ROS-Responsive Antioxidant Hydrogel with Immunomodulatory Activity for Promoting Diabetic Wound Healing

The accumulation of reactive oxygen species (ROS) in the microenvironment of diabetic wounds can trigger oxidative stress and hinder wound healing. This study developed a novel ROS-responsive antioxidant hydrogel relying on boronated ester bond. GMOP/TA hydrogel is constructed using methacrylic acid modified gelatin (GelMA) and phenylboronic acid modified oxidized hyaluronic acid (OHA-PBA) as the crosslinking framework, with tannic acid (TA) loaded as the active antioxidant component. GelMA and OHA-PBA crosslink through covalent bond and Schiff base, and the reversible properties of their imine and boronate ester groups enables responsive TA release under high ROS conditions. GMOP/TA hydrogel exhibits suitale mechanical properties, excellent biocompatibity and ROS-responsive antioxidant capabilities. In vivo evaluation results show that this hydrogel can effectively alleviates oxidative stress, accelerating cell migration, proliferation, and angiogenesis. Transcriptome sequencing analysis further revealed that its pro-healing effects is mechanistically associated with key signaling pathways, especially through PI3K-AKT, PPAR signaling pathway to facilitate cell proliferation and suppress inflammation. Overall, the hydrogel provides a straightforward but effective platform for chronic diabetic wound healing.