Abstract

Persistent inflammatory response and impaired angiogenesis both contribute to delayed diabetic wound healing. Combined counteracting inflammation and facilitating angiogenesis showed considerable potential in diabetic wound management. Herein, a natural collagen-based thermosensitive hydrogel encapsulated with costunolide and copper ions was constructed. The collagen was cross-linked with EDC (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide)/NHS (N-hydroxysuccinimide) and soaked with ammonium sulfate to augment its mechanical strength. The composite hydrogel demonstrated a thermosensitive release of costunolide and copper ions (in response to physiological temperature), coupled with remarkable biocompatibility. The hydrogel system significantly promoted the proliferation of fibroblasts and endothelial cells and concurrently enhanced the migration of endothelial cells in vitro . Meanwhile, the composite hydrogel exerted an anti-inflammatory effect by reducing the expression of pro-inflammatory cytokines in lipopolysaccharide (LPS)-activated macrophages. Moreover, treatment with the multifunctional hydrogel resulted in an improved inflammatory microenvironment and enhanced angiogenesis, which subsequently promoted cell proliferation, collagen deposition and re-epithelialization, and ultimately accelerated wound healing in a diabetic rat model. In conclusion, the natural collagen-based thermosensitive multifunctional hydrogel, as an advanced wound dressing, offers a novel therapeutic delivery strategy for the treatment of diabetic wounds.