Bindarit-loaded hydrogel sustained-release system alleviates periodontitis in mice via CC motif chemokine ligand 2-dependent monocyte chemotaxis.

Periodontitis is a chronic inflammatory disease driven by dysregulated host immune responses to bacterial biofilms, leading to tissue destruction and systemic health risks. Current treatments often fail to resolve persistent inflammation, highlighting the need for novel therapy targeting immune modulation. Monocytes and macrophages play a central role in the progression of periodontitis. CC motif chemokine ligand 2 (CCL2) is critical for monocyte recruitment, rendering its inhibition a promising therapeutic strategy. Bindarit is a selective inhibitor of CCL2. Our previous work first established the efficacy of its local application in controlling periodontal inflammation and bone loss, but its clinical application is limited by poor solubility and short local retention. To address this, we developed an injectable thermosensitive hydrogel (chitosan/β-glycerophosphate/Gelatin/sodium bicarbonate) for sustained Bindarit delivery. This hydrogel exhibited rapid gelation at 37 °C, excellent biocompatibility, and prolonged drug release. In vitro, Bindarit-loaded hydrogel reduced inflammation response in lipopolysaccharide-stimulated human periodontal ligament cells and RAW264.7 cells, and effectively inhibited monocyte chemotaxis. In vivo, Bindarit-loaded hydrogel inhibited the production of CCL2, decreased inflammatory monocytes and macrophages infiltration, reduced the expression levels of proinflammatory cytokines, and attenuated periodontal inflammation and bone loss in mice. Crucially, the hydrogel's efficacy matched that of daily free Bindarit injection and significantly outperformed free-drug administration at an identical dosing frequency. All these effects were reversed by CCL2 overexpression, confirming a CCL2-dependent mechanism. This study establishes a promising immunomodulatory strategy for periodontitis, highlighting the potential of sustained-release hydrogels in treating inflammatory diseases.