Dual-Cross-Linking Alginate-Based Hydrogels with Borate Ester for Antioxidant Therapy of Diabetes Ulcer Wounds

Diabetic foot is a difficult-to-cure chronic wound. Scavenging excessive reactive oxygen species (ROS) generated in ulcer wound tissue and cells is an effective therapy to accelerate wound healing. This study investigated the performance of a dual-cross-linked alginate-based hydrogels containing antioxidants in accelerating wound healing of diabetic ulcers. A photopolymerizable quaternary ammonium salt of phenylboronic acid pinacol ester was synthesized through quaternization and then mixed with sodium alginate. In the presence of a water-soluble photoinitiator and cross-linker, physically and chemically dual-cross-linked, semi-interpenetrating, biomass-based hydrogels were prepared. In vitro antioxidant tests demonstrated that the synthesized quaternary ammonium salt of phenylboronic acid pinacol ester exhibited excellent antioxidant capacity. In vitro cellular experiments indicated that the hydrogels possessed good biocompatibility. Furthermore, and in vivo experiments showed that compared to the blank and control groups, this antioxidant hydrogels had the ability to promote chronic wound healing. Comprehensive analyses showed that the ABE hydrogel scavenges >90% of ABTS radicals, markedly reduces intracellular ROS in H₂O₂-injured L929 cells and restores their viability. In diabetic mice, full-thickness wounds closed to 8.5% of original area within 12 days (vs 39% blank, 16.7% control). Histology revealed dense, well-aligned collagen, the highest Masson-positive area, and significantly lower TNF-α/IL-6 together with elevated TGF-β, CD31, VEGF, and β-FGF, confirming potent wound healing efficacy. The hydrogels feature a simple preparation method, good biocompatibility, and effective promotion of chronic wound healing, highlighting their high potential for clinical translation. It also provides insights into the treatment of other ROS-related diseases.