Hyaluronic acid-based responsive hydrogel with sequential drug release: targeting oxidative stress and angiogenesis to accelerate diabetic wound healing

The healing of diabetic wounds is impaired by persistent Infection, oxidative stress, vascular dysfunction and restricted regenerative capacity. While functional hydrogels enable localized delivery of drugs, achieving stage-specific drug release aligned with the healing phases remains a significant challenge. To address this, a novel responsive HSGI hydrogel was successfully constructed based on phenylboronic acid-modified hyaluronic acid methacryloyl and sodium alginate methacryloyl, in which gallic acid-grafted ε-poly-l-lysine (EG) and icariin-grafted ε-poly-l-lysine (EI) were incorporated via borate ester bonds and electrostatic interactions. HSGI hydrogel exhibited strong tissue adhesiveness, rapid hemostatic performance, good Antibacterial and antioxidant activities, as well as the capabilities to promote angiogenesis and matrix secretion. In a diabetic rat model, HSGI hydrogel enabled spatiotemporal regulation across different stages of diabetic wound healing: in the early phase, the excellent adhesion of HSGI promoted wound hemostasis and then EG was released upon exposure to Reactive Oxygen Species via cleavage of borate ester bonds, thereby alleviating oxidative stress and preventing Bacterial infection. During the mid and late stages, the continuously released EI synergized with EG for antioxidant and Antibacterial effects, and subsequently promoting angiogenesis, matrix secretion, and tissue remodeling. This multifunctional hydrogel opens up a new avenue for the treatment of diabetic wounds.