Journal of Cosmetic Dermatology

REVIEW ARTICLE OPEN ACCESS

Microfocused Ultrasound in Regenerative Aesthetics:

A Narrative Review on Mechanisms of Action and
Clinical Outcomes
Vasanop Vachiramon1 | Tatjana Pavicic2 | Gabriela Casabona3 | Jeremy B. Green4 | Jennifer Levine5 |
6 7 8 9
Je-­Young Park | Julieta Spada | Mariana Muniz | John Akers | Matthew Jackson 9 | Alec McCarthy 9

1Division of Dermatology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand | 2Private Practice for Dermatology &
Aesthetics, Munich, Germany | 3Ocean Clinic Marbella, Málaga, Spain | 4 Skin Research Institute & Skin Associates of South Florida, Coral Gables,
Florida, USA | 5Lenox Hill Hospital and Manhattan Eye, Ear, and Throat Hospital, New York, New York, USA | 6Apkoo-­Jung Oracle Dermatology Clinic,
Seoul, Republic of Korea | 7Julieta Spada Dermatology & Aesthetics, Buenos Aires, Argentina | 8Dermatology Private Office, São Paulo, Brazil | 9Global
Medical Affairs, Merz Aesthetics, Raleigh, North Carolina, USA

Correspondence: Alec McCarthy ([email protected])

Received: 14 August 2024 | Revised: 10 October 2024 | Accepted: 17 October 2024

Funding: This work was supported by Merz Aesthetics Global Medical Affairs.

Keywords: energy-­based devices | MFU-­V | microfocused ultrasound with visualization | regenerative aesthetics | Ultherapy

ABSTRACT
Background: Microfocused ultrasound with visualization (MFU-­V) is widely used in aesthetic medicine for skin tightening and
rejuvenation. However, its role in regenerative aesthetics and its precise mechanism of action are not fully understood.
Objective: This narrative review aims to contextualize and articulate the mechanism of action of MFU-­V, evaluate its role in
regenerative aesthetics, and assess its effectiveness based on existing clinical, histological, and skin-­mechanical studies.
Methods: A comprehensive literature search was performed to collect and analyze studies on MFU's biological mechanisms,
clinical outcomes, and impact on extracellular matrix (ECM) regeneration. The review integrates findings from clinical trials,
histological analyses, and biomechanical assessments to provide a cohesive understanding of MFU-­V 's role in aesthetic medicine.
Results: MFU-­V emits focused ultrasound energy that penetrates multiple skin layers and the superficial musculoaponeurotic
system, creating localized thermal coagulation points. These points initiate biological responses that recruit fibroblasts and stim-
ulate the production of new collagen and elastin fibers. Enhanced ECM protein synthesis leads to significant improvements in
skin biomechanics and quality, reducing skin laxity and enhancing appearance. Clinical studies support these findings, showing
improvements in skin firmness and texture following MFU-­V treatment.
Conclusion: Through analyzing the underlying biological mechanisms and the observable clinical outcomes, this narrative re-
view sets the stage for a comprehensive understanding of the mechanism of action and role of MFU-­V in regenerative aesthetics.

1   |   Introduction regenerative pathways to address the aesthetic impact of aging

[1, 2]. Since its introduction, various aesthetic treatments have
Regenerative aesthetics is a sub-­
f ield of regenerative med- self-­identified as regenerative aesthetic treatments, many artic-
icine focusing on returning skin and deeper tissues, such as ulating a unique approach and mechanism to achieving regen-
the superficial musculoaponeurotic system (SMAS), to a more eration of tissues or their primary constituents. For example,
youthful structure and function by leveraging the body's stem cells or tissue fragments can modify their environment

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is
properly cited.

© 2024 The Author(s). Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.

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through cellular differentiation or via the recruitment and microfocused ultrasound (MFU) devices. Key factors that dif-
modulation of endogenous stem cells [1, 3]. In addition, biocues ferentiate MFU from HIFU are the consistency and spacing of
may stimulate cell signaling to improve the targeted tissue's the denatured tissue areas, the size and shape of the denatured
microenvironment. Bio-­cue treatments may include platelet-­ tissue area, the consistency of the energy levels delivered to
rich plasma (PRP) injections, exosomes, polymicronutrients, or the tissues, and how these factors affect the surrounding tis-
growth factors or their stimulation with energy-­based devices sue such as the epidermis and hypodermis/adipose tissue [18].
(EBDs) [4–6]. Acellular regenerative scaffolds made of natural Ultherapy (Merz North America, Inc. Raleigh, N.C., USA)
or synthetic materials such as calcium hydroxylapatite (CaHA; utilizes two ultrasound modalities—precise microfocused ul-
Radiesse) and poly-­ l-­
lactic acid (PLLA; Sculptra) leverage trasound energy delivery and real-­time visualization through
mechanoregulation or localized subclinical inflammation, re- collimated ultrasound or microfocused ultrasound with vi-
spectively, to initiate signaling pathways that can affect cellular sualization (MFU-­ V ) [19]. Ultherapy is US-­ F DA-­cleared to
function down to the level of gene expression [7–11]. Chiefly, achieve lifting of the brow, lifting of lax submental and neck
and despite having different mechanisms of action and treat- areas, improving lines and wrinkles on the décolleté, and vi-
ment regimens, such treatments accomplish aesthetic correc- sualization of the dermal and subdermal tissue layers. Other
tion by sufficiently regenerating components of target tissues worldwide indications include noninvasive dermatological
to improve the overall tissue function, resulting in an aesthetic sculpting and lifting of the dermis in the upper face, lower
improvement. Since energy-­based devices (EBDs) achieve aes- face, neck, and décolleté, treatment of axillary hyperhidrosis,
thetic corrections without implanted gels or biomaterials and and sagging jawline lift.
the direct delivery of cells or biocues, it is reasonable to as-
sume that aesthetic correction from such devices results from
the body's physiological response to the treatment. The aim of 3.2   |   Structural and Functional Components
this narrative review was to evaluate the evidence supporting of the ECM
EBDs, specifically microfocused ultrasound (MFU), in regen-
erative aesthetics. The ECM serves as a foundational and functional scaffold in
regenerative aesthetics, influencing cellular behaviors through
mechanisms encompassing growth factor modulation, cellu-
2   |   Methods lar adhesion, cytokine activity, cellular migration, differentia-
tion, growth, and cell death [20]. The structural complexity of
A systematic literature search was conducted using established the ECM is evidenced by its diverse components, notably col-
databases (PubMed, Scopus, and Web of Science) to identify rel- lagens—particularly type I and type III in regenerative aes-
evant peer-­reviewed articles published up to July 2024. Search thetics—elastin, proteoglycans, glycosaminoglycans (GAGs),
terms included combinations of “microfocused ultrasound,” including hyaluronic acid, laminins, and fibronectin [21].
“MFU-­V,” “Ultherapy,” “energy-­based devices,” “regenerative
aesthetics,” “extracellular matrix,” “collagen,” “elastin,” “skin Collagen can be categorized into fibril-­forming collagens like
biomechanics,” and related terms. Studies investigating the type I and III or network-­forming collagens like the base-
cellular, histological, and functional changes in target tissues ment membrane collagen IV, providing structural support to
following MFU treatment for aesthetic purposes were included. the ECM. The ratios of collagen I to collagen III are import-
Data extraction and analysis were performed by two indepen- ant for gauging tissue strength and health [7, 22]. Elastin is
dent reviewers, with discrepancies resolved through consen- an extensively crosslinked protein that provides elastic recoil
sus. The findings were synthesized narratively, focusing on the and extensibility within the skin, among other tissues [23].
mechanism of action, efficacy, and safety of MFU in the context Collagen-­to-­elastin ratios are crucial in maintaining skin in-
of regenerative aesthetics. tegrity, elasticity, and wound healing, with imbalances leading
to aging and connective tissue disorders. Elastin also pro-
vides bio-­feedback to influence fibroblast activity and ECM
3   |   Results and Discussion remodeling [24]. Proteoglycans consist of the polysaccharide
chains, GAG, bound to central proteins to construct a stabiliz-
3.1   |   EBDs in Regenerative Aesthetics ing ground substance in the ECM, providing hydration, resis-
tance to external pressures, and aiding cell migration [25, 26].
As regenerative aesthetics has matured, claims have surfaced Hyaluronic acid (HA) is a GAG date providing tissue hydration
involving regenerative mechanisms of action among devices and osmotic balance among its many functions [27]. Laminin
with variable levels of evidence. Some EBDs with potential protein plays a role in proliferation, differentiation, migration,
regenerative properties or with current regenerative science and adhesion within the ECM and can improve tissue regen-
include lasers [12], radio frequency [13], microneedling, [14] eration after injuries [28]. Fibronectin, an ECM protein, forms
microneedling with radiofrequency [15], and high-­intensity fo- fibrillar scaffolds for other ECM proteins, including collagens
cused ultrasound (HIFU) [16]. Most energy-­based devices use and proteoglycans. It supports maturation and attachment, cel-
heat or mechanical wounding to induce ECM protein synthe- lular migration, and mechanosignalling and plays a major role
sis, eventually resulting in a wide range of aesthetic outcomes in wound healing [29].
ranging from tissue tightening to skin quality improvements.
Applications of HIFU target the multilayer dermis and fibro- The complexity of the ECM is profound, as even a brief exam-
muscular layers rich in fibroblasts to stimulate a regenerative ination of its structure and function shows the array and inter-
effect [17]. Within the broad category of HIFU devices are dependency of its various components. Regenerative aesthetics

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treatments that target different tissue planes of the skin and 4   |   MFU-­V Mechanism of Action
fibromuscular layer can affect the ECM to promote a healthy,
youthful environment. These effects are externally observable 4.1   |   Introduction to the Dual Ultrasound MOA
and substantiated across multiple established aesthetic end-
points in various clinical trials, details of which will be covered MFU-­V 's regenerative mechanism of action can be broken down
in the subsequent sections. into four steps. The first is the delivery of energy and precise
denaturation of the local tissue. This initiates the body's natu-
ral healing process through the creation of thermal coagulation
3.3   |   The Role of Tissue Planes in ECM points (TCP), followed by temporary inflammation, cellular pro-
Regeneration liferation, and tissue remodeling, ultimately leading to signifi-
cant increases in mature collagen and elastin (Figure 2) [38, 39].
Due to multiple factors, including age, sex, and body mass index Table 2 provides detailed information on studies exploring the
(BMI), the skin thickness and anatomy of the skin varies be- regenerative potential of Microfocused Ultrasound (MFU).
tween each unique patient [30–33]. Patient assessment is vital
to delivering personalized, quality care to each individual. The
visualization component of MFU-­V allows providers to analyze 4.2   |   Denaturation
the anatomy of the skin up to 8 mm below the surface, integral
in targeting the optimal tissue layers, including the dermis, deep Collimated ultrasound visualization is utilized in real-­time to
dermis, the fibromuscular layer partially consisting of the su- identify appropriate treatment planes, where precise microfo-
perficial musculoaponeurotic system (SMAS) and fibromuscu- cused ultrasound waves are delivered. These waves create vi-
lar layer (Figure 1) [34]. Applying varying amounts of pressure brations within targeted tissue molecules, raising temperatures
based on the providers' discretion while maintaining proper that induce collagen fibril denaturation and contraction, begin-
coupling can increase this depth by up to 1.5 mm. Notably, ning with the disruption of intramolecular hydrogen bonds at
MFU-­V 's real-­time visualization and microfocused energy fea- approximately 57°C–58°C. This leads to immediate collagen
tures allow for trained practitioners to bypass layers, including contraction, as demonstrated in a cadaver study by White et al.
the epidermis, to minimize or prevent patient downtime and [40]. Complete denaturation occurs at 65°C. The arrangement
reduce the risk of post-­inflammatory hyperpigmentation (PIH) of TCPs, approximately 1 mm3 in size and shaped like inverted
associated with resurfacing lasers, ultimately providing safe and cones, in surrounding healthy tissue is critical for triggering a
effective single and repeat treatments [35]. Furthering person- temporary immune response and promoting efficient healing
alized treatment, MFU-­V allows for further customization of (Figure 3). This process allows the body to attract cells that in-
treatment depths, treatment transducer (TD) width, and energy filtrate and remodel the treated area. By assessing a patient's
settings to address the specific needs of each unique patient for unique anatomical features with the collimated ultrasound,
optimized lifting and tightening (Table 1). MFU-­V can target providers can optimize the delivery of microfocused ultrasound
and treat deeper tissue planes than many other EBD and HIFU to these critical tissue planes while also visualizing and avoid-
while maintaining similar patient comfort compared to more ing structures that should not be treated, such as vessels, nerves,
superficial aesthetic ultrasound [36]. Features of MFU-­V pro- and bone. The ultrasound treatment bypasses the skin's surface
vide the tools to precisely treat the correct tissue planes, leading to deliver energy directly to collagen-­rich dermal and fibromus-
to an optimal response within the surrounding tissue and extra- cular layers. This denaturing of proteins and other components
cellular matrix (ECM) [37]. within these targeted layers initiates the intrinsic collagen and

FIGURE 1    |    MFU-­V transducers targeting various skin layers (SMAS, reticular/papillary dermis) at specific depths (4.5 mm, 3.0 mm, 1.5 mm),
demonstrating precise depth-­controlled thermal coagulation. DS, DeepSee.

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TABLE 1    |    Transducer setting and associated energy levels in Joules (J).

Thermal coagulation point intensity

Depth Level Level Level Level Level
Transducer Clinical application (mm) 4 (J) 3 (J) 2 (J) 1 (J) 0 (J)
DS 4-­4.5 Deep dermis and SMAS 4.5 1.20 1.00 0.90 0.75 0
DS 7-­4.5 SMAS 4.5 1.05 0.90 0.75 0.66 0
DS 7-­3.0 Dermis 3.0 0.45 0.35 0.30 0.25 0
DS 7-­3.0N Dermis (narrow) 3.0 0.45 0.35 0.30 0.25 0
DS 10-­1.5 Superficial dermis 1.5 0.25 0.20 0.18 0.15 0
DS 10-­1.5N Superficial dermis (narrow) 1.5 0.25 0.20 0.18 0.15 0
Abbreviation: DS, DeepSee.

FIGURE 2    |    MFU-­V 's mechanism of action for skin regeneration. (A) Three phases: Inflammation (TCP triggers immune response), Proliferation
(fibroblasts produce new collagen/elastin), and Remodeling (collagen/elastin mature, restructuring skin). (B) Conceptual timeline and illustrative
relative intensity of biological processes over 100 days. The y-­a xis represents qualitative intensity.

elastin regeneration processes. The MFU-­V process is marked cells by binding pattern recognition receptors to stimulate tem-
by TCPs, which are discrete, consistent in size, and optimally porary inflammatory pathways. This is followed by the release
spaced when compared to those produced by other HIFU de- of cytokines and chemokines, which attract numerous cell
vices [13]. types, including macrophages, involved in the healing process
[41, 42]. In a 2024 animal study, skin tissue around TCPs was
excised following the application of energy levels 2 and 4 at
4.3   |   Temporary Immune Response depths of 1.5, 3.0-­, and 4.5-­mm [38]. Histological analysis in-
dicated the TCPs consisted of collagen, which exhibited a loss
The inflammatory portion of the body's healing response is ini- of its fine fibrillar structure, indicative of denaturation. From
tiated by damage-­associated molecular patterns (DAMPs) that Day 14 to Day 90, there were observable changes in TCP size,
are released by affected tissue. These signals activate immune cellular activity, and collagen maturity. Although the presence

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 TABLE 2    |    Overview of studies investigating the regenerative potential of microfocused ultrasound (MFU).

Study characteristics Participants characteristics Exposure/intervention Outcomes

Follow-­up No. partici­ Sex Health status/ Device

Author, year Country Design period pants (%F) characteristics Age Ethnicity Treated sites (Brand) Treatment Categories

Denaturation

Kist et al. n/s In vivo study Immediate, 3 n/s Healthy n/s n/s Pre-­auricular region Thermacool Multiple pass, Multiple low-­
2006 [13] with 3 subjects 24 h, and 6 m device low-­energy RF energy passes (97 J)
treatment (varying increased collagen
Joules and passes) damage similar to
versus single single high-­energy
pass, high-­energy (166 J) pass, with
RF treatment 50% collagen
replacement in
6 months, enhancing
skin tightening

White et al. USA In vivo study No follow-­up 6 cadavers 33% n/a 49–72 years Mixed Superficial Ulthera Ultrasound Intense ultrasound
2007 [40] on cadaveric female musculoaponeurotic (Ultherapy), therapy to create therapy created
facial tissue (2/6) system (SMAS) Intense thermal injury thermal injury
Ultrasound zones in the zones up to
System SMAS layer 7.8 mm deep in the
SMAS layer, with
precise targeting
and minimal
surrounding
tissue damage

Temporary immune response

Marquardt Germany, Non-­clinical 14 and n/a n/a Yucatan n/s n/a Face and Ulthera Microfocused Inflammation was
et al. 2024 [38] USA study on 90 days Miniature subcutaneous (MFU-­V, Merz ultrasound mild and transient
histological Swine models tissue (SMAS) Aesthetics) targeting depths following treatment;
evolution of 1.5, 3.0, and Demonstrates
of TCPs 4.5 mm, TCP elastin neogenesis
post-­M FU-­V formation, and neocollagenesis
treatment collagen after MFU-­V
remodeling, and treatment;
elastin neogenesis significant fibroblast
recruitment to
the TCP areas

Suh et al. South Prospective 2m 11 90.9% Patients with 35–64 years Asian Face and neck Doublo Intense focused Increased collagen
2015 [39] Korea study with female facial skin laxity (HIRONIC Co.) ultrasound fibers without signs
histologic (10/11) (IFUS) for facial of inflammation
evaluation tightening; two or fat necrosis;
handpieces with increased fibrosis
3 and 4.5 mm between fat
focal depths layers confirmed
histologically

(Continues)

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 TABLE 2    |    (Continued)

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Study characteristics Participants characteristics Exposure/intervention Outcomes

Follow-­up No. partici­ Sex Health status/ Device

Author, year Country Design period pants (%F) characteristics Age Ethnicity Treated sites (Brand) Treatment Categories

Vachiramon Thailand Prospective, 56 days 13 92.3% Healthy subjects, Mean age Fitzpatrick Abdomen (filler Ulthera (MFU), MFU performed HA degradation
et al. 2023 pilot study on female HA filler 37.8 years skin types injection sites) Belotero on the same observed when
[43] combined HA recipients III-­V Balance HA day, day 14, and MFU performed
filler and MFU filler (Merz day 28 after HA within 14 days
treatments Aesthetics) filler injection, post-­H A injection;
histological no significant
analysis of HA histological changes
loss at different after 28 days; no
intervals inflammatory
reactions or
granuloma

Casabona Brazil Clinical and 180 days 1 100% Healthy subject 45 years n/s Inner thighs and Ulthera (MFU-­ MFU-­V combined Neocollagenesis and
et al. 2014 histological female undergoing inner retroauricular area V), Radiesse with Radiesse neoelastogenesis
[44] study thigh surgery (CaHA) and hyaluronic after combined
acid fillers treatment; filler
safety with MFU-­V

Keagle et al. USA Animal study 1, 2, 5, 14, 3 rodents n/a Healthy n/a n/a Dermis and epidermis n/a Wounding Heat shock proteins
2001 [45] on linear rodent and 28 days followed by (HSPs) Hsp 47, 72,
wound healing expression 32 expression in
analysis of heat wound healing;
shock proteins collagen synthesis
involvement

Hantash et al. USA Prospective, 10 weeks n/s n/s Healthy n/a n/a Dermis Renesis System Bipolar fractional Induction of
2009 [46] histological (bipolar RF treatment neocollagenesis and
study fractional RF) neoelastogenesis,
dermal remodeling,
collagen
replacement

Ishida et al. Japan Review article n/a n/a n/a n/a n/a n/a n/a n/a Molecular Collagen
2011 [47] chaperone HSP47 maturation,
interaction molecular
with collagen chaperones

Proliferation

(Continues)

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 TABLE 2    |    (Continued)

Study characteristics Participants characteristics Exposure/intervention Outcomes

Follow-­up No. partici­ Sex Health status/ Device

Author, year Country Design period pants (%F) characteristics Age Ethnicity Treated sites (Brand) Treatment Categories

Marquardt Germany, Non-­clinical 14 and n/a n/a Yucatan n/s n/a Face and Ulthera Microfocused Inflammation was
et al. 2024 [38] USA study on 90 days Miniature subcutaneous (MFU-­V, Merz ultrasound mild and transient
histological Swine models tissue (SMAS) Aesthetics) targeting depths following treatment;
evolution of 1.5, 3.0, and demonstrates elastin
of TCPs 4.5 mm, TCP neogenesis and
post-­M FU-­V formation, neocollagenesis after
treatment collagen MFU-­V treatment;
remodeling, and significant fibroblast
elastin neogenesis recruitment to
the TCP areas

ECM rejuvenation via maturation/remodeling

White et al. USA In vivo study No follow-­up 6 cadavers 33% n/a 49–72 years Mixed Superficial Ulthera Ultrasound Selective thermal
2007 [40] on cadaveric female musculoaponeurotic (Ultherapy), therapy to create injury targeting
facial tissue (2/6) system (SMAS) Intense thermal injury SMAS for
Ultrasound zones in the noninvasive facial
System SMAS layer rejuvenation,
thermal collagen
denaturation

Marquardt Germany, Non-­clinical 14 and n/a n/a Yucatan n/s n/a Face and Ulthera Microfocused Inflammation was
et al. 2024 [38] USA study on 90 days Miniature subcutaneous (MFU-­V, Merz ultrasound mild and transient
histological Swine models tissue (SMAS) Aesthetics) targeting depths following treatment;
evolution of 1.5, 3.0, and demonstrates elastin
of TCPs 4.5 mm, TCP neogenesis and
post-­M FU-­V formation, neocollagenesis after
treatment collagen MFU-­V treatment;
remodeling, and significant fibroblast
elastin neogenesis recruitment to
the TCP areas

Suh et al. South Prospective 2m 11 90.9% Facial laxity 35–64 years Asian Face and neck Doublo Intense focused Increased collagen
2015 [39] Korea study, histologic female (HIRONIC Co.) ultrasound with fibers without signs
evaluation 3.0 and 4.5 mm of inflammation
transducers, or fat necrosis;
multiple passes increased fibrosis
per treated area between fat
layers confirmed
histologically

Laubach et al. USA In vitro study n/a n/a n/a Postmortem skin n/a n/s Dermis Ulthera Inc. Intense focused Thermal
2008 [48] on postmortem prototype ultrasound (IFUS) damage, collagen
skin samples device for precise thermal denaturation
coagulation

(Continues)

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 TABLE 2    |    (Continued)

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Study characteristics Participants characteristics Exposure/intervention Outcomes

Follow-­up No. partici­ Sex Health status/ Device

Author, year Country Design period pants (%F) characteristics Age Ethnicity Treated sites (Brand) Treatment Categories

Gliklich et al. USA Open-­label, Immediate 15 60% Patients Mean n/s Face, neck Prototype Intense ultrasound Evaluation of
2007 [49] phase 1 study (within 24 h) scheduled for 53 years device (Ulthera therapy to deep clinical safety,
and delayed rhytidectomy (SD ± 7) Inc.) dermal facial skin histologic
(4–12 weeks) and subcutaneous features, pain, and
tissues inflammation

Suh et al. South Prospective 2m 22 90.9% Facial laxity Mean age Fitzpatrick Nasolabial fold, Ulthera (IFUS) Intense focused Improvement
2011 [50] Korea study, histologic female 48.5 years types jawline ultrasound for in nasolabial
analysis III–VI facial tightening, folds and jawline
histologic laxity; increased
evaluation dermal collagen
of collagen and straighter
production elastic fibers in
reticular dermis

Suh et al. South Prospective 2–3 m 10 100% Periorbital 45–73 years Fitzpatrick Periorbital Ulthera System Intense focused Moderate to good
2019 [51] Korea study, histologic female wrinkles types (crow's feet) (Ulthera Inc.) ultrasound improvement in
analysis III-­I V using 1.5 mm periorbital wrinkles;
transducer, increased collagen
targeting fine and and elastic fiber
deep wrinkles in density, minimal
periorbital area side effects (welts,
erythema)

Yutskovskaya Russia Randomized, 15 m 20 100% Age-­related 35–45 years n/s Lower face, neck, Ulthera (MFU-­ Combination of Improvement
et al. 2020 split-­face skin laxity décolleté, abdomen V) + Radiesse diluted CaHA in age-­related
[52] comparative (CaHA diluted) and MFU-­V; changes, high
clinical study increased collagen patient satisfaction;
and elastin histological
fibers, enhanced evaluation of
neocollagenesis, collagen I/III, Ki67,
and skin angiogenesis
remodeling

Suh et al. South Prospective, 6m 15 86.67% Infraorbital laxity 27–69 years Fitzpatrick Lower eyelid Ulthera System Intense-­focused Improved
2012 [53] Korea clinical study female types III–V (infraorbital laxity) (Ulthera Inc.) ultrasound for infraorbital
on infraorbital infraorbital laxity, increased
laxity treatment laxity, applied collagen and elastic
with a 7.0 MHz, fiber density;
3.0 mm focal minimal side
depth transducer effects (erythema,
edema, purpura)

(Continues)

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 TABLE 2    |    (Continued)

Study characteristics Participants characteristics Exposure/intervention Outcomes

Follow-­up No. partici­ Sex Health status/ Device

Author, year Country Design period pants (%F) characteristics Age Ethnicity Treated sites (Brand) Treatment Categories

Lin 2020 [54] Australia Prospective, 3 and 6 m 21 100% Postpartum 25–40 years Mostly Lower abdomen Ulthera System MFU-­V using 1.5-­, Significant
clinical study female lower abdominal Asian, (postpartum (Ulthera Inc.) 3.0-­, and 4.5-­mm improvement in skin
on postpartum skin laxity some skin laxity) transducers, 1140 laxity, increased
lower Caucasian lines total across collagen and fibrous
abdominal lower abdomen septae thickness,
laxity no significant
adverse events, high
patient satisfaction
at 6 months

Vachiramon Thailand Randomized, 1, 3, and 30 (28 100% Abdominal Mean age Fitzpatrick Abdomen (single-­ Ulthera System MFU-­V with Significant
et al. 2020 prospective, 6 m post-­ completed) female skin laxity 43.3 years skin type and dual-­plane) (Ulthera, Inc.) 4.5 and 3.0 mm reduction in waist
[55] comparative treatment III transducers circumference
study on (single and dual-­ for childbirth
abdominal plane treatment patients, comparable
skin laxity for abdominal improvement for
skin laxity) both protocols, pain
scores recorded,
transient erythema,
and edema

Meyer et al. Brazil, Experimental 45 and 30 100% Patients with 30–60 years Mixed Full face Heros HIFU Single MFU Clinical
2021 [56] USA, study on the 90 days post-­ female facial skin aging (Fismatek) session using 1.5, improvement in
Chile effects of treatment (tissue laxity, 3, and 4.5 mm facial symmetry,
MFU on facial wrinkles) transducers, increased collagen
rejuvenation energy ranging type I, improved
from 0.1 to 2.0 J firmness and
wrinkle reduction;
transient hyperemia
and pain during
treatment

Sasaki et al. USA Prospective, 6 weeks 2 100% Healthy subjects, 30–65 years n/s Pre-­auricular Ultherapy Dual density Increased Type I and
2021 [57] single-­center, female scheduled for region (face) (MFU-­V; MFU-­V (30 lines Type III collagen
single-­blinded, rhytidectomy Merz North using 7–3.0 mm synthesis (26% and
nonrandomized America, Inc.) transducer, 60% increases,
study on 30 lines using respectively); no
collagen 4–4.5 mm adverse events;
synthesis transducer) heavy water method
post-­M FU-­V to measure in vivo
collagen synthes

(Continues)

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 TABLE 2    |    (Continued)

Study characteristics Participants characteristics Exposure/intervention Outcomes

10 of 22
Follow-­up No. partici­ Sex Health status/ Device
Author, year Country Design period pants (%F) characteristics Age Ethnicity Treated sites (Brand) Treatment Categories

Casabona Spain Case study of 6m 1 100% Healthy 60-­year-­ 60 years n/s Face (pre-­ Ultherapy MFU-­V combined Increased dermal
et al. 2023 a combined female old patient auricular areas) (MFU-­V ), with calcium and epidermal
[58] collagen undergoing Radiesse hydroxylapatite-­ thickness,
stimulation facelift surgery (Ca-­H A filler), based filler and most effective
procedure Belotero Revive hyaluronic acid in combined
(HA filler), filler, along with treatments; collagen
Dermapen microneedling organization
microneedling improved; enhanced
neocollagenesis
in SMAS and
retinacula cutis

MFU-­V mechanism of action

Vachiramon Thailand Prospective, 56 days 13 92.3% Healthy subjects, Mean age Fitzpatrick Abdomen (filler Ulthera (MFU), MFU performed HA degradation
et al. 2023 pilot study on female HA filler 37.8 years skin types injection sites) Belotero on the same observed when
[43] combined HA recipients III–V Balance HA day, day 14, and MFU performed
filler and MFU filler (Merz day 28 after HA within 14 days
treatments Aesthetics) filler injection, post-­H A injection;
histological no significant
analysis of HA histological changes
loss at different after 28 days; no
intervals inflammatory
reactions or
granuloma

Marquardt Germany, Non-­clinical 14 and n/a n/a Yucatan n/s n/a Face and Ulthera Microfocused Inflammation was
et al. 2024 [38] USA study on 90 days Miniature subcutaneous (MFU-­V, Merz ultrasound mild and transient
histological Swine models tissue (SMAS) Aesthetics) targeting depths following treatment;
evolution of 1.5, 3.0, and demonstrates elastin
of TCPs 4.5 mm, TCP neogenesis and
post-­M FU-­V formation, neocollagenesis after
treatment collagen MFU-­V treatment;
remodeling, and significant fibroblast
elastin neogenesis recruitment to
the TCP areas

White et al. USA In vivo study No follow-­up 6 cadavers 33% n/a (cadaveric) 49–72 years Mixed Superficial Ulthera Ultrasound Selective thermal
2007 [40] on cadaveric (cadaveric female musculoaponeurotic (Ultherapy), therapy to create injury targeting
facial tissue study) (2/6) system (SMAS) Intense thermal injury SMAS for
Ultrasound zones in the noninvasive facial
System SMAS layer rejuvenation,
thermal collagen
denaturation

Abbreviations: n/a, not applicable; n/s, not stated.

Journal of Cosmetic Dermatology, 2024

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FIGURE 3    |    (A) Hematoxylin & Eosin (H&E) staining shows the inverted cone appearance of thermal coagulation points (TCPs) 14 days post-­
treatment with an R&D transducer using 0.25 J at a 1 mm depth with 10 MHz. (B) Safranin-­Hematoxylin–Eosin (SHE) staining reveals collagen
degradation (darker arrowheads) and early fibroplasia (arrows) 14 days after treatment with ~0.8 J at a 3.0 mm depth. (C) Masson's Trichrome (MT)
staining highlights TCPs and hyalinized collagen within and around the TCP (green circle) 14 days post-­treatment with ~0.8 J at a 3.0 mm depth.
Photos courtesy of Merz Aesthetics Skin Lab.

of macrophages and giant cells were noted, no inflammation III is converted into collagen type I. The creation of TCPs via
was seen at 90 days. These findings were supported by a clin- targeted application of MFU-­V energy causes localized protein
ical trial that collected 11 tissue samples from patients after a denaturing at the dermal planes [40, 48, 49]. This induces pro-
single MFU-­V treatment at the 4.5 mm depth and 4.4 MHz fre- tein regeneration and ECM restructuring via healing processes
quency, revealing no epidermal changes or inflammatory reac- to resemble a youthful-­associated ECM environment. Clinical
tions at 2 months [39]. Additionally, Vachiramon et al. found studies utilizing qualitative and quantitative measures of skin
no inflammation at Day 56 in a clinical trial of 14 subjects quality and physiological function lend scientific support to the
studying the treatment combination of MFU-­V and hyaluronic reasoning that dermal restructuring occurs through the regen-
acid (CPM-­H A 22.5 mg/mL, Belotero Balance, Merz Aesthetics, eration and reorganization of proteins and key components.
Raleigh, NC, USA) [43]. Studies of the face, neck, and lower abdomen have shown struc-
tural ECM recovery at the microanatomical level [50–52].
Animal tissue analyzed through H&E staining showed cells, in-
cluding fibroblasts, macrophages, T-­cells, and a small number Histological analysis from Suh et al. on skin biopsies taken
of giant cells, infiltrating and accumulating around the edges from the lateral cheek of 11 MFU-­V-­treated female patients be-
of the TCP at 14 days. By 90 days, these cells had significantly fore treatment and 2 months prior showed a 23.7% (p < 0.001)
infiltrated the TCP [38]. increase from baseline in collagen at the reticular dermis,
with dermal mean thickness increasing from 1.32 to 1.63 mm
(+65.9%, p < 0.001) supporting neocollagenesis. Elastin fibers
4.4   |   Proliferation were found straighter and more parallel following treatment,
suggesting MFU-­V-­induced reorganization to a more youthful
The healing process requires a balance of protein degradation state [50]. Performing a similar histological analysis of biopsies
and synthesis. Throughout the proliferative phase of the heal- from 11 patient cheeks 2 months after MFU non-­v isual treat-
ing process, matrix metalloproteinases (MMPs) expressed by ment with a specified 4 MHz, 4.5 mm probe at an energy level of
fibroblasts and macrophages degrade denatured proteins to be 1.2 J, Suh et al. visualized increased collagen density of the retic-
replaced with granulation tissue consisting of immature collagen, ular dermis [39]. In a 2019 study of a single MFU-­V treatment to
fibronectin, and proteoglycans. Granulation tissue forms a scaf- the periorbital region with a 19 MHz, 1.5 mm probe at an energy
fold for the cells involved in the healing process to migrate and level of 0.15–0.25 J, Suh et al. obtained three patients before-­
differentiate, promoting mature tissue deposition [41]. Heat shock and-­after biopsies at 2 to 3 months post-­treatment. While the
proteins (HSPs) also play a role during collagen and elastin regen- histometric assessment was non-­significant, collagen density
eration in response to EBD treatment [44–46]. The collagen chap- increased by 28.22% in the upper papillary dermis and 14.95%
erone, Hsp47, assists in collagen replacement at TCP sites [47]. in the lower reticular dermis. The elastic fiber was reported to
Marquardt et al. found a higher number of Hsp47-­positive cells increase by 23.59% and 33.04% in the papillary and reticular der-
in the tissue surrounding the TCP at 14 days, with 85.0% of cells mis layers, respectively [51]. From Suh et al., two subjects receiv-
being Hsp47-­positive but remaining on the border of the TCP. At ing a single treatment of MFU-­V had punch biopsies from their
90 days, 98.9% of the cells were Hsp47 positive and in significantly lower eyelids, with significant loss of collagen and elastic fibers
higher concentrations within the TCP than in the surrounding tis- before treatment and showing regeneration of collagen and elas-
sue indicating infiltration leading to proliferation [38]. tic fibers 6 months post-­treatment [53]. In addition, the elastin-­
positive area in the TCPs of swine tissue at 14 days, compared to
90 days, was strongly increased [38].
4.5   |   ECM Rejuvenation via Remodeling
In a study treating lower abdomen laxity postpartum, Lin ap-
Maturation, or remodeling, is the final step in the healing pro- plied MFU-­V within 6 months of childbirth using three stan-
cess. Mature elastin and collagen are formed, and collagen type dard transducers with variable frequency and focal depth to

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target specific anatomical layers of the anterior abdominal wall thickness. These findings underline the potential of MFU-­V
[54]. A single patient sample recovered from lower abdomino- as a noninvasive option for skin rejuvenation, offering sig-
plasty 6 weeks post-­M FU-­V treatment showed a significant nificant improvements in skin quality and structure, thereby
increase in total collagen in both the dermis and subcutane- contributing to the broader goals of aesthetic and therapeutic
ous tissue of pretreated samples compared to controls with dermatology.
standard microscopy at 10× magnification, with further ex-
amination at 40× revealing denser and larger collagen bun-
dles. Additionally, deeper analysis demonstrated an increase 5   |   Improved Skin Physiological Function
in the number and thickness of fibrous septae within the ad-
ipose layer between the dermis and Scarpa's fascia. However, In regenerative aesthetics, it is crucial to recover structural ECM
adipocyte sizes in superficial and deeper fat compartments re- proteins and quantify improved skin function. For instance, “re-
mained unchanged. These septae are thought to contribute to generative” treatments should stimulate enough collagen to no-
the smoothness/tautness of the skin surface. Despite a short ticeably enhance skin firmness [1]. Various functional aspects
interval and limited sample size, Lin and Suh et al. targeted the of skin are pertinent in aesthetics, each linked to specific ECM
fascia and connecting fibrous septae at the SMAS and appeared proteins. These include but are not limited to skin firmness (col-
to contribute to improved skin quality with MFU treatment. A lagen), elasticity (elastin), hydration (proteoglycans), and oxy-
similar finding was demonstrated by Vachiramon et al., with genation (angiogenesis) [10].
both single-­(4.5 mm) and dual-­plane (4.5 and 3.0 mm) having
similar effectiveness in treating abdominal skin laxity, partic- A noticeable manifestation of physical aging includes changes in
ularly in patients who had undergone childbirth [55]. In addi- skin biomechanics. When cells age and ECM protein production
tion to neocollagenesis and protein fiber reorganization, Meyer slows, the mechanical implications include decreased firmness
et al. demonstrated significant changes within a three-­patient and elasticity, which contribute to increasing wrinkle severity
histological sample collected 45 days following a single MFU and skin laxity [59, 60]. Thus, validating regenerative aesthetic
treatment across facial regions. A substantial rise in collagen treatments requires measuring structural regeneration and
type I compared to type III was seen, along with significant skin mechanics. The Cutometer is a widely used, clinically vali-
increases in fibroblasts (p = 0.02) blood vessels (p = 0.0062), dated, noninvasive tool to measure skin biomechanics. It applies
suggesting angiogenesis in dermal remodeling and inflamma- suction to the skin and measures its resistance to deformation
tory cells (p = 0.0036). Immunohistochemistry confirmed the (firmness) and elastic recoil (elasticity) [61, 62]. In Cutometer
presence of the CD68 macrophage marker, IHQ, indicating measurements, R2 and R5 assess skin elasticity. R2, known as
phagocytosis of necrotic adipose tissue and matched with fi- “gross elasticity,” measures the skin's overall elasticity [63]. On
brosis associated with increased fibroblast activity and colla- the other hand, R5, known as “net elasticity,” also measures the
gen synthesis [56]. Sasaki et al. conducted a case series of two skin's elastic recovery after being stretched. Using cutometry,
subjects involving a split-­face MFU-­V treatment on one side of Kerscher et al. conducted a 22-­patient study that evaluated the
the face in the pre-­auricular region and no treatment on the short and long-­term impact of a single MFU-­V targeting pre-
other side as the control [57]. The treatment included a triple-­ selected depths of 4.5 and 3.0 mm on skin biomechanics [64].
depth, high density, 30 lines of treatment per transducer in- Short-­term results indicated no significant reductions in skin
volving the following transducers and energy levels/frequency: temperature, erythema, hydration, or barrier function. The re-
4 MHz, 4.5 mm (0.90 J), 7 MHz, 3.0 mm (0.30 J), and 10 MHz, sults showed a significant decrease in R2 and R5 values 4 weeks
1.5 mm (0.18 J). At 1 month, collagen synthesis increased 8.4% post-­treatment, suggesting a physiological restructuring of col-
for Collagen I and 16.8% for Collagen III compared to the tis- lagen tissue. However, both elasticity parameters significantly
sue on the control side. Collagen I synthesis increased by 26% increased at 12-­and 24-­week post-­treatment, indicating an im-
on average, and Collagen III increased by 60% on the treated provement in skin firmness. This pattern of initial reduction
side of the two subjects' faces compared to baseline. In a sin- followed by improvement in elasticity aligns with the expected
gle patient case study undergoing sub-­SMAS facelift surgery, outcomes of collagen and elastin remodeling induced by MFU-­V
histological analysis from Casabona et al. on a tissue sample treatment [64].
of monotherapy MFU-­V saw a modest improvement in SMAS
thickness with a slight improvement in skin thickness overall A 22-­patient split-­face study by Lee et al. evaluated the differ-
and parallel organization of collagen fibers [58]. ences in pore size and skin biomechanics following a single
treatment using the 10-­MHz 1.5 mm on one side of the face and
The emerging research surrounding MFU and MFU-­V treat- the 7-­MHz 3.0 mm transducer on the other. When assessing R2
ments highlights a promising advancement in dermatolog- (gross elasticity), R5 (net elasticity), and R7 (biological elasticity)
ical therapy by focusing on the rejuvenation and structural using a Cutometer, it was found that within the first 3 weeks,
refinement of the dermal ECM. Studies have consistently R2, R5, and R7 were most improved with a 1.5 mm transducer.
demonstrated that targeted MFU-­ V energy can effectively However, 6 months post-­treatment, skin treated with a 3.0 mm
induce a regenerative process in the skin, leading to the re- transducer had significantly higher elastic values across all
structuring of critical ECM components, primarily collagen three R measures. This suggests that a multiple, deeper-­depth
and elastin. This enhances the skin's mechanical properties treatment holds advantages over a single-­depth superficial treat-
and functional integrity and replicates a more youthful ECM ment in restoring skin elasticity [65]. These results suggest that
architecture. The histological evidence from various studies an initial thermal degradation of collagen is followed by colla-
supports the efficacy of MFU-­V in promoting neocollagenesis, gen and elastin synthesis, resulting in improved skin firmness
reorganizing elastin fibers, and increasing skin turgidity and and elasticity relative to baseline, highlighting the advantages

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of targeting deeper skin layers to improve the biomechanical In addition to combinations with CaHA, several studies have
properties of the skin. explored combinations of MFU-­ V with polymer injections.
PLLA is a thermoplastic biopolymer that, when injected into
In addition to modulating skin biomechanics, another import- the skin, can restore several proteins in the ECM, leading to
ant hallmark of youthful skin is the presence of oxygen [10]. gradual volumization [70]. Of the three studies combining
Oxygen is crucial for the physiological function of skin cells and MFU-­V and PLLA, none investigated histological, biomechan-
tissues and exerts anti-­inflammatory and anti-­hypoxic effects ical, or volumetric changes but rather made clinical sugges-
on skin tissues [66]. In aesthetics, other regenerative treatments tions and showcased favorable outcomes with before-­and-­after
have been shown to increase markers of angiogenesis, improve photographs [71–73]. Jerdan and Fabi postulate on the clinical
vascular density and perfusion, increase skin hemoglobin con- synergy of PLLA and MFU-­V by suggesting concurrent, multi-­
tent, and improve skin radiance [6, 52, 67, 68]. A study by Araco plane induction of ECM protein stimulation [73]. In addition to
evaluated the hemoglobin content in a cohort of patients treated PLLA, a single study has reported the combination of MFU-­V
with the 1.0, 3.0, and 4.5 mm transducers in a single session. and polymethylmethacrylate-­collagen filler (PMMA; Bellafill,
Hemoglobin content was measured with Antera 3D and revealed Suneva Medical, San Diego, CA). PMMA is a permanent filler
that 12 months post-­treatment, a 39.3% increase in hemoglobin that has been shown to drive neocollagenesis. This study con-
content was achieved [68]. ducted post-­treatment histology to examine evidence of energy
treatment, inflammation, presence of PMMA, and intactness
of the PMMA. Samples treated with both PMMA and MFU-­V
6   |   MFU in Regenerative Combination Treatments show that PMMA particles were present, intact, accompanied
by inflammation, and had histological evidence of the energy
Combining MFU-­V with injectable treatments like CaHA, PLLA, treatments. This study concluded that the lymphohistiocytic ef-
and HA fillers is an emerging strategy in regenerative aesthet- fect was mostly attributed to the PMMA microspheres and that
ics. This approach leverages the ECM regenerating properties of energy delivered from the MFU-­V was sufficiently low to pre-
MFU-­V alongside the volumizing and biostimulatory effects of serve their structure and stability in situ [74].
various fillers and regenerative biostimulators. Such a combina-
tion has gained clinical favorability, as it targets multiple aspects Several studies have also evaluated the combination treatment
of skin aging, including laxity and volume loss, in a single treat- of MFU-­V with HA dermal fillers. These studies have shown
ment protocol. Combination treatments utilizing MFU-­V and HA that combining MFU-­V with HA fillers yields improvements
fillers may enhance the overall visual outcomes of treatments, as in volumization and pore size reduction [75]. Like studies com-
the mechanical support from fillers potentially complements the bining MFU-­V and CaHA or PLLA, the treatment order must
tissue tightening induced by MFU-­V. Similarly, combination with be considered, as treating areas previously filled with HA filler
regenerative biostimulators may multiply the biostimulatory effect results in filler volume loss and network integrity compromise
on ECM proteins. In addition, MFU-­V is occasionally deployed [43]. Despite the accidental degradation of HA gels, such treat-
alongside other EBDs or with multiple adjunctive therapies. ments are safe and do not hinder the collagen-­synthesizing ef-
fect of MFU-­V [44]. Noting these observations, it is suggested
The combination of MFU-­V and CaHA fillers, particularly CaHA, that MFU-­V before dermal filler may yield the most effective
is the most widely reported combination treatment, with at least outcomes. In cases where volumization or superficial line treat-
18 publications demonstrating their combined use and efficacy. ment may augment the skin tightening effect of MFU-­V, such
Central to the rationale of combining CaHA and MFU-­V is the combination treatments may be deployed.
understanding that both modalities have different mechanisms
of action that may function synergistically. Additionally, as with In addition to fillers, MFU-­V has been evaluated with many
other fillers, undiluted or minimally diluted CaHA can create other aesthetic treatments, including botulinumtoxinA, ascorbic
volume, while MFU-­V can tighten the skin around the added vol- acid, lasers, and other EBDs [72, 76–81]. Most studies evaluating
ume, enhancing its perceived effect. Studies combining diluted unique combinatorial uses highlight their safety and efficacy. A
or hyperdiluted CaHA would rely on a synergistic regenerative list of the study types, clinical targets, and combination thera-
mechanism of action, as diluting CaHA beyond a 1:1 dilution pies used are given in Table 3.
ratio minimizes the direct volumizing effect [69]. One study by
Casabona et al. examined the histological results of combined
treatments deployed at different time intervals, observing that 7   |   Adverse Events
MFU-­V followed immediately by CaHA injections yielded the
most efficacious results [58]. It is hypothesized that treating EBDs The safety profile of MFU-­V has been well-­established across
first may yield enhanced results, as the mechanism of action, multiple studies and at various anatomies, generally showing
TCP induction, may damage new collagen created as a founda- only mild and transient adverse events [18]. The most common
tion from the CaHA injections. Yutskovskaya et al. evaluated the adverse events include erythema, edema, and welts, which
combination of (MFU-­V) and CaHA diluted 1:2 with normal sa- typically appear shortly after treatment and resolve within a
line in 20 subjects. The results showed significant improvement in few days or weeks. A 52-­patient clinical study by Harris and
age-­related changes, with marionette line scores improving from Sundaram investigated the safety of MFU-­V in Fitzpatrick
2.47 ± 0.8 to 1.8 ± 0.7 (p ≤ 0.00003), jawline contour scores from skin types III to VI, historically a patient demographic that is
2.2 ± 0.7 to 1.89 ± 0.56 (p ≤ 0.005), and neck scores from 2.1 ± 0.7 considered higher risk of adverse events following EBD treat-
to 1.7 ± 0.6 (p ≤ 0.005) after 15 months, alongside high patient sat- ments, and reported only three adverse events (one moderate
isfaction and minimal adverse effects [52]. and two mild) that were self-­limiting and included prolonger

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 TABLE 3    |    Combination uses of MFU-­V and other aesthetic procedures.

Pathology Age, sex,

14 of 22
Reference Study type treated Adjunctive therapy Location ethnicity Outcome
Aksenenko, 2019 Controlled, comparative study Facial aging Fractional CO2 laser Russia 47–55 years, 100% Skin density increased by
[77] female, n/s 22.5% (combined group) versus
13% (control); recovery time
reduced from 22 to 10 days
Barbarino, 2021 [87] Case series Tear trough HA filler (Belotero USA, 35–65 years, 100% Physicians rated 90% “very
deformities balance) Netherlands, female, n/s much improved” after combined
Australia treatment versus 0% initially; all
10 participants very satisfied
Bartsch et al., 2020 Randomized interventional Skin laxity & CaHA filler (Radiesse), Austria, Spain, 37.2 ± 6.8 years, Showed the highest improvement
[88] prospective study dimpling tissue stabilized guided USA, Germany, 100% female, n/s in skin laxity (2.23 odds)
subcision (Cellfina) Philippines and dimpling (1.79 odds)
Bozkurt & Tatar, Case report Burn scars Fractional CO2 laser, Turkey 18 years, 100% Reduced burn scar hardness,
2021 [89] nanofat injections female, n/s swelling, and itching in two sessions
Carruthers et al., Consensus Aesthetic HA (Belotero) and USA, Canada n/s, mixed, n/s Expert consensus recommends
2016 [90] correction CaHA (Radiesse) fillers using MFU-­V before injectable
agents like BoNT and fillers for
optimal facial rejuvenation
Casabona & Objective, nonrandomized Stretch marks Dilute CaHA (Radiesse), Brazil 21–34 years, 100% Significantly improved stretch marks,
Marchese, 2017 [91] study microneedling, and female, n/s decreasing scar scores by 4.9 points.
ascorbic acid
Casabona & Histological Aesthetic HA filler (Juvederm Brazil 45 years, 100% Enhanced collagen and
Michalany, 2014 collagen loss Voluma), CaHA female, n/s elastin production without
[44] filler (Radiesse) causing granulomas or
altering filler properties
Casabona & Pereira, Retrospective; histological Skin laxity CaHA filler (Radiesse) Brazil 18–55 years, 100% Significantly improved cellulite
2017 [92] and cellulite female, n/s severity in 90 days, with a 4.5-­
point CSS improvement
Casabona & Retrospective Skin laxity and CaHA filler (Radiesse) Brazil 35–55 years, 100% Improved neck and décolletage lines
Teixeira, 2018 [93] lines of the neck female, n/s by at least one grade in 90 days
& décolletage

(Continues)

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 TABLE 3    |    (Continued)

Pathology Age, sex,

Reference Study type treated Adjunctive therapy Location ethnicity Outcome
Casabona et al., Histological Aesthetic HA filler (Belotero), Spain, USA, 60 years, 100% Tripled epidermal and dermal
2023 [58] collagen loss CaHA filler (Radiesse) Serbia, female, n/s thickness, showing a synergistic
Germany effect in collagen production
Casabona, 2018 [78] Prospective pilot study Atrophic CaHA filler (Radiesse) Brazil 35–55 years, Significantly improved atrophic
acne scars 100% female, acne scars, reducing severity
not specified scores by 50% in 90 days
Casabona, 2019 [94] Objective, nonrandomized Stretch marks CaHA filler (Radiesse), Spain 18–55 years, 100% Reduced Manchester Scar
study microneedling, and female, n/s Scale scores by 33%, achieving
ascorbic acid high satisfaction
Casabona, 2022 [95] Case series Skin laxity of the CaHA filler (Radiesse) Spain 38–60 years, 75% Improved chest and buttock skin
chest & buttocks female, n/s laxity by 2 grades after 2–3 treatment
sessions, with customized protocols
Chao et al., 2017 Consensus Aesthetic HA fillers, BONT-­A , Taiwan, India, n/a, n/a, Asian Pan-­A sian consensus recommends
[96] correction CaHA filler Australia, combining MFU-­V with fillers
USA, Germany, and BoNT-­A for customizing
Hong Kong, facial enhancements,
Thailand focusing on oval shape
Coleman & Pozner, Case series Skin laxity Subcision, fat USA n/s, not Combining MFU-­V with other
2016 [97] and cellulite transplantation specified, n/s treatments for thigh and buttock
rejuvenation enhances outcomes
by targeting multiple layers safely
Fabi et al., 2016 [98] Consensus Aesthetic BONT-­A , HA filler, USA n/a, n/a, all Consensus recommends combining
correction CaHA filler (Radiesse) Fitzpatrick MFU-­V with fillers and BoNT
skin types for optimal rejuvenation of the
neck, décolletage, and hands
Fabi et al., 2016 [99] Retrospective chart review Aesthetic BONT-­A , HA filler USA n/s, aesthetic No serious adverse events
correction (Belotero Balance), treatment patients, in 101 subjects, confirming
CaHA filler (Radiesse) face and neck safe co-­treatment
Friedmann et al., Case series Aging face IPL, PLLA (Sculptra) USA Not specified, Safe, effective facial rejuvenation
2014 [72] not specified, with minimal adverse
not specified events in 90 patients

(Continues)

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 TABLE 3    |    (Continued)

Pathology Age, sex,

16 of 22
Reference Study type treated Adjunctive therapy Location ethnicity Outcome
Hart et al., 2015 [71] Case series Aging of the PLLA (Sculptra) USA n/s, n/a, n/s Efficiently improved face, neck,
face, neck, and and décolletage rejuvenation with
décolletage reduced downtime in one session
Jeon et al., 2018 Prospective, evaluator-­ Horizontal BONT-­A South Korea 24–50 years, 100% Significantly reduced neck wrinkle
[100] blinded study neck lines (IncobotulinumtoxinA), female, Asian length by 59% in 6 months
HA filler (Belotero),
CaHA filler (Radiesse)
Jerdan & Fabi, 2016 Expert opinion Aging face PLLA (Sculptra), USA n/a, n/a, not Effectively tightened off-­face
[73] IPL, NIR specified areas like neck, chest, and thighs,
showing significant improvement
in skin laxity and wrinkles
Kwon et al., 2018 Randomized interventional Facial laxity TPIG South Korea 39–69 years, 100% Histologic analysis confirmed
[79] prospective study female, Fitzpatrick increased dermal collagen fibers
skin type III and IV post-­treatment, indicating enhanced
skin tightening and lifting efficacy
Kwon et al., 2018 Prospective, evaluator-­ Facial laxity MPRF (Thermage South Korea 39–69 years, 100% 90% of patients showing moderate
[79] blinded study CPT System) female, Fitzpatrick to marked improvement in facial
skin type III and IV skin laxity after 20 weeks
Park et al., 2020 Prospective, evaluator-­ Periocular HA filler (Belotero South Korea 24–58 years, 100% Improved eyebrow height by 3.9 mm,
[101] blinded study rejuvenation Balance, Belotero female, Asian showing significant periocular
Soft), BONT-­A rejuvenation in 12 weeks
(IncobotulinumtoxinA)
Park et al., 2023 [80] Retrospective Enlarged BONT-­A South Korea 36.9 ± 5.5 years, Reduced facial pore count by 62%
facial pores (IncobotulinumtoxinA) 95% female, Asian in 6 months, showing sustained
improvement without rebound
Ramirez & Puah, Prospective, single-­arm Brachial CaHA filler (Radiesse) Singapore 35–65 years, 100% Improved brachial skin laxity,
2021 [102] skin laxity female, 25% Asian, increasing skin firmness by 16% in
75% Caucasian 24 weeks, with high satisfaction
Salomao et al., 2016 Case report Facial Erbium-­YAG laser, Brazil 35–65 years, 100% Significantly improved skin
[76] photoageing radiofrequency female, n/s laxity and wrinkles in 40 days
microneedle

(Continues)

Journal of Cosmetic Dermatology, 2024

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 TABLE 3    |    (Continued)

Pathology Age, sex,

Reference Study type treated Adjunctive therapy Location ethnicity Outcome
Vanaman et al., Case study and expert opinion Neck IPL, QS 532694755 nm, USA n/s, n/a, n/s Improved neck skin laxity by
2016 [103] rejuvenation CO2 fractionated 2 grades in 85% of patients,
laser, deoxycholate with minimal downtime
Woodward et al., Retrospective Face and Fractional CO2 laser USA n/s, not Combining MFU-­V with fractional
2014 [104] neck laxity specified, n/s CO₂ laser improved skin laxity
in 78% of patients, with an 80%
satisfaction rate post-­treatment
Wu et al., 2016 [105] Histological Aesthetic PMMA filler (Bellafill) USA n/s, 100% Combining MFU-­V with PMMA-­
collagen loss female, n/s collagen filler showed no histological
changes in PMMA, confirming safe
co-­treatment without adverse effects
Yusova & Stepanov, Randomized, Aging face PRP Russia 40–50 years, 94.29% Improved skin quality, increasing
2020 [81] comparative study female, n/s dermal thickness by 19.03%
compared to 10.46% with
MFU-­V alone in 6 months
Yutskovskaya et al., Randomized, split-­ Skin laxity CaHA filler (Radiesse) Russia 35–45 years, Improved marionette lines, jawline
2020 [52] face comparative 100% female, contour, and neck scores by 27%,
not specified 14%, and 19% in 15 months
Zaleski-­Larsen Expert opinion Acne scars Fractional CO2 laser, USA n/s, n/a, n/s Synergistic improvement in
et al., 2016 [106] microneedling acne scars, with enhanced
texture and skin tightening
Abbreviations: n/a, not applicable; n/s, not stated.

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 14732165, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jocd.16658 by CAPES, Wiley Online Library on [27/12/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
erythema with mild scabbing (moderate) and mild edema MFU-­V has also shown promise in combination with other
and welts (mild) [82]. The most frequently reported adverse treatments, such CaHA and HA fillers, potentially enhancing
event in the majority of studies was mild to moderate pain. outcomes through a synergistic approach. However, more rigor-
Pain levels varied based on the treatment area and depth of ous studies are required to fully understand the extent and dura-
penetration, with most studies noting that discomfort could be bility of these combined effects.
managed with topical analgesics or oral pain medicine [83–85].
Rare but notable adverse events include burns, scabbing, and In summary, MFU-­V operates through mechanisms involving
prolonged erythema, but have been almost entirely linked to TCPs that induce collagen and elastin fiber regeneration, re-
improper device use, such as inadequate coupling between the sulting in noticeable improvements in skin structure, firmness,
transducers and patient skin [86]. Overall, proper training and and elasticity. These changes are associated with enhanced skin
device usage are critical for mitigating moderate to severe ad- quality and a reduction in skin laxity, contributing to a more re-
verse events. At the same time, pain management strategies juvenated appearance. While MFU-­V demonstrates a capacity
can minimize the most frequent complications associated with to remodel the ECM and improve skin biomechanics, further
MFU-­V treatment. research is needed to fully elucidate the impact and optimal
use within the field of regenerative aesthetics. Future studies
should focus on expanding patient diversity and employing ob-
8   |   Limitations jective assessments to deepen our understanding of MFU-­V 's
role in aesthetic medicine and its potential applications, par-
The current narrative review has several limitations. It does not ticularly when used in combination with other treatments like
represent a meta-­analysis or a systematic review but rather a CaHA and HA fillers.
narrative review of scientific and clinical insights from existing
literature selected through keyword-­driven searches from vari-
ous academic sources. The review examines the mechanism of Author Contributions
action and the supporting evidence for soft tissue regeneration
All authors made equally significant contributions to the concept, de-
through MFU-­V without offering specific clinical practices or sign, and execution as this consensus method manuscript.
guidelines. Future meta-­analyses and systematic reviews into
the efficacy of MFU-­V are warranted, as are systematic reviews Acknowledgments
on adverse events. Despite these constraints, the review provides
a comprehensive overview, starting from the basic properties of The authors acknowledge Dr. Erin Scholz, an employee of Merz
Aesthetics, for her expert assistance in creating the figures for this
MFU-­V to its role in enhancing soft tissue's structural and func-
manuscript. This publication was supported by Merz Aesthetics Global
tional recovery. Medical Affairs (Raleigh, NC). MERZ AESTHETICS is a trademark
and/or registered trademark of Merz Pharma GmbH & Co KGaA in
the United States and/or certain other countries; ULTHERA and
9   |   Conclusions ULTHERAPY are trademarks and/or registered trademarks in the
United States and/or certain other countries. All other trademarks and/
or registered trademarks are property of their respective owners.
The presented evidence indicates that MFU-­V can induce sig-
nificant changes in skin biomechanics, firmness, and elasticity,
Disclosure
suggesting its potential for regenerative effects. While studies
vary in design, including in vivo and in vitro investigations, an- Drs. Akers, Jackson, and McCarthy are employed by Merz Aesthetics
imal models, and cadaveric tissue analyses, they provide foun- (Raleigh, NC).
dational insights into MFU-­V 's mechanism of action. Existing
literature outlines the generation of TCPs in the dermis, subcu- Ethics Statement
tis, and SMAS. These points induce the denaturation of colla- No human participants or animals were involved in the manuscript.
gen and supraphysiological tissue heating, initiating a biological This manuscript represents original work conducted with commitment
process that leads to the synthesis of new collagen and elastin. to ethical research practices.
The transient inflammation related to the body's healing pro-
cess results in enhanced fibroblast activity and subsequent Conflicts of Interest
ECM protein secretion, improving the structural integrity and
Dr. Vachiramon is a consultant and speaker for Merz Aesthetics,
elasticity of the skin. Beiersdorf, and L’Oreal. Dr. Pavicic is a consultant and speaker
for Merz Aesthetics and Advanced Aesthetic Technologies, and an
While the evidence is promising, there is a need for more quan- investigator for Merz Aesthetics, AbbVie, AAT, LG, and Croma.
titative basic research and randomized controlled trials with Dr. Casabona consults for Merz Aesthetics. Dr. Green speaks, ad-
standardized methodologies and objective outcome measures vises, and conducts clinical trials for Allergan Aesthetics, Croma-­
to elucidate regenerative pathways and capabilities further. Pharma GmbH, Crown Pharmaceuticals, Inc., Cutera, Galderma,
L’Oreal USA, Merz Aesthetics, Revance Therapeutics, Inc., Revelle
Additionally, the current research predominantly focuses on fe-
Aesthetics, Silk Medical Aesthetics, Inc., and SkinBetter Science. Dr.
male subjects and specific ethnic groups, limiting the generaliz- Levine consults and speaks for Allergan and BTL, advises Galderma
ability of the findings, with future research needing to diversify and Merz Aesthetics, and speaks for RVL. Dr. Park consults for Merz
patient demographics to validate MFU's efficacy across different Pharmaceuticals, Allergan, and LG Chem. Dr. Spada is a consultant
populations. and speaker for Merz Aesthetics. Dr. Muniz is a medical consultant

18 of 22 Journal of Cosmetic Dermatology, 2024

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and speaker for Merz Aesthetics. Drs. Akers, Jackson, and McCarthy 15. E. Dayan, P. Rovatti, S. Aston, C. T. Chia, R. Rohrich, and S.
are employees of Merz Aesthetics. Theodorou, “Multimodal Radiofrequency Application for Lower Face
and Neck Laxity,” Plastic and Reconstructive Surgery–Global Open 8
(2020): e2862.
Data Availability Statement
16. A. Antonino and A. Francesco, “Prospective and Randomized
Data sharing not applicable to this article as no datasets were generated
Comparative Study of Calcium Hydroxylapatite vs Calcium
or analysed during the current study.
Hydroxylapatite Plus HIFU in Treatment of Moderate-­To-­Severe Acne
Scars,” Journal of Cosmetic Dermatology 20 (2021): 53–61.
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