Injectable hydrogel harnessing foreskin mesenchymal stem cell-derived extracellular vesicles for treatment of chronic diabetic skin wounds

Chronic skin wounds are a serious complication of diabetes with a high incidence rate, which can lead to disability or even death. Previous studies have shown that mesenchymal stem cells derived extracellular vesicles (EVs) have beneficial effects on wound healing. However, the human foreskin mesenchymal stem cell (FSMSCs)-derived extracellular vesicle (FM-EV) has not yet been isolated and characterized. Furthermore, the limited supply and short lifespan of EVs also hinder their practical use. In this study, we developed an injectable dual-physical cross-linking hydrogel (PSiW) with self-healing, adhesive, and antibacterial properties, using polyvinylpyrrolidone and silicotungstic acid to load FM-EV. The EVs were evenly distributed in the hydrogel and continuously released. In vivo and vitro tests demonstrated that the synergistic effect of EVs and hydrogel could significantly promote the repair of diabetic wounds by regulating macrophage polarization, promoting angiogenesis, and improving the microenvironment. Overall, the obtained EVs-loaded hydrogels developed in this work exhibited promising applicability for the repair of chronic skin wounds in diabetes patients. A multifunctional extracellular vesicles-hydrogel complex comprised of a novel foreskin mesenchymal stem cells (FSMSCs)-derived extracellular vesicles can realize immunomodulation with macrophages reprogramming and inducing angiogenesis, resulting in effectively chronic wound repair and hair growth in a diabetic wound model via in situ hydrogel injection. This study not only provides new information on the role of the FSMSCs-derived extracellular vesicles in immunoregulation and tissue regeneration but also provides an efficient strategy to achieve non-invasive and precise skin repaire. [Display omitted]