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Human Adipose Stem Cells: Current Clinical Applications

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Human Adipose Stem Cells: Current
Clinical Applications
         Phanette Gir, M.D.
                                      Summary: Adipose-derived stem cells are multipotent cells that can easily be
       Georgette Oni, M.D.            extracted from adipose tissue, are capable of expansion in vitro, and have the
   Spencer A. Brown, Ph.D.            capacity to differentiate into multiple cell lineages, which have the potential for
   Ali Mojallal, M.D., Ph.D.          use in regenerative medicine. However, several issues need to be studied to
       Rod J. Rohrich, M.D.           determine safe human use. For example, there are questions related to isolation
    Dallas, Texas; and Lyon, France   and purification of adipose-derived stem cells, their effect on tumor growth, and
                                      the enforcement of U.S. Food and Drug Administration regulations. Numerous
                                      studies have been published, with the interest in the potential for regenerative
                                      medicine continually growing. Several clinical trials using human adipose stem
                                      cell therapy are currently being performed around the world, and there has
                                      been a rapid evolution and expansion of their number. The purpose of this
                                      article was to review the current published basic science evidence and ongoing
                                      clinical trials involving the use of adipose-derived stem cells in plastic surgery and
                                      in regenerative medicine in general. The results of the studies and clinical trials
                                      using adipose-derived stem cells reported in this review seem to be promising not
                                      only in plastic surgery but also in a wide variety of other specialties. Nevertheless,
                                      those reported showed disparity in the way adipose-derived stem cells were used.
                                      Further basic science experimental studies with standardized protocols and larger
                                      randomized trials need to be performed to ensure safety and efficacy of adipose-
                                      derived stem cells use in accordance with U.S. Food and Drug Administration
                                      guidelines. (Plast. Reconstr. Surg. 129: 1277, 2012.)




H
        uman adipose-derived stem cells are multi-                that clinical practices using adipose-derived stem
        potent autologous mesenchymal stem cells.                 cells have not been substantiated by rigorous scien-
        These multipotent cells are recognized as a               tific evidence. To address some of these concerns, in
potential regenerative tool that may be beneficial                May of 2011, the American Society of Plastic Sur-
in a wide variety of medical therapies in recon-                  geons and the American Society for Aesthetic Plastic
structive surgery and in a multitude of other med-                Surgery published a joint position statement con-
ical disciplines.1 The clinical potential of adipose-             cerning stem cells.2 This document reported that the
derived stem cells has proven to be a source of                   scientific evidence was very limited in terms of as-
considerable enthusiasm and scientific curiosity in               sessing the safety and efficacy of stem cell therapies
academic circles and more recently commercially                   in aesthetic medicine. This statement included the
as an emerging business opportunity. Clinicians                   recommendations of the Task Force, which stated in
and patients alike have high expectations that ad-                general terms that stem cell procedures should be
ipose-derived stem cells may well be the answer to                performed in compliance with U.S. Food and Drug
curing many recalcitrant diseases or reconstruct-                 Administration regulatory guidelines, and that the
ing anatomical defects.                                           preparation and processing of adipose-derived stem
     As clinical applications using adipose-derived               cells should be conducted in accordance with cur-
stem cells have been increasingly reported, there                 rent good manufacturing practice guidelines.3
has been growing concern, generating criticism                         The aim of this report is to collate the results
                                                                  of published reports that specifically look at the
 From the Department of Plastic Surgery, University of Texas      basic science behind adipose-derived stem cell
 Southwestern Medical Center, and the Department of Plastic
 Surgery, Edouard Herriot Hospital, University of Lyon.
 Received for publication October 11, 2011; accepted January
 3, 2012.                                                           Disclosure: The authors have no financial interest
 Copyright ©2012 by the American Society of Plastic Surgeons        to declare in relation to the content of this article.
 DOI: 10.1097/PRS.0b013e31824ecae6

                                                 www.PRSJournal.com                                                    1277
                                                                Plastic and Reconstructive Surgery • June 2012

therapies from different units across the globe. In                  Adipose-derived stem cells possess the ability
so doing, we hope to provide a comprehensive                     to readily be expanded in vitro and the capacity to
review of the current literature across all medical              undergo adipogenic, osteogenic, chondrogenic,
disciplines that describe the clinical uses of adi-              and myogenic (cardiomyocyte and skeletal myo-
pocyte-derived stem cells in clinical medicine.                  cyte) differentiation.4 Neurogenic differentiation
                                                                 potential has also been described in vitro,7–10 as
    ADIPOSE-DERIVED STEM CELLS:                                  has pancreatic endocrine phenotype expressing
    DEFINITION, EXTRACTION, AND                                  insulin,11 hepatic,12,13 and endothelial differentia-
             PROPERTIES                                          tion (Fig. 2).14
     Adipose-derived stem cells were identified as                   The metabolic properties of adipose-derived
such by Zuck et al. in 2001; these authors defined               stem cells (angiogenic, antioxidative, immunotol-
the stem cell characteristics of adipose-derived                 erance) have been demonstrated in bench exper-
stem cells by their ability to differentiate into sev-           iments and increasingly in preclinical models.15–24
eral mesenchymal lineages.4 Adipose-derived stem                 First, adipose-derived stem cells secrete a favorable
cell extraction from adipose tissue requires a mul-              cytokine profile that is angiogenic, immunosup-
tistep laboratory-based process. The majority of                 pressive, and antioxidative.25 The cytokine profile
laboratories use collagenases that generate a cell               of adipose-derived stem cells contains large amounts
pellet following centrifugation that has been                    of vascular endothelial growth factor, transforming
termed the stromal vascular fraction. The stromal                growth factor- , hepatocyte growth factor, platelet-
vascular fraction consists of multiple cell types,               derived growth factor, placental growth factor, and
including circulating blood cells, fibroblasts, peri-            basic fibroblast growth factor, which explains their
cytes, endothelial cells, and adipose-derived stem               impressive angiogenic capacity and their ability to
cells.5 Adipose-derived stem cells can be isolated               induce tissue neovascularization.16
from the stromal vascular fraction through cul-                      Second, adipose-derived stem cells have been
turing on plastic as, unlike the other cell types in             shown to be immune-privileged because of a lack
the stromal vascular fraction, they adhere to plas-              of human leukocyte antigen–DR expression and
tic. In addition, they can be identified by means of             the suppression of the proliferation of activated
fluorescence-activated cell sorting, as they have                allogenic lymphocytes.26,27 Adipose-derived stem
several specific surface markers: CD73 , CD90 ,                  cells have also been shown to inhibit the produc-
CD105 , CD45–, CD34–, CD14 or CD11b, CD79– or                    tion of inflammatory cytokines and to stimulate
CD19–, and HLA-DR6 (Fig. 1).                                     the production of antiinflammatory cytokines.28,29




                 Fig. 1. Extraction and culture of adipose-derived stem cells (ASCs).


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Volume 129, Number 6 • Human Adipose-Derived Stem Cells




                         Fig. 2. Differentiation of adipose-derived stem cells (ASC) into several lineages.


The immunomodulatory properties of adipose-de-                       growth.36 – 41 Conversely, others report that adi-
rived stem cells have been demonstrated in vitro and                 pose-derived stem cells could have a tumor-sup-
in vivo.30 –33 The correlations of the data sets derived             pressive effect.42– 44 The answer to that question
from these models are currently being tested in sev-                 remains unknown, and further studies are neces-
eral clinical studies to be reviewed later.                          sary to determine the effect of adipose-derived
     There is still concern regarding adipose-de-                    stem cells on tumor formation.
rived stem cell use in a clinical setting. In a recent                   Lastly, the production of a clinically accept-
review, published in March of 2011, Locke et al.                     able grade of adipose-derived stem cells requires
emphasized that the literature revealed consider-                    careful assessment of the risks and benefits. It is
able uncertainty about the true clinical potential                   important to identify and control all possible mol-
of adipose-derived stem cells.34 According to these                  ecules that may affect the efficacy of the adipose-
authors, first, the differentiation of adipose-de-                   derived stem cell preparation, which should be
rived stem cells into cell lineages in vivo has not                  performed in accordance with current good man-
been conclusively demonstrated in many studies                       ufacturing practice guidelines.
because of the use of rather simplistic approaches
to the confirmation of differentiation. An exam-
ple of this would be neurogenic differentiation of                            U.S. FOOD AND DRUG
adipose-derived stem cells.35 Second, adipose-de-                        ADMINISTRATION REGULATIONS,
rived stem cells prepared from human liposuction                        GOOD MANUFACTURING PRACTICE,
from different studies differ in purity and molec-                        AND THE EUROPEAN POSITION
ular phenotype, with many studies using cell prep-                      The U.S. Food and Drug Administration has
arations that are likely to contain heterogeneous                    developed a regulatory framework based on
populations of cells, making it uncertain whether                    three areas45:
adipose-derived stem cells themselves are respon-
sible for effects observed. They concluded that the                     1. Prevention of use of contaminated tissues or
full clinical potential of adipose-derived stem cells                      cells.
awaits much deeper investigation of their funda-                        2. Prevention of inadequate handling or pro-
mental biology.                                                            cessing that may damage or contaminate
     The immunologic and angiogenic properties                             those tissues or cells.
of adipose-derived stem cells raise the question of                     3. Clinical safety of all tissues or cells that may
the relation of these cells with promoting cancer.                         be processed, used for functions other than
Several contradictory studies have been pub-                               normal function, combined with compo-
lished, with some reports demonstrating that ad-                           nents other than tissues, or used for meta-
ipose-derived stem cells could promote tumor                               bolic purpose.

                                                                                                                     1279
                                                         Plastic and Reconstructive Surgery • June 2012

      In the United States, adipose-derived stem         and efficacious for its intended use. While in the
cells are considered in the context of human cells,      development stage, such products may be distrib-
tissues, or cellular and tissue– based products, and     uted for clinical use for humans only if the sponsor
their production must comply with Current Good           has an investigational new drug application in ef-
Tissue Practice requirements, under the Code of          fect as specified by U.S. Food and Drug Adminis-
Federal Regulations, Title 21, Part 1271.46 Human        tration regulations (Title 21, Code of Federal Reg-
cells, tissues, or cellular and tissue– based products   ulations, Part 312).47
are defined as articles containing or consisting of           In Europe, adipose-derived stem cells are con-
human cells or tissues that are intended for im-         sidered Advanced Therapy Medicinal Products, as
plantation, infusion, or transfer into a human re-       defined by the European Regulation (European
cipient. The essential Current Good Tissue Prac-         Commission) 1394/2007, which contains rules for
tice requirements are related to preventing the          “authorization, supervision, and technical re-
introduction, transmission, or spread of commu-          quirements regarding the summary of products
nicable disease by human cells, tissues, or cellular     characteristics, labeling, and the package leaflet of
and tissue– based products.3                             Advanced Therapy Medicinal Products that are pre-
      Two levels of regulation apply: for a low level    pared following industrials methods and in aca-
of risk, a human cell, tissue, or cellular and tissue–   demic institutions.”47 This regulation refers to the
based product is regulated solely under Section          European good manufacturing process rules.48
361 of the Public Health System Act.46 This is true           The process of converting research-based pro-
if it meets all the following criteria (Part 1271.10):   tocols using adipose-derived stem cells into a safe
                                                         manufacturing process that is good manufactur-
  1. The human cell, tissue, or cellular and tissue–
                                                         ing process– compliant requires protocols that
     based product is minimally manipulated.
                                                         have had careful consideration of all the risks and
  2. The human cell, tissue, or cellular and tis-
                                                         benefits for the patient end user. In particular,
     sue– based product is intended for homolo-
                                                                 ´
                                                         Sensebe et al. stated that the following parameters
     gous use only.
                                                         should be considered: sources and collection
  3. The manufacture of the human cell, tissue,
                                                         methods, cell seeding, proliferation rate, and cul-
     or cellular and tissue– based product does
                                                         ture medium. They went on to identify steps for
     not involve the combination of the cells or
                                                         quality control that must be carried out at cell
     tissues with another article.
                                                         harvest and during the various phases of adipose-
  4. That the human cell, tissue, or cellular and
                                                         derived stem cell production.49
     tissue– based product does not have a sys-
                                                              Furthermore, automated devices for separat-
     temic effect and is not dependent on meta-
                                                         ing adipose stem cells are regulated as class III
     bolic activity of living cells for its primary
                                                         medical devices by the U.S. Food and Drug
     function or the human cell, tissue, or cellu-
                                                         Administration.50 Currently, no such device is ap-
     lar and tissue– based product has a systemic
                                                         proved for human use in the United States. These
     effect or is dependent on the metabolic ac-
                                                         are considered as research tools and should only
     tivity of living cells for its primary function,
                                                         be used under and approved by the Product De-
     and is for autologous use.
                                                         velopment Protocol.51 Because of the rigors of
     In this case, the U.S. Food and Drug Admin-         safe, reproducible, quality-controlled adipose-de-
istration sanctioned clinical trials as an investiga-    rived stem cell production as required by the U.S.
tional new drug and a formal U.S. Food and Drug          Food and Drug Administration, it is easy to see why
Administration approval process for the specific         the use of adipose-derived stem cells in clinical
therapy is not required. For a higher level of risk      trials or for clinical applications is still very rare in
(more than minimal manipulation, e.g., ex vivo           the United States.
expansion, combination with nontissue compo-
nents, or transduction), the human cell, tissue, or
cellular and tissue– based product is considered a       CLINICAL APPLICATIONS OF ADIPOSE-
drug, device, or biological product and is regu-           DERIVED STEM CELLS: PUBLISHED
lated under Section 351 of the Public Health Sys-        LITERATURE AND ONGOING CLINICAL
tem Act. Consequently, at the higher level of risk,                    TRIALS
to introduce adipose-derived stem cells or deliver           This section reports the different publications
them for clinical use, as a drug, a valid biologics      found concerning the clinical use of adipose-de-
license must be in effect. Such licenses are issued      rived stem cells and also the clinical trials currently
only after the product has been shown to be safe         being performed around the world. These appli-

1280
Volume 129, Number 6 • Human Adipose-Derived Stem Cells

cations were organized into two areas: plastic sur-




                                                                                                                                                                                                                                                                Belgium, Italy,
                                                                                                               Location




                                                                                                                                                                                                                                                                  Kingdom
gery and the other medical specialties.




                                                                                                                                                                                                                                                                  United
                                                                                                                                                                                                                                                                  Spain,




                                                                                                                                                                                                                                                                                             States




                                                                                                                                                                                                                                                                                                                                  †Kim M, Kim I, Lee SK, Bang SI, Lim SY. Clinical trial of autologous differentiated adipocytes from stem cells derived from human adipose tissue. Dermatol Surg. 2011;37:750 –759.
     In a review published in June of 2011, Lin-




                                                                                                                                                                                                                                                                                            United
                                                                                                                                                                                      Korea


                                                                                                                                                                                                                           Korea
                                                                                                                                            Brazil
droos et al. found 18 clinical trials concerning the
use of adipose-derived stem cells in regenerative
medicine.52 A search performed on www.clinical-




                                                                                                                                            Clinical evaluation of the transplanted
trials.gov with the search term “adipose stem cell




                                                                                                                                                                                                                           Evaluation of the scar improvement
                                                                                                                                                                                      Evaluation of the volume change of
therapy,” performed in August of 2011, revealed




                                                                                                                                                                                                                                                                  functional and cosmetic results,
                                                                                                                                                                                                                             and the safety (adverse effect)



                                                                                                                                                                                                                                                                  improvement in overall breast
                                                                                                                                                                                                                                                                  deformity measured at 12 mo
33 studies based on adipose-derived stem cell ther-




                                                                                                                                              area (volume improvement)




                                                                                                                                                                                                                                                                Evaluation of satisfaction with
                                                                                                                                                                                        fatty layer using 3D camera
apy, which demonstrates the rapid evolution and




                                                                                                               Evaluation
expansion of clinical use of adipose-derived stem




                                                                                                                                                                                                                                                                Evaluation of the device
                                                                                                                                                                                                                                                                  compared to baseline
cells. Five clinical trials were found for the plastic
surgery area (Table 1), and 28 were found in the
other specialties (Table 2).
     Table 3 represents the location of the clinical
trials in the world. Spain and Korea are the two
leaders in this area, with 10 studies performed in
each country. Only three trials are currently being
performed in the United States, which is attribut-
able to the high level of exigency of the U.S. Food



                                                                                                                                              enriched with autologous




                                                                                                                                              enriched with autologous
                                                                                                                                            Local injection of fat graft
                                                                                                                                            Intramuscular infusion of
and Drug Administration regulations.




                                                                                                                                                                                                                                                                                                                                  ASC, adipose-derived stem cell; MSCs, mesenchymal stem cells; 3D, three-dimensional; SVF, stromal vascular fraction.
                                                                                                                                              autologous ASCs (107

                                                                                                                                              autologous ASCs into
                                                                                                                                            From 0.11–4.63 107
                                                                                                               No. of ASCs
 PUBLISHED CLINICAL APPLICATIONS                                                                                                            Local lipoinjection
  AND CLINICAL TRIALS IN PLASTIC




                                                                                                                                                                                                                                                                                            —
                                                                                                                                              cells/500 l)
            SURGERY


                                                                                                                                              each scar
    Plastic surgery is a field where the clinical use
                                                                                                                                              ASCs




                                                                                                                                              ASCs
of adipose-derived stem cells is well developed.
The cells are usually in the form of autologous
stromal vascular fraction cells or noncultured ad-
                                                                                                                                            Active; 5 patients enrolled




ipose-derived stem cells, with one treatment given
                                                                                                                                                                                                                           Completed; 36 patients



in a local immediate administration mainly in
                                                                                                                                                                                      Completed; 5 patients




                                                                                                                                                                                                                                                                Completed; estimated




                                                                                                                                                                                                                                                                                            Recruiting; estimated
combination with fat grafts. Within the literature,
adipose-derived stem cells have been used or stud-
                                                                                                                                                                                                                                                                 enrollment, 71
                                                                                                               Status




ied in three main areas: soft-tissue augmentation,                                                                                                                                                                                                                                           enrollment, 4
wound healing, and tissue engineering.
                                                                                                                                                                                       enrolled

                                                                                                                                                                                                                            enrolled




Published Clinical Applications
                                                         Table 1. Current Clinical Trials in Plastic Surgery




    Soft-Tissue Augmentation
                                                                                                                                                                                                                                                                  II and III




    Yoshimura et al.53–55 reported several studies
                                                                                                               Phase




                                                                                                                                                                                                                                                                                                                                  *All clinical trials taken from www.clinicaltrials.gov.




using the cell-assisted lipotransfer technique for
                                                                                                                                                                                                                                                                  IV
                                                                                                                                                                                      II




treatment of facial lipoatrophy, cosmetic breast
                                                                                                                                            I




                                                                                                                                                                                                                                                                                            I




augmentation, or immediate breast augmentation
                                                                                                                                                                                                                             cultured adipocytes in patients with



                                                                                                                                                                                                                             reconstruct breast deformities after
                                                                                                                                            Study of autologous adipose-derived



                                                                                                                                              derived MSCs in Romberg disease




                                                                                                                                                                                                                                                                                              preparation process in extraction




after breast implant removal (Table 4).53– 61 The
                                                                                                                                                                                                                           Study of autologous fat enhanced
                                                                                                                                                                                                                           Safety and efficacy of autologous




principle of this technique is to enrich the fat
                                                                                                                                            Effect of human adipose tissue–



                                                                                                                                                                                                                             depressed scar (AdipoCell)†
                                                                                                                                              stem cell transplantation in




                                                                                                                                                                                                                             lumpectomy (RESTORE-2)




grafting material with stromal vascular fraction. In
                                                                                                                                              patients with lipodystrophy




                                                                                                                                                                                                                                                                                              of SVF from adipose tissue
                                                                                                                                                                                                                                                                                              effectiveness of Antria cell
                                                                                                                                                                                                                             with ASCs transplanted to




their breast augmentation study, the authors
                                                                                                                                                                                                                                                                                            Study to demonstrate the
                                                                                                               Trials in Plastic Surgery*




stated that “augmentation effects were apparently
increased with the cell-assisted lipotransfer tech-
nique compared with patients who underwent tra-
ditional lipoinjection,” but no comparative con-
trol group was used.54 In their facial lipoatrophy
study, one half of the face was treated with cell-
assisted lipotransfer and the contralateral side
was treated by the traditional lipoinjection

                                                                                                                                                                                                                                                                                                                                                                            1281
       Table 2. Current Clinical Trials in Other Specialties




1282
       Trial*                                         Phase           Status                  No. of ASCs                        Evaluation                      Location
       Digestive diseases
         Crohn disease fistula
           Study AdipoPlus: efficacy and safety of    I       Completed; 9 patients     Local injection of           Closure of the fistula and             Korea
             autologous ASCs for Crohn fistula                 enrolled                   autologous ASCs              adverse events
           Study ALOREVA: efficacy and safety of      I–IIa   Recruiting; 10 patients   Intralesional injection of   Efficacy (closure of the               Spain
             allogenic ASCs for treatment of                   enrolled                   20–40 106 allogenic          fistula), adverse events
             rectovaginal fistulas in Crohn disease                                       ASCs
           Phase II AdipoPlus                         II      Recruiting; estimated     Local injection of 107       Efficacy and adverse events            Korea
                                                               enrollment, 40             autologous ASCs
           Study of efficacy and safety of            I–IIa   Completed; 24 patients    Intralesional injection of   Adverse events, closure of the         Spain
            expanded allogenic ASCs for                        enrolled                   20–40 106 allogenic         fistulas, reduction of the
            treatment of complex perianal                                                 ASCs                        number of draining fistulas
            fistulas in perianal Crohn disease
           Treatment of fistulous Crohn disease       I–II    Recruiting; estimated     Autologous ASCs              Healing efficiency, quality of life,   Spain
            by autologous ASCs                                 enrollment, 15                                         change of systemic Crohn
                                                                                                                      disease, characterization of the
                                                                                                                      cell product
           Follow-up of autologous cultured           III     Recruiting; estimated     Autologous ASCs              Durability of efficacy and safety      Korea
            ASCs for the Crohn fistula                         enrollment, 40                                         of AdipoPlus injection 6 mo
            (AdipoPlus)                                                                                               after injection
           Safety and efficacy of ASCs to treat       III     Completed; 56 patients    Intralesional injection of   Randomized, single-blind,              Austria, Spain, The
            complex perianal fistulas in Crohn                                            20–40 106                   placebo-controlled,                    Netherlands
            disease (FATT)                                                                autologous ASCs             multicenter study
         Complex perianal fistula not associated
            with Crohn disease
           Nonsurgical treatment of complex           II      Completed; 50 patients    Local injection of           Multicenter, randomized study;         Spain
            perianal fistula with ASCs†                                                  autologous ASCs               complete closure at week 8;
                                                                                                                       no recurrence after 1 yr
           FATT-1 trial: efficacy and safety of       III     Completed; 214            Intralesional injection of   Closure of the fistulas, adverse       Spain, Germany,
            ASCs to treat perianal fistulas not                enrolled                   20–40 106                    effects                                United Kingdom
            associated with Crohn disease                                                 autologous ASCs
           Long-term safety of FATT-1 trial           III     Completed; 148            Intralesional injection of   Adverse events, closure of the         Spain
                                                               patients enrolled          20–40 106                   fistula
                                                                                          autologous ASCs
           Efficacy and safety of ASCs on the         II      Recruiting; estimated     Local injection of           Complete closure of the                Korea
            complex fistula patients                           enrollment, 40             1–2 107 autologous          fistula, investigator’s
                                                                                          ASCs                        satisfaction, adverse events
         Fecal incontinence
           Safety of autologous ASCs for fecal        I       Terminated                Local injection of ASCs      Wexner score evaluation,               Korea
             incontinence                                                                                             adverse events
       Autoimmune diseases
         Safety and efficacy of autologous ASCs       I–II    Estimated enrollment,     Intravenous injection of     Lowering of insulin                    Philippines
             in patients with diabetes mellitus                 30                        SVF cells from 100 ml       dependence and HbA1C,
             type 1                                                                       of fat                      increase of C-peptide levels
         Safety and efficacy of autologous ASCs       I–II    34 patients enrolled      Intravenous injection of     Lowering of blood glucose,             Philippines
             in type 2 diabetics                                                          SVF cells from 100 ml       decrease of hyperglycemic
                                                                                          of fat                      medication dosages, well-
                                                                                                                      being of patients
                                                                                                                                                                    (Continued)
                                                                                                                                                                                  Plastic and Reconstructive Surgery • June 2012
       Table 2. (Continued)
       Trial*                                                Phase               Status                      No. of ASCs                           Evaluation                       Location
         Autologous transplantation of ASCs in                I–II      Recruiting; estimated          Intramuscular injection          Treadmill walking distance,             Korea
           Buerger disease                                               enrollment, 18                  of 5 106 cells/kg                safety evaluation
         ASCs in patients with chronic graft-                 I         Recruiting; estimated          Intravenous injection of         Adverse events, reduction of            Spain
           versus-host disease                                           enrollment, 30                  1–3 106 allogenic                corticosteroid treatment,
                                                                                                         ASCs/kg                          disease-free survival
       Cardiovascular diseases
         PRECISE trial: ASCs in treatment of                  I         Active; estimated              Injection into left              Major adverse cardiac and               Denmark, The
          nonrevascularizable myocardium                                 enrollment, 36                  ventricle of autologous         cerebral events, feasibility,           Netherlands,
                                                                                                         ASCs                            cardiac function                        Spain
         APOLLO trial: ASCs in treatment of                   I         Active; estimated              Autologous ASCs                  Major adverse cardiac and               The Netherlands,
          patients with ST-segment elevation                             enrollment, 48                                                  cerebral events, feasibility,           Spain
          myocardial infarction                                                                                                          cardiac function
         ASCs in diabetic patients with chronic               I–II      Recruiting; estimated          Intraarterial femoral            Adverse events, clinical                Spain
          limb ischemia                                                  enrollment, 36                  injection of                    outcome
                                                                                                         0.5–1 106 cells/kg
                                                                                                         autologous ASCs
         ASCs for critical limb ischemia for                  I–II      Recruiting; estimated          Intraarterial femoral            Angiographic assessment of              Spain
          diabetic patients                                              enrollment, 36                  injection of                    neovasculogenesis, adverse
                                                                                                         0.5–2 106 cells/kg              events
                                                                                                         autologous ASCs
         ACELLDream (patients with peripheral                 I–II      Recruiting; estimated          Intramuscular injection          Adverse events                          France
           vascular disease not amenable to                              enrollment, 15                  of 100 106
           bypass or angioplasty)                                                                        autologous ASCs
         Feasibility study of ASC-coated ePTFE                I–II      Recruiting; estimated          Autologous ASC–coated            Graft patency, limb salvage,            United States
           vascular graft                                                 enrollment, 60                 vascular graft                  wound healing, rest pain
         Treatment of diabetic lower extremity                I–II      Estimated enrollment,          Local injection of               Wound healing                           United States
           wounds and venous stasis ulcers with                           250                            adipose tissue
           lipoaspirate injection                                                                        containing ASCs
       Skeletal regeneration
         ASCs in patients with degenerative                   I–II      Recruiting; estimated          Intraarticular injection         Safety, WOMAC index                     Korea
           arthritis                                                     enrollment, 18                  of 1 107 to 1 108/
                                                                                                         3 ml autologous ASCs
         ASCROD                                               I–II      Started; estimated             Local implantation of            Hyaline cartilage production,           Spain
                                                                                                                                                                                                          Volume 129, Number 6 • Human Adipose-Derived Stem Cells




                                                                          enrollment, 30                 106 autologous ASCs/            clinical and functional
                                                                                                         cm2 lesion                      evaluation, adverse events
        Development of bone grafts using ASCs                 I         Recruiting; estimated                      —                    Bone formation                          Switzerland
          and different scaffolds                                        enrollment, 100
       Neurologic diseases
        Autologous ASCs in patients with spinal               I         Completed; 8 patients          Intravenous injection of         Safety evaluation                       Korea
          cord injury‡                                                                                   4 108 autologous
                                                                                                         SVFcells
         Autologous ASCs in patients with                     I–II      Recruiting; estimated          Intravenous injection of         Safety and tolerability of ASC          Spain
          secondary progressive multiple                                 enrollment, 30                  1–4 106 autologous               injection
          sclerosis                                                                                      ASCs
       ASCs, adipose-derived stem cells; FATT, fistula advanced therapy trial; SVF, stromal vascular fraction; PRECISE, Phase III Randomized Evaluation of Convection Enhanced Delivery of Il13-Pe38qqr
       with Survival Endpoint; APOLLO, Acute Myocardial Infarction and Coronary Artery Disease; ACELLDream, Adipose Cell Derived Regenerative Endothelial Angiogenic Medicine; ASCROD,
       Autologous ASCs vs. Chondrocytes for the Repair of Chondral Knee Defects; WOMAC, Western Ontario and McMaster Universities Arthritis Index; ePTFE, expanded polytetrafluoroethylene.
       *All clinical trials were taken from www.clinicaltrials.gov.
       †Garcia-Olmo D, Herreros D, Pascual M, et al. Treatment of enterocutaneous fistula in Crohn’s Disease with adipose-derived stem cells: A comparison of protocols with and without cell
       expansion. Int J Colorectal Dis. 2009;24:27–30.
       ‡Ra JC, Shin IS, Kim SH, et al. Safety of intravenous infusion of human adipose tissue-derived mesenchymal stem cells in animals and humans. Stem Cells Dev. 2011;20:1297–1308.




1283
                                                                         Plastic and Reconstructive Surgery • June 2012

Table 3. Repartition of Clinical Trials in the World                      into mature adipocytes for facial depressed scars,
Country                         No. of Clinical Trials                    but again with no comparative control group.58
Americas                             4
                                                                          Adipose-derived stem cells were isolated from ad-
  United States                      3                                    ipose tissue harvested by liposuction, expanded in
  Brazil                             1                                    culture, and differentiated into mature adi-
Asia                                12
  Korea                             10                                    pocytes, which they termed “AdipoCell” (Table 1).
  Philippines                        2                                    AdipoCell preparations were injected subcutane-
Europe                              17                                    ously into the depressed scars, and the volume of
  Spain         10 ( 5 multicenter studies with: Belgium,
                  Italy, United Kingdom, Austria, The                     each scar was measured using three-dimensional
                  Netherlands, Germany, Denmark)                          scans. They observed 74.6 percent mean recovery
  Switzerland                        1
  France                             1                                    in volume when the received dose of AdipoCell
Total                               33                                    was equivalent to three-eighths of the cell volume
                                                                          of the defect and that the volume was stable at 1
                                                                          year after treatment. They concluded that this
technique.55 They reported that transplanted ad-                          technique represented a new safe and effective
ipose tissue was absorbed faster in the non– cell-                        therapy for soft-tissue augmentation.
assisted lipotransfer group compared with the cell-                           Wound Healing
assisted lipotransfer–treated group over the long                             In 2007, Rigotti et al. published a study con-
term.                                                                     cerning 20 patients undergoing therapy for side
     In 2011, two additional noncontrolled trials                         effects of radiation treatment with severe symp-
using the cell-assisted lipotransfer strategy were                        toms and irreversible functional damage from ra-
published. In the first, by Tiryaki et al., the authors                   diation wounds.59 Fat was harvested by manual
observed not only a better graft take but also a
                                                                          liposuction and centrifuged, and the purified li-
subjective gradual regeneration of the skin over-
                                                                          poaspirate was injected into the irradiated treat-
lying the graft, in 29 patients undergoing soft-
tissue augmentation.56 They stated that the tech-                         ment site. An improvement of tissue wound heal-
nique was particularly successful in secondary                            ing was observed, and the authors postulated that
cases that had been previously treated with fat                           the lipoaspirate was rich in native adipose-derived
grafting without significant improvement. The                             stem cells that contributed to the observed effect.
second study, by Kamakura and Ito, reported 20                                In 2010, Akita et al. reported on a case of one
cases of breast augmentation using the cell-as-                           patient with an intractable wound in the sacro-
sisted lipotransfer technique and concluded that                          coccygeal region secondary to radiation therapy.60
this technique is a safe and effective method for                         The wound healed with a combination treatment
breast augmentation.57                                                    of a human recombinant basic fibroblast growth
     In 2011, Kim et al. published the result of a                        factor, artificial skin substitute, and autologous
clinical trial involving 31 patients treated with ad-                     adipose-derived stem cells, some of which were
ipose-derived stem cells that were differentiated                         injected into the wound. However, the true effect


Table 4. Clinical Applications of Adipose-Derived Stem Cells in Plastic Surgery
                                   No. of Patients
References                            Treated                                    Dose of ASCs and Administration
Soft-tissue augmentation
  Yoshimura et al.53                       15            263.5 ml of fat enriched with SVF injected into each breast
  Yoshimura et al.54                       40            272.7 ml of fat enriched with SVF injected into each breast
  Yoshimura et al.55                                     133 ml fat injection in the non-CAL group, 100 ml fat enriched with SVF
                                                           in the CAL group
  Tiryaki et al.56                         29            10–390 ml of fat enriched with SVF (CAL) by local administration
  Kamakura and Ito57                       20            240 ml of fat enriched with SVF in each breast (CAL)
  Kim et al.58                             31            0.11–4.63 107 autologous ASCs into each scar
Wound healing
  Rigotti et al.59                         20            7.4    3.6 105 autologous SVF in each wound (60–80 ml of fat tissue)
  Akita et al.60                            1            3.8    107 autologous SVF into the wound
Tissue engineering
  Stillaert et al.61                      12             0.67–1.4     106 ASCs per scaffold
Total                                    174
ASCs, adipose-derived stem cells; SVF, stromal vascular fraction; CAL, cell-assisted lipotransfer.


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Volume 129, Number 6 • Human Adipose-Derived Stem Cells

of adipose-derived stem cells was confounded by         onstrate the effectiveness of their digestive en-
the presence of other treatment modalities.             zymes for human use (Antria Cell Preparation
     Tissue Engineering                                 Process) for extraction of stromal vascular fraction
     The use of adipose-derived stem cells seeded       from adipose tissue.
onto natural or synthesized scaffolds has been re-           In summary, the patients treated with adipose-
ported as a method of soft-tissue engineering or        derived stem cells in plastic surgery represent, thus
tissue regeneration. However, the clinical results      far, 174 published cases to our knowledge (Table
to date remain inconclusive. One clinical study         4). One hundred twenty-one patients are or have
was performed by Stillaert et al. in 2008, who sub-     been enrolled in clinical trials (Table 1). In all
cutaneously implanted hyaluronic acid scaffolds         published cases, no major adverse effects have
seeded with adipose-derived stem cells into 12          been reported. The results were encouraging in
volunteers.61 The authors observed no new adi-          soft-tissue augmentation and in wound healing.
pose tissue formation, and concluded that this was
attributable to a deficient angiogenic response to
sustain the long-term adipose-derived stem cell          PUBLISHED CLINICAL APPLICATIONS
viability and no adverse effect.                          AND CLINICAL TRIALS IN OTHER
                                                                   SPECIALTIES
Clinical Trials
    Five clinical trials involving adipose-derived      Published Clinical Applications
stem cell therapies were found, and three studies            To date, a wide variety of specialties have used
have been completed (Table 1). However, not all         adipose-derived stem cell therapy, but the number
published results are available. The main focus of      of patients who have been treated with adipose-
these clinical trials was soft-tissue augmentation.     derived stem cells is still very limited and repre-
    A phase I study of autologous adipose-derived       sents 115 patients around the world (Table 5).62– 84
stem cell transplantation is currently ongoing in       Most of the publications retrieved are case reports
Brazil in patients with lipodystrophy. Lipoinjec-       and noncontrolled studies of level 4/5 evidence,
tion enriched with adipose-derived stem cells is        and results, although encouraging, have not been
being performed, and five subjects are enrolled.        subject to the scientific rigors of a controlled trial.
The primary outcome measure is the volume im-                From 2006 to 2011, Fang et al. used allogenic
provement of the transplanted area.                     adipose-derived stem cells in the treatment of
    A phase II study in Korea is examining the          hematologic and immunologic disorders: graft-
effect of adipose-derived stem cells in Romberg         versus-host disease, idiopathic thrombocytopenic
disease, and five subjects are enrolled. The pri-       purpura, or pure red cell aplasia.62– 67 In each case,
mary outcome measure is the evaluation of the           patients received intravenous infusion of allogenic
volume change of the fatty layer using three-di-        adipose-derived stem cells isolated from adipose
mensional image analysis.                               tissue of healthy donors. No adverse effects after
    Phase II and III studies were studying the safety   the treatment were observed, and significant im-
and efficacy of autologous cultured adipose-de-         provements were documented with recovery
rived stem cells in patients with depressed scars,      from graft-versus-host disease and pure red cell
and 36 subjects were enrolled to receive cultured       aplasia, and remission in the idiopathic throm-
autologous adipose-derived stem cells that had been     bocytopenic purpura cases. These results pro-
differentiated into mature adipocytes (AdipoCell).      vide evidence that the immunomodulatory ef-
The primary outcome measures were to assess scar        fects of adipose-derived stem cells may be used
improvement and safety.                                 in treating immunologic disorders.
    A phase IV postmarket study, RESTORE-2,                  In diabetes mellitus type 1, in 2008, Trivedi et
examined autologous fat enhanced with adi-              al. treated five patients with allogenic adipose-de-
pose-derived stem cells for reconstructing breast       rived stem cells cultured and differentiated into
deformities after lumpectomy. Primary outcome           insulin-making mesenchymal stem cells trans-
measures were patient and physician satisfaction        fused mixed with unfractionated autologous cul-
assessments with functional and cosmetic im-            tures of bone marrow.68 No adverse effects were
provement in overall breast deformity correction        reported, all subjects were reported to be health-
at 12 months. This study was conducted in Bel-          ier and gaining weight, and biological markers
gium, Italy, Spain, and the United Kingdom.             were also improved. The authors concluded that
    In the United States, a phase II proof-of-con-      adipose-derived stem cell therapy may be a solu-
cept study by Antria is currently recruiting to dem-    tion for the treatment of insulinopenic patients.

                                                                                                         1285
                                                                        Plastic and Reconstructive Surgery • June 2012

Table 5. Clinical Applications of Adipose-Derived Stem Cells in Other Specialties
                                                                     No. of Patients
Specialties                                   References                Treated             Dose of ASCs and Administration
Hematologic and immunologic
  disorders                             Fang et al.62–67                      14       1–2 106 allogenic ASCs/kg, IV
Diabetes mellitus                       Trivedi et al.68                       5       3.15 106 allogenic ASCs injected by
                                                                                         intraportal infusion under general
                                                                                         anesthesia during minilaparotomy
                                        Vanikar et al.69                      11
Digestive diseases                      Garcia-Olmo et al.70–75               63       3    106 to 2 107 autologous ASCs into
                                                                                         the fistula
Autoimmune diseases                     Ichim et al.76                         1       53 106 autologous SVF in two IV infusions
                                        Riordan et al.77                       3       25–75 106 autologous SVF IV
Tracheomediastinal fistula              Alvarez et al.78                       1       4.9 106 autologous SVF into the fistula
                                                                                         cavity
Bone tissue repair                      Lendeckel et al.79                     1       295 106 autologous SVF
                                        Mesimaki et al.80
                                              ¨                                1       13 106 autologous ASCs
                                        Taylor81                               1       28 ml of solid fraction from fresh autologous
                                                                                         lipoaspirate
                                        Pak82                                  4       10 cm3 autologous SVF
Urologic disorder                       Yamamoto et al.83                      2       2.4–3.2 107 autologous SVF into urethral
                                                                                         sphincter
Neurologic disease                      Ra et al.84                           8        4 108 autologous ASCs IV
Total                                                                       115
ASCs, adipose-derived stem cells; IV, intravenously; SVF, stromal vascular fraction.



    In 2010, Vanikar et al. reported the results                         derived stem cell therapy may be a treatment for
obtained on 11 diabetic patients using the same                          rheumatoid arthritis and postulated that this was
treatment.69 Again, no adverse events were re-                           because of the immune-tolerance induced by ad-
ported and a gradual decrease in insulin require-                        ipose-derived stem cells.
ments was noted. The authors concluded that easy                             In 2009, Riordan et al. reported the treatment
and repeatable access to adipose tissue provided a                       of three multiple sclerosis patients with intrave-
clear advantage over isolation of mesenchymal                            nous infusions of autologous stromal vascular
stem cells from bone marrow for the treatment of                         fraction cells with multiple intrathecal and
diabetes mellitus by stem cell therapy.                                  intravenous infusions of allogenic CD34 and
    From 2003 to 2010, Garcıa-Olmo et al. pub-
                                 ´                                       mesenchymal stem cells within a 10-day period.77
lished several articles concerning the treatment of                      No adverse effects were documented, and by 3
complex perianal or enterocutaneous fistulas, per-                       months, all patients reported significant improve-
forming phase I and II clinical trials. These in-                        ment of their symptoms. The authors concluded
cluded patients with digestive fistulas associated or                    that further clinical evaluation of autologous stro-
not with Crohn disease using autologous adipose-                         mal vascular fraction cells is warranted in autoim-
derived stem cells isolated mixed with fibrin glue                       mune conditions.
and injected into the fistulous tract.70 –75 In all the                      In 2008, Alvarez et al. reported the case of a
studies, no adverse effects were reported and a                          67-year-old man suffering from lung cancer
significant healing rate was observed in patients                        complicated with tracheomediastinal fistula and
who received adipose-derived stem cells (71 per-                         treated by autologous adipose-derived stem cells
cent of healing compared with 16 percent). They                          mixed with fibrin glue, injected into the fistula
concluded that adipose-derived stem cell therapy                         during bronchoscopy.78 The patient’s recovery
associated with fibrin glue is a safe and effective                      was uneventful, and epithelialization of the fis-
method of treating complex perianal fistula.                             tula was observed after 3 months. One year after
    Rheumatoid arthritis treatments were exam-                           treatment, the fistula was closed, and 2 years
ined in a case report in 2010 by Ichim et al. of a                       after stem cell therapy, the patient was in com-
67-year-old woman.76 The patient was treated by                          plete remission.
intravenous infusions of autologous stromal vas-                             There are four published case reports regard-
cular fraction cells isolated from a liposuction pro-                    ing bone tissue repair. In 2004, Lendeckel et al.
cedure. The authors observed no side effects, and                        published the case of a 7-year-old girl suffering
the patient reported a considerable resolution of                        from widespread calvarial defects after severe
her pain joint and stiffness, with a decrease in                         head injury.79 The patient was treated with a
rheumatoid factor. They concluded that adipose-                          combination of cancellous bone grafts from the

1286
Volume 129, Number 6 • Human Adipose-Derived Stem Cells

ilium and autologous stromal vascular fraction         tomy, who were treated with autologous adipose-
cells obtained from adipose tissue. Postopera-         derived stem cells isolated using the Celution Sys-
tive healing was uneventful and the clinical fol-      tem (Cytori Therapeutics, Inc., San Diego, Calif.)
low-up demonstrated symmetrical calvarial con-         and injected (mixed with adipose tissue) in the
tour. At 3 months postoperatively, the computed        external urethral sphincter under endoscopic
tomographic scan showed a marked ossification          vision.83 The authors observed no adverse effects.
in the defect areas.                                   Urinary incontinence improved progressively af-
                     ¨
    In 2009, Mesimaki et al. reported the case of a    ter 2 weeks, up to 12 weeks. Sphincter function of
65-year-old patient who underwent a hemimaxillec-      the urethra was improved in both cases, and mag-
tomy because of a large keratocyst.80 The patient’s    netic resonance imaging showed a bulking effect
reconstruction was performed using a preformed         at the site of injection. They concluded that adi-
titanium cage filled with autologous cultured ad-      pose-derived stem cell therapy was a safe and fea-
ipose-derived stem cells, combined with synthetic      sible treatment for stress urinary incontinence.
bioresorbable beta–tricalcium phosphate gran-               In 2011, Ra et al. published a study of eight
ules. No adverse effects were reported, and bone       patients suffering from spinal cord injury who
regeneration was observed by biopsy. They con-         were treated with intravenous infusions of autol-
cluded that the presence of adipose-derived stem       ogous adipose-derived stem cells.84 The authors
cells may have enhanced the osteogenic and an-         observed no serious adverse effects. At 12 weeks,
giogenic conditions of the construct in vivo.          motor function was improved in four patients. The
    In 2010, Taylor published the case of a 14-        authors concluded that they could not determine
year-old boy suffering from Treacher Collins syn-      the efficacy of adipose-derived stem cell therapy
drome whose severe biorbitozygomatic hypoplasia        because of their small patient group and the short
was treated with tissue-engineered bone using a        follow-up period.
combination of sculpted bone allograft, bone                In summary, these studies reported no major
morphogenetic protein-2, periosteal grafts, and        adverse effects after treatment by adipose-derived
autologous fresh adipose-derived stem cells.81 At 4    stem cells, and the results were promising in the
months, computed tomographic scanning showed           115 published cases (Table 5). The characteristics
complete bone reconstruction of the bilateral zy-      of adipose-derived stem cell therapy in these spe-
gomas, and 6 months after surgery, a biopsy spec-      cialties were as follows:
imen showed lamellar bone with small marrow
elements. The authors concluded that that type of        1. Adipose-derived stem cells used were allogenic
engineered construct may provide an alternative             or autologous; stromal vascular fraction cells
method to both osteocutaneous free flaps and                or cultured adipose-derived stem cells.
large structural allografts.                             2. In some cases, additive treatments (e.g., bone
    In 2011, Pak reported two cases of patients             marrow, growth factor, fibrin glue) were used.
suffering from osteonecrosis of the femoral head         3. The administration doses were variable, as was
and two cases of patients suffering from knee               the number of adipose-derived stem cells per
osteoarthritis.82 All the patients were treated by a        dose.
combination of percutaneously injected autolo-           4. Adipose-derived stem cells were administered
gous adipose-derived stem cells, hyaluronic acid,           systemically (intravenous infusion) or locally
platelet-rich plasma, and calcium chloride. At 3            (intralesional injection).
months, in all cases, pain and mobilization were
improved. Magnetic resonance imaging scans
showed a significant filling of bone defects, with     Clinical Trials
a possibility of bone matrix formation at the site          Twenty-eight clinical trials using adipose
of osteonecrosis and a significant increase in the     and/or adipose-derived stem cells were listed;
thickness and the height of meniscus cartilage.        eight of these studies have been completed. The
The authors conclude that these good results           studies are separated by topic, clinical phase, pri-
can be explained either by a direct differentia-       mary site location, and study status (Table 2). The
tion of adipose-derived stem cells or by the           trials have been organized into five categories:
trophic effects of adipose-derived stem cells on       digestive disease, autoimmune disease, cardiovas-
existing tissues.                                      cular disease, skeletal regeneration, and neuro-
    In 2010, Yamamoto et al. reported two cases of     logic disorder.
patients with stress urinary incontinence, which is         In summary, adipose-derived stem cells have
a distressing complication of radical prostatec-       been used in a wide variety of ways:

                                                                                                     1287
                                                           Plastic and Reconstructive Surgery • June 2012

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Description: Summary: Adipose-derived stem cells are multipotent cells that can easily be extracted from adipose tissue, are capable of expansion in vitro, and have thecapacity to differentiate into multiple cell lineages, which have the potential for use in regenerative medicine. However, several issues need to be studied todetermine safe human use. For example, there are questions related to isolation and purification of adipose-derived stem cells, their effect on tumor growth, andthe enforcement of U.S. Food and Drug Administration regulations. Numerous studies have been published, with the interest in the potential for regenerativemedicine continually growing. Several clinical trials using human adipose stem cell therapy are currently being performed around the world, and there hasbeen a rapid evolution and expansion of their number. The purpose of this article was to review the current published basic science evidence and ongoingclinical trials involving the use of adipose-derived stem cells in plastic surgery and in regenerative medicine in general. The results of the studies and clinical trials using adipose-derived stem cells reported in this review seem to be promising not only in plastic surgery but also in a wide variety of other specialties. Nevertheless, those reported showed disparity in the way adipose-derived stem cells were used. Further basic science experimental studies with standardized protocols and larger randomized trials need to be performed to ensure safety and efficacy of adiposederived stem cells use in accordance with U.S. Food and Drug Administration guidelines. (Plast. Reconstr. Surg. 129: 1277, 2012.)