BIO-ARTIFICIAL LIVER

Presented by

Rituparna Addy
12/BT/23
Department of Biotechnology
Haldia Institute of Technology
THE LIVER
• Largest internal organ
• Hepatic cells (hepatocytes) responsible for liver functions
• Regenerative
• Removing and excreting
body wastes, hormones,
Drugs, bacteria
• Synthesizing plasma
Proteins, bile, immune
factors, helping the body
fight infection
• Storing certain vitamins,
minerals, and sugars
• Excretion of bilirubin.
COMPLICATIONS
• Recurrent bile duct infections
• Cancer and drug damage
• Alcohol damage
• Cirrhosis Reasons for Receiving Liver Transplant
• Fatty liver Alpha antitrypsin
Fulminant liver failure
• Infected ascites deficiency
3%
3%

Budd-Chiari Other diseases

Syndrome 10%
Primary Biliary
Alcoholic Liver 4% Cirrhosis
disease 16%
4%

Cholangiocarcinoma
4%

Primary Sclerosing Other cirrhosis

cholangitis (nonalcoholic)
5% 12%
Chronic Active Biliary atresia
Hepatitis Hepatocellular 11%
8% carcinoma
9% Retransplantation
11%
TREATMENTS
Liver Transplant
• Most effective treatment for
acute liver failure
• High survival rates
• Part of donor’s liver is
transplanted to recipient

Bio-artificial Liver
• Temporary fix
• Keep the patient alive until
transplant is available
• Liver regeneration
 Stem cells are used to grow a new liver on the connective tissue
and blood vessel scaffold of an old liver.
BIO ARITIFICIAL LIVER DEVICE
• Viable and active cellular component
• Cellular preparation must not transmit any infectious diseases
• Can introduce the therapeutic and regulatory molecules
• Blood must perfuse properly through system
• Can filter substances from the blood
• Immunocompatible
LIVER DIALYSIS UNIT
• FDA approved in 1994.
• Plate dialyzer with blood on
one side, dialysate is a
mixture of sorbents, activated
charcoal being the essential
component.
• For a substance to be
removed, must be dialyzable
and able to bind to charcoal.
• “Bridge to recovery” for treat
acute hepatic encephalopathy
and overdoses of drugs.
• Post-market trials have
shown the LDU to be effective
in improving physiological
and neurological status.
MARS® [Molecular Absorbent
Recycling System ]
• Limited to investigational use in
US.
• Hollow fiber membrane
haemodialyzer.
• Blood on one side, human
albumin on other.
• Albumin recycled through circuit
containing another dialyzer &
carbon and anion exchanger
adsorption columns.
• Removes both water-soluble &
protein bound substances.
• Keep valuable proteins.
• Trials have found it safe and
associated with clinical
improvement.
ELAD® [Extracorporeal Liver
Assist Device ]

• Uses cultured human hepatocytes express normal liver-specific

metabolic pathways. hollow fiber dialyzer.
• Dialyzer cartridge connected to continuous hemodialysis
machines, like those used for renal therapy.
• Blood separated into a cellular component and a plasma
component.
• Plasma through dialyzer, hepatocytes on outside of hollow fibers.
• Currently involved in a phase 2 clinical trial to evaluate the safety
and efficiency.
BLSS [Bioartificial Liver Support
System ]
• Extracorporeal hemofiltration hollow fiber membrane
bioreactor with 100 grams of primary porcine hepatocytes.
• Whole blood is filtered.
• Contains blood pump, heat exchanger, oxygenator to control
oxygenation and pH, and hollow fiber bioreactor.
• Currently undergoing phase I/II clinical trials.
• Patients show some improvement.
MELS [Modular Extracorporeal
Liver System ]
• Parallel plate design.
• Human hepatocytes
attached to
semipermeable
membranes on parallel
plate.
• Plasma separator, then
plasma passes into the
bioreactor.
• In the bioreactor, the
plasma flows over the
semipermeable
membrane where the
hepatocytes are
adhered.
• Current trials in Europe
show promise.
HEPASSIST 2000 SYSTEM
• Four components: a hollow
fiber bioreactor containing
porcine hepatocytes, two
charcoal filters, a membrane
oxygenator, and a pump.
• Must be used in conjunction
with a commercially
available plasma separation
machine.
• Blood separated; plasma
processed through charcoal
filters to remove particulates,
bacteria, then enters
bioreactor.
• Hepatocytes must be heated
and oxygenated.
• FDA mandated full Phase III
trials.
LIVERx2000
• Hollow fiber cartridge.
• Primary porcine hepatocytes
suspended in a cold collagen
solution and injected inside
fibers.
• Blood circulates outside the
hollow fibers.
• Designed to treat both acute
and chronic liver failure.
• Phase I/II clinical trials are
underway to test the safety of
efficacy of this device.
• Anyone treated with the
LIVERx2000 will be monitored
for PERV.
BIO ENGINES IMPLANTABLE
DEVICE
• Designed to take place in a
liver or a portion of the liver.
• Polymer grid-like mesh used
as artificial vasculature
resembling that of an actual
liver.
• Patterned silicon wafers
serve as molds for polymer
sheets.
• Currently being tested on
pigs.
• Clotting issues.
AT PRESENT
• Patients are in waiting list due to Liver Transplant Statistics in 2000

20000
unavailability of donor. 18000
16000
• Use of immunosuppressants may 14000

Patients
12000

be needed. 10000
8000

• These devices currently

6000
4000
2000
undergoing clinical trials. 0
Transplants Waiting List

• Hepatocyte function can be

optimized.
• Survival benefit has not been
clearly demonstrated.
• Clinical trials are for safety and
efficacy.
FUTURE CHALLENGES
• Research in cell sources/viability, Bioreactor design, Filtering
techniques, Packaging for implantable devices.
• Should provide at least 10% of liver functioning.
• Controversy over the use of porcine cells due to possible
transmission of infections.
• Hepatocytes and plasma have very different physio-chemical
properties.
• Hepatocyte cells undergo a lot of stress inside of bio-artificial
liver.
• Limited volume of the bioreactor.
• Proteins greater than pore size cannot be released.
• To achieve density of cells needed to replace liver, an estimated
1000m of hollow fibers would be needed.
• The risk of rejection is always present.
REFERENCES
• Allen JW, Hassanein T, Bhatia SN (2001) “Advances in bioartificial liver devices. Hepatology.” 34:
447-455.
• Kinasiewicz A, Dudziński K, Chwojnowski A, Weryński A, Kawiak J (2007) “Three-dimensional
culture of hepatocytes on spongy polyethersulfone membrane developed for cell
transplantation.” Transplant Proc 39: 2914-2916.
• Carpentier B, Gautier A, Legallais C (2009) “Artificial and bioartificial liver devices: present and
future.” Gut 58: 1690-1702.
• Chen G, Palmer AF (2010) “Hemoglobin regulates the metabolic, synthetic, detoxification, and
biotransformation functions of hepatoma cells cultured in a hollow fiber bioreactor.” Tissue Eng
Part A 16: 3231-3240.
• Pan XP, Li LJ (2012) “Advances in cell sources of hepatocytes for bioartificial liver.” Hepatobiliary
Pancreat Dis Int 11: 594-605.
• Hannan NR, Segeritz CP, Touboul T, Vallier L (2013) “Production of hepatocyte-like cells from
human pluripotent stem cells.” Nat Protoc 8: 430-437.
THANK YOU