Bioactive agarose-based hydrogels with granulated microstructures for accelerating diabetic wound healing

Agarose hydrogels, known for their unique gelling properties and excellent biocompatibility, have been widely utilized in bio-applications. However, the inherent bioinert nature of agarose limits its practical application. In this study, we report a novel strategy to prepare bioactive agarose-based hydrogels with granulated microstructures. By leveraging amine-epoxy "click" chemistry and in situ formation of poly(amino alcohol ethers) prepolymers with ligninsulfonate (LS) complexation-mediated phase separation, we developed a series of agarose-based hydrogels (AMS) that exhibit promising properties. These hydrogels exhibit cationic features, well-defined granulated microstructures, excellent hemocompatibility and cytocompatibility. Notably, the granulated microstructures not only include well-defined hydrophobic compartments for drug encapsulation and inherent amine groups for cytophilicity, but also are capable of antioxidative properties. Furthermore, resveratrol-loaded AMS3 hydrogel shows significant potential in regulating macrophage responses, promoting angiogenesis, and accelerating diabetic wound healing both in vitro and in vivo. Overall, this study capitalizes on cationic features, well-defined granulated microstructures, and antioxidative properties synergistically and integrates them into the development of advanced bioactive agarose-based materials, which provides a new design paradigm for bioactive agarose-based hydrogels, offering a promising approach for applications in drug delivery and chronic wound healing.