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SPECIAL TOPIC
Human Adipose Stem Cells: CurrentClinical Applications
Phanette Gir, M.D.Georgette Oni, M.D.
Spencer A. Brown, Ph.D.Ali Mojallal, M.D., Ph.D.
Rod J. Rohrich, M.D.
Dallas, Texas; and Lyon, France
Summary: Adipose-derived stem cells are multipotent cells that can easily beextracted from adipose tissue, are capable of expansion in vitro, and have thecapacity to differentiate into multiple cell lineages, which have the potential foruse in regenerative medicine. However, several issues need to be studied todetermine safe human use. For example, there are questions related to isolationand purification of adipose-derived stem cells, their effect on tumor growth, andthe enforcement of U.S. Food and Drug Administration regulations. Numerousstudies have been published, with the interest in the potential for regenerativemedicine continually growing. Several clinical trials using human adipose stemcell therapy are currently being performed around the world, and there hasbeen a rapid evolution and expansion of their number. The purpose of thisarticle was to review the current published basic science evidence and ongoingclinical trials involving the use of adipose-derived stem cells in plastic surgery andin regenerative medicine in general. The results of the studies and clinical trialsusing adipose-derived stem cells reported in this review seem to be promising notonly 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 largerrandomized trials need to be performed to ensure safety and efficacy of adipose-derived stem cells use in accordance with U.S. Food and Drug Administrationguidelines. (Plast. Reconstr. Surg. 129: 1277, 2012.)
Human adipose-derived stem cells are multi-potent autologous mesenchymal stem cells.These multipotent cells are recognized as a
potential regenerative tool that may be beneficialin a wide variety of medical therapies in recon-structive surgery and in a multitude of other med-ical disciplines.1 The clinical potential of adipose-derived stem cells has proven to be a source ofconsiderable enthusiasm and scientific curiosity inacademic circles and more recently commerciallyas an emerging business opportunity. Cliniciansand patients alike have high expectations that ad-ipose-derived stem cells may well be the answer tocuring many recalcitrant diseases or reconstruct-ing anatomical defects.
As clinical applications using adipose-derivedstem cells have been increasingly reported, therehas been growing concern, generating criticism
that clinical practices using adipose-derived stemcells have not been substantiated by rigorous scien-tific evidence. To address some of these concerns, inMay of 2011, the American Society of Plastic Sur-geons and the American Society for Aesthetic PlasticSurgery published a joint position statement con-cerning stem cells.2 This document reported that thescientific evidence was very limited in terms of as-sessing the safety and efficacy of stem cell therapiesin aesthetic medicine. This statement included therecommendations of the Task Force, which stated ingeneral terms that stem cell procedures should beperformed in compliance with U.S. Food and DrugAdministration regulatory guidelines, and that thepreparation and processing of adipose-derived stemcells should be conducted in accordance with cur-rent good manufacturing practice guidelines.3
The aim of this report is to collate the resultsof published reports that specifically look at thebasic science behind adipose-derived stem cellFrom the Department of Plastic Surgery, University of Texas
Southwestern Medical Center, and the Department of PlasticSurgery, Edouard Herriot Hospital, University of Lyon.Received for publication October 11, 2011; accepted January3, 2012.Copyright ©2012 by the American Society of Plastic Surgeons
DOI: 10.1097/PRS.0b013e31824ecae6
Disclosure: The authors have no financial interestto declare in relation to the content of this article.
www.PRSJournal.com 1277
therapies from different units across the globe. Inso doing, we hope to provide a comprehensivereview of the current literature across all medicaldisciplines that describe the clinical uses of adi-pocyte-derived stem cells in clinical medicine.
ADIPOSE-DERIVED STEM CELLS:DEFINITION, EXTRACTION, AND
PROPERTIESAdipose-derived stem cells were identified as
such by Zuck et al. in 2001; these authors definedthe stem cell characteristics of adipose-derivedstem cells by their ability to differentiate into sev-eral mesenchymal lineages.4 Adipose-derived stemcell extraction from adipose tissue requires a mul-tistep laboratory-based process. The majority oflaboratories use collagenases that generate a cellpellet following centrifugation that has beentermed the stromal vascular fraction. The stromalvascular fraction consists of multiple cell types,including circulating blood cells, fibroblasts, peri-cytes, endothelial cells, and adipose-derived stemcells.5 Adipose-derived stem cells can be isolatedfrom the stromal vascular fraction through cul-turing on plastic as, unlike the other cell types inthe stromal vascular fraction, they adhere to plas-tic. In addition, they can be identified by means offluorescence-activated cell sorting, as they haveseveral specific surface markers: CD73�, CD90�,CD105�, CD45–, CD34–, CD14 or CD11b, CD79– orCD19–, and HLA-DR6 (Fig. 1).
Adipose-derived stem cells possess the abilityto readily be expanded in vitro and the capacity toundergo adipogenic, osteogenic, chondrogenic,and myogenic (cardiomyocyte and skeletal myo-cyte) differentiation.4 Neurogenic differentiationpotential has also been described in vitro,7–10 ashas pancreatic endocrine phenotype expressinginsulin,11 hepatic,12,13 and endothelial differentia-tion (Fig. 2).14
The metabolic properties of adipose-derivedstem cells (angiogenic, antioxidative, immunotol-erance) have been demonstrated in bench exper-iments and increasingly in preclinical models.15–24
First, adipose-derived stem cells secrete a favorablecytokine profile that is angiogenic, immunosup-pressive, and antioxidative.25 The cytokine profileof adipose-derived stem cells contains large amountsof vascular endothelial growth factor, transforminggrowth factor-�, hepatocyte growth factor, platelet-derived growth factor, placental growth factor, andbasic fibroblast growth factor, which explains theirimpressive angiogenic capacity and their ability toinduce tissue neovascularization.16
Second, adipose-derived stem cells have beenshown to be immune-privileged because of a lackof human leukocyte antigen–DR expression andthe suppression of the proliferation of activatedallogenic lymphocytes.26,27 Adipose-derived stemcells have also been shown to inhibit the produc-tion of inflammatory cytokines and to stimulatethe production of antiinflammatory cytokines.28,29
Fig. 1. Extraction and culture of adipose-derived stem cells (ASCs).
Plastic and Reconstructive Surgery • June 2012
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The immunomodulatory properties of adipose-de-rived stem cells have been demonstrated in vitro andin vivo.30–33 The correlations of the data sets derivedfrom these models are currently being tested in sev-eral clinical studies to be reviewed later.
There is still concern regarding adipose-de-rived stem cell use in a clinical setting. In a recentreview, published in March of 2011, Locke et al.emphasized that the literature revealed consider-able uncertainty about the true clinical potentialof adipose-derived stem cells.34 According to theseauthors, first, the differentiation of adipose-de-rived stem cells into cell lineages in vivo has notbeen conclusively demonstrated in many studiesbecause of the use of rather simplistic approachesto the confirmation of differentiation. An exam-ple of this would be neurogenic differentiation ofadipose-derived stem cells.35 Second, adipose-de-rived stem cells prepared from human liposuctionfrom different studies differ in purity and molec-ular phenotype, with many studies using cell prep-arations that are likely to contain heterogeneouspopulations of cells, making it uncertain whetheradipose-derived stem cells themselves are respon-sible for effects observed. They concluded that thefull clinical potential of adipose-derived stem cellsawaits much deeper investigation of their funda-mental biology.
The immunologic and angiogenic propertiesof adipose-derived stem cells raise the question ofthe relation of these cells with promoting cancer.Several contradictory studies have been pub-lished, with some reports demonstrating that ad-ipose-derived stem cells could promote tumor
growth.36–41 Conversely, others report that adi-pose-derived stem cells could have a tumor-sup-pressive effect.42–44 The answer to that questionremains unknown, and further studies are neces-sary to determine the effect of adipose-derivedstem cells on tumor formation.
Lastly, the production of a clinically accept-able grade of adipose-derived stem cells requirescareful assessment of the risks and benefits. It isimportant to identify and control all possible mol-ecules that may affect the efficacy of the adipose-derived stem cell preparation, which should beperformed in accordance with current good man-ufacturing practice guidelines.
U.S. FOOD AND DRUGADMINISTRATION REGULATIONS,
GOOD MANUFACTURING PRACTICE,AND THE EUROPEAN POSITION
The U.S. Food and Drug Administration hasdeveloped a regulatory framework based onthree areas45:
1. Prevention of use of contaminated tissues orcells.
2. Prevention of inadequate handling or pro-cessing that may damage or contaminatethose tissues or cells.
3. Clinical safety of all tissues or cells that maybe processed, used for functions other thannormal function, combined with compo-nents other than tissues, or used for meta-bolic purpose.
Fig. 2. Differentiation of adipose-derived stem cells (ASC) into several lineages.
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In the United States, adipose-derived stemcells are considered in the context of human cells,tissues, or cellular and tissue–based products, andtheir production must comply with Current GoodTissue Practice requirements, under the Code ofFederal Regulations, Title 21, Part 1271.46 Humancells, tissues, or cellular and tissue–based productsare defined as articles containing or consisting ofhuman cells or tissues that are intended for im-plantation, infusion, or transfer into a human re-cipient. The essential Current Good Tissue Prac-tice requirements are related to preventing theintroduction, transmission, or spread of commu-nicable disease by human cells, tissues, or cellularand tissue–based products.3
Two levels of regulation apply: for a low levelof risk, a human cell, tissue, or cellular and tissue–based product is regulated solely under Section361 of the Public Health System Act.46 This is trueif it meets all the following criteria (Part 1271.10):
1. The human cell, tissue, or cellular and tissue–based product is minimally manipulated.
2. The human cell, tissue, or cellular and tis-sue–based product is intended for homolo-gous use only.
3. The manufacture of the human cell, tissue,or cellular and tissue–based product doesnot involve the combination of the cells ortissues with another article.
4. That the human cell, tissue, or cellular andtissue–based product does not have a sys-temic effect and is not dependent on meta-bolic activity of living cells for its primaryfunction or the human cell, tissue, or cellu-lar and tissue–based product has a systemiceffect or is dependent on the metabolic ac-tivity of living cells for its primary function,and is for autologous use.
In this case, the U.S. Food and Drug Admin-istration sanctioned clinical trials as an investiga-tional new drug and a formal U.S. Food and DrugAdministration approval process for the specifictherapy is not required. For a higher level of risk(more than minimal manipulation, e.g., ex vivoexpansion, combination with nontissue compo-nents, or transduction), the human cell, tissue, orcellular and tissue–based product is considered adrug, device, or biological product and is regu-lated under Section 351 of the Public Health Sys-tem Act. Consequently, at the higher level of risk,to introduce adipose-derived stem cells or deliverthem for clinical use, as a drug, a valid biologicslicense must be in effect. Such licenses are issuedonly after the product has been shown to be safe
and efficacious for its intended use. While in thedevelopment stage, such products may be distrib-uted for clinical use for humans only if the sponsorhas an investigational new drug application in ef-fect as specified by U.S. Food and Drug Adminis-tration regulations (Title 21, Code of Federal Reg-ulations, Part 312).47
In Europe, adipose-derived stem cells are con-sidered Advanced Therapy Medicinal Products, asdefined by the European Regulation (EuropeanCommission) 1394/2007, which contains rules for“authorization, supervision, and technical re-quirements regarding the summary of productscharacteristics, labeling, and the package leaflet ofAdvanced Therapy Medicinal Products that are pre-pared following industrials methods and in aca-demic institutions.”47 This regulation refers to theEuropean good manufacturing process rules.48
The process of converting research-based pro-tocols using adipose-derived stem cells into a safemanufacturing process that is good manufactur-ing process–compliant requires protocols thathave had careful consideration of all the risks andbenefits for the patient end user. In particular,Sensebe et al. stated that the following parametersshould be considered: sources and collectionmethods, cell seeding, proliferation rate, and cul-ture medium. They went on to identify steps forquality control that must be carried out at cellharvest and during the various phases of adipose-derived stem cell production.49
Furthermore, automated devices for separat-ing adipose stem cells are regulated as class IIImedical devices by the U.S. Food and DrugAdministration.50 Currently, no such device is ap-proved for human use in the United States. Theseare considered as research tools and should onlybe used under and approved by the Product De-velopment Protocol.51 Because of the rigors ofsafe, reproducible, quality-controlled adipose-de-rived stem cell production as required by the U.S.Food and Drug Administration, it is easy to see whythe use of adipose-derived stem cells in clinicaltrials or for clinical applications is still very rare inthe United States.
CLINICAL APPLICATIONS OF ADIPOSE-DERIVED STEM CELLS: PUBLISHED
LITERATURE AND ONGOING CLINICALTRIALS
This section reports the different publicationsfound concerning the clinical use of adipose-de-rived stem cells and also the clinical trials currentlybeing performed around the world. These appli-
Plastic and Reconstructive Surgery • June 2012
1280
cations were organized into two areas: plastic sur-gery and the other medical specialties.
In a review published in June of 2011, Lin-droos et al. found 18 clinical trials concerning theuse of adipose-derived stem cells in regenerativemedicine.52 A search performed on www.clinical-trials.gov with the search term “adipose stem celltherapy,” performed in August of 2011, revealed33 studies based on adipose-derived stem cell ther-apy, which demonstrates the rapid evolution andexpansion of clinical use of adipose-derived stemcells. Five clinical trials were found for the plasticsurgery area (Table 1), and 28 were found in theother specialties (Table 2).
Table 3 represents the location of the clinicaltrials in the world. Spain and Korea are the twoleaders in this area, with 10 studies performed ineach country. Only three trials are currently beingperformed in the United States, which is attribut-able to the high level of exigency of the U.S. Foodand Drug Administration regulations.
PUBLISHED CLINICAL APPLICATIONSAND CLINICAL TRIALS IN PLASTIC
SURGERYPlastic surgery is a field where the clinical use
of adipose-derived stem cells is well developed.The cells are usually in the form of autologousstromal vascular fraction cells or noncultured ad-ipose-derived stem cells, with one treatment givenin a local immediate administration mainly incombination with fat grafts. Within the literature,adipose-derived stem cells have been used or stud-ied in three main areas: soft-tissue augmentation,wound healing, and tissue engineering.
Published Clinical ApplicationsSoft-Tissue AugmentationYoshimura et al.53–55 reported several studies
using the cell-assisted lipotransfer technique fortreatment of facial lipoatrophy, cosmetic breastaugmentation, or immediate breast augmentationafter breast implant removal (Table 4).53–61 Theprinciple of this technique is to enrich the fatgrafting material with stromal vascular fraction. Intheir breast augmentation study, the authorsstated that “augmentation effects were apparentlyincreased 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 lipoatrophystudy, one half of the face was treated with cell-assisted lipotransfer and the contralateral sidewas treated by the traditional lipoinjection Ta
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Volume 129, Number 6 • Human Adipose-Derived Stem Cells
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Plastic and Reconstructive Surgery • June 2012
1282
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Volume 129, Number 6 • Human Adipose-Derived Stem Cells
1283
technique.55 They reported that transplanted ad-ipose tissue was absorbed faster in the non–cell-assisted lipotransfer group compared with the cell-assisted lipotransfer–treated group over the longterm.
In 2011, two additional noncontrolled trialsusing the cell-assisted lipotransfer strategy werepublished. In the first, by Tiryaki et al., the authorsobserved not only a better graft take but also asubjective gradual regeneration of the skin over-lying the graft, in 29 patients undergoing soft-tissue augmentation.56 They stated that the tech-nique was particularly successful in secondarycases that had been previously treated with fatgrafting without significant improvement. Thesecond study, by Kamakura and Ito, reported 20cases of breast augmentation using the cell-as-sisted lipotransfer technique and concluded thatthis technique is a safe and effective method forbreast augmentation.57
In 2011, Kim et al. published the result of aclinical trial involving 31 patients treated with ad-ipose-derived stem cells that were differentiated
into mature adipocytes for facial depressed scars,but again with no comparative control group.58
Adipose-derived stem cells were isolated from ad-ipose tissue harvested by liposuction, expanded inculture, and differentiated into mature adi-pocytes, which they termed “AdipoCell” (Table 1).AdipoCell preparations were injected subcutane-ously into the depressed scars, and the volume ofeach scar was measured using three-dimensionalscans. They observed 74.6 percent mean recoveryin volume when the received dose of AdipoCellwas equivalent to three-eighths of the cell volumeof the defect and that the volume was stable at 1year after treatment. They concluded that thistechnique represented a new safe and effectivetherapy for soft-tissue augmentation.
Wound HealingIn 2007, Rigotti et al. published a study con-
cerning 20 patients undergoing therapy for sideeffects of radiation treatment with severe symp-toms and irreversible functional damage from ra-diation wounds.59 Fat was harvested by manualliposuction and centrifuged, and the purified li-poaspirate was injected into the irradiated treat-ment site. An improvement of tissue wound heal-ing was observed, and the authors postulated thatthe lipoaspirate was rich in native adipose-derivedstem cells that contributed to the observed effect.
In 2010, Akita et al. reported on a case of onepatient with an intractable wound in the sacro-coccygeal region secondary to radiation therapy.60
The wound healed with a combination treatmentof a human recombinant basic fibroblast growthfactor, artificial skin substitute, and autologousadipose-derived stem cells, some of which wereinjected into the wound. However, the true effect
Table 4. Clinical Applications of Adipose-Derived Stem Cells in Plastic Surgery
ReferencesNo. of Patients
Treated Dose of ASCs and Administration
Soft-tissue augmentationYoshimura et al.53 15 263.5 ml of fat enriched with SVF injected into each breastYoshimura et al.54 40 272.7 ml of fat enriched with SVF injected into each breastYoshimura et al.55 133 ml fat injection in the non-CAL group, 100 ml fat enriched with SVF
in the CAL groupTiryaki et al.56 29 10–390 ml of fat enriched with SVF (CAL) by local administrationKamakura 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 healingRigotti 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 engineeringStillaert et al.61 12 0.67–1.4 � 106 ASCs per scaffold
Total 174ASCs, adipose-derived stem cells; SVF, stromal vascular fraction; CAL, cell-assisted lipotransfer.
Table 3. Repartition of Clinical Trials in the World
Country No. of Clinical Trials
Americas 4United States 3Brazil 1
Asia 12Korea 10Philippines 2
Europe 17Spain 10 (�5 multicenter studies with: Belgium,
Italy, United Kingdom, Austria, TheNetherlands, Germany, Denmark)
Switzerland 1France 1
Total 33
Plastic and Reconstructive Surgery • June 2012
1284
of adipose-derived stem cells was confounded bythe presence of other treatment modalities.
Tissue EngineeringThe use of adipose-derived stem cells seeded
onto natural or synthesized scaffolds has been re-ported as a method of soft-tissue engineering ortissue regeneration. However, the clinical resultsto date remain inconclusive. One clinical studywas performed by Stillaert et al. in 2008, who sub-cutaneously implanted hyaluronic acid scaffoldsseeded with adipose-derived stem cells into 12volunteers.61 The authors observed no new adi-pose tissue formation, and concluded that this wasattributable to a deficient angiogenic response tosustain the long-term adipose-derived stem cellviability and no adverse effect.
Clinical TrialsFive clinical trials involving adipose-derived
stem cell therapies were found, and three studieshave been completed (Table 1). However, not allpublished results are available. The main focus ofthese clinical trials was soft-tissue augmentation.
A phase I study of autologous adipose-derivedstem cell transplantation is currently ongoing inBrazil in patients with lipodystrophy. Lipoinjec-tion enriched with adipose-derived stem cells isbeing performed, and five subjects are enrolled.The primary outcome measure is the volume im-provement of the transplanted area.
A phase II study in Korea is examining theeffect of adipose-derived stem cells in Rombergdisease, and five subjects are enrolled. The pri-mary outcome measure is the evaluation of thevolume change of the fatty layer using three-di-mensional image analysis.
Phase II and III studies were studying the safetyand efficacy of autologous cultured adipose-de-rived stem cells in patients with depressed scars,and 36 subjects were enrolled to receive culturedautologous adipose-derived stem cells that had beendifferentiated into mature adipocytes (AdipoCell).The primary outcome measures were to assess scarimprovement and safety.
A phase IV postmarket study, RESTORE-2,examined autologous fat enhanced with adi-pose-derived stem cells for reconstructing breastdeformities after lumpectomy. Primary outcomemeasures were patient and physician satisfactionassessments with functional and cosmetic im-provement in overall breast deformity correctionat 12 months. This study was conducted in Bel-gium, Italy, Spain, and the United Kingdom.
In the United States, a phase II proof-of-con-cept study by Antria is currently recruiting to dem-
onstrate the effectiveness of their digestive en-zymes for human use (Antria Cell PreparationProcess) for extraction of stromal vascular fractionfrom adipose tissue.
In summary, the patients treated with adipose-derived stem cells in plastic surgery represent, thusfar, 174 published cases to our knowledge (Table4). One hundred twenty-one patients are or havebeen enrolled in clinical trials (Table 1). In allpublished cases, no major adverse effects havebeen reported. The results were encouraging insoft-tissue augmentation and in wound healing.
PUBLISHED CLINICAL APPLICATIONSAND CLINICAL TRIALS IN OTHER
SPECIALTIES
Published Clinical ApplicationsTo date, a wide variety of specialties have used
adipose-derived stem cell therapy, but the numberof patients who have been treated with adipose-derived stem cells is still very limited and repre-sents 115 patients around the world (Table 5).62–84
Most of the publications retrieved are case reportsand noncontrolled studies of level 4/5 evidence,and results, although encouraging, have not beensubject to the scientific rigors of a controlled trial.
From 2006 to 2011, Fang et al. used allogenicadipose-derived stem cells in the treatment ofhematologic and immunologic disorders: graft-versus-host disease, idiopathic thrombocytopenicpurpura, or pure red cell aplasia.62–67 In each case,patients received intravenous infusion of allogenicadipose-derived stem cells isolated from adiposetissue of healthy donors. No adverse effects afterthe treatment were observed, and significant im-provements were documented with recoveryfrom graft-versus-host disease and pure red cellaplasia, and remission in the idiopathic throm-bocytopenic purpura cases. These results pro-vide evidence that the immunomodulatory ef-fects of adipose-derived stem cells may be usedin treating immunologic disorders.
In diabetes mellitus type 1, in 2008, Trivedi etal. treated five patients with allogenic adipose-de-rived stem cells cultured and differentiated intoinsulin-making mesenchymal stem cells trans-fused mixed with unfractionated autologous cul-tures of bone marrow.68 No adverse effects werereported, all subjects were reported to be health-ier and gaining weight, and biological markerswere also improved. The authors concluded thatadipose-derived stem cell therapy may be a solu-tion for the treatment of insulinopenic patients.
Volume 129, Number 6 • Human Adipose-Derived Stem Cells
1285
In 2010, Vanikar et al. reported the resultsobtained on 11 diabetic patients using the sametreatment.69 Again, no adverse events were re-ported and a gradual decrease in insulin require-ments was noted. The authors concluded that easyand repeatable access to adipose tissue provided aclear advantage over isolation of mesenchymalstem cells from bone marrow for the treatment ofdiabetes mellitus by stem cell therapy.
From 2003 to 2010, Garcıa-Olmo et al. pub-lished several articles concerning the treatment ofcomplex perianal or enterocutaneous fistulas, per-forming phase I and II clinical trials. These in-cluded patients with digestive fistulas associated ornot with Crohn disease using autologous adipose-derived stem cells isolated mixed with fibrin glueand injected into the fistulous tract.70–75 In all thestudies, no adverse effects were reported and asignificant healing rate was observed in patientswho received adipose-derived stem cells (71 per-cent of healing compared with 16 percent). Theyconcluded that adipose-derived stem cell therapyassociated with fibrin glue is a safe and effectivemethod of treating complex perianal fistula.
Rheumatoid arthritis treatments were exam-ined in a case report in 2010 by Ichim et al. of a67-year-old woman.76 The patient was treated byintravenous infusions of autologous stromal vas-cular fraction cells isolated from a liposuction pro-cedure. The authors observed no side effects, andthe patient reported a considerable resolution ofher pain joint and stiffness, with a decrease inrheumatoid factor. They concluded that adipose-
derived stem cell therapy may be a treatment forrheumatoid arthritis and postulated that this wasbecause of the immune-tolerance induced by ad-ipose-derived stem cells.
In 2009, Riordan et al. reported the treatmentof three multiple sclerosis patients with intrave-nous infusions of autologous stromal vascularfraction cells with multiple intrathecal andintravenous infusions of allogenic CD34 andmesenchymal stem cells within a 10-day period.77
No adverse effects were documented, and by 3months, all patients reported significant improve-ment of their symptoms. The authors concludedthat further clinical evaluation of autologous stro-mal vascular fraction cells is warranted in autoim-mune conditions.
In 2008, Alvarez et al. reported the case of a67-year-old man suffering from lung cancercomplicated with tracheomediastinal fistula andtreated by autologous adipose-derived stem cellsmixed with fibrin glue, injected into the fistuladuring bronchoscopy.78 The patient’s recoverywas uneventful, and epithelialization of the fis-tula was observed after 3 months. One year aftertreatment, the fistula was closed, and 2 yearsafter stem cell therapy, the patient was in com-plete remission.
There are four published case reports regard-ing bone tissue repair. In 2004, Lendeckel et al.published the case of a 7-year-old girl sufferingfrom widespread calvarial defects after severehead injury.79 The patient was treated with acombination of cancellous bone grafts from the
Table 5. Clinical Applications of Adipose-Derived Stem Cells in Other Specialties
Specialties ReferencesNo. of Patients
Treated Dose of ASCs and Administration
Hematologic and immunologicdisorders 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 byintraportal infusion under generalanesthesia during minilaparotomy
Vanikar et al.69 11Digestive diseases Garcia-Olmo et al.70–75 63 3 � 106 to 2 � 107 autologous ASCs into
the fistulaAutoimmune diseases Ichim et al.76 1 53 � 106 autologous SVF in two IV infusions
Riordan et al.77 3 25–75 � 106 autologous SVF IVTracheomediastinal fistula Alvarez et al.78 1 4.9 � 106 autologous SVF into the fistula
cavityBone tissue repair Lendeckel et al.79 1 295 � 106 autologous SVF
Mesimaki et al.80 1 13 � 106 autologous ASCsTaylor81 1 28 ml of solid fraction from fresh autologous
lipoaspiratePak82 4 10 cm3 autologous SVF
Urologic disorder Yamamoto et al.83 2 2.4–3.2 � 107 autologous SVF into urethralsphincter
Neurologic disease Ra et al.84 8 4 � 108 autologous ASCs IVTotal 115ASCs, adipose-derived stem cells; IV, intravenously; SVF, stromal vascular fraction.
Plastic and Reconstructive Surgery • June 2012
1286
ilium and autologous stromal vascular fractioncells obtained from adipose tissue. Postopera-tive healing was uneventful and the clinical fol-low-up demonstrated symmetrical calvarial con-tour. At 3 months postoperatively, the computedtomographic scan showed a marked ossificationin the defect areas.
In 2009, Mesimaki et al. reported the case of a65-year-old patient who underwent a hemimaxillec-tomy because of a large keratocyst.80 The patient’sreconstruction was performed using a preformedtitanium cage filled with autologous cultured ad-ipose-derived stem cells, combined with syntheticbioresorbable beta–tricalcium phosphate gran-ules. No adverse effects were reported, and boneregeneration was observed by biopsy. They con-cluded that the presence of adipose-derived stemcells may have enhanced the osteogenic and an-giogenic conditions of the construct in vivo.
In 2010, Taylor published the case of a 14-year-old boy suffering from Treacher Collins syn-drome whose severe biorbitozygomatic hypoplasiawas treated with tissue-engineered bone using acombination of sculpted bone allograft, bonemorphogenetic protein-2, periosteal grafts, andautologous fresh adipose-derived stem cells.81 At 4months, computed tomographic scanning showedcomplete bone reconstruction of the bilateral zy-gomas, and 6 months after surgery, a biopsy spec-imen showed lamellar bone with small marrowelements. The authors concluded that that type ofengineered construct may provide an alternativemethod to both osteocutaneous free flaps andlarge structural allografts.
In 2011, Pak reported two cases of patientssuffering from osteonecrosis of the femoral headand two cases of patients suffering from kneeosteoarthritis.82 All the patients were treated by acombination of percutaneously injected autolo-gous adipose-derived stem cells, hyaluronic acid,platelet-rich plasma, and calcium chloride. At 3months, in all cases, pain and mobilization wereimproved. Magnetic resonance imaging scansshowed a significant filling of bone defects, witha possibility of bone matrix formation at the siteof osteonecrosis and a significant increase in thethickness and the height of meniscus cartilage.The authors conclude that these good resultscan be explained either by a direct differentia-tion of adipose-derived stem cells or by thetrophic effects of adipose-derived stem cells onexisting tissues.
In 2010, Yamamoto et al. reported two cases ofpatients with stress urinary incontinence, which isa distressing complication of radical prostatec-
tomy, who were treated with autologous adipose-derived stem cells isolated using the Celution Sys-tem (Cytori Therapeutics, Inc., San Diego, Calif.)and injected (mixed with adipose tissue) in theexternal urethral sphincter under endoscopicvision.83 The authors observed no adverse effects.Urinary incontinence improved progressively af-ter 2 weeks, up to 12 weeks. Sphincter function ofthe urethra was improved in both cases, and mag-netic resonance imaging showed a bulking effectat the site of injection. They concluded that adi-pose-derived stem cell therapy was a safe and fea-sible treatment for stress urinary incontinence.
In 2011, Ra et al. published a study of eightpatients suffering from spinal cord injury whowere treated with intravenous infusions of autol-ogous adipose-derived stem cells.84 The authorsobserved no serious adverse effects. At 12 weeks,motor function was improved in four patients. Theauthors concluded that they could not determinethe efficacy of adipose-derived stem cell therapybecause of their small patient group and the shortfollow-up period.
In summary, these studies reported no majoradverse effects after treatment by adipose-derivedstem cells, and the results were promising in the115 published cases (Table 5). The characteristicsof adipose-derived stem cell therapy in these spe-cialties were as follows:
1. Adipose-derived stem cells used were allogenicor autologous; stromal vascular fraction cellsor cultured adipose-derived stem cells.
2. In some cases, additive treatments (e.g., bonemarrow, growth factor, fibrin glue) were used.
3. The administration doses were variable, as wasthe number of adipose-derived stem cells perdose.
4. Adipose-derived stem cells were administeredsystemically (intravenous infusion) or locally(intralesional injection).
Clinical TrialsTwenty-eight clinical trials using adipose
and/or adipose-derived stem cells were listed;eight of these studies have been completed. Thestudies are separated by topic, clinical phase, pri-mary site location, and study status (Table 2). Thetrials have been organized into five categories:digestive disease, autoimmune disease, cardiovas-cular disease, skeletal regeneration, and neuro-logic disorder.
In summary, adipose-derived stem cells havebeen used in a wide variety of ways:
Volume 129, Number 6 • Human Adipose-Derived Stem Cells
1287
1. Stromal vascular fraction cells or culturedadipose-derived stem cells.
2. Autologous or allogenic.3. Varied doses and methods of administra-
tion.
Some clinical trials were based on immuno-logic or angiogenic properties of adipose-derivedstem cells, for example, trials concerning the treat-ment of autoimmune diseases, limb ischemia, ordiabetic wounds in the lower extremity. Othertrials use differentiation of adipose-derived stemcells into several lineages to study their use in thetreatment of degenerative arthritis, cardiac insuf-ficiency, or spinal cord injury. Of the eight trialsalready completed, to our knowledge, only twohave published results,73,84 which are described inthe previous section, and in both of those, therehave been no adverse effects, and encouragingoutcomes were reported.
CONCLUSIONSThe important role of adipose-derived stem
cells in regenerative medicine is now coming un-der closer scrutiny. This is because adipose-de-rived stem cells are easily available and demon-strate several interesting properties, and evidencefrom preclinical studies suggests potential clinicalpromise in many medical disciplines. From thisreview, it can be noted that there is no standardprotocol for adipose-derived stem cell use or clin-ical application in terms of type of cells used (stro-mal vascular fraction cells or cultured and purifiedadipose-derived stem cells). In addition, there isno consensus on the number of cells required perdose or treatment or how many treatments arerequired before an improved clinical outcome canbe documented. Consequently, further basic sci-ence experimental studies with standardized pro-tocols and larger randomized controlled trialsneed to be performed to ensure the safety andefficacy of adipose-derived stem cells in accor-dance with U.S. Food and Drug Administrationguidelines. This review aims to make plastic sur-geons aware, because of their unique privilegedaccess to adipose tissue, of the development ofadipose-derived stem cell therapies not onlywithin plastic surgery but also, as evidenced by thisreview, the more frequent use in other medicalspecialties.
Rod J. Rohrich, M.D.Department of Plastic Surgery
University of Texas Southwestern Medical Center1801 Inwood Road
Dallas, Texas [email protected]
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