Multifunctional injectable hydrogel with Zn-metformin coordination for synergistic anti-infection, antioxidant, and osteogenic therapy in periodontitis

Periodontitis, a chronic inflammatory disease induced by pathogenic microorganisms. Effective management requires the elimination of plaque biofilms, the suppression of oxidative stress, and the regeneration of periodontal bone. Nevertheless, current treatments are often constrained by inadequate debridement of complex periodontal pockets, potential adverse effects, and emerging antibiotic resistance. To address these deficiencies, this work develops an injectable protocatechuic acid-grafted carboxymethyl chitosan hydrogel incorporating Zn-Metformin coordination (PgC@ZM). This hydrogel targets the complex pathological microenvironment of periodontitis by integrating the intrinsic antibacterial activity of carboxymethyl chitosan and zinc ions, osteogenic potential of metformin, and the potent antioxidant capacity of protocatechuic acid. Cross-linked by π-π stacking and H-bonding interactions, PgC@ZM exhibits injectability for complete filling of irregular periodontal pockets. Moreover, the Zn-Metformin complex dramatically enhances the antibacterial efficacy of PgC@ZM against periodontal pathogens. In vitro, PgC@ZM demonstrates excellent biocompatibility, efficient ROS scavenging capability, and induces osteogenic differentiation in periodontal ligament stem cells, as evidenced by increased alkaline phosphatase activity and mineralized nodule formation. In vivo, PgC@ZM effectively accelerates osteogenic therapy in rat periodontitis by synchronously alleviating tissue inflammation and inhibiting alveolar bone resorption. Overall, this multifunctional hydrogel presents a comprehensive and promising approach for treating periodontitis, with significant potential for clinical translation.