Efficacy of Stem Cell-Derived Exosomes in Promoting Diabetic Foot Ulcer Healing: A Meta-Analysis of Preclinical Animal Studies.

Abstract

OBJECTIVE: The objective of the study is to systematically evaluate the efficacy and mechanisms of action of stem cell-derived exosomes from various sources (including adipose tissue [AD-MSCs] and bone marrow [BM-MSCs]) in treating diabetic foot ulcers (DFUs) based on preclinical evidence. METHOD: A computerized search was performed across multiple databases including PubMed, CBM, Web of Science, Embase, Wanfang, CNKI, the Cochrane Library, and VIP. The search period covered the period from their inception through December 2024. The search is aimed at identifying all relevant randomized controlled trials (RCTs) using animal models of DFU. Ten studies involving 239 animals were included in the final meta-analysis. Data synthesis and statistical analysis were performed using RevMan 5.4. The risk of bias was assessed with SYRCLE's tool. RESULTS: The pooled results demonstrated that stem cell-derived exosomes significantly promoted wound healing, evidenced by increased wound healing rates on Day 7 (SMD = 8.41, 95% CI: 4.06-12.75, p < 0.001; I= 91%) and Day 14 (SMD = 4.89, 95% CI: 3.63-6.14, p < 0.001; I= 0%). Furthermore, exosome treatment enhanced neovascularization density (SMD = 7.78, 95% CI: 6.04-9.52, p < 0.001), collagen deposition (SMD = 8.59, 95% CI: 2.16-15.03, p < 0.05), and reduced levels of inflammatory markers (TNF-&#x3b1; and CD86). Subgroup analyses revealed that the administration dose was a major source of heterogeneity, with a nonlinear dose-response relationship observed. Funnel plots indicated potential publication bias. CONCLUSION: Stem cell-derived exosomes represent a highly effective preclinical therapeutic strategy for DFU by accelerating wound closure and improving key wound healing parameters. However, the clinical translation of these findings requires further validation due to the high heterogeneity, potential publication bias, and the inherent limitations of animal studies. TRIAL REGISTRATION: ClinicalTrials.gov identifier: CRD420251110272.