Modified chitosan-based hydrogel for sustained release of tetramethylpyrazine and polydatin to promote diabetic wound healing

Diabetic wound healing remains a clinical challenge due to impaired repair, often leading to complications such as infection and tissue necrosis. Here, we present a novel dual-drug-loaded hydrogel formulated using oxidized hyaluronic acid (OHA) and catechol-modified chitosan (CS-pC). This system is engineered to enhance the local bioavailability of polydatin (PD) and delay the release of tetramethylpyrazine (TMP), achieving superior release performance and synergistic effects compared to single-drug formulations; thus, this system enables synergistic modulation of the target inflammatory microenvironment and promotes angiogenesis, thereby facilitating effective diabetic wound healing. The hydrogel exhibited a porous structure (100–200 μm) and moderate swelling (119.67% ± 6.66% at 24 h). Approximately 80% of TMP and PD were sustainably released within 48–52 h, aligning with clinical dressing intervals. In diabetic mice, it accelerated wound closure to 98.01% within 14 d—20.63% higher than controls. Most notably, the hydrogel significantly promoted wound healing, as evidenced by: (1) upregulation of vascular endothelial growth factor (VEGF) and α-SMA expression (RT-qPCR: 3.2-fold for VEGF and 3.7-fold for α-SMA vs control); (2) enhanced cell migration (3.1-fold vs control) and angiogenesis (1.3-fold vs control); and (3) increased expression of CD31, TGF-β1 and collagen types I and III (IHC). These results demonstrate the therapeutic potential of the OHA/CS-pC/TMP/PD hydrogel for diabetic wound healing.