Research

Aesthetic Surgery Journal

Adipose-Derived Stem Cells in Aesthetic 2018, Vol 38(2) 199–210

© 2017 The American Society for
Aesthetic Plastic Surgery, Inc.
Surgery: A Mixed Methods Evaluation of the Reprints and permission:
journals.permissions@oup.com

Current Clinical Trial, Intellectual Property, DOI: 10.1093/asj/sjx093

www.aestheticsurgeryjournal.com

and Regulatory Landscape

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Zeeshaan Arshad; Celine-Lea Halioua-Haubold; Mackenna Roberts;
Fulvio Urso-Baiarda, MD, FRCS; Oliver A. Branford, MD, PhD, FRCS;
David A. Brindley, MEng, DPhil; Benjamin M. Davies, MD, DPhil; and
David Pettitt, BSc, MD

Abstract
Background:  Adipose tissue, which can be readily harvested via a number of liposuction techniques, offers an easily accessible and abundant source
of adipose-derived stem cells (ASCs). Consequently, ASCs have become an increasingly popular reconstructive option and a novel means of aesthetic
soft tissue augmentation.
Objectives:  This paper examines recent advances in the aesthetic surgery field, extending beyond traditional review formats to incorporate a com-
prehensive analysis of current clinical trials, adoption status, and the commercialization pathway.
Methods:  Keyword searches were carried out on clinical trial databases to search for trials using ASCs for aesthetic indications. An intellectual property
landscape was created using commercial software (Thomson Reuters Thomson Innovation, New York, NY). Analysis of who is claiming what in respect of
ASC use in aesthetic surgery for commercial purposes was analyzed by reviewing the patent landscape in relation to these techniques. Key international
regulatory guidelines were also summarized.
Results:  Completed clinical trials lacked robust controls, employed small sample sizes, and lacked long-term follow-up data. Ongoing clinical trials still
do not address such issues. In recent years, claims to intellectual property ownership have increased in the “aesthetic stem cell” domain, reflecting com-
mercial interest in the area. However, significant translational barriers remain including regulatory challenges and ethical considerations.
Conclusions:  Further rigorous randomized controlled trials are required to delineate long-term clinical efficacy and safety. Providers should consider
the introduction of patient reported outcome metrics to facilitate clinical adoption. Robust regulatory and ethical policies concerning stem cells and aes-
thetic surgery should be devised to discourage further growth of “stem cell tourism.”

Editorial Decision date: April 25, 2017; online publish-ahead-of-print June 7, 2017.

Dr Davies is an Orthopedic Surgery Registrar, Division of Trauma

Mr Arshad and Ms Roberts are Research Associates, UCL Centre
for the Advancement of Sustainable Medical Innovation, University
of Oxford, Oxford, UK; Ms Halioua-Haubold is an Undergraduate
Student, University of Texas, Austin, TX, USA; Dr Urso-Baiarda is
a Consultant Plastic Surgeon, Heatherwood Hospital, London, UK;
Dr Branford is a Consultant Plastic Surgeon, The Royal Marsden
NHS Foundation Trust, London, UK; Dr Brindley is a Research
Fellow, Department of Pediatrics, University of Oxford, Oxford, UK;
and Orthopaedic Surgery, University of Cambridge, Addenbrooke’s
Hospital, Cambridge, UK and Dr Pettitt is a Research Associate,
Department of Pediatrics, University of Oxford, Oxford, UK.
Corresponding Author:
Mr Zeeshaan Arshad, School of Medicine, North Haugh, St.
Andrews, Fife, KY16 9AJ, United Kingdom.
E-mail: za23@st-andrews.ac.uk
200
Adipose-derived stem cells (ASCs) are progenitor cells that
can be isolated from the stromal vascular faction (SVF)
component of lipoaspirate. They are of mesenchymal ori-
gin1 and are considered multipotent due to their ability
to differentiate into a range of adult cell types including
adipocytes, osteoblasts, myocytes, and neurons.2 This
offers considerable application within medical and surgi-
cal fields for a variety of indications that employ both tis-
sue engineering and regenerative medicine principles for
clinical application.3-5 Due to the relatively abundant sup-
ply of these cells and the ability to harvest them through
standard liposuction techniques,6,7 ASCs have become an
increasingly popular resource for tissue engineering and,
in particular, offer a novel means of aesthetic soft tissue
augmentation.8
This has subsequently led to refinement of conven-
tional autologous fat transfer, whereby fat is harvested
from one anatomical region and transferred to another
more aesthetically desirable one. Originally described in
1983,9 the procedure has been subject to numerous modi-
fications and is employed by a number of plastic surgeons
for indications such as breast,10 buttock,11 and facial aug-
mentation.12 Although cell assisted lipotransfer (CAL) will
not replace implants or reconstructive procedures (due to
the shape and projection profiles they are able to achieve
in the breast, for example), it has the potential to serve
as an adjunct for small corrections or volume increases,
and may serve as a less invasive option for patients hop-
ing to achieve subtle aesthetic enhancements or facial
augmentation.
With a demonstrable safety profile, reported graft
retention in conventional fat transfer varies from 55% to
82%, so the efficacy has the potential to be improved.13-15
This resorbtion is thought to result from poor graft vascu-
larization and consequent necrosis of a large proportion
of the transplanted fat.4 The challenges surrounding poor
graft vascularization and necrosis have been somewhat
mitigated through “cell-assisted” lipotransfer techniques.
In this procedure, autologous fat grafts are enriched with
SVFs containing much higher progenitor cell numbers.
SVF is the portion of fat abundant with progenitor cells
including ASCs and preadipocytes, which are thought
to enhance graft viability and improve long-term out-
comes.14 Although fat in conventional autologous trans-
fer is rich in SVF and progenitor cells, it is at insufficient
levels to cause desirable effects. The explanation for this
is that most of the progenitor cells lie in close proximity
to adipose vasculature, which is disrupted when liposuc-
tion occurs. Additionally, a substantial number of these
cells remain in the fluid portion of the harvested fat that
is not utilized in grafting.4,16 To overcome this, a portion
of aspirated fat is used to isolate and concentrate the SVF
and formulate a graft containing high stem cell popula-
tions (Figure 1).
Aesthetic Surgery Journal 38(2)
Although a promising technique, there are a number of
significant translational barriers impeding development of
these technologies.17,18 CAL is impeded by barriers affect-
ing the entire field of stem cell therapeutics, including a
lack of regulation relating to cell therapy safety and effi-
cacy, and a poor understanding of long-term outcomes of
such therapeutics.19 However, a number of barriers are
specifically applicable to aesthetic surgery—for example
stem cell tourism or the ethical considerations applying
to nontherapeutic research. This paper examines recent
advances in the field and goes beyond traditional review
formats by offering comprehensive analyses of current
clinical studies, clinical adoption, and commercialization.
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The latter is achieved through an advanced technical col-
lation of the current global clinical trial and intellectual
property landscapes related to these procedures to provide
a holistic glimpse at the clinical and commercial aspects
of ASCs and their role as powerful cellular therapies in
cutting-edge aesthetic applications. To date, no review has
analyzed the commercial landscape employing a quanti-
tative metric for evaluation. Here, we present for the first
time the global patent landscape for the use of ASCs in
aesthetic surgical procedures and examine its implications
for the commercialization of these platform technologies.
Ultimately, we identify and discuss translational barriers to
the clinical adoption of these aesthetic procedures.
METHODS
The search carried for clinical trials relating to CAL and
aesthetic indications was conducted and reported accord-
ing to the PRISMA guidelines.20 The only inclusion crite-
ria that was applied was that the clinical trial must apply
cell assisted lipotransfer for an aesthetic indication, in part
or in whole. The clinical trial landscape of CAL therapeu-
tics was identified through targeted searches (by Z.A.) of
the following databases: ISRCTN (International Standard
Randomised Controlled Trial Number), clinicaltrials.gov,
EU Clinical Trials Registers, NIH (National Institute of
Health) Clinical Trials Search, WHO International Clinical
Trials Registry Platform, Clinical Research Information
Service (CRiS), South African National Clinical Trials
Register, Japan Primary Registries Network (JPRN),
Registro Brasileiro de Ensaios Clínicos, ANZCTR, and the
Pan-African clinical trials registry (PACTR). See Appendix
A (available online as Supplementary Material at www.
aestheticsurgeryjournal.com) for full search term method-
ologies. Information pertaining to indication, phase, start
year, institution, inclusion/exclusion criteria, as well as
primary and secondary outcome measures was recorded
and summarized in tabular form. A second independent
reviewer verified this information (C.H.). Databases were
searched from their inception to January 2017.
Arshad et al201

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Figure 1.  The cell-assisted lipotransfer procedure. In the cell-assisted lipotransfer procedure fat is harvested from a patient’s
donor site. This harvested fat is then separated with one half being used to harvest adipose-derived stem cells and the other
being processed for use as a fat graft. The 2 constituents are then combined and placed within the recipient site. Note that the
black arrows indicates the procedure for a conventional autologous fat transfer procedure. Adapted from Arshad et al.19

The patent search was conducted and reported accord-
ing to preliminary guidelines published by our group.21
To construct the patent landscape examining the use of
adipose-derived stem cells in aesthetic surgery, patent
applications from 2002 to present (January 2017) were har-
vested using Thomson Innovation competitive intelligence
software. In order to identify relative patent records, key-
word searches were performed on the title, abstract, and
claims sections of a patent. Both granted patents and pub-
lished patent applications were searched across a global
dataset of over 50 patent authorities. All patents were sub-
ject to manual review: the inclusion criteria were that the
claims of each patent had to involve the use of cell assisted
lipotransfer for an aesthetic indication, in part or in whole
(Z.A.). Patent selection was reproduced by C.H. Search
terms can be found in Appendix A. Temporal, geographi-
cal, assignee, and claims analyses were then performed on
the resulting patents. This information was summarized in
graphical form.
RESULTS
Clinical Trial Landscape
A total of 1250 ongoing clinical trials were identified
through searches of the clinical trial databases. After
screening, 12 were included. The studies found through
our search of key clinical trial registries are summarized
in Table 1. Inclusion and exclusion criteria applied within
each trial are summarized in Table 2.
In total, 12 clinical trials report the use of CAL for at
least one cosmetic indication; half of these involved CAL in
breast augmentation procedures, 3 examined CAL in facial
augmentation procedures, one evaluated the use of CAL in
buttock augmentation, and one further study used CAL to
treat scarring. Eight of the 12 trials are based in academic
centers and 4 studies are being conducted by commercial
organizations: two by Biomaster Inc. (Yokohama, Japan),
a Japanese company developing adipose-derived stem cell
regenerative technology, and two by Antria (Greensburg,
PA), an American company developing autologous adult
stem cell techniques. Figure 2 demonstrates the global dis-
tribution of ongoing trials. The majority are located in the
United States, with 6 ongoing trials, followed by 3 trials
in Japan, and one trial in each of Denmark, China, and
Pakistan.
Trial variables and control group evaluations were
also carried out on the 12 studies identified through
search of clinical trial databases. The results are pre-
sented in Table 1. Control groups are lacking in cur-
rent trials (Figure 3). Five of the 12 identified studies
plan to use one. In the majority of the current trials
identified, a parallel assignment model is to be used in
which the control group is expected to receive conven-
tional autologous fat grafts. We also found that a large
proportion of the trials are in the patient recruitment
stage, which possibly indicates a difficulty in recruit-
ing a large number of participants (Figure 4). Because
many of these trials are in such early phases (Table 1
highlights that current trials are predominantly early
202 Aesthetic Surgery Journal 38(2)

Table 1.  Summary of Clinical Trials Identified Through Clinical Trial Database Searches
Clinical trial ID Indication Phase Year Country of Institution Primary outcome Secondary outcome Other Database
trial

NCT02116933 Breast 2 2013 United Tower Outpatient Qualitative analysis Qualitative analysis To define clinicaltrials.gov
augmentation States Surgical of the cosmetic of the size of the candidates
Centre outcome breasts to deter- that would
mine fat retention benefit from
CAL

NCT00775788 Breast 2 2008 United Louisiana State three-dimensional Patient satisfaction — clinicaltrials.gov
augmentation States University volumetric and
Health photographic
Sciences analysis for graft
Center in New take
Orleans

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01012014 Breast 2 2014 Denmark Dept of Plastic Graft take Radiological changes — EU Clinical Trials
augmentation Surgery, in the breast Registers
Breast Surgery
& Burns,
Copenhagen

UMIN000008772 Breast 2 2012 Japan Juntendo Improvement of — — ISRCTN

augmentation University contour

UMIN000002454 Breast 2 2009 Japan Ritz Cosmetic Tissue volume, — — ISRCTN

augmentation Surgery Clinic external contour of
the tissue

C000000456 Breast 2 2006 United Biomaster, Inc. Chest circumference — — NIPH Clinical Trials
augmentation States Search

NCT02526576 Facial 2 2015 United Antria Volume retention Safety of SVF Changes to the clinicaltrials.gov
augmentation States administration quality of
along with skin
autologous facial
fat grafts via
laboratory results

NCT01828723 Facial 1 2013 United Antria To evaluate the To demonstrate the — clinicaltrials.gov
augmentation/ States safety of the efficacy of the
wrinkles administration of a addition of SVF
concentrated SVF- by by observing
enriched fat graft graft survival
time, volume, and
quality of facial
re-contouring

NCT02494752 Facial 2 2015 Pakistan King Edward Change from baseline Change from — clinicaltrials.gov
augmentation Medical in thickness of base line in
University subcutaneous post operative
tissue appearance

NCT02546882 Scar deformity 2 2015 China Shanghai Measure the texture Occurrence of major — clinicaltrials.gov
Jiao Tong and colour change adverse events
University of the skin
School of
Medicine

C000000456 Buttock 2 2006 United Biomaster, Inc. Buttock — — NIPH Clinical Trials
augmentation States circumference Search

UMIN000008772 Facial 2 2012 Japan Juntendo Improvement of — — ISRCTN

augmentation University contour

SVF, stromal vascular faction.

phase—with just a single trial in phase one and the of monitoring and long-term patient outcomes. Due to
rest in phase 2) there was limited information available the large number of trials with an absence of follow-up
relating to the intended longevity of the study in terms data, it is unclear whether future trials will follow-up
Arshad et al203

Table 2.  Summary of Inclusion/Exclusion Criteria for Each Clinical Trial

Clinical trial ID Indication Inclusion criteria Exclusion criteria

NCT02116933 Breast Female of any race, age 21-65
augmentation Patients must desire a small breast augmentation with a ½-1
cup size increase in their breast volume
Patients must have a normal physical exam with no breast
masses, no nipple discharge, no fibrocystic disease, no
axillary adenopathy, and/or history of abnormal bleeding
Patients must not be pregnant or lactating when enrolled in
the study and must agree to have a pregnancy test (urine
or blood) prior to the surgical procedure
Patients must have a stable weight and not be fluctuating in
their weight
Patients must not be anemic at the time of the procedure
(Hg < 10)
Patients must have no history of abnormal bleeding during
Patients with prior radiation to the chest wall
Patients with a positive pregnancy test
Patients with an abnormal breast exam
Patients with a bleeding disorder who are on anticoagulants
Patients with a known positive BRACA1 or BRCA2 gene mutation
Patients who are anemic despite iron supplementation and treatment of the underlying cause of
the anemia
Patients with Fibromyalgia, regional pain syndrome, or chronic fatigue
Patients with positive HIV, HBV, or HCV at screening indicative of current of pass infection
Patients with a bleeding diathesis
Patients with a positive urinalysis for pregnancy or urinary tract infection
Patients whose diabetes is not adequately controlled (HgA1c > 7)
Patients with a history of local anesthetic allergy
Severe psychological disease (eg, schizophrenia, manic-depressive disorder, severe depression,

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surgery, bruising and no personal/family history of etc/)
coagulopathy Body dysmorphia syndromes, ie, anorexia, bulimia, etc.
Patients must be off aspirin and other NSAIDs for two weeks Somatoform disorders
Patients must have normal renal function Potential research participants with a substance abuse (including tobacco and alcohol)

NCT00775788 Breast Women with the following conditions micromastia, breast
augmentation ptosis, post mastectomy breast reconstruction, asymmetric
breasts, congenital malformations of breast development,
and for treatment of complications associated with implant
augmentation mammoplasty
A volunteer who has a positive pregnancy test
A volunteer who has had a cardiac stent placed within the last 2 months
A volunteer with a known, current substance abuse
A volunteer with a bleeding diathesis
Untreated breast cancer
A volunteer who smokes cigarettes
Medical conditions including untreated hypertension, renal disease, diabetes mellitus

01012014 Breast Not reported Not reported

augmentation

UMIN000008772 Breast Age between 20 and 79 Patients who have suffered from breast cancer
augmentation Patients who want treatment for cosmetic purposes, trauma, Patients with collagen disease or diabetes
or rombergs disease Patients on oral steroids

UMIN000002454 Breast Over the ago of 10 Poor health (not defined in protocol)
augmentation Enough tissue to carry out fat transfer (further information
not provided)

C000000456 Breast Not stated Patients with history of breast cancer

augmentation

NCT02526576 Facial Female or male, age 18 to 70 years old
augmentation Patients that are eligible for liposuction and facial fat grafting
procedures for cosmetic purposes and facial atrophy
Patients must require augmentation to the inframalar region.
Furthermore, facial engraftment to additional, nonstudy
related regions is optional, but not required
Inframalar atrophy assessment scale of 2 to 4
Facial volume defect range: 2 to 10 mL
BMI between and including 22 and 29
Fitzpatrick Scale 1 to 6
Currently taking or have taken NSAIDs within last 2 weeks or corticosteroids within the last
6 weeks prior to screening
Diagnosis of any of the following medical conditions:
◦ Active malignancy (diagnosed within 5 years), except for treated nonmelanoma skin cancer or
other noninvasive or in situ neoplasm (eg, cervical cancer)
◦ Active infection
◦ Type I or Type II diabetes
◦ Skin/bone deformities in the face, including scaring or hyperpigmentation within the graft site
Patients who are unlikely to comply with the protocol (eg, uncooperative attitude, inability to return
for subsequent visits, dementia, and/or otherwise considered by the investigator to be unlikely
to complete the study)
Patients with a known drug or alcohol dependence within the past 12 months as judged by the
investigator
Dermal fillers or facial reconstruction within the past 24 months, subjects must also refrain from
such procedures during the duration of the study.
Patients with major illnesses involving the renal, hepatic, cardiovascular, and/or nervous systems.
Patients with elevated kidney and/or liver functions
Any other disease condition or laboratory results that in the opinion of the investigator may be
clinically significant and render the subject inappropriate for the study procedure(s), may alter
the accuracy of study results, or increase risk for subjects.
Patients with life-expectancies less than 9 months
Patients with known collagenase allergies
Patients with idiopathic or drug-induced coagulopathy
Pregnant females
On radiotherapy or chemotherapy agents
Taking strong CYP450 inhibitors
Patients with a history of keloids or hypertrophic scar formations
Previous treatment with any synthetic fillers in the inframalar area
204 Aesthetic Surgery Journal 38(2)

Table 2.  Continued
Clinical trial ID Indication Inclusion criteria Exclusion criteria

NCT01828723 Facial Female or male, age 18 years or older
augmentation/ Patients that are scheduled for liposuction and facial fat
wrinkles grafting procedures for cosmetic purposes
Facial volume defects which could be treated with a total
graft volume of between 1 mL and 50 mL
BMI between and including 23 and 28
Currently taking or have taken NSAIDs within last 2 weeks or corticosteroids within the last 6
weeks prior to screening
Diagnosis of any of the following medical conditions:
◦ Active malignancy (diagnosed within 5 years), except for treated nonmelanoma skin cancer or
other noninvasive or in situ neoplasm
Active infection
Type I or Type II diabetes
Patients who are unlikely to comply with the protocol (eg, uncooperative attitude, inability to return
for subsequent visits, dementia, and/or otherwise considered by the investigator to be unlikely
to complete the study)
Patients with a known drug or alcohol dependence within the past 12 months as judged by the
investigator
Patients with major illnesses involving the renal, hepatic, cardiovascular, and/or nervous systems
Patients with elevated kidney and/or liver functions

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Any other disease condition or laboratory results that in the opinion of the investigator may be
clinically significant and render the subject inappropriate for the study procedure(s), may alter
the accuracy of study results, or increase risk for subjects.
Patients with life-expectancies less than 9 months
Patients with known collagenase allergies
Patients with idiopathic or drug-induced coagulopathy
Pregnant females
On radiotherapy or chemotherapy agents
Taking strong CYP450 inhibitors such as protease inhibitors (ritonavir, indinavir, nelfinavir,
saquinavir), macrolide antibiotics (clarithromycin, telithromycin), chloramphenicol, azole
antibiotics (ketoconazole, itraconazole), and nefazodone.
Patients with a history of keloids or hypertrophic scar formations

NCT02494752 Facial Patients with congenital and acquired contour deformities • Patients with contour deformities in which skin is adherent to facial skeleton
augmentation of face requiring soft tissue augmentation.Must be • Contour deformities underlying skin grafted areas of face
16-60 years of age • Abdominal skin pinch thickness less than 3 inch
• Must be ASA class 1 and 2

NCT02546882 Scar deformity With symmetrical scar or soft tissue deficiencies requiring Not fit for skin graft treatment
skin graft therapy Evidence of infection, ischemia, ulcer, or other pathological changes within the targeting area
Age of 3 to 70. which defined as not suitable for skin grafting; or history of delayed healing, radiational therapy
Have no underlying disease except skin scar deformity Significant renal, cardiovascular, hepatic, and psychiatric diseases
Have enough healthy donor site skin for both sides of Significant medical diseases or infection (including but not limited to the carrier of HBV virus or
receiving area HIV)
BMI > 30;
Alcohol abuse
History of any hematological disease, including leukopenia, thrombocytopenia, or thrombocytosis
Evidence of malignant diseases or unwillingness to participate

C000000456 Buttock Not stated Patients with history of breast cancer

augmentation

UMIN000008772 Facial Age between 20 and 79 Patients who have suffered from breast cancer
augmentation Patients who want treatment for cosmetic purposes, trauma, Patients with collagen disease or diabetes
or rombergs disease Patients on oral steroids

ASA, American Society of Anesthesiology; BMI, body mass index; HBV, hepatitis B; HCV, hepatitis C; HIV, human immunodeficiency; NSAIDs, none steroid anti-inflammatory drugs.

patients sufficiently long enough to evaluate long-term
outcomes (Figure 5). Further clarity is required in rela-
tion to optimum follow-up duration in order to confirm
the long-term safety profile of this technique.
Patent Landscape
A total of 950 patents were identified through our search;
after manual review, 115 were included in our analysis. The
commercial potential for adopting ASCs in a wide range of
aesthetic applications is reflected by the patenting activity
in this area—companies are actively seeking to establish
best practice standards in a dynamic and competitive field.
Intellectual property safeguards inventions so companies
may profit at the exclusion of competition (for a period
of twenty years) in exchange for publishing their inven-
tion. It therefore serves as a powerful tool to incentivize
research into the development of products.22 Patenting is
consequently an essential step in the commercialization of
a therapeutic product or inventive technique.23 Here, key
patents that have been filed relating to CAL and aesthetic
indications are examined, to inform readers of the status of
CAL technologies and provide an indication of both trans-
lational stage and cosmetic market appetite.
Arshad et al205
Figure 2.  The global distribution of ongoing clinical trials.
The majority of trials are occurring in the United States.
Figure 4.  Summary of the stage ongoing trials are in. The
figure highlights that the majority of ongoing trials are in the
recruitment phase.
In total, we found 115 relevant patent documents from
the years 2005 to 2015 (Figure 6), with the number of pat-
ents filed in relation to CAL and aesthetic indications signifi-
cantly increasing in recent years. Supplementary Figure 1
identifies the leading innovating countries with the highest
number of patents relating to the use of CAL technologies
in aesthetic procedures. The United States dominates the
market and is home to several companies that are devel-
oping ASC technologies, including Cytori Therapeutics Inc.
(San Diego, CA), which is based in San Diego, and cur-
rently the number one patent owner (Supplementary Figure
2). Cytori is currently focused on developing cell based
therapies from adult adipose tissues and have developed
the CAL-related product, Celution System (see Appendix
B for case study), that processes adipose tissue to isolate
and concentrate adipose-derived stem cells.23 The Celution
System has been used in several clinical trials.24-26
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Figure 3.  Summary of the use of comparison groups in
ongoing trials. The figure highlights that a larger proportion
of ongoing trials are controlled.
Figure 5.  Summary of planned follow-up times in ongoing
trials. The figure highlights that it is still unclear whether
ongoing clinical trials have a follow-up time long enough to
demonstrate oncological risk and long-term safety.
Supplementary Figure 3 depicts a themescape map
and provides an overview of the different aspects of CAL
that have been patented. Thomson Innovation was used
to electronically search through the title, abstract, claims,
and uses section of each patent document to cluster pat-
ents containing key words (represented by the white dots).
Related patents are grouped in contours and the more pat-
ents that are related to certain key themes, the higher the
elevation of the contour. Generally, the map reveals a frag-
mented landscape with a number of distinct peaks high-
lighting the lack of overlap in CAL technologies. White
peaks, areas of high activity, largely concern methods of
extracting, processing, and injection of enriched fat grafts.
The peak entitled “centrifuge” and “concentration” refer to
patents on products used to concentrate adipose-derived
stem cells from fat such as the Celution System created by
Cytori Therapeutics. A number of patents have been filled
206
Figure 6.  The figure shows how the number of patents filed
in relation to CAL and aesthetic surgery has been increasing
in recent years.
in relation to breast augmentation and antiscarring indica-
tions as highlighted by white peaks labeled respectively.
Regulation of ASCs in the United States,
European Union, and Japan
Regulation is an important consideration when discussing
the translation of therapies from the “bench to bedside.”
Aside from dictating the use of a therapy in a particular
jurisdiction, regulations ensure the clinical safety and effi-
cacy of a product. Here, we briefly summarize penitent
legislation in the regulatory jurisdictions identified as
being key through our clinical trial and intellectual prop-
erty landscaping searches. This section also highlights the
differing regulatory definitions, and requirements, that
products containing ASCs will have to navigate to be uti-
lized on a global level.
In the United States, for example, ASCs are regulated
underneath the broader category Human Cells, Tissues,
and Cellular and Tissue-Based Products (HCT/Ps). HCT/
Ps are further divided as 361 or 351 products, a categoriza-
tion, which determines how stringently the Food and Drug
Administration (FDA) regulates their access to the market.
The 351 products are regulated as a drug and therefore
are subject to pharmaceutical regulations and stringent
clinical trials in order to gain US market approval. In con-
trast, 361 products do not require market approval and
must only comply with The Public Health Services Act and
Current Good Tissue Practice legislations, under the Code
of Federal Regulations, Title 21, Part 1271.27 To be regu-
lated as a 361 product, the product must be only minimally
manipulated, intended for homologous use and not used
in conjunction with another article. Minimal manipulation
is defined by FDA guidance as: cutting; grinding; shaping;
centrifugation; soaking in antibiotic solution; sterilization
by ethylene oxide treatment or irradiation; cell separation;
Aesthetic Surgery Journal 38(2)
density gradient separation; lyophilization; freezing; cry-
opreservation; selective removal of B-cells, T-cells, malig-
nant cells, red blood cells, or platelets. Additionally, the
cell product must have no systemic effect or rely on the
metabolic effect of the patients’ living cells, with the excep-
tion being autologous cells, those donated from a first- or
second-degree blood relative or intended for reproductive
use.28
In 2014 the FDA released the draft guidance docu-
ment Human Cells, Tissues, and Cellular and Tissue-
Based Products (HCT/Ps) from Adipose Tissue: Regulatory
Considerations29 indicating that the current FDA opinion is
that adipose-derived stem cells are substantially manipu-
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lated (beyond mere isolation and purification techniques).
In particular, the report stated that stromal vascular frac-
tion is to be treated and regulated as a drug. The FDA
classifies adipose tissue as a structural tissue for regulatory
concerns. Therefore, the isolation of SVF via centrifugation
is considered substantial manipulation, as the isolation of
purified SVF alters the tissue function, regulating such
therapeutics as 351 products. However, this is only a draft
guidance and not a legally binding document, so at this
time, the use of ASCs in a manner compliant with Section
361 still qualifies such therapies for patient use without
clinical trials.30
In the European Union (EU), such therapeutics are reg-
ulated as advanced therapy medicinal products (ATMPs).
ATMPs are further divided into a gene therapy medicinal
product (GTMP), somatic cell therapy medicinal product
(SCTMP), tissue-engineered product (TEP), or combina-
tion product. ATMPs are subject to European Medicines
Agency (EMA) regulation and require market approval.
Similar to the United States, a product containing ASCs
may be subject to only public health legislation if it is not
substantially manipulated, is used in a homologous man-
ner, and is not combined with another article.31
Of particular interest is the ability of some ASC prod-
ucts to be regulated as 361 products in the United States
or non-ATMP in the EU, therefore circumventing the mar-
ket approval process. Alarmingly, this has resulted in the
advent “stem cell clinics,” where patients may pay sig-
nificant fees to be treated with unproven stem cell ther-
apies for a variety of indications.32 One analysis found
that 61% of these clinics used adipose-derived stem cells.
Such unproved, inadequately tested treatments are often
ineffective and furthermore, may significantly compromise
patient safety.33
Japan has specific regulation solely for regenerative med-
icine products, regulating such products separately from
classical drugs and biologics, under the label “cell/tissue
engineered product.” Nonhomologous use or “process-
ing” of the cells automatically delegates the product
under this category. Regenerative medicines are offered
special initiatives in clinical trials in order to encourage
Arshad et al207
development of this incipient field. Consequently, such
therapeutics may receive conditional market approval
after demonstrating probable benefit and safety in a small
sample size. During this conditional approval, data is
continuously collected for reevaluation and final market
approval (within 7 years).
DISCUSSION
The unique aspects of our study are the intellectual
landscape, discussion of ongoing clinical trials, and dis-
cussion of regulatory guidelines as they relate to the
technology. These are essential areas that will be of
extensive utility to academics and industry-related work-
ers involved in the development of CAL-related technol-
ogy. CAL technology is being utilized at a number of
centers globally, it remains to be seen as to whether it
will be widely adopted. Extensive research and devel-
opment has been invested into this area, and owing to
a number of clinical trials focusing on its applications,
there appears to progressive commercial interest indi-
cated by the relatively large proportion of studies being
carried out by private entities. The results of our patent
landscaping analysis suggest an increasing commercial
appetite for these technologies: indicated by the increas-
ing number of published patents in recent years (Figure
6). Our analysis of patented claims also indicates that the
use and procedures are distinct enough that researchers
are not likely to need to innovate in order to circumnavi-
gate each other’s inventive steps in using these technol-
ogies. This is indicated by the distinct white peaks in
Supplementary Figure 3.
To facilitate clinical adoption of CAL in aesthetic sur-
gery, however, there are a number of obstacles that must
be overcome aside from FDA and EU regulation that has
already been discussed. Our clinical trial landscape iden-
tified 12 ongoing clinical trials using CAL for aesthetic
indications. The majority (50%) used CAL for breast aug-
mentation, with the remainder for facial/ buttock augmen-
tation or scar indications. The commercial appetite for
such technologies is exemplified by a significant increase
in patents in this area, in addition to a large number of
trials being organized by commercial entities rather than
conventional academic centers.
Current studies are attempting to ascertain complication
rates, cosmetic outcomes, and the degree of graft reten-
tion. Cosmetic outcomes have generally been assessed
by patient reported outcome measures (PROMs) and/or
surgeon reported outcomes, and clinical measurements of
skin quality (Table 1). Interestingly, a systematic review
by Arshad et al also found that the reporting of patient
reported outcomes was significantly biased as the meth-
ods and/or tools used to collect this information was not
adequately described. We suggest in future investigators
use validated PROMs such as BREAST-Q to allow more
consistent and reproducible results. BREAST-Q also takes
a holistic approach to patient satisfaction; taking into
account factors such as psychosocial, physical, and sexual
well being.34
Graft retention can be measured in a number of ways
extending beyond qualitative observation, making use of
tissue thickness, and physical measurements. Variability
in assessment methodologies makes it difficult to compare
results from different studies. This is exacerbated by con-
founding factors in the procedure’s heterogeneous study
populations; characterized by differences in age, breast
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cancer susceptibility, nulliparity vs gravidity, breastfeed-
ing status, and variable hormone profiles. Such factors
may account for a significant variation in outcomes and
it is therefore critical to appropriately define initial patient
cohorts and fully delineate the potential advantages this
procedure may offer.
In the past, clinical trial results have been criticized
for their poor trial design for reasons including insuffi-
cient monitoring of long-term outcomes or inadequately
addressed safety issues. A recent systematic review and
meta-analysis by Zhou et al of cell assisted lipotransfer
(CAL) for clinical indications (including cosmetic), con-
cluded that when CAL was used for facial indications
it reduced fat resorption and complications, while also
decreasing the need for reoperation.18 However, no such
statistically significant advantages were found to apply
to the use of CAL for breast surgery. A further systematic
review by Arshad et al concluded that there was no evi-
dence supporting the superiority of CAL over conventional
autologous fat transfer techniques. It concluded that fur-
ther, higher quality trials are required that employ larger
sample sizes, use of statistical techniques to delineate the
significance of any findings, and longer-term follow up
to ascertain the full safety profile of CAL—most notably
the risk of malignancy.19 Other high level studies pub-
lished in the area are concurrent with these conclusions.35
Although the safety profile of autologous fat transfer has
been demonstrated,13,36,37 this is not true of CAL. More
specifically, preclinical models have suggested there is an
increased incidence of locally occurring malignancy and
metastasis with the use of ASCs in the breast.38 As this
technique is being incorporated into cosmetic surgical pro-
cedures that already carry an inherent complication risk, it
is particularly important that such techniques are carefully
evaluated from a risk−benefit perspective due to the fact
that such surgeries are usually not medically necessitated.
Although the majority of studies investigating CAL for aes-
thetic indications generally report favorable outcomes, they
are largely limited by small sample sizes, short follow up, and
lack of appropriate control groups. A number of current clin-
ical trials have expressed uncertainty in the exact mechanism
208
by which adipose stem cells exert their effect, alongside lim-
ited knowledge regarding dosages or patient populations who
might most benefit. Future clinical trials should address these
issues before the clinical adoption of CAL.
In our analysis of ongoing clinical trials we found five
out of 12 utilizing control groups. This raises concerns
with regards to methodological rigor and the ability to
carry out statistically meaningful comparisons of CAL
to conventional procedures. In terms of follow up, it is
unclear whether ongoing clinical trials will be able to
delineate long-term outcomes, in particular the risk of
malignancy, as this metric was poorly reported on clinical
trial databases. Adequate long-term results would require
the risk of malignancy to be evaluated. Therefore, ade-
quate follow up would be 10/20 years. In addition, future
trials are expected to recruit a substantially larger num-
ber of participants, which will enhance study power.
With uncertain long-term outcomes it can be seen as
unethical to be utilizing this procedure for what is a non-
therapeutic indication by putting patients through unnec-
essary risks. Without controlled clinical trials employing
long-term follow-up periods, it is not possible for patients
to provide adequate informed consent. This is concern-
ing in the sense that a number of cosmetic surgeons are
advertising adipose stem cell based therapies to patients
and contributing to an unregulated “stem cell tourism”
industry. A study examining the claims of stem cell ther-
apy applications in cosmetic surgery across 50 websites38
revealed alarming results; it identified numerous false
claims, including the advertisement of platelet-enriched
plasma as a stem cell-based therapy39 and adverts for
“stem cell facelifts”40—a procedure that does not itself per
se have antiaging effects but rather increases facial vol-
ume to give a rejuvenated appearance. It is important to
ensure appropriate regulation of these direct-to-consumer
activities and safeguard patients with accurate and ethical
marketing strategies. This will help mitigate any unprec-
edented adverse events and potential public backlash
towards what might be a promising aesthetic application.
Until such issues can be overcome and clinical trials can
demonstrate safe long-term outcomes, the use of such pro-
cedures should be limited to regulated and well-organized
clinical trials.
Limitations
There are a number of limitations inherent to this study.
Although we used broad search terms to identify per-
tinent patent documents and clinical trial records, it is
possible that some may have been inadvertently missed.
Notably, our methodology only searched four clinical
trial registries, namely: the ISRCTN, clinicaltrials.com,
Aesthetic Surgery Journal 38(2)
EU Clinical Trials Registers, and the NIPH Clinical Trials
Search. This represents the major databases that are
available on an open access basis, but it is possible that
some may not be included in either of these registries.
It may also be possible that some patents were missed
despite our thorough search on commercially available
software.
CONCLUSIONS
The use of adipose-derived stem cells is progressing
within the field of aesthetic surgery with a number of
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clinical phase trials already completed. Secondary ana-
lysis of these studies has found a lack of methodological
rigor with regards to a lack of sufficient sample sizes
and control groups, making it difficult to ascertain the
statistical significance of these studies. There is also a
lack of long-term follow-up data to determine long-term
safety and efficacy. Our search for ongoing clinical trials
identified a global effort to evaluate these therapies in
the clinic with trials ongoing in Europe, North America,
and Asia. Ongoing clinical trials attempt to address
issues raised in the quality of completed studies with
larger sample sizes. Nonetheless, it is unclear whether
they will employ follow-up times that are long enough
to delineate long-term efficacy and safety, as only 6
ongoing trials report this information. We would rec-
ommend that future clinical trial organizers take note
of this fact to add to the clinical data that are already
available concerning the use of stem cells in aesthetic
surgery. Adequate long-term results would require the
risk of malignancy to be evaluated. Therefore, adequate
follow up would be 10/20 years. Less than half plan on
using a control group. Furthermore, 115 relevant patents
were also identified, with temporal analysis suggesting
a rapid growth in the number of patents published in
the area. This, along with the fact that 50% of trials
are being carried out by commercial entities, indicates
both commercial and consumer appetite, implying that
there is need for novel techniques in the aesthetic sur-
gery domain. Our analysis also highlighted gaps in inno-
vation that could be exploited to generate intellectual
property. Before the clinical adoption of such technolo-
gies can occur, there are a number of translational bar-
riers these technologies face. These include regulatory
challenges, ethical concerns, and marketing practices.
Harmonizing global regulatory requirements and tight-
ening regulation with regards to advertising through
appropriate bodies will somewhat address these issues.
If future clinical trial data suggest these technologies are
effective and safe, this will pave the way for their use by
cosmetic surgeons.
Arshad et al209
Supplementary Material
This article contains supplementary material located online at
www.aestheticsurgeryjournal.com.
Disclosures
Dr Brindley is a stockholder in Translation Ventures Ltd
(Charlbury, Oxfordshire, UK) and IP Asset Ventures Ltd
(Oxford, Oxfordshire, UK), companies that provide cell therapy
biomanufacturing, regulatory, and financial advice to pharma-
ceutical clients (among other services). He is subject to the
CFA Institute’s codes, standards, and guidelines; this paper is
provided for academic interest only and must not be construed
in any way as an investment recommendation. Dr Davies is a
senior associate with IP Asset Ventures Ltd The other authors
declared no potential conflicts of interest with respect to the
research, authorship, and publication of this article.
Funding
The authors received no financial support for the research,
authorship, and publication of this article.
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