A carboxymethyl chitosan-based responsive dual-crosslinked hydrogel loaded with diosmetin for traumatic wound healing

Traumatic wounds, characterized by irregular geometries and intricate microenvironments, present a formidable therapeutic challenge wherein tissue regeneration is severely impeded by bacterial invasion, oxidative stress, alongside persistent inflammation. Traditional debridement, inherently invasive in nature, inevitably inflicts collateral damage on healthy tissues while failing to provide sustained therapeutic intervention. Herein, an intelligent pH-responsive dual-crosslinked hydrogel (CODEXD) encapsulating the bioactive flavonoid diosmetin (DIO) is engineered based on CMCSMA and oxidized dextran (ODex). The integration of dynamic Schiff base linkages and photo-initiated free radical polymerization endows the system with excellent injectability and in situ gelation capabilities, while simultaneously enabling on-demand drug release responsive to the bacterial acidic microenvironment. In vitro assessments substantiate that the hydrogel exhibits potent antibacterial, anti-inflammatory, and antioxidant, effectively orchestrating the phenotypic polarization of macrophages from a pro-inflammatory M1 state to a pro-healing M2 state. In vivo evaluation using a C57BL/6 mice infected full-thickness skin defect model demonstrates that CODEXD significantly accelerates wound closure by promoting angiogenesis and enhancing collagen deposition. Overall, the developed hydrogel offers a promising therapeutic strategy for the effective management of traumatic wounds.