Extracellular vesicles secreted by bone marrow stem cells mediate angiogenesis for the treatment of diabetic ulcers: A systematic review and meta-analysis of preclinical studies.

Background: Diabetic ulcers (DUs) typically occur in patients with vascular diseases and diabetes. Extracellular vesicles secreted by bone marrow-derived stem cells (BMSC-EVs) represent a cell-free therapy that has emerged as a promising alternative for treating DU, especially due to significant advancements in the understanding of their role in promoting angiogenesis; however, their application in DU treatment remains in the preclinical stage, and their effectiveness is still uncertain. Therefore, we conducted this meta-analysis to evaluate the therapeutic efficacy of BMSC-EVs in treating DU and to expedite the clinical translation of BMSC-EV therapy for DU. Methods: We conducted a comprehensive search of PubMed, Cochrane Library, MEDLINE, EMBASE, China National Knowledge Infrastructure (CNKI), Wanfang Database, VIP Database, and our self-constructed database of Chinese Biomedical Literature up to May 2023 to identify preclinical studies related to the therapeutic use of extracellular vesicles secreted by bone marrow-derived stem cells for treating diabetic ulcers. Outcome measures included wound healing rate, neovascularization density, a-sma, and CD31. RevMan 5 software was employed for all statistical analyses. Results: In this meta-analysis, a total of 11 studies involving 103 animals were identified. The pooled analysis indicated that BMSC-EV treatment showed a superior wound healing rate compared to that of the control group (SMD = 1.06, 95% CI [0.52, 1.60], P = 0.0001). In the subgroup analysis, EV combined with new materials or drug therapy performed better than the sole injection of extracellular vesicles (SMD = 1.85, 95% CI [0.87, 2.82], P < 0.00001). BMSC-EV treatment also resulted in a higher number of neovascular structures compared to the control group(SMD = 5.80, 95% CI[0.89,10.71], P = 0.006). In the subgroup analysis, EV combined therapy showed a significant difference in the number of blood vessels compared to the sole injection of extracellular vesicles (SMD = 4.90, 95% CI[2.64,7.15], P < 0.00001). However, BMSCs-EV treatment did not demonstrate any statistically significant difference in the angiogenesis-related indicators CD31 and α-SMA compared to the control group (SMD = 1.61, 95% CI[-0.51,3.74], P = 0.14). Conclusion: According to the current meta-analysis, BMSC-EV therapy can enhance the healing of diabetic ulcers and promote wound angiogenesis, particularly when used in combination with novel dressings or other drugs, which further accelerates the healing process of diabetic ulcers. To establish the most effective parameters for EV treatment in diabetic ulcers, future research should promptly progress into clinical trials.