Polyphenol-integrated Carboxymethyl Chitosan Hydrogels with Immunoregulatory Properties Remodeling of Inflammatory Microenvironment for Spinal Cord Injury Repair

Spinal cord injury (SCI) creates an inflammatory microenvironment characterized by immune cell activation and oxidative stress imbalance, which exacerbates secondary damage and impedes neural regeneration. Locoregional strategies that inhibit the infiltration and polarization of inflammatory cells remain largely unexplored for SCI treatment. Here, an immunoregulatory hydrogel (defined as CSGA) was designed and developed by integrating non-covalent and covalent interactions between carboxymethyl chitosan (CS) and gallic acid (GA). Bioinspired by mussels, the functional modules and assembly pattern endowed this polyphenol-based hydrogel with multiple functionalities, including tissue adhesiveness, injectability, self-healing, anti-oxidation, and anti-inflammation, to satisfy complex treatment requirements. The optimal formulation was hierarchically screened based on in vitro properties and in vivo activities. Therapeutically, local treatment with CSGA hydrogel significantly prevented the infiltration of macrophages/microglia and induced a rapid switch from a detrimental (M1) phenotype to a beneficial (M2) phenotype. Importantly, CSGA treatment significantly promoted neural regeneration and attenuated scar formation, thus improving neurological functional recovery and electrophysiological restoration in a contusion SCI model. Consequently, this study constructs a promising platform for the development of a next-generation immunoregulatory hydrogel to improve SCI therapy.