Reduction of osteoarthritis progression in active joints via a self-healing hydrogel

Sustained intra-articular delivery of disease modifying osteoarthritis drugs (DMOADs) holds promise for preventing the progression of post-traumatic osteoarthritis (PTOA). DMOADs are likely to work best in early disease, when patients are physically active. Drug delivery systems thus need to withstand repeated mechanical loading without pre-mature drug release. We report a thixotropic hydrogel that exhibits rapid self-healing following mechanical loading at levels relevant to running human knees, while maintaining sustained release of the cathepsin-K inhibitor L-006235, used here as a proof-of-concept DMOAD. Non-covalent, hydrophobic interaction of L-006235 with the hydrogel was found to be critical to prevent pre-mature release and loss of L-006235 during mechanical loading. Hydrogel injected into mouse knee joints showed similar release kinetics of a hydrophobic fluorescent dye in treadmill-running versus non-running mice and sustained release of L-006235 in treadmill-running mice. In a PTOA model with treadmill-running mice, L-006235 hydrogel was more effective than free L-006235 and reduced cartilage degeneration score by 43% compared to mice treated with solvent vehicle. Overall, our data suggest non-covalent encapsulation of DMOADs in a thixotropic hydrogel as a promising approach for reducing PTOA progression in active joints.