Perinatal tissue-derived extracellular vesicles for diabetic wound healing: a translational proposal

Diabetic foot ulcers (DFUs) represent one of the most frequent complications of diabetes and constitute a major clinical challenge due to the impaired healing capacity of diabetic patients. They are associated with high recurrence and amputation rates, leading to a substantial social and economic burden. This study explores the use of extracellular vesicles (EVs) isolated from human mesenchymal stem cells (hMSCs) derived from afterbirth tissues as a poorly immunogenic, cell-free therapeutic strategy to promote DFU healing [1-3]. Thirty healthy women undergoing caesarean section were enrolled, and primary hMSCs were obtained from amniotic membranes and umbilical cords through enzymatic and/or mechanical processing. EVs were isolated from serum-free conditioned media using tangential flow filtration (TFF) or ultracentrifugation and characterized by Nanoparticle Tracking Analysis, showing a size distribution mainly between 100 and 300 nm. Western blotting and proteomic analyses confirmed the presence of EV-associated markers and proteins related to vesicle biological activity and structure. To evaluate biological activity, human dermal fibroblasts were cultured under inflammatory and hyperglycemic conditions mimicking DFUs and treated with 20 µg EVs. MTS and scratch assays demonstrated increased cell viability, migration, and motility in EV-treated fibroblasts compared with untreated controls. In parallel, a combined approach using EVs embedded in gellan gum modified with ethylenediamine (GG-EDA) scaffolds enriched with lipoic acid and elastin was assessed. Preliminary in vivo studies in a limited number of female mice indicated that the scaffolds were biocompatible, did not impair wound repair, and that EV-loaded scaffolds enhanced wound closure within 48-72 hours. Although additional studies are required to validate these findings, our results highlight the therapeutic potential of hMSC-derived EVs, either alone or in combination with biocompatible scaffolds, as a promising translational strategy for DFU treatment.