We searched the following databases: PubMed, EMBASE, Scopus, Web of Science, Cochrane Central Register of Controlled Trials, and Latin American & Caribbean Health Sciences Literature (LILACS) from inception to October 2024, using a well-developed search strategy that included terms such as “ulcer”, “adipose stem cell”, and “wound”, along with their synonyms. We conducted a manual search of references in eligible studies and ongoing clinical trials listed in trials registries (ClinicalTrials.gov) and conference proceedings. The complete search strategy can be found in the Appendix 1.

During preliminary screening, two independent authors (L.S. and N.A.) reviewed articles for inclusion based on the title, abstract, and methods of each article. Full-text articles were retrieved in the second round of screening, and articles were included based on the following eligibility criteria: clinical trials involving (I) individuals with any form of wounds or scars subjected to various fat derivative treatments and (II) participants of all genders and age groups. Studies involving animals, laboratory experiments, in vitro research, conference presentations, reviews, and book chapters; as well as study designs such as case reports, case series, and cross-sectional studies; and non-English studies were excluded. Any discrepancies were resolved through discussion with a third reviewer (C.P.C).

A uniform data extraction form was developed, and two independent authors (L.S. and N.A.) extracted pertinent data from each eligible study. The extracted information included the following domains: reference (first author and year of publication), study design, sample size, demographic characteristics (i.e., age and gender), intervention, control, success of the intervention (wound healing), and observed adverse events post-intervention. Given the heterogeneous nature of the studies included, conducting a meta-analysis was not feasible. As a result, a qualitative synthesis approach was adopted, and these studies' findings were compared descriptively.

We used the Cochrane risk-of-bias tool for randomized trials (RoB v2) to conduct a quality assessment of the included studies (17).We evaluated the following domains: the randomization process, deviations from intended interventions, missing outcome data, outcome measurements, and selection of the reported results.

The database search yielded 589 records. After removing duplicates, 199 studies underwent an initial screening based on titles and abstracts. Of these, 174 did not meet our inclusion criteria. Full-text copies of 23 studies were then obtained for further evaluation, and two ongoing trials were assessed using published data on clinical registries. Through a collaborative review by all authors, 7 studies were excluded, leaving 18 studies that met the inclusion criteria for this systematic review (refer to Figure 1) (17–34).

The overall assessment of the risk of bias for the 16 randomized clinical trials included in this review, conducted using the Cochrane risk-of-bias tool (ROB v2), yielded the following results: -

Eight studies were assessed as having a low risk of bias (17, 20, 26, 27, 29–32).

In terms of selection bias, all the included studies exhibited a low risk (see Table 1) (17–32).

By searching clinical trial registries, two ongoing randomized clinical trials were identified. The first study explores the use of fat grafting in treating Post-Mastectomy Radiation Injury in breast cancer patients (33), while the other aims to assess the efficacy of microsized adipose tissue in treating diabetic foot ulcers (Refer to Table 2) (34).

Table 3 provides an overview of the demographic characteristics of patients across all clinical trials. Our review included 537 patients, excluding those lost to follow-up, with an age range spanning from 15 to 78 years. The studies included a wide variety of wound and ulcer types: six studies focused on the effects of adipose tissue treatments on chronic lower leg ulcers (19, 21, 23, 25, 31, 32), while four examined post-surgical and traumatic scars (17, 22, 24, 29), including two that specifically addressed post-reduction mammoplasty scars (22, 24). Additionally, two trials explored treatments for acne scars (26, 27), and one study delved into the role of adipose tissue and its derivatives in post-laser resurfacing scars (18). Furthermore, two clinical trials centered on patients with ischemic digital ulcers due to systemic sclerosis (20, 30), and one trial focused on patients with superficial and deep dermal burn wounds (28).

The first randomized clinical trial we included was published in 2012 (17). The largest number of studies, totaling nine, was published in the years 2022–2023 (24–32). Among these, three studies were conducted in Italy (17, 19, 20), two in the UK (21, 25), two in Egypt (23, 28), and two in Iran. The remaining studies were conducted in China (18), Turkey (22), the Netherlands (24), South Korea (29), Mexico (30), Germany (31), and Indonesia (32).

Our review included two RCTs investigating the use of ADSC-CM in wound healing (18, 32). Zhou et al. recruited patients with scars following anti-photoaging therapy—ablative fractional carbon dioxide laser resurfacing (FxCR)—and compared adipose-derived stem cell-conditioned medium (ADSC-CM) to Dulbecco's Modified Eagle Medium (DMEM) without fetal bovine serum (FBS). Alinda et al. investigated the effect of using topical ADSC-CM on treating chronic plantar ulcers after Leprosy, comparing it to Framycetin gauze dressing (Refer to Table 4).

Seven RCTs included in our review investigated the use of stromal vascular fraction in the management and healing of wounds, scars, and ulcers (19, 23, 24, 26, 27, 29, 30).

We included three studies investigating the effect of using Fat Grafting with Platelet-Rich Plasma (FG + PRP) in the management of scars and ulcers (17, 21, 25). Cervelli et al. explored the effect of (FG + PRP) on traumatic scars by dividing the patients into three groups: two intervention groups receiving (FG + PRP) alone and (FG + PRP) with non-ablative resurfacing laser therapy, respectively, while the control group received non-ablative resurfacing laser therapy alone (17). Smith et al. and Nolan et al. studies, two papers reporting the results of the same clinical trial, investigated the role of (FG + PRP) in the healing of diabetic foot ulcers (21, 25). The trial included three arms: FG alone, (FG + PRP), both compared with standard podiatry care as the control (Table 4) (21, 25).

In our systematic review, we included four clinical trials investigating the use of fat graft injection in the wound healing process (20, 22, 28, 31). Del Papa et al. compared the effects of fat injection to normal saline injection on the healing of ischemic digital ulcers in systemic sclerosis patients, while Thamm et al. studied the effects of the same intervention and control on chronic ulcer wounds, including venous, arterial, mixed arterial–venous, diabetogenic, and compressive ulcers (20, 31). Both Kemaloğlu et al. and Abouzaid et al. examined the effects of using nanofat (22, 28). Kemaloğlu et al. divided post-reduction mammoplasty patients into three groups: the first intervention group received fat injection, the second group received nanofat injection, while the control group did not receive any additional post-surgical treatment for scars (22). On the other hand, Abouzaid et al. combined both fat injection and nanofat dressing as interventions in patients with superficial and deep dermal burn wounds, comparing them to conventional dressing (Table 4) (28).

Wound persistence significantly impacts individuals' quality of life and increases morbidity and mortality rates. Regenerative medicine is a promising approach, offering opportunities to accelerate and enhance the process of wound healing. The evolving field of regenerative medicine coupled with personalized medicine could foster the advancement of wound healing therapies (35).

Our systematic review included 16 randomized clinical trials and two ongoing studies that evaluated safety and efficacy of adipose tissue and fat derivatives for various wounds in 537 patients. Different types of adipose tissue and fat derivatives were used across the studies; seven studies used adipose-derived stromal vascular fraction (19, 23, 24, 26, 27, 29, 30), two studies used adipose derived stem cells-conditioned media (18, 32), two studies used fat grafting (20, 22, 28, 31), and two studies used fat grafting with platelet rich plasma (17, 21, 25).

Our findings demonstrated that adipose tissue and fat derivatives significantly enhance wound healing parameters, reduce pain, and improve cosmetic appearance, patient satisfaction and health-related quality of life compared to conventional treatments.

The majority of studies reported no serious adverse events related to intervention, indicating a favorable safety profile. Mild and transient adverse events like perilesional dermatitis, post-intervention local infection, and mild localized pain were reported in twelve patients across different interventions (19, 21, 23, 25, 29, 31).

It is critical to note that multiple “positive” outcomes reported were derived from clinical trials that we labelled as having high or some concerns risk of bias via our risk assessment, especially in the domains of deviation from the intended interventions, missing outcome data, and outcome measurement domains. This highlights the possibility that observed benefits may be overestimated. Thus, the strength of evidence surrounding adipose-derived therapies promising potential remains limited due to methodological weaknesses, caution should be taken while interrupting these findings.

Easier accessibility from subcutaneous liposuction in large numbers and the absence of ethical and political issues concerning the collection process make adipose-derived stem cells superior over other stem cells (36, 37). ADSCs are collected, isolated and then cultured mostly under standard conditions. Conventionally, this involves Dulbecco's modified Eagle medium (DMEM) with 10% fetal bovine serum (FBS) and 1% antibiotics, maintained under 37°C and 5% CO2 in monolayer dishes (37). After 48–72 h of in vitro culture, ADSC-CM is collected via centrifugation (38).

Two mechanisms of action have been proposed to explain the role of ADSCs in wound healing, mainly by direct differentiation into skin cells and through paracrine secretion of growth factors, immune factors, chemokines and exosomes (39). Other studies have demonstrated the role of ADSC-CM in stimulating the migration of dermal fibroblasts and keratinocytes after wounds, reducing the wound size and accelerating the reepithelialization process at the wound edges (40–42).

Our review highlighted the positive effects of using ADSC-CM in treating superficial scars and chronic ulcers by reducing erythema, hyperpigmentation, and ulcer size and depth (18, 32). Our findings agree with Heydari et al., which investigated the efficacy of Mesenchymal stromal cell (MSC)-conditioned medium (CM) on skin wound healing in vitro models (43). Their findings showed the efficacy of all types of MSC-CM, including ADSC-CM, in promoting wound healing (43). This alignment suggests that ADSC-CM's positive results are not only observed in vitro but also in vivo, which helps guide further clinical studies for personalized use of ADSC-CM in skin wounds, especially chronic ulcers.

Despite the lack of actual adipose stem cells, limiting the potential of direct cell replacement, and the challenges due to the variability in preparation compositions, ADSC-CM has multiple advantages in clinical practice. ADSC-CM can be directly applied to the skin without causing immune reactions, unlike allogeneic ADSCs, reflecting the safety profile of ADSC-CM (18). Additionally, the feasibility of mass manufacturing using well-monitored laboratory systems and storage without the use of toxic cryopreservatives are further advantages (44).

ADSVF is composed of smooth muscle cells, fibroblasts, endothelial cells, pericytes and ADSCs acquired through washing, enzymatic digestion, filtration, and centrifugation of adipose tissue (11, 45). Although the proposed mechanism of action is similar to ADSCs, the presence of additional cellular components in ADSVF augments the mechanical framework of repaired tissues and help in the regeneration of damaged tissues by secreting cytokines (46, 47).

Our review covered seven clinical trials investigating ADSVF's role in skin wound healing across various conditions including chronic ulcers, post-traumatic and surgical scars, acne scars, and systemic sclerosis digital ulcers (19, 23, 24, 26, 27, 29, 30). The overarching finding is that ADSVF consistently promotes significant improvements in wound healing outcomes regardless of the clinical assessment parameters used.

In scar management, our findings are consistent with Mbiine et al. and Stachura et al., where they investigated the role of ADSVF in the management of hypertrophic, keloid, and scar treatment (48, 49). Both studies demonstrated the efficacy of ADSVF in improving scar appearance, similar to our findings (48, 49). Similarly, studies on ADSVF in breast surgery were also consistent with our findings demonstrating better outcomes and increased patient satisfaction (50, 51). However, Li and Chen (2021) found no significant differences between ADSVF and conventional fat grafting, especially in terms of fat survival rate, mainly due to the heterogeneity of methods used for ADSVF extraction in the included studies (52).

A recent systematic review, investigating the efficacy and safety evaluation of autologous fat transplantation, platelet-rich plasma, and stromal vascular fraction in acne scars, found that 73% of cases showed excellent improvement, indicating the effectiveness of ADSVF (53). Similarly, two studies in our review indicated significant improvement in scar variables and scar sonographic measurements (26, 27).

Cao et al. studied various adipose tissue and fat derivatives in digital ulcer management in patients with systemic sclerosis. ADSVF showed the least change in terms of pain score and similar effects on wound healing to ADSCs and autologous fat (47). In our review, the ADSVF group showed significant improvement in the number of digital ulcers, Raynaud phenomenon, quality of life, and pain assessment. However, ADSVF was not compared to other adipose tissue and fat derivatives therapeutic modalities (30, 47).

Compared to ADSCs, ADSVF has an easy acquisition process and a variable cellular composition which contributes to better healing outcomes (23, 54, 55). However, limited expansion ability and wide variability of extraction methods are the primary challenges in clinical use of ADSVF (52).

FG consists of mature adipocytes, preadipocytes, stem cells and multiple growth factors (11). The process of preparing FG includes, selecting a suitable donor site, typically the inner thighs and lower abdomen due to the high amount of viable adipocyte volume compared to other areas, followed by fat harvesting, processing and injection (56). While the primary mechanism of action of FG is volume enhancement, it also aids in tissue damage and improves the appearance of scars through various properties of adipocytes, stromal components and growth factors.

FG is less likely to cause an immunogenic response and is easier to process than ADSCs (57, 58). However isolated ADSCs or ADSVF have the regenerative potential of conventional FG without the need for large volume fat transfer (59).

Our review included four clinical trials across a wide variety of scar and wound types: ischemic digital ulcers in systemic sclerosis patients (20), chronic ulcers (arterial, venous, mixed arteriovenous, diabetogenic, and compressive types) (31), post-reduction mammoplasty scars, and superficial-deep burn wounds (22, 28). Patients with ischemic digital ulcers and burn wounds had better outcomes with FG treatment (20, 28), while patients with chronic ulcers and post-surgical scars had no significant improvement in wound healing parameters compared to control groups (22, 31). The broad range of wounds included in our review and the insufficient studies in literature for analysis make it difficult to draw conclusions on the effectiveness of FG in wound healing. These results were consistent with Malik et al. systematic review on the use of autologous fat grafting in the treatment of acute and chronic cutaneous wounds (59).

A recent systematic review investigated adipose-derived stem cells and their derivatives in burn treatment, was in line with our findings regarding the effectiveness of fat derivatives in vitro, but further clinical studies are needed (60). The addition of platelet-rich plasma (PRP) to adipose tissue and fat derivatives as therapeutic modalities is another emerging area of study in the field of regenerative medicine. PRP is used as an adjuvant to FG due to its role in increasing fat survival and potentiating its regenerative capabilities (61).

Our review found promising results regarding the use of PRP with FG for wound healing, especially concerning scar healing parameters and health-related quality of life (17, 21, 25). However, despite the positive outcomes, a final conclusion requires further studies sufficient for formal analysis. This is consistent with Smith et al. (62), which could not confirm PRP's benefit with FG for wound healing, due to the lack of standardized procedure protocols (62).

The positive outcomes reported with adipose tissue and fat derivatives in preclinical and clinical studies support a promising future for their use in regenerative medicine in general and wound healing specifically. However, concerns still exist regarding publication bias and underreporting of equivocal and negative results, an issue that has been raised before (59, 63). By examining multiple therapeutic modalities, including adipose tissue and fat derivatives, our review provides a holistic overview of adipose tissue's therapeutic potential, ensuring practitioners and researchers are well-informed about the extent of available strategies, their respective benefits, limitations, and gaps to address in future research. The development of standardized protocols for adipose tissue and fat derivative isolation, characterization, and application, as well as the endpoints investigated, is important to facilitate comparison across studies. Furthermore, large-scale randomized clinical trials comparing adipose tissue and fat derivatives to conventional treatments in skin wounds are needed, and trials aiming to compare the different adipose tissue modalities are encouraged. Additionally, investigating long-term safety profiles is crucial as well.

Our review showed that adipose-derived therapies illustrated benefits across different wound types. Nevertheless, the significant heterogeneity among the included studies; differences in adipose-derivatives types, wound types and underlying etiologies, chronicity, preparation techniques and delivery protocols, as well as outcomes assessment tools—limited our ability to conclude a direct head-to-head comparison between subgroups.

However, particular patterns are noted: ADSC-enriched therapies were promising in the treatment of chronic ischemic ulcers through their angiogenic and immunomodulatory mechanisms, while fat grafting combined with PRP appeared more beneficial in scar remodeling. Such observations can be regarded as hypothesis-generating for future high quality RCTs that will help provide effective subgroup comparisons. The development of standardized protocols for adipose tissue and fat derivative isolation, characterization, and application, as well as the endpoints investigated, is important to facilitate comparison across studies. Furthermore, large-scale randomized clinical trials comparing adipose tissue and fat derivatives to conventional treatments in skin wounds are needed, and trials aiming to compare the different adipose tissue modalities are encouraged. Additionally, investigating long-term safety profiles is crucial as well.

Although our study is the first to our knowledge to present an overview of the current landscape of adipose tissue and fat derivative therapeutics in wound healing and scar management, a couple of challenges limit the generalizability of findings. The heterogeneity of the clinical trials in terms of procedure protocols, endpoints, and outcome measurements, poses a significant challenge to conducting a formal analysis. Definitive conclusions are not possible, as large-scale studies with high quality and low risk of bias are required. Furthermore, five included studies exhibited a high risk of bias, particularly in the domain of deviation from intended interventions and outcome measurement domain. Despite the fact that we provide comprehensive study-level extraction tables and supplementary tables, the extensive heterogeneity of studies included prevented us from summarizing findings in terms of a unified effect direction or pooled estimate. We believe that such aggregation would risk presenting specific results that would be misrepresenting and misleading.

Additionally, the exclusion of non-english studies may introduce language bias to our review, further systematic reviews should attempt to include multilingual literature to provide more comprehensive review. These methodological limitations may have introduced bias into the reported effects and should be considered when interpreting our findings.

The results of our review highlights two sides of adipose-derived therapies benefits; (1)Functional outcomes including;(pain reduction, wound healing and recurrence reduction), (2) Cosmetic and aesthetic outcomes like; (pigmentation reduction, and scar quality).Still, the clinical benefits differ based on wound type and intervention used. Preliminary evidence concluded from our review suggests that ADSVF-enriched interventions showed promise in chronic ulcers, while fat grafting—especially when combined with PRP was associated with better functional outcomes in scars treatment.