Abstract

Osteoarthritis (OA) is a progressive joint disorder that predominantly affects elderly and postmenopausal individuals. Current therapies offer only transient symptom relief and are associated with significant adverse effects. Mesenchymal stem cell (MSC) therapy holds promise for OA treatment, but challenges such as poor in vivo persistence and migration away from target sites hinder its clinical application. Here, we develop a bioactive, thermosensitive hydroxypropyl chitin (HPCT) hydrogel as an injectable platform to enhance MSC-based therapy. In both papain-induced early-stage and surgically induced late-stage OA models, intra-articular injections of MSCs combined with HPCT hydrogel significantly enhance therapeutic efficacy within the osteoarthritic joint environment. This bioactive, thermosensitive hydrogel is associated with attenuation of mechanical-stress-related ferroptotic signatures in chondrocytes through the establishment of a protective biomechanical microenvironment. MSCs embedded within the hydrogel adopt a spheroidal configuration, which improves their viability, enhances their anti-inflammatory properties, and prolongs their retention at the site of injury. These combined effects promote cartilage repair, regeneration, and sustained joint homeostasis. Mechanistically, these effects are accompanied by modulation of mechanotransduction-related pathways, including reduced Piezo1 expression and restoration of GPX4-associated antioxidant capacity. Our findings highlight HPCT-based tissue engineering as a promising therapeutic strategy for addressing OA pathophysiology and improving long-term clinical outcomes.