Decellularized Extracellular Matrix Hydrogel With Schwann Cell Conditioned Medium Accelerates Skin Wound Healing in Diabetic Mice

Background: Chronic nonhealing wounds represent a major complication of diabetes mellitus and impose a substantial clinical burden worldwide. Impaired reparative function of Schwann cells (SCs), along with the subsequent loss of paracrine repair signals, has been identified as a critical pathologic driver of delayed diabetic wound healing. Decellularized dermal matrix hydrogels have emerged as promising biomimetic platforms for local factor delivery and tissue regeneration. Nevertheless, the therapeutic potential of combining SC-derived conditioned medium with decellularized extracellular matrix hydrogels (dECMMA) for diabetic wound repair remains unexplored. Materials and Methods: In this study, a photocrosslinkable methacrylated porcine dermal dECMMA loaded with RSC96 SC conditioned medium (dECMMA@RC) was fabricated. The microstructure of the hydrogels was characterized through scanning electron microscopy. In vitro, cytocompatibility, cell proliferation, and migration were evaluated in L929 fibroblasts, and pro-angiogenic capacity was assessed using a human umbilical vein endothelial cell tube formation assay. In vivo, full-thickness skin wounds were established in streptozotocin-induced type 1 diabetic mice. Wound healing outcomes were systematically evaluated by gross observation, histologic staining, immunofluorescence, and quantitative real-time polymerase chain reaction. Results: The dECMMA@RC hydrogel maintained a favorable porous microstructure and exhibited no obvious cytotoxicity. Compared with the control and pure dECMMA groups, dECMMA@RC significantly promoted L929 cell proliferation and migration, as well as capillary-like tube formation of human umbilical vein endothelial cells in vitro. In diabetic mice, dECMMA@RC treatment markedly accelerated wound closure, enhanced reepithelialization, and increased the number of regenerated hair follicles and sebaceous glands. Mechanistic analysis revealed that dECMMA@RC downregulated the mRNA levels of pro-inflammatory cytokines (interleukin-6, tumor necrosis factor alpha), and upregulated the expression of angiogenic markers ( CD31 , VEGF-A ) and neuroregenerative markers (growth associated protein 43, nerve growth factor) in wound tissues. Conclusions: The dECMMA@RC composite hydrogel effectively accelerates diabetic wound healing through the synergistic effects of anti-inflammation, pro-angiogenesis, and neuroregeneration. This strategy provides a novel and feasible approach for the development of bioactive dressings for chronic diabetic wounds.