Immunomodulatory thermosensitive hydroxypropyl chitin hydrogel platform maintains cartilage-synovium homeostasis for enhanced osteoarthritis therapy.

Abstract

Osteoarthritis (OA) progression is fueled by a self-perpetuating cycle of synovitis and cartilage degradation. Current clinical therapies exhibit suboptimal efficacy, primarily due to the lack of strategies that target the multifactorial pathogenesis of OA. Herein, we developed an injectable thermosensitive hydroxypropyl chitin hydrogel (HPCH) loaded with an optimized concentration of dimethyloxalylglycine (DMOG), designated as HD₂₅, to disrupt this pathological cycle and achieve multi-modal OA therapy. HD₂₅ reprograms macrophages toward an anti-inflammatory M2 phenotype via the JAK-STAT pathway, thereby attenuating synovitis and inflammation-driven matrix degradation. In parallel, HD₂₅ provides favorable lubrication to ameliorate mechanical stress-induced wear and tear, promotes mesenchymal stem cell recruitment and chondrogenesis, and directly protects cartilage by suppressing chondrocyte hypertrophy, apoptosis, and extracellular matrix catabolism. In surgery-induced OA mice, HD₂₅ treatment effectively preserved cartilage integrity, attenuated synovitis, and restored subchondral bone remodeling. At 10 weeks, HD₂₅ reduced the proportion of MMP13-positive chondrocytes from approximately 35% to 13%. Moreover, it decreased the proportion of pro-inflammatory F4/80⁺iNOS⁺ synovial macrophages from approximately 60% to 20%, while increasing anti-inflammatory F4/80⁺CD206⁺ macrophages from approximately 15% to 30%. Crucially, in situ macrophage-depletion experiments confirmed that the therapeutic efficacy of HD₂₅ largely depends on macrophage reprogramming, underscoring the superiority of immunomodulation over cell clearance. This multifunctional hydrogel platform orchestrates chondroprotection, immunomodulation, and tissue remodeling to break the OA vicious cycle, presenting a promising disease-modifying strategy for OA management.