plethora of growth factors,
that are of the highest quality possible. The lab team
cytokines, mRNA and other proteins.
consists of multiple PhD’s working in ISO Certified,
cGMP compliant clean rooms to ensure quality They are exceptionally helpful in cell to cell
assurance that exceeds USA FDA standards. The communication, and very effective for reducing

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 G U I D E TO S T E M C E L L A N D E XO S O M E T H E R A P Y F O R H E A R T D I S E A S E

inflammation when they become ingested MSCs do not express major

by their recipient cell. They act as shuttles histocompatibility complex (MHC)
to send nucleic acids and proteins to antigens of the class II subtype and
other cells, in this way, allowing cell-to- contain low levels of MHC molecules
cell communication and transporting of the class I subtype. MSCs also lack
molecules among both close and the co-stimulatory molecules essential
distant cells. In general, these released for immune detection, including CD40,
proteins are important regulators of CD80, and CD86.
intracellular information.
Therefore, MSCs generally have low
Exosomes could be the mediators of many immunogenicity and can avoid immune
stem cell-associated therapeutic activities. Considering rejection by the recipient, which serves as the
they are 100 times smaller than stem cells, they do not foundation for their successful application without
have any issues passing through the blood-brain-barrier needing to match the donor to the recipient. Scientists
to reach the brain from the bloodstream. call this being “immunologically privileged”.
Exosomes can be derived from many different types Another question often asked is “Is there a chance of
of stem cells including umbilical cord, cardiosphere- a tumor forming?” Once again the answer is NO. The
derived cells, cardiac stem cells, embryonic, induced mesenchymal stem cells and exosomes used during
pluripotent, mesenchymal and endothelial progenitor treatment have never been shown to have tumor
cells. They can carry and deliver mRNAs, miRNAs forming potentials. In fact, they have been shown to be
and proteins to the injured heart muscle and play a anti-tumor forming.
significant role in resident cardiac stem cell activity,
cardiomyocyte proliferation, beneficial cardiac Treatment Protocol
remodeling, apoptosis reduction, angiogenesis, anti- For the past decade, R3 has been
inflammatory response and a decrease in infarct size. successfully treating patients with
The advantages for effective exosome therapy include stem cell and exosome therapies
the cell free component, long-term stability and low or with injection, infusion, intranasal,
no immune response intrathecal and nebulizer procedures.

Is stem cell therapy safe? For heart disease, R3’s providers use between one
and two million stem cells per kilogram (depends
After a decade of performing over 24,000 stem cell
on patient weight). In addition, billions of stem cell
procedures worldwide, R3 knows that the regenerative
exosomes and platelet rich plasma therapy (PRP) are
procedures are safe. The quality control employed
included at no cost.
during the stem cell production is second to none, and
the side effects R3 sees are usually mild to moderate R3 Stem Cell’s heart disease treatment protocol
and temporary. includes an IV therapy combining mesenchymal stem
cells and exosomes, along with a multivitamin IV as
They may include itching, dizziness, lightheadedness,
well. Safety is paramount with the biologics products
low grade fever, chills, headache, nausea. These are
being rigorously tested prior to use, and expert
typically temporary. If a patient has an allergic reaction
providers managing each treatment as if you are a
to the multivitamin or a preservative, all of R3’s Centers
family member! This is why we don’t perform the heart
have the medications to resolve it quickly.
catheterization application, as patients in some studies
One of the questions we get asked a lot is, “Will the have suffered significant adverse events as a result
stem cells get rejected?” The answer is NO.

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 G U I D E TO S T E M C E L L A N D E XO S O M E T H E R A P Y F O R H E A R T D I S E A S E

Why does R3 Stem Cell use donor tissue for R3 Stem Cell offers free consultations for individuals to
its stem cells? discuss whether regenerative therapy is indicated for
your heart disease. Simply call +1 (844) GET-STEM to
Although autologous (your own) stem cells provide schedule yours!
significant advantages, allogeneic (donor) stem cells
References:
have more advantages. First of all, autologous MSCs
1. Peruzzi et al, State of the Art on the Evidence Base in Cardiac
need a long time to culture and expand, which limits Regenerative Therapy: Overview of 41 Systematic Reviews,
its application in treatment, while allogeneic stem cells Hindawi Publishing Corporation BioMed Research International
can be obtained and expanded more quickly, thus Volume 2015, Article ID 613782, 7 pages http://dx.doi.
org/10.1155/2015/613782
avoiding the delay of time window. 2. Muller et al, Stem Cell Therapy in Heart Diseases – Cell Types,
Mechanisms and Improvement Strategies, Cell Physiol Biochem
Second, age is a factor that affects the physiological 2018;48:2607-2655.
characteristics of MSCs. Studies have shown that stem 3. Xie et al, What is the impact of human umbilical cord
cells from elderly donors have decreased proliferation mesenchymal stem cell transplantation on clinical treatment?
Xie et al. Stem Cell Research & Therapy (2020) 11:519 https://doi.
and differentiation ability. This means they are less in org/10.1186/s13287-020-02011-z
number and less effective! 4. Bartolucci J, Verdugo FJ, González PL, Larrea RE, Abarzua E, Goset
C, Rojo P, Palma I, Lamich R, Pedreros PA, Valdivia G, Lopez VM,
Affordability Nazzal C, Alcayaga-Miranda F, Cuenca J, Brobeck MJ, Patel AN,
Figueroa FE, Khoury M. Safety and efficacy of the intravenous
Stem cell therapy for psoriasis may be infusion of umbilical cord mesenchymal stem cells in patients with
heart failure: a phase 1/2 randomized controlled trial (RIMECARD
the key step to completely changing a trial [randomized clinical trial of intravenous infusion umbilical
person’s quality of life, and we want to cord mesenchymal stem cells on cardiopathy]). Circ Res. 2017;
make it affordable for as many individuals as possible. 5. Terashvili et al, Stem Cell Therapies in Cardiovascular Disease, J
Our global volume has allowed us to keep our patient Cardiothorac Vasc Anesth. Author manuscript; available in PMC
2020 January 01.
cost as low as possible. 6. Mostafavian et al, Effect of Stem Cell Therapy on Patients’ Quality
of Life in Heart Failure with Reduced Ejection Fraction, Journal of
Unfortunately, stem cell clinics in Colombia, China Medicine and Life Vol. 11, Issue 4, October-December 2018, p_p_._
and Panama charge over $20,000 USD for psoriasis _3_5_9_–3_6_4_ _
treatment. How are individuals supposed to budget 7. Bolli et al, Cell therapy in patients with heart failure: a
comprehensive review and emerging concepts , Cardiovascular
for that?? R3 Stem Cell’s fees are typically less than Research (2022) 118, 951–976, doi:10.1093/cvr/cvab135
half that for full treatment, which also includes free 8. Chen et al, The application of umbilical cord-derived MSCs in
exosomes, PRP and a multivitamin infusion! cardiovascular diseases, J Cell Mol Med. 2021;25:8103–8114.
9. Florea et al, Dose Comparison Study of Allogeneic Mesenchymal
R3’s Experience Stem Cells in Patients with Ischemic Cardiomyopathy (The
TRIDENT Study), Circ Res. Author manuscript; available in PMC
For the past decade, R3 Stem Cell’s Centers globally 2022 January 08.
have performed over 24,000 regenerative procedures 10.Tompkins et al, Comparison of Mesenchymal Stem Cell Efficacy in
Ischemic Versus Nonischemic Dilated Cardiomyopathy, J Am Heart
in six countries. Patient satisfaction across all conditions
Assoc. 2018;7:e008460. DOI: 10.1161/JAHA.117.008460.)
treated is very high, at 85%. R3 has treated many
11.Yamada et al, Cell Therapy Improves Quality-of-Life in Heart
patients with varying types of heart disease. Failure: Outcomes From a Phase III Clinical Trial, Stem Cells
Translational Medicine, 2024, 13, 116–124 https://doi.
R3 combines safety, effectiveness and affordability org/10.1093/stcltm/szad078 Advance access publication 24
for the therapies. Internationally, the Intellicell is used, November
which is culturing the most active mesenchymal stem
cells to create the “smartest” stem cell in the world!

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 R3 Consumer Guide for Stem Cell and Exosome Therapy

Guide to Stem Cell

and Exosome
Therapy for
Inflammatory
Bowel Diseases

Brought to you by

* No portion of this Document may be reproduced without the Express Written Consent of R3 Stem Cell.
Disclaimer: This guide’s education does not constitute medical advice. The USA FDA considers stem cell
therapy experimental. Any claims made in the Guide refer to procedures performed outside the USA.
140
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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR INFLAMMATORY BOWEL DISEASES

Guide to Stem Cell and Exosome Therapy

for Inflammatory Bowel Diseases
Every day, R3 Stem Cell receives inquiries worldwide (UC), Crohn’s disease (CD), and unclassified IBDs.
from individuals asking if stem cell therapy can help
for inflammatory bowel diseases, such as Ulcerative According to epidemiology, the prevalence of IBDs in
Colitis and Crohn’s Disease. Spoiler alert: It can help Western countries is significantly higher than that in
a lot! In this guide, we’ll go through the basics of Eastern countries, but it is also rapidly increasing in
how stem cells and exosomes work for IBD relief, the Asian countries.
latest research, and what to expect with a
Both male and female are affected
regenerative procedure.
equally, specially adults aged 30–40
Conventional treatments for years. The incidence of Ulcerative
Inflammatory Bowel Diseases Colitis (UC) has been increasing
(IBD) have improved dramatically around the world. The highest
over the past decade. Despite the annual incidence reported was 24.3
efforts being made to optimize per 100,000 person-years in Europe,
use of the existing drugs, the current 6.3 per 100,000 person-years in Asia
situation is far from ideal. Up to half of and the Middle East, and 19.2 per 100,000
all IBD patients stop responding to conventional person-years in North America.
medications, and continue to suffer complications
that may end up with surgery, fistulas and Furthermore, in the last few decades there has been
hospitalizations. an increase in the disease in low-incidence zones as
South Korea, China, India, Iran, Lebanon, Thailand, the
Stem cell therapy for IBD is turning out to be an French West Indies, North Africa and Japan. IBD poses
excellent opportunity for individuals to potentially an important health problem, since its worldwide
achieve remission, improve function and to avoid the incidence is increasing.
need for potentially risky surgery. Let’s dig in!
The condition affects young people and persists for
A Significant Global Issue life - exerting a strong impact upon quality of life,
Inflammatory bowel diseases (IBDs) represent a in the professional setting, and in patients’ personal
group of chronic inflammatory disorders of the relations. Furthermore, IBD is associated with
gastrointestinal (GI) tract including ulcerative colitis considerable healthcare costs

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What causes Inflammatory Bowel What are the symptoms of IBD?

Diseases? The clinical signs and symptoms
At present, IBD is regarded as of the IBDs mainly include
the result of an abnormal enteritis, diarrhea, recurrent
host immune response hemorrhage, abdominal
to intraluminal antigens pain, reduced appetite, and
occurring in a genetically weight loss. Currently, there
predisposed individual, is still no cure for IBDs.
with the production of
People may experience ulcers
chronic inflammation of
and inflammation of the inner
the gastrointestinal tract,
lining of the colon , that may also
accompanied by tissue destruction. lead to rectal bleeding.
IBD is an autoimmune disorder, meaning
the body’s immune system attacks healthy tissues. It Common IBD symptoms include:
is not yet known what triggers these attacks and why • Abdominal pain (pain in the stomach area)
IBD develops in some people and not in others.
• Diarrhea, sometimes with blood
The cause of IBDs is very complicated and has • Urgency to have a bowel movement and fecal
not yet been completely understood. IBD is the incontinence
consequence of complex interaction among genetic,
• Rectal bleeding
environmental and microbial factors, producing
sustained inflammation at intestinal level, favored by • Weight loss
alteration of the mucosal barrier and immune system • Fever
defects. Among the environmental factors, smoking, • Anemia
drug use, diet habits, mental stress, and many other
external factors are related to the occurrence of • Malnutrition and delayed growth in people who
IBDs. develop IBD as children
• Anxiety and depression
In particular, smoking increases the risk of CD and
is related with an increase in the recurrence rate. Air If inflammation is not controlled, over time IBD can
pollution can also increase the risk of CD and UC damage the intestines, causing
disease. At the same time, Bitton et al. also proposed
• Abscesses: pockets of infection that can result in
that people with less stress would have less chance of tearing of the intestinal wall.
developing IBDs.
• Strictures: areas of narrowing in the bowel.
In addition, IBDs has a strong genetic tendency,
especially in the first-degree relatives of patients who • Fistulas: abnormal passageways between two
are at higher risk for IBDs. Compared with fraternal organs or vessels that normally do not connect.
twins, identical twins have a higher prevalence rate Fistulas happen when inflammation and
of IBDs. Genetic studies have reached a consistent pressure inside the bowel break down tissue,
conclusion: genetic factors play an important but and can cause bowel contents to leak into the
non-decisive role in the occurrence of IBDs. bladder, urethra or vagina.
• Long-term inflammation in the colon
increases the risk of colon cancer.

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In some people with IBD, the inflammation can affect

areas of the body outside the intestines:
• Eyes: redness and inflammation
due to episcleritis (inflammation
between the inner eyelids and
the white of the eye) or uveitis
(inflammation inside the eye).
Experts estimate that 10% to
43% of people with IBD develop
eye problems, and regular visits
to the eye doctor are important.
• Mouth: inflammation (stomatitis),
mouth sores and ulcers
• Liver: fat in the liver (steatosis)
• Biliary tract: gallstones and inflammation of the • Pain medications
bile duct system (sclerosing cholangitis)
• Antibiotics
• Kidneys: kidney stones, hydronephrosis (swollen
kidneys caused by a backup of urine), fistulas • Steroids
and urinary tract infections
If medications do not calm the inflammation, over
• Skin: erythema nodosum (tender, red bumps time the intestines can become damaged, making
on the shins), pyoderma gangrenosum, a rare symptoms worse and increasing the need for surgery.
condition that causes severe skin ulcers on the About half of people with IBD may need surgery at
legs. some point in their lives to:
• Joints and spine: spondylolysis (stress fracture • Remove areas of the intestine
of the vertebrae), sacroiliitis(inflammation of • Repair blockages, strictures, abscesses or fistulas.
the joints connecting the lower spine with the The majority of ulcerative colitis (UC) patients
pelvis) and IBD in the limbs would be subject to medications including anti-
• Blood circulation: including phlebitis inflammatory agents such as 5-aminosalicylic
(inflammation of blood vessels) acids (5-ASA), systemic corticosteroids, and topical
corticosteroids, as well as immunomodulators like
Traditional Treatments azathioprine, 6-mercaptopurine (6-MP), cyclosporine,
Medications are key to treating IBD. The goal and methotrexate.
is easing symptoms, halting inflammation and Unfortunately, 74% of UC patients experience at
reducing flare-ups. least one relapse during 5-year observation in a
prospective population-based cohort study. A meta-
Conventional medication options include analysis conducted by Ford et al. has shown that 887
• Immunosuppressants for IBD (60.3%) of 1470 UC patients fell short of achieving
remission in randomized to receive 5-ASA, indicating
• Topical anti-inflammatory medications that more than half of UC patients may not be able to
have a positive response to traditional medications.

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What is more, taking these drugs could lead to the

occurrence of various adverse effects. The use of
corticosteroids is confirmed to be associated with
cutaneous effects, weight gain, hyperglycemia,
osteoporosis, adrenal insufficiency, and cataracts.
Moreover, corticosteroid therapy is capable
of increasing risk of opportunistic infections,
especially when administered in combination with
other immunosuppressive drugs. The intolerance
or potential occurrence of myelotoxicity and
hepatotoxicity generated by immunomodulators
could make nearly one fourth of patients discontinue
the treatments.
Among the recently available therapies, anti-tumor
necrosis factor α (anti-TNFα) agents are the most Stem Cell Therapy for IBD
notable predecessors (infliximab, adalimumab, The effects of systemic administration of autologous
etc.), resulting in improved health outcomes and or allogeneic MSCs have been evaluated in clinical
decreased need for surgical intervention. However, trials., indicating that the systemic administration of
treatment failure is observed in many patients mesenchymal stem cells significantly improved the
treated with anti-TNFα agents, including primary and clinical outcome and prognosis for IBDs.
secondary nonresponders. Additionally, anti-TNF-α
agents are associated with rare but serious adverse Stem Cells have been found to inhibit intestinal
effects, including serious infection, paradoxical inflammation, promote long-term intestinal mucosal
autoimmune reactions, and a small but increased risk healing, and significantly improve patient quality
of malignancy. of life, making them a valuable alternative IBD
treatment.

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R3 Stem Cell does not use Hematopoietic Stem cell therapies are performed that do not involve
Cell Therapy (HSCT). This treatment actually has an knocking out a person’s immune system.
unfortunate name, because hematopoietic stem
cells are a component of umbilical cord blood. R3 Wang et al published a meta-analysis in 2021 where
uses cord blood internationally in some locations for they evaluated 18 human studies on IBD, including
treatments, but not HSCT. Let me explain. 360 patients. In the studies that looked at remission
rates with mesenchymal stem cells, rates at 1, 3, 5, 12,
HSCT is a treatment where a patient receives 24, and 36 months after stem cell therapy were 43%,
a myeloablation. This involves administering a 68%, 73%, 54%, 52%, and 46%, respectively, thus
chemotherapy regimen to knock out a person’s both high and stable.
immune system, and then applying a person’s
own bone marrow for replenishing the immune In 2006, Onken et al published an abstract on
system. It’s basically a cancer style treatment with an mesenchymal stem cells used to treat 10 patients
autologous bone marrow transplant. with active Crohn’s Disease (CDAI >220, C-reactive
protein ≥ 5 mg/L) refractory to treatment with
While there are some very good published results, corticosteroids, immune modulators and infliximab.
there are significant risks associated with HSCT. One
may experience opportunistic infection, anemia, The patients were randomized to two groups, both
and death in rare circumstances. So R3 Stem Cell of which received two intravenous doses of MSCs,
does not perform HSCT, rather, mesenchymal stem spaced one week apart. One group received high-

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dose MSCs (8 million MSCs/kg), while the other group patients were randomly selected to receive a total
received low dose MSCs (2 million MSCs/kg). The of four peripheral intravenous infusions of 1 million
primary endpoint was percentage clinical response, umbilical cord stem cells/kg, with one infusion per
defined as a reduction in the CDAI score of ≥ 100 week. Patients were followed up for 12 months.
points.
The Crohn’s disease activity index (CDAI), Harvey-
All subjects presented a mean reduction in CDAI Bradshaw index (HBI), and corticosteroid dosage
score of 105 points on day 28. The CDAI scores were assessed. Twelve months after treatment, the
decreased to a greater extent in the high-dose group. CDAI, HBI, and corticosteroid dosage had decreased
by 62.5, 3.4, and 4.2 mg/day, respectively, in the UC-
In 2014, Forbes et al published a study looking at MSC group
donor mesenchymal stem cells in patients with
luminal Crohn’s Disease who were nonresponders In the control group, the CDAI, HBI, and
to traditional therapies. Sixteen patients were given corticosteroid dosage had decreased by 23.6, 1.2 and
intravenous infusions of allogeneic MSCs (2 million 1.2mg/day, respectively.
stem cells/kg body weight) weekly for 4 weeks.
The superiority of umbilical cord mesenchymal
Among the 15 patients who completed the study, the stem cells was statistically significant, and patients
mean CDAI score was reduced from 370 to 203 at day were able to avoid the side effects of chronic steroid
42 (P < .0001). That’s a decrease of 46%! use! No serious adverse events were observed. The
conclusion was that umbilical cord mesenchymal
The mean CDAI scores decreased after each MSC stem cells were effective in the treatment of Crohn’s
infusion (370 before administration, 269 on day 7, Disease and produced mild side effects.
240 on day 14, 209 on day 21, 182 on day 28, and 203
on day 42). Twelve patients had a clinical response, 8 Below you will see before and after endoscopic
had clinical remission. results of two
patients in the study
In 2018, Zhang et al who received the
published the BEST mesenchymal stem
study to date on cells. Complete colon
umbilical cord MSC’s healing!
for Crohn’s Disease.
The study sought to Below is a table of
investigate the efficacy several clinical trials
and safety of UC-MSCs showing the dose
for the treatment of of stem cells used,
Crohn’s Disease. number of patients,
follow up duration
Eighty-two patients and the outcome. The
who had been results are extremely
diagnosed with CD impressive!
and had received
steroid maintenance
therapy for more than 6
months were included
in this study. Forty-one

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How do Stem Cells Work in the Body?

They act through:
1. Angiogenesis – provokes formation of new 4. Cellular signaling – the biologics are able
blood vessels. to perform “cell to cell” communication. This
promotes recipient cells to proliferate their
2. Reduce inflammation – IBD is associated with
growth factor production, protein production
significant inflammation, and the regenerative
and regenerate tissues that are damaged.
biologics reduce it nicely.
5. Prevent cell death – most cells have a timed
3. Immune system modulation – the stem cells
death, where they are only allowed to live a
and exosomes modulate the immune system
certain length of time. This is called apoptosis. The
very differently than steroids. Instead of
regenerative biologics allow normally functioning
blanketly suppressing the immune system, the
cells (i.e. chondrocytes) to live longer, and spare
regenerative biologics tamp down the harmful
them from the pre-programmed death. This can
processes while amping up the beneficial ones.
reduce the rate of cartilage loss in a joint!
This includes ramping up production of several
helpful growth factors and cytokines, while 6. Preventing scar tissue –Once that scar tissue
tamping down harmful ones. forms, it becomes nonfunctional. Stem Cells and
exosomes are great at preventing scar tissue
(anti-fibrosis).

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Stem Cells can also release a huge variety of Where do the stem cells and exosomes
molecules into the extracellular environment. These come from?
molecules, which include extracellular vesicles
R3 Stem Cell’s regenerative biologics originate from
(exosomes), lipids, free nucleic acids, and soluble
umbilical cord tissue that has been donated after a
proteins, exert crucial roles in repairing damaged
scheduled c-section. No baby (or mother) is harmed
tissue. Along with offering stem cells for treatment
during the c-section procedure. The umbilical cord
of IBD, R3 Stem Cell includes stem cell exosomes,
tissue is normally discarded, but if the mother passes
which are a type of extracellular vesicle participating
screening test then the umbilical cord is immediately
in extensive cell to cell communication for cartilage
sent to the lab.
tissue repair and regeneration.
The lab carefully processes the umbilical cord to
The stem cells administered by R3 are not the
generate large amounts of stem cells and exosomes
ones that become a patient’s new mucosal cell.
that are of the highest quality possible. The lab team
The administered mesenchymal stem cells are
consists of multiple PhD’s working in ISO Certified,
not specifically designed to replace damaged and
cGMP compliant clean rooms to ensure quality
lost cells in the intestines, but rather coordinate
assurance that exceeds USA FDA standards. The
and enhance this repair response by one’s own
proprietary production process combines the highest
mechanisms.
potency, safety and affordability for providers to
confidently offer exosome procedures.

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Millions of dollars have been invested Is stem cell therapy safe?

into the pharmaceutical grade After a decade of performing over
production of the biologics 24,000 stem cell procedures
including first rate clean rooms, worldwide, R3 knows that the
bioreactors, nano-particle regenerative procedures are safe
tracking analyzers, cytometers, at our clinics. The quality control
PCR, tangential flow machines employed during the stem cell
and real time environmental production is second to none, and
monitoring. The quality assurance the side effects R3 sees are usually
testing complies with screening and mild to moderate and temporary.
testing stan¬dards consistent with the
American Association of Tissue Banks, cGMP They may include itching, dizziness,
standards, FDA regulations and the highest level of lightheadedness, low grade fever, chills, headache,
any regulatory agency globally. nausea. These are typically temporary. If a patient
has an allergic reaction to the multivitamin or a
Stem Cell Derived Exosomes preservative, all of R3’s Centers have the medications
to resolve it quickly.
R3 Stem Cell’s Centers of Excellence globally include
umbilical cord stem cell derived exosomes with One of the questions we get asked a lot is, “Will the
umbilical cord stem cells to provide enhanced stem cells get rejected?” The answer is NO.
results. Exosomes are lipid bound vesicles (acellular)
produced by cells which contain a plethora of growth MSCs do not express major histocompatibility
factors, cytokines, mRNA and other proteins. complex (MHC) antigens of the class II subtype and
contain low levels of MHC molecules of the class I
They are exceptionally helpful in cell to cell subtype. MSCs also lack the co-stimulatory molecules
communication, and very effective for reducing essential for immune detection, including CD40, CD80,
inflammation when they become ingested by their and CD86.
recipient cell. They act as shuttles to send nucleic
acids, cytokines, growth factors and proteins to Therefore, MSCs generally have low immunogenicity
the recipient cells, in this way, allowing cell-to-cell and can avoid immune rejection by the recipient,
communication and transporting molecules among which serves as the foundation for their successful
both close and distant cells. application without needing to match the
donor to the recipient. Scientists call this being
As IBD involves significant intestinal inflammation, “immunologically privileged”.
the exosomes will travel there and be ingested
by cells. Then they will release their “payload” and Another question often asked is “Is
facilitate mucosal repair. there a chance of a tumor forming?”
Once again the answer is NO.
Exosomes are most likely the mediators of most The mesenchymal stem cells and
stem cell-associated therapeutic activities. Therefore, exosomes used during treatment
adding them along with the mesenchymal stem cells have never been shown to have
during the therapy acts as a “1-2 punch” for patient tumor forming potentials. In fact, they have been
outcomes shown to be anti-tumor forming.

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Treatment Protocol from elderly donors have decreased proliferation

and differentiation ability. This means they are less in
For the past decade, R3 has been successfully treating
IBD patients with stem cell and exosome infusion number and less effective!
therapy. The cells and exosomes are attracted
to inflammation, which is a large component of
What are the Outcomes?
inflammatory bowel diseases. Similar to the research mentioned above, R3
Stem Cell’s outcomes for IBD patients have been
R3’s providers use between one to three million exceptional! The patient satisfaction rate is 85% year
stem cells per kilogram (depends on severity of over year. Patients typically see exceptional pain
IBD). R3 Stem Cell’s IBD treatment protocol includes relief, less bleeding, less urgency and long term
intravenous mesenchymal stem cells and exosomes complications (e.g. fistulas).
along with a multivitamin. Safety is paramount with
the biologics products being rigorously tested prior to It may take six to twelve weeks for the results to kick
use, and expert providers managing each treatment as in, although we have had patients symptomatically
if you are a family member! feel much better within the first couple of weeks. It
should be noted, again, that stem cell therapy does
Why does R3 Stem Cell use donor tissue for not eliminate IBD, and may need to be repeated every
its stem cells? one to two years.
Although autologous (your own) stem cells provide Affordability
significant advantages, allogeneic (donor) stem cells
have more advantages. First of all, autologous MSCs Because stem cell therapy for IBD
need a long time to culture and expand, which limits is not a “one and done” cure, it’s
its application in treatment, while allogeneic stem cells important to make it affordable.
can be obtained and expanded more quickly, thus Repeat therapies every few years
avoiding the delay of time window. can help people achieve continued
pain relief and functional
Second, age is a factor that improvements. So a lot
affects the physiological of IBD patients seek
characteristics of additional treatments
MSCs. Studies at R3 Stem Cell
have shown every one to two
that stem cells years.

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Unfortunately, stem cell clinics in Colombia, China and 3. Bernardi et al, TRANSPLANTATION OF ADIPOSE-
DERIVED MESENCHYMAL STEM CELLS IN REFRACTORY
Panama charge over $20,000 USD for IBD treatment.
CROHN’S DISEASE: SYSTEMATIC REVIEW, ABCD Arq
Because the one treatment cost so much, how are Bras Cir Dig 2019;32(4):e1465 DOI: /10.1590/0102-
individuals supposed to budget for that every few 672020190001e1465.
years?? R3 Stem Cell’s fees are less than half that for full 4. Shi et al. Stem Cell Research & Therapy (2019) 10:266,
treatment, which also includes free exosomes and a https://doi.org/10.1186/s13287-019-1336-4Mesenchymal
multivitamin infusion! stem cells for the treatment of ulcerative colitis: a
systematic review and meta-analysis of experimental and
R3’s Experience clinical studies
5. Martinez-Montiel et al, Therapy with stem cells in
For the past decade, R3 Stem Cell’s Centers globally
inflammatory bowel disease, World J Gastroenterol 2014
have performed over 24,000 regenerative procedures February 7; 20(5): 1211-1227
in six countries. Over a thousand have been for IBD.
6. Mao et al, Mesenchymal stem cells and their therapeutic
Patient satisfaction across all conditions treated is 85%! applications in inflammatory bowel disease, Oncotarget,
2017, Vol. 8, (No. 23), pp: 38008-38021
R3 combines safety, effectiveness and affordability 7. Eiro, N.; Fraile, M.; González-Jubete, A.; González, L.O.;
for the therapies. Internationally, the Intellicell is used, Vizoso, F.J. Mesenchymal (Stem) Stromal Cells Based as
which is culturing the most active mesenchymal stem New Therapeutic Alternative in Inflammatory Bowel
cells to create the “smartest” stem cell in the world! Disease: Basic Mechanisms, Experimental and Clinical
Evidence, and Challenges. Int. J. Mol. Sci. 2022, 23, 8905.
https://doi.org/10.3390/ijms23168905
R3 Stem Cell offers free consultations for individuals to
discuss whether regenerative therapy is indicated for 8. Kim Y, Can Umbilical Cord Mesenchymal Stem Cells
Treatment Be a Hope for Patients with Refractory Crohn’s
your IBD pain relief. Simply call +1 (844) GET-STEM to Disease?, Gut and Liver, Vol. 12, No. 1, January 2018, pp.
schedule yours! 5-6.
9. Wang Y, Huang B, Jin T,Ocansey DKW, Jiang
References: J and Mao F(2022) Intestinal Fibrosis in
1. Che Z, Ye Z, Zhang X, Lin B, Yang Inflammatory Bowel Disease and the
W, Liang Y and Zeng J (2022) Prospects of Mesenchymal Stem
Mesenchymal stem/stromal Cell Therapy. Front. Immunol.
cells in the pathogenesis 13:835005.doi: 10.3389/
and regenerative therapy fimmu.2022.835005
of inflammatory bowel 10. Zhang et al, Umbilical
diseases. Front. Immunol. Cord Mesenchymal Stem Cell
13:952071. doi: 10.3389/ Treatment for Crohn’s Disease: A
fimmu.2022.952071. Randomized Controlled Clinical
2. Wang et al. Stem cell therapy Trial, Gut and Liver, Vol. 12, No. 1,
for Crohn’s disease: systematic January 2018, pp. 73-78
review and meta‑analysis of
preclinical and clinical studies, Stem Cell
Res Ther (2021) 12:463https://doi.org/10.1186/
s13287-021-02533-0.

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R3 Stem Cell
Kidney/Renal
Guide

Brought to you by

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How common is chronic kidney disease?

The number of individuals affected with chronic 4. Severe with GFR 15-29, anemia and high blood
kidney disease (CKD) is rising worldwide, mainly pressure.
due to a remarkable increase in atherosclerosis, type 5. GFR drops below 15, this is critical.
2 diabetes and high blood pressure. An estimated
8–16% of the general population has CKD, and When symptoms do occur, they may consist of:
its prevalence increases with age to about 30% in
people aged over 70 years (4). u Itching
u Muscle cramps
What does the kidney do?
u Feeling sick and throwing up
The kidneys are critical for so many functions. They
remove waste products and excess fluid from the u Not feeling hungry
body. They control the production of red blood u Lethargic
cells and produce an active form of Vitamin D that
u Swelling in your hands and feet
promotes strong bones. They release hormones that
regulate blood pressure, and remove a lot of drugs u Back pain
from the body. u Urinating (peeing) more or less than normal
All in all, healthy kidneys filter about 200 liters of u Trouble breathing
blood per day. u Trouble sleeping
How does chronic
kidney disease Existing
occur? Treatments
There is no “cure”
High blood pressure
for chronic kidney
and diabetes are the
disease, but patients
two most common
can help themselves
causes of kidney failure.
tremendously with
13% of all US adults
lifestyle changes. These
have CKD. There are
may include ceasing
various medications
smoking, exercising,
which may also
limiting alcohol intake,
lead to CKD, such as
restricting salt intake
chronic use of NSAIDS,
and eating a healthy,
transplant medications,
balanced diet.
diuretics, and others.
Medications are aimed at helping the conditions that
There are five stages of kidney disease as follows:
caused CKD. This may include medications for high
1. Mild disease where the GFR is still over blood pressure, diabetes, high cholesterol, etc.
90 ml/min.
2. Mild with GFR from 60-89. What’s the endgame?
3. Moderate with GFR 30-59. Eventually, CKD patients end up with end stage
disease. This is where the economic burden becomes

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evident. Dialysis is not only expensive, but it’s 4. Cellular signaling – the biologics are able
“annoying” as patients have to devote several days to perform “cell to cell” communication. This
per week, hours at a time, to being hooked up to promotes recipient cells to proliferate their
a machine. The average lifespan of a patient who growth factor production, protein production
begins dialysis ranges from five to ten years. and regenerate tissues that are damaged.
Undergoing a renal transplant is also expensive, 5. Prevent cell death – most cells have a timed
with potential risks that may include rejection. death, where they are only allowed to live a
Patients need to take immune suppression drugs certain length of time. This is called apoptosis.
for life, which opens the possibility to opportunistic The regenerative biologics allow normally
infections. The average wait time for a transplant functioning cells to live longer, and spare them
is 3.5 years, with 13 people dying daily in the USA from the pre-programmed death.
waiting. 6. Preventing scar tissue – CKD patients
experience significant scarring of the kidney
Stem Cell Therapy For CKD parenchyma. Once that scar tissue forms, it
If a new technology such becomes nonfunctional.
as mesenchymal stem cell Stem Cells and exosomes
and exosome therapy could are great at preventing scar
either reverse CKD or slow tissue (anti-fibrosis).
the progression, it would
It’s important to understand
and should become first line
that while stem cells are
therapy.
incredible for improving
Stem cells and exosomes act kidney function, some
in the body through several patients are too far gone.
mechanisms. They do NOT For those whose kidneys
become part of a patient’s have shrunk significantly
DNA, which means they do and the eGFR is below 7,
not engraft into the person’s stem cell therapy is most
existing cells. likely not indicated.

They act through: However, we have seen plenty of patients do great

even while receiving dialysis. Some patients who
1. Angiogenesis – provokes formation of new
haven’t urinated in over a year are able to improve
blood vessels.
to the point of getting off dialysis and urinating just
2. Reduce inflammation – most chronic disease is fine! It’s important to note that outcomes will vary
associated with significant inflammation, and the and are not guaranteed.
regenerative biologics reduce it nicely.
3. Immune system modulation – the stem cells Where do the stem cells and exosomes
and exosomes modulate the immune system come from?
very differently than steroids. Instead of R3 Stem Cell’s regenerative biologics originate from
blanketly suppressing the immune system, the umbilical cord tissue that has been donated after a
regenerative biologics tamp down the harmful scheduled c-section. No baby (or mother) is harmed
processes while amping up the beneficial ones. during the c-section procedure. The umbilical cord

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tissue is normally discarded, but

if the mother passes screening
test then the umbilical cord is
immediately sent to the lab.
The lab carefully processes
the umbilical cord to generate
large amounts of stem cells and
exosomes that are of the highest
quality possible. The lab team
consists of multiple PhD’s working in
ISO Certified, cGMP compliant clean
rooms to ensure quality assurance
that exceeds USA FDA standards.
The proprietary production process
combines the highest potency,
safety and affordability for providers
creatinine from 9 mg/dl to 2 mg/dl. She had started
to confidently offer exosome procedures.
urinating on her own as well, which she wasn’t doing
Millions of dollars have been invested into the at all for the previous two years (1)!
pharmaceutical grade production of the biologics
In a 2016 clinical trial randomizing 40 CKD patients
including first rate clean rooms, bioreactors,
evenly between IV exosomes versus IV saline as a
nano-particle tracking analyzers, cytometers,
control, the participants were followed for a year (2).
PCR, tangential flow machines and real time
While the control group showed no improvements,
environmental monitoring. The quality assurance
the exosome group displayed:
testing complies with screening and testing
stan¬dards consistent with the American Association • eGFR increase from 31 ml/min average to
of Tissue Banks, cGMP standards, FDA regulations and 47 ml/min.
the highest level of any regulatory agency globally.
• Creatinine reduced from 3.4 average to 2.2.
Is there research to back up stem cell and
In a 2014 Chinese study evaluating 81 patients with
exosome therapy for chronic kidney disease? renal failure secondary to lupus, the participants were
Absolutely! There are too many studies to mention treated with umbilical cord mesenchymal stem cells
all of them in this guide, but we’ll touch on some at 1 million/kg. Sixty one percent of the participants
compelling ones. achieved remission for the year. GRF increased from
an average of 59 to 70 ml/min. There were no adverse
In 2017, a 62 year old Indonesian woman with
events, and patients routinely were able to taper
chronic kidney disease on hemodialysis underwent
both steroid and immunosuppressive drugs.
umbilical cord mesenchymal stem cell therapy. Prior
to treatment, her creatinine level was 11 mg/dl. In a stem cell review for kidney disease published by
USC, the authors noted an excellent reduction of BUN
After treatment with approximately 180 million
and improved glomerulosclerosis after MSC therapy in
umbilical cord stem cells, her creatinine dropped
several studies (4). Their review showed no significant
to 9mg/dl within 3 weeks. After a few months, she
adverse events in any study.
received a second treatment which dropped her

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R3’s experience with stem cell and exosome therapy Exosomes could be the mediators of many stem cell-
for CKD has been similar to these results. In the vast associated therapeutic activities. Considering they are
majority of patients, improvements in eGFR, creatinine, 100 times smaller than stem cells, they
BUN and quality of life are seen. Patients report do not have any issues passing through
increased energy, renewed vitality and are amazed the lungs to reach the kidneys from the
that their labs actually improve while traditional bloodstream
treatments are failing.
Is stem cell therapy safe?
References: After a decade of performing over
1. Improvement of renal function after human umbilical 23,000 stem cell procedures worldwide, R3 knows
cord mesenchymal stem cell treatment on chronic renal that the regenerative procedures are safe. The quality
failure and thoracic spinal cord entrapment: a case report. control employed during the stem cell production
Rahyussalim et al. Journal of Medical Case Reports (2017) is second to none, and the side effects R3 sees are
2. Umbilical cord mesenchymal stem cells derived usually mild to moderate and temporary.
extracellular vesicles can safely ameliorate the
progression of chronic kidney diseases, Nassar et al. They may include itching, dizziness, lightheadedness,
Biomaterials Research (2016) low grade fever, chills, headache, nausea. These are
3. Allogeneic mesenchymal stem cell transplantation typically temporary. If a patient has an allergic reaction
for lupus nephritis patients refractory to conventional to the multivitamin or a preservative, all of R3’s Centers
therapy, Gu et al, Clin Rheumatol (2014).
have the medications to resolve it quickly.
4. Mesenchymal Stem Cell-Based Therapy for Kidney
Disease: A Review of Clinical Evidence, Peired et al, Stem One of the questions we get asked a lot is, “Will the
Cells Int. 2016. stem cells get rejected?” The answer is NO, as the
stem cells do not have MHC 2 markers. Those are the
Stem Cell Derived Exosomes ones that would cause an immunologic reaction. But
R3 Stem Cell’s Centers of Excellence globally include they are not there, so the cells are “immunologically
umbilical cord stem cell derived exosomes with privileged.”
umbilical cord stem cells to provide enhanced
results. Exosomes are lipid bound vesicles
(acellular) produced by cells which contain a
plethora of growth factors, cytokines, mRNA
and other proteins.
They are exceptionally helpful in cell to cell
communication, and very effective for reducing
inflammation when they become ingested by
their recipient cell. They act as shuttles to send
nucleic acids and proteins to other cells, in this
way, allowing cell-to-cell communication and
transporting molecules among both close
and distant cells. In general, these released
proteins are important regulators of intracellular
information.

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So, for example,

if a person has
CKD secondary to
diabetes, the cells
and exosomes
will also go to the
pancreas to assist
with function
there too. There
are Centers that
promote injections
directly into the
kidney, or renal
artery/vein. This is
not necessary and
entails additional
risk!
R3’s providers
will calculate the
amount of stem
cells based on
Another question often asked is “Is there a chance of patient weight and CKD severity. It will range from
a tumor forming?” Once again the answer is NO. The 1 to 3 million stem cells/kg. Depending on the total
mesenchymal stem cells and exosomes used during amount, treatment may need to be broken up into
treatment have never been shown to have tumor two sessions, three at the most for optimal safety.
forming potentials. In fact, they have been shown to
be anti-tumor forming. R3 Stem Cell’s renal disease protocols are based
on the latest research along with Best Practice
Protocol Protocols developed over the past decade to help
patients achieve the best outcomes possible. Safety
For the past decade, R3 has been successfully
is paramount with the biologics products being
treating CKD patients with IV stem cell and exosome
rigorously tested prior to use, and expert providers
therapy. The cells and exosomes are attracted to
managing each treatment as if it was a family member!
inflammation, which is a large component of CKD. So
they will go predominantly to the kidney, but also, to
areas that are experiencing disease as well.

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Affordability R3’s Experience

Because stem cell therapy for CKD is not a permanent For the past decade, R3 Stem Cell’s Centers globally
cure, it’s important to make it affordable. Repeat have performed over 23,000 regenerative procedures
therapies can help maintenance and/or achieve in six countries. Over a thousand have been for CKD.
additional improvements for CKD. So a lot of patients Patient satisfaction across all conditions treated is 85%!
seek additional treatments at R3 Stem Cell every six
to eighteen months. R3 combines safety, effectiveness and affordability
for the autism therapies. Internationally, the
Unfortunately, stem cell clinics in Colombia, China Intellicell is used, which is culturing the most active
and Panama charge over $20,000 USD for CKD mesenchymal stem cells to create the “smartest” stem
treatment. Because the one treatment cost so much, cell in the world!
how are individuals supposed to budget for that R3 Stem Cell offers free consultations for individuals
every year?? R3 Stem Cell’s fees are less than half that to discuss whether regenerative therapy is indicated
for 100 million high quality stem cells! for their CKD. Simply call +1 (844) GET-STEM or +1
(480) 808-7057 to schedule yours!

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Guide to
Stem Cell Therapy
for Liver Failure

Brought to you by

* No portion of this Document may be reproduced without the Express Written Consent of R3 Stem Cell.

159
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 GUIDE TO STEM CELL THERAPY FOR LIVER FAILURE

Guide to Stem Cell Therapy for Liver Failure

Every day, R3 Stem Cell receives inquiries worldwide Less common liver pathologies that can lead to
from individuals asking if stem cell therapy can help the development of the end-stage liver disease
with liver failure. Spoiler alert: It can help a lot! In this include autoimmune hepatitis, primary biliary
guide, we’ll go through the basics of how stem cells cirrhosis, primary sclerosing cholangitis, and
work for the liver, the latest research, and what to hemochromatosis-associated cirrhosis. With the
expect with a regenerative procedure. aggravation of liver fibrosis, the body’s dysfunction
would eventually develop into cirrhosis,
Unlike having two kidneys, humans and even liver cancer.
are only blessed with one liver.
It’s the heaviest organ in Traditional therapies for
one’s body, and it’s the end-stage liver disease
ONLY organ in the body are basically just
that can regenerate symptomatic and only
itself. In fact, you can organ transplantation
actually remove up can considerably help
to 70% of the liver patients with cirrhosis.
and the rest will Only a small number
regenerate! of people, though,
receive transplantation
Because of this, there due to economic and
is a higher potential for social circumstances.
stem cells to facilitate actual Immunosuppressive medications
regeneration of the organ. Like need to be taken afterwards for life,
a lizard’s tail, stem cell therapy has the and there’s always the chance of rejection
potential to facilitate regrowth of diseased and anyway.
nonfunctioning parts of one’s liver.
A Significant Global Issue What does it do??
Chronic liver diseases represent a substantial With the liver serving critical roles in the human body,
economic and social problem worldwide. Estimates it’s important to keep it functioning properly. The
show that over 800 million people around the globe liver stores, produces, excretes, detoxifies and purifies
suffer with chronic liver diseases and about 2 million substances including the following:
of them die annually. u Bile production and excretion
Cirrhosis is the end-stage of chronic liver disease u Excretion of bilirubin, cholesterol, hormones,
(CLD). Cirrhosis stays asymptomatic for a long time and drugs
in most people, which leads to late diagnosis of CLD. u Metabolism of fats, proteins, and
Chronic liver disease is the 14th most common global
carbohydrates
cause of death in adults.
u Storage of glycogen, vitamins, and minerals
The major causes of cirrhosis are chronic liver
u Synthesis of plasma proteins, such as
damage, such as infection with hepatitis C and
albumin, and clotting factors
B viruses (HCV and HBV), alcoholic liver disease,
and non-alcoholic fatty liver disease (NAFLD). u Blood detoxification and purification

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What are the reasons a liver might fail? Overall, liver failure typically follows several
The liver may experience failure due to a number of consistent steps. Initially, chronic inflammation is
reasons, some of which are preventable, while others involved, similar to other diseases. Then, fibrosis
involve genetics. Globally, chronic alcohol abuse is occurs, which is where scar tissue leads to inability of
a leading cause of liver failure. Over-using certain the liver to properly perform its many functions. As a
prescription medications or herbal compounds may result of significant scarring, liver cirrhosis sets in. As
lead to issues as well. this progresses, people head into end-stage failure.

Here is a list of other issues: What are the symptoms of liver failure?
• Infectious Long-term liver injury gradually results in the loss
of liver function and accumulation of extracellular
o Hepatitis A, B & C
matrix (ECM), leading to the occurrence of liver
• Immune System fibrosis. The end stage of liver fibrosis is cirrhosis,
o Autoimmune Hepatitis and patients with decompensated cirrhosis
develop multiple complications; the most common
o Primary Biliary Cholangitis
clinical manifestations are ascites and
o Primary Sclerosing gastroesophageal variceal bleeding.
Cholangitis
Late complications include
• Genetics
jaundice, coagulopathy,
o Hemochromatosis hepatic encephalopathy,
o Wilson’s Disease acute kidney injury, and
o Alpha-1 hepatorenal syndrome (HRS).
Antitrypsin Deficiency With traditional treatments
only managing symptoms,
• Cancer most patients die within a
o Liver Cancer median time of approximately
o Bile Duct Cancer 2 years without receiving a
transplant.
o Liver Adenoma
Traditional Treatments
Various risk factors have been shown to elevate
Conventional therapies for liver failure are not great,
one’s chances of experiencing liver disease. These
to put it mildly. If a person is an alcoholic, obviously
include heavy alcohol intake over a long period of
front line therapy is to cease intake, which should be
time, obesity and Type 2 diabetes, family history of
accomplished under a physician’s supervision. Weight
liver disease, and exposure to certain chemicals or
loss is recommended for obese patients along with
toxins.
consuming a healthy, balanced diet.
When it comes to hepatitis specifically, risks include
Certain medications may be indicated, such as
injecting drugs with shared needles, being exposed
blood pressure medicine or a diuretic. But no
to people’s blood and body fluids, having a tattoo or
medications have been shown to actually directly
body piercing, unprotected sex and having a blood
improve liver function, much less reverse the liver
transfusion prior to 1992.
damage.

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When a person has kidney failure, dialysis may

be implemented to help replace the kidney
function. There is no such machine to assist
with liver function. If a patient suffers
from portal hypertension, a TIPS
procedure (Transjugular intrahepatic
portosystemic shunt (TIPS) may
help considerably by creating new
connections between two blood
vessels in your liver. R3 Stem Cell
has had several patients get OFF
liver transplant lists by undergoing
regenerative therapies in conjunction
with TIPS procedures!
Those who have end-stage liver failure may be put
onto a transplant list. The cost of a liver transplant
in the USA has been reported to be over $800,000 the person’s existing cells.
USD, with an average wait time being 240 days. They act through:
Worldwide, there are significant exclusions to
getting on the list. It’s actually rare for someone over 1. Angiogenesis – provokes formation of new
the age of 70 to be offered a liver transplant. blood vessels.
2. Reduce inflammation – chronic liver disease is
Stem Cell Therapy for Liver Failure associated with significant inflammation, and the
If a new technology such as mesenchymal stem cell regenerative biologics reduce it nicely.
and exosome therapy could either reverse liver failure 3. Immune system modulation – the stem cells
or slow the progression, it would and should become and exosomes modulate the immune system
first line therapy. Remember, unlike the kidneys, very differently than steroids. Instead of
the liver can regenerate. Therefore, a regenerative blanketly suppressing the immune system, the
therapy that can initiate restoration of liver function regenerative biologics tamp down the harmful
and is a safe option should receive consideration. processes while amping up the beneficial ones.
Although liver transplantation is still a viable option This includes ramping up production of several
for many people globally, there are several limitations helpful growth factors and cytokines, while
including a lack of donor organs, immune rejection, tamping down harmful ones.
and postoperative complications. As a result, 4. Cellular signaling – the biologics are able
there is a definite need NOW for a different type of to perform “cell to cell” communication. This
therapeutic approach. Recent research has shown promotes recipient cells to proliferate their
that the administration of mesenchymal stem cells growth factor production, protein production
(MSCs) is an attractive treatment option for repairing and regenerate tissues that are damaged.
liver injury and enhancing regeneration. 5. Prevent cell death – most cells have a timed
Stem cells and exosomes act in the body through death, where they are only allowed to live a
several mechanisms. They do NOT become part of a certain length of time. This is called apoptosis.
patient’s DNA, which means they do not engraft into

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pharmaceutical grade production of the biologics

The regenerative biologics allow normally
including first rate clean rooms, bioreactors, nano-
functioning cells (i.e. hepatocytes) to live longer,
particle tracking analyzers,
and spare them from the pre-programmed
cytometers, PCR, tangential
death.
flow machines and real
6. Preventing scar tissue – – Liver failure patients time environmental
experience significant scarring throughout the monitoring. The quality
organ. Once that scar tissue forms, it becomes assurance testing complies
nonfunctional. Stem Cells and exosomes are with screening and testing
great at preventing scar tissue (anti-fibrosis). standards consistent with the American Association
of Tissue Banks, cGMP standards, FDA regulations and
MSCs can also release a huge variety of molecules the highest level of any regulatory agency globally.
into the extracellular environment. These molecules,
which include extracellular vesicles, lipids, free Is there research to back up stem cell and
nucleic acids, and soluble proteins, exert crucial roles exosome therapy for liver disease?
in repairing damaged tissue. Along with offering
MSCs for treatment of liver failure, R3 Stem Cell Numerous clinical trials worldwide have shown
includes stem cell exosomes, which are a type of that stem cells for liver failure display exceptional
extracellular vesicle participating in extensive cell outcomes. In a study of 45 chronic hepatitis B
to cell communication for liver tissue repair and patients with decompensated liver cirrhosis (LC),
regeneration. there was a significant reduction in the volume
of ascites in patients treated with Umbilical Cord
Where do the stem cells and exosomes Mesenchymal Stem Cell (UC‐MSC) transfusion when
come from? compared to controls.

R3R3 Stem Cell’s regenerative biologics originate In addition, UC‐MSC therapy also significantly
from umbilical cord tissue that has been donated improved liver function, as indicated by the increase
after a scheduled c-section. No baby (or mother)
is harmed during the c-section procedure. The
umbilical cord tissue is normally discarded, but if the
mother passes screening test then the umbilical cord
is immediately sent to the lab.
The lab carefully processes the umbilical
cord to generate large amounts of stem
cells and exosomes that are of the highest
quality possible. The lab team consists of
multiple PhD’s working in ISO Certified, cGMP
compliant clean rooms to ensure quality
assurance that exceeds USA FDA standards.
The proprietary production process combines
the highest potency, safety and affordability for
providers to confidently offer exosome procedures.
Millions of dollars have been invested into the

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per kilogram of allogeneic MSCs weekly,

for 4 weeks, and were followed
up for 24 weeks. Compared
with the control group,
the allogeneic MSC
treatment markedly
improved the
clinical laboratory
measurements,
including the
serum total
bilirubin and
MELD scores.

In the largest long

term study of its kind
looking at stem cell
therapy for liver failure
due to Hepatitis B, Zheng et
al enrolled 219 patients with HBV-
related decompensated liver cirrhosis into
a prospective, open-labeled, randomized controlled
in serum albumin levels, decrease in total serum study. Participants were divided into control group
bilirubin levels, and decrease in the sodium model for (n = 111) and umbilical cord-derived MSC (UC-MSC)-
MELD scores. treated group (n = 108). After treatment, participants
received follow-up checks for seven years. The
A total of 43 acute‐on‐chronic liver failure (ACLF) treated patients received three UC-MSC infusions at
patients were associated with hepatitis B virus (HBV) 4-week intervals plus conventional treatment that
infection in another clinical trial published in 2012 was only used for control group.
out of China. The UC‐MSC transfusions significantly
increased the survival rates in ACLF patients,
Stem Cell Derived Exosomes
reduced the MELD scores, increased the serum
albumin, cholinesterase and prothrombin activity, R3 Stem Cell’s Centers of Excellence globally include
and increased the platelet count. Furthermore, the umbilical cord stem cell derived exosomes with
serum total bilirubin and alanine aminotransferase umbilical cord stem cells to provide enhanced
levels significantly decreased after the UC‐MSC results. Exosomes are lipid bound vesicles (acellular)
transfusions. produced by cells which contain a plethora of growth
factors, cytokines, mRNA and other proteins.
From 2010 to 2013, 110 patients with HBV‐related
acute‐on‐chronic liver failure were enrolled in this They are exceptionally helpful in cell to cell
open‐label, nonblinded randomized controlled communication, and very effective for reducing
study by Bing‐Liang et al published in Journal of inflammation when they become ingested by their
Translational Medicine. The experimental group recipient cell. They act as shuttles to send nucleic
(n = 56) was infused with one million stem cells acids and proteins to other cells, in this way, allowing

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cell-to-cell communication and transporting but they don’t all stay there. After 12-24 hours,
molecules among both close and distant cells. In the vast majority are released to go to areas with
general, these released proteins are important inflammation, such as a failing liver.
regulators of intracellular information.
So, for example, if a person has liver failure secondary
Exosomes could be the mediators of many stem cell- to diabetes, the cells and exosomes will also go to
associated therapeutic activities. Considering they the pancreas to assist with function there too. There
are 100 times smaller than stem cells, they do not are Centers that promote injections directly into the
have any issues passing through the lungs to reach liver, or hepatic artery/vein. This is not necessary and
the liver from the bloodstream. entails additional risk!

Protocol R3’s providers will calculate the amount of stem cells

based on patient weight and liver failure severity.
For the past decade, R3 has been successfully treating
It will range from 1 to 3 million stem cells/kg.
liver failure patients with IV stem cell and exosome
Depending on the total amount, treatment may need
therapy. The cells and exosomes are attracted to
to be broken up into two sessions, three at the most
inflammation, which is a large component of liver
for optimal safety.
failure. So they will go predominantly to the
liver, but also, to areas that are experiencing
R3 Stem Cell’s liver disease protocols are based
disease as well.
on the latest research along with Best Practice
Protocols developed over the past decade
Some people ask us, “I heard the stem cells
to help patients achieve the best outcomes
get caught in the lungs and die, is that true?”
possible. Safety is paramount with the biologics
The answer is mesenchymal stem cells do
products being rigorously tested prior to use,
often temporarily get caught up in the lungs,

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 GUIDE TO STEM CELL THERAPY FOR LIVER FAILURE

and expert providers managing each treatment as if that every year?? R3 Stem Cell’s fees are less than half
it was a family member! that for 100 million high quality stem cells!

Outcomes R3’s Experience

Similar to the research mentioned above, R3 For the past decade, R3 Stem Cell’s Centers
Stem Cell’s outcomes for liver failure globally have performed over 23,000
have been exceptional! The patient regenerative procedures in six
satisfaction rate is 85% year over countries. Several hundred have
year. Patients typically see been for liver failure. Patient
increased energy, cognition, satisfaction across all conditions
reduced ascites and treated is 85%!
improved function. R3 combines safety,
In addition, just like the effectiveness and affordability
research studies R3 sees for the therapies. Internationally,
improvements in the vast the Intellicell is used, which
majority of patients with regards is culturing the most active
to liver function tests, albumin levels, mesenchymal stem cells to create the
cholinesterase and prothrombin activity, and “smartest” stem cell in the world!
increased the platelet count. Furthermore, the serum R3 Stem Cell offers free consultations for individuals to
total bilirubin and alanine aminotransferase levels discuss whether regenerative therapy is indicated for
typically decrease significantly after the UC‐MSC their liver disease. Simply call +1 (844) GET-STEM or +1
transfusions. (480) 808-7057 to schedule yours!
It may take several months to see all of the
improvements, although we have had patients References:
symptomatically feel much better within the first 1. 1. Mesenchymal Stem Cells in the Adult Human Liver: Hype
or Hope?,Irina V. Kholodenko Cells 2019, 8, 1127.
couple of weeks. It should be noted, again, that stem
cell therapy is not a cure for chronic liver disease, and 2. Mesenchymal stromal cells: promising treatment for liver
cirrhosis, Yao et al. Stem Cell Research & Therapy (2022)
will need to be repeated every 6 to 12 months for 13:308.
continued benefit.
3. The role of mesenchymal stem cells in liver injury, Sun et al,
Cell Biol Int. 2022;46:501–511.
Affordability
4. Human mesenchymal stem cell transfusion is safe
Because stem cell therapy for liver and improves liver function in acute-on-chronic liver
failure is not a permanent cure, it’s failure patients, Shi et al, Stem Cells Transl Med, 2012
important to make it affordable. Repeat Oct;1(10):725-31.
therapies can help maintenance and/or achieve 5. Clinical performance of stem cell therapy in patients with
additional improvements for the liver. So a lot of acute-on-chronic liver failure: a systematic review and
patients seek additional treatments at R3 Stem Cell meta-analysis, Xue et al, J Transl Med. 2018; 16: 126.
every six to eighteen months. 6. Mesenchymal stem cell therapy in decompensated liver
cirrhosis: a long‑term follow‑up analysis of the randomized
Unfortunately, stem cell clinics in Colombia, China controlled clinical trial, Shi et al, Hepatology International
and Panama charge over $20,000 USD for liver (2021) 15:1431–1441.
disease treatment. Because the one treatment cost
so much, how are individuals supposed to budget for

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One of the questions we get asked a lot is, “Will the Affordability
stem cells get rejected?” The answer is NO.
Because stem cell therapy for Lyme
MSCs do not express major histocompatibility complex Disease is not typically a permanent
(MHC) antigens of the class II subtype and contain low cure, it’s important to make it affordable.
levels of MHC molecules of the class I subtype. MSCs Repeat therapies can help maintenance and/or
also lack the co-stimulatory molecules essential for achieve additional improvements for pain relief. So a
immune detection, including CD40, CD80, and CD86. lot of patients seek additional treatments at R3 Stem
Therefore, MSCs generally have low immunogenicity Cell every twelve to eighteen months.
and can avoid immune rejection by the recipient, R3 Stem Cell’s fees are less than half what comparable
which serves as the foundation for their successful (and reputable) regenerative clinics charge. Be wary
application without needing to match the donor to the of clinics trying to pass off PRP as a stem cell therapy.
recipient. Scientists call this being “immunologically If they mention only taking your blood for the
privileged”. treatment, it is NOT a stem cell treatment!
Another question often asked is “Is there a chance of a
tumor forming?” Current research has concluded that R3’s Experience
the answer is NO. The mesenchymal stem cells and For the past decade, R3 Stem Cell’s Centers globally have performed
exosomes used during treatment have never been over 25,000 regenerative procedures in six countries. Patient
shown to have tumor forming potentials. In fact, they satisfaction across all conditions treated is 85%!
have been shown to be anti-tumor forming.
R3 combines safety, effectiveness and affordability for the therapies.
Protocol Internationally, the Intellicell is used, which is culturing the most active
For the past decade, R3 has been mesenchymal stem cells to create the “smartest” stem cell in the world!
successfully treating Lyme Disease with R3 Stem Cell offers free consultations for individuals to discuss whether
stem cell and exosome procedures. regenerative therapy is indicated for their Trigeminal Neuralgia. Simply
The regenerative biologics are applied
depending on the person’s symptoms. call +1 (844) GET-STEM or +1 (888) 988-0515 to schedule yours!
R3 may incorporate direct injections, intravenous Disclaimer: This guide’s education does not constitute medical advice. The USA FDA
application and maybe intrathecal too. considers stem cell therapy experimental. Any claims made in this Guide refer to
procedures performed outside of the USA.
R3’s providers use one to two million stem cells per
kilogram, to make sure that patients achieve the References:
absolute best outcome possible. Between 50 and 100
billion exosomes are included with each procedure. 1. Geeta Shroff, Transplantation of Human Embryonic Stem Cells
in Patients with Multiple Sclerosis and Lyme Disease, Am J Case
Outcomes Rep, 2016; 17: 944-949
Similar to the research mentioned above, R3 2. Horowitz et al, Improvement of common variable
Stem Cell’s outcomes for Lyme Disease have been immunodeficiency using embryonic stem cell therapy in a
exceptional! The patient satisfaction rate is 85% year patient with lyme disease: a clinical case report, Clinical Case
over year. Patients typically experience less pain and Reports 2018; 6(6): 1166–1171
fatigue, along with improved mental clarity and less 3. Geeta Shroff, Single-photon emission tomography imaging
brain fog. Keep in mind results cannot be guaranteed in patients with Lyme disease treated with human embryonic
and will vary between individuals. stem cells, Neuroradiol J. 2018 Apr; 31(2): 157–167

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 R3 Consumer Guide for Stem Cell and Exosome Therapy

Guide to
Stem Cell and
Exosome Therapy
for Systemic Lupus
Erythematosus

Brought to you by

* No portion of this Document may be reproduced without the Express Written Consent of R3 Stem Cell.
Disclaimer: This guide’s education does not constitute medical advice. The USA FDA considers stem cell
therapy experimental. Any claims made in the Guide refer to procedures performed outside the USA.
168
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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR SYSTEMIC LUPUS ERYTHEMATOSUS

Guide to Stem Cell and Exosome Therapy

for Systemic Lupus Erythematosus
Every day, R3 Stem Cell receives inquiries worldwide in multiple organs, including blood vessels, joints,
from individuals asking if stem cell therapy can help kidneys, and skin.
for Systemic Lupus Erythematosus (SLE). Spoiler alert:
It can help a lot! In this guide, we’ll go through the Renal involvement, termed lupus nephritis (LN),
basics of how stem cells and exosomes work for the occurs in approximately 50–60% of the patients
autoimmune disease, the latest research, and what to and remains one of the most serious visceral
expect with a regenerative procedure. complications in SLE. Men with SLE tend
to have more aggressive disease
Conventional treatments for SLE with higher rates of renal and
are not able to regenerate and cardiovascular involvements and
repair joint tissue significantly. are more likely to develop kidney
They are very limited and mostly failure than women.
“band aids.” For example, steroid
injections do not repair joint tissue What are the symptoms of
at all, and actually contribute to more SLE?
joint degeneration. The patients with SLE may present with
Stem cell therapy for SLE is turning out to be an various systemic manifestations. The general
excellent opportunity for individuals to achieve pain symptoms include: fever, malaise, arthralgias,
relief, improved function and to potentially achieve myalgias, headache, and loss of appetite and weight.
long lasting remission. Let’s dig in! Nonspecific fatigue, fever, arthralgia, and weight
changes are the most common symptoms in new
What happens during SLE? cases or recurrent active SLE flares.
Lupus is a lifelong disease that can cause pain, SLE affects the immune system, thus reducing the
redness, and swelling in any part of the body. The body’s ability to prevent and fight infection. In
Lupus Foundation of America estimates that 1.5 addition, many of the drugs used to treat SLE also
million Americans, and at least five million people suppress the function of the immune system, thereby
worldwide, have a form of lupus. Anyone can develop further depressing the ability to fight infection. The
lupus, but 90% of lupus diagnoses are in women most common infections involve the respiratory tract,
aged 15-44 years. urinary tract, and skin. Other opportunistic infections,
particularly Salmonella, herpes zoster, and Candida
Some people call lupus an “invisible illness” because it infections, are more common in patients with SLE
is often not recognizable to others. The mechanisms because of altered immune status.
underlying the cause of SLE remain unclear.
Joint pain is one of the most common reasons for
Systemic lupus erythematosus (SLE) is a life- the initial clinical presentation in patients with
threatening autoimmune inflammatory disease SLE. Arthralgia, arthritis, osteonecrosis (avascular
involving a variety of autoantibodies, which are necrosis of bone), and myopathy are the principal
produced by overactivated B cells and circulate in manifestations. Arthritis and arthralgias have been
peripheral blood or deposit in organs [1]. Deposition noted in up to 95 percent of patients with SLE.
of autoantibodies triggers the formation of immune Cutaneous manifestations of SLE comprise four
complexes and then leads to tissue inflammation

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diagnostic criteria and multiple other Traditional Treatments

clues to a potential diagnosis of
Currently, the classic methods
lupus. The first is malar rash,
for SLE treatment are
which is characterized by an
corticosteroids and
erythematous rash over the
immunosuppressors, which
cheeks and nasal bridge. It
chronically prolong the
lasts from days to weeks and
disease course and mostly
is occasionally painful or
exhibit chronic remission-
pruritic.
relapse, whereas a few
The second feature is patients achieve long-term
photosensitivity, which may be remission.
elicited from patients who are asked
Importantly, immunosuppressive
if they have any unusual rash or symptom
therapies fail to prevent disease relapse in more
exacerbation after sun exposure. The third feature
than half of the patients, and high-dose treatment
may be discoid rash. Discoid lesions often also
may even increase the risk of severe infection and
develop in sun-exposed areas but are plaque like
death. Additionally, most patients exhibit damage
in character, with follicular plugging and scarring.
to the kidneys or other organs, partly limiting the
They may be part of systemic lupus or may represent
application of immunosuppressive therapy.
discoid lupus without organ involvement, which is a
separate diagnostic entity. In the past 60 years, belimumab has been the only
Alopecia is the fourth and often less-specific biological agent approved by the US FDA for SLE
cutaneous feature of SLE. It often affects the temporal treatment; however, this agent utilizes a single
regions or creates a patch like pattern of hair loss. target and cannot inhibit plasma cells and switched
memory B cells. Also, other biological agents, such as
The kidney is the most commonly involved visceral tabalumab, do not significantly improve the disease
organ in SLE. Although only approximately 50% of conditions and even have adverse side effects in
patients with SLE develop clinically evident renal patients with SLE.
disease, biopsy studies demonstrate some degree of
renal involvement in almost all patients. Renal failure Corticosteroids and cyclophosphamide (CTX)
and sepsis are two main causes of death in patients and mycophenolate mofetil (MMF) are the most
with SLE. classically and widely administered medications,
which have led to a signifi¬cant improvement in
Common manifestations may include arthralgias
survival over the last few decades and decreased the
and arthritis, malar and other skin rashes, pleuritis
progression to end-stage multi-organ failure.
or pericarditis, renal or CNS involvement, and
hematologic cytopenias. Disease severity is wide In addition to conventional immunosuppressive
ranging, SLE can present major challenges because therapies, several new strategies have been
of accrued organ damage, coagulation defects. SLE developed to target specif¬ic activation pathways
is characterized by an autoantibody response to relevant to SLE pathogenesis,[1] such as rituximab
nuclear and cytoplasmic antigens. It is potentially (B-cell depleting therapy), epratuzumab (B-cell
fatal depending on organ involvement. modulating therapy), belimumab (inhibition of B-cell
survival), abatacept and toralizumab (inhibition of
T-cell function), to-cilizumab (IL-6 inhibition), and
sifalimumab and rontalizumab (type I interferon

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inhibitors). Although these drugs have led to a

markedly improved outcome in SLE, disease control
remains unsatisfactory in a subset of patients.
Moreover, use of these agents often leads to
serious adverse effects or re¬lapses after
discontinuation.
Aside from the poor efficacy, long-term
usage of nonspecific immunosuppressive
regimens may increase the risk of serious
infection and secondary malignant tumors;
besides, because of its high cost, the use of
biological agents is also limited.

Stem Cell Therapy for SLE

If a new technology such as mesenchymal stem cell A 2014 study from China by Wang et al looked
and exosome therapy could improve the quality of at forty patients with active SLE were recruited
life for SLE patients, achieve remission and avoid the from four clinical centers. Donor umbilical cord
secondary complications and risky side effects, it mesenchymal stem cells were infused intravenously
would and should become first line therapy. on days 0 and 7. The primary endpoints were safety
profiles.
Here is a rundown of research outcomes worldwide
regarding stem cell therapy for SLE. The secondary endpoints included major clinical
response (MCR), partial clinical response (PCR) and
Guo et al performed a meta-analysis in 2018 to see relapse. Clinical indices, including Systemic Lupus
if stem cell therapy worked well for SLE. A meta- Erythematosus Disease Activity Index (SLEDAI) score,
analysis involves compiling available research studies and renal functional indices, were also taken into
and combining them for statistical evaluation. Eight account.
studies involving 213 patients were included and
The stem cells were well tolerated, and no
three of the studies were randomized controlled trials
transplantation-related adverse events were
with 66 patients involved.
observed. Thirteen and eleven patients achieved
The MSC group showed that the SLE disease activity MCR (13 of 40, 32.5%) and PCR (11 of 40, 27.5%),
index decreased significantly [standard mean respectively, during 12 months of follow up. Three
difference (SMD)=-1.76, 95% confidence interval and four patients experienced disease relapse at 9
(CI):-2.00 to -1.51, P<0.001), the 24 h urine protein months (12.5%) and 12 months (16.7%) of follow-up,
decreased significantly (SMD=-1.74, 95%CI:-2.46 respectively, after a prior clinical response. SLEDAI
to -1.03, P<0.001), as well as the complement C3 scores significantly decreased at 3, 6, 9 and 12
increased significantly (SMD=1.28, 95%CI: 0.93 to months follow-up.
1.62, P<0.001). Among those patients with lupus nephritis, 24-hour
The conclusion was the current evidences proteinuria declined after transplantation, with
showed that mesenchymal stem cells could statistically differences at 9 and 12 months. Serum
improve the disease activity, proteinuria and creatinine and urea nitrogen decreased to the lowest
hypocomplementemia in SLE patients. level at 6 months, but these values slightly increased
at 9 and 12 months in seven relapse cases.

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In addition, serum levels of albumin and complement Additionally, the doses of concomitant prednisone
3 increased after MSCT, peaked at 6 months and then and immunosuppressive drugs were tapered. No
slightly declined by the 9- and 12-month follow- transplantation-related adverse event was observed.
up examinations. Serum antinuclear antibody and Allogeneic MSCT resulted in renal remission for active
anti-double-stranded DNA antibody decreased after LN patients within 12-month visit, confirming its use
MSCT, with statistically significant differences at as a potential therapy for refractory LN.
3-month follow-up examinations.
In a 2013 study by Wang et al, eighty-seven patients
The authors noted in conclusion that umbilical with persistently active SLE who were refractory to
cord mesenchymal stem cell therapy resulted standard treatment or had life-threatening visceral
in satisfactory clinical response in SLE patients. involvement were enrolled. Umbilical cord-derived
However, they had several patients experience MSCs were infused intravenously (1 × 10(6) cells/kg
disease relapse after 6 months, indicating the of body weight).
potential necessity to repeat mesenchymal stem cell
During the 4-year follow-up and with a mean follow-
therapy after 6 months.
up period of 27 months, complete clinical remission
In another 2014 study out of China, 81 patients rate was 28% at 1 year (23/83), 31% at 2 years (12/39),
with active and refractory lupus nephritis (LN) were 42% at 3 years (5/12), and 50% at 4 years (3/6). Rates
enrolled. Umbilical cord-derived mesenchymal stem of relapse were 12% (10/83) at 1 year, 18% (7/39) at 2
cells (MSCs) were administered intravenously at the years, 17% (2/12) at 3 years, and 17% (1/6) at 4 years.
dose of 1 million cells per kilogram of bodyweight.
The overall rate of relapse was 23% (20/87). Disease
During the 12-month follow-up, 60.5 % (49/81) of the activity declined as revealed by significant changes
patients achieved renal remission. Eleven of 49 (22.4 in the SLEDAI score, levels of serum autoantibodies,
%) patients experienced renal flare by the end of 12 albumin, and complements. No transplantation-
months after a previous remission. related adverse event was observed. Allogeneic
Glomerular filtration rate (GFR) improved significantly MSCT resulted in the induction of clinical remission
12 months after MSCT (mean ± SD, from 58.55 ± and improvement in organ dysfunction in drug-
19.16 to 69.51 ± 27.93 mL/min). Total disease activity resistant SLE patients.
evaluated by Systemic Lupus Erythematosus Disease In the diagram below, you can see how mesenchymal
Activity Index (SLEDAI) scores also decreased after stem cells modulate the immune system cells to
treatment (mean ± SD, from 13.11 ± 4.20 at baseline effectively work against SLE to improve a patients’
to 5.48 ± 2.77 at 12 months). energy, vitality, sleep patterns, relieve pain and
promote remission.

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Stem cells and exosomes act in the body through several mechanisms. They do NOT become part of a patient’s
DNA, which means they do not engraft into the person’s existing cells.

They act through: 4. Cellular signaling – the biologics are able

to perform “cell to cell” communication. This
1. Angiogenesis – provokes formation of new promotes recipient cells to proliferate their
blood vessels. growth factor production, protein production and
2. Reduce inflammation – SLE is associated with regenerate tissues that are damaged.
significant inflammation, and the regenerative 5. Prevent cell death – most cells have a timed
biologics reduce it nicely. death, where they are only allowed to live a
certain length of time. This is called apoptosis. The
3. Immune system modulation – the stem cells
regenerative biologics allow normally functioning
and exosomes modulate the immune system
cells (i.e. chondrocytes) to live longer, and spare
very differently than steroids. Instead of blanketly
them from the pre-programmed death. This can
suppressing the immune system, the regenerative
reduce the rate of cartilage loss in a joint!
biologics tamp down the harmful processes while
amping up the beneficial ones. This includes 6. Preventing scar tissue –Once that scar tissue
ramping up production of several helpful growth forms, it becomes nonfunctional. Stem Cells and
factors and cytokines, while tamping down exosomes are great at preventing scar tissue (anti-
harmful ones. fibrosis).

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Stem Cells can also release a huge variety of scheduled c-section. No baby (or mother) is harmed
molecules into the extracellular environment. These during the c-section procedure. The umbilical cord
molecules, which include extracellular vesicles tissue is normally discarded, but if the mother passes
(exosomes), lipids, free nucleic acids, and soluble screening test then the umbilical cord is immediately
proteins, exert crucial roles in repairing damaged sent to the lab.
tissue. Along with offering stem cells for treatment of
SLE, R3 Stem Cell includes stem cell exosomes, which The lab carefully processes the umbilical cord to
are a type of extracellular vesicle participating in generate large amounts of stem cells and exosomes
extensive cell to cell communication for tissue repair that are of the highest quality possible. The lab team
and regeneration. consists of multiple PhD’s working in ISO Certified,
cGMP compliant clean rooms to ensure quality
The stem cells administered by R3 are not the assurance that exceeds USA FDA standards. The
ones that become a patient’s new cartilage cell. proprietary production process combines the highest
The administered mesenchymal stem cells are not potency, safety and affordability for providers to
specifically designed to replace damaged and lost confidently offer exosome procedures.
cartilage, but rather coordinate and enhance this
Millions of dollars have been invested into the
repair response by one’s own mechanisms.
pharmaceutical grade production of the biologics
Where do the stem cells and exosomes including first rate clean rooms, bioreactors,
come from? nano-particle tracking analyzers, cytometers,
PCR, tangential flow machines and real time
R3 Stem Cell’s regenerative biologics originate from environmental monitoring. The quality assurance
umbilical cord tissue that has been donated after a testing complies with screening and testing

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standards consistent with the American Association MSCs do not express major histocompatibility
of Tissue Banks, cGMP standards, FDA regulations and complex (MHC) antigens of the class II subtype and
the highest level of any regulatory agency globally. contain low levels of MHC molecules of the class I
subtype. MSCs also lack the co-stimulatory molecules
Stem Cell Derived Exosomes essential for immune detection, including CD40, CD80,
R3 Stem Cell’s Centers of Excellence globally include and CD86.
umbilical cord stem cell derived exosomes with Therefore, MSCs generally have low immunogenicity
umbilical cord stem cells to provide enhanced results. and can avoid immune rejection by the recipient,
Exosomes are lipid bound vesicles (acellular) produced which serves as the foundation for their successful
by cells which contain a plethora of growth factors, application without needing to match the
cytokines, mRNA and other proteins. donor to the recipient. Scientists call this being
They are exceptionally helpful in cell to cell “immunologically privileged”.
communication, and very effective for reducing Another question often asked is “Is there a chance of
inflammation when they become ingested by their a tumor forming?” Once again the answer is NO. The
recipient cell. They act as shuttles to send nucleic acids mesenchymal stem cells and exosomes used during
and proteins to other cells, in this way, allowing cell- treatment have never been shown to have tumor
to-cell communication and transporting molecules forming potentials. In fact, they have been shown to
among both close and distant cells. In general,
be anti-tumor forming.
these released proteins are important regulators of
intracellular information. Treatment Protocol
Exosomes could be the mediators of many stem cell- For the past decade, R3 has been
associated therapeutic activities. Considering they are successfully treating SLE patients
100 times smaller than stem cells, they do not have with stem cell and exosome infusion
any issues passing through the blood-brain-barrier to therapy. The cells and exosomes are
reach the brain from the bloodstream. attracted to inflammation, which is a large component
of autoimmune diseases such as SLE.
Is stem cell therapy safe?
R3’s providers use between 1 million stem cells up to
After a decade of performing over 24,000 stem cell 4 million per kilogram. R3 Stem Cell’s SLE treatment
procedures worldwide, R3 knows that the regenerative protocol includes a multivitamin, stem cell and
procedures are safe. The quality control employed exosome infusion along with direct injections into
during the stem cell production is second to none, and painful joints as necessary. Safety is paramount with
the side effects R3 sees are usually mild to moderate the biologics products being rigorously tested prior to
and temporary. use, and expert providers managing each treatment as
They may include itching, dizziness, lightheadedness, if you are a family member!
low grade fever, chills, headache, nausea. These are
typically temporary. If a patient has an allergic reaction
Why does R3 Stem Cell use donor tissue for
to the multivitamin or a preservative, all of R3’s Centers its stem cells?
have the medications to resolve it quickly. Although autologous (your own) stem cells provide
significant advantages, allogeneic (donor) stem cells
One of the questions we get asked a lot is, “Will the have more advantages. First of all, autologous MSCs
stem cells get rejected?” The answer is NO. need a long time to culture and expand, which limits

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its application in treatment, while allogeneic stem cells in six countries. Hundreds have been for SLE. Patient
can be obtained and expanded more quickly, thus satisfaction across all conditions treated is 85%!
avoiding the delay of time window.
R3 combines safety, effectiveness and affordability
Second, age is a factor that affects the physiological for the therapies. Internationally, the Intellicell is used,
characteristics of MSCs. Studies have shown that stem which is culturing the most active mesenchymal stem
cells from elderly donors have decreased proliferation cells to create the “smartest” stem cell in the world!
and differentiation ability. This means they are less in
number and less effective! Our experience with regenerative medicine has been
extensive, and our Success Stories on R3’s YouTube
Channel are impressive. You can visit the channel
What are the Outcomes?
Success Story Playlist HERE.
Similar to the research mentioned above, R3
Stem Cell’s outcomes for SLE patients have been R3 Stem Cell offers free consultations for individuals to
exceptional! The patient satisfaction rate is 85% year discuss whether regenerative therapy is indicated for
over year. Patients typically see exceptional pain relief, your SLE. Simply call +1 (844) GET-STEM to schedule
increased range of motion, improved function and less yours!
need for traditional medications.
References:
It may take four to six weeks for the results to kick in, 1. Li A, Guo F, Pan Q, Chen S, Chen J, Liu H-f and Pan Q (2021)
although we have had patients symptomatically feel Mesenchymal Stem Cell Therapy: Hope for Patients With
Systemic Lupus Erythematosus. Front. Immunol. 12:728190.
much better within the first couple of weeks. It should
doi: 10.3389/fimmu.2021.728190
be noted, again, that stem cell therapy does not
2. Guo et al, Efficacy of mesenchymal stem cells on systemic
eliminate SLE, and may need to be repeated every one
lupus erythematosus:a meta-analysis, Journal of Peking
to three years. University(Health Sciences) ›› 2018, Vol. 50 ›› Issue (6): 1014-
1021. doi: 10.19723/j.issn.1671-167X.2018.06.013
Affordability 3. Wang D, Li J, Zhang Y, Zhang M, Chen J, Li X, et al. Umbilical
Because stem cell therapy for SLE is not cord mesenchymal stem cell transplantation in active and
a “one and done” cure, it’s important to refractory systemic lupus erythematosus: a multicenter
make it affordable. Repeat therapies clinical study. Arthritis Res Ther. 2014; 16(2): R79.
every few years can help people achieve continued 4. Deng D, Zhang P, Guo Y, Lim TO. A randomized double-
blind, placebo-controlled trial of allogeneic umbilical cord-
pain relief and functional improvements. So a lot of
derived mesenchymal stem cell for lupus nephritis. Ann
SLE patients seek additional treatments at R3 Stem Cell Rheum Dis. 2017; 76(8): 1436–9.
every one to three years.
5. Wang D, Zhang H, Liang J, Li X, Feng X,vWang H, et al.
Unfortunately, stem cell clinics in Colombia, China and Allogeneic mesenchymal stemvcell transplantation in
severe and refractoryvsystemic lupus erythematosus: 4
Panama charge over $20,000 USD for SLE treatment. years of experience.vCell Transplant. 2013; 22(12): 2267–
Because the one treatment cost so much, how are v77.
individuals supposed to budget for that every few 6. Gu F, Wang D, Zhang H, Feng X, Gilkeson GS, Shi S, et al.
years?? R3 Stem Cell’s fees are less than half that for Allogeneic mesenchymal stem cell transplantation for lupus
full treatment, which also includes free PRP and a nephritis patients refractory to conventional therapy. Clin
multivitamin infusion! Rheumatol. 2014 Nov; 33(11): 1611–9.
7. Li et al, An Update for Mesenchymal Stem Cell Therapy in
R3’s Experience Lupus NephritisKidney Dis 2021;7:79–89
For the past decade, R3 Stem Cell’s Centers globally
have performed over 24,000 regenerative procedures

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 R3 Consumer Guide for Stem Cell and Exosome Therapy

Consumer Guide
to Stem Cell
Treatment for
Lyme Disease

Brought to you by

* No portion of this Document may be reproduced without the Express Written Consent of R3 Stem Cell.
Disclaimer: This guide’s education does not constitute medical advice. The USA FDA considers stem cell therapy experimental. Any claims
made in the Guide refer to procedures performed outside the USA.
177
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 C O N S U M E R G U I D E T O S T E M C E L L T R E A T M E N T F O R LY M E D I S E A S E

Consumer Guide to Stem Cell Treatment

for Lyme Disease
Every day, R3 Stem Cell receives inquiries worldwide It is considered as a multi-organ-system infectious
from individuals asking if stem cell therapy can help disease as its typical symptoms include fever, muscle
with Lyme Disease. Spoiler alert: It can help a lot! In and joint pain, swollen lymph nodes, headache,
this guide, we’ll go through the basics of how stem fatigue, and erythema migrans (rash with a bull’s eye
cells and exosomes work, the latest research, and appearance). If left untreated, it affects joints, heart,
what to expect with a regenerative procedure. eyes, etc. However, the nervous system, i.e. central
nervous system (CNS), the peripheral nervous system
A Significant Global Issue (PNS), and the autonomic nervous system (ANS),
Lyme disease is a bacterial infection you get from the appear to be its primary targets.
bite of an infected tick. At first, Lyme disease usually
causes symptoms such as a rash, fever, headache, and Current Treatment Options for
fatigue. But if it is not treated early, the infection can Lyme Disease
spread to your joints, heart, and nervous system.
Antibiotics, usually doxycycline or amoxicillin, are
The first recognition of Lyme disease, also effective treatments for Lyme disease. How
called borreliosis, began in 1975 long your treatment lasts depends
when many children received on the stage of infection. In
a diagnosis of juvenile general, it’s true that the
rheumatoid arthritis in sooner you’re treated,
Lyme, Connecticut, and the quicker and more
two neighboring towns. complete the recovery.
Researchers found that
bites from infected deer Why does Post
ticks were responsible for Treatment Lyme
the outbreak of arthritis. Disease, known as
The species of Ixodes ticks Chronic Lyme Disease,
which transmit the disease occur?
are commonly found throughout
Up to 20% of those with Lyme Disease
temperate regions of North America, Europe, and
experience long term symptoms, which can seriously
Asia. Currently, the Centers for Disease Control and
affect quality of life. This may be due to initially
Prevention (CDC) estimate approximately 300,000
undiagnosed Lyme, or Lyme that failed treatment.
new cases of Lyme disease in the United States alone
each year. However, due to climate change, shifting “Post-treatment Lyme disease syndrome (PTLDS) is
land use patterns, and the relative abundance and a real disorder that causes severe symptoms in the
distribution of reservoir hosts, it is anticipated that the absence of clinically detectable infection,” says John
geographic range of the tick vector will continue to N. Aucott, M.D., associate professor of medicine at
expand. For instance, the number of reported cases in the Johns Hopkins University School of Medicine and
Canada has increased six-fold over the past decade, director of the Johns Hopkins Lyme Disease Clinical
with particular increases in the eastern provinces of Research Center.
Nova Scotia and Ontario

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The cause of post-treatment Lyme disease syndrome • Recurring episodes of swollen joints (arthritis).
is unknown and is a huge source of debate in the This typically affects large joints like the knee.
medical community. But there are a few theories.
• Difficulty concentrating, known as “brain fog.”
One theory is that there are leftover reservoirs of the This is a form of encephalopathy or damage to
bacteria that causes Lyme disease after antibiotic the brain.
treatment. Others argue that people who develop
• Damage to nerves all over your body, including
PTLDS have an underlying autoimmune condition,
your skin, muscles and organs (polyneuropathy).
as Lyme disease can alter and weaken the immune
system. Lyme disease is also often misdiagnosed Antibiotic-refractory late Lyme arthritis, the most
as an autoimmune disorder such as Rheumatoid studied post-treatment manifestation of Lyme
Arthritis. disease, is thought to be autoimmune in nature,
as B. burgdorferi (the tick bacteria) can no longer
Some other possible theories include:
be found in the joint or surrounding
• Persistent immune tissue in patients who have been
activation thoroughly treated.
• Damage from the Stem Cell Therapy
original infection for Chronic Lyme
• Changes in the Disease
brain chemistry
Research into stem
that affects pain
cell therapy for
pathways and
chronic lyme disease
cognition
is limited, but what
• Persistent does exist has been
infection very positive.
Researchers have been In the first case report
able to find a correlation published on stem cell therapy
between more severe symptoms for Lyme disease, an 18-year-old
at presentation, more widely spread white male with a past medical history
symptoms, and delayed antibiotic treatment with the significant for Lyme disease and other infections
development of PTLDS in those same patients. presented with chief complaints of moderate fatigue,
About 50 percent of the PTLDS patients reported sore throats that would come and go, frequent sinusitis,
severe fatigue, about 28 percent reported severe diarrhea once a month, back stiffness and neck pain,
pain, about 23 percent reported severe cognitive mild tremors of the hands, insomnia, and moderate
complaints and about 31 percent reported severe cognitive difficulties.
sleep difficulty. He was diagnosed with Lyme Disease at the age of
Signs and symptoms of untreated Lyme disease (or 10 after a tick bite one year prior. The initial test was
those with failed treatment), which may happen from negative, but turned positive for Lyme on subsequent
months to a year after infection, may include: testing. Since the patient continued to suffer from
recurrent infections with frequent relapses on IVIG,

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at age 18, the patient and his mother

decided to undergo human
embryonic stem cell treatment.
The source of cells was
not described, and the
number of cells wasn’t
reported either.
Of note, R3 Stem
Cell does NOT use
embryonic stem
cells. Rather, R3 uses
mesenchymal or
hematopoietic stem cells.
They work well and are very
safe.
The 1st set of treatments were performed
in 2016 for 8 weeks in New Delhi, India; the 2nd
set of treatments were for 4 weeks six months later,
and the last set of treatments were over two weeks, six monthly IVIG. By the end of follow up, he was at a high
months after that. These were given through multiple level of normal functioning.
routes, primarily IM and IV, although several were given
A 2018 study out of India included 59 patients
through the cervical intrathecal route.
with Lyme disease whose single-photon emission
After the stem cell therapy, the patient has clinically tomography imaging was performed before and
stabilized with fewer sinus infections and his IgG after human embryonic stem cell therapy. The single-
immunoglobulin levels and subclasses have remained photon emission tomography imaging was used to
within normal limits. The patient’s Lyme disease assess the hypoperfused lesions/regions in the brain
symptoms also improved. He no longer complained prior to the therapy, as well as the improvement in
of significant fatigue or insomnia, and only required perfusion after human embryonic stem cell treatment.
low dose Adderall for his ADHD (5 mg/day) to help
The author noted that patients with LD usually suffer
concentrate at school.
from poor circulation in brain regions affecting
There remained only mild neck and back pain, but it memory and cognition, with an overflow in the
was positional, with no other associated joint pain or occipital lobe. This might be the cause of poor
neuropathy. Recent testing for Lyme disease showed concentration, cognitive disabilities and highly
decreased Borrelia-specific bands on the Western blot sensitive eyes in LD patients.
(31 kDA, i.e., Osp A, as well as a decrease in the 39 kDA
Of note, R3 Stem Cell does NOT use embryonic stem
band) with negative whole blood PCRs.
cells. R3 uses mesenchymal and hematopoietic stem
He remained clinically stable without relapses while off cells obtained from ethical sources.
all antibiotics, and only required a seven-day course of
The SPECT imaging was performed for all the patients,
a cephalosporin for a sinus infection during his first year
before and after the treatment. A clear and noticeable
of college. Previously, he had suffered from an average
improvement was observed and reported after
of 10–15 infections per year, despite being on
comparing the reports of SPECT

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imaging before and after the therapy. Patients with LD in 2012. She was prescribed an antibiotic regime
significant improvement showed more than 60% without much beneficial results.
improvement. The clinical improvement was based
The patient received stem cell therapy along with
on the brain perfusion state of patients. After
antibiotics and physiotherapy. The treatment period
comparing the SPECT imaging results of prior and
for the patient included six months, and was poorly
after therapy, it was observed that the patients
described in the paper. Following the first treatment
showed an improvement. They were observed with
phase, the patient reported remarkable improvement
severe/moderate/mild brain hypoperfusions prior
in her lower limb strength, decreased spasticity, and
to therapy. After receiving stem cell therapy, their
had no longer fatigue issues. Also, she was able to walk
perfusion level upgraded to moderate/mild/minimal
upright now with support.
and even normal perfusion levels.
After her second visit, improvement in muscle strength,
Another study performed by Shroff in 2016 evaluated
movement of left upper arm, spasticity of left lower,
a patient with diagnoses of Lyme Disease and Multiple
and left upper limb was observed. The patient was able
Sclerosis (MS). Globally, MS prevalence parallels
to walk independently
the circulation of the Lyme disease (LD), which is
characterized by white matter lesions in the brain for up to 40–50 minutes around the room. An
similar to those found in MS patients. improvement was observed in parameters like muscle
weakness, walking distance, balance, fatigue, pain,
In the study, a 30-year-old female presented with
blurring of eyes, and deformity.
chief complaints of inability to walk, wheel chair
dependence, unable to stand without support, Why Doesn’t R3 Stem Cell Use A Person’s
spasticity of lower limbs with foot drop on the left foot, Own Stem Cells for Treatment?
weakness of the left arm and spasticity of the left hand,
severe fatigue with myalgia, and joint pains especially R3 used to perform autologous therapies, where a
in the shoulder (left >right). After further deterioration patient’s own bone marrow or adipose stem cells
of her condition, she was tested and found positive for were used. However, a lot of stem cells in one’s body

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are as old as that person is, and hence not very active. How do the Stem Cells and Exosomes Work
Their ability to successfully increase sufficient blood for Lyme Diseases?
flow and allow for tissue regeneration is inferior to
umbilical cord stem cells, which are young, potent Stem cells and exosomes act in the body through
and extremely active. several mechanisms. They do NOT become part of
a patient’s DNA, which means they do not engraft
Specifically, the therapeutic potential of autologous into the person’s existing cells. The predominant
bone marrow or adipose stem cells in the treatment method of action is thought to be through paracrine
of older patients is impaired by a number of age- mechanisms, which means “cell to cell” interaction.
related factors such as oxidative stress, telomere
length, DNA damage, disease, and long-term use of They act through:
some medications. 1. .Angiogenesis – provokes formation of new
This is in stark contrast to the youthful genotype blood vessels.
and phenotype of neonatal tissue-derived stem 2. Reduce inflammation – Chronic Lyme Disease
cells, such as from the umbilical cord. They are better is associated with significant acute and chronic
at facilitating repair and regeneration of tissue inflammation, and the regenerative biologics
damage, creating new blood flow with superior reduce it nicely.
anti-inflammatory and immunomodulatory efficacy 3. Immune system modulation – the stem cells
compared to mature stem cells from one’s adipose or and exosomes modulate the immune system
bone marrow. very differently than steroids. Instead of blanketly
As a result of the inferiority of autologous stem cells suppressing the immune system, the regenerative
due to the reasons above and better results being biologics tamp down the harmful processes while
seen with umbilical cord stem cells, R3 only uses the amping up the beneficial ones. This includes
donor stem cells today. ramping up production of several helpful growth
factors and cytokines, while tamping down
harmful ones.
4. Cellular signaling – the biologics are able
to perform “cell to cell” communication. This
promotes recipient cells to proliferate their
growth factor production, protein production
and regenerate tissues that are damaged.
5. Prevent cell death – most cells have a timed
death, where they are only allowed to live a
certain length of time. This is called apoptosis.
The regenerative biologics allow normally
functioning cells to live longer, and spare them
from the pre-programmed death.
6. Preventing scar tissue – While scar tissue resulting
from Lyme Diseases is not known to occur, it is a
problematic issue in many conditions. Once that
scar tissue forms, it becomes nonfunctional. Stem
Cells and exosomes are great at preventing scar
tissue (anti-fibrosis).Stem Cells can also release

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a Stem Cells can also release a huge variety of with screening and testing standards consistent with
molecules into the extracellular environment. These the American Association of Tissue Banks, cGMP
molecules, which include extracellular vesicles, standards, FDA regulations and the highest level of any
lipids, free nucleic acids, and soluble proteins, exert regulatory agency globally.
crucial roles in repairing damaged tissue.
Stem Cell Derived Exosomes
Along with offering MSCs for treatment of Lyme
R3 Stem Cell’s Centers of Excellence globally include
Diseases, R3 Stem Cell includes stem cell exosomes,
umbilical cord stem cell derived exosomes with
which are a type of extracellular vesicle participating
umbilical cord stem cells to provide enhanced results.
in extensive cell to cell communication for new blood
Exosomes are lipid bound vesicles (acellular) produced
flow creation.
by cells which contain a plethora of growth factors,
Where do the stem cells and exosomes cytokines, mRNA and other proteins.
come from? They are exceptionally helpful in cell to cell
R3 Stem Cell’s regenerative biologics originate communication, and very effective for reducing
from umbilical cord tissue that has been inflammation when they become ingested
donated after a scheduled c-section. by their recipient cell. They act as shuttles
No baby (or mother) is harmed to send nucleic acids and proteins
during the c-section procedure. The to other cells, in this way, allowing
umbilical cord tissue is normally cell-to-cell communication and
discarded, but if the mother transporting molecules among
passes screening tests then the both close and distant cells. In
umbilical cord is immediately general, these released proteins
sent to the lab. The screening are important regulators of
tests are extremely rigorous, and intracellular information.
mandated by the USA FDA. Exosomes could be the mediators
of many stem cell-associated
The lab carefully processes the
therapeutic activities. We have seen
umbilical cord to generate large
them to be “faster acting” than stem cells,
amounts of stem cells and exosomes that
so R3 frequently uses them in conjunction to
are of the highest quality possible. The lab team
provide a “1-2 punch” for patient outcomes.
consists of multiple PhD’s working in ISO Certified,
cGMP compliant clean rooms to ensure quality Is stem cell therapy safe?
assurance that exceeds USA FDA standards. The After a decade of performing over 25,000 stem cell
proprietary production process combines the highest procedures worldwide, R3 knows that the regenerative
potency, safety and affordability for providers to procedures are safe. The quality control employed
confidently offer exosome procedures. during the stem cell production is second to none, and
Millions of dollars have been invested into the the side effects R3 sees are usually mild to moderate
pharmaceutical grade production of the biologics and temporary.
including first rate clean rooms, bioreactors, They may include itching, dizziness, lightheadedness,
nano-particle tracking analyzers, cytometers, PCR, low grade fever, chills, nausea. These are typically
tangential flow machines and real time environmental temporary. If a patient has an allergic reaction to the
monitoring. The quality assurance testing complies multivitamin or a preservative, all of R3’s Centers have
the medications to resolve it quickly.

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One of the questions we get asked a lot is, “Will the Affordability
stem cells get rejected?” The answer is NO.
Because stem cell therapy for Lyme
MSCs do not express major histocompatibility complex Disease is not typically a permanent
(MHC) antigens of the class II subtype and contain low cure, it’s important to make it affordable.
levels of MHC molecules of the class I subtype. MSCs Repeat therapies can help maintenance and/or
also lack the co-stimulatory molecules essential for achieve additional improvements for pain relief. So a
immune detection, including CD40, CD80, and CD86. lot of patients seek additional treatments at R3 Stem
Therefore, MSCs generally have low immunogenicity Cell every twelve to eighteen months.
and can avoid immune rejection by the recipient, R3 Stem Cell’s fees are less than half what comparable
which serves as the foundation for their successful (and reputable) regenerative clinics charge. Be wary
application without needing to match the donor to the of clinics trying to pass off PRP as a stem cell therapy.
recipient. Scientists call this being “immunologically If they mention only taking your blood for the
privileged”. treatment, it is NOT a stem cell treatment!
Another question often asked is “Is there a chance of a
tumor forming?” Current research has concluded that R3’s Experience
the answer is NO. The mesenchymal stem cells and For the past decade, R3 Stem Cell’s Centers globally have performed
exosomes used during treatment have never been over 25,000 regenerative procedures in six countries. Patient
shown to have tumor forming potentials. In fact, they satisfaction across all conditions treated is 85%!
have been shown to be anti-tumor forming.
R3 combines safety, effectiveness and affordability for the therapies.
Protocol Internationally, the Intellicell is used, which is culturing the most active
For the past decade, R3 has been mesenchymal stem cells to create the “smartest” stem cell in the world!
successfully treating Lyme Disease with R3 Stem Cell offers free consultations for individuals to discuss whether
stem cell and exosome procedures. regenerative therapy is indicated for their Trigeminal Neuralgia. Simply
The regenerative biologics are applied
depending on the person’s symptoms. call +1 (844) GET-STEM or +1 (888) 988-0515 to schedule yours!
R3 may incorporate direct injections, intravenous Disclaimer: This guide’s education does not constitute medical advice. The USA FDA
application and maybe intrathecal too. considers stem cell therapy experimental. Any claims made in this Guide refer to
procedures performed outside of the USA.
R3’s providers use one to two million stem cells per
kilogram, to make sure that patients achieve the References:
absolute best outcome possible. Between 50 and 100
billion exosomes are included with each procedure. 1. Geeta Shroff, Transplantation of Human Embryonic Stem Cells
in Patients with Multiple Sclerosis and Lyme Disease, Am J Case
Outcomes Rep, 2016; 17: 944-949
Similar to the research mentioned above, R3 2. Horowitz et al, Improvement of common variable
Stem Cell’s outcomes for Lyme Disease have been immunodeficiency using embryonic stem cell therapy in a
exceptional! The patient satisfaction rate is 85% year patient with lyme disease: a clinical case report, Clinical Case
over year. Patients typically experience less pain and Reports 2018; 6(6): 1166–1171
fatigue, along with improved mental clarity and less 3. Geeta Shroff, Single-photon emission tomography imaging
brain fog. Keep in mind results cannot be guaranteed in patients with Lyme disease treated with human embryonic
and will vary between individuals. stem cells, Neuroradiol J. 2018 Apr; 31(2): 157–167

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 R3 Consumer Guide for Stem Cell and Exosome Therapy

Consumer Guide
to Stem Cell
Treatment for
Migraines and
Chronic Headaches

Brought to you by

* No portion of this Document may be reproduced without the Express Written Consent of R3 Stem Cell.
Disclaimer: This guide’s education does not constitute medical advice. The USA FDA considers stem cell therapy experimental. Any claims
made in the Guide refer to procedures performed outside the USA.
185
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 CONSUMER GUIDE TO STEM CELL TREATMENT FOR MIGRAINES AND CHRONIC HEADACHES

Consumer Guide to Stem Cell Treatment

for Migraines and Chronic Headaches
Every day, R3 Stem Cell receives inquiries worldwide While it is generally agreed that migraine is a
from individuals asking if stem cell therapy can help heterogeneous neurological disorder, the detail
with Migraines and Chronic Headaches Spoiler alert: of why they occur are as yet unconfirmed with
It can help a lot! In this guide, we’ll go through the inheritance thought to be as high as 50%. A migraine
basics of how stem cells work, the latest research, and attack can take place over hours to days and include
what to expect with a regenerative procedure. four overlapping phases: pre- monitory, aura,
headache and postdrome, with the mechanisms
A Significant Global Issue leading to an attack largely unknown.
Migraine is a common, episodic neurological
disorder. It manifests as episodes of recurrent severe Stem Cell Therapy for Migraines and
headaches, typically unilateral and throbbing, Chronic Headaches
which may be associated with nausea, vomiting,
photophobia or phonophobia. Approximately As you will see from the study results below,
one-third of patients with migraine stem cell therapy for migraines and
also experience ‘aura’ – transient chronic headaches has been very
neurological symptoms which successful. Considering that
are most frequently visual, traditional therapies often
but may involve speech fail, regenerative therapies
and/or other senses. are an excellent option for
patients who desire an
Both migraine with and improved quality of life.
without aura are three
times more common A 2012 study in Headache
in females than males. evaluated 24 patients
Tension-type headache suffering from cervicogenic
(TTH) differs slightly in that headaches and occipital
it is defined clinically as a mild neuralgia. Mesenchymal stem cell
or moderate bilateral headache, with a therapy was administered with various
pressing or tightening quality. These headaches can injections in the neck including facets, medial
last from 30 minutes to 7 days and are associated with branch regions and occipital nerve area.
phonophobia and photophobia. In 19 cases (79.2%), a good clinical response was
Both migraine and TTH are significant public health recorded. At 6- month follow-up analysis, recurrence
problems, impacting greatly on both individuals of occipital pain was recorded in 7 cases (29.2%);
and society. Migraine is currently treated both there is a significant reduction in disability and pain
acutely and prophylactically utilizing: non-steroidal scores, and also a significant reduction of need
anti-inflammatory drugs (NSAIDs), triptans, anti- for pharmacologic treatment and a fast return to
epileptics, beta-blockers, and Ca2+ channel blockers. previous work capacities.
Unfortunately, due to the heterogeneity of these The technique was minimally invasive, and no
headache syndromes–particularly migraine–the complications were recorded; indeed, the procedure
current treatments vary greatly in their effectiveness. was safe and effective.

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A 2017 study from the New York Headache Center the ages 36 and 44 years who had long histories of
included 3 patients with refractory chronic migraines migraine headaches and who met the International
receiving between 2.5 and 8.6 mesenchymal stem Classification of Headache Disorders criteria for
cells obtained from adipose tissue. Between 8 and Chronic Migraine or Tension-type Headaches were
10 mL of SVF were injected into the temporalis, included. All 4 women experienced substantial
occipitalis, neck, and trapezius muscles. improvement in their headache frequency and
were able to substantially reduce their use of
One male and 8 female patients were enrolled in the pain medication for 18 months after the stem cell
study. The mean age was 48 years, the mean duration injections.
of headaches was 16 years, and the mean number of
prophylactic drugs tried was 10. an average baseline Why Doesn’t R3 Stem Cell Use A Person’s
score of 122 on the Migraine Disability Assessment Own Stem Cells for Treatment?
(MIDAS) who had not improved after receiving
botulinum toxin injections and at least R3 used to perform autologous
3 prophylactic medications. therapies, where a patient’s own
bone marrow or adipose
Three months after the stem cells were used.
procedure the MIDAS However, a lot of stem
score dropped in 7 cells in one’s body are
out of 9 patients. as old as that person
The PGIC scale was is, and hence not
reported as 1 very very active. Their
much improved, 1 ability to successfully
much improved, 4 increase sufficient
minimally improved, blood flow and allow
2 no change, and 1 for tissue regeneration
min- imally worse. One is inferior to umbilical cord
of the patients reporting stem cells, which are young,
minimal improvement had a potent and extremely active.
dramatic improve- ment within the
first month and until she lowered the dose of Specifically, the therapeutic potential of
her topiramate. autologous bone marrow or adipose stem cells in the
treatment of older patients is impaired by a number
These case reports of patients afflicted with of age-related factors such as oxidative stress,
refractory chronic migraines suggest that some such telomere length, DNA damage, disease, and long-
patients may improve with stem cell therapy. Stem term use of some medications.
cells may relieve migraines through their proven
anti-inflammatory properties because neurogenic This is in stark contrast to the youthful genotype
inflammation is one of the major aspects of migraine and phenotype of neonatal tissue-derived stem
pathogenesis. cells, such as from the umbilical cord. They are better
at facilitating repair and regeneration of tissue
In one case study from 2014, Australian researchers damage, creating new blood flow with superior
used stem cell therapy for the treatment of migraine anti-inflammatory and immunomodulatory efficacy
and tension headaches. A total of 4 women between compared to mature stem cells from one’s adipose or
bone marrow.

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As a result of the inferiority of

autologous stem cells due to the
reasons above and better
results being seen with
umbilical cord stem
cells, R3 only uses
the donor stem cells
today.
How do the
Stem Cells and
Exosomes Work
for Migraines and
Chronic Headaches?
Stem cells and exosomes act in the
body through several mechanisms. They
do NOT become part of a patient’s DNA, which
means they do not engraft into the person’s existing
cells. The predominant method of action is thought to
be through paracrine mechanisms, which means “cell
to cell” interaction.
They act through: 4. Cellular signaling – the biologics are able
to perform “cell to cell” communication. This
1. .Angiogenesis – provokes formation of new
promotes recipient cells to proliferate their
blood vessels.
growth factor production, protein production
and regenerate tissues that are damaged.
2. Reduce inflammation – Chronic migraines and
headaches are associated with significant acute 5. Prevent cell death – most cells have a timed
and chronic inflammation, and the regenerative death, where they are only allowed to live a
biologics reduce it nicely. certain length of time. This is called apoptosis.
The regenerative biologics allow normally
3. Immune system modulation – the stem cells functioning cells to live longer, and spare them
and exosomes modulate the immune system from the pre-programmed death.
very differently than steroids. Instead of
blanketly suppressing the immune system, the 6. Preventing scar tissue – While scar tissue
regenerative biologics tamp down the harmful resulting from migraines or chronic headaches
processes while amping up the beneficial ones. is not known to occur, it is a problematic issue
This includes ramping up production of several in many conditions. Once that scar tissue forms,
helpful growth factors and cytokines, while it becomes nonfunctional. Stem Cells and
tamping down harmful ones. exosomes are great at preventing scar tissue
(anti-fibrosis).

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Stem Cells can also release a huge variety of molecules consists of multiple PhD’s working in ISO Certified,
into the extracellular environment. These molecules, cGMP compliant clean rooms to ensure quality
which include extracellular vesicles, lipids, free nucleic assurance that exceeds USA FDA standards. The
acids, and soluble proteins, exert crucial roles in proprietary production process combines the highest
repairing damaged tissue. potency, safety and affordability for providers to
confidently offer exosome procedures.
Along with offering MSCs for treatment of Migraines
and Chronic Headaches, R3 Stem Cell includes stem Millions of dollars have been invested into the
cell exosomes, which are a type of extracellular vesicle pharmaceutical grade production of the biologics
participating in extensive cell to cell communication for including first rate clean rooms, bioreactors,
new blood flow creation. nano-particle tracking analyzers, cytometers, PCR,
tangential flow machines and real time environmental
Where do the stem cells and exosomes
monitoring. The quality assurance testing complies
come from? with screening and testing stan¬dards consistent
R3 Stem Cell’s regenerative biologics originate from with the American Association of Tissue Banks, cGMP
umbilical cord tissue that has been donated after a standards, FDA regulations and the highest level of any
scheduled c-section. No baby (or mother) is harmed regulatory agency globally.
during the c-section procedure. The umbilical cord
tissue is normally discarded, but if the mother passes
Stem Cell Derived Exosomes
screening tests then the umbilical cord is immediately R3 Stem Cell’s Centers of Excellence globally include
sent to the lab. The screening tests are extremely umbilical cord stem cell derived exosomes with
rigorous, and mandated by the USA FDA. umbilical cord stem cells to provide enhanced results.
Exosomes are lipid bound vesicles (acellular) produced
The lab carefully processes the umbilical cord to
by cells which contain a plethora of growth factors,
generate large amounts of stem cells and exosomes
cytokines, mRNA and other proteins.
that are of the highest quality possible. The lab team

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They are exceptionally helpful in cell to cell

communication, and very effective for
reducing inflammation when they
become ingested by their recipient
cell. They act as shuttles to send
nucleic acids and proteins to
other cells, in this way, allowing
cell-to-cell communication
and transporting molecules
among both close and distant
cells. In general, these released
proteins are important regulators
of intracellular information.
Exosomes could be the mediators of
many stem cell-associated therapeutic
activities. We have seen them to be “faster
acting” than stem cells, so R3 frequently uses them
in conjunction to provide a “1-2 punch” for patient which serves as the foundation for their successful
outcomes. application without needing to match the donor to the
recipient. Scientists call this being “immunologically
Is stem cell therapy safe? privileged”.
After a decade of performing over 24,000 stem cell Another question often asked is “Is there a chance of a
procedures worldwide, R3 knows that the regenerative tumor forming?” Current research has concluded that
procedures are safe. The quality control employed the answer is NO. The mesenchymal stem cells and
during the stem cell production is second to none, and exosomes used during treatment have never been
the side effects R3 sees are usually mild to moderate shown to have tumor forming potentials. In fact, they
and temporary. have been shown to be anti-tumor forming.
They may include itching, dizziness, lightheadedness, Protocol
low grade fever, chills, nausea. These are typically
temporary. If a patient has an allergic reaction to the For the past decade, R3 has been
multivitamin or a preservative, all of R3’s Centers have successfully treating Migraines and Chronic
the medications to resolve it quickly. Headaches with stem cell and exosome
procedures. The regenerative biologics
One of the questions we get asked a lot is, “Will the are applied directly into the neck and
stem cells get rejected?” The answer is NO. surrounding tissues with direct injections, and also
MSCs do not express major histocompatibility complex infused through an IV. Depending on each patient’s
(MHC) antigens of the class II subtype and contain low unique history, R3’s providers may also incorporate an
levels of MHC molecules of the class I subtype. MSCs intra-nasal or intrathecal application.
also lack the co-stimulatory molecules essential for R3’s providers use one to two million stem cells per
immune detection, including CD40, CD80, and CD86. kilogram, to make sure that patients achieve the
Therefore, MSCs generally have low immunogenicity absolute best outcome possible. Between 50 and 100
and can avoid immune rejection by the recipient, billion exosomes are included with each procedure.

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Outcomes Disclaimer: This guide’s education does not constitute medical

advice. The USA FDA considers stem cell therapy experimental. Any
Similar to the research mentioned above, R3 Stem
Cell’s outcomes for migraine and chronic headaches claims made in this Guide refer to procedures performed outside of
have been exceptional! The patient satisfaction rate the USA.
is 85% year over year. Patients typically experience
less headaches with less severity and a reduced need References:
for medications. Keep in mind results cannot be
guaranteed and will vary between individuals. 1. Gaetani et al, Treatment of Chronic Headache of Cervical Origin
With Lipostructure: An Observational Study, Headache, https://
Affordability doi.org/10.1111/j.1526-4610.2012.02267.x
Because stem cell therapy for migraines 2. Mauskop et al, Stem Cells in the Treatment of Refractory
and chronic headaches is not a Chronic Migraines Case Rep Neurol 2017;9:149–155
permanent cure, it’s important to make
it affordable. Repeat therapies can help maintenance 3. Bright R, Bright M, Bright P, et al. Migraine and tension-type
and/or achieve additional improvements for pain headache treated with stromal vascular fraction: a case series. J
relief. So a lot of patients seek additional treatments at Med Case Rep. 2014;8:237.
R3 Stem Cell every twelve to eighteen months.
4. Caviggioli et al, Therapeutic Role of Fat Injection in the
R3 Stem Cell’s fees are less than half what comparable Treatment of Recalcitrant Migraine Headaches , Plastic and
(and reputable) regenerative clinics charge. Be wary Reconstructive Surgery • January 2020
of clinics trying to pass off PRP as a stem cell therapy.
If they mention only taking your blood for the
treatment, it is NOT a stem cell treatment!

R3’s Experience
For the past decade, R3 Stem Cell’s Centers
globally have performed over 24,000
regenerative procedures in six countries.
Several hundred have been for SCI. Patient
satisfaction across all conditions treated is
85%!
R3 combines safety, effectiveness and
affordability for the therapies. Internationally,
the Intellicell is used, which is culturing the most
active mesenchymal stem cells to create the “smartest”
stem cell in the world!
R3 Stem Cell offers free consultations for individuals to
discuss whether regenerative therapy is indicated for
their headaches. Simply call +1 (844) GET-STEM or +1
(888) 988-0515 to schedule yours!

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Guide to Stem Cell

and Exosome
Therapy for
Multiple Sclerosis

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* No portion of this Document may be reproduced without the Express Written Consent of R3 Stem Cell.
Disclaimer: This guide’s education does not constitute medical advice. The USA FDA considers stem cell
therapy experimental. Any claims made in the Guide refer to procedures performed outside the USA.
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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR MULTIPLE SCLEROSIS

Every day, R3 Stem Cell receives inquiries worldwide Multiple sclerosis is more common in Europe and the
from individuals asking if stem cell therapy can help US, with a prevalence rate of 100 to 200 per 100,000
for Multiple Sclerosis (MS). Spoiler alert: It can help individuals. Asia is a low-incidence area.
a lot! In this guide, we’ll go through the basics of
how stem cells and exosomes work for MS, the latest Multiple sclerosis cannot be completely cured.
research, and what to expect with a regenerative As the disease develops, dysfunction is gradually
procedure. progressive, resulting in disability. The main
principle of treatment is immunosuppression and
What is Multiple Sclerosis? immunomodulation, but these still cannot prevent
Multiple sclerosis (MS) is an immune-mediated recurrence. The proportion of patients with disease
inflammatory disease in which the immune system progression and the incidence of long-term disability
progressively destroys its own myelinated do not reduce. Therefore, effective treatment
axons in the central nervous system, methods with few side effects are
in episodes lasting from a few urgently needed.
months to many years in Although an interplay of
duration. genetic and environmental
It is induced by attack of factors are likely to be
autoreactive lymphocytes contributory, the precise cause
on the myelin sheath and of MS remains unresolved.
endogenous remyelination Its pathological hallmarks
failure, eventually leading to include multi-focal inflammation,
accumulation of neurological disability. primary demyelination (where axons
As a consequence, neuronal impulses are not pathologically lose their investing myelin
adequately transmitted and patients develop sheaths), acute and chronic axonal damage and
neurological symptoms. It is one of the main causes astrogliosis.
of disability in young adults and its incidence is In MS, a dysregulated immune response, possibly
increasing. It is classified as an autoimmune disease. trigged by environmental factors such as a microbial
MS is characterized by demyelination, progressive trigger, occurs in genetically susceptible individuals.
neurological dysfunction, and remission and relapse. In this scenario, autoimmunity prone T cells are
The eventual demyelination and axonal degeneration activated in the periphery by a pathogen, possibly
can cause serious and debilitating motor, sensory, due to an inefficient control by regulatory systems,
balance and cognitive problems, disability, serious such as regulatory T cells, and, as a consequence,
complications, and negatively impact quality of life. upregulate adhesion molecules necessary to cross
the brain endothelium.
A Global Concern
Upon migration into the CNS, autoreactive T cells
MS affects approximately 2.5 million people are further activated by local antigen-presenting
worldwide and is thought to be the most commonly cells (APCs), such as microglia, and initiate a
acquired neurological disease of young adults. complex attack against myelin antigens through the
Women are typically affected twice as frequently as recruitment of several other immune cells, including
men, and most patients are diagnosed between 20 B cells, overall leading to myelin disintegration and
and 40 years of age. impairment of nerve conduction.

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An uncontrolled autoimmune response is likely as Mitoxantrone for PPMS patients are limited
to sustain recruitment of other pathogenic cells to symptomatic treatments and the long-term
from the periphery leading, at later stages, to the prognosis is generally poor. Future therapeutic
compartmentalization of the pathogenic attack strategies are aimed to achieve neuroprotection,
inside the CNS. Chronic aggression against the myelin remyelination and regeneration of new
sheath will eventually lead to axonal sufferance and oligodendrocytes and neurons.
subsequent loss of neurons and oligodendrocytes,
the biological basis of irreversible disability. The Treatments available include steroids for temporary
ideal treatment for MS should therefore target the flareups, disease-modifying drugs, and drugs
autoimmune attack and support tissue repair or at targeting specific symptoms. While these may reduce
least tissue protection. Indeed, tissue repair without the frequency of exacerbations and slow disease
the arrest of the cause of tissue damage would be progression, none have myelin or nerve regenerative
ineffective. capability to restore the cumulative damage already
in place.
The majority of patients experience Currently, there isn’t an effective
two disease phases; relapsing- therapeutic conventional treatment
remitting (RR) followed by model for MS disease. Current
a secondary progressive medications are costly and
(SP) course. The former is are focused on lessening
pathologically characterised the symptoms and chronic
by inflammatory activity inflammation, but not
while SPMS is dominated curing the disease or
by neurodegeneration repairing the damaged
and variable remyelination. myelin. Furthermore, the
Major recent advances in anti- symptoms were recurrent or
inflammatory disease modifying became aggravated after drug
treatments (DMTs) have transformed withdrawal.
the outlook of newly diagnosed RRMS
patients. Adding to this is the unfortunate reality that
medicines with immunomodulatory and
What are traditional treatments for MS? immunosuppressant properties provide partial
Currently, there is no cure for MS. During efficacy to ameliorate autoimmune reactions.
the past decades, therapies for MS are either This is the reason why disease progression can
immunomodulatory or immunosuppressive]. lead to approximately 50% of affected patients to
Immunomodulatory and anti-inflammatory agents develop chronic progressive disease with a poor
are effective in the relapsing–remitting stage by prognosis. Recent evidence has suggested that an
reducing the frequency of relapses, and decreasing appropriate treatment should be centered on the
the formation of inflammatory lesions, but they modulation or suppression of aggressive immune
do not influence the course of progressive MS and response, protection of neurons and axons against
therefore are not sufficient enough to cure chronic degenerative process, as well as improvement of
neurological disability. repair or remyelination
The permanent neuronal loss that starts early Although immunomodulatory therapies are proving
and characterizes the progressive stage of MS to be increasingly effective in controlling the initial
remains untreatable. Therapeutic options such relapsing-remitting phase of MS, the secondary

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progressive phase, in which there is continual

atrophy of demyelinated axons, remains largely
untreatable. Indeed, axon degeneration
occurs despite immunomodulatory
therapies, suggesting that axon
integrity and protection may occur
through mechanisms independent of
inflammation.
Several lines of evidence suggest
that the basis of axon atrophy in
chronically demyelinated lesions is
due, in part, to the absence of myelin-
associated trophic signals that are critical for
maintaining axon integrity. None of the available
traditional medications act on axon integrity,
protetction or remyelination.
function deficits in animal models. Unfortunately,
What is the Theory Behind Stem Cell however, remyelination ultimately fails to keep pace
Therapy for MS? with disease progression and neurological deficit
accumulates. Understanding why endogenous
There are 2 principal components in treating MS: remeylination appears to fail in some patients
1) the prevention of damage, usually involving an and is variable across different lesions in the same
immunomodulatory approach; and 2) the repair of individual is critical to guiding therapeutic strategy.
damage, involving the regeneration of new myelin
sheaths (remyelination). Indeed in MS post-mortem tissue, axon preservation
is seen in remyelinated lesions; again reinforcing
Protection of neurons and their axons, the loss the concept of a supportive role for myelin in axon
of which is the principal anatomical correlate protection. Such studies raise the hypothesis that
of progressive clinical deterioration, might be there are oligodendroglia-derived factors that protect
considered a third component. Indeed, the axons; indeed insulin like growth factor 1 (IgF1) and
overarching goal of all MS therapy is to identify glial derived neurotrophic factor (GDNF) have been
strategies to prevent axonal loss. Axon protection shown to be produced by oligodendrocytes in cell
can be achieved directly as a result of intervention culture where they do exert axon-protective effects.
in the mechanisms by which axons are injured or
degenerate. However, axon protection can also be Despite classic dogma from early neuroanatomists,
achieved as a consequence of immunomodulatory the adult mammalian CNS does indeed contain
therapies and by the promotion of remyelination. The populations of resident, proliferating and multipotent
human central nervous system does possess some neural stem cells. These adult stem cells are diffusely
capacity for variable degrees of remyelination, which distributed throughout the neuraxis in the form
can even be extensive in some cases. oligodendrocyte precursor cells (OPCs). The OPC
may well have the potential to behave as a neural
Although remyelination results in thinner and stem cell in the context of injury, representing
shorter myelin sheath “internodes” than would be a new approach to brain repair. An increasing
expected for a given diameter of axon], its potential body of evidence suggests that remyelinating
as a reparative strategy is clearly demonstrated oligodendrocytes arise from adult OPCs.
by experimental association with resolution of

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This means there are neural stem cells and OPCs

throughout the Central Nervous System, ready to
be “activated” and create new myelin on demand.
One of the main beneficial functions seen with
mesenchymal stem cells being applied into the
central nervous system is exactly this activation!
The properties of MSCs that have been shown
to be of potential therapeutic value for MS are as
follows:
1. Myelin repair: differentiation into cells of
neuroendothelial origin and replacement in
the injured CNS, stimulation of proliferation
of endogenous CNS neural stem cells, and
guidance of their differentiation towards
oligodendrocyte lineages. such as immunomodulatory, or through their use as
2. Suppression of inflammation and a vehicle following ex-vivo manipulation to secrete
immunomodulation - - transforming the central growth factors as mentioned above.
nervous system microenvironment from hostile
to supportive
What Do Research Studies Show on Stem
Cells for MS?
3. Neuroprotection through neuroprotective,
Currently, R3 Stem Cell centers offer umbilical
antioxidant agents, promotion of CNS neurite
cord mesenchymal stem cell therapy along with a
outgrowth and remodeling.
couple centers offering autologous adipose derived
4. Reduced formation of gliotic scar: through stem cell treatment. Amongst the research studies
their paracrine action, they can modify brain’s described below, it is important to understand the
cellular microenvironment leading to a term EDSS. The Expanded Disability Status Scale
significant reduction of the lesion area. (EDSS) is a method of quantifying disability in
multiple sclerosis and monitoring changes in the
5. Promotion of angiogenesis (new blood flow), level of disability over time. It is widely used in clinical
enhances tissue repair. trials and in the assessment of people with MS.
6. Cell fusion: a mechanism of neuroprotection,
The EDSS scale ranges from 0 to 10 in 0.5 unit
whereby healthy nuclei or functional genes are
increments that represent higher levels of disability.
introduced into damaged cells and help rescue
Scoring is based on an examination by a neurologist.
them and restore function
In a 2009 Panama study of 20 patients with
Stem cells can also be isolated from non-neural
MS (relapsing-remitting, primary or secondary
tissues (e.g., mesenchymal stem cells isolated
from umbilical cord tissue). Although these cell progressive), patients received intravenous infusions
populations do not reliably generate functional of umbilical cord mesenchymal stem cells.
neural derivatives, their therapeutic potential arises Enrolled subjects received 140 million umbilical cord
from their biological properties through either the mesenchymal stem cells (UCMSC) intravenously over
direct constitutive actions of the cells in question, the course of seven visits (20 million stem cells each)

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separated by 1–4 days. In our case, the statistically human umbilical cords (UC), or from his own child
significant (p < 0.03) change in EDSS mean scores from umbilical cord. The mesenchymal stem cell (MSC)
baseline to 1 month reflects a change in disability treatment was well tolerated with no significant side
category, which could translate into an improved effects.
ability to walk and work a full day with minimal, if any,
assistance. The intravenous infusion of UCMSC over A 27-year-old male started treatment in 2008, who
several days is safe in subjects with MS. was diagnosed as relapsing remitting MS From 2008
to January 2010, he received 3 intravenously as well
Additionally, UCMSC infusions may hold benefits, as 3 intrathecal infusion of BM-MSCs. As the patient
since this small study group saw improvement in stabilized, UC-MSCs were subsequently used for the
bladder, bowel, and sexual dysfunction, walking, transplantation. From August 2009 to December
upper extremity physical function, energy and 2018, he received a total of 12 intravenous infusions
fatigue, general perspective of a positive health of UC-MSCs, in absence of any other disease-
change and improved quality of life, and MRI modifying therapy (DMT).
lesions. Most subjects (83.3%) showed no disease
progression or new lesions in their MRIs. They looked at the long term effect of multiple MSCs
infusions in an MS patients to a period of some
In 2022, a case report was published of an MS patient 11 years. It is noteworthy that following the MSC
treated for 11 years, with multiple infusions of MSCs treatment, the patient with a progressive MS, showed
derived from either his bone marrow (BM), pooled a significant improvement in his EDSS score

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over time and this was in the absence of any disease

modifying therapy (eg glucocorticoid pulse). The
treatment which consisted of 16 MSCs infusions,
administrated over more than a decade period,
was overall well tolerated and lead to an apparent
clinical and radiological disease recovery. Indeed,
the MRI examinations performed from 2008 until
2018, confirmed the absence of subclinical disease
activity, a finding in agreement with other MSCs
transplantation studies in MS.
Of particular note is the continuous improvement
we witnessed over the 10 years of treatment both
clinically and pathologically. The table below details
his EDSS score improvements.
A 2018 study published out of China evaluated two
patients with multiple sclerosis, who received several
mesenchymal stem cell infusions over a two year
period.
Intravenous transfusions were performed with 1 to 2
million stem cells/kg at 3-month intervals for 7 times.
Patients in the treatment group received seven
times of UCMSCs treatments. During that period of
time, they didn’t undergo other drug treatment. The
patients in the control group (2 additional patients)
continued those medications they had already been
taking, including methylprednisolone, glucocorticoid
hormones, interferon, human immunoglobulin,

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neurotrophic factor, and traditional Chinese medicines. A newly published study (2024) titled: “Human
However, their conditions were still progressively Umbilical Cord–Derived Mesenchymal Stem Cells in
aggravated. the Treatment of Multiple Sclerosis Patients: Phase I/
In this study, UCMSC transplantation was used to II Dose-Finding Clinical Study” looked at umbilical
treat two patients with multiple sclerosis for a cord mesenchymal stem cell therapy in two different
total of seven times of treatments. dosings.
No obvious adverse reactions Patients were divided into two
or residual pathological groups: Group A comprised 20
syndromes appeared during MS patients who received two
transplantation. The doses, each with a total of
physiological examination 150 million UC-MSCs divided
and MRI results revealed into two injections, 50 million
normal indexes. Toxic administered through the
reactions of the UCMSCs were IV route, and 100 million
not detected during the 8-year administered through intrathecal
follow-up. Clinical signs and (IT) route. A month later, another
symptoms were mitigated in the similar dose was administered.
two patients after transplantation. At 3 months 8 to 10 ml of UC-MSCs
The onset frequency was compared within the Conditioned Media was delivered IT.
same time after transplantation, and the average On the other hand, Group B comprised 15 MS patients
annual onset frequency in the transplant patients were who received one dose of 150 million UC-MSCs
remarkably less than before transplantation. The EDSS divided into 50 million administered through the IV
scores demonstrated that the clinical symptoms were route and 100 million administered through IT route.
mitigated in Patient 1. At the time of this writing, his At 3 months, 8 to 10 ml UC-MSCs Conditioned Media
symptom was stable and not progressive. was delivered IT. Prior to each IT treatment, the same
After the first and second transplantations, the volume injected was withdrawn as CSF to maintain
symptoms of Patient 2 were progressive. Therefore, the CNS pressure and decrease the potential post-IT
we shortened the time interval and administered cell injection headache.
therapy. His condition was stable at the time of this So Group A received TWO treatments (a month
writing. The MRI findings showed that the number apart) and Group B received just one. Both received
of foci was obviously reduced after transplantation, conditioned media IT at 3 months.
suggesting that UCMSC transplantation promoted Although the intravenous (IV) administration of
remyelination. stem cells is the most common, a combined route
The researchers wrote, “In summary, UCMSCs play of UC-MSCs injection could be an important efficacy
an important role in immune regulation and neural element, as tracking studies have shown that MSCs
protection. UCMSCs can regulate pathological injected intrathecally (IT) migrate to the site of injury
immune responses and antibody attacks in the body. in the white matter of the brain. The migration of
The neuroprotective effect is strongly associated allogenic MSCs injected IT was found to be through
with the mechanism of promoting remyelination. the cerebrospinal fluid (CSF), reaching different
Our findings confirm that UCMSCs have functions of locations of the CNS where they would persist without
immune regulation and nerve protection, indicating the need for immune suppressants.
the feasibility of UCMSC transplantation for multiple The results indicated that both stem cell treatment
sclerosis.

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protocols halted the overall progressive deterioration accumulate in damaged tissue or inflamed areas. They
in the EDSS during the 12-month follow-up period. An also have their own advantages that makes them
improvement at all time points for both groups, except the choice of MS therapy. First, the separation of the
for the 3 months for Group A, was observed. The cells from the UC is easy, painless, and without ethical
walking and balance results are in line with the EDSS issues. Second, the amount of stem cells produced per
outcomes in Group B, while a gradual deterioration unit area is high. Third, the cost of stem cell transfusion
was noted in Group A. from the UC is not expensive.
In summary, this study demonstrated the safety Fourth, these cells are very safe to use. Based on the
and efficacy of both treatment protocols with studies presented in the section about UCMSCs, these
comprehensive assessment tools, using an allogenic cells would be considered as a safe and alternative
stem cell source originating from a single option for treatment of the neurological
umbilical cord donor and expanded parameters of MS, through results
in vitro. The various aspects confirmed by EDSS, the nine-
studied point to halting and hole peg test, the expanded
reversing MS symptoms EDSS rating neurologic
using stem cell therapy impairment, and the 25-
with parallel effects on foot walking time.
the cellular and gene How Does Stem Cell
expression levels.
Therapy Work?
There is an advantage of
If a new technology such
administering two doses
as mesenchymal stem cell
compared to one, which
and exosome therapy could
warrants more extensive
provide excellent MS benefits
studies on larger numbers of MS
with improved quality of life and
patients. Examining the addition of
lower overall healthcare costs for an
more doses and a more extended follow-
individual, it would and should become a pre-
up period is recommended for future studies.
emptive therapy. Stopping disease progression and
The findings of this study emphasize the critical role of receiving potentially some regression of the disease
regenerative medicine in managing MS. Optimizing are highly desirable, with the adage being, “Health is
the dose of treatment is an essential milestone for Wealth”.
the standardization of protocols to attain a safe
MSC-based therapy reduces inflammation,
cellular treatment of MS symptoms. The many aspects
modulates the immune system and involves
studied detected a reversal of some MS symptoms
improving local microenvironmental, immune-
and stabilization of others. The clear advantage of
regulation and anti-inflammatory biological activities
administering two doses of UC-MSCs instead of
through the secretion of exosomes, growth factors,
one in this study, in addition to one dose of CM, is
cytokines, anti-inflammatory factors and other
encouraging.
bioactive molecules.
Of the several types of MSCs, UCMSCs are the best
Stem cells and exosomes act in the body through
option for MS treatment for several reasons. These
several mechanisms. They do NOT become part of a
cells can do a faster self renewal than other MSCs,
patient’s DNA, which means they do not engraft into
can differentiate into three germ layers, and can
the person’s existing cells.

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They act through: 4. Cellular signaling – the biologics are able

to perform “cell to cell” communication. This
1. Angiogenesis – provokes formation of new promotes recipient cells to proliferate their
blood vessels. growth factor production, protein production
and regenerate tissues that are damaged.
2. Reduce inflammation – chronic disease is
associated with significant inflammation, and the 5. Prevent cell death – most cells have a timed death,
regenerative biologics reduce it nicely. where they are only allowed to live a certain length
of time. This is called apoptosis. The regenerative
3. Immune system modulation – the stem cells
biologics allow normally functioning cells (i.e.
and exosomes modulate the immune system
chondrocytes) to live longer, and spare them from
very differently than steroids. Instead of
the pre-programmed death. This can promote
blanketly suppressing the immune system, the
healthy, new tissue growth!
regenerative biologics tamp down the harmful
processes while amping up the beneficial ones. 6. Preventing scar tissue –Once that scar tissue
This includes ramping up production of several forms, it becomes nonfunctional. Stem Cells and
helpful growth factors and cytokines, while exosomes are great at preventing scar tissue
tamping down harmful ones. (anti-fibrosis).

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Stem Cells can also release a huge variety of generate large amounts of stem cells and exosomes
molecules into the extracellular environment. These that are of the highest quality possible. The lab team
molecules, which include extracellular vesicles consists of multiple PhD’s working in ISO Certified,
(exosomes), lipids, free nucleic acids, and soluble cGMP compliant clean rooms to ensure quality
proteins, exert crucial roles in repairing damaged assurance that exceeds USA FDA standards. The
tissue. Along with offering stem cells for MS, R3 Stem proprietary production process combines the highest
Cell includes stem cell exosomes, which are a type potency, safety and affordability for providers to
of extracellular vesicle participating in extensive confidently offer exosome procedures.
cell to cell communication for tissue repair and
regeneration. Millions of dollars have been invested into the
pharmaceutical grade production of the biologics
The stem cells administered by R3 are not the including first rate clean rooms, bioreactors,
ones that become a patient’s new specialty cells. nano-particle tracking analyzers, cytometers,
The administered mesenchymal stem cells are not PCR, tangential flow machines and real time
specifically designed to replace damaged and lost environmental monitoring. The quality assurance
cells “themselves”, but rather coordinate and enhance testing complies with screening and testing
this repair response by one’s own mechanisms. stan¬dards consistent with the American Association
Where do the stem cells and exosomes of Tissue Banks, cGMP standards, FDA regulations
come from? and the highest level of any regulatory agency
globally.
R3 Stem Cell’s regenerative biologics originate from
umbilical cord tissue that has been donated after a Stem Cell Derived Exosomes
scheduled c-section. No baby (or mother) is harmed
R3 Stem Cell’s Centers of Excellence globally include
during the c-section procedure. The umbilical cord
umbilical cord stem cell derived exosomes with
tissue is normally discarded, but if the mother passes
umbilical cord stem cells to provide enhanced
screening test then the umbilical cord is immediately
results. Exosomes are lipid bound vesicles (acellular)
sent to the lab.
produced by cells which contain a
The lab carefully plethora of growth factors,
processes the cytokines, mRNA and
umbilical cord to other proteins.

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They are exceptionally helpful in cell to cell the side effects R3 sees are usually mild to moderate
communication, and very effective for reducing and temporary.
inflammation when they become ingested by their
They may include itching, dizziness, lightheadedness,
recipient cell. They act as shuttles to send nucleic
low grade fever, chills, headache, nausea. These are
acids and proteins to other cells, in this way, allowing
typically temporary. If a patient has an allergic reaction
cell-to-cell communication and transporting
to the multivitamin or a preservative, all of R3’s Centers
molecules among both close and distant cells. In
have the medications to resolve it quickly.
general, these released proteins are important
regulators of intracellular information. One of the questions we get asked a lot is, “Will the
Exosomes could be the mediators of many stem stem cells get rejected?” The answer is NO.
cell-associated therapeutic activities. Considering
MSCs do not express major histocompatibility
they are 100 times smaller than stem cells, they do
complex (MHC) antigens of the class II subtype and
not have any issues passing through the blood-brain-
contain low levels of MHC molecules of the class I
barrier to reach the brain from the bloodstream
subtype. MSCs also lack the co-stimulatory molecules
So what are the benefits seen with stem cell essential for immune detection, including CD40, CD80,
therapy for MS? and CD86.
While it’s great to know that the stem cells and Therefore, MSCs generally have low immunogenicity
exosomes work hard on neuroprotection, reduce and can avoid immune rejection by the recipient,
neuro-inflammation, promote remyelination and which serves as the foundation for their successful
prevent scar tissue, what benefits do patients notice? application without needing to match the
donor to the recipient. Scientists call this being
• Increased energy levels
“immunologically privileged”.
• Increase in walking ability
Another question often asked is “Is there a chance of
• Improvements in Balance
a tumor forming?” Once again the answer is NO. The
• Reversal of some MS symptoms and stabilization mesenchymal stem cells and exosomes used during
of others treatment have never been shown to have tumor
• Improved memory forming potentials. In fact, they have been shown to
be anti-tumor forming.
• Better concentration and focus
• Reduced Brain Fog Treatment Protocol
• Better sleep patterns For the past decade, R3 has been
Disclaimer: Results will vary and are not guaranteed.
successfully offering stem cell and
exosome therapy for multiple
As mentioned in the above research studies, stem cell therapy
for MS is typically very successful. However, it is not a cure, and
sclerosis. We use a combination
repeat therapies are beneficial for continuing the improvements approach, with the biologics being
and prevent disease progression. offered both intravenous along with
intrathecal for optimal outcome.
Is stem cell therapy safe?
R3’s providers use between one million stem cells per
After a decade of performing over 24,000 stem cell kilogram up to three million stem cells per kilogram.
procedures worldwide, R3 knows that the regenerative Why such a variable amount? The reason is MS
procedures are safe. The quality control employed patients are different! Some are in earlier phases
during the stem cell production is second to none, and

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than others, patient body weights are different and What are the Outcomes?
some patients have comorbidities that need to be Similar to the research mentioned above, R3 Stem
addressed. Cell’s outcomes for MS patients have been exceptional!
Others have multiple chronic diseases, drink alcohol, The patient satisfaction rate is 85% year over year.
smoke cigarettes, etc. We’re not here to judge, just Patients typically see exceptional pain relief, increased
want to make sure enough cells are provided to obtain range of motion, improved function and mobility, and
the desired effects. So our providers use judgment on all of the benefits mentioned above.
the cell quantity needed. It may take four to six weeks for the
Safety is paramount with the results to kick in, although
biologics products being we have had patients
rigorously tested prior symptomatically feel
to use, and expert much better within the
providers managing first couple of weeks.
each treatment as It should be noted,
if you are a family again, that stem
member! cell therapy is not
a “one and done”
Why does R3 procedure, and may
Stem Cell use need to be repeated
donor tissue for every one to two
years.
its stem cells?
Although autologous Affordability
(your own) stem cells provide Because stem cell therapy is not
significant advantages, allogeneic a “one and done” cure, it’s important
(donor) stem cells have more advantages. First to make it affordable. Repeat
of all, autologous MSCs need a long time to culture therapies every year can help people
and expand, which limits its application in treatment, achieve continued improvements.
while allogeneic stem cells can be obtained and So a lot of patients seek additional
expanded more quickly, thus avoiding the delay of MS treatments at R3 Stem Cell
time window. repetitively.
Second, age is a factor that affects the physiological Unfortunately, stem cell clinics in Colombia, China and
characteristics of MSCs. Studies have shown that stem Panama charge over $25,000 USD for MS treatment.
cells from elderly donors have decreased proliferation Because the one treatment cost so much, how are
and differentiation ability. This means they are less in individuals supposed to budget for that every few
number and less effective! years?? R3 Stem Cell’s fees are less than half that for
full treatment, which also includes free PRP and a
multivitamin infusion!

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R3’s Experience References:

For the past decade, R3 Stem Cell’s Centers globally 1. Riordan et al. Clinical feasibility of umbilical cord
tissue‑derived mesenchymal stem cells in the treatment
have performed over 24,000 regenerative procedures of multiple sclerosisJ Transl Med (2018) 16:57, https://doi.
in six countries. Hundreds have been for MS. Patient org/10.1186/s12967-018 1433-7.
satisfaction across all conditions treated is 85%! 2. Multiple transplantation of mesenchymal stem cells in a
patient with active progressive multiple sclerosis: Long
R3 combines safety, effectiveness and affordability term therapeutic outcomes, Liu et al, Clinical Neurology
for the therapies. Internationally, the Intellicell is used, and Neurosurgery 223 (2022) 107475.
which is culturing the most active mesenchymal stem 3. Meng et al, Umbilical cord mesenchymal stem cell
cells to create the “smartest” stem cell in the world! transplantation in the treatment of multiple sclerosis, Am
J Transl Res 2018;10(1):212-223, www.ajtr.org /ISSN:1943-
Our experience with all types of patients has been 8141/AJTR0059423
extensive, and our Success Stories on R3’s YouTube 4. Christodoulou et al, Cell replacement therapy with stem
Channel are impressive. You can visit the channel cells in multiple sclerosis, a systematic review, Human
Success Story Playlist HERE. Cell (2024) 37:9–53, https://doi.org/10.1007/s13577-023-
01006-1
R3 Stem Cell offers free consultations for individuals to 5. Huang et al, Myelin Regeneration in Multiple Sclerosis:
discuss whether regenerative therapy is indicated for Targeting Endogenous Stem Cells, Neurotherapeutics
you. Simply call +1 (844) GET-STEM to schedule yours! (2011) 8:650–658, DOI 10.1007/s13311-011-0065-x
6. Jamali et al, Human Umbilical Cord–Derived Mesenchymal
Stem Cells in the Treatment of Multiple Sclerosis
Patients:Phase I/II Dose-Finding Clinical Study, 2024, Cell
Transplantation Volume 33: 1–18.
7. Patani et al, Experimental and Therapeutic Opportunities
for Stem Cells in Multiple Sclerosis, Int. J. Mol. Sci. 2012, 13,
14470-14491; doi:10.3390/ijms131114470.
8. Dulamea A, Mesenchymal stem cells in multiple sclerosis
- translation to clinical trials, Journal of Medicine and Life
Vol. 8, Issue 1, January-March 2015, pp.24-27.
9. Alanazi et al, Mesenchymal stem cell therapy: A review of
clinical trials for multiple Sclerosis, Regenerative Therapy
21 (2022) 201e209..

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Guide to
Stem Cell and
Exosome Therapy
for Osteoarthritis

Brought to you by

* No portion of this Document may be reproduced without the Express Written Consent of R3 Stem Cell.
Disclaimer: This guide’s education does not constitute medical advice. The USA FDA considers stem cell
therapy experimental. Any claims made in the Guide refer to procedures performed outside the USA.
206
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Guide to Stem Cell and Exosome Therapy for Osteoarthritis

Every day, R3 Stem Cell receives inquiries worldwide What happens during osteoarthritis
from individuals asking if stem cell therapy can help development?
for arthritis pain relief. Spoiler alert: It can help a lot!
In this guide, we’ll go through the basics of how stem Osteoarthritis (OA) refers to a common chronic
cells work for osteoarthritis, the latest research, and degenerative joint disease, namely the degenerative
what to expect with a regenerative procedure. injury of articular cartilage caused by multiple
factors (e.g., aging, obesity, fatigue injury, trauma,
Conventional treatments for arthritis are
joint congenital abnormalities, joint
not able to regenerate and repair
deformity, etc). Pathological
joint tissue significantly. They
changes largely include
are very limited and mostly
articular cartilage
“band aids.” For example,
destruction, subchondral
steroid injections do
not repair joint tissue osteosclerosis and
at all, and actually synovial hyperplasia.
contribute to more OA occurs primarily
joint degeneration. after middle age, and it
is more widespread in
Stem cell therapy for women than in men.
arthritis is turning out to
Age related ’wear and tear’,
be an excellent opportunity
chondrocytes’ poor response
for individuals to achieve long
to growth factors, altered bio-
lasting relief, improved function and to
mechanical properties of articular cartilage,
avoid the need for potentially risky surgery. Let’s
mitochondrial dysfunction, oxidative stress and
dig in!
inflammation are all implicated in the pathogenesis
A Significant Global Issue of OA, highlighting the multifactorial and complex
Worldwide, over 528 million individuals suffer with nature of this degenerative joint disease. Eventual
osteoarthritis pain, with the knee being the most decreases in the number of chondrocytes with age
common affected joint. The amount of people results in impaired production of extracellular matrix
affected has increased by over 100% within the past proteins.
twenty years and will increase by another 100% over What are the reasons degenerative
the next twenty!.
arthritis occurs?
Interestingly, women (60%) are more commonly Various risk factors increase your chances of
affected than men, with the majority of those developing osteoarthritis:
affected being over age 55 (70%). Osteoarthritis
u Older age. The risk of osteoarthritis increases
can greatly reduce one’s quality of life. It makes
with age.
movement painful and difficult, which can stop
people from participating in home, work or social u Sex. Women are more likely to develop
activities. This can lead to mental health impacts, osteoarthritis, though it isn’t clear why.
trouble sleeping and problems in relationships. u Obesity. Carrying extra body weight
contributes to osteoarthritis in several ways,
and the more you weigh, the greater your

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risk. Increased weight adds stress to weight- • Pain. Affected joints might hurt during or after
bearing joints, such as your hips and knees. movement.
Also, fat tissue produces proteins that can • Stiffness. Joint stiffness might be most
cause harmful inflammation in and around noticeable upon awakening or after being
your joints. inactive.
u Joint injuries. Injuries, such as those that occur
• Tenderness. Your joint might feel tender when
when playing sports or from an accident, can
you apply light pressure to or near it.
increase the risk of osteoarthritis. Even injuries
that occurred many years ago and seemingly • Loss of flexibility. You might not be able
healed can increase your risk of osteoarthritis. to move your joint through its full range of
motion.
u Repeated stress on the joint. If your job or a sport
you play places repetitive stress on a joint, that • Grating sensation. You might feel a grating
joint might eventually develop osteoarthritis. sensation when you use the joint, and you
might hear popping or crackling.
u Genetics. Some people inherit a tendency to
develop osteoarthritis. • Bone spurs. These extra bits of bone, which
feel like hard lumps, can form around
u Bone deformities. Some
the affected joint.
people are born with
malformed joints or • Swelling. This might
defective cartilage. be caused by soft tissue
inflammation around the
u Certain metabolic
joint.
diseases. These
include diabetes and Traditional
a condition in which Treatments
your body has too much
Traditional treatments for
iron (hemochromatosis).
osteoarthritis have not changed
Joint cartilage exists in much over the past few decades.
every body joint, regardless of Understandably, this can be very
whether it’s a rotating joint or not. Normally, frustrating for patients who are seeking nonoperative
cartilage formation is equal to cartilage solutions for pain relief.
degradation, which makes for a happy, healthy
joint. Unfortunately, with one of the above Patients are typically offered the following:
risk factors, the normal “homeostasis” of the • Non-steroidal anti inflammatory medication
joint may become altered. Cartilage loss may (NSAIDs)
exceed cartilage formation, which may cause • Bracing
considerable pain and disability for a person.
• Steroid (cortisone) injections
What are the symptoms of osteoarthritis?
• Cane, Walker
The symptoms of osteoarthritis typically develop
slowly and worsen over time. They often wax and • Physical therapy
wane, with chronic pain often causing debilitating • Hyaluronic acid injection
quality of life for those affected. • Glucosamine and Chondroitin supplements.
• Narcotics for when the pain is severe.

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As you may have figured out, NONE of the traditional

treatments actually help to create new cartilage
in the joint. They are meant to simply
suppress pain symptoms, like a band-aid.
In fact, there are several studies now
showing that cortisone injections
actually accelerate joint degradation.
A 2023 study in Cureus (Khan et al),
showed that the effect of cortisone
injections for knee arthritis were
short term and actually hastened the
patient’s need for total knee replacement!

Stem Cell Therapy for OA

If a new technology such as mesenchymal stem
cell and exosome therapy could improve the Stem cells and exosomes act in the body through
ability of osteoarthrits patients to avoid the need several mechanisms. They do NOT become part of a
for potentially risky surgery, it would and should patient’s DNA, which means they do not engraft into
become first line therapy. Cortisone injections cause the person’s existing cells.
more harm than good, and quite a few insurance
companies no longer pay for hyaluronic acid They act through:
injections as the results are so conflicting.
1. Angiogenesis – provokes formation of new
Cell-based therapy has been a promising option in blood vessels.
OA because it is aimed at reversing the symptoms 2. Reduce inflammation – arthritis is associated
and pathophysiology of OA. The ability of MSCs to with significant inflammation, and the
differentiate between multiple lineages including regenerative biologics reduce it nicely.
musculoskeletal tissue supports the use of MSCs as
3. Immune system modulation – the stem cells
an excellent source for degenerative musculoskeletal
and exosomes modulate the immune system
conditions such as in OA.
very differently than steroids. Instead of
The therapeutic potential of MSCs in the treatment of blanketly suppressing the immune system, the
OA is aimed at cartilage repair and restoration MSC- regenerative biologics tamp down the harmful
based therapy reduces inflammation, modulates processes while amping up the beneficial ones.
the immune system and helps to alter the ratio of This includes ramping up production of several
cartilage formation versus cartilage loss. helpful growth factors and cytokines, while
tamping down harmful ones.
MSCs are capable of significantly improving local
4. Cellular signaling – the biologics are able
microenvironmental, immune-regulation and
to perform “cell to cell” communication. This
anti-inflammatory biological activities through the
promotes recipient cells to proliferate their
secretion of exosomes, growth factors, cytokines,
growth factor production, protein production
anti-inflammatory factors and other bioactive
and regenerate tissues that are damaged.
molecules, thereby gradually becoming the simplest
and easiest method to treat OA.

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5. Prevent cell death – most cells have a timed

death, where they are only allowed to live a
certain length of time. This is called apoptosis.
The regenerative biologics allow normally
functioning cells (i.e. chondrocytes) to live
longer, and spare them from the pre-
programmed death. This can reduce the rate
of cartilage loss in a joint!
6. Preventing scar tissue – Preventing scar
tissue –Once that scar tissue forms, it
becomes nonfunctional. Stem Cells and
exosomes are great at preventing scar tissue
(anti-fibrosis).

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that are of the highest quality possible. The

lab team consists of multiple PhD’s
working in ISO Certified, cGMP
compliant clean rooms to
ensure quality assurance
that exceeds USA
FDA standards.
The proprietary
production
process combines
the highest
potency, safety
and affordability
for providers to
confidently offer
exosome procedures.
MSCs Millions of dollars have
can been invested into the
also release pharmaceutical grade production
a huge variety of the biologics including first rate clean
of molecules into the rooms, bioreactors, nano-particle tracking analyzers,
extracellular environment. These molecules, which cytometers, PCR, tangential flow machines and
include extracellular vesicles, lipids, free nucleic real time environmental monitoring. The quality
acids, and soluble proteins, exert crucial roles in assurance testing complies with screening and
repairing damaged tissue. Along with offering testing stan¬dards consistent with the American
MSCs for treatment of liver failure, R3 Stem Cell Association of Tissue Banks, cGMP standards, FDA
includes stem cell exosomes, which are a type of regulations and the highest level of any regulatory
extracellular vesicle participating in extensive cell agency globally
to cell communication for liver tissue repair and
regeneration. Is there research to back up stem cell and
exosome therapy for osteoarthritis?
Where do the stem cells and exosomes
come from? Yes there has been a lot of research performed on
stem cells for osteoarthtisis!
R3 Stem Cell’s regenerative biologics originate from
umbilical cord tissue that has been donated after a A recent 2021 study in Regenerative Medicine
scheduled c-section. No baby (or mother) is harmed evaluated ultrasound-guided intra-articular injection
during the c-section procedure. The umbilical cord of expanded umbilical cord mesenchymal stem cells
tissue is normally discarded, but if the mother passes in knee osteoarthritis. The study showed impressive
screening test then the umbilical cord is immediately results. The researchers observed functional and pain
sent to the lab. improvement at 12 and 48 months (p < 0.0001), with
statistically significant improvement on MRI scans
The lab carefully processes the umbilical cord to at 12 months in cartilage loss, osteophytes, bone
generate large amounts of stem cells and exosomes marrow lesions, effusion and synovitis (p < 0.01),

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and highly significant improvement in subchondral A study of 36 patients was conducted in China
sclerosis (p < 0.0001). comparing umbilical cord stem cells versus
hyaluronic acid for knee arthritis treatment (Wang
Their conclusion; “WJMSCs are safe and potentially et al). Significant improvements were seen in the
effective in producing significant improvement umbilical cord stem cell treated group for pain relief
in KOOS and MRI scores when administered intra- and functional improvements at both six months and
articularly in knee osteoarthritis cases under one year!
ultrasound guidance.
As a combination treatment, Mead and Mead
In a double-blind, placebo-controlled clinical trial, 20 injected a lyophilized mixture of amniotic membrane
patients with symptomatic knee OA were randomly (AM) and umbilical cord (UC) particulate into 42
divided into two groups to receive intra-articular participant knees who scored either 3 or 4 on the
injection of either 50 million allogenic placenta- Kellgren-Lawrence knee osteoarthritis scale.
derived MSCs or normal saline.
Participants were followed for 12 months, with 74%
Significant improvements were seen in quality of of patients rating their knee pain and function as
life, activity of daily living, sport/recreational activity “much improved” or “very much improved” at the
and decreased OA symptoms in the MSC-injected final follow up. The study also noted that intra-
group throughout the six month follow up. Chondral articular injection of AM/ UC particulate is generally
thickness was improved in about 10% of the total knee safe as there were no reported complications or
joint area in the intervention group at six months. adverse events aside from one case of knee swelling
The conclusion of the authoris was that “Single intra- within 36 hours of injection.
articular allogenic placental MSC injection in knee OA
is safe and can result in clinical improvements in 24 An observational study of 55 participants receiving
weeks follow-up.” cryopreserved human umbilical cord allograft

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injections for knee arthritis looked at pain, stiffness umbilical cord stem cell derived exosomes with
and functional recovery over a 90 day post-injection umbilical cord stem cells to provide enhanced
period. The Wharton’s Jelly used in the study was results. Exosomes are lipid bound vesicles (acellular)
combined with sterile saline and 5% Dimethyl produced by cells which contain a plethora of growth
Sulfoxide (5%) cryoprotectant. The study was non- factors, cytokines, mRNA and other proteins.
blinded, non-randomized and incorporated
no control group. They are exceptionally helpful in
cell to cell communication, and
Ultrasound guidance was very effective for reducing
utilized for injection accuracy. inflammation when they
At the 90 day follow up, become ingested by their
statistically significant recipient cell. They act as
improvements were noted shuttles to send nucleic
in NPRS scores and WOMAC acids and proteins to other
outcomes for Pain Relief, cells, in this way, allowing
Stiffness and Physical Function. cell-to-cell communication
The NPRS showed an average and transporting molecules
90 day pain decrease of 31.48%. No among both close and distant cells.
adverse events or adverse reactions were In general, these released proteins are
reported. important regulators of intracellular information.
Exosomes could be the mediators of many stem cell-
In a 2021 Case Report published in Pharmaceuticals,
associated therapeutic activities. Considering they
a 27 year old male was treated with a 2 mL non-
are 100 times smaller than stem cells, they do not
expanded umbilical cord-derived Wharton’s jelly (UC-
have any issues passing through the lungs to reach
derived WJ) formulation. The individual had KL Grade
the inflamed and painful joints.
II OA and a history of ACL reconstruction in the past.

During the 3 month follow up, No adverse or severe Stem Cell Derived Exosomes
adverse effects from the injection were reported. R3 Stem Cell’s Centers of Excellence globally include
No significant difference nor progression in OA via umbilical cord stem cell derived exosomes with
X-rays compared to baseline was observed. The NPRS umbilical cord stem cells to provide enhanced
displayed a 50% reduction in pain, while his SF-36 results. Exosomes are lipid bound vesicles (acellular)
displayed a 25% improvement in overall health score. produced by cells which contain a plethora of growth
The overall KOOS score improved by 10%. factors, cytokines, mRNA and other proteins.

In their conclusion, the authors noted, “UC derived WJ They are exceptionally helpful in cell to cell
has potential in mitigating the progression and the communication, and very effective for reducing
symptoms of OA. Larger long-term, non-randomized inflammation when they become ingested by their
and randomized control trials are warranted to recipient cell. They act as shuttles to send nucleic
adequately assess the safety and efficacy of UC- acids and proteins to other cells, in this way, allowing
derived WJ and its ultimate clinical use.” cell-to-cell communication and transporting
molecules among both close and distant cells. In
general, these released proteins are important
Stem Cell Derived Exosomes
regulators of intracellular information.
R3 Stem Cell’s Centers of Excellence globally include

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Exosomes could be the mediators of many stem Treatment Protocol

cell-associated therapeutic activities. Considering
For the past decade, R3 has been successfully
they are 100 times smaller than stem cells, they do
treating arthritis patients with stem
not have any issues passing through the blood-brain-
cell and exosome injection therapy.
barrier to reach the brain from the bloodstream.
The cells and exosomes are attracted
Is stem cell therapy safe? to inflammation, which is a large
component of inflammatory arthritis.
After a decade of performing over 24,000 stem cell
procedures worldwide, R3 knows that the regenerative R3’s providers use between 15 million
procedures are safe. The quality control employed stem cells up to 30 million per joint
during the stem cell production is second to none, and (depends on size of joint). R3 Stem Cell’s arthritis
the side effects R3 sees are usually mild to moderate treatment protocol includes ultrasound guidance
and temporary. for accuracy, along with platelet rich plasma therapy
to increase the effectiveness of the therapy. Safety
They may include itching, dizziness, lightheadedness, is paramount with the biologics products being
low grade fever, chills, headache, nausea. These are rigorously tested prior to use, and expert providers
typically temporary. If a patient has an allergic reaction managing each treatment as if you are a family
to the multivitamin or a preservative, all of member!
R3’s Centers have the medications to
resolve it quickly. Why does R3 Stem Cell use
One of the questions we get donor tissue for its stem cells?
asked a lot is, “Will the stem cells Although autologous (your
get rejected?” The answer is NO. own) stem cells provide
significant advantages,
MSCs do not express major
allogeneic (donor) stem cells
histocompatibility complex (MHC)
have more advantages. First of all,
antigens of the class II subtype and
autologous MSCs need a long time
contain low levels of MHC molecules
to culture and expand, which limits its
of the class I subtype. MSCs also lack the
application in treatment, while allogeneic
co-stimulatory molecules essential for immune
stem cells can be obtained and expanded more
detection, including CD40, CD80, and CD86.
quickly, thus avoiding the delay of time window.
Therefore, MSCs generally have low immunogenicity
Second, age is a factor that affects the physiological
and can avoid immune rejection by the recipient,
characteristics of MSCs. Studies have shown that
which serves as the foundation for their successful
stem cells from elderly donors have decreased
application without needing to match the
proliferation and differentiation ability. This means
donor to the recipient. Scientists call this being
they are less in number and less effective!
“immunologically privileged”.
Another question often asked is “Is there a chance of What are the Outcomes??
a tumor forming?” Once again the answer is NO. The Similar to the research mentioned above, R3 Stem
mesenchymal stem cells and exosomes used during Cell’s outcomes for arthritis patients have been
treatment have never been shown to have tumor exceptional! The patient satisfaction rate is 85% year
forming potentials. In fact, they have been shown to over year. Patients typically see exceptional pain
be anti-tumor forming.

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relief, increased range of motion, improved function Our experience with

and mobility. arthritis patients has been
extensive, and our Success
It may take four to six weeks for the results to kick Stories on R3’s YouTube
in, although we have had patients symptomatically Channel are impressive.
feel much better within the first couple of weeks. It You can visit the channel
should be noted, again, that stem cell therapy does Success Story Playlist HERE.
not eliminate arthritis, and may need to be repeated
every one to four years. R3 Stem Cell offers free consultations for individuals
to discuss whether regenerative therapy is indicated
Affordability for your arthritis pain relief.
Because stem cell therapy for arthritis is
Simply call +1 (844) GET-STEM to schedule yours!
not a “one and done” cure, it’s important
to make it affordable. Repeat therapies
every few years can help people achieve continued References:
pain relief and functional improvements. So a lot of 1. World Health Organization, Osteoarthritis, https://www.
arthritis patients seek additional treatments at R3 who.int/news-room/fact-sheets/detail/osteoarthritis,
accessed April 14, 2024.
Stem Cell every one to four years.
2. Application of mesenchymal stem cell therapy for the
Unfortunately, stem cell clinics in Colombia, China treatment of osteoarthritis of the knee: A concise review,
and Panama charge over $15,000 USD for arthritis Wang et al, World J Stem Cells. 2019 Apr 26; 11(4): 222–235.
treatment. Because the one treatment cost so much, 3. Ultrasound-guided intra-articular injection of expanded
how are individuals supposed to budget for that umbilical cord mesenchymal stem cells in knee
osteoarthritis: a safety/efficacy study with MRI data,
every few years?? R3 Stem Cell’s fees are less than half Samara et al, Regen.Med. (2022) 17(5), 299–312.
that for full treatment, which also includes free PRP
4. Olivia G Mead & Leon P Mead (2020) Intra-Articular
and a multivitamin infusion! Injection of Amniotic Membrane and Umbilical Cord
Particulate for the Management of Moderate to Severe
R3’s Experience Knee Osteoarthritis, Orthopedic Research and Reviews,
For the past decade, R3 Stem Cell’s Centers globally 161-170, DOI: 10.2147/ORR.S272980.
have performed over 24,000 regenerative procedures 5. Evaluation of the Efficacy of Cryopreserved Human
in six countries. Approximately half have been for Umbilical Cord Tissue Allografts to Augment Functional
and Pain Outcome Measures in Patients with Knee
arthritis. Patient satisfaction across all conditions
Osteoarthritis: An Observational Data Collection Study,
treated is 85%! Davis et al, Physiologia 2022, 2, 109–120. https://doi.
org/10.3390/physiologia2030010.
R3 combines safety, effectiveness and affordability for
6. Safety and efficacy of allogenic placental mesenchymal
the therapies. Internationally, the Intellicell is used,
stem cells for treating knee osteoarthritis: a pilot study,
which is culturing the most active mesenchymal stem Soltani et al, Cytotherapy, 2019 Jan;21(1):54-63.
cells to create the “smartest” stem cell in the world!
7. CURATIVE EFFECT OF HUMAN UMBILICAL CORD
MESENCHYMAL STEM CELLS BY INTRA-ARTICULAR
INJECTION FOR DEGENERATIVE KNEE OSTEOARTHRITIS,
Wang et al, 2016 Dec 8;30(12):1472-1477.

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 R3 Consumer Guide for Stem Cell and Exosome Therapy

Guide to
Stem Cell and
Exosome Therapy
for Parkinson’s
Disease

Brought to you by

* No portion of this Document may be reproduced without the Express Written Consent of R3 Stem Cell.
Disclaimer: This guide’s education does not constitute medical advice. The USA FDA considers stem cell
therapy experimental. Any claims made in the Guide refer to procedures performed outside the USA.
216
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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR PARKINSON’S DISEASE

Guide to Stem Cell and Exosome Therapy

for Parkinson’s Disease
Every day, R3 Stem Cell receives inquiries worldwide anxiety, depression, orthostatic hypotension, urinary
from individuals asking if stem cell therapy can help dysfunction, rapid eye movement sleep behavior
for Parkinson’s Disease (PD). Spoiler alert: It can disorder, and cognitive dysfunction. A proportion
help a lot! In this guide, we’ll go through the of PD patients also develop mental health
basics of how stem cells and exosomes problems, such as depression and
work for PD, the latest research, and dementia. PD with dementia often
what to expect with a regenerative develops years after the onset of
procedure. motor dysfunction and is estimated
Conventional treatments for PD in 30–80% of affected individuals.
are often not able to regenerate Currently, we can distinguish
and repair neurons or halt at least three main types of this
progression significantly. There disease. In the first type—sporadic,
has therefore been a keen interest in which the cause of the disease
in stem cell therapy, as it may actually is unknown, we can only assume a
slow down or repair the underlying disease nucleotide change in some genes, but their
process. direct effect is not specified.
A Significant Global Issue The second type—environmental, is the effect of
chemical poisons known for years, which specifically
Parkinson’s disease (PD) is a common progressive destroy dopaminergic neurons. The third type—
neurodegenerative disorder characterised by the familial Parkinson’s disease, is caused by a specific
loss of specific populations of neurons and the mutation in one of the genes: alpha-synuclein,
accumulation of protein aggregates in the brain. parkin, ubiquitin L1 hydrolase, and PINK1 kinase.
The disease affects more than 1% of the population The protein kinase PINK1 is involved in the control
over the age of 60, and as the population ages this of the state of the mitochondria. It manifests itself
frequency is likely to increase. in a constantly progressive disturbance of motor
Its main clinical manifestations are motor functions.
dysfunctions, including tremor, bradykinesia, rigidity Traditional Treatments
and postural instability. However, many non‐motor
While there are no disease-modifying treatments
symptoms may precede years before motor
for PD; dopamine replacement therapies (such
Symptoms. Olfactory impairment is one of the most as carbidopa/levodopa) can help alleviate some
common and characteristic non‐motor features of of the motor deficits, but do not slow or halt the
PD, with a prevalence of 50–90%. progression of the disease nor do they affect
many of the non-motor symptoms. These drugs
What are the reasons Parkinson’s Disease do not save dopaminergic neurons and prevent
occurs? disease progression, although they do provide
Motor impairment in patients with PD is common some short‐term improvement in motor function.
and increases markedly with age. The most common Dopaminergic neuronal death can have various
symptom of PD is tremor, which usually occurs at rest causes, including oxidative stress, neuroinflammation
but decreases with voluntary movement]. Additional and mitochondrial damage.
nonmotor symptoms include hyposmia, constipation,
Furthermore with time they produce their own

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side-effects such as drug induced dyskinesias and

behavioural and neuropsychiatric problems.
There has therefore been a keen interest in
developing strategies that actually slow
down or repair the underlying disease
process.
Many current PD therapies only
deal with symptoms, not the
neurodegeneration underlying
Parkinson’s disease. Several medications
can help manage the symptoms of
Parkinson’s disease. These include levodopa,
dopamine agonists, MAO-B inhibitors, and
COMT inhibitors. Physical therapy can help
improve the mobility and balance of people with
Parkinson’s disease. It can include exercises to In 2020, Boika et al transplanted mesenchymal stem
improve muscle strength and coordination and cells to 12 patients with PD through intravenous and
stretching and flexibility exercises. tandem (intranasal + intravenous) injections. The
effectiveness of the therapy was evaluated 1 and 3
Stem Cell Therapy for Parkinson’s Disease months post-transplantation. There was a statistically
The neurotrophic factors secreted by mesenchymal significant decrease in motor and non motor
stem cells may stimulate differentiation of the symptoms in the study group in the post-transplant
resident stem cells and protect regenerated neurons period. MSCs transplantation was deemed to be a
against stress-induced apoptosis (a neuroprotective disease-modifying therapeutic strategy in PD.
effect). Initial studies in animals have shown
Zhao et al conducted a meta-analysis in 2024, which
incredible results of MSC’s for PD.
included nine articles totaling 129 individuals. Stem
In a mouse study evaluating intranasal umbilical cell transplantation was an effective treatment for
cord stem cell exosomes, the exosomes had no Parkinson’s disease, with neural stem cells, umbilical
trouble crossing the blood–brain barrier, increasing cord mesenchymal stem cells (UCMSCs), and bone
neuronal activity in the olfactory bulb of PD mice, marrow mesenchymal stem cells (BMMSCs) being
and promoting self repair mechanisms. This method effective cell sources for transplantation. Stem cell
can save dopaminergic neurons from death, reduce transplantation was shown to be effective for at least
glial activation in the olfactory bulb and substantia 12 months, but its long-term effectiveness remained
nigra region, decrease inflammatory responses, and unknown due to the studies not monitoring patients
improve the local microenvironment in PD mice. All for more than 1 year.
these findings support the restoration of olfactory
Data from the controlled trials suggested that stem
and motor functions in mice with a PD model. The
cell transplantation as a therapy for Parkinson’s
intranasal administration of hUCMSC‐Exos may be
disease can be effective for at least 12 months. The
a promising strategy for the clinical prevention and
factors that may influence its curative effect are time
early treatment of PD.
after transplantation and stem cell types.

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Stem cells and exosomes act in the body through several mechanisms. They do NOT become part of a patient’s
DNA, which means they do not engraft into the person’s existing cells.

They act through: 4. Cellular signaling – the biologics are able

to perform “cell to cell” communication. This
1. Angiogenesis – provokes formation of new
promotes recipient cells to proliferate their
blood vessels.
growth factor production, protein production and
2. Reduce inflammation – PD is associated with regenerate tissues that are damaged.
significant inflammation, and the regenerative
5. Prevent cell death – most cells have a timed
biologics reduce it nicely.
death, where they are only allowed to live a
3. Immune system modulation – the stem cells certain length of time. This is called apoptosis. The
and exosomes modulate the immune system regenerative biologics allow normally functioning
very differently than steroids. Instead of blanketly cells (i.e. neurons) to live longer, and spare them
suppressing the immune system, the regenerative from the pre-programmed death.
biologics tamp down the harmful processes while
6. Preventing scar tissue –Once that scar tissue
amping up the beneficial ones. This includes
forms, it becomes nonfunctional. Stem Cells and
ramping up production of several helpful growth
exosomes are great at preventing scar tissue
factors and cytokines, while tamping down
(anti-fibrosis).
harmful ones.

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR PARKINSON’S DISEASE

Stem Cells can also release a huge potency, safety and affordability for
variety of molecules into the providers to confidently offer
extracellular environment. exosome procedures.
These molecules, which
Millions of dollars have
include extracellular
been invested into
vesicles (exosomes),
the pharmaceutical
lipids, free nucleic
grade production
acids, and soluble
of the biologics
proteins, exert
including first
crucial roles in
rate clean rooms,
repairing damaged
bioreactors, nano-
tissue. Along with
particle tracking
offering stem cells for
analyzers, cytometers, PCR,
treatment of PD, R3 Stem
tangential flow machines and
Cell includes stem cell exosomes,
real time environmental monitoring.
which are a type of extracellular vesicle
The quality assurance testing complies with
participating in extensive cell to cell communication
screening and testing stan¬dards consistent with
for central nervous system tissue repair and
the American Association of Tissue Banks, cGMP
regeneration.
standards, FDA regulations and the highest level of
The stem cells administered by R3 are not the any regulatory agency globally.
ones that become a patient’s new neurons. The
Stem Cell Derived Exosomes
administered mesenchymal stem cells are not
specifically designed to replace damaged and lost RR3 Stem Cell’s Centers of Excellence globally include
neural network, but rather coordinate and enhance a umbilical cord stem cell derived exosomes with
repair response by one’s own mechanisms. umbilical cord stem cells to provide enhanced results.
Exosomes are lipid bound vesicles (acellular) produced
Where do the stem cells and exosomes by cells which contain a plethora of growth factors,
come from? cytokines, mRNA and other proteins.
R3 Stem Cell’s regenerative biologics originate from They are exceptionally helpful in cell to cell
umbilical cord tissue that has been donated after a communication, and very effective for reducing
scheduled c-section. No baby (or mother) is harmed inflammation when they become ingested by their
during the c-section procedure. The umbilical cord recipient cell. They act as shuttles to send nucleic acids
tissue is normally discarded, but if the mother passes and proteins to other cells, in this way, allowing cell-
screening test then the umbilical cord is immediately to-cell communication and transporting molecules
sent to the lab. among both close and distant cells. In general,
The lab carefully processes the umbilical cord to these released proteins are important regulators of
generate large amounts of stem cells and exosomes intracellular information.
that are of the highest quality possible. The lab team Exosomes could be the mediators of many stem cell-
consists of multiple PhD’s working in ISO Certified, associated therapeutic activities. Considering they are
cGMP compliant clean rooms to ensure quality 100 times smaller than stem cells, they do not have
assurance that exceeds USA FDA standards. The any issues passing through the blood-brain-barrier to
proprietary production process combines the highest reach the brain from the bloodstream.

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Is stem cell therapy safe? Therefore, MSCs generally have low immunogenicity
and can avoid immune rejection by the recipient,
AfAfter a decade of performing over 24,000 stem cell
which serves as the foundation for their successful
procedures worldwide, R3 knows that the regenerative
application without needing to match the donor to the
procedures are safe. The quality control employed
recipient. Scientists call this being “immunologically
during the stem cell production is second to none, and
privileged”.
the side effects R3 sees are usually mild to moderate
and temporary. Another question often asked is “Is there a chance of
a tumor forming?” Once again the answer is NO. The
They may include itching, dizziness, lightheadedness,
mesenchymal stem cells and exosomes used during
low grade fever, chills, headache, nausea. These are
treatment have never been shown to have tumor
typically temporary. If a patient has an allergic reaction
forming potentials. In fact, they have been shown to be
to the multivitamin or a preservative, all of R3’s Centers
anti-tumor forming.
have the medications to resolve it quickly.
One of the questions we get asked a lot is, “Will the Treatment Protocol
stem cells get rejected?” The answer is NO. For the past decade, R3 has been
successfully treating patients with
MSCs do not express major histocompatibility complex
stem cell and exosome therapies with
(MHC) antigens of the class II subtype and contain low
injection, infusion, intranasal, intrathecal
levels of MHC molecules of the class I subtype. MSCs
and nebulizer. For PD treatment, a
also lack the co-stimulatory molecules essential for
combination of intravenous and intrathecal is used,
immune detection, including CD40, CD80, and CD86.

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR PARKINSON’S DISEASE

or possibly IV and intranasal in certain circumstances. How are individuals supposed to budget for that??
Most patients, over 75%, begin to see improvements R3 Stem Cell’s fees are less than half that for full
within three months and last between 12 and 24 treatment, which also includes free exosomes, PRP and
months. a multivitamin infusion!
For PD, R3’s providers use between one to three million R3’s Experience
stem cells per kilogram. In addition, billions of stem cell
exosomes are included. Safety is paramount with the For the past decade, R3 Stem Cell’s Centers globally
biologics products being rigorously tested prior to use, have performed over 24,000 regenerative procedures
and expert providers managing each treatment as if in six countries. Patient satisfaction across all conditions
you are a family member! treated is very high, at 85%. However, MSC treatment for
PD is a MUCH newer option, so satisfaction percentages
Why does R3 Stem Cell use donor tissue for haven’t been definitively established.
its stem cells? R3 combines safety, effectiveness and affordability
Although autologous (your own) stem cells provide for the therapies. Internationally, the Intellicell is used,
significant advantages, allogeneic (donor) stem cells which is culturing the most active mesenchymal stem
have more advantages. First of all, autologous MSCs cells to create the “smartest” stem cell in the world!
need a long time to culture and expand, which limits R3 Stem Cell offers free consultations for individuals to
its application in treatment, while allogeneic stem cells discuss whether regenerative therapy is indicated for
can be obtained and expanded more quickly, thus your PD. Simply call +1 (844) GET-STEM to schedule
avoiding the delay of time window. yours
Second, age is a factor that affects the physiological References:
characteristics of MSCs. Studies have shown that stem
1. 1. Ali et al, Stem cells and the treatment of Parkinson’s disease,
cells from elderly donors have decreased proliferation Experimental Neurology, Volume 260, October 2014, Pages
and differentiation ability. This means they are less in 3-11
number and less effective! 2. Huang et al, Intranasal Administration of Umbilical Cord
Mesenchymal Stem Cell Exosomes Alleviates Parkinson’s
Affordability Disease, Neuroscience 549 (2024) 1–12.
3. Cecerska‑Heryć et al, The Use of Stem Cells as a Potential
Stem cell therapy for PD may be the Treatment Method for Selected Neurodegenerative Diseases:
key step in achieving a stoppage Review, Cellular and Molecular Neurobiology (2023) 43:2643–
of disease progression along with 2673, https://doi.org/10.1007/s10571-023-01344-6.
functional improvements, and we 4. Zhao J, Qu K, Jia S, Yang R, Cui Z, Li J, Yu P and Dong M
(2024) Efficacy and efficacy-influencing factors of stem
want to make it affordable for as
cell transplantation on patients with Parkinson’s disease:
many individuals as possible. Our global volume has a systematic review and meta-analysis. Front. Neurol.
allowed us to keep our patient cost as low as possible. 15:1329343. doi: 10.3389/fneur.2024.1329343
Especially considering that most patients will need 5. Aleksandra Glavaski-Joksimovic , Martha C. Bohn,
repeat therapies every one to two years, treatment Mesenchymal stem cells and neuroregeneration in Parkinson’s
Disease, Experimental Neurology, Volume 247, September
cost is extremely important. 2013, Pages 25-38
Unfortunately, stem cell clinics in Colombia, China and 6. Liu et al, Stem Cell-Based Therapies for Parkinson Disease, Int. J.
Mol. Sci. 2020, 21, 8060; doi:10.3390/ijms21218060
Panama charge over $20,000 USD for PD treatment.

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 R3 Consumer Guide for Stem Cell and Exosome Therapy

Guide to Stem Cell

and Exosome
Therapy for
Peripheral
Neuropathy

Brought to you by

* No portion of this Document may be reproduced without the Express Written Consent of R3 Stem Cell.
Disclaimer: This guide’s education does not constitute medical advice. The USA FDA considers stem cell therapy experimental. Any claims
made in the Guide refer to procedures performed outside the USA.
223
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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR PERIPHERAL NEUROPATHY

Guide to Stem Cell and Exosome Therapy

for Peripheral Neuropathy
Every day, R3 Stem Cell receives inquiries worldwide What are the reasons PN occurs?
from individuals asking if stem cell therapy can help
for Peripheral Neuropathy (PN). Spoiler alert: It can There are MANY different causes of peripheral
help a lot! In this guide, we’ll go through the basics of neuropathy. Here is a list of some of the more
how stem cells and exosomes work for PN, the latest common types
research, and what to expect with a regenerative
1. Diabetic polyneuropathy
procedure.
2. Chemotherapy induced
Conventional treatments for neuropathy are often
not able to regenerate and repair damaged nerves 3. Alcoholic induced
significantly. For those who desire reduced pain 4. Post-radiation
along with improved balance and sensation, failure 5. Trigeminal neuralgia
with conventional treatments is disappointing and
no improvements have been seen for a 6. Postherpetic neuralgia
long time. 7. Charcot Marie Tooth Disease
Stem cell therapy for 8. Fabry Disease
PN is turning out 9. Leprosy
to be an excellent 10. HIV neuropathy
opportunity for
individuals to 11. Vitamin Deficiency
achieve meaningful 12. Carpal Tunnel Syndrome
long term results. Let’s
13. Phantom Limb Pain
dig in!
14. Painful radiculopathy
A Significant Global Issue
Peripheral neuropathy is characterized with
Neuropathic pain is one of the most difficult chronic progressive neuronal loss, demyelination, and
pain conditions to treat and affects approximately 6% damaged nerve regeneration with ultimately
of the population and can be caused by any number dysfunction of nerve fibers impairing both the
of events. Word descriptor qualities of neuropathic autonomic and somatic divisions of the nervous
pain that patients report are typically sharp, shooting, system. As there are many different causes of
burning, cramping, crushing, electric, or lancinating. peripheral neuropathy, most of them lead to
The most common type of peripheral neuropathy increased oxidative stress and low-grade, chronic
is secondary to diabetes (type 1 or 2). Diabetic inflammation. When chronically seen, this leads
peripheral neuropathy (DPN) is a complication of to leads to impairment in sensory, motor, and
diabetes that affects an estimated 50% of patients autonomic nerves. Symptoms may include pain,
with the disease. numbness, tingling and loss of balance in the legs,
along with loss of dexterity in the hands.
Despite significant advances in peripheral The symptoms may worsen at night, leading to
neuropathy treatment, safe and effective treatment difficulty sleeping. Patients may experience muscle
options targeting neuropathic pain are lacking. weakness and a loss of reflexes as the disease

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progresses, increasing the risk of falls and injuries.

Diabetic peripheral neuropathy (DPN) is a significant
contributor to diabetic foot risk. According
to a study, patients with DPN and sensory
deficiencies have a seven-fold more
significant likelihood of developing
diabetic foot ulcers than those without
these conditions.
The loss of protective sensation and the
lack of muscular coordination in the foot
and leg that result from neuropathy raise
the mechanical stress placed on the body
during movement, which causes severe
foot defects like claw toes or hammer toes, and
twisted ankles. It is challenging to treat diabetic
foot; even if the ulcer heals, the recurrence rate is
30%–40% after a year. medications (such as lidocaine plaster and
capsaicin patch) are recommended as second-line
Traditional Treatments pharmacological treatments. As third-line drugs,
Current medicinal therapies for neuropathy include strong opioids, such as morphine and oxycodone, are
tricyclic antidepressants, anticonvulsants, opioids, used.
serotonin and norepinephrine reuptake inhibitors, and
topical agents [18]. However, none of these therapies Compliance with anti-neuropathic medication can be
directly target the in- flammatory milieu, most have problematic for patients with potential side effects of
untoward side ef- fects, and there is little consensus weight gain, drowsiness, dry mouth, negative mood
on the optimal regimen [18], with less than 30% of changes, and increased suicide risk.
patients receiving adequate pain relief.
Nonpharmacological treatment options for drug-
Neuropathy treatment is a real challenge for refractory neuropathic pain include the following
physicians. NP management primarily targets approaches: Interventional therapies (e.g., peripheral
clinical symptoms instead of causative factors. nerve blockade, epidural steroid injection, sympathetic
Currently, available treatment options include nerve/ganglion blockade, intrathecal morphine
both pharmacological and nonpharmacological delivery, and peripheral and central neurostimulation),
approaches. physical therapies (e.g., massage, ultrasound,
transcutaneous electrical nerve stimulation), and
Regarding pharmacological therapies of NP, tricyclic psychological therapies, such as cognitive behavioral
antidepressants (e.g., amitriptyline, nortriptyline), therapy.
serotonin-norepinephrine reuptake inhibitors (e.g.,
duloxetine and venlafaxine), and gabapentinoids (i.e., Spinal cord stimulation (SCS) or dorsal column
gabapentin and pregabalin) are recommended as first- stimulation constitutes an advanced neuromodulation
line drugs. procedure enabling to potentially decrease
neuropathic pain in many syndromes, such as in failed
Weak opioid analgesics, such as tramadol, are back surgery syndrome (FBSS), complex regional pain
recommended as second-line drugs. Topical syndrome (CRPS) type I and II, postherpetic neuralgia,

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and pure radicular pain. been demonstrated to ameliorate disease

symptoms through the integration
Facial neuropathic pain is of new graft-derived cells, which
particularly difficult to treat. It provide trophic support to
responds poorly to opioid and endogenous cells and facilitate
over- the-counter analgesics. immunomodulation.
First-line anti-neuropathic
medication for facial pain typically In addition to that, MSCs show
utilizes tricyclic antidepressants and their immunomodulatory effects via
anticonvulsants, with only about 25% secreted cytokines and growth factors
responding. via direct cell interactions, as well as strong
paracrine influences. MSCs secrete biological factors
Stem Cell Therapy for Peripheral via extracellular vesicles (i.e. exosomes), which are
Neuropathy divided into microvesicles (>200-nmdiameter) and
exosomes (50–200 nm diameter). Extracellular vesicles
Stem cell therapy for peripheral neuropathy is expected are composed of thousands of proteins, messenger
to have a transformative influence in the future and RNA, and/or microRNA, many of which are reported
provide patients with this crippling ailment with new to enhance neuronal growth and health in model
hope. Stem cell therapy demonstrates potential for systems.
treating the root causes of the condition, fostering
nerve regeneration, and easing peripheral neuropathy Researchers at Nanyang Medical College in China
symptoms. performed a a double-blind, randomly paired trial with
inclusion criteria of type 2 diabetes and neuropathy.
The capacity for regeneration offered by stem cell 112 patients were divided into the control group
therapy is one of its most significant advantages. The (n=56) and the observation group (n=56). The
ability of stem cells to encourage nerve regeneration observation group was administered bone marrow
and return to normal function is feasible by mesenchymal stem cells (dose not reported). The
administering stem cells to the damaged areas. Patients symptom effective rate, average limb nerve conduction
with diabetic peripheral neuropathy, for example, have velocity, and clinical symptom score were associated
had encouraging improvements in nerve conduction, with an improvement in the observation group
pain relief, and sensory function due to pre- clinical and compared with the control group.
early-phase clinical research.
The symptom effective rate in the observation versus
Over the last decade, stem cell transplantation has control group at 3 years was 84% (47 of 56) versus 43%
exhibited remarkable potential for the repair of (24 of 56; p<0·0001). Average limb nerve conduction
nervous system damage in neuropathic syndromes velocity was 52·75 m/s in the observation group
rather than simply providing temporary palliation. versus 41·32 m/s in the control group 3 years after
The molecular mechanisms through which treatment (p<0·0001). The clinical symptom scores in
mesenchymal stem cells (MSCs) exert their the observation group versus the control group was
beneficial effects with regard to pain are yet to be 4·05 versus 7·79 (p<0·0001) 3 years after treatment.
clarified. However, a previous study reported that There were no adverse events in control group. In both
MSCs migrated to injured tissue and mediated groups, no serious adverse events were reported.
functional recovery following brain, spinal cord, and The authors concluded that patients given stem cell
peripheral nerve lesions, suggesting that these cells transplantation in addition to standard treatment for
could modulate pain generation following nerve diabetic peripheral neuropathy were associated with
constriction. Further, transplanted stem cells have an improved average limb nerve conduction velocity

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR PERIPHERAL NEUROPATHY

and clinical symptom scores compared with those on the results suggest that MSC transfusion may be a
standard treatment alone. promising therapeutic option for patients with diabetic
Riad et al published their findings in 2023 on 10 peripheral neuropathy. In addition to evaluating clinical
Egyptian patients with diabetic peripheral neuropathy symptoms, the study also assessed laboratory test
(DPN) who were between the ages of 33 and 45, had results at baseline and 90 days post-MSC transfusion.
type I or type II diabetes. They had DPN confirmed The results showed a significant improvement in levels
by diagnostic testing and nerve conduction, and had of hemoglobin, fasting and post- prandial glucose, and
not received therapy for DPN. The stem cells were cholesterol at the 90-day follow-up period compared to
obtained from the patient’s own bone marrow, and baseline.
then injecting 1 million MSCs/kg into the patients in These findings are consistent with previous
one session (IV infusion). Follow-up evaluations were research, which has suggested that MSC transfusion
done after 3 months and included clinical examination, may be effective in managing intractable pain
laboratory tests, and nerve conduction studies. and improving neurological function through
Results showed that all patients exhibited neurorestorative mechanisms, including neuro-
improvement in at least one symptom post-transfusion. constructive interventions, immunomodulation, and
Laboratory analysis revealed significant differences in microcirculation enhancement.
hemoglobin, glucose, and cholesterol levels at 90 days In the table below, you can see the outcomes of ten
post-transfusion compared to baseline levels. Nerve randomized
conduction and controlled
studies clinical
revealed trials on the
that most effectiveness
improved of stem cells
after MSC for diabetic
transfusion. neuropathy
Overall, and diabetic
foot. Ulcers
healed well,

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR PERIPHERAL NEUROPATHY

balance and sensation the injection sites (n=36

improved, along with walking intraoral sites and n=5 facial sites)
ability. Circulation improved dramatically as well. nor evidence of general or medical health issues
at any follow-up stage (to 6 months).
With regard to diabetes, MSCs improve glycemic
control, accompanied by improved renal function and The results showed a reduction in pain intensity
regeneration of normal β pancreatic islets. MSCs secret scores from the stem cell treatment in 7/9 patients
neurotrophic and angiogenic factors to ameliorate (two with marginal improvement and five subjects
diabetic neuropathy (DN), and offer a novel therapeutic with good-to-excellent pain reduction). Five of these
option to treat DN. MSCs modulate the central nervous positive responders also reduced their need for
system-injured environment and promote repair as they gabapentin medication, three required the same level
secrete anti-inflammatory, antiapoptotic molecules, of medication, and one subject com-menced multiple
and trophic factors to support axonal growth, medication trials within the 6-month period without
immunomodulation, angiogenesis, remyelination, and any pain relief, with all medication subsequently
protection from apoptotic cell death. discontinued
MSCs are known to support angiogenesis mostly The majority of subjects, however, reported a positive
through a paracrine effect, which augments the effect from stem cell therapy with pain reduction in
microcirculation supporting peripheral nerves. This addition to lowering anti-neuropathic medication
impaired vascular supply has been implicated in the dose to enable an improved quality of life with fewer
lead-up to DN. drug side effects. Seven out of nine overall had positive
responses.
MSC study for trigeminal neuralgia
How do Stem Cells and Exosomes Act in the
In a stem cell therapy study for trigeminal neuralgia, ten
subjects (all females) were recruited for the procedure
Body?
with a mean age of 55 years. Stem cells and exosomes act in the body through
several mechanisms. They do NOT become part of a
No subject showed any side effects of the treatment, patient’s DNA, which means they do not engraft into
which included local injections. There was no evidence the person’s existing cells.
of unusual localized swellings or lesions at any of

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They act through: 4. Cellular signaling – the biologics

are able to perform “cell to cell”
1. Angiogenesis – provokes communication. This promotes
formation of new blood vessels. recipient cells to proliferate their
2. Reduce inflammation – PN growth factor production, protein
is associated with significant production and regenerate nerve
inflammation, and the tissues that are damaged.
regenerative biologics reduce it 5. Prevent cell death – most
nicely. cells have a timed death, where
3. Immune system modulation – the they are only allowed to live a certain
stem cells and exosomes modulate the length of time. This is called apoptosis.
immune system very differently than steroids. The regenerative biologics allow normally
Instead of blanketly suppressing the immune functioning cells (i.e. neuron cells) to live longer,
system, the regenerative biologics tamp down and spare them from the pre-programmed
the harmful processes while amping up the death.
beneficial ones. This includes ramping up 6. Preventing scar tissue –Once that scar tissue
production of several helpful growth factors and forms, it becomes nonfunctional. Stem Cells and
cytokines, while tamping down harmful ones. exosomes are great at preventing scar tissue
(anti-fibrosis).

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Stem Cells can also release a huge variety of molecules for providers to confidently offer exosome procedures.
into the extracellular environment. These molecules, Millions of dollars have been invested into the
which include extracellular vesicles (exosomes), pharmaceutical grade production of the biologics
lipids, free nucleic acids, and soluble proteins, exert including first rate clean rooms, bioreactors,
crucial roles in repairing damaged tissue. Along with nano-particle tracking analyzers, cytometers, PCR,
offering stem cells for treatment of PN, R3 Stem Cell tangential flow machines and real time environmental
includes stem cell exosomes, which are a type of monitoring. The quality assurance testing complies
extracellular vesicle participating in extensive cell with screening and testing stan¬dards consistent
to cell communication for ovarian tissue repair and with the American Association of Tissue Banks, cGMP
regeneration. standards, FDA regulations and the highest level of any
The stem cells administered by R3 are not the ones regulatory agency globally.
that become a patient’s new follicle. The administered
mesenchymal stem cells are not specifically designed
Stem Cell Derived Exosomes
to replace damaged and lost follicles, but rather R3 Stem Cell’s Centers of Excellence globally include
coordinate and enhance an ovarian repair response by umbilical cord stem cell derived exosomes with
one’s own mechanisms. umbilical cord stem cells to provide enhanced results.
Exosomes are lipid bound vesicles (acellular) produced
Where do the stem cells and exosomes come by cells which contain a plethora of growth factors,
from? cytokines, mRNA and other proteins.
R3 Stem Cell’s regenerative biologics originate from
They are exceptionally helpful in cell to cell
umbilical cord tissue that has been donated after a
communication, and very effective for reducing
scheduled c-section. No baby (or mother) is harmed
inflammation when they become ingested by their
during the c-section procedure. The umbilical cord
recipient cell. They act as shuttles to send nucleic acids
tissue is normally discarded, but if the mother passes
and proteins to other cells, in this way, allowing cell-
screening test then the umbilical cord is immediately
to-cell communication and transporting molecules
sent to the lab.
among both close and distant cells. In
The lab carefully processes the general, these released proteins
umbilical cord to generate large are important regulators of
amounts of stem cells and intracellular information.
exosomes that are of the
highest quality possible. Exosomes could be the
The lab team consists of mediators of many
multiple PhD’s working stem cell-associated
in ISO Certified, cGMP therapeutic activities.
compliant clean rooms Considering they are
to ensure quality 100 times smaller than
assurance that exceeds stem cells, they do not
USA FDA standards. The have any issues passing
proprietary production through the blood-brain-
process combines the highest barrier to reach the brain
potency, safety and affordability from the bloodstream.

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR PERIPHERAL NEUROPATHY

Is stem cell therapy safe? forming potentials. In fact, they have been shown to
After a decade of performing over 24,000 stem cell be anti-tumor forming.
procedures worldwide, R3 knows that the regenerative Treatment Protocol
procedures are safe. The quality control employed
during the stem cell production is second to none, and For the past decade, R3 has been
the side effects R3 sees are usually mild to moderate successfully treating patients with stem
and temporary. cell and exosome therapies with injection,
infusion, intranasal, intrathecal and nebulizer
They may include itching, dizziness, lightheadedness, procedures.
low grade fever, chills, headache, nausea. These are
typically temporary. If a patient has an allergic For Peripheral Neuropathy, R3’s providers use between
reaction to the multivitamin or a one and three million stem cells per
preservative, all of R3’s Centers kilogram (depends on patient
have the medications to resolve weight). In addition, billions
it quickly. of stem cell exosomes and
platelet rich plasma therapy
One of the questions (PRP) are included at no
we get asked a lot is, cost.
“Will the stem cells get
rejected?” The answer R3 Stem Cell’s PN
is NO. treatment protocol
includes an IV
MSCs do not therapy combining
express major mesenchymal stem
histocompatibility cells and exosomes,
complex (MHC) antigens along with a multivitamin
of the class II subtype IV as well. R3 has
and contain low levels of developed a proprietary
MHC molecules of the class I injection protocol for the legs
subtype. MSCs also lack the co- combining the biologics along
stimulatory molecules essential for with platelet rich plasma therapy to
immune detection, including CD40, CD80, increase the effectiveness of the therapy.
and CD86. Safety is paramount with the biologics products being
rigorously tested prior to use, and expert providers
Therefore, MSCs generally have low immunogenicity
managing each treatment as if you are a family
and can avoid immune rejection by the recipient,
member!
which serves as the foundation for their successful
application without needing to match the Why does R3 Stem Cell use donor tissue for
donor to the recipient. Scientists call this being its stem cells?
“immunologically privileged”.
Although autologous (your own) stem cells provide
Another question often asked is “Is there a chance of significant advantages, allogeneic (donor) stem cells
a tumor forming?” Once again the answer is NO. The have more advantages. First of all, autologous MSCs
mesenchymal stem cells and exosomes used during need a long time to culture and expand, which limits its
treatment have never been shown to have tumor application in treatment, while allogeneic stem cells can

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR PERIPHERAL NEUROPATHY

be obtained and expanded more quickly, thus avoiding R3 combines safety, effectiveness and affordability
the delay of time window. for the therapies. Internationally, the Intellicell is used,
which is culturing the most active mesenchymal stem
Second, age is a factor that affects the physiological cells to create the “smartest” stem cell in the world!
characteristics of MSCs. Studies have shown that stem
cells from elderly donors have decreased proliferation R3 Stem Cell offers free consultations for individuals to
and differentiation ability. This means they are less in discuss whether regenerative therapy is indicated for
number and less effective! your PN. Simply call +1 (844) GET-STEM to schedule
yours!
Affordability
References:
Stem cell therapy for PN may be the key
step to completely changing a person’s 1. Waterman et al, Anti-Inflammatory Mesenchymal Stem Cells
(MSC2) Attenuate Symptoms of Painful Diabetic Peripheral
quality of life, and we want to make it
Neuropathy, STEM CELLS TRANSLATIONAL MEDICINE
affordable for as many individuals as 2012;1:557–565 www.StemCellsTM.com
possible. Our global volume has allowed us to keep our
2. Shi et al, Efficacy and safety of autologous marrow stem
patient cost as low as possible.
cell transplantation in patients with diabetic peripheral
neuropathy: a double-blind, randomly paired trial, www.
Unfortunately, stem cell clinics in Colombia, China and thelancet.com/diabetes-endocrinology , 2016.
Panama charge over $20,000 USD for PN
treatment. How are individuals 3. Joshi,H.P.;Jo,H.-J.;Kim, Y.-H.; An, S.-B.; Park,
C.-K.; Han, I. Stem Cell Therapy for
supposed to budget for that?? Modulating Neuroinflammation in
R3 Stem Cell’s fees are Neuropathic Pain. Int. J. Mol. Sci.
typically less than half 2021, 22, 4853. https://doi.
that for full treatment, org/10.3390/ijms22094853
which also includes free 4. Sharma et al, Role of
exosomes, PRP and a Regenerative Therapeutics
multivitamin infusion! in Diabetic Peripheral
Neuropathy: Current
Advances and Future
R3’s Experience Prospects, European Journal
of Medical and Health
FFor the past decade, R3 Sciences Vol 6 | Issue 2 | March
Stem Cell’s Centers globally 2024 ISSN 2593-8339
have performed over 24,000
5. E Russell Vickers, Elisabeth Karsten,
regenerative procedures in six John Flood & Richard Lilischkis (2014)
countries. Patient satisfaction across A preliminary report on stem cell therapy for
all conditions treated is very high, at 85%. R3 neuropathic pain in humans, Journal of Pain Research, ,
255-263, DOI: 10.2147/JPR.S63361
has treated hundreds of patients with varying types of
peripheral neuropathy, and over a thousand patients 6. Riad et al, Effect of MSC Transfusion on DPN, International
with diabetes. Journal of Chemical Sciences, IJCBS, 24(8) 2023: 46-51.

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 R3 Consumer Guide for Stem Cell and Exosome Therapy

Guide to
Stem Cell and
Exosome Therapy
for Premature
Ovarian Failure

Brought to you by

* No portion of this Document may be reproduced without the Express Written Consent of R3 Stem Cell.
Disclaimer: This guide’s education does not constitute medical advice. The USA FDA considers stem cell
therapy experimental. Any claims made in the Guide refer to procedures performed outside the USA.
233
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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR PREMATURE OVARIAN FAILURE

Guide to Stem Cell and Exosome Therapy

for Premature Ovarian Failure
Every day, R3 Stem Cell receives inquiries worldwide reproductive senescence or menopause when
from individuals asking if stem cell therapy can their reserve is depleted. There are around 6 to 7
help for Premature Ovarian Failure (POF). Spoiler million germ cells in a female fetus. Approximately
alert: It can help a lot! In this guide, we’ll go 400,000 to 500,000 primordial follicles persist
through the basics of how stem cells and by the time a girl enters adolescence.
exosomes work for POF, the latest Approximately 1000 follicles each
research, and what to expect with a month are lost after menarche.
regenerative procedure.
Around age 50, there are only
Conventional treatments for POF
around 1000 follicles left after
are often not able to regenerate
the number of follicles reduces to
and repair ovarian tissue and
about 25,000 after age 37, and the
follicular activation significantly.
rate of follicular loss increases. Thus,
For women who desire conception
throughout a woman’s reproductive
spontaneously or with IVF, failure with
conventional treatments is disappointing life, only about 400 follicles will develop
and entails a significant time factor with it. and ovulate, with the large bulk never doing so.

Stem cell therapy for POF is turning out to be an POF affects approximately 1% of women of
excellent opportunity for individuals to achieve childbearing age. Although 5–10% of patients
functional restoration of the ovaries. Let’s dig in! may conceive naturally, conventional infertility
treatments, including assisted reproductive
A Significant Global Issue technology, often prove ineffective for the majority.
The ovaries are complex and critical reproductive For infertile patients with POF, oocyte donation or
organs in the female body. Multiple factors can adoption exist, although a prevalent desire persists
affect the function of ovaries leading to infertility among them to have biological children. Stem cells,
in females. The outside layer of the ovaries contains which are characterized by their undifferentiated
unique structures known as follicles. nature, self-renewal capability, and potential to
differentiate into various cell types, have emerged as
These follicles produce an oocyte (immature egg), promising avenues for treating POF. Stem cell therapy
which becomes mature into a fertilizable egg by a can potentially reverse the diminished ovarian
process known as folliculogenesis. Ovarian follicles endocrine function and restore fertility.
include three categories of cells: oocytes, theca and
granulosa. Follicle growth and development depends Premature ovarian failure (POF), aka (POI) Primary
on the follicle-stimulating hormone (FSH) and ovarian insufficiency or early menopause, is a
luteinizing hormone (LH) receptors, which are found puzzling and complex condition. POF affects one in
in the granulosa and theca cells. Folliculogenesis is every 250 women under 35 years and one in every
a well-planned and regulated process. The process 100 women under 40 year. POF has significant health
involves the development of primordial follicles into implications for women.
primary, preantral, and ultimately antral follicles. POF diminishes the likelihood of a natural pregnancy
Ovulation happens after this stage. The number of significantly.
primordial follicles is restricted during a woman’s Vaginal dryness, discomfort, and itching are the most
reproductive life. Females are said to have entered prevalent urogenital symptoms. Sexual function

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR PREMATURE OVARIAN FAILURE

is further hampered by urogenital atrophy and

hypoestrogenism. A decline in bone mineral density
(BMD) is a hazard to POF patients. In addition to
experiencing psychological anguish, investigations
on POF women have found that they have a higher
chance of developing neurodegenerative disorders.
Generally, POF women’s life span is decreased
due to cardiovascular illness, osteoporosis and
sexual dysfunction. Hypergonadotropinism
and amenorrhea are also among the main POF
characteristics that lead to premenopausal syndrome
and female infertility.
What are the reasons POF occurs? replacement therapy (HRT) is the most prevalent POF
The essential processes in POF are follicle depletion treatment.
and follicular dysfunction. The quality of the oocytes
The role of HRT in boosting fertility, on the other
and follicular pool can be affected by genetic,
hand, is still debatable. Alternative therapies should
paracrine, endocrine, mitochondrial dysfunction, and
be used to lessen the symptoms and risks associated
metabolic variables, yet the origin of POF is unknown.
with POF, as HRT is regarded as dangerous in women
A high FSH level is a clear indicator of ovarian
who have a history of ovarian cancer or breast cancer;
failure.
it also raises the risk of blood clots, cancer, strokes,
Among the leading causes of POF are Iatrogenic and other complications.
factors, such as pelvic surgery and chemotherapy,
environmental factors, such as viral infections, Egg donation is the last and most hopeful option for
radiation, and toxins, autoimmune diseases with most POF women. However, donation of egg supplies
anti-ovarian antibodies causing ovarian damage, and is limited, and patients who receive these eggs will not
genetic changes, such as point mutation, chromosome be able to produce biological children of their own.
imbalances involving the X chromosome or As a result, specialists are on the lookout for more
autosomes. Over 50% of POF cases are still idiopathic effective and innovative POF treatments. Scientists
despite improvements in medicine. are turning to alternate therapies, such as stem cell
Genetics may directly cause the disease or merely therapy, to treat POF and other kinds of infertility due
predispose a person to it. Regarding POF, certain to adverse effects connected with HRT therapy used
elements may be found in around 20–25% of to treat POF and different types of infertility.
instances. POF is inherited in 4–31% of cases, with an
X-chromosome aberration playing a crucial part in Stem Cell Therapy for POF
the condition. SC therapy has shown encouraging outcomes thus
Traditional Treatments far, with spontaneous pregnancies occurring in
women with a poor ovarian reserve who had bone
Conventional treatments for POF include marrow Stem Cell therapy. Extensive investigations
hormone replacement therapy, androgen, on SCs capable of producing oocytes have been
counseling, synthesized bioidentical hormones, carried out in mice and humans. These findings give
Dehydroepiandrosterone, donated oocytes, exercise a reason for optimism in developing novel POF/POI
and diet, and stem cell treatment. Hormone therapies. By increasing the number of primordial

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR PREMATURE OVARIAN FAILURE

follicles, decreasing granulosa cell (GC) mortality,

and restoring ovary sex hormone activity, SCs
from diverse sources may aid and support the
restoration of ovarian function.
It has been demonstrated in several
investigations that these UCMSCs can
repair compromised ovarian function by
producing cytokines and other factors
involved in proliferation and tissue
formation. Here is a proposed explanation of
the fundamental mechanism of action that stem
cells are thought to have (see figure below).
The first clinical studies were conducted on people
using MSCs from bone marrow (BM) with iliac crest

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR PREMATURE OVARIAN FAILURE

aspiration for cell collection, stem cell isolation, and human menstrual blood stem cells were injected
invitro culture methods. A stem cell therapy resulting into the left ovary of women with POI, resulting in
in the live birth of a 2.7 kg female baby by a 45-year- natural pregnancies in 4 of 15 women 3 months after
old perimenopausal lady was reported by Gupta et al. transplantation. The control group that underwent
When R3 Stem Cell performs the POF procedure, a routine intracytoplasmic sperm injection did not
transvaginal ultrasound probe guides the cannula achieve pregnancy during the same period. Clinical
into each ovary, where stem cells and exosomes pregnancies were observed in 7 of 15 women in
are injected. It’s a safe, effective and well tolerated the experimental group, with 5 of 7 successfully
procedure. giving birth. No significant differences in the AMH
levels, mean antral follicle count (AFC), or oocyte
Positive results with a similar technique, with 10 number were observed between the two groups.
POF younger women, showed a restoration of However, the oocyte fertilization rate and embryo
menstruation in two patients and a pregnancy with number improved in the stem cell group, suggesting
live birth. paracrine effects rather than oocyte differentiation.
A pilot study on 17 POF women looked at the effects Zhu et al. further compared the efficacy of
of stem cell ovarian transplant (SCOT) on ovarian intraovarian injection of UC-MSCs with intravenous
reserve. As a result, six pregnancies and three injection, noting faster restoration of ovarian function
different newborns were accomplished, and 81.3 in the intraovarian injection group, although the
percent of women had improved ovarian function long-term restoration was similar in both groups. This
biomarkers (AMH and AFC). was an animal study.
A preclinical meta-analysis looked at 37 studies Most human studies on MSC therapy have
involving 1079 animals in 2023. The meta-analysis demonstrated the effectiveness of stem cells in
result indicated that the transplantation of MSCs treating POF, with evidence showing that these
might exert therapeutic effects on animal models cells may develop into ovarian follicles and regain
of POF, and these effects might be associated ovarian function. The therapeutic action of MSCs is
with improving the disorder of the sexual cycle, generally regulated by a complex web of biological
modulating serum hormone expressions to a better processes rather than a single component. Following
state, and restoring ovarian function. MSC migration to the damaged ovary, paracrine
To date, several studies on bone marrow stem effects control ovarian cell proliferation, induction
cells have reported promising results, including of apoptosis and autophagy, immunization, fibrosis,
an increased ovarian volume, elevated E2 levels, and oxidative stress.
restoration of the menstrual cycle, improved The mesenchymal stem cells that are extracted from
menopausal symptoms, increased anti-Mullerian the human umbilical cord (hUC-MSCs) comprise
hormone (AMH) levels, an increased number of antral umbilical cord tissue-derived stem cells, and they
follicles, higher pregnancy rates, and decreased retain not only mesenchymal stem cells’ essential
apoptosis. Three studies using bone marrow stem characteristics but also have a strong capacity for
cells were conducted in humans. One study reported proliferation and differentiation.
a live birth after SCT and another study revealed five
pregnancies. None of these human studies reported Stem cells and exosomes act in the body through
any adverse events. several mechanisms. They do NOT become part of a
patient’s DNA, which means they do not engraft into
In a 2020 study by Zafardoust et al, autologous the person’s existing cells.

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR PREMATURE OVARIAN FAILURE

They act through: 4. Cellular signaling – the biologics are able

to perform “cell to cell” communication. This
1. Angiogenesis – provokes formation of new promotes recipient cells to proliferate their
blood vessels. growth factor production, protein production and
2. Reduce inflammation – POF is associated with regenerate tissues that are damaged.
significant inflammation, and the regenerative 5. Prevent cell death – most cells have a timed
biologics reduce it nicely. death, where they are only allowed to live a
3. Immune system modulation – the stem cells certain length of time. This is called apoptosis. The
and exosomes modulate the immune system regenerative biologics allow normally functioning
very differently than steroids. Instead of blanketly cells (i.e. ovary granulosa cells) to live longer, and
suppressing the immune system, the regenerative spare them from the pre-programmed death.
biologics tamp down the harmful processes while 6. Preventing scar tissue –Once that scar tissue
amping up the beneficial ones. This includes forms, it becomes nonfunctional. Stem Cells and
ramping up production of several helpful growth exosomes are great at preventing scar tissue (anti-
factors and cytokines, while tamping down fibrosis).
harmful ones.

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR PREMATURE OVARIAN FAILURE

Stem Cells can also release a huge variety of during the c-section procedure. The umbilical cord
molecules into the extracellular environment. These tissue is normally discarded, but if the mother passes
molecules, which include extracellular vesicles screening test then the umbilical cord is immediately
(exosomes), lipids, free nucleic acids, and soluble sent to the lab.
proteins, exert crucial roles in repairing damaged The lab carefully processes the umbilical cord to
tissue. Along with offering stem cells for treatment generate large amounts of stem cells and exosomes
of POF, R3 Stem Cell includes stem cell exosomes, that are of the highest quality possible. The lab team
which are a type of extracellular vesicle participating consists of multiple PhD’s working in ISO Certified,
in extensive cell to cell communication for ovarian cGMP compliant clean rooms to ensure quality
tissue repair and regeneration. assurance that exceeds USA FDA standards. The
The stem cells administered by R3 are not the proprietary production process combines the highest
ones that become a patient’s new follicle. The potency, safety and affordability for providers to
administered mesenchymal stem cells are not confidently offer exosome procedures.
specifically designed to replace damaged and lost Millions of dollars have been invested into the
follicles, but rather coordinate and enhance an pharmaceutical grade production of the biologics
ovarian repair response by one’s own mechanisms. including first rate clean rooms, bioreactors,
nano-particle tracking analyzers, cytometers,
Where do the stem cells and exosomes PCR, tangential flow machines and real time
come from? environmental monitoring. The quality assurance
R3 Stem Cell’s regenerative biologics originate from testing complies with screening and testing
umbilical cord tissue that has been donated after a stan¬dards consistent with the American Association
scheduled c-section. No baby (or mother) is harmed of Tissue Banks, cGMP standards, FDA regulations and
the highest level of any regulatory agency globally.

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Stem Cell Derived Exosomes Therefore, MSCs generally have low immunogenicity
and can avoid immune rejection by the recipient,
R3 Stem Cell’s Centers of Excellence globally include
which serves as the foundation for their successful
umbilical cord stem cell derived exosomes with
application without needing to match the donor to the
umbilical cord stem cells to provide enhanced results.
recipient. Scientists call this being “immunologically
Exosomes are lipid bound vesicles (acellular) produced
privileged”.
by cells which contain a plethora of growth factors,
cytokines, mRNA and other proteins. Another question often asked is “Is there a chance of
a tumor forming?” Once again the answer is NO. The
They are exceptionally helpful in cell to cell
mesenchymal stem cells and exosomes used during
communication, and very effective for reducing
treatment have never been shown to have tumor
inflammation when they become ingested by their
forming potentials. In fact, they have been shown to be
recipient cell. They act as shuttles to send nucleic acids
and proteins to other cells, in this way, allowing cell- anti-tumor forming
to-cell communication and transporting molecules
among both close and distant cells. In general,
Treatment Protocol
these released proteins are important regulators of For the past decade, R3 has been
intracellular information. successfully treating patients with
stem cell and exosome therapies with
Exosomes could be the mediators of many stem cell- injection, infusion, intranasal, intrathecal
associated therapeutic activities. Considering they are and now, intra-ovarian procedures.
100 times smaller than stem cells, they do not have
any issues passing through the blood-brain-barrier to For POF, R3’s providers use between 100
reach the brain from the bloodstream. million stem cells up to 150 million stem cells (depends
on patient weight). In addition, billions of stem cell
Is stem cell therapy safe? exosomes and platelet rich plasma therapy (PRP) are
After a decade of performing over 24,000 stem cell included at no cost.
procedures worldwide, R3 knows that the regenerative R3 Stem Cell’s POF treatment protocol includes
procedures are safe. The quality control employed transvaginal ultrasound guidance for accuracy and
during the stem cell production is second to none, and safety, along with exosomes and platelet rich plasma
the side effects R3 sees are usually mild to moderate therapy to increase the effectiveness of the therapy.
and temporary. IV treatment is also part of the protocol. Safety
They may include itching, dizziness, lightheadedness, is paramount with the biologics products being
low grade fever, chills, headache, nausea. These are rigorously tested prior to use, and expert providers
typically temporary. If a patient has an allergic reaction managing each treatment as if you are a family
to the multivitamin or a preservative, all of R3’s Centers member!
have the medications to resolve it quickly.
Why does R3 Stem Cell use donor tissue for
One of the questions we get asked a lot is, “Will the its stem cells?
stem cells get rejected?” The answer is NO.
Although autologous (your own) stem cells provide
MSCs do not express major histocompatibility complex significant advantages, allogeneic (donor) stem cells
(MHC) antigens of the class II subtype and contain low have more advantages. First of all, autologous MSCs
levels of MHC molecules of the class I subtype. MSCs need a long time to culture and expand, which limits
also lack the co-stimulatory molecules essential for its application in treatment, while allogeneic stem cells
immune detection, including CD40, CD80, and CD86. can be obtained and expanded more quickly, thus

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR PREMATURE OVARIAN FAILURE

avoiding the delay of time window. percentages haven’t been definitively established.
Second, age is a factor that affects the physiological R3 combines safety, effectiveness and affordability
characteristics of MSCs. Studies have shown that stem for the therapies. Internationally, the Intellicell is used,
cells from elderly donors have decreased proliferation which is culturing the most active mesenchymal stem
and differentiation ability. This means they are less in cells to create the “smartest” stem cell in the world!
number and less effective! R3 Stem Cell offers free consultations for individuals to
discuss whether regenerative therapy is indicated for
What are the Outcomes? your POF. Simply call +1 (844) GET-STEM to schedule
Similar to the research mentioned above, R3 yours!
Stem Cell’s outcomes for SLE patients have been References:
exceptional! The patient satisfaction rate is 85% year 1. Herraiz, S., Romeu, M., Buigues, A., Martinez, S., Diaz-Garcia, C.,
over year. Patients typically see exceptional pain relief, G.mez-Segu., I., … & Pellicer, A. (2018). Autologous stem cell
increased range of motion, improved function and less ovarian transplantation to increase reproductive potential in
need for traditional medications. patients who are poor responders. Fertility and sterility, 110(3),
496-505.e1.
It may take four to six weeks for the results to kick in, 2. Guo C, Ma Y, Situ Y, Liu L, Luo G, Li H, Ma W, Sun L, Wang W,
Weng Q, Wu L and Fan D (2023) Mesenchymal stem cells
although we have had patients symptomatically feel therapy improves ovarian function in premature ovarian
much better within the first couple of weeks. It should failure: a systematic review and meta-analysis based on
be noted, again, that stem cell therapy does not preclinical studies. Front. Endocrinol. 14:1165574. doi: 10.3389/
eliminate SLE, and may need to be repeated every one fendo.2023.1165574
to three years. 3. Gupta, S., Lodha, P., Karthick, M. S., & Tandulwadkar, S.
(2018). Role of Autologous Bone Marrow-Derived Stem Cell
Therapy for Follicular Recruitment in Premature Ovarian
Affordability Insufficiency: Review of Literature and a Case Report of
Stem cell therapy for POF may be the key step in World’s First Baby with Ovarian Autologous Stem Cell Therapy
in a Perimenopausal Woman of Age. Journal of human
achieving a successful pregnancy, and we want to reproductive sciences, 11(2), 125–130. https:// doi. org/ 10.
make it affordable for as many individuals as possible. 4103/ JHRS. JHRS_ 57_ 18
Our global volume has allowed us to keep our patient 4. Herraiz, S., Buigues, A., D.az-Garc.a, C., Romeu, M., Mart.nez,
cost as low as possible. S., G.mez-Segu., I., … & Pellicer, A. (2018). Fertility rescue and
ovarian follicle growth promotion by bone marrow stem cell
Unfortunately, stem cell clinics in Colombia, China and infusion. Fertility and sterility, 109(5.
Panama charge over $20,000 USD for POF treatment. 5. Amna Umer1 · Nasar Khan1,2 · David Lawrence Greene1,2 ·
How are individuals supposed to budget for that?? R3 Umm E. Habiba1 · Sabiha Shamim1 ·Asma Umer Khayam3,
Stem Cell’s fees are less than half that Stem Cell Reviews and Reports, The Therapeutic Potential
of Human Umbilical Cord Derived Mesenchymal Stem Cells
for full treatment, which also includes for the Treatment of Premature Ovarian Failure, https://doi.
free exosomes, PRP and a multivitamin org/10.1007/s12015-022-10493-y
infusion! 6. Zafardoust,S.;Kazemnejad,S.;Darzi,M.;Fathi-Kazerooni,M.;Rast
egari,H.;Mohammadzadeh,A.ImprovementofPregnancy Rate
R3’s Experience and Live Birth Rate in Poor Ovarian Responders by Intraovarian
Administration of Autologous Menstrual Blood Derived-
For the past decade, R3 Stem Cell’s Centers globally Mesenchymal Stromal Cells: Phase I/II Clinical Trial. Stem Cell
have performed over 24,000 regenerative procedures Rev. Rep. 2020, 16, 755–763.
in six countries. Patient satisfaction across all conditions 7. Kim, H.K.; Kim, T.J. Current Status and Future Prospects of
Stem Cell Therapy for Infertile Patients with Premature
treated is very high, at 85%. However, MSC treatment
Ovarian Insufficiency. Biomolecules2024,14,242. https:// doi.
for POF is a MUCH newer option, so satisfaction org/10.3390/biom14020242

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 R3 Consumer Guide for Stem Cell and Exosome Therapy

Guide to
Stem Cell and
Exosome Therapy
for Psoriasis

Brought to you by

* No portion of this Document may be reproduced without the Express Written Consent of R3 Stem Cell.
Disclaimer: This guide’s education does not constitute medical advice. The USA FDA considers stem cell therapy experimental. Any claims
made in the Guide refer to procedures performed outside the USA.
242
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 G U I D E TO ST E M C E L L A N D E XO S O M E T H E R A P Y F O R P S O R I A S I S

Guide to Stem Cell and

Exosome Therapy for Psoriasis
Every day, R3 Stem Cell receives inquiries worldwide stated that 57% of moderate-to-severe psoriasis
from individuals asking if stem cell therapy can help patients currently under treatment do not achieve
for Psoriasis. Spoiler alert: It can help a lot! In this clear/almost clear status, confirming earlier findings
guide, we’ll go through the basics of how stem cells about most psoriasis patients worldwide are
and exosomes work for psoriasis, the latest research, inadequately treated.
and what to expect with a regenerative procedure.
Chronic skin inflammatory diseases including atopic
Conventional treatments for psoriasis are often not dermatitis (AD) and psoriasis have been considered
able to stop the disease progression and control the uncontrolled inflammatory responses, which have
topical plaques and joint erosion. For those usually troubled patients around the
who desire reduced pain along with world. Moreover, the recent method
improved skin appearance, failure to treat AD and psoriasis has been
with conventional treatments is based on the inhibition, not
disappointing and occurs all regulation, of the abnormal
too often. inflammatory response, which
Stem cell therapy for can induce a number of side
psoriasis is turning out to effects and drug resistance in
be an excellent opportunity long-term treatment.
for individuals to achieve
Unlike AD, psoriasis accounts for
meaningful long term results. Let’s
approximately 1% of children and
dig in!
11% of adults in an epidemiological study
A Significant Global Issue of 20 countries. Moreover, the age distribution of
psoriasis has a bimodal onset including before the
Psoriasis is considered a chronic, inflammatory,
age of 40 years accounting for 75% of cases and after
and immune-mediated systemic disease with
the age of 40 years for the rest.
involvement of both skin and other organs, including
at least cardiovascular and articular systems and What are the reasons Psoriasis occurs?
gastrointestinal district, with various degrees of
involvement variable from patient to patient. An over-reactive immune system that creates
inflammation in your skin causes psoriasis.
Psoriasis affects 0.51–11.43% of the adult population,
If you have psoriasis, your immune system is
and it is associated with a psychological burden that
supposed to destroy foreign invaders, like bacteria, to
can lead to mental disorders, including depression
keep you healthy and prevent you from getting sick.
and anxiety.
Instead, your immune system can mistake healthy
The phenomenon of the undertreatment and non- cells for foreign invaders. As a result, your immune
treatment of psoriasis is still diffuse worldwide, system creates inflammation or swelling, which you
including Europe and the USA, and even worse in see on the surface of your skin as skin plaques.
those developing countries where psoriasis patients Psoriasis runs in families. There may be a genetic
with the moderate-to-severe disease have poor or component to psoriasis because biological parents
not all access to these new expensive treatments. A may pass the condition down to their children.
recent global survey named “Clear about Psoriasis”

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Traditional Treatments
Several treatment options can relieve psoriasis
symptoms. Common psoriasis treatments
include:
• Steroid creams.
• Moisturizers for dry skin.
• Medication to slow skin cell
production (anthralin).
• Medicated lotions or shampoos.
• Vitamin D3 ointment.
• Vitamin A or retinoid creams.
If your symptoms of psoriasis don’t improve after
treatment, or if you have large areas of involvement
(10% of your skin or more), your healthcare provider
may recommend the following treatments: Stem Cell Therapy for Psoriasis
There have been several studies published over the
• Light therapy: LED lights at specific
past few years showcasing just how well stem cells
wavelengths can decrease skin inflammation
work for psoriasis. In 2022, Chang et al evaluated
and help slow your skin cell production.
human umbilical cord mesenchymal stem cells for
• PUVA: This treatment combines a medication psoriasis in 18 patients.
called psoralen with exposure to a special form
of ultraviolet light. At the sixth month, 47% had at least 40%
improvement, 35% had more than 75% improvement
• Retinoids: These vitamin A-related drugs can
and 18% had more than 90% improvement in the
help your psoriasis symptoms but may cause
PASI score (Psoriasis Area Severity Index). However,
side effects, including birth defects.
the remaining 9 patients did not show significant
• Immune therapies: Newer immune improvement. Three patients showed no sign of
therapy medications (biologics and small disease (a score of 0) or minimal disease (a score
molecule inhibitors) work by blocking your of 1) based on the PGA score (Physician’s Global
body’s immune system so it can’t cause an Assesment). Furthermore, we found that the efficiency
autoimmune reaction. of female patients (66.7%, 6/9) was higher than
• Methotrexate: Providers recommend this that of male patients (25%, 2/8), and we did not find
medication for severe cases of psoriasis. It may significant differences in other aspects, such as the
cause liver disease. If you take it, your provider severity of the disease, between female and male
will monitor your progress with blood tests. You patients.
may need periodic liver biopsies to check your
In this study, the clinical trial demonstrated that
liver health.
the application of clinical-grade umbilical cord
• Cyclosporine: This medicine can help severe mesenchymal stem cells is safe and partly effective in
psoriasis but it may cause high blood pressure patients with psoriasis, and the efficacy appears to be
and kidney damage. related to sex, with this treatment being more

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effective in women than in men. Among

the 6 patients who had at least 75%
improvement in PASI, 3 of the patients
received a single dose of 1.5 × 106/kg, and
the remaining 3 patients received a single
dose of 2.0 × 106/kg, 2.5 × 106/kg and 3.0 ×
106/kg, respectively.
However, the role of mesenchymal stem
cells in vivo is not permanent. In the present
study, recurrence occurred in 2 patients
who had an improvement of PASI 90. They
had disease relapse at 8 and 9 months,
respectively, after the infusions. The
recurrence may be ascribed to the limited
duration of UMSCs and the persistence
of pathogenic factors. A repeated
UMSC infusion is feasible and necessary
after several months to avoid disease
relapse. Notably, one patient who had an
improvement of PASI 90 at the 6-month
follow-up maintained one-year relapse-free
status without using any other traditional
drugs.
Interestingly, we found that UMSC
treatment for psoriasis was more effective
in females, with a response rate of 66.7%.
See various before and after pictures below.
In 2016, Chen et al. described two cases
of psoriasis Vulgaris successfully treated
with infusion of umbilical cord-derived
mesenchymal stem cells (UC-MSCs) with
remission maintained for 5 years without
relapse.
More recently, Wang et al. treated a 19-year-
old man with a 5-year history of severe
plaque psoriasis refractory to multiple
topical and systemic therapies with an
infusion of allogeneic human mesenchymal
stem cells. Complete regression was achieved
after 5 infusions with no adverse reactions, and he
experienced 3 years of disease-free status.

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How do Stem Cells and Exosomes Act

in the Body?
Stem cells and exosomes act in the body through
several mechanisms. They do NOT become part of a
patient’s DNA, which means they do not engraft into
the person’s existing cells
They act through: 4. Cellular signaling – the biologics are able
to perform “cell to cell” communication. This
1. Angiogenesis – provokes formation of new
promotes recipient cells to proliferate their
blood vessels.
growth factor production, protein production
2. Reduce inflammation – Psoriasis is associated and regenerate nerve tissues that are damaged.
with significant inflammation, and the
5. Prevent cell death – most cells have a timed
regenerative biologics reduce it nicely.
death, where they are only allowed to live a
3. Immune system modulation – the stem cells certain length of time. This is called apoptosis.
and exosomes modulate the immune system The regenerative biologics allow normally
very differently than steroids. Instead of functioning cells (i.e. neuron cells) to live longer,
blanketly suppressing the immune system, the and spare them from the pre-programmed
regenerative biologics tamp down the harmful death.
processes while amping up the beneficial ones.
6. Preventing scar tissue –Once that scar tissue
This includes ramping up production of several
forms, it becomes nonfunctional. Stem Cells and
helpful growth factors and cytokines, while
exosomes are great at preventing scar tissue
tamping down harmful ones.
(anti-fibrosis).

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Stem Cells can also release a huge variety of molecules during the c-section procedure. The umbilical cord
into the extracellular environment. These molecules, tissue is normally discarded, but if the mother passes
which include extracellular vesicles (exosomes), screening test then the umbilical cord is immediately
lipids, free nucleic acids, and soluble proteins, exert sent to the lab.
crucial roles in repairing damaged tissue. Along with
offering stem cells for treatment of psoriasis, R3 Stem The lab carefully processes the umbilical cord to
Cell includes stem cell exosomes, which are a type generate large amounts of stem cells and exosomes
of extracellular vesicle participating in extensive cell that are of the highest quality possible. The lab team
to cell communication for ovarian tissue repair and consists of multiple PhD’s working in ISO Certified,
regeneration. cGMP compliant clean rooms to ensure quality
assurance that exceeds USA FDA standards. The
The stem cells administered by R3 are not the ones proprietary production process combines the highest
that become part of a patient’s DNA. The administered potency, safety and affordability for providers to
mesenchymal stem cells are not specifically designed confidently offer exosome procedures.
to replace damaged and lost epithelial cells, but rather
coordinate immune system modulation. Millions of dollars have been invested into the
pharmaceutical grade production of the biologics
Where do the stem cells and exosomes come including first rate clean rooms, bioreactors,
from? nano-particle tracking analyzers, cytometers, PCR,
R3 Stem Cell’s regenerative biologics originate from tangential flow machines and real time environmental
umbilical cord tissue that has been donated after a monitoring. The quality assurance testing complies
scheduled c-section. No baby (or mother) is harmed with screening and testing stan¬dards consistent with

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the American Association of Tissue Banks, MSCs do not express major

cGMP standards, FDA regulations and histocompatibility complex (MHC)
the highest level of any regulatory antigens of the class II subtype and
agency globally. contain low levels of MHC molecules
of the class I subtype. MSCs also
Stem Cell Derived Exosomes lack the co-stimulatory molecules
R3 Stem Cell’s Centers of Excellence essential for immune detection,
globally include umbilical cord stem including CD40, CD80, and CD86.
cell derived exosomes with umbilical Therefore, MSCs generally have low
cord stem cells to provide enhanced immunogenicity and can avoid immune
results. Exosomes are lipid bound vesicles rejection by the recipient, which serves as the
(acellular) produced by cells which contain a plethora foundation for their successful application without
of growth factors, cytokines, mRNA and other proteins. needing to match the donor to the recipient. Scientists
They are exceptionally helpful in cell to cell call this being “immunologically privileged”.
communication, and very effective for reducing Another question often asked is “Is there a chance of
inflammation when they become ingested by their a tumor forming?” Once again the answer is NO. The
recipient cell. They act as shuttles to send nucleic acids mesenchymal stem cells and exosomes used during
and proteins to other cells, in this way, allowing cell-to- treatment have never been shown to have tumor
cell communication and transporting molecules among forming potentials. In fact, they have been shown to be
both close and distant cells. In general, these released anti-tumor forming.
proteins are important regulators of intracellular
information. Treatment Protocol
Exosomes could be the mediators of many stem cell- For the past decade, R3 has been
associated therapeutic activities. Considering they are successfully treating patients with stem
100 times smaller than stem cells, they do not have any cell and exosome therapies with injection,
issues passing through the blood-brain-barrier to reach infusion, intranasal, intrathecal and
the brain from the bloodstream. nebulizer procedures.

Is stem cell therapy safe? For psoriasis, R3’s providers use between one and two
million stem cells per kilogram (depends on patient
After a decade of performing over 24,000 stem cell weight). In addition, billions of stem cell exosomes and
procedures worldwide, R3 knows that the regenerative platelet rich plasma therapy (PRP) are included at no
procedures are safe. The quality control employed cost.
during the stem cell production is second to none, and
the side effects R3 sees are usually mild to moderate R3 Stem Cell’s psoriasis treatment protocol includes
and temporary. an IV therapy combining mesenchymal stem cells
and exosomes, along with a multivitamin IV as well.
They may include itching, dizziness, lightheadedness, R3 has developed a proprietary injection protocol for
low grade fever, chills, headache, nausea. These are the legs combining the biologics along with platelet
typically temporary. If a patient has an allergic reaction rich plasma therapy to increase the effectiveness of
to the multivitamin or a preservative, all of R3’s Centers the therapy. Safety is paramount with the biologics
have the medications to resolve it quickly. products being rigorously tested prior to use, and
One of the questions we get asked a lot is, “Will the expert providers managing each treatment as if you are
stem cells get rejected?” The answer is NO. a family member!

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Why does R3 Stem Cell use donor tissue for R3’s Experience
its stem cells? For the past decade, R3 Stem Cell’s Centers globally
Although autologous (your own) stem cells provide have performed over 24,000 regenerative procedures
significant advantages, allogeneic (donor) stem cells in six countries. Patient satisfaction across all conditions
have more advantages. First of all, autologous MSCs treated is very high, at 85%. R3 has treated hundreds of
need a long time to culture and expand, which limits patients with varying types of peripheral neuropathy,
its application in treatment, while allogeneic stem cells and over a thousand patients with diabetes.
can be obtained and expanded more quickly, thus R3 combines safety, effectiveness and affordability
avoiding the delay of time window. for the therapies. Internationally, the Intellicell is used,
Second, age is a factor that affects the physiological which is culturing the most active mesenchymal stem
characteristics of MSCs. Studies have shown that stem cells to create the “smartest” stem cell in the world!
cells from elderly donors have decreased proliferation R3 Stem Cell offers free consultations for individuals
and differentiation ability. This means they are less in to discuss whether regenerative therapy is indicated
number and less effective! for your psoriasis. Simply call +1 (844) GET-STEM to
schedule yours!
Affordability
Stem cell therapy for psoriasis may be References:
the key step to completely changing a 1. Cheng et al, Human umbilical cord mesenchymal stem cells for
person’s quality of life, and we want to psoriasis: a phase 1/2a, single-arm study, Signal Transduction
make it affordable for as many individuals as possible. and Targeted Therapy (2022)7:263
Our global volume has allowed us to keep our patient 2. Diotallevi, F.; Di Vincenzo, M.; Martina, E.; Radi, G.; Lariccia, V.;
cost as low as possible. Offidani, A.; Orciani, M.; Campanati, A. Mesenchymal Stem Cells
and Psoriasis: Systematic Review. Int. J. Mol.Sci.2022,23,15080.
Unfortunately, stem cell clinics in Colombia, China https:// doi.org/10.3390/ijms232315080
and Panama charge over $20,000 USD for psoriasis .
treatment. How are individuals supposed to
budget for that?? R3 Stem Cell’s fees
are typically less than half that
for full treatment, which also
includes free exosomes,
PRP and a multivitamin
infusion!

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 R3 Consumer Guide for Stem Cell and Exosome Therapy

Guide to
Stem Cell and
Exosome Therapy
for Rheumatoid
Arthritis

Brought to you by

* No portion of this Document may be reproduced without the Express Written Consent of R3 Stem Cell.
Disclaimer: This guide’s education does not constitute medical advice. The USA FDA considers stem cell therapy experimental. Any claims
made in the Guide refer to procedures performed outside the USA.
250
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Guide to Stem Cell and Exosome Therapy

for Rheumatoid Arthritis
Every day, R3 Stem Cell receives inquiries worldwide prevalence of 460 per 100,000 population between
from individuals asking if stem cell therapy can help 1980 and 2019. Women are affected three times more
for Rheumatoid Arthritis (RA). Spoiler alert: It than men, with a mean age of 55 years old
can help a lot! In this guide, we’ll go
The advanced form of the disease
through the basics of how stem
is characterized by severe and
cells and exosomes work for RA,
debilitating chronic pain that
the latest research, and what
compromises patients’ quality
to expect with a regenerative
of life. Inadequate management
procedure.
further results in disease
Conventional treatments for RA progression, which ultimately
are often not able to successfully leads to joint erosion, destruction
promote remission significantly. and deformities.
For those who desire reduced pain Previously, more than 50% of RA patients
along with less swelling and improved energy were disabled, incapable of serving on a full-time
and functional abilities, failure with conventional
work basis, and were subject to increased mortality.
treatments is disappointing and occurs all too often.
However, the 21st Century has led to a better
Stem cell therapy for RA is turning out to be an understanding of disease pathophysiology and
excellent opportunity for individuals to achieve remarkable progress in the treatment of RA. This
meaningful long term results. Let’s dig in! has resulted in the development of more efficient
treatment approaches with the improvement of
A Significant Global Issue the disease activity control, the degree of pain and
Rheumatoid joint damage.
arthritis (RA) is a Nevertheless, up
chronic systemic to half of patients
disease that causes fail current
damage to joints, conventional
connective tissues, treatment
muscle, tendons, options.
and fibrous tissue,
and, as a result, has What are the
a major impact on reasons RA
society. According occurs?
to the evidence, Rheumatoid
the prevalence arthritis is an
of rheumatic autoimmune
diseases such as disease, and it is
RA has increased associated with
in the last decades, intense, chronic
with a global inflammation.

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There is growing evidence that RA involves chronic

inflammation resulting from innate and adaptive
immune system dysfunction, including
immune responses to autoantigens,
abnormalities in the cytokine signaling
network, and complement activation by
immune complexes.
This disease initially affects the synovial
joints (see figure below) and later
progresses to the skin, eyes, heart,
kidneys, and lungs. Ultimately, the patient
suffers from joint failure characterized by
cartilage damage and severely weakened
tendons and ligaments.
Essentially, one forms autoantibodies versus
synovial tissue in joints. This is very different that
osteoarthritis (wear and tear). Some of the immune bone and cartilage destruction. Previously, NSAIDs
cells responsible for inflammation are monocytes, were considered as first-line drugs, however low
macrophages, T lymphocytes, and B cells. The effectiveness in prevention of damage progression
synovial membrane and cartilage undergo significant and side effects at high doses such as nausea,
inflammation, causing hyperplastic synovium and abdominal pain, ulcers and gastrointestinal bleeding,
cartilage destruction that eventually lead to bone limited the implementation of these drugs.
erosion, significant swelling, deformity and pain. Among the above indicated conventional treatments,
DMARDs demonstrated a high potential to reduce
Traditional Treatments disease symptoms and prevent disease progression
The main goal in RA treatment is to achieve clinical in patients with RA, however, they constitute high
remission or to reduce disease progression by financial costs and exhibit serious side effects.
inhibiting joint inflammation. Currently available Additionally, despite significant pain reduction
conventional treatment methods include synthetic reported in numerous randomized controlled trials,
and biologic DMARDs (disease modifying anti- many patients still experience clinically meaningful
rheumatic drugs) along with glucocorticoids (GCs). levels of remaining pain despite the treatment,
and continue to be intolerant or resistant to these
DMARDs are the mainstay of RA therapy, which therapies
include heterogeneous drugs that inhibit disease
progression and control symptoms. About 30–50% of RA patients require long-term treatment, and
patients are unresponsive to conventional DMARDs. according to the evidence, currently available drugs
If a 2–6 month treatment with methotrexate mono- have limited efficacy; in fact, some patients do
or combinational therapy is inadequate, additional not achieve remission and disease control despite
DMARDs should be added. being treated with multiple conventional disease-
modifying antirheumatic drugs (DMARDs) alone
NSAIDs are commonly used as adjuvants to DMARDS. and in combination. Consequently, persistent
They are applied to decrease pain and inflammation inflammation leads to progressive joint and end-
during RA, however NSAIDs are not able to reduce

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organ damage; therefore, the mesenchymal stem cells in patients

prognosis of these patients with active RA. In the study, 172
is poor and evidence the RA patients who failed to
need for new therapeutic respond to conventional
options. treatment were enrolled.
The control group of
Approximately 30% of patients received culture
RA patients may not medium without UC
respond to treatment or MSCs. The experimental
experience severe side group of patients received
effects, including bone a single dose of 4 × 107 UC
marrow suppression, blood, MSCs (40 million). All groups
liver, and/or kidney dysfunction, of patients received DMARD
and infection. Moreover, DMARDs treatment.
are contraindicated for RA patients with
compromised immunity due to the heightened risk The results of the clinical study showed that UC MSCs
of opportunistic infections treatment did not induce any adverse effects and
resulted in the following clinical improvements: a
Surgery is the final treatment approach for RA moderate reduction in inflammatory cytokines and
therapy in cases when the nonsurgical methods are chemokines, an increase in percentage of Tregs in
not sufficiently effective, which are becoming less peripheral blood and upregulation of IL-4-producing
frequent. Nowadays, various types of surgery are Th2 cells.
being applied, among them are tenosynovectomy,
radiosynovectomy, arthroscopy, osteotomy and joint In addition, a significant disease remission was
replacement. The final goal of surgical management observed by the ACR improvement criteria,
is to relieve pain and restore joint function. the DAS28 score and the Health Assessment
Questionnaire (HAQ), which were maintained for 3–6
Stem Cell Therapy for Rheumatoid Arthritis months without repeated IV injection of UC MSCs.
Since the 21st Century began, multiple small and Moreover, an additional clinical study demonstrated
large clinical trials have evaluated mesenchymal stem that UC MSCs treatment can exert long-term
cells for both safety and effectiveness in rheumatoid beneficial effects in RA patients for up to 3 years.
arthritis. Thus, this clinical trial showed that IV administration
of allogeneic umbilical cord mesenchymal stem cells
In 2013, a group of researchers performed a in combination with DMARDs was safe and effective
phase 1/2 clinical trial to evaluate the safety and in ameliorating disease activity in refractory RA
efficacy of IV injection of allogeneic umbilical cord patients, compared to the control group that

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received culture Ontario and

medium without UC McMaster
MSCs. Universities
Arthritis Index
Overall, our study
(WOMAC), visual
demonstrated the
analogue scale
long-term safety
(VAS), time to
and efficacy of
jelling and pain-
UC-MSC therapy
free walking
in RA patients. The
distance up to 12
therapeutic effects
months. Based
of UC-MSC can be
on these data, the authors have suggested that intra-
maintained for 3 years, with stable clinical outcomes,
articular knee injection of BM MSCs is generally safe
which significantly improved RA patients’ quality of
and well tolerated in RA patients.
life.
Recently, Ghoryani and colleagues completed
Above are some photos from the study of patient
a successful clinical trial on the effects of IV
outcomes.
administration of autologous mesenchymal stem
From 2011 to 2013, 30 RA patients were recruited for cells on the various immunological, clinical and
a randomized, triple-blind placebo-controlled phase para- clinical indicators that are associated with the
1/2 clinical trial to study the safety and tolerability of pathogenesis of RA in patients with refractory RA.
intra-articular injection of autologous bone marrow They showed that a single IV injection of 1 × 106 BM
mesenchymal stem cells in RA patients. The results MSCs/kg resulted in a significant decrease in Th17
published in 2018 showed that MSCs administration cell number, disease activity score 28-erythrocyte
does not exert any adverse effects in RA patients. sedimentation rate (DAS28-ESR) and VAS at 12
Moreover, it was revealed that in comparison to the months after MSC therapy. Taken together, these
patients in the placebo group, patients who received clinical data suggested that autologous BM MSCs can
intra-articular injection of BM MSCs demonstrated significantly ameliorate the severity and activity of
superior clinical results according to the Western refractory RA.

Recent Clinical Trials with MSCs for RA

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How do the Stem Cells and Exosomes Act in amping up the beneficial ones. This includes
the Body? ramping up production of several helpful growth
Stem cells and exosomes act in the body through factors and cytokines, while tamping down
several mechanisms. They do NOT become part of a harmful ones.
patient’s DNA, which means they do not engraft into
4. Cellular signaling – the biologics are able to
the person’s existing cells.
perform “cell to cell” communication. This promotes
recipient cells to proliferate their growth factor
They act through: production, protein production and regenerate
1. Angiogenesis – provokes formation of new nerve tissues that are damaged.
blood vessels. 5. Prevent cell death – most cells have a timed death,
2. Reduce inflammation– RA is associated with where they are only allowed to live a certain length
significant inflammation, and the regenerative of time. This is called apoptosis. The regenerative
biologics reduce it nicely. biologics allow normally functioning cells (i.e.
neuron cells) to live longer, and spare them from
3. Immune system modulation – the stem cells the pre-programmed death.
and exosomes modulate the immune system
very differently than steroids. Instead of blanketly 6. Preventing scar tissue –Once that scar tissue
suppressing the immune system, the regenerative forms, it becomes nonfunctional. Stem Cells and
biologics tamp down the harmful processes while exosomes are great at preventing scar tissue (anti-
fibrosis).

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Stem Cells can also release a huge particle tracking analyzers, cytometers,
variety of molecules into the PCR, tangential flow machines
extracellular environment. and real time environmental
These molecules, which monitoring. The quality
include extracellular vesicles assurance testing complies
(exosomes), lipids, free with screening and testing
nucleic acids, and soluble stan¬dards consistent with
proteins, exert crucial roles the American Association of
in repairing damaged tissue. Tissue Banks, cGMP standards,
Along with offering stem cells FDA regulations and the highest
for treatment of RA, R3 Stem Cell level of any regulatory agency globally.
includes stem cell exosomes, which are a type
of extracellular vesicle participating in extensive cell Stem Cell Derived Exosomes
to cell communication for ovarian tissue repair and R3 Stem Cell’s Centers of Excellence globally include
regeneration. umbilical cord stem cell derived exosomes with
The stem cells administered by R3 are not the ones umbilical cord stem cells to provide enhanced results.
that become a patient’s new follicle. The administered Exosomes are lipid bound vesicles (acellular) produced
mesenchymal stem cells are not specifically designed by cells which contain a plethora of growth factors,
to replace damaged and lost follicles, but rather cytokines, mRNA and other proteins.
coordinate and enhance an ovarian repair response by They are exceptionally helpful in cell to cell
one’s own mechanisms. communication, and very effective for reducing
Where do the stem cells and exosomes come inflammation when they become ingested by their
recipient cell. They act as shuttles to send nucleic acids
from? and proteins to other cells, in this way, allowing cell-
R3 Stem Cell’s regenerative biologics originate from to-cell communication and transporting molecules
umbilical cord tissue that has been donated after a among both close and distant cells. In general,
scheduled c-section. No baby (or mother) is harmed these released proteins are important regulators of
during the c-section procedure. The umbilical cord intracellular information.
tissue is normally discarded, but if the mother passes
screening test then the umbilical cord is immediately Exosomes could be the mediators of many stem cell-
sent to the lab. associated therapeutic activities. Considering they are
100 times smaller than stem cells, they do not have
The lab carefully processes the umbilical cord to any issues passing through the blood-brain-barrier to
generate large amounts of stem cells and exosomes reach the brain from the bloodstream.
that are of the highest quality possible. The lab team
consists of multiple PhD’s working in ISO Certified, Is stem cell therapy safe?
cGMP compliant clean rooms to ensure quality
After a decade of performing over 24,000 stem cell
assurance that exceeds USA FDA standards. The
procedures worldwide, R3 knows that the regenerative
proprietary production process combines the highest
procedures are safe. The quality control employed
potency, safety and affordability for providers to
during the stem cell production is second to none, and
confidently offer exosome procedures.
the side effects R3 sees are usually mild to moderate
Millions of dollars have been invested into the and temporary.
pharmaceutical grade production of the biologics
including first rate clean rooms, bioreactors, nano- They may include itching, dizziness, lightheadedness,

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low grade fever, chills, headache, For Rheumatoid Arthritis, R3’s providers
nausea. These are typically use between one and three
temporary. If a patient has million stem cells per
an allergic reaction to kilogram (depends on
the multivitamin or a patient weight). In
preservative, all of addition, billions
R3’s Centers have of stem cell
the medications exosomes and
to resolve it platelet rich
quickly. plasma therapy
(PRP) are
One of the included at no
questions we get cost.
asked a lot is,“Will
the stem cells get R3 Stem Cell’s
rejected?”The answer RA treatment
is NO. protocol includes an
IV therapy combining
MSCs do not express major mesenchymal stem cells and
histocompatibility complex exosomes, along with a multivitamin
(MHC) antigens of the class II subtype IV as well. The RA protocols are customized to
and contain low levels of MHC molecules of the class I each patient’s needs. For example, if an individual has
subtype. MSCs also lack the co-stimulatory molecules several painful joints, R3’s providers may perform some
essential for immune detection, including CD40, CD80, direct injections along with the IV therapy. Safety is
and CD86. paramount with the biologics products being rigorously
Therefore, MSCs generally have low immunogenicity tested prior to use, and expert providers managing each
and can avoid immune rejection by the recipient, treatment as if you are a family member!
which serves as the foundation for their successful
application without needing to match the
Why does R3 Stem Cell use donor tissue for
donor to the recipient. Scientists call this being its stem cells?
“immunologically privileged”. Although autologous (your own) stem cells provide
significant advantages, allogeneic (donor) stem cells
Another question often asked is “Is there a chance of have more advantages. First of all, autologous MSCs
a tumor forming?” Once again the answer is NO. The need a long time to culture and expand, which limits its
mesenchymal stem cells and exosomes used during application in treatment, while allogeneic stem cells can
treatment have never been shown to have tumor be obtained and expanded more quickly, thus avoiding
forming potentials. In fact, they have been shown to the delay of time window.
be anti-tumor forming.
Second, age is a factor that affects the physiological
Treatment Protocol characteristics of MSCs. Studies have shown that stem
For the past decade, R3 has been cells from elderly donors have decreased proliferation
successfully treating patients with stem and differentiation ability. This means they are less in
cell and exosome therapies with injection, number and less effective!
infusion, intranasal, intrathecal and nebulizer
procedures.

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR RHEUMATOID ARTHRITIS

Affordability the Intellicell is used, which is culturing the most active

mesenchymal stem cells to create the “smartest” stem
Stem cell therapy for RA may be the
cell in the world!
key step to completely changing a
person’s quality of life, and we want R3 Stem Cell offers free consultations for individuals to
to make it affordable for as many discuss whether regenerative therapy is indicated for
individuals as possible. Our global volume has allowed your RA. Simply call +1 (844) GET-STEM to schedule
us to keep our patient cost as low as possible. yours!
Unfortunately, stem cell clinics in Colombia, China and References:
Panama charge over $20,000 USD for RA treatment. 1. Sarsenova,M.;Issabekova, A.; Abisheva, S.; Rutskaya-Moroshan,
How are individuals supposed to budget for that?? R3 K.; Ogay, V.; Saparov, A. Mesenchymal Stem Cell-Based Therapy
Stem Cell’s fees are typically less than half that for full for Rheumatoid Arthritis. Int. J. Mol. Sci. 2021, 22, 11592.
treatment, which also includes free exosomes, PRP and https://doi.org/10.3390/ ijms222111592
a multivitamin infusion! 2. Hwang JJ, Rim YA, Nam Y and Ju JH (2021) Recent
Developments in Clinical Applications of Mesenchymal
R3’s Experience Stem Cells in the Treatment of Rheumatoid Arthritis and
Osteoarthritis. Front. Immunol. 12:631291. doi:
For the past decade, R3 Stem 10.3389/fimmu.2021.631291
Cell’s Centers globally have 3. Mesa LE, Lopez JG, Lopez Quiceno
performed over 24,000 L, Barrios Arroyave F, Halpert K,
regenerative procedures Camacho JC (2023) Safety and
efficacy of mesenchymal stem
in six countries. Patient
cells therapy in the treatment of
satisfaction across all rheumatoid arthritis disease: A
conditions treated is systematic review and meta-
very high, at 85%. R3 analysis of clinical trials. PLoS
ONE 18(7): e0284828. https://
has treated hundreds doi.org/10.1371/journal.
of patients with varying pone.0284828
types of peripheral
4. Shimizu, Y.; Ntege,
neuropathy, and over a E.H.; Azuma, C.; Uehara, F.;
thousand patients with Toma, T.; Higa, K.; Yabiku, H.;
diabetes. Matsuura, N.; Inoue, Y.; Sunami,
H. Management of Rheumatoid
R3 combines safety, Arthritis: Possibilities and Challenges
effectiveness and affordability of Mesenchymal Stromal/Stem
Cell-Based Therapies. Cells2023,12,1905.
for the therapies. Internationally, https:// doi.org/10.3390/cells12141905

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 R3 Consumer Guide for Stem Cell and Exosome Therapy

Consumer
Guide to
Stem Cell
Treatment for
Rotator Cuff
Disease

Brought to you by

* No portion of this Document may be reproduced without the Express Written Consent of R3 Stem Cell.
Disclaimer: This guide’s education does not constitute medical advice. The USA FDA considers stem cell
therapy experimental. Any claims made in the Guide refer to procedures performed outside the USA.
259
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 CONSUMER GUIDE TO STEM CELL TREATMENT FOR ROTATOR CUFF DISEASE

Consumer Guide to Stem Cell Treatment

for Rotator Cuff Disease
Every day, R3 Stem Cell receives inquiries worldwide Surgery, while generally successful, has some
from individuals asking if stem cell therapy can help drawbacks, including the potential for complications,
with rotator cuff related pain. Spoiler alert: It can a lengthy recovery, and some authors report that
help a lot! In this guide, we’ll go through the it may not be better than conservative
basics of how stem cells work for rotator management..
cuff disease, the latest research, and
what to expect with a regenerative Stem Cell Therapy for
procedure. Rotator Cuff Disease
If a new technology such as
A Significant Global Issue mesenchymal stem cell and
Shoulder pain has been known exosome therapy could provide a
as the third most common long term solution for rotator cuff
musculoskeletal pain (16%) next disease, it would and should become
to back (23%) and knee (19%) pain in first line therapy. A regenerative therapy
the general population. However, it is the that can relieve pain and improve shoulder
most common in the age group of the highest function that is a safe, nonsurgical option should
productivity, 40–59 years, posing a substantial receive consideration.
socioeconomic burden. Rotator cuff disease or
tendinopathy is the leading cause of shoulder pain Some people ask us if PRP, platelet rich plasma
accounting for up to 70% with more than 4.5 million therapy, is sufficient for treatment of rotator cuff
physician visits and 300,000 repairs per year in just disease. The answer is no! Two recent reports (a
the USA alone. meta-analysis and a double-blinded, randomized
controlled trial (RCT)) concluded that injection of
Traditional Treatments for Rotator Cuff PRP is NOT beneficial in nonoperative treatment
Disease of rotator cuff disease. Considering the potential
Initial treatment for patients with rotator cuff disease, mismatch between growth factors released by PRP
even for patients with a full-thickness tear, would be and an insufficient number of stem cells in partial
conservative treatments such as rest, physiotherapy, thickness rotator cuff tears to be stimulated by these
non-steroidal anti-inflammatory drugs, and growth factors, the application of mesenchymal stem
corticosteroid injection. But, despite generally cells PLUS PRP appears to be the better option for
favorable outcomes after conservative treatments, treating rotator cuff disease.
a considerable number of patients (41%) showed
In animal models, injections of adult stem cells into
persistent symptoms after 1 year of nonoperative
pathologic rotator cuff tissues has been shown to
treatments.
produce a number of beneficial effects, including
Especially, subacromial corticosteroid injection, one decreased number of inflammatory cells, improved
of the most heavily used conservative treatments, has regeneration of tendons with less scarred healing,
been reported to provide only short-term pain relief improved collagen fiber arrangement, higher load-
without modifying the natural course of the disease, to-failure, and higher tensile strength of the treated
or even, it may be worse in the intermediate and tendons.
long terms. Of further concern, corticosteroid could
induce depletion of tendon stem cells resulting in Application of MSCs via injection, not surgery, should
tendon tear. provide invaluable treatment opportunity to patients

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 CONSUMER GUIDE TO STEM CELL TREATMENT FOR ROTATOR CUFF DISEASE

if it could be translated into routine clinical practice immediately following treatment, at weeks 1 and 5,
as it would avoid surgery and concomitant risks as months 3, 6 and 12 by Numerical Pain Scale (NPS)
well expedite recovery. and The American Shoulder and Elbow Surgeons
Score (ASES). NPS (p<0.00008), ASES (p< 0.00017).
In a first-in-human clinical trial published in 2018 The average improvement of NPS was from 7.5 to 3.6
from Korea, 19 participants received mesenchymal at one year. The average ASES from 33.7 to 69.2 at
stem cells with intratendinous injections performed one year (0-100 scale 100 perfect function). No post
under ultrasound guidance. procedural complications or serious adverse events
Over the two year follow up period, injection of were reported.
MSCs also significantly alleviated shoulder pain with The results demonstrated significant improvements
more than 70% reduction from the baseline in the in pain, function disability and quality of life as
high-dose group that is far beyond the clinically represented by positive outcomes in all measured
meaningful pain reduction of approximately 30%. scores through twelve months with no adverse
MRI examination showed that volume of the bursal- events reported.
side defect significantly decreased by 90% in the
high-dose group.
Arthroscopic examination demonstrated that
volume of the articular- and bursal-side defects
decreased by 83% in the mid-dose group, and
90% in the high-dose groups, respectively.
Taken together, these results suggest that
intratendinous injection of mesenchymal
stem cells for the treatment of rotator cuff
disease is safe, and effective with evidences
of regeneration of tendon defect WITHOUT
surgery.
In a 2020 study published in the USA, Hurd et
al evaluated 20 participants with rotator cuff
disease. They were randomized to receive either
cortisone injection or mesenchymal stem cells.
The results of this pilot study suggested that
the use of mesenchymal stem cells in subjects
with partial thickness rotator cuff repair is
safe and leads to improved shoulder function
without adverse effects.
In a recent USA pilot study from Striano et al,
20 participants received shoulder injections
with mesenchymal stem cells. Significant
improvement was noted through all time
points to one year. Outcomes assessed

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 CONSUMER GUIDE TO STEM CELL TREATMENT FOR ROTATOR CUFF DISEASE

In R3’s experience, 90% of patients with rotator cuff mechanisms, which means “cell to cell” interaction.
disease achieve success with stem cell and exosome
therapy. It’s an exciting option for patients! They act through:
Why Doesn’t R3 Stem Cell Use A Person’s Own Stem 1. Angiogenesis – provokes formation of new
Cells for rotator cuff disease? blood vessels.
R3 used to perform autologous therapies, where a 2. Reduce inflammation – lack of blood flow
patient’s own bone marrow or adipose stem cells to the shoulder is associated with significant
were used. However, a lot of stem cells in one’s body inflammation, and the regenerative biologics
are as old as that person is, and hence not very reduce it nicely.
active. Their ability to successfully increase sufficient
blood flow and allow for shoulder repair is inferior to 3. Immune system modulation – the stem cells
umbilical cord stem cells. and exosomes modulate the immune system
very differently than steroids. Instead of blanketly
Specifically, the therapeutic potential of autologous suppressing the immune system, the regenerative
bone marrow or adipose stem cells in the treatment biologics tamp down the harmful processes while
of older patients is impaired by a number of age- amping up the beneficial ones. This includes
related factors such as oxidative stress, telomere ramping up production of several helpful growth
length, DNA damage, disease, and long-term use of factors and cytokines, while tamping down
some medications. harmful ones.
This is in stark contrast to the youthful genotype 4. Cellular signaling – the biologics are able
and phenotype of neonatal tissue-derived stem to perform “cell to cell” communication. This
cells, such as from the umbilical cord. They are better promotes recipient cells to proliferate their
at facilitating repair and regeneration of tissue growth factor production, protein production and
damage, creating new blood flow with superior regenerate tissues that are damaged.
anti-inflammatory and immunomodulatory efficacy
compared to mature stem cells from one’s adipose or 5. Prevent cell death – most cells have a timed
bone marrow. death, where they are only allowed to live a
certain length of time. This is called apoptosis. The
As a result of the inferiority of autologous stem cells regenerative biologics allow normally functioning
due to the reasons above and better results being cells (i.e. neurons) to live longer, and spare them
seen with umbilical cord stem cells, R3 only uses the from the pre-programmed death.
donor stem cells today.
6. Preventing scar tissue –Rotator cuff disease
How do the Stem Cells and Exosomes Work patients may experience significant scarring
for rotator cuff disease? throughout the shoulder. Once that scar tissue
forms, it becomes nonfunctional. Stem Cells and
Stem cells and exosomes act in the body through exosomes are great at preventing scar tissue (anti-
several mechanisms. They do NOT become part of fibrosis).
a patient’s DNA, which means they do not engraft
Stem Cells can also release a huge variety of
into the person’s existing cells. The predominant
molecules into the extracellular environment. These
method of action is thought to be through paracrine
molecules, which include extracellular vesicles, lipids,

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free nucleic acids, and soluble stan¬dards consistent with the

proteins, exert crucial roles in American Association of Tissue
repairing damaged tissue. Banks, cGMP standards,
Along with offering FDA regulations and the
MSCs for treatment highest level of any
of rotator cuff regulatory agency
disease, R3 Stem globally.
Cell often includes Stem Cell
stem cell exosomes, Derived
which are a type
Exosomes
of extracellular
vesicle participating R3 Stem Cell’s Centers of
in extensive cell to cell Excellence globally include
communication for new blood umbilical cord stem cell derived
flow creation. exosomes with umbilical cord stem
cells to provide enhanced results. Exosomes are
Where do the stem cells and exosomes lipid bound vesicles (acellular) produced by cells which
come from? contain a plethora of growth factors, cytokines, mRNA
R3 Stem Cell’s regenerative biologics originate from and other proteins.
umbilical cord tissue that has been donated after a They are exceptionally helpful in cell to cell
scheduled c-section. No baby (or mother) is harmed communication, and very effective for reducing
during the c-section procedure. The umbilical cord inflammation when they become ingested by their
tissue is normally discarded, but if the mother recipient cell. They act as shuttles to send nucleic acids
passes screening tests then the umbilical cord is and proteins to other cells, in this way, allowing cell-
immediately sent to the lab. The screening tests are to-cell communication and transporting molecules
extremely rigorous, and mandated by the USA FDA. among both close and distant cells. In general,
The lab carefully processes the umbilical cord to these released proteins are important regulators of
generate large amounts of stem cells and exosomes intracellular information.
that are of the highest quality possible. The lab team Exosomes could be the mediators of many stem cell-
consists of multiple PhD’s working in ISO Certified, associated therapeutic activities. We have seen them
cGMP compliant clean rooms to ensure quality to be “faster acting” than stem cells, so R3 frequently
assurance that exceeds USA FDA standards. The uses them in conjunction to provide a “1-2 punch” for
proprietary production process combines the highest patient outcomes.
potency, safety and affordability for providers to
confidently offer exosome procedures. Is stem cell therapy safe?
Millions of dollars have been invested into the After a decade of performing over 24,000 stem cell
pharmaceutical grade production of the biologics procedures worldwide, R3 knows that the regenerative
including first rate clean rooms, bioreactors, procedures are safe. The quality control employed
nano-particle tracking analyzers, cytometers, during the stem cell production is second to none, and
PCR, tangential flow machines and real time the side effects R3 sees are usually mild to moderate
environmental monitoring. The quality assurance and temporary.
testing complies with screening and testing

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They may include itching, dizziness, lightheadedness, the answer is NO. The mesenchymal stem cells and
low grade fever, chills, headache, nausea. These are exosomes used during treatment have never been
typically temporary. If a patient has an allergic reaction shown to have tumor forming potentials. In fact, they
to the multivitamin or a preservative, all of R3’s Centers have been shown to be anti-tumor forming.
have the medications to resolve it quickly.
Protocol
One of the questions we get asked a lot is, “Will the
For the past decade, R3 has been
stem cells get rejected?” The answer is NO.
successfully treating rotator cuff disease
MSCs do not express major histocompatibility complex with stem cell and exosome injections.
(MHC) antigens of the class II subtype and contain low The providers often use ultrasound
levels of MHC molecules of the class I subtype. MSCs guidance to ensure the highest accuracy.
also lack the co-stimulatory molecules essential for
Each patient receives a combination
immune detection, including CD40, CD80, and CD86.
of the mesenchymal stem cells along
Therefore, MSCs generally have low immunogenicity with platelet rich plasma therapy. The PRP provides
and can avoid immune rejection by the recipient, an excellent scaffold for tissue repair, and patients are
which serves as the foundation for their successful given a multivitamin IV drip too.
application without needing to match the donor to the
R3’s providers use approximately 25 million stem cells
recipient. Scientists call this being “immunologically
for the procedure. PRP, short for platelet rich plasma
privileged”.
therapy, is also included at no additional charge. The
Another question often asked is “Is there a chance of a procedure takes less than an hour!
tumor forming?” Current research has concluded that

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Why does R3 Stem Cell use donor tissue for health. So a lot of patients seek additional treatments
its stem cells? at R3 Stem Cell every few years.

Although autologous (your own) stem cells provide R3 Stem Cell’s fees are less than half what comparable
significant advantages, allogeneic (donor) stem cells (and reputable) regenerative clinics charge. Be wary of
have more advantages. First of all, autologous clinics trying to pass off PRP as a stem cell therapy. If
MSCs need a long time to culture and they mention only taking your blood for
expand, which limits its application the treatment, it is NOT a stem cell
in treatment, while allogeneic treatment!
stem cells can be obtained
and expanded more quickly, R3’s Experience
thus avoiding the delay of For the past decade, R3
time window. Stem Cell’s Centers globally
have performed over 24,000
Second, age is a factor that regenerative procedures in
affects the physiological seven countries. Over a thousand
characteristics of MSCs. Studies have been for rotator cuff disease.
have shown that stem cells from Patient satisfaction across all conditions
elderly donors have decreased proliferation treated is 85%!
and differentiation ability. This means they are less in
number and less effective! R3 combines safety, effectiveness and affordability
for the therapies. Internationally, the Intellicell is used,
Outcomes which is culturing the most active mesenchymal stem
Similar to the research mentioned above, R3 Stem cells to create the “smartest” stem cell in the world!
Cell’s outcomes for rotator cuff disease have been R3 Stem Cell offers free consultations for individuals to
exceptional! The patient satisfaction rate is 85% year discuss whether regenerative therapy is indicated for
over year. Patients typically experience pain reduction their rotator cuff disease. Simply call +1 (844) GET-STEM
along with improved shoulder function. Keep in mind to schedule yours!
results cannot be guaranteed and will vary between
individuals. Disclaimer: This guide’s education does not constitute medical
advice. The USA FDA considers stem cell therapy experimental. Any
It may take a couple months to see all the claims made in this Guide refer to procedures performed outside of
the USA
improvements, as it can take that long to build up new
blood flow. It should be noted, again, that stem cell References:
therapy is not a cure , and may need to be repeated 1. Jo et al, Intratendinous Injection of Autologous Adipose
Tissue-Derived Mesenchymal Stem Cells for the Treatment
every few years or so for continued benefit. of Rotator Cuff Disease: A First-In- Human Trial, STEM CELLS
2018;36:1441–1450 www.StemCells.com
Affordability 2. Hurd et al, Safety and efficacy of treating symptomatic, partial-
Because stem cell therapy for rotator thickness rotator cuff tears with fresh, uncultured, unmodified,
autologous adipose-derived regenerative cells, Journal of
cuff disease is not a permanent cure,
Orthopaedic Surgery and Research (2020) 15:122
it’s important to make it affordable. 3. Striano RD, Malanga GA, Bilbool N, Azatullah K (2018)
Repeat therapies can help maintenance and/or Refractory Shoulder Pain with Osteoarthritis, and Rotator Cuff
achieve additional improvements for musculoskeletal Tear,, Treated With Micro-Fragmented Adipose Tissue. Orthop
Spine Sports Med 2: JOSSM 014.

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 R3 Consumer Guide for Stem Cell and Exosome Therapy

Consumer Guide
to Stem Cell
Treatment for
Spinal Cord
Injury

Brought to you by

* No portion of this Document may be reproduced without the Express Written Consent of R3 Stem Cell.
Disclaimer: This guide’s education does not constitute medical advice. The USA FDA considers stem cell therapy experimental. Any claims
made in the Guide refer to procedures performed outside the USA.
266
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 CONSUMER GUIDE TO STEM CELL TREATMENT FOR SPINAL CORD INJURY

Consumer Guide to Stem Cell Treatment

for Spinal Cord Injury
Every day, R3 Stem Cell receives inquiries worldwide surgical decompression and fixation, the injection of
from individuals asking if stem cell therapy can help neurotropic factors, anti-inflammatory medications
with Spinal Cord Injury (SCI). Spoiler alert: It can help and physical rehabilitation, satisfactory therapeutic
a lot! In this guide, we’ll go through the basics of how effects remain elusive. Although a steadily accruing
stem cells work for SCI, the latest research, and what body of evidence points to the central nervous
to expect with a regenerative procedure. system possessing a means for self-repair, this
capacity appears quite limited as a sole clinical
A Significant Global Issue approach.
Global estimates suggest that in 2021,
approximately 15.4 million people The complex pathology of SCI may
were living with SCI. Males are be divided into primary and
more commonly affected by secondary injury. The primary
SCI than females. Reports injury is characteristically
have indicated that induced by mechanical
cervical, thoracic and damage and resultant
lumbar spine injuries hemorrhage. Myriad
account for 4.9%, 28.0%, factors contributing
and 65.9% of total to secondary injury
thoracolumbar spinal include: excitatory amino
injuries, respectively. acid toxicity, oxidative
damage, inflammation and
Life expectancy in people autoimmune response. These
with SCI strongly correlates with combined injury mechanisms,
neurological impairment and preventable leading to glial and neuronal cell death,
secondary conditions. People with SCI often die demyelinization and axonal degeneration, are
earlier because of health system factors such as manifested as a severe impairment in neurological
insufficient access to or poor quality health services. function
For people with SCI, the in hospital mortality rate is
nearly three times higher in low- and middle-income Currently, the only approved medication to
countries than in high-income countries. treat SCI in clinic is a high dose of corticosteroid.
Neuroprotective treatment can be performed
Spinal cord injury (SCI) often results in lifelong in acute phases with ganglioside (GM-1), mouse
disability, muscle palsy, sensory disturbances, nerve growth factor (NGF), etc.. Conventional
autonomic dysfunction, and neuropathic pain, as rehabilitation therapy was the preferred treatment for
well as bowel and bladder incontinence, depending convalescence and sequelae-phase spinal cord injury.
on the SCI severity. There is no effective method that Occupational therapy, limb massage, functional
reverses the trauma, partly because of the extremely breathing and defecation training, etc. can to some
limited self-regeneration abilities of the spinal cord. extent delay disuse muscle atrophy and retain a
portion of limb function.
Traditional Treatments for
Spinal Cord Injury Stem Cell Therapy for Spinal Cord Injury
Despite current treatment strategies, including Human umbilical cord mesenchymal stem cells (hUC-
MSC) are a promising choice for SCI therapy. Their

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use has many benefits, including in revascularization transplantation group, the rehabilitation therapy
support, control of inflammation, inhibition of group, and the blank control group. The stem
cellular apoptosis, and production of multiple trophic cell group received 40 million umbilical cord
factors, as well as the differentiation of hUC-MSCs mesenchymal stem cells through intrathecal
into oligodendrocytes and neurons. Moreover, application on two separate procedures, 10 days
additional advantages, including their apart.
lack of contamination, easy
obtainability, low immuno- Through scaled ratings and
genicity, and rapid urodynamic examinations,
proliferation, make this study proved that
them a highly suitable transplantation
candidate for SCI of UCMSCs has
therapy advantages in
neurofunctional
Of the numerous recovery in
possible comparison with
transplantation rehabilitation therapy
routes, it has been and self-healing
demonstrated that cell alone. The stem cell
engraftment and tissue transplantation group
sparing are significantly improved significantly in
better after intrathecal delivery, motor function (P = 0.012); that
and that the host immune response is, the muscle strength of the waist,
is reduced with subarachnoid infusion. It has abdomen, and lower limbs increased. Seven of the
also been reported that intrathecal administration 10 patients had their muscle strength increased
of stem cells results in better functional recovery from level 0 to level 1 or 2 (data not shown), and
than other approaches of cellular delivery. Whether motor function of the paralyzed limbs improved
any engraftment actually occurs with stem cell as muscle strength increased. The rehabilitation
transplantion is debatable in these situations. group and blank control group also showed some
A 2014 study in the Journal of Translational Medicine improvements but the difference was not statistically
evaluated umbilical cord mesenchymal stem cells significant
for transplantation and compared neurofunctional Regarding muscle tension, excessive muscle tension
outcomes of patients suffering sequelae of significantly decreased (P = 0.007) after stem cell
thoracolumbar spinal cord injury that were treated transplantation. Eight patients showed excessive
with stem cell transplantation, rehabilitation training, muscle tension before treatment, and 7 of them
or no treatment. (87.5%) had their muscle tension decreased (data not
34 cases of thoracolumbar spinal cord injury that shown); the rehabilitation group and blank control
were graded ‘A’ by the AIS grading system were group showed no significant improvements in
randomly divided into 3 groups: the stem cell muscle tension (P > 0.05).

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As to self-care ability, the stem cell transplantation after therapy, algesia, tactile sensation, motion
group significantly improved in activities such as and activity of daily living scale were significantly
bed-chair transfer, bowel and urinary retention, and improved.
ground movements, which are related to a decrease
in excessive muscle tension and an improvement In a phase I and II clinical trials in Hong Kong (HK),
in movement ability of the paralyzed limbs. The researchers injected umbilical cord blood into the
rehabilitation group showed some improvements spinal cords of people with chronic (1–19 years after)
but the differences were not statistically significant complete SCI. In the phase I trial in HK, eight patients
(P > 0.05). The self-care ability of the blank control received a total of 1.6 or 3.2 million UCB-MNCs
group decreased (P > 0.05), most likely representing transplanted into the spinal cord. None of these
functional decline of the limbs due to lack of patients recovered any motor function.
treatment and use.
In the phase II trial in Kunming, 20
This study demonstrated that patients with chronic (average
umbilical cord mesenchymal of 7 years after injury)
stem cell transplantation complete C5–T11 SCI were
is effective in the sequentially assigned to
treatment for sequelae five treatment groups of
of thoracolumbar increasing cord blood
spinal cord injury. This cell dosing. Over half of
method can alleviate the patients recovered
lower limb muscle tension, walking with minimal
increase limb strength, or no assistance by 6–12
and improve urinating 7. months after UCB-MNC
function. The method’s efficacy transplants and locomotor
is more significant in comparison with training, as well as increased
rehabilitation therapy, and no adverse effects independence in activities of daily living,
were found. including self-care, bowel and bladder management,
and mobility. This was an unprecedented recovery for
A 2013 study out of China evaluated 22 patients with complete chronic SCI.
SCI treated with umbilical cord mesenchymal stem
cells via intrathecal injection. The dosage was one The conclusion was that the data indicated that
million stem cells/kg body weight once a week given UCB-MNCs can be safely transplanted into the
four times as a course. Treatment was effective in 13 spinal cords of people with chronic SCI, intensive
of 22 patients; nine patients had no response. locomotor training is essential for motor recovery,
and UCB-MNC transplants combined with intensive
Among patients with incomplete SCI, the response locomotor recovery can lead to significant locomotor,
to treatment was 81.25%; there was no response to bowel, and bladder recovery in people with chronic
treatment among six patients with complete SCI. Five complete SCI.
patients with a response to treatment received two to
three courses of therapy, and effects in these patients However, the patients did not recover much
were further enhanced. In most patients in whom voluntary motor function. Some patients recovered
treatment was effective, motor or sensory functions, sensory dermatomes close to the injury site, and
or both, were improved, and bowel and bladder as many as a quarter of the patients recovered anal
control ability was improved. In 22 patients 1 month sensation and voluntary sphincter contraction,
converting from AIS A to B and C.

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In 2021, A prospective, single-center, single-arm and ASIA total scores at the final follow-up—showed
study in which subjects received four subarachnoid remarkable improvements when compared with
transplantations of human umbilical cord baseline data, indicating the therapeutic efficacy of
mesenchymal stem cells, hUC-MSCs (1 x 106 cells/ hUC-MSCs in treating SCI.
kg) monthly and were seen in follow-up four times
(1, 3, 6 and 12 months after final administration) was Subgroup analysis also demonstrated that stem cell
conducted and published out of China. A total of 102 therapy could improve neurological dysfunction
participants were treated, and side effects included regardless of injury characteristics, including lesions
headache, fever, dizziness and transient increase in at the cervical, thoracic and thoracolumbar levels;
muscle tension. The amount of cells administered complete and incomplete damage; and early and late
equaled 1 million stem cells per kilogram times four chronic phases. Perhaps the aforementioned positive
treatments. results are due to sufficient quantity of transplanted
stem cells and long observation period.
All subjects enrolled in this trial were suffering long-
standing and stable neurological dysfunction, and In addition, in different aspects of neurological
those subjects with SCI in the acute phase were disability caused by chronic paraplegia, sensation
excluded. For the purpose of accurate assessment of was found to recover more quickly and significantly
the therapeutic efficacy of hUC-MSCs, the authors than motion and sphincter after intrathecal
only recruited subjects whose chronicity of SCI transplantation of hUCMSCs. Moreover, the
was no less than 2 months. In the authors’ study, it secondary outcomes, including muscle spasm,
is possibly due to the great severity of injury that autonomic system and bladder and bowel functions,
some subjects showed no significant recovery of improved remarkably, supporting the application of
neurological function after hUC-MSC administration. stem cell therapy in clinic.

In the authors’ study, the two primary outcomes— Regarding other secondary efficacy indicators, early
IANR-SCIFRS (SCI Functional Rating Scale of the and progressive improvement of muscle spasticity is
International Association of Neurorestoratology) a beneficial outcome of cytotherapy, and a decrease

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in residual urine volume can be observed

prior to restoration of other neurological
functions. Another positive function
is eliminating glial scars within
damaged spinal cord and
thus benefiting regeneration
of remyelinated axons. The
authors’ present protocol
demonstrates that intrathecal
administration of allogeneic
hUC-MSCs at a dose of one
million stem cells per kilogram
once a month for 4 months is safe
and effective and leads to significant
improvement in neurological dysfunction
and recovery of quality of life.
A 2017 study out of Spain evaluated ten patients of improvement in sensitivity and motor function.
with established incomplete SCI receiving four Sexual function improved in two of the eight male
subarachnoid administrations of 30 million patients. Neuropathic pain was present in four
autologous bone marrow MSCs, supported in patients before treatment; it disappeared in two of
autologous plasma, at months 1, 4, 7 and 10 of them and decreased in another. Clear improvement
the study, and were followed until the month 12. in bladder and bowel control were found in all
Urodynamic, neurophysiological and neuroimaging patients suffering previous dysfunction. Urodynamic
studies were performed studies showed variability
at months 6 and 12, and between patients, but
compared with basal 80% of them showed
studies. improvement in bladder
compliance, reflecting the
Variable improvement improvement in bladder
was found in the patients function after cell therapy.
of the series. All of them See the graphs below
showed some degree

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detailing significant improvements through several On subgroup analysis, it was found that early
variables. intervention and more than one dose of BMMNCs
demonstrate a better functional outcome.
From the published research over the years regarding
mesenchymal stem cells for spinal cord injury, it Patients were divided into two groups: Intervention
appears that multiple treatments over a period of six administered within 12 months from injury and
to 12 months is better. after 12 months from injury. It was observed that
FIM scores improved in 77.04% of patients who
As reported by Oh et al in 2015, “We found in our underwent cellular therapy within 12 months
current investigation that a single MSC of injury and in 65% of patients who
application therapy is very safe, underwent cellular therapy after
but only produces a weak 12 months.
therapeutic effect. Therefore,
an alternative method Fifty-four patients
is needed to raise the underwent a second
effectiveness of MSC dose. It was observed
therapy. Multiple MSC that higher percentage
injections may be more of patients (79.62%)
effective as seen in our who were administered
previous study.” the second dose showed
improvements as compared
In 2021, a Mumbai group to those who underwent
conducted an open-label a single dose of cellular
study including 180 sub-acute transplantation (65.07%).
and chronic SCI patients. All patients
received intrathecal autologous BMMNCs along with Why doesn’t R3 Stem Cell use a person’s
neurorehabilitation. 80–100 mL of bone marrow was own stem cells for SCI?
aspirated and BMMNCs were obtained using density
gradient separation. An average of 1.06 × 108 cells R3 used to perform autologous therapies, where a
(106 million) with 97% viability was administered patient’s own bone marrow or adipose stem cells were
through lumbar puncture. After transplantation, all used. However, a lot of stem cells in one’s body are as
patients underwent neurorehabilitation. Patients old as that person is, and hence not very active. Their
were followed up after an average of 9 ± 7 months. ability to successfully increase sufficient blood flow and
They were assessed for functional symptomatic allow for tissue regeneration is inferior to umbilical cord
changes and the outcome measures used were stem cells.
functional independence measure (FIM) and walking Specifically, the therapeutic potential of autologous
index for SCI (WISCI). bone marrow or adipose stem cells in the treatment of
Patients showed symptomatic improvement in older patients is impaired by a number of age-related
sitting/standing balance, bed mobility, trunk stability, factors such as oxidative stress, telomere length,
upper limb function, mobility, sensation, bowel/ DNA damage, disease, and long-term use of some
bladder functions, and activities of daily living medications.
with no serious adverse events. Scores on FIM and This is in stark contrast to the youthful genotype and
WISCI showed statistically significant improvement. phenotype of neonatal tissue-derived stem cells, such

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as from the umbilical cord. They are better at facilitating

repair and regeneration of tissue damage, creating
new blood flow with superior anti-inflammatory and
immunomodulatory efficacy compared to mature
stem cells from one’s adipose or bone marrow.
As a result of the inferiority of autologous
stem cells due to the reasons above and
better results being seen with umbilical
cord stem cells, R3 only uses the donor
stem cells today
How do the Stem Cells and
Exosomes Work for Spinal Cord
Injury?
Stem cells and exosomes act in the body
through several mechanisms. They do NOT
become part of a patient’s DNA, which means
they do not engraft into the person’s existing cells.
The predominant method of action is thought to be
through paracrine mechanisms, which means “cell to
cell” interaction.

They act through:

1. Angiogenesis – provokes formation of new 4. Cellular signaling – the biologics are able
blood vessels. to perform “cell to cell” communication. This
promotes recipient cells to proliferate their
2. Reduce inflammation – lack of blood flow is growth factor production, protein production
associated with significant inflammation, and the and regenerate nerve tissues that are damaged.
regenerative biologics reduce it nicely. 5. Prevent cell death – most cells have a timed
death, where they are only allowed to live a
3. Immune system modulation – the stem cells certain length of time. This is called apoptosis.
and exosomes modulate the immune system The regenerative biologics allow normally
very differently than steroids. Instead of functioning cells (i.e. neuron cells) to live longer,
blanketly suppressing the immune system, the and spare them from the pre-programmed
regenerative biologics tamp down the harmful death.
processes while amping up the beneficial ones. 6. Preventing scar tissue –Spinal Cord Injury
This includes ramping up production of several patients may experience significant scarring
helpful growth factors and cytokines, while throughout the shoulder. Once that scar tissue
tamping down harmful ones. forms, it becomes nonfunctional. Stem Cells and
exosomes are great at preventing scar tissue
(anti-fibrosis).

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Stem Cells can also release a huge variety of molecules with screening and testing standards consistent with
into the extracellular environment. These molecules, the American Association of Tissue Banks, cGMP
which include extracellular vesicles, lipids, free nucleic standards, FDA regulations and the highest level of any
acids, and soluble proteins, exert crucial roles in regulatory agency globally.
repairing damaged tissue.
Stem Cell Derived Exosomes
Along with offering MSCs for treatment of Spinal Cord
Injury, R3 Stem Cell often includes stem cell exosomes, R3 Stem Cell’s Centers of Excellence globally include
which are a type of extracellular vesicle participating in umbilical cord stem cell derived exosomes with
extensive cell to cell communication for new umbilical cord stem cells to provide enhanced
blood flow creation. results. Exosomes are lipid bound
vesicles (acellular) produced by
Where do the stem cells cells which contain a plethora
and exosomes of growth factors, cytokines,
come from? mRNA and other proteins.
R3 Stem Cell’s They are exceptionally
regenerative biologics helpful in cell to cell
originate from umbilical communication, and
cord tissue that has been very effective for reducing
donated after a scheduled inflammation when they
c-section. No baby (or become ingested by their
mother) is harmed during the recipient cell. They act as shuttles
c-section procedure. The umbilical to send nucleic acids and proteins to
cord tissue is normally discarded, but if the other cells, in this way, allowing cell-to-cell
mother passes screening tests then the umbilical cord communication and transporting molecules among
is immediately sent to the lab. The screening tests are both close and distant cells. In general, these released
extremely rigorous, and mandated by the USA FDA. proteins are important regulators of intracellular
information.
The lab carefully processes the umbilical cord to
generate large amounts of stem cells and exosomes Exosomes could be the mediators of many stem cell-
that are of the highest quality possible. The lab team associated therapeutic activities. We have seen them to
consists of multiple PhD’s working in ISO Certified, be “faster acting” than stem cells, so R3 frequently uses
cGMP compliant clean rooms to ensure quality them in conjunction to provide a “1-2 punch” for patient
assurance that exceeds USA FDA standards. The outcomes.
proprietary production process combines the highest Is stem cell therapy safe?
potency, safety and affordability for providers to
confidently offer exosome procedures. After a decade of performing over 24,000 stem cell
procedures worldwide, R3 knows that the regenerative
Millions of dollars have been invested into the procedures are safe. The quality control employed
pharmaceutical grade production of the biologics during the stem cell production is second to none, and
including first rate clean rooms, bioreactors, the side effects R3 sees are usually mild to moderate
nano-particle tracking analyzers, cytometers, PCR, and temporary.
tangential flow machines and real time environmental
monitoring. The quality assurance testing complies They may include itching, dizziness, light headedness,

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low grade fever, chills, headache, nausea. These are Protocol

typically temporary. If a patient has an allergic reaction
For the past decade, R3 has been successfully treating
to the multivitamin or a preservative, all of R3’s Centers
Spinal Cord Injury with stem cell and
have the medications to resolve it quickly.
exosome procedures. The regenerative
One of the questions we get asked a lot is, “Will the biologics are applied directly into the spinal
stem cells get rejected?” The answer is NO. cord with an intrathecal application, and
MSCs do not express major histocompatibility complex also infused through an IV. Typically, more
(MHC) antigens of the class II subtype and contain than one session is required for optimal
low levels of MHC molecules of the class benefit.
I subtype. MSCs also lack the co- R3’s providers use one to two million
stimulatory molecules essential stem cells per kilogram, to make
for immune detection, sure that patients achieve
including CD40, CD80, and the absolute best outcome
CD86. possible. Between 50 and
Therefore, MSCs 150 billion exosomes
generally have low are included with each
immunogenicity and can procedure.
avoid immune rejection Outcomes
by the recipient, which
serves as the foundation Similar to the research
for their successful application mentioned above, R3 Stem
without needing to match the donor Cell’s outcomes for SCI have been
to the recipient. Scientists call this being exceptional! The patient satisfaction
“immunologically privileged”. rate is 75% year over year for SCI. Patients typically
experience symptomatic improvement in sitting/
Another question often asked is “Is there a chance of a standing balance, bed mobility, trunk stability, upper
tumor forming?” Current research has concluded that limb function, mobility, sensation, bowel/bladder
the answer is NO. The mesenchymal stem cells and functions, and activities of daily living. Keep in mind
exosomes used during treatment have never been results cannot be guaranteed and will vary between
shown to have tumor forming potentials. In fact, they individuals.
have been shown to be anti-tumor forming.
It may take a few months to see the improvements, as
Therefore, MSCs generally have low immunogenicity it can take that long to build up new blood flow and
and can avoid immune rejection by the recipient, create neurological repair.
which serves as the foundation for their successful
application without needing to match the donor to the Affordability
recipient. Scientists call this being “immunologically
privileged”. Because stem cell therapy for SCI is not a
permanent cure, it’s important to make
Another question often asked is “Is there a chance of a it affordable. Repeat therapies can help
tumor forming?” Current research has concluded that maintenance and/or achieve additional
the answer is NO. The mesenchymal stem cells and improvements for pain relief. So a lot of patients seek
exosomes used during treatment have never been additional treatments at R3 Stem Cell every twelve to
shown to have tumor forming potentials. In fact, they eighteen months.
have been shown to be anti-tumor forming.

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R3 Stem Cell’s fees are less than half what comparable References:
(and reputable) regenerative clinics charge. Be wary 1. Yang Y, Pang M, Chen YY, Zhang LM, Liu H, Tan J, Liu B, Rong LM
of clinics trying to pass off PRP as a stem cell therapy. (2020) Human umbilical cord mesenchymal stem cells to treat
If they mention only taking your blood for the spinal cord injury in the early chronic phase: study protocol for
treatment, it is NOT a stem cell treatment! a prospective, multicenter, randomized, placebo-controlled,
single-blinded clinical trial. Neural Regen Res 15(8):1532-1538.
doi:10.4103/1673-5374.274347
R3’s Experience
2. Cheng et al. Journal of Translational Medicine 2014, 12:253
For the past decade, R3 Stem Cell’s Centers globally http://www.translational-medicine.com/content/12/1/253
have performed over 24,000 regenerative procedures in
six countries. Several hundred have been for SCI. Patient 3. Liu et al, Clinical analysis of the treatment of spinal cord injury
with umbilical cord mesenchymal stem cells, Cytotherapy,
satisfaction across all conditions treated is 85%! 2013; 15: 185e191.
R3 combines safety, effectiveness and affordability 4. Zhu et al, Phase I–II Clinical Trial Assessing Safety and Efficacy
for the therapies. Internationally, the Intellicell is used, of Umbilical Cord Blood Mononuclear Cell Transplant Therapy
which is culturing the most active mesenchymal stem of Chronic Complete Spinal Cord Injury, Cell Transplantation,
Vol. 25, pp. 1925–1943, 2016
cells to create the “smartest” stem cell in the world!
5. Albu et al, Clinical effects of intrathecal administration of
R3 Stem Cell offers free consultations for individuals to expanded Wharton jelly mesenchymal stromal cells in patients
discuss whether regenerative therapy is indicated for with chronic complete spinal cord injury: a randomized
their AS. Simply call +1 (844) GET-STEM or +1 (480) 808- controlled study, Cytotherapy 23 (2021) 146 156
7057 to schedule yours! 6. Yang et al, Repeated subarachnoid administrations of
allogeneic human umbilical cord mesenchymal stem cells
for spinal cord injury: a phase 1/2 pilot study, Cytotherapy 23
(2021) 57 64
Disclaimer: This guide’s education does not constitute medical
advice. The USA FDA considers stem cell therapy experimental. Any 7. Vaquero et al, Repeated subarachnoid administrations
claims made in this Guide refer to procedures performed outside of of autologous mesenchymal stromal cells supported in
the USA. autologous plasma improve quality of life in patients suffering
incomplete spinal cord injury, Cytotherapy, 2017; 19: 349–359

8. Oh et al, A Phase III Clinical Trial Showing Limited Efficacy of

Autologous Mesenchymal Stem Cell Therapy for Spinal Cord
Injury, Neurosurgery, VOLUME 78 | NUMBER 3 | MARCH 2016.

9. Sharma et al, Intrathecal transplantation of autologous bone

marrow mononuclear cells in patients with sub-acute and
chronic spinal cord injury: An open-label study, International
Journal of Health Sciences, Vol. 14, Issue 2 (March - April 2020).

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 R3 Consumer Guide for Stem Cell and Exosome Therapy

Guide to
Stem Cell & Exosome
Therapy for Stroke

Brought to you by

* No portion of this Document may be reproduced without the Express Written Consent of R3 Stem Cell.

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR STROKE

Guide to Stem Cell and Exosome Therapy for Stroke

Every day, R3 Stem Cell receives inquiries worldwide What happens in a stroke?
from individuals asking if stem cell therapy can help
Typically, stroke can be categorized into ischemic stroke
after a stroke. Spoiler alert: It can help a lot! In this
and hemorrhagic stroke. Ischemic stroke is caused by a
guide, we’ll go through the basics of how stem cells
blocked blood vessel that reduces blood flow to specific
work after a stroke, the latest research, and what to
expect with a regenerative procedure. areas of the brain. Hemorrhagic stroke is caused by a
blood vessel rupture in the brain, causing bleeding in
Conventional treatments after a stroke are the brain or subarachnoid space.
not able to regenerate and repair
brain tissue significantly. They If the blockage occurs locally in the
are very limited and mostly brain, the condition is called
“band aids.” People often thrombosis. If the blood clot
have to rely on others travels from somewhere
to complete their else in the body, it is called
activities of daily living, an embolism. Ischemic
or figure out other strokes are classified
ways to achieve them specifically based on
as the deficits become where in the brain the
permanent. blockage occurs and where
in the body an embolism
Stem cell therapy for stroke developed.
is turning out to be an excellent
opportunity for individuals to achieve An insight into the biology of ischemic
speech, function and mobility improvements that are stroke indicates that a stream of molecular events
simply NOT possible with traditional therapies. Let’s initiates instantly after the onset of ischemic
dig in! stroke, such as oxidative stress, increased level of
intracellular calcium, excitotoxicity, and inflammation
A Significant Global Issue which results in apoptotic or necrotic neuronal cell
Stroke is the third leading cause of death and death.
disability worldwide that brings a huge burden to
the healthcare system. Incredibly, one in six people Basically, in an effort to help the situation, the natural
will suffer from stroke in their lifetime, with over reaction from the surrounding area is to make it
13.7 million occurring strokes every year (more than WORSE! The increased inflammation kills cells, harms
one per second) and causing 5.8 million deaths. the tissue surrounding nerves (myelin), and leads to
The major type of stroke is the ischemic stroke, significant fibrosis (scar tissue).
which approximately accounts for 70 percent of all According to previously established studies, the
strokes. ischemic avalanche followed by a stroke is comprised
Although advanced treatment methods for ischemic of three phases:
stroke treatment have been dug up in recent years,
1. acute phase
no therapy has been able to efficiently improve the
overall prognosis of patients. 2. the subacute phase
3. the chronic phase

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Further insights into its molecular events indicate What are the symptoms of a stroke?
that the acute phase takes almost 2 weeks to
Prior to having a true stroke, a person may experience
complete after the incidence of the injury. The
a transient ischemic attack, known as a TIA. Also
subacute or secondary phase continues its
known as a “mini stroke”, the symptoms go away
deleterious events up to 6 months after the onset of
within a few mintues.
the lesion. The duration of the chronic phase could
take months to years after stroke and may last for the From the CDC website, here are the signs of a
rest of the patient’s life along with its neurological stroke:
damage.
• Sudden numbness or weakness in the face, arm,
The range of therapeutic interventions has remained or leg, especially on one side of the body.
very limited. Stem cell therapeutic strategies have
shown the potential to combat the deleterious • Sudden confusion, trouble speaking, or difficulty
effects of acute, subacute, and chronic phases of understanding speech.
ischemic stroke. We’ll discuss shortly how. • Sudden trouble seeing in one or both eyes.
What are the reasons a stroke occurs? • Sudden trouble walking, dizziness, loss of
There are several risk factors for strokes, some of balance, or lack of coordination.
which are controllable:
• Sudden severe headache with no known
• Physical inactivity cause.
• Poor diet
• Smoking
Traditional Treatments
• High Blood Pressure Traditional therapies for
ischemic stroke include acute
• Obesity
medications, and then those
• Diabetes meant for chronic use. An
• High Cholesterol IV injection of recombinant
• Coronary or Carotid tissue plasminogen activator
artery disease (TPA) is the gold standard
• Atrial fibrillation treatment for ischemic stroke.
Endovascular therapy has been
• Heart valve disease shown to improve outcomes
• Sleep apnea and reduce long-term disability after
• Kidney disease ischemic stroke.
Interestingly age is a risk factor, with strokes being Surgery entailing a carotid endarterectomy,
more common under the age of 1 and for older angioplasty and/or stents can lower your risk of
adults. Strokes occur more often in certain ethnicities, having another stroke or transient ischemic attack.
such as African Americans, American Indians, Typically long term anti-coagulants are prescribed.
Hispanics and others.
For a hemorrhagic stroke, blood thinners may need to
Increased air pollution may contribute, and certain be reversed. Surgery may be needed to decompress
genetic issues may predispose along with having a the pressure. Procedures such as clipping, coiling, or
family history. stereotactic radiosurgery may help.

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Some people recover fully, while others have long-

term or lifelong disabilities. This may include issues
with speech, memory, swallowing, eating, muscles,
nerves, bowel and/or bladder.
The natural course of recovery (chronic phase) may
last for one to 1.5 years. At that point, no previous
medications or therapies have been shown to alter
the stroke’s effects. People either need to live with
the deficits or figure out other ways to get things
accomplished.

Stem Cell Therapy for Stroke

If a new technology such as mesenchymal stem This includes reducing inflammation through
cell and exosome therapy could improve the ability immunomodulation, releasing trophic (growth)
of stroke victims to recover, it would and should factors to promote therapeutic effects, inducing
become first line therapy. Remember, in the natural angiogenesis (new blood vessels), promoting
course of the brain trying to assist with recovery, neurogenesis, reducing the infarct volume, replacing
there are actually quite a few detrimental effects. damaged cells, and secreting extracellular vehicles
These may include additional neuro inflammation (exosomes), which all play therapeutic roles.
with accompanying cell death, myelin sheath
degradation and fibrosis (scar tissue). Stem cell-based therapies for stroke offer promise
because of their potential to provide neurorestorative
MSC-based therapy could potentially reduce the benefits. Stem cell-based therapies aim to promote
inflammatory response and neuronalcell apoptosis neurogenesis and replacement of lost neurons
(death) by modulating the immune system and or protect surviving neurons in order to improve
impeding the secondary damage after ischemic neurological recovery. The mechanism through
stroke. which stem cell treatments mediate their therapeutic
Further studies have indicated that stem cells derived effect is largely dependent on the type of stem cell
from umbilical cord lining (UC-MSCs) are profoundly and route of administration.
immunological immature cells, and this property Additionally, although stroke is a disease of the
makes them a promising vasculature, it induces a significant immune
candidate for the treatment of response. The immune response is linked to healing,
stroke. The immaturity makes but also includes a neuroinflammatory component
them very powerful along with implicated in exacerbating the initial injury through
not getting rejected from the destruction of neuronal tissue. As if the stroke itself
recipient. wasn’t bad enough, patients have to deal with their
Umbilical cord stem cells can potentially reduce own body’s recovery efforts making it worse!
the infarct size and ameliorate the functional Some stem cell populations have demonstrated the
recovery by elevating the expression of growth ability to modulate the immune system, and offer the
and neuroprotective factors such as brain-derived promise of neuroprotective and neuroregenerative
neurotrophic factor (BDNF) and vascular and effects, enhancing the healing effects while
endothelial growth factor (VEGF) mitigating inflammatory damage.

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Stem cells and exosomes act in the body through

several mechanisms. They do NOT become part of a 4. Cellular signaling – the biologics are able
patient’s DNA, which means they do not engraft into to perform “cell to cell” communication. This
the person’s existing cells. promotes recipient cells to proliferate their
growth factor production, protein production
They act through: and regenerate tissues that are damaged.
1. Angiogenesis – provokes formation of new 5. Prevent cell death – most cells have a timed
blood vessels. death, where they are only allowed to live a
2. Reduce inflammation – – stroke is associated certain length of time. This is called apoptosis.
with significant neuro-inflammation, and the The regenerative biologics allow normally
regenerative biologics reduce it nicely. functioning cells (i.e. glial cells) to live longer,
3. Immune system modulation – the stem cells and spare them from the pre-programmed
and exosomes modulate the immune system death.
very differently than steroids. Instead of
6. Preventing scar tissue – – Stroke patients
blanketly suppressing the immune system, the
experience significant scarring throughout the
regenerative biologics tamp down the harmful
affected area of the brain. Once that scar tissue
processes while amping up the beneficial ones.
forms, it becomes nonfunctional. Stem Cells and
This includes ramping up production of several
exosomes are great at preventing scar tissue
helpful growth factors and cytokines, while
(anti-fibrosis).
tamping down harmful ones.

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The lab carefully processes the umbilical

cord to generate large amounts of
stem cells and exosomes that
are of the highest quality
possible. The lab team
consists of multiple
PhD’s working in
ISO Certified, cGMP
compliant clean
rooms to ensure
quality assurance
that exceeds USA
FDA standards.
The proprietary
production process
combines the highest
potency, safety and
affordability for providers
to confidently offer exosome
procedures.
Millions of dollars have been invested into the
Stem Cells can also release a huge variety of pharmaceutical grade production of the biologics
molecules into the extracellular environment. These including first rate clean rooms, bioreactors,
molecules, which include extracellular vesicles nano-particle tracking analyzers, cytometers,
(exosomes), lipids, free nucleic acids, and soluble PCR, tangential flow machines and real time
proteins, exert crucial roles in repairing damaged environmental monitoring. The quality assurance
tissue. Along with offering stem cells for treatment testing complies with screening and testing
of stroke, R3 Stem Cell includes stem cell exosomes, stan¬dards consistent with the American Association
which are a type of extracellular vesicle participating of Tissue Banks, cGMP standards, FDA regulations and
in extensive cell to cell communication for brain the highest level of any regulatory agency globally.
tissue repair and regeneration.
Is there research to back up stem cell and
Where do the stem cells and exosomes exosome therapy for stroke?
come from? In recent years, a large number of studies have
R3 Stem Cell’s regenerative biologics originate from proved that the application of mesenchymal stem
umbilical cord tissue that has been donated after a cells can reduce the area of cerebral infarction
scheduled c-section. No baby (or mother) is harmed after ischemia and promote the recovery of neural
during the c-section procedure. The umbilical cord function. The therapeutic mechanism of stem cells
tissue is normally discarded, but if the mother passes in ischemic stroke has not been fully understood,
screening test then the umbilical cord is immediately which may be related to its neuron replacement,
sent to the lab. neurogenesis, angiogenesis, and anti-inflammatory
effects.

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The extracellular vesicles (exosomes) produced upper and lower limbs. He received umbilical cord-
by MSCs may also play an important role in this derived stem cells twice with an eight day interval. At
process. In conclusion, stem cells contribute to 65 weeks after transplantation, the patient returned
the reconstruction of neural circuits by inducing to his previous occupation as a veterinarian with no
endogenous neurogenesis, promoting axonal adverse reactions.
budding and myelin regeneration, and specific
signaling pathways remain to be investigated. One month after the first transplantation, the
patient recovered from the left upper limb and facial
To date a single phase I trial has investigated paralysis. The patient was able to lift his left arm
umbilical cord blood for treatment of stroke. up to chest level, and recovery of his left arm and
Umbilical cord blood was infused IV in 10 male hand muscles allowed the patient to control the
patients three to nine days post-onset of stroke brakes ofhis wheelchair. After 8 weeks, the patient
symptoms. Patients were followed for 12 months recovered from left leg paralysis and could walk with
and showed no adverse events related to treatment, an orthosis.
and by three months all patients had demonstrated
improvements to neurological recovery (Laskowitz After 15 weeks, the patient showed recovery of the
et al., 2018). Umbilical cord stem cell therapies left lower limb muscles and could walk without an
for stroke may offer the most applicable neuro- orthosis. After 60 weeks, recovery from left-sided
protective benefits because they have the potential paralysis, restoration of the respective muscular
to be readily available to meet the critical window for function, and sense of balance allowed the patient
intervention, are immune tolerant, and demonstrate to climb up and down the stairs without an
robust immunomodulatory properties. orthosis Moreover, his left arm no longer suffered
from tremors, enabling the patient to perform
A recent case report showcased a 55-year-old man sophisticated tasks. After 65 weeks, the patient,
suffered an acute stroke, causing paralysis in the left previously a veterinarian, could return to work, as

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the patient had recovered to the point that they often temporarily get caught up in the lungs,
could maintain a standing position for a long time as but they don’t all stay there. After 12-24 hours,
required in surgery. the vast majority are released to go to areas with
inflammation, such as a failing liver.
Stem Cell Derived Exosomes
So, for example, if a person has liver failure
R3 Stem Cell’s Centers of Excellence
secondary to diabetes, the cells
globally include umbilical cord
and exosomes will also go to the
stem cell derived exosomes
pancreas to assist with function
with umbilical cord stem cells
there too. There are Centers
to provide enhanced results.
that promote injections
Exosomes are lipid bound
directly into the liver, or
vesicles (acellular) produced
hepatic artery/vein. This is
by cells which contain a
not necessary and entails
plethora of growth factors,
additional risk!
cytokines, mRNA and other
proteins. R3’s providers will calculate the
amount of stem cells based on patient
They are exceptionally helpful in cell
weight and liver failure severity. It will range
to cell communication, and very effective for
from 1 to 3 million stem cells/kg. Depending on the
reducing inflammation when they become ingested
total amount, treatment may need to be broken
by their recipient cell. They act as shuttles to send
up into two sessions, three at the most for optimal
nucleic acids and proteins to other cells, in this way,
safety.
allowing cell-to-cell communication and transporting
molecules among both close and distant cells. In
R3 Stem Cell’s liver disease protocols are based
general, these released proteins are important
on the latest research along with Best Practice
regulators of intracellular information.
Protocols developed over the past decade to help
Exosomes could be the mediators of many stem patients achieve the best outcomes possible. Safety
cell-associated therapeutic activities. Considering is paramount with the biologics products being
they are 100 times smaller than stem cells, they do rigorously tested prior to use, and expert providers
not have any issues passing through the blood-brain- managing each treatment as if it was a family
barrier to reach the brain from the bloodstream. member!

Is stem cell therapy safe? Treatment Protocol

For the past decade, R3 has been successfully treating For the past decade, R3 has been successfully treating
liver failure patients with IV stem cell and exosome stroke patients with IV stem cell and exosome
therapy. The cells and exosomes are attracted to therapy along with either intrathecal or intranasal
inflammation, which is a large component application. The cells and exosomes are
of liver failure. So they will go predominantly attracted to inflammation, which is a large
to the liver, but also, to areas that are component of stroke aftermath. Because the
experiencing disease as well. blood-brain-barrier (BBB) prevents a lot of
stem cells reaching the brain, the intrathecal
Some people ask us, “I heard the stem cells and intranasal applications are effective at
get caught in the lungs and die, is that true?” bypassing the BBB.
The answer is mesenchymal stem cells do

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR STROKE

An animal study looking at intranasal

stem cells showed that diffusion
into the frontal part of the brain
occurred within 30 minutes
after administration, and
distributed throughout
the whole brain
after three hours.
The intranasal
procedure
takes less than
twenty minutes!
The intrathecal
application is
performed by R3’s
experienced anesthesia
doctors. Not only is it very
safe, but it also permits a very
large amount of stem cells to reach
the brain without encountering the BBB.
And thankfully, no drilling of the skull is necessary!
its application in stroke treatment, while allogeneic
R3’s providers will calculate the amount of stem cells stem cells can be obtained and expanded from the
based on patient weight and stroke severity. It will freezer more quickly, thus avoiding the delay of time
range from 1 to 4 million stem cells/kg. Depending on window.
the total amount, treatment may need to be broken Stroke patients need a LOT of stem cells for the
up into two sessions, three at the most for optimal outcome to be satisfactory, which is just not
safety. obtainable from one’s own stem cell harvesting.
Considering that the viability of donor stem cells
R3 Stem Cell’s stroke treatment protocols are based
after cryopreservation averages 87%, patients are
on the latest research along with Best Practice
able to achieve the amount of cells needed without
Protocols developed over the past decade to help
the harvesting procedure.
patients achieve the best outcomes possible. Safety
is paramount with the biologics products being Second, patients with ischemic stroke usually take
rigorously tested prior to use, and expert providers antiplatelet or anticoagulant
managing each treatment as if it was a family drugs, and the application of autologous MSCs may
member! lead to secondary hemorrhage. Allogeneic stem cells
from healthy donors have no such concerns.
Why does R3 Stem Cell use donor tissue for
Third, age is a factor that affects the physiological
its stem cells?
characteristics of MSCs. Studies have shown that
Although autologous (your own) stem cells provide stem cells from elderly donors have decreased
significant advantages, allogeneic (donor) stem cells proliferation and differentiation ability. This means
have more advantages. First of all, autologous MSCs they are less effective!
need a long time to culture and expand, which limits

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR STROKE

What are the Outcomes? cells to create the “smartest” stem cell in the world!
Similar to the research mentioned above, Our experience with stroke patients has been
R3 Stem Cell’s outcomes for stroke extensive, and our Success Stories on R3’s
patients have been exceptional! The YouTube Channel are impressive. You
patient satisfaction rate is 85% can visit the channel Success Story
year over year. Patients typically Playlist HERE.
see increased energy, cognition, R3 Stem Cell offers free
speech abilities, improved consultations for individuals to
function and mobility. discuss whether regenerative
It may take several months to see therapy is indicated for their stroke
all of the improvements, although recovery. Simply call +1 (844) GET-
we have had patients symptomatically STEM or +1 (480) 808-7057 to schedule
feel much better within the first couple of yours!
weeks. It should be noted, again, that stem cell therapy References:
does not bring patients back to pre-stroke function, 1. 1. Classification and Characteristics of Mesenchymal
and will need to be repeated every 6 to 12 months for Stem Cells and Its Potential Therapeutic Mechanisms and
additional benefits. Applications against Ischemic Stroke, Gong et al, Stem
Cells International, Volume 2021, Article ID 2602871, 13
Affordability pages.
Because stem cell therapy for stroke 2. Ischemic Brain Stroke and Mesenchymal Stem Cells: An
does benefit from repeat treatments, Overview of Molecular Mechanisms and Therapeutic
it’s important to make it affordable. Potential, Jingli et al, Stem Cells International, Volume
2022, Article ID 5930244, 15 pages
Repeat therapies can help people
achieve additional speech, function and mobility 3. International Journal of Molecular Sciences Review,
Mesenchymal Stem Cells: Therapeutic Mechanisms for
improvements. So a lot of patients seek additional Stroke, Yuchen Zhang, Int. J. Mol. Sci. 2022, 23, 2550.
treatments at R3 Stem Cell every six to twelve months.
4. Efficacy of stem cell-based therapies for stroke, Matthew
Unfortunately, stem cell clinics in Colombia, China R. Chrosteka, Brain Res. 2019 November 01; 1722: 146362.
doi:10.1016/j.brainres.2019.146362.
and Panama charge over $20,000 USD for stroke
treatment. Because the one treatment cost so much, 5. Progress in Mesenchymal Stem Cell Therapy for Ischemic
Stroke, Yinghan Guo, Stem Cells International, Volume
how are individuals supposed to budget for that 2021, Article ID 9923566, 24 pages.
every year?? R3 Stem Cell’s fees are less than half that
6. Treatment of acute ischemic stroke by minimally
for 100 million high quality stem cells! manipulated umbilical cord-derived mesenchymal stem
cells transplantation: A case report, Ahn et al, World J Stem
R3’s Experience Cells 2021 August 26; 13(8): 1151-1159
For the past decade, R3 Stem Cell’s Centers globally 7. The role of mesenchymal stem cell transplantation for
have performed over 23,000 regenerative procedures ischemic stroke and recent research developments, Zhou
in six countries. Several hundred have been for either et al, Frontiers in Neurology, 16 November 2022.
ischemic or hemorrhagic strokes. Patient satisfaction 8. Combination of Stem Cells and Rehabilitation Therapies
across all conditions treated is 85%! for Ischemic Stroke, Reed Berlet, Biomolecules 2021, 11,
1316. https://doi.org/10.3390/biom11091316
R3 combines safety, effectiveness and affordability 9. Neuroinflammation as a target for treatment of stroke
for the therapies. Internationally, the Intellicell is used, using mesenchymal
which is culturing the most active mesenchymal stem

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 R3 Consumer Guide for Stem Cell and Exosome Therapy

Guide to Stem Cell

and Exosome
Therapy for
Systemic Sclerosis
(Scleroderma)

Brought to you by

* No portion of this Document may be reproduced without the Express Written Consent of R3 Stem Cell.
Disclaimer: This guide’s education does not constitute medical advice. The USA FDA considers stem cell therapy experimental. Any claims
made in the Guide refer to procedures performed outside the USA.
287
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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR SYSTEMIC SCLEROSIS

Guide to Stem Cell and Exosome Therapy

for Systemic Systemic Sclerosis (Scleroderma)
Every day, R3 Stem Cell receives inquiries worldwide All of these symptoms are responsible for increased
from individuals asking if stem cell therapy can help morbidity and lead to functional disability (reduced
for Systemic Systemic Sclerosis . Spoiler alert: It can mouth opening and loss of hand function, for
help a lot! In this guide, we’ll go through the basics example), pain, and psychological consequences.
of how stem cells and exosomes work for Systemic
Sclerosis , the latest research, and what to expect In at least half of the cases, patients will die from
with a regenerative procedure. SSc-related disorders and the other half from higher
incidence of malignancies and cardiovascular
Conventional treatments for Systemic Systemic diseases compared to the general population.
Sclerosis are often not able to stop the
disease progression and control the What are the reasons Systemic
topical plaques and joint erosion. Sclerosis occurs?
For those who desire reduced
pain along with improved The cause of Systemic Sclerosis
skin appearance, failure with is a complex interplay of
conventional treatments is genetic and environmental
disappointing and occurs all factors, leading to fibroblast
too often. activation and endothelial
impairment. The role of
Stem cell therapy for Systemic
endogenous and/or exogenous
Sclerosis is turning out to be an
oxidative stress in Systemic Sclerosis
excellent opportunity for individuals to
is crucial, as shown by the link between
achieve meaningful long term results. Let’s dig in!
environmental exposure to oxidants and professional
A Significant Global Issue disease.
Systemic Systemic Sclerosis (SSc) is a rare The cause of scleroderma is unknown. However,
autoimmune disease, which affects most frequently researchers think that the immune system overreacts
middle age patients with a prevalence ranging from and causes inflammation and injury to the cells that
100 to 300 per million depending on the country. line blood vessels. This triggers connective tissue
Scleroderma makes your body produce too much cells, especially a cell type called fibroblasts, to make
collagen, a protein that you need for healthy skin and too much collagen and other proteins.
tissue. It’s an autoimmune condition, which means Traditional Treatments
your immune system attacks your body instead of
There is no treatment that can cure or stop the
protecting it.
overproduction of collagen that is characteristic of
The disease is characterized by vascular damage scleroderma. But a variety of treatments can help
and diffuse fibrosis, which mainly affects skin and control symptoms and prevent complications.
lung tissues but heart and digestive tract could
To date, treatment of Systemic Sclerosis patients
also be involved. One of the earliest and most
is mostly palliative, based on symptomatic drugs
frequent symptom is the Raynaud’s Phenomenon
alleviating Raynaud’s phenomenon, gastro-
but vasculopathy is also responsible for other clinical
esophageal reflux, pain, and immunosuppressants
signs such as digital ulcers, pulmonary arterial
(methotrexate, mycophenolate mofetil, and
hypertension, and telangiectasia.
cyclophosphamide), or organ transplantation in case

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR SYSTEMIC SCLEROSIS

of severe cardio-pulmonary involvement. Although fingers was noticed. In 2011, the same team reported
new drugs have been developed for the treatment, four supplementary cases of allogeneic BM-MSC
SSc general prognosis and mortality have not systemic injection. Here again, improvement of
changed in the last 40 years. vasculopathy and skin fibrosis was observed.
Stem Cell Therapy for Systemic Sclerosis It has become increasingly evident that MSCs and
Considering immunomodulatory, angiogenic and MSCEVs are advantageous in treating autoimmune-
antifibrotic capabilities of mesenchymal stem cells related fibrotic skin diseases (SSc and Scl-GVHD). These
(MSC), MSC-based therapy could represent a complete therapies have shown particular promise in three main
breakthrough in this severe life-threatening disease areas:
with unmet medical need. (1) rebalancing immune and inflammatory
The first patient who received MSCs in the treatment disorders
of progressive diffuse SSc has been reported in 2008. A (2) enhancing antioxidant defenses, and
young female patient had severe disease, refractory to
all immunosuppressive drugs. At time of implantation, (3) inhibiting overactivated fibrosis.
she presented with six painful ulcerations and received
60 million intravenous administration of allogeneic The safety of MSC-based therapy in clinics has been
donor MSCs. proved, and it is considered as a potentially effective
option for treating systemic Systemic Sclerosis . The
No adverse events were reported and 3 months table below summarizes clinical trials that have been
after treatment, a significant decrease in the performed for systemic Systemic Sclerosis . In the Main
patient’s painful ulcerations was measured. Vascular results column, notice how prominent the beneficial
improvement in the blood circulation of hands and outcomes have been!

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR SYSTEMIC SCLEROSIS

How do Stem Cells and Exosomes Act in the

Body?
Stem cells and exosomes act in the body through
several mechanisms. They do NOT become part of a
patient’s DNA, which means they do not engraft into
the person’s existing cells
They act through: 4. Cellular signaling – the biologics are able
to perform “cell to cell” communication. This
1. Angiogenesis – provokes formation of new promotes recipient cells to proliferate their
blood vessels. growth factor production, protein production
2. Reduce inflammation – Systemic Sclerosis is and regenerate nerve tissues that are damaged.
associated with significant inflammation, and the 5. Prevent cell death – most cells have a timed
regenerative biologics reduce it nicely. death, where they are only allowed to live a
3. Immune system modulation – the stem cells certain length of time. This is called apoptosis.
and exosomes modulate the immune system The regenerative biologics allow normally
very differently than steroids. Instead of functioning cells (i.e. neuron cells) to live longer,
blanketly suppressing the immune system, the and spare them from the pre-programmed
regenerative biologics tamp down the harmful death.
processes while amping up the beneficial ones. 6. Preventing scar tissue –Once that scar tissue
This includes ramping up production of several forms, it becomes nonfunctional. Stem Cells and
helpful growth factors and cytokines, while exosomes are great at preventing scar tissue
tamping down harmful ones. (anti-fibrosis).

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Stem Cells can also release a huge variety of molecules The lab carefully processes the umbilical cord to
into the extracellular environment. These molecules, generate large amounts of stem cells and exosomes
which include extracellular vesicles (exosomes), lipids, that are of the highest quality possible. The lab team
free nucleic acids, and soluble proteins, exert crucial consists of multiple PhD’s working in ISO Certified,
roles in repairing damaged tissue. Along with offering cGMP compliant clean rooms to ensure quality
stem cells for treatment of Systemic Sclerosis , R3 Stem assurance that exceeds USA FDA standards. The
Cell includes stem cell exosomes, which are a type proprietary production process combines the highest
of extracellular vesicle participating in extensive cell potency, safety and affordability for providers to
to cell communication for ovarian tissue repair and confidently offer exosome procedures.
regeneration.
Millions of dollars have been invested into the
The stem cells administered by R3 are not the ones pharmaceutical grade production of the biologics
that become part of a patient’s DNA. The administered including first rate clean rooms, bioreactors,
mesenchymal stem cells are not specifically designed nano-particle tracking analyzers, cytometers, PCR,
to replace damaged and lost epithelial cells, but rather tangential flow machines and real time environmental
coordinate immune system modulation monitoring. The quality assurance testing complies
with screening and testing stan¬dards consistent
Where do the stem cells and exosomes come
with the American Association of Tissue Banks, cGMP
from? standards, FDA regulations and the highest level of any
R3 Stem Cell’s regenerative biologics originate from regulatory agency globally.
umbilical cord tissue that has been donated after a
scheduled c-section. No baby (or mother) is harmed Stem Cell Derived Exosomes
during the c-section procedure. The umbilical cord R3 Stem Cell’s Centers of Excellence globally include
tissue is normally discarded, but if the mother passes umbilical cord stem cell derived exosomes with
screening test then the umbilical cord is immediately umbilical cord stem cells to provide enhanced results.
sent to the lab.

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Exosomes are lipid bound vesicles (acellular) and can avoid immune rejection by the
produced by cells which contain a recipient, which serves as the foundation
plethora of growth factors, cytokines, for their successful application without
mRNA and other proteins. needing to match the donor to the
recipient. Scientists call this being
They are exceptionally helpful in
“immunologically privileged”.
cell to cell communication, and very
effective for reducing inflammation Another question often asked is “Is
when they become ingested by there a chance of a tumor forming?”
their recipient cell. They act as shuttles Once again the answer is NO. The
to send nucleic acids and proteins to mesenchymal stem cells and exosomes
other cells, in this way, allowing cell-to-cell used during treatment have never been
communication and transporting molecules among shown to have tumor forming potentials. In fact, they
both close and distant cells. In general, these released have been shown to be anti-tumor forming.
proteins are important regulators of intracellular
information. Treatment Protocol
For the past decade, R3 has been
Exosomes could be the mediators of many stem cell-
successfully treating patients with stem
associated therapeutic activities. Considering they are
cell and exosome therapies with injection,
100 times smaller than stem cells, they do not have any
infusion, intranasal, intrathecal and
issues passing through the blood-brain-barrier to reach
nebulizer procedures.
the brain from the bloodstream.
For Systemic Sclerosis , R3’s providers use between
Is stem cell therapy safe? one and two million stem cells per kilogram (depends
After a decade of performing over 24,000 stem cell on patient weight). In addition, billions of stem cell
procedures worldwide, R3 knows that the regenerative exosomes and platelet rich plasma therapy (PRP) are
procedures are safe. The quality control employed included at no cost.
during the stem cell production is second to none, and
R3 Stem Cell’s Systemic Sclerosis treatment protocol
the side effects R3 sees are usually mild to moderate
includes an IV therapy combining mesenchymal stem
and temporary.
cells and exosomes, along with a multivitamin IV as
They may include itching, dizziness, lightheadedness, well. R3 has developed a proprietary injection protocol
low grade fever, chills, headache, nausea. These are for the legs combining the biologics along with platelet
typically temporary. If a patient has an allergic reaction rich plasma therapy to increase the effectiveness of
to the multivitamin or a preservative, all of R3’s Centers the therapy. Safety is paramount with the biologics
have the medications to resolve it quickly. products being rigorously tested prior to use, and
expert providers managing each treatment as if you are
One of the questions we get asked a lot is, “Will the
a family member!
stem cells get rejected?” The answer is NO.
MSCs do not express major histocompatibility complex Why does R3 Stem Cell use donor tissue for
(MHC) antigens of the class II subtype and contain low its stem cells?
levels of MHC molecules of the class I subtype. MSCs Although autologous (your own) stem cells provide
also lack the co-stimulatory molecules essential for significant advantages, allogeneic (donor) stem cells
immune detection, including CD40, CD80, and CD86. have more advantages. First of all, autologous MSCs
Therefore, MSCs generally have low immunogenicity need a long time to culture and expand, which

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 GUIDE TO STEM CELL AND EXOSOME THERAPY FOR SYSTEMIC SCLEROSIS

limits its application in treatment, while of patients with varying types of peripheral
allogeneic stem cells can be obtained neuropathy, and over a thousand
and expanded more quickly, thus patients with diabetes.
avoiding the delay of time window.
R3 combines safety, effectiveness
Second, age is a factor that affects and affordability for the therapies.
the physiological characteristics Internationally, the Intellicell is used,
of MSCs. Studies have shown that which is culturing the most active
stem cells from elderly donors mesenchymal stem cells to create the
have decreased proliferation and “smartest” stem cell in the world!
differentiation ability. This means they are
less in number and less effective! R3 Stem Cell offers free consultations for
individuals to discuss whether regenerative therapy
Affordability is indicated for your Systemic Sclerosis . Simply call +1
(844) GET-STEM to schedule yours!
Stem cell therapy for Systemic Sclerosis
may be the key step to completely References:
changing a person’s quality of life, and 1. Rozier P, Maria A, Goulabchand R, Jorgensen C, Guilpain P and
we want to make it affordable for as Noël D (2018) Mesenchymal Stem Cells in Systemic Systemic
many individuals as possible. Our global volume has Sclerosis : Allogenic or Autologous Approaches for Therapeutic
Use? Front. Immunol. 9:2938. doi: 10.3389/fimmu.2018.02938
allowed us to keep our patient cost as low as possible.
2. Alexandre At Maria, et al, Adipose Derived Mesenchymal
Unfortunately, stem cell clinics in Colombia, China Stem Cells in Autoimmune Disorders: State of the Art and
and Panama charge over $20,000 USD for Systemic Perspectives for Systemic Systemic Sclerosis . Clinical Reviews
Sclerosis treatment. How are individuals supposed to in Allergy and Immunology, 2017, 52(2), 234-259.
budget for that?? R3 Stem Cell’s fees are typically less 3. Rozier P, Maria A, Goulabchand R, Jorgensen C, Guilpain P and
than half that for full treatment, which also includes Noël D (2018) Mesenchymal Stem Cells in Systemic Systemic
free exosomes, PRP and a multivitamin infusion! Sclerosis : Allogenic or Autologous Approaches for Therapeutic
Use? Front. Immunol. 9:2938. doi: 10.3389/fimmu.2018.02938
R3’s Experience 4. Yang et al. Stem Cell Research & Therapy (2023) 14:372 https://
For the past decade, R3 Stem Cell’s Centers globally doi.org/10.1186/s13287-023-03543-w.
have performed over 24,000 regenerative procedures 5. Granel B, Daumas A, Jouve E, et al. Ann Rheum Dis
in six countries. Patient satisfaction across all conditions 2015;74:2175–2182.
treated is very high, at 85%. R3 has treated hundreds

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 R3 Consumer Guide for Stem Cell and Exosome Therapy

Consumer Guide
to Stem Cell
Treatment for
Traumatic Brain
Injury

Brought to you by

* No portion of this Document may be reproduced without the Express Written Consent of R3 Stem Cell.
Disclaimer: This guide’s education does not constitute medical advice. The USA FDA considers stem cell therapy experimental. Any claims
made in the Guide refer to procedures performed outside the USA.
294
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 CONSUMER GUIDE TO STEM CELL TREATMENT FOR TRAUMATIC BRAIN INJURY

Consumer Guide to Stem Cell Treatment

for Traumatic Brain Injury
Every day, R3 Stem Cell receives inquiries worldwide Traditional Treatments for
from individuals asking if stem cell therapy can help Traumatic Brain Injury
with Traumatic Injury (TBI). Spoiler alert: It can help a
lot! In this guide, we’ll go through the basics of how Treatment of TBI patients has not changed much
stem cells work for TBI, the latest research, and what in the last 20 years, consisting only of supportive
to expect with a regenerative procedure. therapy directed

A Significant Global Issue at prevention, early detection and treatment of

Traumatic brain injury (TBI) is a leading cause second insults. Neuroprotective treatments are
of death and disability, with a high urgently needed for this condition.
burden on patients, their With improving medical
families, and society. Long- technology, the survival
term mortality in TBI is rate of patients with
substantial, and TBI TBI has increased
survivors have a life significantly. After
expectancy shortened emergent treatment
by 6 years. with neurosurgical
Of all types of injury, decompression,
those to the brain craniotomy and shunts
are among the most if necessary, patients
likely to result in death or often face a long road
permanent disability. Brain ahead. Various types of
injury is the leading cause of disabilities result such as
death and disability worldwide. Every body motor dysfunction, language
day, 153 people in the United States die from and communication difficulties, mental
injuries that include TBI. problems along with psychological and cognitive
defects.
Motor Vehicle Crashes account for 50% of all TBIs.
This includes autos, trucks, motorcycles, bicycles, and After surgical treatments are completed, symptomatic
pedestrians hit by vehicles. The leading causes of TBI treatments ensue with PT, OT and medications as
vary by age: falls are the leading cause of TBI among needed for issues like spasm, seizures, etc.
persons aged 65 years and older; transportation is the Stem Cell Therapy for Traumatic Brain Injury
leading cause of TBI among persons under the age of
65 years. Estimates suggest that sports related brain HAs you will see from the studies below, there is a
injury accounts for close to 300,000 injuries each year. better option for TBI patients than to just receive
symptomatic treatments. While not all TBI patients
TBI results in neuroinflammation, cortical will respond dramatically to stem cell treatment, the
degeneration, white matter damage, neuronal vast majority experience noticeable quality of life
loss, and blood–brain barrier (BBB) dysfunction. improvements. Especially with a treatment regimen
As a consequence, approximately 30% of patients of multiple injections.
experience the development of progressive
neurological deficits. In 2017, a Case Study was published out of Turkey.

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The patient involved was a 29-year-old male that The participant endured the process excellently and
experienced a motor vehicle crash and had a serious did not have any serious injection related side effects.
TBI in March 2017. He underwent He had only early, temporary complications such as
subfebrile fever, moderate headache, and muscle
decompressive craniectomy (DC) and
pain related to intramuscular injection which was
ventriculoperitoneal (VP) shunt, and a couple months
settled by symptomatic medical care within 24-48
after, his craniectomy flap was placed back on his
hours.
skull.
The participant demonstrated changes in his speech,
He was conscious but did not respond, tetraplegic
mental skills, ability to focus, concentrating, short-
with high-degree muscle spasms, and
term memory and fine and gross motor
could not speak, control movements in our present
his sphincter and case report. His degree of
communicate. He autonomy increased,
completed almost as demonstrated
a year in a by the one-year
rehabilitation follow-up
clinic but improvement
did not of his
show much Functional
progress.
Injections of
botulinum
toxin against
muscle spasms Independence
provided only Measure motor
partial relief. His scale score from
upper extremities 13/91 at baseline
were hyperflexed in a to 46/91. His cognitive
decorticated pose, and his score progress was much
lower extremities stretched. His higher than his motor score,
muscle tone was improved, and the everyday improving from 9/35 at baseline to 27/35 on
tasks such as mobilization and bathing became the third month follow-up. His cognitive score was
considerably difficult. At this point, the patient was 30/35, at the last follow-up.
referred for the MSC trial. A Korean group performed a pilot trial in 2013,
The patient received six rounds of treatment with where 3 severe TBI patients were treated with
umbilical cord mesenchymal stem cells over a period intravascular umbilical cord blood (UCB) therapy
of six months (one month apart). Each treatment twice with non-myeloablative immunosuppression
consisted of a combination of 1 million stem cells per and concomitant EPO injection.
kilogram applied the following:
Three patients with severe TBI received two UCB
1. Intrathecal = 1 million MSC’s per kilogram. therapies. Severe TBI was defined as a Glasgow Coma
2. Intravenous = 1 million MSC’s per kilogram. Scale (GCS) score of 8 or less, or loss of consciousness
(LOC) for more than 1day.
3. Intramuscular = 1 million MSC’s per kilogram.

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All patients received comprehensive and in-patient- At 4 years post injury, he received 46 million
based rehabilitation continuously. nucleated cells per kilogram IV and then 8 months
The minimum number of UCB cells, as total nucleated later received cord blood again with 32 million
cells (NCs), was twenty five million per kilogram. nucleated cells per kilogram. After the second
Because a single cord blood unit did not contain UCB therapy, spasticity decreased, from grade 2
sufficient numbers of nucleated cells, multiple to grade 1, He began to maintain table sitting for
UCB units were infused in each patient. Before a few seconds without assistance and sit from the
infusion, UCB units were washed to remove dimethyl decubitus position using his right
sulfoxide. The UCB was administered through upper extremity. Approximately 17 months after the
intravenous or intra-arterial routes. second UCB therapy, he was able to swallow a honey-
For patient 1, she was unable to stand like and nectar-like dysphagia diet without
alone due to right side weakness aspiration in a swallowing study.
and could not walk even with Patient 3 was 20 yo and injured
a one-man assist before the in a car accident. A brain MRI
first UCB therapy. She had taken at 11 months post-
a short attention span and injury showed extensive
low cognition, along with encephalomalacia with
global aphasia and her brain atrophy. At 7 months
aphasia quotient (AQ) was after the accident, he
0. She tried to grab anyone received 27 million nucleated
with her left hand and bite cells/kilogram and then again
anything in her hands. She was 5 months later with 38 million
19 yo at the time of her car accident, NC/kg. The vegetative status was
and received umbilical cord stem cell not changed by UCB Therapy. Spasticity
therapy starting at 3 years, 10 months post accident. improved though.In 2013, Wang et all recruited forty
Regarding her status at 14 months after the second patients with sequelae of TBI and randomly assigned
administration, she became able to control herself them to either the stem cell treatment group or the
and understand simple verbal commands, and control group. The patients in the stem cell treatment
attentive activities appeared. She became able to group underwent 4 stem cell transplantations via
stand from a sitting position by herself while holding lumbar puncture. Ten million stem cells were slowly
a handle on the wall and to walk for approximately injected intrathecal 4 times over a period of 5-7 days.
50m with minimal-to-moderate assistance by one The two groups showed equivalent baseline scores,
therapist. indicating they were comparable. At the 6 month
Patient 2 was 32 yo and also sustained a severe TBI follow up, the stem cell group showed significant
from a car accident. He could not control improvements with motor, sensation and balance
scores in both upper and lower extremities. In
his head, turn his body, or maintain a sitting posture
addition, the stem cell group showed significant
due to poor trunk control. Language evaluation
improvements in the self- care sub-score, mobility
showed Broca’s aphasia and his AQ was 12.8 (8th
sub-score, locomotion sub-score and communication
percentile). On an activities of daily living (ADL)
sub-score. All in all, the study results confirmed
evaluation, he was totally dependent. He constantly
that the umbilical cord mesenchymal stem cell
showed impulsive and aggressive behaviors. He
transplantation improved the neurological function
could not sit alone or stand, even with maximal
and self-care in patients with TBI sequelae.
assistance from a therapist.

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Why doesn’t R3 Stem Cell use a person’s They act through:

own stem cells for Traumatic Brain Injury
1. Angiogenesis – provokes formation of new
R3 used to perform autologous therapies, where a blood vessels.
patient’s own bone marrow or adipose stem cells were
used. However, a lot of stem cells in one’s body are as 2. Reduce inflammation – TBI is associated with
old as that person is, and hence not very active. Their significant acute and chronic inflammation, and
ability to successfully increase sufficient blood flow and the regenerative biologics reduce it nicely.
allow for tissue regeneration is inferior to umbilical cord
3. Immune system modulation – the stem cells
stem cells.
and exosomes modulate the immune system
Specifically, the therapeutic potential very differently than steroids. Instead of
of autologous bone marrow or blanketly suppressing the immune
adipose stem cells in the system, the regenerative
treatment of older patients biologics tamp down the
is impaired by a number of harmful processes while
age-related factors such as amping up the beneficial
oxidative stress, telomere ones. This includes
length, DNA damage, ramping up production
disease, and long-term of several helpful growth
use of some medications. factors and cytokines,
while tamping down
This is in stark contrast to harmful ones.
the youthful genotype and
phenotype of neonatal tissue- 4. Cellular signaling –
derived stem cells, such as from the the biologics are able to perform
umbilical cord. They are better at facilitating “cell to cell” communication. This promotes
repair and regeneration of tissue damage, creating recipient cells to proliferate their growth factor
new blood flow with superior anti-inflammatory and production, protein production and regenerate
immunomodulatory efficacy compared to mature stem nerve tissues that are damaged.
cells from one’s adipose or bone marrow.
5. Prevent cell death – most cells have a timed
As a result of the inferiority of autologous stem cells death, where they are only allowed to live a
due to the reasons above and better results being seen certain length of time. This is called apoptosis.
with umbilical cord stem cells, R3 only uses the donor The regenerative biologics allow normally
stem cells today. functioning cells (i.e. neuron cells) to live longer,
and spare them from the pre-programmed
How do the Stem Cells and Exosomes Work death.
for Traumatic Brain Injury?
6. Preventing scar tissue –TBI patients may
Stem cells and exosomes act in the body through experience significant scarring throughout the
several mechanisms. They do NOT become part of a shoulder. Once that scar tissue forms, it becomes
patient’s DNA, which means they do not engraft into nonfunctional. Stem Cells and exosomes are
the person’s existing cells. The predominant method of great at preventing scar tissue (anti-fibrosis).
action is thought to be through paracrine mechanisms,
which means “cell to cell” interaction.

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Stem Cells can also release a huge variety

of molecules into the extracellular
environment. These molecules, which
include extracellular vesicles, lipids,
free nucleic acids, and soluble
proteins, exert crucial roles in
repairing damaged tissue.
Along with offering MSCs for
treatment of Traumatic Brain
Injury, R3 Stem Cell includes
stem cell exosomes, which are
a type of extracellular vesicle
participating in extensive cell to cell
communication for new blood flow
creation.
Where do the stem cells and exosomes
come from? with screening and testing stan¬dards consistent
with the American Association of Tissue Banks, cGMP
R3 Stem Cell’s regenerative biologics originate from standards, FDA regulations and the highest level of any
umbilical cord tissue that has been donated after a regulatory agency globally.
scheduled c-section. No baby (or mother) is harmed
during the c-section procedure. The umbilical cord Stem Cell Derived Exosomes
tissue is normally discarded, but if the mother passes
screening tests then the umbilical cord is immediately R3 Stem Cell’s Centers of Excellence globally include
sent to the lab. The screening tests are extremely umbilical cord stem cell derived exosomes with
rigorous, and mandated by the USA FDA. umbilical cord stem cells to provide enhanced results.
Exosomes are lipid bound vesicles (acellular) produced
The lab carefully processes the umbilical cord to by cells which contain a plethora of growth factors,
generate large amounts of stem cells and exosomes cytokines, mRNA and other proteins.
that are of the highest quality possible. The lab team
They are exceptionally helpful in cell to cell
consists of multiple PhD’s working in ISO Certified,
communication, and very effective for reducing
cGMP compliant clean rooms to ensure quality
inflammation when they become ingested by their
assurance that exceeds USA FDA standards. The
recipient cell. They act as shuttles to send nucleic acids
proprietary production process combines the highest
and proteins to other cells, in this way, allowing cell-to-
potency, safety and affordability for providers to
cell communication and transporting molecules among
confidently offer exosome procedures.
both close and distant cells. In general, these released
Millions of dollars have been invested into the proteins are important regulators of intracellular
pharmaceutical grade production of the biologics information.
including first rate clean rooms, bioreactors, Exosomes could be the mediators of many stem cell-
nano-particle tracking analyzers, cytometers, PCR, associated therapeutic activities. We have seen them to
tangential flow machines and real time environmental be “faster acting” than stem cells, so R3 frequently uses
monitoring. The quality assurance testing complies

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them in conjunction to provide a “1-2 punch” for patient Protocol

outcomes. For the past decade, R3 has been
Is stem cell therapy safe? successfully treating Traumatic Brain Injury
with stem cell and exosome procedures.
After a decade of performing over 24,000 stem cell The regenerative biologics are applied
procedures worldwide, R3 knows that the regenerative directly into the spinal cord with an intrathecal
procedures are safe. The quality control employed application, and also infused through an IV. Typically,
during the stem cell production is second to none, and more than one session is required for optimal benefit.
the side effects R3 sees are usually mild to This was shown in the studies described in
moderate and temporary. this Guide, where better outcomes
They may include itching, were associated with multiple
dizziness, lightheadedness, procedures.
low grade fever, chills, R3’s providers use one to
headache, nausea. two million stem cells per
These are typically kilogram, to make sure
temporary. If a patient that patients achieve the
has an allergic reaction absolute best outcome
to the multivitamin or possible. Between 50 and
a preservative, all of R3’s 150 billion exosomes are
Centers have the medications included with each procedure.
to resolve it quickly.
One of the questions we get asked a
Outcomes
lot is, “Will the stem cells get rejected?” The Similar to the research mentioned above, R3
answer is NO. Stem Cell’s outcomes for TBI have been exceptional!
The patient satisfaction rate is 75% year over year
MSCs do not express major histocompatibility complex
for RBI. Patients typically experience symptomatic
(MHC) antigens of the class II subtype and contain low
improvement in sitting/standing balance, bed
levels of MHC molecules of the class I subtype. MSCs
mobility, trunk stability, upper limb function, mobility,
also lack the co-stimulatory molecules essential for
sensation, bowel/bladder functions, and activities of
immune detection, including CD40, CD80, and CD86.
daily living. Keep in mind results cannot be guaranteed
Therefore, MSCs generally have low immunogenicity and will vary between individuals.
and can avoid immune rejection by the recipient,
which serves as the foundation for their successful It may take a few months to see the improvements, as
application without needing to match the donor to the it can take that long to build up new blood flow and
recipient. Scientists call this being “immunologically create neurological repair.
privileged”.
Affordability
Another question often asked is “Is there a chance of a
tumor forming?” Current research has concluded that Because stem cell therapy for TBI is not a
the answer is NO. The mesenchymal stem cells and permanent cure, it’s important to make
exosomes used during treatment have never been it affordable. Repeat therapies can help maintenance
shown to have tumor forming potentials. In fact, they and/or achieve additional improvements for pain
have been shown to be anti-tumor forming relief. So a lot of patients seek additional treatments at
R3 Stem Cell every twelve to eighteen months.

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R3 Stem Cell’s fees are less than half what comparable References:
(and reputable) regenerative clinics charge. Be wary 1. Zanier et al, MesenchymAl stromal cells for Traumatic
of clinics trying to pass off PRP as a stem cell therapy. bRain Injury (MATRIx): a study protocol for a multicenter,
If they mention only taking your blood for the double‑blind, randomised, placebo‑controlled phase II trial,
treatment, it is NOT a stem cell treatment! Intensive Care Medicine Experimental (2023) 11:56

2. Kabatas et al, Functional Recovery After Wharton’s Jelly-

R3’s Experience Derived Mesenchymal Stem Cell Administration in a Patient
with Traumatic Brain Injury: A Pilot Study, Turk Neurosurg
FFor the past decade, R3 Stem Cell’s Centers globally 30(6):914-922, 2020.
have performed over 24,000 regenerative procedures in
3. Wang et al, Umbilical cord mesenchymal stem cell
six countries. Several hundred have been for SCI. Patient transplantation significantly improves neurological function in
satisfaction across all conditions treated is 85%! patients with sequelae of traumatic brain injury, Brain Research
1532, 2013.
R3 combines safety, effectiveness and affordability
4. Min et al, Allogenic umbilical cord blood therapy combined
for the therapies. Internationally, the Intellicell is used,
with erythropoietin for patients with severe traumatic
which is culturing the most active mesenchymal stem brain injury: Three case reports, Restorative Neurology and
cells to create the “smartest” stem cell in the world! Neuroscience 31 (2013) 397–410

R3 Stem Cell offers free consultations for individuals to

discuss whether regenerative therapy is indicated for
their AS. Simply call +1 (844) GET-STEM or +1
(480) 808-7057 to schedule yours!
Disclaimer: This guide’s education does
not constitute medical advice. The
USA FDA considers stem cell therapy
experimental. Any claims made in this
Guide refer to procedures performed
outside of the USA.

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 R3 Consumer Guide for Stem Cell and Exosome Therapy

Consumer Guide
to Stem Cell
Treatment for
Trigeminal
Neuralgia

Brought to you by

* No portion of this Document may be reproduced without the Express Written Consent of R3 Stem Cell.
Disclaimer: This guide’s education does not constitute medical advice. The USA FDA considers stem cell therapy experimental. Any claims
made in the Guide refer to procedures performed outside the USA.
302
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 CONSUMER GUIDE TO STEM CELL TREATMENT FOR TRIGEMINAL NEURALGIA

Consumer Guide to Stem Cell Treatment

for Trigeminal Neuralgia
Every day, R3 Stem Cell receives inquiries worldwide Current Treatment Options for Trigeminal
from individuals asking if stem cell therapy can help Neuralgia
with Trigeminal Neuralgia. Spoiler alert: It can help a
lot! In this guide, we’ll go through the basics of how Neuropathic pain responds poorly to opioid
stem cells and exosomes work, the latest research, and over-the-counter analgesics. First-line
and what to expect with a regenerative procedure. antineuropathic medication utilizes tricyclic
antidepressants and anticonvulsants administered
A Significant Global Issue to approximately 40% of people with facial
Chronic orofacial pain is prevalent in the United States neuropathies. However, pain relief experienced with
and impacts approximately 20% of the population. these treatments is only moderate. On average, a
Chronic orofacial pain (CP) is a persistent and minimum of three peripheral and central chronic
debilitating condition that affects the face, mouth, pain patients need to be treated before one patient
and jaw and can have a significant impact will experience a 50% improvement in pain
on an individual’s quality of life symptoms.
by posing problems to eat,
speak, and perform everyday The current front-line drugs
activities. for the treatment of
neuropathic pain exhibit
Trigeminal neuralgia minimal efficacy. For
is one of the types of example, gabapentin is
CP. Others include TMJ, one of the most favorable
myofascial pain and drugs on the market. At its
headaches originating maximum dose (3,600 mg),
from the face, head or neck. it provides pain relief to less
Trigeminal neuralgia (TN), than 60% of patients, with an
also known as tic douloureux, NNT (numbers needed to treat)
is sometimes described as the most value of four.
excruciating pain known to humanity. The pain
typically involves the lower face and jaw, although In addition, approximately 25% of people with facial
sometimes it affects the area around the nose and neuropathies receive no treatment at all. Compliance
above the eye. This intense, stabbing, electric shock- with antineuropathic medication can be problematic
like pain is caused by irritation of the trigeminal nerve, for patients with potential side effects of weight gain,
which sends branches to the forehead, cheek and drowsiness, dry mouth, negative mood changes, and
lower jaw. It usually is limited to one side of the face. increased suicide risk.

Over 150,000 individuals per year are newly Why does it occur?
diagnosed with TN, with women being twice as There are two types of TN — primary and secondary.
likely to have it. Managing chronic orofacial pain The exact cause of TN is still unknown, but the pain
may require a comprehensive and multidisciplinary associated with it represents an irritation of the
approach to address the underlying mechanisms nerve. Primary trigeminal neuralgia has been linked
contributing to its persistence. to the compression of the nerve, typically in the base

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of the head where the brain meets the spinal cord. This hypothesis has been tested in animal models of
This is usually due to contact between a healthy trigeminal neuropathic pain, diabetic neuropathy,
artery or vein and the trigeminal nerve at the base and hind paw neuropathic pain, all of which showed
of the brain. This places pressure on the nerve as it promising results, with a significant reduction in
enters the brain and causes the nerve to misfire. neuropathic pain symptoms.
Secondary TN is caused by pressure on the nerve The immunosuppressive and immunomodulatory
from a tumor, MS, a cyst, facial injury or another properties of stem cells have been shown to contribute
medical condition that damages the myelin sheaths. to this pain relief. Additionally, the secretome of stem
The prevalence of TN due to damages to peripheral cells (e.g. exosomes) are also sufficient to produce
branches of the trigeminal nerve after implants, these effects, suggesting that paracrine (cell to cell)
orthognathic surgery, third molar extractions, release of cytokines and other factors are necessary.
mid-face ruptures, or root canal surgery reaches
approximately 3%-5%. These observations provide evidence
of MSCs producing behavioral
There is increased incidence pain relief associated with
of anxiety, depression, and orofacial injury and
insomnia in patients indicate suppression of
affected by TN. When trigeminal neuronal
severe, individuals hyperexcitability.
with TN suffer during
speaking, chewing, Stamatoski and
swallowing, and it’s Fidoski [2017] have
described as the investigated PRP
most excruciating administration in
pain known to a clinical pilot study
humanity. The main conducted with twenty-
medication side effects nine patients with TN.
of concern were drowsiness, PRP was applied around the
affecting work per¬formance trigeminal region (either through
and social activities, and weight gain, facial or intraoral route). PRP application
affecting personal esteem. was carried out five times, at seven-day intervals, in
either male or female patients.
Stem Cell Therapy for Trigeminal Neuralgias
and Chronic Headaches Patients were assessed before each PRP injection and
subjected to the visual analogue scale for pain, which
The use of mesenchymal stem cells (MSCs) in the was also applied at the second and sixth follow-up
treatment of neuropathic pain is a rapidly expanding months. The outcomes were extremely positive, since
field due to a few core properties of these cells. MSCs the magnitude of pain had significantly decreased over
have been reported to exert an anti-inflammatory seven examinations and fully disappeared at the third
effect through cytokine release that may com¬bat the follow-up month.
increased inflammation involved in neuropathic pain,
and have been shown to play an important role in A 2014 study out of Australia evaluated the use of
nerve healing and regeneration. mesenchymal stem cells for ten female subjects with a

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diagnosis of chronic trigeminal neuralgia.

Each patient received between 40
million and 160 million MSC’s
with local injections around
the trigeminal nerve.
No subject showed
any side effects of
the treatment. There
was no evidence of
unusual localized
swellings or lesions at
any of the injection sites
nor evidence of general or
medical health issues at any
follow-up stage (to 6 months).
The primary treatment outcome to be
measured was change in pain intensity and the
secondary outcome measure was any reduction in the
daily consumption of anti-neuropathic medication. (motor branch of the trigeminal nerve). In addition, no
Subjects were reviewed for safety evaluation for any infection of the environment was observed where the
clinical sign of trigeminal nerve deficit (paresthesia, stem cells were injected.
dysesthesia), facial nerve paresis, infection, and unusual Neuropathic pain is recognized as a difficult and
swellings or lesions at the injection sites. chal¬lenging pain state to obtain meaningful and
The results showed a reduction in pain intensity scores prolonged pain reduction. Prior to the trial, the subjects
from the stem cell treatment in 7/9 patients (one were undergoing pain management for months to
patient was lost to follow up). Five of the most positive years on appropriate anti-neuropathic medication
responders also reduced their need for gabapentin at therapeutic dose ranges. Despite utilizing proven
medication. The majority of subjects, however, pharmacotherapy, the mean pain intensity of 7.5
reported a positive effect from stem cell therapy with still revealed a major deficiency in treating chronic
pain reduction in addition to lowering anti-neuropathic neuropathic pain to achieve an acceptable quality of
medication dose to enable an improved quality of life life. This trial showed a good response to a single dose
with fewer drug side effects. of MSCs.

There were no visible deleterious changes at any of The majority of the subjects in the study were on a slow
the injection sites. In addition, there were no changes but escalating dose of medication, with the likelihood
to normal nerve physiology of the involved cranial of increased medication requirements for the next 30–
nerves where stem cells were administered; specifically, 40 years of their life, assuming normal life expectancy.
no numb¬ness, tingling, dysesthesia on the lower lip, The current front-line drugs for the treatment of
chin, lateral border of the tongue or face (trigeminal neuropathic pain exhibit minimal efficacy. For example,
nerve branches V2 and V3), and no report of motor gabapentin is one of the most favorable drugs on the
nerve dysfunction to the face (C7, facial nerve) or jaw market. At its maximum dose (3,600 mg), it provides
pain relief to less than 60% of patients, with an NNT

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(numbers needed to treat) value of four. In our study, pregabalin or carbamazepine, and opioids (tramadol,
the near significant reduc¬tion in gabapentin use hydrocodone, or oxycodone), in a multimodal
and minor reduction in amitriptyline suggested that regimen, with poor pain relief (EVA pain scale > 7) but
stem cells may exhibit biological priority in recovering with burdensome adverse effects associated to the
myelinated fibers over unmyelinated fibers. pharmacological regime.
A Colombian study in 2018 evaluated 45 patients with None of the included patients specifically had
neuropathic pain treated with simply platelet rich trigeminal neuralgia. Patients with involvement of
plasma therapy. 45 patients with shooting, burning, peripheral nerves were managed with ultrasound
electric, or lancinating pain and allodynia, with approach for the nerve injections, and a volume of 10
refractory multimodal-approach to pharmacologic ml PRP was injected.
management for more than 3 months were included in
the study. The treatment improved pain and function in 39 out
of the 45 patients after the first therapeutic injection
Causes of the peripheral NP included; 23 patients with of platelet rich plasma. On VAS scale, pain was reduced
post herpetic neuralgia (PHN) affecting: the brachial by 50 % one month following PRP injection and 70 %
plexus (9 patients), the occipital nerve (2 patients) at the end of three months, scaling down from 9/10 to
or the intercostal nerve (12 patients); 14 patients 2/10. Half of patients (20 patients) reported complete
with peripheral nerve injury following trauma, and resolution of symptoms and were able to discontinue
8 patients with chronic post-surgical pain (CPSP) the use of all pain medication, and opioid use was
following abdominal surgery but with clear clinical also withdrawn in another 15 patients, in whom pain
involvement of the ilioinguinal nerve. So none actually control was possible with paracetamol and pregabalin
had trigeminal neuralgia in this study. alone.
Prior to inclusion in the PRP study, all patients had As a consequence of the reduction of pain intensity,
been receiving pharmacologic management for more patients were able to reduce doses of pain medication,
than 3 months, including tricyclic antidepressants, thereby reducing the side effects of the

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drugs and thus improving their quality of life.

In our opinion, the basic and important
concept in understanding of the
cause of neuropathic pain and
the subsequent treatment
proposals that may arise is the
consideration that all types of
central and peripheral neural
lesions, whether ischemic,
traumatic, infectious, metabolic,
malignant, toxic or immune
mediated, are associated to
an inflammatory reaction, with
increased activity of neutrophils and
macrophages that rapidly invade the
injured axons and dorsal root ganglion.
Most of the time, such inflammation has neurotrophic
and neuroprotective effects but this inflammatory
activity can also result in neuronal damage that related factors such as oxidative stress, telomere
could contribute to the persistence of neuropathic length, DNA damage, disease, and long-term use of
pain. According to the authors, their evidence-based some medications.
hypothesis was, alike to lidocaine, that PRP could
This is in stark contrast to the youthful genotype
effectively control neuroinflammation and could
and phenotype of neonatal tissue-derived stem
contribute to the relief of neuropathic pain, similar to
cells, such as from the umbilical cord. They are better
lidocaine or even better, not only by blocking noxious
at facilitating repair and regeneration of tissue
inputs and avoiding the subsequent neural tissue
damage, creating new blood flow with superior
damage but through its anti-inflammatory effect and
anti-inflammatory and immunomodulatory efficacy
its important role in nerve healing and regeneration.
compared to mature stem cells from one’s adipose or
Why Doesn’t R3 Stem Cell Use A Person’s bone marrow.
Own Stem Cells for Treatment? As a result of the inferiority of autologous stem cells
due to the reasons above and better results being
R3 used to perform autologous therapies, where a seen with umbilical cord stem cells, R3 only uses the
patient’s own bone marrow or adipose stem cells donor stem cells today.
were used. However, a lot of stem cells in one’s body
are as old as that person is, and hence not very active. How do the Stem Cells and Exosomes Work
Their ability to successfully increase sufficient blood for Trigeminal Neuralgias?
flow and allow for tissue regeneration is inferior to
umbilical cord stem cells, which are young, potent Stem cells and exosomes act in the body through
and extremely active. several mechanisms. They do NOT become part of
a patient’s DNA, which means they do not engraft
Specifically, the therapeutic potential of autologous into the person’s existing cells. The predominant
bone marrow or adipose stem cells in the treatment method of action is thought to be through paracrine
of older patients is impaired by a number of age- mechanisms, which means “cell to cell” interaction.

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They act through: 4. Cellular signaling – the biologics are able

to perform “cell to cell” communication. This
1. .Angiogenesis – provokes formation of new promotes recipient cells to proliferate their
blood vessels. growth factor production, protein production
and regenerate tissues that are damaged.
2. Reduce inflammation – Chronic Trigeminal
Neuralgia is associated with significant acute 5. Prevent cell death – most cells have a timed
and chronic inflammation, and the regenerative death, where they are only allowed to live a
biologics reduce it nicely. certain length of time. This is called apoptosis.
The regenerative biologics allow normally
3. Immune system modulation – the stem cells functioning cells to live longer, and spare them
and exosomes modulate the immune system from the pre-programmed death.
very differently than steroids. Instead of 6. Preventing scar tissue – While scar tissue
blanketly suppressing the immune system, the resulting from Trigeminal Neuralgias is not
regenerative biologics tamp down the harmful known to occur, it is a problematic issue in
processes while amping up the beneficial ones. many conditions. Once that scar tissue forms,
This includes ramping up production of several it becomes nonfunctional. Stem Cells and
helpful growth factors and cytokines, while exosomes are great at preventing scar tissue
tamping down harmful ones. (anti-fibrosis).

Stem Cells can also release a huge variety of molecules screening tests then the umbilical cord is immediately
into the extracellular environment. These molecules, sent to the lab. The screening tests are extremely
which include extracellular vesicles, lipids, free nucleic rigorous, and mandated by the USA FDA.
acids, and soluble proteins, exert crucial roles in
repairing damaged tissue. The lab carefully processes the umbilical cord to
generate large amounts of stem cells and exosomes
Along with offering MSCs for treatment of Trigeminal that are of the highest quality possible. The lab team
Neuralgias, R3 Stem Cell includes stem cell exosomes, consists of multiple PhD’s working in ISO Certified,
which are a type of extracellular vesicle participating cGMP compliant clean rooms to ensure quality
in extensive cell to cell communication for new blood assurance that exceeds USA FDA standards. The
flow creation. And according to the research discussed proprietary production process combines the highest
above, platelet rich plasma is very effective for TN as potency, safety and affordability for providers to
well. So R3 actually includes all three biologics, which confidently offer exosome procedures.
are referred to as the TRIFECTA!
Millions of dollars have been invested into the
Where do the stem cells and exosomes pharmaceutical grade production of the biologics
come from? including first rate clean rooms, bioreactors,
nano-particle tracking analyzers, cytometers, PCR,
R3 Stem Cell’s regenerative biologics originate from
tangential flow machines and real time environmental
umbilical cord tissue that has been donated after a
monitoring. The quality assurance testing complies
scheduled c-section. No baby (or mother) is harmed
with screening and testing stan¬dards consistent
during the c-section procedure. The umbilical cord
with the American Association of Tissue Banks, cGMP
tissue is normally discarded, but if the mother passes
standards, FDA regulations and the highest level of any
regulatory agency globally.

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 CONSUMER GUIDE TO STEM CELL TREATMENT FOR TRIGEMINAL NEURALGIA

Stem Cell Derived Exosomes (MHC) antigens of the class II subtype and contain low
levels of MHC molecules of the class I subtype. MSCs
R3 Stem Cell’s Centers of Excellence globally include also lack the co-stimulatory molecules essential for
umbilical cord stem cell derived exosomes with immune detection, including CD40, CD80, and CD86.
umbilical cord stem cells to provide enhanced results.
Exosomes are lipid bound vesicles (acellular) produced Therefore, MSCs generally have low immunogenicity
by cells which contain a plethora of growth factors, and can avoid immune rejection by the recipient,
cytokines, mRNA and other proteins. which serves as the foundation for their successful
application without needing to match the donor to the
They are exceptionally helpful in cell to cell recipient. Scientists call this being “immunologically
communication, and very effective for reducing privileged”.
inflammation when they become ingested by their
recipient cell. They act as shuttles to send nucleic acids Another question often asked is “Is there a chance of a
and proteins to other cells, in this way, allowing cell- tumor forming?” Current research has concluded that
to-cell communication and transporting molecules the answer is NO. The mesenchymal stem cells and
among both close and distant cells. In general, exosomes used during treatment have never been
these released proteins are important shown to have tumor forming potentials.
regulators of intracellular In fact, they have been shown to be
information. anti-tumor forming.

Exosomes could be the Protocol

mediators of many stem For the past
cell-associated therapeutic decade, R3 has
activities. We have seen been successfully
them to be “faster acting” than treating Trigeminal
stem cells, so R3 frequently uses Neuralgia with
them in conjunction to provide a “1-2 stem cell and exosome procedures.
punch” for patient outcomes. As mentioned earlier, R3 also includes PRP
Is stem cell therapy safe? derived from the patient’s own blood. The three
biologics together are referred to as the TRIFECTA! The
After a decade of performing over 25,000 stem cell regenerative biologics are applied directly around the
procedures worldwide, R3 knows that the regenerative trigeminal neve and surrounding tissues with direct
procedures are safe. The quality control employed injections, and also infused through an IV. Depending
during the stem cell production is second to none, and on each patient’s unique history, R3’s providers
the side effects R3 sees are usually mild to moderate may also incorporate an intra-nasal or intrathecal
and temporary. application.
They may include itching, dizziness, lightheadedness, R3’s providers use one to two million stem cells per
low grade fever, chills, nausea. These are typically kilogram, to make sure that patients achieve the
temporary. If a patient has an allergic reaction to the absolute best outcome possible. Between 50 and 100
multivitamin or a preservative, all of R3’s Centers have billion exosomes are included with each procedure.
the medications to resolve it quickly.
Outcomes
One of the questions we get asked a lot is, “Will the
stem cells get rejected?” The answer is NO. Similar to the research mentioned above, R3 Stem
Cell’s outcomes for Trigeminal Neuralgia have been
MSCs do not express major histocompatibility complex

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 CONSUMER GUIDE TO STEM CELL TREATMENT FOR TRIGEMINAL NEURALGIA

exceptional! The patient satisfaction rate is 85% year R3 Stem Cell offers free consultations for individuals to
over year. Patients typically experience less pain with
less severity and a reduced need for medications. Keep
discuss whether regenerative therapy is indicated for
in mind results cannot be guaranteed and will vary their Trigeminal Neuralgia. Simply call +1 (844) GET-
between individuals. STEM or +1 (888) 988-0515 to schedule yours!
Affordability Disclaimer: This guide’s education does not constitute medical
Because stem cell therapy for Trigeminal
advice. The USA FDA considers stem cell therapy experimental. Any
Neuralgia is not typically a permanent claims made in this Guide refer to procedures performed outside of
cure, it’s important to make it affordable. the USA.
Repeat therapies can help maintenance and/or
achieve additional improvements for pain relief. So a References:
lot of patients seek additional treatments at R3 Stem
Cell every twelve to eighteen months. 1. 1. Ren K, Vickers R, Murillo J and Ruparel NB (2023)
Revolutionizing orofacial pain management: the promising
R3 Stem Cell’s fees are less than half what comparable potential of stem cell therapy. Front. Pain Res. 4:1239633.
(and reputable) regenerative clinics charge. Be wary
of clinics trying to pass off PRP as a stem cell therapy. 2. Duran et al, USING PLATELET-RICH PLASMA AGAINST
If they mention only taking your blood for the TRIGEMINAL NEURALGIA: IS IT AN ALTERNATIVE? A MINI-
treatment, it is NOT a stem cell treatment! REVIEW, University of Campinas (UNICAMP), Campinas, SP,
Brazil.
R3’s Experience
3. Vickers et al, A preliminary report on stem cell therapy for
For the past decade, R3 Stem Cell’s Centers globally neuropathic pain in humans, Journal of Pain Research 2014:7
have performed over 25,000 regenerative procedures 255-263
in six countries. Patient satisfaction across all conditions 4. Lopez et al, Platelet-rich plasma in treating peripheral
treated is 85%! neuropathic pain. Preliminary report, Rev Soc Esp Dolor, 2018;
25(5): 263-270
R3 combines safety, effectiveness and affordability
for the therapies. Internationally, the Intellicell is used,
which is culturing the most active mesenchymal stem
cells to create the “smartest” stem cell in the world!

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 About R3 Stem Cell

David Greene, MD, PhD, MBA, Founder/CEO

R3 Stem Cell offers treatments that bring

patients hope and options. Hope that
surgery can be avoided, and tissue injury
can be repaired with patients being able to
get back to desired activities.

Founder and CEO David Greene, MD, PhD,

MBA writes extensively on regenerative
medicine and gives many seminars
worldwide on a regular basis. With over
forty Centers of Excellence globally, R3 is at
the forefront of regenerative therapies.
R3’s Centers have successfully performed
over 24,000 regenerative procedures to
date. Call today for your free consultation
+1 (844) GET-STEM!

No portion of this Document may be reproduced without the

Express Written Consent of R3 Stem Cell.

Disclaimer: This guide’s education does not constitute medical advice.

The USA FDA considers stem cell therapy experimental. Any claims made in
the Guide refer to procedures performed outside the USA.

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