Thermo-responsive Hydroxybutyl-chitosan hydrogel for oxidative stress modulation and cartilage regeneration in temporomandibular joint osteoarthritis

Temporomandibular joint osteoarthritis (TMJ-OA) is a degenerative disease marked by oxidative stress, cartilage loss, and inflammation. Current therapies are largely palliative and fail to restore joint structure or function. Here, we developed an injectable multifunctional hydroxybutyl-chitosan hydrogel (HBC@ZIrK) with thermo-responsive sol-gel transition property that integrates iridium nanozymes (Ir NPs), zeolitic imidazolate framework-8 (ZIF-8), and the chondrogenic molecule kartogenin (KGN) for synergistic therapy. ZIF-8 stabilized ultra-small Ir NPs, preserved their multi-enzyme activity, and enabled efficient KGN loading with sustained release in the inflamed microenvironment. The hydroxybutyl-chitosan matrix ensured injectability in sol state at room temperature, and underwent rapid gelation at body temperature to form a localized depot, achieving prolonged intra-articular retention of therapeutic components. In vitro studies proved that HBC@ZIrK showed excellent cytocompatibility, potent reactive oxygen species scavenging, apoptosis inhibition, and sustained KGN release. In a rat TMJ-OA model, micro-CT and histological analyses confirmed that the HBC@ZIrK hydrogel preserved subchondral bone, reduced osteophytes, suppressed inflammatory cytokines, and enhanced cartilage matrix synthesis. Remarkably, the joint morphology in the HBC@ZIrK group was statistically indistinguishable from that of healthy controls, which highlights the synergy between KGN and nanozyme-mediated antioxidation. Collectively, these results demonstrate that HBC@ZIrK is a minimally invasive and effective therapeutic platform, offering a dual-action strategy for microenvironmental modulation and structural regeneration in TMJ-OA.