In-situ-forming zwitterionic hydrogel does not ameliorate osteoarthritis in vivo, despite protective effects ex vivo

Osteoarthritis (OA) is one of the most common degenerative joint diseases, with no effective therapeutic options available. In this study, we aimed to develop an interpenetrating, in-situ-forming hydrogel based on biocompatible and anti-fouling zwitterionic (ZI) polymers for early-stage OA treatment. We hypothesized that the anti-fouling properties of zwitterions could provide tissue protection, and the high charge density of these polymers would enhance tissue penetration and lubrication. The hydrogel comprises carboxybetaine acrylamide as the ZI backbone and tyramine acrylamide as a functional comonomer to enable enzymatic and tissue-adhesive crosslinking. The hydrogel demonstrated exceptional tissue penetration and long-term retention in bovine cartilage explants. Moreover, hydrogel application protected cartilage in inflammatory media, enhanced lubrication, and decreased permeability. However, ZI hydrogel injection in collagenase-induced osteoarthritis model in rats did not prevent cartilage degeneration, and similar levels of tissue degradation and surface roughness were observed in rats injected with the ZI hydrogel and in OA controls. Additionally, ZI polymer without in-situ crosslinking resulted in increased cartilage degradation compared to both hydrogel and OA control. Furthermore, synovial tissue inflammation and significantly increased immune cell infiltration were observed in response to ZI materials. This study highlights the potential immunogenicity effect of ZI polymers in our disease model, contributing to impaired protective effects as well as exacerbated degeneration. •Osteoarthritis (OA) is the most common degenerative joint disease.•An in-situ-forming zwitterionic hydrogel is developed as a protective therapy for early-stage OA.•Ex vivo studies in cartilage explants showed lubrication, reinforcement, and protective effects.•In vivo studies in collagenase-induced OA rat model did not show any protective effects.•Zwitterionic formulations resulted in synovial inflammation and immune cell infiltration.