DÄ internationalArchive15/2015Cell-Assisted Lipotransfer

Original article

Cell-Assisted Lipotransfer

A Critical Appraisal of the Evidence

Dtsch Arztebl Int 2015; 112: 255-61. DOI: 10.3238/arztebl.2015.0255

Grabin, S; Antes, G; Stark, G B; Motschall, E; Buroh, S; Lampert, F M

Background: Because of their easy accessibility and versatile biological properties, mesenchymal stem cells taken from fatty tissue (adipose-derived stem cells, ADSC) are attractive for various potential clinical uses. For example, ADSC can be added to fatty tissue before transplantation in the hope of improving the outcome of autologous lipotransfer: the modified procedure is called cell-assisted lipotransfer. The clinical use and commercial promotion of this novel stem-cell treatment (and others) are spreading rapidly, even though there is not yet any clear clinical evidence for its safety and efficacy.

Methods: In cooperation with the German Cochrane Center, we systematically searched the literature according to the PRISMA criteria. Eight major medical databases were searched. The retrieved publications were examined by two independent reviewers and assessed using objective criteria.

Results: After screening of the 3161 retrieved publications by title, abstract, and (where appropriate) full text, 78 were still considered relevant. 13 of these were reports of clinical studies; only 3 of the 13 met criteria for grade II or III evidence. The studies that were analyzed involved a total of 286 cell-assisted lipotransfer procedures with a longest follow-up time of 42 months. Oncological safety was not demonstrated.

Conclusion: The studies published to date have not shown that cell-assisted lipotransfer is generally superior to conventional autologous lipotransfer. They dealt with safety aspects inappropriately or not at all. The case of cell-assisted lipotransfer illustrates the indispensability of high-quality clinical evidence before the introduction of novel stem-cell-based treatments.

LNSLNS

For several decades now, the widespread introduction of clinical stem-cell therapies has been said to be just around the corner. Stem-cell research continues to be a highly dynamic field, yet there is still only one routine and widespread treatment employing stem cells, i.e., hematopoietic stem-cell transplantation (1). A number of therapeutic procedures that are claimed to exploit various properties of “stem cells” are now being promoted, sometimes aggressively, in both the scientific literature and the lay press. Increasingly, direct advertising to potential patients is being broadcast over the Internet (24).

Stem cells from fatty tissue (adipose-derived stem cells, ADSC) are a relatively recent member of the stem-cell family. ADSC are an adult mesenchymal stem-cell population with many advantageous features for potential clinical use. They are plentiful in human fatty tissue, and they can easily be obtained by liposuction. Their phenotypes and functions closely resemble those of stem cells from bone marrow. They have been shown to be able to differentiate into many different types of cells, including chondro-, osteo-, adipo-, myo-, and neurogenic lines, as well as endothelial cells (5). Their accessibility and versatility make them appealing not only to researchers and clinicians designing new treatments, but also to physicians who see in them a lucrative opportunity in the growing market for cosmetic treatments.

The basic elements of autologous lipotransfer were developed more than a century ago: fatty tissue is removed by excision or suction, purified, and immediately reimplanted into the same patient (6). Over the years, the technique has seen many improvements, mostly with the goal of lessening the invasiveness of cell harvesting and processing, or else simplifying and standardizing the process of reimplantation. Conventional autologous lipotransfer now consists of aspiration lipectomy with low suction, followed by purification steps and then by cell concentration by either flotation or centrifugation; finally, the purified fatty tissue is reimplanted for soft-tissue augmentation (Figure 1).

Conventional compared to cell-assisted autologous lipotransfer
Figure 1
Conventional compared to cell-assisted autologous lipotransfer

Typical applications of autologous lipotransfer include the correction of contour deficits after cancer surgery or radiotherapy; purely esthetic procedures (mainly on the breasts); and the treatment of facial atrophy due to HIV and antiretroviral drugs, systemic lupus erythematosus, or scleroderma. The limitations of this technique arise from the need for revascularization of the transplanted cells, which restricts the tissue volume that can be transplanted at once. The transplantation of an excessive volume of tissue is likely to be followed by adipocyte necrosis, volume loss, and oil cyst formation (7). Loss of transplant volume over the long term has been reported to be between 30% and 70%, even with small transplants (7, 8).

Both in vitro and in vivo experiments have yielded findings suggesting a supportive effect of ADSC on the surrounding cells in autologous lipotransfer. This has prompted the development of cell-assisted lipotransfer as a putative means of improving the outcome of transplantation. The aspirated fatty tissue is divided into two aliquots, and the ADSC-containing stromal vascular fraction is then isolated from one of the aliquots and added to the other one (Figure 1). The mixture of cells generated by this process is called the cell-enriched lipoaspirate (9).

Commercial systems for processing lipografts have been developed to make cell-assisted lipotransfer possible in a single operative sitting. These systems enable the rapid, automated generation of a cell-enriched lipoaspirate. Part of the aspirated fatty tissue is broken up and freed from the surrounding tissue matrix by application of a mixture of proteolytic enzymes; this tissue is then washed, and “regenerative cells” are removed from it by centrifugation and added to the rest of the aspirated fatty tissue to make the cell-enriched lipoaspirate (10, 11).

The cell-enriched lipoaspirate can be reimplanted anywhere in the body, depending on the indication. The most common indications at present are esthetic breast augmentation and breast reconstruction after tumor surgery (12).

The rationale behind cell-assisted lipotransfer lies in the hope that the higher concentration of ADSCs in the cell-enriched lipoaspirate, compared to the lipoaspirate of conventional autologous lipotransfer, will enable better vascularization of the graft, thereby lessening the likelihood of necrosis and adipocyte resorption, and in the hope that the transplanted ADSC will differentiate into mature adipocytes (13). If these things happen, one should be able to transplant much larger volumes of fatty tissue at one time; in the future, one might even be able to transplant autologous fatty tissue in cases where silicon breast implants are used now. This would be a veritable revolution in reconstructive and esthetic surgery, yielding major benefits of various kinds—not least financial.

There have been some encouraging findings from basic research, but hardly any clinical data on cell-assisted lipotransfer are available to date. Nor is anything known about safety issues such as the risk of inappropriate tissue differentiation or of neoplasia, an inherent danger of any stem-cell-based treatment (14, 15). The practitioners of cell-assisted lipotransfer are becoming more numerous, the advertising promoting it more intense; nonetheless, there are still no reliable figures on the frequency with which this techniques is performed (Paul Ehrlich Institute, personal communications).

This state of affairs prompted us to examine the available evidence for the promising, yet controversial technique of cell-assisted lipotransfer. In accordance with the PRISMA Statement (16), we asked the following question, to be answered by application of the PICO criteria (participants, intervention, comparison, outcome): “What evidence can be found in the current scientific literature about the clinical use of fatty tissue enriched with ADSC for the purpose of regeneration and augmentation of the soft tissues?”

Methods

We conducted a systematic review of the literature in collaboration with the German Cochrane Center. A dedicated search strategy was developed with the aim of optimally representing the state of the evidence. Eight major scientific databases were searched: Medline, Medline in Process, Web of Science, BIOSIS, Scopus, LILACS, the Cochrane Library, as well as the relevant databases for registered clinical trials, including ClinicalTrials.gov, ISRCTN, the German Clinical Trials Register (DRKS), the EU Clinical Trials Register, and the Japan Primary Registries Network. The search algorithm (described in detail in the eSupplement) was adapted to the syntax of each database. After the initial run of the search algorithm, the data were continually and automatically updated (Figure 2).

Search history following the PRISMA criteria
Figure 2
Search history following the PRISMA criteria
Database(s): Ovid MEDLINE(R) search strategies
eSupplement
Database(s): Ovid MEDLINE(R) search strategies

Results

The search yielded 3161 hits, not including duplicates; independent screening of their titles and abstracts by two independent reviewers (SG and FL), as required by the “four-eyes principle,” yielded 228 that were judged to be potentially relevant. 78 were still considered relevant when their full text had been read, two of which turned out to be different language versions of the same content. Only 10 (13%) contained primary data (9, 12, 14, 17–22, [Asano Y, Yoshimura K: Cell-assisted lipotransfer for breast reconstruction after breast conserving therapy. EJC Supplements 2010; 8: 3.]). Of the remaining 67 publications, 50 were reviews, only two of which were acceptable as systematic reviews by current standards (2325). The rest consisted of letters to the editor, editorials, comments, expert opinion, discussion contributions, book abstracts, and a company profile. Three further studies were identified by the updating system and will be discussed separately below (11, 26, 27).

The studies were too heterogeneous for meta-analysis and were therefore all analyzed as recommended in the PRISMA Statement to assure reproducible comparability and categorization (16). Each study was assigned an evidence level according to the Oxford Classification Criteria of 2011 (28).

The commonest inclusion criteria for the analyzed studies were breast reconstruction and augmentation, followed by congenital, traumatic, iatrogenic, and disease-related soft-tissue defects, facial atrophy in Parry-Romberg syndrome or systemic lupus erythematosus, pectus excavatum, facial dermatofibroses, and radiation-induced soft-tissue damage (12).

Patients were typically followed up for 6 to 12 months, with the evaluation of outcomes generally based on subjective volume estimation and descriptive reports of clinical examinations, or else on photographs and videoclips. In the few studies that employed objective evaluative methods (mammography, CT/MRI volumetry), these methods often did not generate any consistent quantitative data.

Only three studies yielded grade II or III evidence; the rest yielded grade IV or V evidence. An overview of the retrieved studies is provided in the Table.

The current state of the evidence regarding cell-assisted lipotransfer
Table 1a
The current state of the evidence regarding cell-assisted lipotransfer
Further studies found by the updating process
Table 1b
Further studies found by the updating process

The reported undesired events included the formation of oil cysts, microcalcifications, fibroses, and indurations. In one case, a 17-year-old girl developed recurrent osteosarcoma after a recurrence-free interval of 10 years, 18 months after undergoing fat transplantation to the arm (14).

The 13 clinical studies involved a total of 286 cell-assisted lipotransfer procedures. The longest follow-up duration was 42 months. Adequate data on oncological safety are not available. This is especially important in view of the fact that many of these procedures were carried out at a site of prior tumor resection, e.g., for reconstruction of the breast after breast cancer surgery.

We will now discuss the three studies identified by the update system in greater detail to illustrate the sparse state of the evidence that we found.

RESTORE-2 was a one-armed, prospective, multicenter trial carried out in 2012 on 71 women with breast contour defects after breast-conserving treatment for cancer (11). Its defined primary endpoints were patient satisfaction and physician satisfaction with the functional and cosmetic outcomes of cell-assisted lipotransfer, and improvement of the pre-procedural breast deformity 12 months after the procedure. Notably, the authors had originally intended to analyze the results by MRI volumetry but could not do so, because a volume defect was demonstrable before lipotransfer in only 51 of the patients. They therefore introduced a subjective scar rating scale while the trial was in progress. This scale also ”did not adequately reflect the clinical improvements,” yet the authors reported that they had found a statistically significant improvement, without any further explanation of this statement. The patients’ quality of life during treatment was reported to be “stable,” and 45 of the 67 patients rated their satisfaction from 4 to 6 on a six-point scale, i.e., no explicit dissatisfaction was mentioned. A far more worrisome flaw of this trial was the fact that oncological safety was not addressed at all, let alone defined as an outcome parameter.

Having followed their patients up for only one year, the authors concluded that “RESTORE-2 has sufficiently demonstrated the safety and efficacy of ADRC-enriched fat grafting in the treatment of soft tissue defects post-BCT” and “this procedure should be considered as an alternative reconstructive option for women with post-BCT defects.” Considering that one patient developed a distant osseous metastasis during follow-up, it seems premature at best to draw this conclusion from the RESTORE-2 trial, which was financed by the manufacturer of the device used in it (29).

In contrast, the trial of Tanikawa et al. (26) shows that high-quality research in this field is, in fact, possible. It is one of only two trials in which cell-assisted lipotransfer was studied with appropriate methodological prudence. This prospective, randomized, controlled, double-blind trial compared cell-assisted and conventional lipotransfer for the treatment of facial soft-tissue defects due to craniofacial microsomia. Despite certain limitations, including a high dropout rate and the small volumes of tissue transplanted in comparison to the amounts that are commonly transplanted in cell-assisted lipotransfer, the authors were able to show that the technique yielded better volume consistency than conventional lipotransfer for this special indication.

Peltoniemi et al. (27) arrived at the opposite conclusion in their prospective, comparative trial of autologous lipotransfer with and without “stem-cell” supplementation for esthetic breast augmentation. In the 18 women who participated in the trial, graft survival was monitored with MRI volumetry, and the percentage of vital cells was analyzed intraoperatively with flow cytometry. Volume retention was slightly lower in the cell-assisted lipotransfer group (50% vs. 54%), but this difference was not statistically significant. The methods of this trial were generally of high quality; its limitations included a short follow-up duration (12 months at most) and a low number of patients because of the early termination of the trial for ethical reasons. The authors concluded that the transplantation of fatty tissue without any added material is “faster [and] cheaper, has a lower risk of contamination, and offers at least an equal take rate.” They stated, “We do not see any advantage in stem-cell enrichment.”

Discussion and conclusion

In summary, despite repeated assurances in recent years that good clinical data would soon be available, there is still no reliable evidence indicating the general superiority of cell-assisted lipotransfer over conventional lipotransfer. The single piece of evidence that favors cell-assisted lipotransfer in any way (in the report of Tanikawa et al., as discussed above) is uninformative concerning the postulated main advantage of the procedure, namely, the long-term volume retention of large grafts. Moreover, safety aspects have often been either inadequately addressed or entirely ignored. Considering that stem cells resemble tumor cells in many ways and their differentiation strongly depends on the local microenvironment, we can only conclude that, from the point of view of safety, cell-assisted lipotransfer cannot simply be considered the equivalent of conventional autologous lipotransfer.

The treatment of disease and the quest for beauty are two strong human desires to which advertisements for “stem-cell treatments” loudly and repeatedly appeal. This is not justified at present.

The fact that the materials needed to perform cell-assisted lipotransfer are generally classified as medical devices rather than pharmaceutical products, has made it easier for this technique to be adopted in routine clinical use, because the requirements for government approval of medical products are much less stringent in most countries. This could change in the future if materials for cell-assisted lipotransfer are classified as Advanced Therapy Medical Products (ATMP) in the European Union. This classification would not only be highly significant for patient safety; it would also give each treating physician special personal responsibility for complications, because the law would then consider the physician to be the manufacturer of a cellular therapeutic agent.

The initial, euphoric phase of stem-cell research is already over, but the field remains one of more innovative and promising areas in all of medicine. Clinical applications must keep pace with basic research and should not outstrip it, as has apparently occurred in the case of cell-assisted lipotransfer.

This technique is clearly a promising addition to the armamentarium of reconstructive and esthetic medicine, yet good evidence for its safety and efficacy is still lacking, and the legal framework for it remains unclear.

The claim that the transplantation of “cell-enriched” autologous fat is an “established stem-cell therapy” with the same safety profile as conventional autologous lipotransfer deviates from the standards of good clinical practice and should not be perpetuated. We strongly advise against the performance of these or similar procedures except under the rigorous conditions of clinical trials (which are urgently needed), in close collaboration with the responsible authorities, until sufficient clinical data are available to permit an assessment of the safety and efficacy of the technique. In order to answer the critical question of oncological long-term safety we consider the introduction of clinical registries indispensable.

Acknowledgement
The authors thank Dr. Gabriel Seifert for his help as a native speaker with the writing and correction of the English version of the manuscript.

Conflict of interest statement

The authors state that they have no conflicts of interest.

Manuscript submitted on 28 July 2014, revised version accepted on
13 January 2015.

Translated from the original German by Ethan Taub, M.D.

Corresponding author
Dr. med. Florian M. Lampert
Klinik für Plastische und Handchirurgie
Universitätsklinikum Freiburg
Hugstetter Str. 55
D-79106 Freiburg
Germany
florian.lampert@uniklinik-freiburg.de

@eSupplement available at:
www.aerzteblatt-international.de/15m0255

1.
Kuehn BM: Groups propose plan to accredit controversial stem cell therapy clinics. JAMA 2012; 308: 553–5 CrossRef MEDLINE
2.
Enserink M: Selling the stem cell dream. Science 2006; 313: 160–3 CrossRef MEDLINE
3.
Taylor PL, Barker RA, Blume KG, et al.: Patients beware: Commercialized stem cell treatments on the web. Cell Stem Cell 2010; 7: 43–9 CrossRef MEDLINE
4.
McArdle A, Senarath-Yapa K, Walmsley G, et al.: The role of stem cells in aesthetic surgery: Fact or fiction? Plast Reconstr Surg 2014; 134: 193–200 CrossRef MEDLINE
5.
Zuk PA, Zhu M, Mizuno H, et al.: Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 2001; 7: 211–28 CrossRef MEDLINE
6.
Lexer E: Die freien Transplantationen: 2 Teile: Verlag von Ferdinand Enke in Stuttgart; 1919.
7.
Gutowski KA, Asps Fat Graft Task Force: Current applications and safety of autologous fat grafts: A report of the ASPS Fat Graft Task Force. Plast Reconstr Surg 2009; 124: 272–80 CrossRef MEDLINE
8.
Tabit CJ, Slack GC, Fan K, Wan DC, Bradley JP: Fat grafting versus adipose-derived stem cell therapy: Distinguishing indications, techniques, and outcomes. Aesthet Plast Surg 2011: 1–10 MEDLINE
9.
Yoshimura K, Sato K, Aoi N, Kurita M, Hirohi T, Harii K: Cell-assisted lipotransfer for cosmetic breast augmentation: supportive use of adipose-derived stem/stromal cells. Aesthet Plast Surg 2008; 32: 48–55; discussion 6–7 MEDLINE PubMed Central
10.
Daniels E: Cytori therapeutics. Inc. Regen Med 2007; 2: 317–20 CrossRef MEDLINE
11.
Perez-Cano R, Vranckx JJ, Lasso JM, et al.: Prospective trial of adipose-derived regenerative cell (ADRC)-enriched fat grafting for partial mastectomy defects: the RESTORE-2 trial. Eur J Surg Oncol 2012; 38: 382–9 CrossRef MEDLINE
12.
Tiryaki T, Findikli N, Tiryaki D: Staged stem cell-enriched tissue (SET) injections for soft tissue augmentation in hostile recipient areas: A preliminary report. Aesthet Plast Surg 2011; 35: 965–71 CrossRef MEDLINE
13.
Zhu M, Zhou Z, Chen Y, et al.: Supplementation of fat grafts with adipose-derived regenerative cells improves long-term graft retention. Annals of Plastic Surgery 2010; 64: 222–8 CrossRef MEDLINE
14.
Perrot P, Rousseau J, Bouffaut A-L, et al.: Safety concern between autologous fat graft, mesenchymal stem cell and osteosarcoma recurrence. PLoS ONE [Electronic Resource] 2010; 5: e10999 CrossRef MEDLINE PubMed Central
15.
Schneider CK, Celis P: Challenges with advanced therapy medicinal products and how to meet them. Nat Rev Drug Discov 2010; 9: 195–201 CrossRef MEDLINE
16.
Moher D, Liberati A, Tetzlaff J, Altman DG, Group P: Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009; 339: b2535 CrossRef MEDLINE PubMed Central
17.
Kamakura T, Ito K: Autologous cell-enriched fat grafting for breast augmentation. Aesthet Plast Surg 2011; 35: 1022–30 CrossRef MEDLINE
18.
Rigotti G, Marchi A, Galie M, et al.: Clinical treatment of radiotherapy tissue damage by lipoaspirate transplant: a healing process mediated by adipose-derived adult stem cells. Plast Reconstr Surg 2007; 119: 1409–22; discussion 23–4 CrossRef MEDLINE
19.
Sterodimas A, de Faria J, Nicaretta B, Boriani F: Autologous fat transplantation versus adipose-derived stem cell-enriched lipografts: a study. Aesthetic Surgery Journal 2011; 31: 682–93 CrossRef MEDLINE
20.
Yoshimura K, Aoi N, Suga H, et al.: Ectopic fibrogenesis induced by transplantation of adipose-derived progenitor cell suspension immediately after lipoinjection. Transplantation 2008; 85: 1868–9 CrossRef MEDLINE
21.
Yoshimura K, Asano Y, Aoi N, et al.: Progenitor-enriched adipose tissue transplantation as rescue for breast implant complications. Breast J 2010; 16: 169–75 CrossRef MEDLINE
22.
Yoshimura K, Sato K, Aoi N, et al.: Cell-assisted lipotransfer for facial lipoatrophy: efficacy of clinical use of adipose-derived stem cells. Dermatol Surg 2008; 34: 1178–85 CrossRef CrossRef MEDLINE
23.
Rosing JH, Wong G, Wong MS, Sahar D, Stevenson TR, Pu LLQ: Autologous fat grafting for primary breast augmentation: A systematic review. Aesthet Plast Surg 2011; 35: 882–90 CrossRef MEDLINE
24.
Garrido I, Leguevaque P, Gangloff D, Mojallal A: The adipose tissue transfer in the mammary parenchyma (part II): Review of the literature on the carcinologic risks. Annales De Chirurgie Plastique Esthetique 2011; 56: 49–58 CrossRef MEDLINE
25.
Eden J, Levitt L, Berg A, Morton S: Finding what works in health care: Standards for systematic reviews: The National Academies Press; 2011.
26.
Tanikawa DY, Aguena M, Bueno DF, Passos-Bueno MR, Alonso N: Fat grafts supplemented with adipose-derived stromal cells in the rehabilitation of patients with craniofacial microsomia. Plast Reconstr Surg 2013; 132: 141–52 CrossRef MEDLINE
27.
Peltoniemi HH, Salmi A, Miettinen S, et al.: Stem cell enrichment does not warrant a higher graft survival in lipofilling of the breast: A prospective comparative study. J Plast Reconstr Aesthet SurgS 2013; 66: 1494–503 CrossRef MEDLINE
28.
OCEBM Levels of Evidence Working Group: The Oxford Levels of Evidence 2. Oxford Centre for Evidence-Based Medicine. www.cebm.net/index.aspx?o=5653 2011. (last accesssed on 19 October 2014).
29.
Lampert FM, Grabin S, Bjorn Stark G: The RESTORE-2 trial: proof of safety and efficacy of „regenerative-cell enriched“ fat-grafting? Eur J Surg Oncol 2012; 38: 1231–2; author reply 3–4 CrossRef MEDLINE
Department of Plastic Surgery, University Medical Center Freiburg:
cand. med. Grabin, Prof. Dr. med. Stark, Dr. med. Lampert
German Cochrane Centre, University Medical Center Freiburg: Prof. Dr. rer. nat. Antes
Center for Medical Biometry and Medical Informatics, University of Freiburg: Motschall
Department of General and Visceral Surgery, University Medical Center Freiburg: Buroh
Conventional compared to cell-assisted autologous lipotransfer
Figure 1
Conventional compared to cell-assisted autologous lipotransfer
Search history following the PRISMA criteria
Figure 2
Search history following the PRISMA criteria
Key messages
The current state of the evidence regarding cell-assisted lipotransfer
Table 1a
The current state of the evidence regarding cell-assisted lipotransfer
Further studies found by the updating process
Table 1b
Further studies found by the updating process
Database(s): Ovid MEDLINE(R) search strategies
eSupplement
Database(s): Ovid MEDLINE(R) search strategies
1.Kuehn BM: Groups propose plan to accredit controversial stem cell therapy clinics. JAMA 2012; 308: 553–5 CrossRef MEDLINE
2.Enserink M: Selling the stem cell dream. Science 2006; 313: 160–3 CrossRef MEDLINE
3.Taylor PL, Barker RA, Blume KG, et al.: Patients beware: Commercialized stem cell treatments on the web. Cell Stem Cell 2010; 7: 43–9 CrossRef MEDLINE
4.McArdle A, Senarath-Yapa K, Walmsley G, et al.: The role of stem cells in aesthetic surgery: Fact or fiction? Plast Reconstr Surg 2014; 134: 193–200 CrossRef MEDLINE
5.Zuk PA, Zhu M, Mizuno H, et al.: Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 2001; 7: 211–28 CrossRef MEDLINE
6.Lexer E: Die freien Transplantationen: 2 Teile: Verlag von Ferdinand Enke in Stuttgart; 1919.
7.Gutowski KA, Asps Fat Graft Task Force: Current applications and safety of autologous fat grafts: A report of the ASPS Fat Graft Task Force. Plast Reconstr Surg 2009; 124: 272–80 CrossRef MEDLINE
8.Tabit CJ, Slack GC, Fan K, Wan DC, Bradley JP: Fat grafting versus adipose-derived stem cell therapy: Distinguishing indications, techniques, and outcomes. Aesthet Plast Surg 2011: 1–10 MEDLINE
9.Yoshimura K, Sato K, Aoi N, Kurita M, Hirohi T, Harii K: Cell-assisted lipotransfer for cosmetic breast augmentation: supportive use of adipose-derived stem/stromal cells. Aesthet Plast Surg 2008; 32: 48–55; discussion 6–7 MEDLINE PubMed Central
10.Daniels E: Cytori therapeutics. Inc. Regen Med 2007; 2: 317–20 CrossRef MEDLINE
11.Perez-Cano R, Vranckx JJ, Lasso JM, et al.: Prospective trial of adipose-derived regenerative cell (ADRC)-enriched fat grafting for partial mastectomy defects: the RESTORE-2 trial. Eur J Surg Oncol 2012; 38: 382–9 CrossRef MEDLINE
12.Tiryaki T, Findikli N, Tiryaki D: Staged stem cell-enriched tissue (SET) injections for soft tissue augmentation in hostile recipient areas: A preliminary report. Aesthet Plast Surg 2011; 35: 965–71 CrossRef MEDLINE
13.Zhu M, Zhou Z, Chen Y, et al.: Supplementation of fat grafts with adipose-derived regenerative cells improves long-term graft retention. Annals of Plastic Surgery 2010; 64: 222–8 CrossRef MEDLINE
14.Perrot P, Rousseau J, Bouffaut A-L, et al.: Safety concern between autologous fat graft, mesenchymal stem cell and osteosarcoma recurrence. PLoS ONE [Electronic Resource] 2010; 5: e10999 CrossRef MEDLINE PubMed Central
15.Schneider CK, Celis P: Challenges with advanced therapy medicinal products and how to meet them. Nat Rev Drug Discov 2010; 9: 195–201 CrossRef MEDLINE
16.Moher D, Liberati A, Tetzlaff J, Altman DG, Group P: Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009; 339: b2535 CrossRef MEDLINE PubMed Central
17.Kamakura T, Ito K: Autologous cell-enriched fat grafting for breast augmentation. Aesthet Plast Surg 2011; 35: 1022–30 CrossRef MEDLINE
18.Rigotti G, Marchi A, Galie M, et al.: Clinical treatment of radiotherapy tissue damage by lipoaspirate transplant: a healing process mediated by adipose-derived adult stem cells. Plast Reconstr Surg 2007; 119: 1409–22; discussion 23–4 CrossRef MEDLINE
19.Sterodimas A, de Faria J, Nicaretta B, Boriani F: Autologous fat transplantation versus adipose-derived stem cell-enriched lipografts: a study. Aesthetic Surgery Journal 2011; 31: 682–93 CrossRef MEDLINE
20.Yoshimura K, Aoi N, Suga H, et al.: Ectopic fibrogenesis induced by transplantation of adipose-derived progenitor cell suspension immediately after lipoinjection. Transplantation 2008; 85: 1868–9 CrossRef MEDLINE
21.Yoshimura K, Asano Y, Aoi N, et al.: Progenitor-enriched adipose tissue transplantation as rescue for breast implant complications. Breast J 2010; 16: 169–75 CrossRef MEDLINE
22.Yoshimura K, Sato K, Aoi N, et al.: Cell-assisted lipotransfer for facial lipoatrophy: efficacy of clinical use of adipose-derived stem cells. Dermatol Surg 2008; 34: 1178–85 CrossRef CrossRef MEDLINE
23.Rosing JH, Wong G, Wong MS, Sahar D, Stevenson TR, Pu LLQ: Autologous fat grafting for primary breast augmentation: A systematic review. Aesthet Plast Surg 2011; 35: 882–90 CrossRef MEDLINE
24.Garrido I, Leguevaque P, Gangloff D, Mojallal A: The adipose tissue transfer in the mammary parenchyma (part II): Review of the literature on the carcinologic risks. Annales De Chirurgie Plastique Esthetique 2011; 56: 49–58 CrossRef MEDLINE
25.Eden J, Levitt L, Berg A, Morton S: Finding what works in health care: Standards for systematic reviews: The National Academies Press; 2011.
26.Tanikawa DY, Aguena M, Bueno DF, Passos-Bueno MR, Alonso N: Fat grafts supplemented with adipose-derived stromal cells in the rehabilitation of patients with craniofacial microsomia. Plast Reconstr Surg 2013; 132: 141–52 CrossRef MEDLINE
27.Peltoniemi HH, Salmi A, Miettinen S, et al.: Stem cell enrichment does not warrant a higher graft survival in lipofilling of the breast: A prospective comparative study. J Plast Reconstr Aesthet SurgS 2013; 66: 1494–503 CrossRef MEDLINE
28.OCEBM Levels of Evidence Working Group: The Oxford Levels of Evidence 2. Oxford Centre for Evidence-Based Medicine. www.cebm.net/index.aspx?o=5653 2011. (last accesssed on 19 October 2014).
29.Lampert FM, Grabin S, Bjorn Stark G: The RESTORE-2 trial: proof of safety and efficacy of „regenerative-cell enriched“ fat-grafting? Eur J Surg Oncol 2012; 38: 1231–2; author reply 3–4 CrossRef MEDLINE