ABSTRACT Altered lubrication of articular cartilage following joint injury increases friction between the sliding cartilage surfaces, leads to deterioration of cartilage, and hastens the development of osteoarthritis (OA). OA due to joint injury, termed as post-traumatic osteoarthritis (PTOA), is estimated to account for at least 12% of all OA cases in the United States and approximately half of the individuals with an anterior cruciate ligament (ACL) injury develop PTOA regardless of the ACL reconstruction. Replenishing the synovial fluid and thereby restoring the articular cartilage lubrication has been demonstrated to benefit the joint. The overarching goal of the proposed study is to investigate the potential of cartilage-adhering, self-healing hyaluronic acid molecules to prevent or delay the degeneration of articular cartilage, and thereby osteoarthritis, following injury or trauma. The molecularly engineered HA-based lubricants are designed to integrate the function of both hyaluronic acid and lubricin, two key components of the synovial fluid, while exhibiting self-repairing ability. The self-healing properties are incorporated to ensure both long-term retention and adaptability of the lubricant within the mechanically active joint, while the cartilage adhering properties are expected to improve boundary lubrication. We hypothesize that the dynamic cartilage-adhering molecules that integrate the molecular features of HA and lubricin and simultaneously exhibit self-healing properties will protect the articular cartilage and prevent or slow down the progression of PTOA. Towards this, we will: (i) develop cartilage-adhering, self-healing HA molecules and determine the effect of molecular architecture-lubrication function relationship, (ii) determine the effect of the molecular architecture of the proposed novel HA-based lubricants on chondroprotection by using a joint-on-chip platform, and (iii) determine the effect of these lubricants on mitigating the development of post-traumatic osteoarthrits. The proposed studies will enable a new paradigm in which intra-articular injection of self-healing HA-bottle brush molecules could be an important treatment following acute injury to ameliorate or delay PTOA, or they could be used as an adjunct after surgical repair to improve the outcome.

The proposed research will provide new understandings on the role of deficient lubrication in the development of osteoarthritis after joint injury. Successful completion of the proposed study will lead to a new class of self- repairing lubricants to treat joint injuries to ameliorate or delay cartilage degeneration or as an adjunct after surgical repair to improve the outcome.