Background
Fat grafting was first reported in 1989, but the use of this technology was restricted due to its unpredictability and low graft survival rate [
1,
2]. In 2008, a new technology based on adipose tissue-derived stromal cells (ADSCs) was reported by Yoshimura and colleagues [
3]. Subsequently, cell-assisted lipotransfer (CAL) has become increasingly popular with the development of autologous fat harvesting, processing, reinjection and storage. Although autologous fat is biocompatible, nonimmunogenic and easily obtained, the fat resorption rate is found to be unstable, ranging from 20 to 80% [
4]. However, the best technology for handling adipose tissue remains controversial.
Several clinical studies with favourable and unfavourable results using CAL compared with conventional lipoinjection have been reported. For example, Zhao et al. asserted that bone marrow-derived mesenchymal stem cell-assisted fat graft was more effective and safe for soft tissue than conventional fat grafting, based on high patient satisfaction and low complication rate [
5]. However, Peltoniemi et al. reported similar survival rates for patients who underwent cell enrichment and water-assisted lipotransfer [
6].
A meta-analysis that supported the superior clinical efficacy of CAL has been reported [
7]. Subsequently, several clinical studies confirmed these findings [
8,
9]. Moreover, although no study has discussed this issue, the transplant site may be one of the factors influencing the efficacy of fat grafting [
10,
11]. Thus, we conducted a meta-analysis to investigate whether CAL could improve fat survival and patient satisfaction rates. We also performed a subgroup analysis stratified by the transplant site.
Methods
Search strategy
The meta-analysis was performed according to PRISMA guidelines. Related articles in PubMed, Embase and the Cochrane library were systematically searched with no language restriction. Articles published before 20 April 2017and containing the following terms were included in the study: (“fat graft” or “fat transplantation” or “lipotransfer” or “lipofilling” or “lipografts” or “autologous fat”) AND (“SVF” or “stem cell” or “ADSC” or “ASC” or “ADRC” or “cell-assisted” or “progenitor-enriched” or “cell-enhanced”).Additionally, to include more available research for meta-analysis, the reference lists of the included articles were also searched.
Study selection
The eligibility of each study was independently assessed by two investigators following the inclusion criteria: (1) the study subjects were patients who had undergone soft tissue reconstruction or filling, (2) studies assessed the clinical efficacy of autologous CAL, (3) patients in the control group were treated with fat grafting alone and (4) fat survival rate and/or patient satisfaction rate were assessed in the studies.
We excluded the following studies: (1) those in which the outcomes, including fat survival and patient satisfaction rates, were not provided or could not be calculated and (2) those studies that did not involve clinical research, such as reviews, letters and conference abstracts. If the same patients were included in more than one study, the latest reference would be included in the meta-analysis.
Data extraction was independently conducted by two investigators following a pre-designed extraction form. The following information would be extracted: the first author’s name, publication year, study area, follow-up period, age, BMI, sample size, intervention strategies and research outcome. The extracted information would be checked by each other after the data extraction work had been completed, and any inconsistencies would be resolved through discussion.
Statistical analysis
Patient satisfaction and fat survival rates were transformed into estimates of the odds ratio (OR) with its 95% confidence interval (95% CI) and weighted mean difference (WMD) with its 95% CI, respectively. Cochran’s Q statistic and
I
2 test were used to analyse heterogeneity among individual studies [
12]. If significant heterogeneity was identified (
P < 0.05 or
I
2 > 50%), random effects model would be used to calculate the combined effect value. Otherwise, fixed effects model would be used to combine the data.
Subgroup analysis was performed upon stratification by the transplant site. Publication bias was assessed using Egger’s test. The stability of the results was also confirmed by sensitivity analysis. All statistical analyses were performed using Stata11.0 software (Stata Corporation, College Station, TX).
Discussion
This study attempted to systematically investigate the clinical efficacy of CAL technology compared with conventional fat grafting. In total, nine articles were included in the meta-analysis. This study demonstrated that fat survival rate was significantly higher for patients using CAL. Although no significant difference was found in patient satisfaction rate between the CAL and control groups, a significantly higher patient satisfaction rate was found among patients who underwent CAL fat graft in the face and arm than in the controls. Thus, we suggest that CAL is superior to conventional lipoinjection with improved fat survival rate. However, the long-term efficacy should be evaluated in a further study.
Human adipose tissue was recommended as an ideal source of autologous cells because it is plentiful and easily obtained. Graft take rate and volume retention could be highly improved using CAL, which transforms poor-adipose derived stromal cells fat grafts into enriched ones [
3]. Although the mechanism associated with fat graft survival remains unclear, lack of adequate neovascularisation has been recognised as one of the reasons for graft loss. Previous evidence supported that CAL had the ability on adipogenesis and angiogenesis in the adipose repair process [
18,
19]. By pooling data from previous clinical data, we proved that CAL was superior to conventional lipoinjection with improved fat survival rate. However, the precise mechanism of CAL on improving fat survival rate should be further studied.
Although a significant improvement in fat survival rate in CAL fat enrichment was demonstrated in the meta-analysis, significant heterogeneity in this variable among the studies should not be ignored. It is known that fat survival rate is affected by the method of obtaining, isolating and preparing cells in different clinical settings [
20,
21]. This would make it difficult to compare studies according to different techniques used in the surgery. Moreover, after transfer, the amount of fibrosis induced and the number of viable fat cells were reported to be the main factors for the clinical longevity of the correction [
22‐
24]. Additionally, the survival of fat cell grafts would also be affected by the anatomic site and the mobility and vascularity of the recipient tissue [
25]. Fat graft results would also depend on the background of patients, technique used and surgeon’s expertise. However, the above factors could not be fully balanced among individual studies in the meta-analysis, which may explain the significant heterogeneity. For the technology of fat grafting, further technical and outcome standardisation is thus required.
No significant difference was found between CAL and conventional fat grafting in breast fat transfer. Patients were more satisfied with CAL in the arm and face than with conventional fat grafting. No recent study has provided evidence regarding the fat transfer site that is superior. However, it should be recommended that clinical efficacy be assessed based on transplant site.
The strengths of this meta-analysis are as follows: First, the clinical efficacy of CAL or fat grafting alone was quantitatively analysed based on case-control studies. Second, although significant heterogeneity was found for data on fat survival rate, the findings of sensitivity analysis guaranteed the stability of the results. Third, no significant publication bias was found in the meta-analysis.
Some limitations should also be noted in the meta-analysis. First, only four out of nine included studies were randomised controlled trials. Although the quality of included studies was fit for the meta-analysis, the type of research design might limit the strength of the conclusion [
9,
14,
16,
17]. Moreover, fat grafts were randomly injected into the posterior part of the right and left upper arms in the study by Kølle et al. [
14]. Therefore, analysis of the quality of the included studies could not be performed in the meta-analysis. Second, the number of included studies was small; therefore, further study is needed to verify the current conclusion by incorporating more randomised controlled trials with high quality.
Conclusion
Numerous methods have been proposed to enhance the survival of fat grafts, but no definitive treatment protocol is available. CAL offers new perspectives for improving fat graft survival. In summary, this study suggests that CAL is superior to conventional lipoinjection with improved fat survival rate. However, its long-term clinical efficacy should be evaluated in a further study.