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. Polydatin(PD), a natural bioactive compound extracted from the rhizomes of Polygonum cuspidatum and other plant parts, exhibits diverse biological activities. To enhance the local bioavailability and therapeutic efficacy of PD, it was combined for the first time with tetramethylpyrazine (TMP) and co-encapsulated in a hydrogel for sustained release, resulting in improved release performance and a synergistic effect outperforming single-drug formulations. In this study, we loaded TMP and PD for the first time into a a hydrogel composed of catechol-modified chitosan and oxidized hyaluronic acid, systematically evaluating its microstructure, swelling, degradation, chemical composition, and drug-release profile. The hydrogel exhibited a porous structure (200-400 μm) and moderate swelling (286.00 ± 6.56% at 24 h). Approximately 80% of TMP and PD were sustainably released within 48-52 h, aligning with clinical dressing intervals. In vitro, the hydrogel promoted Human umbilical vein endothelial cells (HUVECs) migration, NCTC clone 929 (L929) proliferation, and tube formation.In diabetic mice, it accelerated wound closure to 98.1% within 14 days-20.63% higher than controls. These results highlight the anti-inflammatory and pro-angiogenic properties of the OHA/CS-pC/TMP/PD hydrogel, demonstrating its therapeutic potential for diabetic wound healing.