Thermosensitive porcine acellular dermal matrix hydrogel loaded with umbilical cord mesenchymal stem cell-derived exosomes for diabetic wound healing repair

Patients with type II diabetes mellitus (DM) often experience severely impaired skin wound healing due to hyperglycemia-induced microvascular dysfunction, peripheral neuropathy, and persistent inflammation, creating an urgent need for new therapeutic strategies. Here, we combined extracellular exosome technology and sol-gel technology to construct a thermosensitive porcine decellularized extracellular matrix (dECM) hydrogel loaded with umbilical cord mesenchymal stem cell-derived exosomes (EXO) for achieving effective type II diabetic wound healing. Results showed that EXO exhibited a typical cup-shaped morphology (average size:122.3 nm) and specific protein expression. Porcine acellular dermal matrix (ADM) had a 94.3 % decellularization rate. The prepared hydrogel demonstrated good injectability, thermosensitive gelation (rapid at 37 °C), porous structure, controllable degradability, and sustained EXO release (≈90.65 % within 72 h). In vitro, the dECM contained EXO (dECM@EXO) hydrogel was non-cytotoxic, promoting L929 cell survival, HaCaT cell proliferation/migration (24-h rate: 85.38 %), and tube formation of endothelial cells. In type II diabetic rats with full-thickness skin wounds, its 14-day healing rate was 97.4 ± 2.6 % (significantly higher than other groups). Immunohistochemical results revealed that dECM@EXO increased the density of CD31⁺ blood vessels and the proportion of CD206⁺ M2-type macrophages, decreased the expression of CD68⁺ macrophages and HSP70, and enhanced the proliferation rate of Ki67⁺ cells. Transcriptome sequencing analysis demonstrated that dECM@EXO upregulated genes related to pathways such as PI3K-Akt and ECM-receptor interaction to promote cell proliferation and angiogenesis, while downregulating genes related to insulin resistance and glucose metabolism to improve the local microenvironment. Through the synergistic effect of "extracellular matrix hydrogel carrier - exosomes", this study promotes diabetic wound healing from multiple dimensions including anti-inflammation, angiogenesis, and metabolic regulation, providing a new strategy for the clinical treatment of DM wounds.