Injectable Dual-Cross-Linked Hydrogels Enabling Sequential Drug Release for Synergistic Periodontitis Therapy

Periodontitis, a chronic infectious disease caused by pathogenic bacteria, characterized by a severe host immune response. Combined antimicrobial and anti-inflammatory strategies can enhance therapeutic efficacy, and a critical factor for the therapeutic efficacy of anti-inflammatory drugs is the maintenance of a localized antimicrobial microenvironment. Therefore, the release profiles of antimicrobial and anti-inflammatory drugs directly affect the treatment outcomes of periodontitis. In this study, a double-cross-linked injectable hydrogel with temperature-responsive and dynamic covalent cross-linking properties is developed as a codelivery carrier for antimicrobial and anti-inflammatory drugs, enabling sequential drug release for synergistic periodontitis therapy. This system adapts to the irregular geometry of the periodontal pocket upon injection and subsequently self-reinforces to resist salivary flow. Notably, the antimicrobial drug metronidazole is sustainedly released over the first 7 days to establish an antimicrobial microenvironment. After 12 h, the anti-inflammatory drug metformin is continuously released over 14 days to suppress the inflammatory response and promote periodontal tissue regeneration. The synergistic antibacterial, anti-inflammatory, and regenerative capabilities of the hydrogel are further validated in a rat model of periodontitis. This injectable and self-reinforcing system for locally sequential drug release demonstrates significant potential for the clinical management of periodontitis.