Adipose-Derived Stem Cell-Enhanced versus Conventional Fat Grafting for Breast Reconstruction: A Systematic Review and Meta-Analysis.

METHODS

Study Design and Search Strategy
This systematic review and meta-analysis was conducted in accordance with PRISMA 2020 guidelines20 and registered in the International Prospective Register of Systematic Reviews (PROSPERO; Safety and Efficacy of Adipose-Derived Stem Cell-Based Approaches for Breast Reconstruction: A Systematic Review and Meta-Analysis Protocol; study CRD42024553984). A comprehensive search of 6 databases (PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials [CENTRAL], Scopus, and Google Scholar) was performed to identify studies published between January of 2000 and November of 2024.
The search strategy was developed in consultation with a medical librarian and adhered to peer-reviewed search methodology standards.21 Four conceptual domains guided the strategy:
Cell-based interventions (eg, ADSCs, SVF)

Grafting techniques (eg, cell-assisted lipotransfer, fat grafting, lipofilling)

Anatomical application (eg, breast reconstruction, breast augmentation, mammaplasty)

Outcomes (eg, complications, safety, efficacy, retention, patient-reported measures)

Controlled vocabulary (eg, MeSH and Emtree terms), free-text keywords, and database-specific syntax were used. To ensure literature saturation, both backward and forward citation tracking were performed. The complete search strategy is available in the Supplemental Digital Content. (See Table, Supplemental Digital Content 2, which shows complete electronic search strategies for this systematic review, https://links.lww.com/PRS/I247.)

Eligibility Criteria
We included randomized controlled trials (RCTs), cohort studies, and case–control studies comparing ADSC-enhanced fat grafting with conventional fat grafting techniques for breast reconstruction. Case series with 10 or more participants and 6 or more months of follow-up were included for technique evaluation. The population comprised adult women (18 years of age or older) undergoing breast reconstruction for any indication.
Studies were excluded if they involved patients with active breast cancer, uncontrolled comorbidities (eg, unmanaged diabetes, severe cardiovascular disease), or concurrent treatments (eg, ongoing chemotherapy, radiotherapy, systemic corticosteroids) likely to confound outcomes. ADSC-enhanced techniques were classified into 3 categories: (1) ex vivo–expanded ADSCs (cultured for 2 to 6 weeks to achieve approximately 1 to 5 × 106 cells/mL); (2) SVF-enhanced grafting (point-of-care enzymatic or mechanical isolation yielding approximately 0.5 to 2 × 106 nucleated cells/mL); and (3) ADSC-seeded scaffolds. The comparator in all included studies was conventional fat grafting without cellular enhancement.

Study Selection and Data Extraction
Two reviewers independently screened titles, abstracts, and full texts using Rayyan software.22 Discrepancies were resolved through discussion or adjudication by a third reviewer. Data extraction was performed using a standardized electronic form,23 and included study characteristics, patient demographics, intervention details, and prespecified outcome variables.

Outcome Measures
The primary outcomes were as follows:
Fat graft retention, measured as a percentage of initial volume using validated imaging techniques

Postoperative complications, categorized as major (requiring surgical intervention) or minor (managed conservatively)

Reoperation rates

Aesthetic outcomes, assessed using validated tools

Patient-reported outcomes (eg, BREAST-Q, visual analog scale [VAS])

For patients with a history of breast cancer, oncologic safety was evaluated by rates of locoregional recurrence, distant metastasis, and survival outcomes.

Risk of Bias and Evidence Certainty Assessment
Risk of bias was independently assessed by 2 reviewers using the Cochrane Risk of Bias 2.0 tool for RCTs,24 the Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) tool for nonrandomized interventional studies,25 and the Newcastle-Ottawa Scale for observational studies.26 Disagreements were resolved through consensus. The overall certainty of evidence was evaluated using the GRADE approach,19 considering 5 domains: risk of bias, inconsistency, indirectness, imprecision, and publication bias.

Data Synthesis and Statistical Analysis
Meta-analyses were conducted using random-effects models (DerSimonian and Laird method) in Review Manager (version 5.3) and R (meta package version 5.2-0). A priori power analysis indicated that a minimum of 8 studies with 40 patients per arm would provide 80% power to detect a 25% difference in fat graft retention.27–29
Effect estimates were reported as mean differences for continuous outcomes and risk ratios (RRs) for dichotomous outcomes, each with 95% CIs. Heterogeneity was assessed using the I² statistic, with values of 25%, 50%, and 75% representing low, moderate, and high heterogeneity, respectively.
Publication bias was evaluated using funnel plots and the Egger regression test when 10 or more studies were available. The trim-and-fill method was applied to adjust for potential bias when indicated.

Subgroup and Sensitivity Analyses
Predefined subgroup analyses examined outcomes by the following:
ADSC preparation method (SVF versus ex vivo–expanded)

Indication (aesthetic versus oncologic reconstruction)

Patient age (younger than 50 years versus 50 years or older)

Follow-up duration (12 months or less versus longer than 12 months)

Previous radiotherapy exposure

Sensitivity analyses were conducted by excluding studies with high risk of bias, small sample size (less than 50 participants), or industry sponsorship.

RESULTS

Study Selection and Characteristics
From 1144 records screened, 31 studies were included, comprising 10 RCTs and 21 observational studies, with a total of 1426 patients (634 receiving ADSC-enhanced grafts and 792 receiving conventional fat grafts).8,18,27–55 The PRISMA flow diagram (Fig. 1) illustrates the selection process from database searches to final inclusion. Studies were published between 2012 and 2024, with a mean follow-up of 18.7 months. Detailed study characteristics are presented in Table 1.
Risk-of-bias assessment identified 2 RCTs at low risk, 5 with some concerns, and 3 at high risk. Among observational studies, 6 were rated low risk, 16 moderate, and 4 high risk. (See Table, Supplemental Digital Content 3, which shows risk of bias assessment for all 31 included studies, https://links.lww.com/PRS/I248.) Based on the GRADE framework, the certainty of evidence was moderate for fat graft retention and complication rates and low for SVF-based and oncologic outcomes due to heterogeneity and imprecision.

Fat Graft Retention
ADSC-enhanced fat grafting significantly improved retention compared with conventional techniques (mean difference [MD], 26.8% [95% CI, 18.2 to 35.5]; P < 0.001; moderate-certainty evidence) (Fig. 2). This improvement translates to fewer surgical procedures and shorter treatment timelines.
Ex vivo–expanded ADSCs achieved the largest benefit (MD, 64.6% [95% CI, 60.5 to 68.7]; P < 0.001). This outcome was reported in 3 studies (n = 87) from centers with advanced cell processing capabilities, suggesting a technique-dependent effect.27,28
SVF-enriched approaches demonstrated a more modest improvement (MD, 17.0% [95% CI, 8.6 to 25.4]; P < 0.001; I² = 78%).29–32
Single-arm studies reported retention rates of 60% to 80% with SVF and 90% to 100% with ex vivo–expanded ADSCs.55 Retention outcomes stratified by follow-up duration are shown in the Supplemental Digital Content. (See Figure, Supplemental Digital Content 4, which presents a forest plot showing mean differences in fat graft retention between ADSC-enhanced and conventional fat grafting, stratified by follow-up duration: short term [4 to 6 months] or medium term [12 months]. Each point represents an individual study.27–32,55]. The vertical dashed line at 0% indicates no difference; points to the right favor ADSC-enhanced grafting, https://links.lww.com/PRS/I249.)

Complications
Overall complication rates were similar between ADSC-enhanced and conventional grafting (18.4% versus 17.2%; RR, 1.07 [95% CI, 0.65 to 1.77]; P = 0.78).29–33 Specific complications occurred at comparable frequencies: fat necrosis (5.4% versus 5.9%), oil cysts (7.8% versus 6.4%), and calcifications (4.2% versus 3.7%). Pooled complication data are shown in Figure 3.

Oncologic Safety
Among 813 patients with a history of breast cancer (57% of the cohort), recurrence rates did not differ significantly between groups (5.3% versus 3.4%; RR, 1.56 [95% CI, 0.10 to 24.3]; P = 0.75).34–36 During the study period, 35 recurrence events occurred across both groups. Medium-term results are reassuring; however, extended follow-up through cancer registries is warranted to detect late recurrences, particularly in hormone receptor–positive disease.16,17 Recurrence outcomes are presented in Figure 4.

Aesthetic and Patient-Reported Outcomes
Thirteen studies evaluated aesthetic and patient-reported outcomes using BREAST-Q, VAS, or 3-dimensional imaging. BREAST-Q scores showed modest but not significant advantages for ADSC-treated groups in satisfaction with breasts (MD, 7.8 points [95% CI, 2.1 to 13.5]) and psychosocial well-being (MD, 5.2 points [95% CI, 0.8 to 9.6]).32,33,37,38 In contrast, VAS scores demonstrated significantly higher satisfaction with ADSC-enhanced grafting (MD, 1.8 points on a 10-point scale; P < 0.01).30,31,38
Objective assessments confirmed improved contour and volume stability with ADSC-enhanced grafts.28,31,50 Blinded evaluators favored ADSC-enhanced results for natural appearance.28,38 Short-term (6 to 12 months) improvements in contour, softness, and patient satisfaction were most pronounced with ex vivo–expanded ADSCs28,29; SVF-based grafts showed moderate, variable results.30,31 These benefits diminished after 18 to 24 months.45,48,55 Digital morphometry confirmed early volumetric advantages that declined over time.
Patients who received aesthetic augmentation reported higher satisfaction than postmastectomy reconstruction patients (mean BREAST-Q difference, 8.2 points; P = 0.008), particularly in nonirradiated fields. Aesthetic and patient satisfaction outcomes are summarized in the Supplemental Digital Content. (See Table, Supplemental Digital Content 5, which shows a summary of aesthetic and patient-reported outcomes from 13 studies, https://links.lww.com/PRS/I250.)

Subgroup Analyses
Prespecified subgroup analyses revealed several key findings. Enzymatic digestion consistently outperformed mechanical isolation for ADSC preparation (Fig. 5). Aesthetic indications yielded higher retention than oncologic reconstructions (difference, 8.7%; P = 0.007). ADSC-enhanced grafting demonstrated substantial benefits in previously irradiated tissue (MD, 15.2%; P < 0.001).30,40 Younger patients (younger than 50 years of age) showed greater retention, although the effect diminished with longer follow-up. Heterogeneity in SVF-based studies (I² = 78%) likely reflected differences in preparation and delivery protocols.

Clinical Relevance
The observed 26.8% improvement in graft retention is clinically meaningful and may reduce the number of procedures required per patient. Ex vivo–expanded ADSCs produced the most consistent and durable results,27,28,55 but require access to GMP-compliant facilities. SVF-based methods offered moderate benefits,29–32 and may be more feasible in routine practice.
Publication bias assessment and the Egger test (P = 0.10) revealed no significant bias. (See Figure, Supplemental Digital Content 6, which shows a funnel plot assessing publication bias for fat graft retention studies comparing ADSC-enhanced with conventional fat grafting. Each point represents an individual study included in the retention meta-analysis.27–32,55 The vertical line indicates the pooled effect estimate [MD]. The Egger test revealed no significant asymmetry (P = 0.10), https://links.lww.com/PRS/I251. See Figure, Supplemental Digital Content 7, which shows a funnel plot assessing publication bias for complication rate studies comparing ADSC-enhanced with conventional fat grafting. Each point represents an individual study included in the complication rate meta-analysis.29–36 The vertical line represents the pooled effect estimate [log RR]. Due to the limited number of studies [n = 5], statistical testing for asymmetry was inconclusive, https://links.lww.com/PRS/I252.) Complication rates were similar between groups; however, ongoing oncologic surveillance is essential, particularly for high-risk patients.34–36
Key limitations include protocol heterogeneity, relatively short follow-up, and a limited number of high-quality RCTs.

DISCUSSION
This systematic review provides comprehensive evidence on ADSC-enhanced fat grafting for breast reconstruction. Our pooled analysis demonstrated a 26.8% improvement in fat graft retention (95% CI, 18.2 to 35.5) compared with conventional techniques, with no significant increase in complication rates or oncologic risk during medium-term follow-up. These findings suggest that ADSC enhancement may reduce the number of procedures needed to achieve optimal reconstructive outcomes.

Fat Graft Retention and Technique Efficacy
The retention gains with ADSC-enhanced techniques—particularly the 64.6% improvement reported with ex vivo–expanded ADSCs—represent a clinically meaningful advance that may reduce operative episodes, costs, and cumulative surgical risks. SVF-based approaches (17.0% improvement)29–32 remain a more accessible option for institutions without specialized cell culture facilities.
Preparation method was a key determinant of outcome. Enzymatic digestion consistently outperformed mechanical isolation, and heterogeneity among SVF-based studies (I² = 78%) largely reflected variation in isolation protocols, cell concentration, and delivery methods.29,39,55 This reinforces the need for standardized procedural techniques to optimize results.

Patient-Centered Outcomes
Beyond retention metrics, aesthetic results and patient satisfaction are critical endpoints. Across 13 studies, ADSC-enhanced cohorts achieved higher scores, although magnitude varied by instrument: BREAST-Q improvements were modest and not statistically significant (MD, 5.2 to 7.8 points),32,33,37,38 whereas VAS scores showed significant gains (P < 0.01).30,31,38 Compared with previous reviews,14,15 these findings are strengthened by a larger pooled sample size and stricter inclusion criteria.
Objective analyses using digital imaging and 3-dimensional volumetry confirmed improved contour, symmetry, and volume stability in ADSC-treated patients,28,31,50 with blinded evaluators more frequently favoring the natural appearance of ADSC-enhanced reconstructions.28,38 These benefits tended to diminish after 18 to 24 months, suggesting a plateau effect that should be addressed during preoperative counseling.45,48,55
In irradiated fields, ADSC enhancement initially improved contour and satisfaction, but showed less predictable long-term stability than in nonirradiated tissue. Aesthetic augmentation patients consistently reported greater satisfaction than postmastectomy reconstruction patients (mean BREAST-Q difference, 8.2 points; P = 0.008).30,31

Subgroup Implications for Clinical Decision-Making
Subgroup findings support an evidence-based framework for patient selection:
Ex vivo–expanded ADSCs provided the most consistent and durable results.

Patients younger than 50 years achieved superior retention.

Aesthetic indications yielded better outcomes than oncologic reconstructions.

ADSC enhancement mitigated—but did not eliminate—the adverse effects of previous radiotherapy.30,40

A tiered clinical approach may be appropriate: ex vivo–expanded ADSCs for high-priority cases, SVF for standard reconstructions with moderate benefit, and conventional fat grafting when cost or access is limiting.

Oncologic and Safety Considerations
Medium-term oncologic safety data are reassuring; however, they are limited by small event numbers and wide CIs. Differentiated strategies may be warranted—current evidence supports ADSC use in low-risk patients (eg, more than 5 years posttreatment, node-negative) under standard surveillance, whereas caution is advised for higher-risk groups, such as patients with hormone receptor–positive or inflammatory breast cancer.34–36
Mechanistic concerns from preclinical models implicate ADSCs in HGF/c-Met–mediated tumor promotion in certain subtypes,16 especially hormone receptor–positive disease. HGF/c-Met inhibitors have shown limited monotherapy efficacy, but combination approaches are under investigation.17 In this review, clinical recurrence rates did not differ significantly between ADSC and conventional cohorts, and complication rates were similar (18.4% versus 17.2%; RR, 1.07 [95% CI, 0.65 to 1.77]; P = 0.78).29–33

Practical and Regulatory Barriers
Although ex vivo–expanded ADSCs deliver superior outcomes, their broader adoption is constrained by GMP requirements, specialized expertise, high costs, and regulatory oversight.27,28,55 The Food and Drug Administration classifies most ADSC methods as “more than minimally manipulated,” requiring investigational approval; European agencies regulate them as Advanced Therapy Medicinal Products; and some Asian countries offer more defined clinical approval pathways.18

Limitations and Future Directions
This review has several limitations. Protocol heterogeneity among SVF techniques contributed to high statistical heterogeneity in some pooled analyses (eg, I² = 78% for SVF-based retention and I² = 81% for oncologic safety). These findings likely reflect variability in patient populations, ADSC processing protocols, outcome measures, and follow-up durations, underscoring the need for standardized methodologies in future research. The number of high-quality RCTs remains limited, and follow-up durations varied considerably. Evidence for ex vivo–expanded ADSCs is based on a small sample (87 patients from 3 GMP-compliant centers), requiring confirmation in larger, multicenter trials.
Oncologic safety conclusions are restricted by relatively short follow-up and a low recurrence event count, particularly in hormone receptor–positive disease. The predominance of single-center studies and geographic clustering may also limit generalizability.
Future research should prioritize multicenter RCTs using standardized ADSC processing protocols, long-term oncologic surveillance registries, and cost-effectiveness analyses. These efforts will be imperative to ensure the safe and equitable integration of ADSC-enhanced fat grafting into reconstructive practice.

CONCLUSIONS
ADSC-enhanced fat grafting significantly improves volumetric retention (26.8% overall improvement) compared with conventional techniques while maintaining comparable safety. The magnitude of benefit varies substantially between ex vivo–expanded ADSCs (64.6% improvement) and SVF-based methods (17.0%), allowing clinical flexibility based on resource availability and patient-specific factors. Ex vivo–expanded ADSCs yielded the most consistent outcomes; however, current evidence derives primarily from centers with GMP–compliant facilities and requires validation in broader clinical settings.
Medium-term oncologic safety data are reassuring, with no significant difference in recurrence rates observed during the study period. Continued surveillance through cancer registries will be essential to confirm long-term safety, particularly in hormone receptor–positive disease.
ADSC-enhanced fat grafting represents a valuable advancement in breast reconstruction. Current evidence supports its judicious integration into practice with careful patient selection, adherence to standardized protocols, and ongoing outcomes monitoring. Future research should focus on protocol harmonization, multicenter validation, and long-term oncologic follow-up to ensure safe and equitable adoption of this promising technique.

DISCLOSURE
The authors have no relevant financial disclosures or conflicts of interest. No funding was received for this work.

DATA AVAILABILITY STATEMENT
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Supplementary Material