pH-responsive, self-lubricating hyaluronic acid-chondroitin sulfate-chitosan hydrogel for articular cartilage repair

Cartilage degradation after joint injury often leads to post-traumatic osteoarthritis, a process accompanied by a drop in synovial pH. Traditional dynamically crosslinked hydrogels overlook how their mechanical and tribological properties change in such acidic, inflammatory environments. Here, we report an arthritis-responsive, injectable hydrogel designed to both regenerate articular cartilage and inhibit its further degradation. The hydrogel is formed via Schiff base chemistry between aldehyde groups of oxidized hyaluronic acid (OHA) and amino groups of adipic acid dihydrazide-grafted chondroitin sulfate (Chs-ADH) and carboxyethyl chitosan (CEC). Under neutral pH, the imine bonds remain stable, allowing precise defect filling and minimizing stress-induced debris; under acidic conditions, their reversible nature enhances lubrication and resists wear. The hydrogel formulation was optimized using molecular dynamics simulations to achieve excellent injectability, shear-thinning behavior, and low friction without impeding normal joint motion. In vitro , the hydrogel exhibited outstanding biocompatibility and stimulated cell migration. In vivo , it accelerated cartilage repair, prevented cartilage degradation, and restored the lubrication of newly formed tissue to levels comparable with healthy cartilage. Together, these findings demonstrate that the pH-sensitive hydrogel is a promising candidate for effective cartilage repair and prevention of cartilage degradation.