Multi-responsive injectable dECM hydrogel for sustained doxycycline delivery in osteoarthritis therapy

Osteoarthritis (OA) is the most prevalent degenerative joint disease worldwide. Current therapeutic approaches are limited by rapid drug clearance from the joint cavity, necessitating frequent administrations and failing to provide sustained therapeutic effects. Injectable hydrogels that can persistently remain within the joint space represent a promising strategy for comprehensive OA treatment. Herein, an injectable hydrogel system based on dermal-derived decellularized extracellular matrix (dECM) engineered with N-isopropylacrylamide, tannic acid, and sodium tetraborate was developed to achieve superior lubrication and strong tissue adhesion. The hydrogel exhibits exceptional lubrication properties and robust tissue adhesion, enabling prolonged retention within the joint cavity while providing continuous cartilage protection. Its excellent shear-thinning behavior and rapid self-healing capability facilitate minimally invasive injection and ensure conformal coverage of defect sites. In vitro and in vivo evaluations demonstrated that the hydrogel promotes cell proliferation, modulates anti-inflammatory responses, and significantly preserves cartilage integrity with enhanced proteoglycan and type II collagen (COL-2) expression. The sustained therapeutic efficacy was attributed to the hydrogel’s ability to maintain prolonged residence time while continuously delivering bioactive components and providing mechanical lubrication. These findings demonstrate that this multifunctional dECM-based injectable hydrogel represents a promising therapeutic platform for OA treatment suitable for clinical translation.