Double-crosslinked self-healing hydrogel alleviates osteoarthritis by protecting from wearing and targeting NF-kB signaling.

Osteoarthritis (OA) is a chronic disease that causes pain, morbidity, and disability. The main strategy for OA treatment focuses on inflammation suppression, inhibition of osteoclastogenesis, and protection of articular cartilage. These functions cannot be performed effectively by monotherapy. Therefore, an effective drug delivery system is required, capable of containing and controlling the efflux of various drugs to alleviate osteoclastogenesis, protect cartilage and subchondral bone, and suppress inflammation. In this work, an encapsulation system is constructed using a self-healing chitosan hydrogel and allocated compound drugs. The self-healing gel is composed of branched-functionalized chitosan, created by simultaneously using polycaprolactone polyethylene glycol azide as a block polymer and the host-guest assembly of β-cyclodextrin and adamantane. Inhibitors of the NFkB pathway are loaded into the cavities of β-cyclodextrin and the spring-like structure of the block polymer, which can be rapidly released upon joint friction (due to the reassembly of β-cyclodextrin and adamantane by shear stress and the stretch of the block polymer). In vitro experiments using BMMs and the ATDC5 cell line confirm that the developed hydrogel can simultaneously suppress osteoclastogenesis and induce chondrogenesis. Additionally, a model of knee arthritis in C57 mice was used to confirm that this double-crosslinked encapsulation system can lubricate the knee joint surface and provide adequate protection on demand through shear-responsive drug release.