Sustained Dexamethasone Delivery to Prevent Onset of PTOA

This proposal is responsive to the Topic Area Post-Traumatic Osteoarthritis (PTOA) as well as a number of the Areas of Encouragement: (1) Research on therapies that target multiple phases of the cellular response pathways that are implicated in development of PTOA, including cell death, inflammation, matrix changes, and changes in catabolic and anabolic responses. (2) Intra-articular treatments that offer sustained (two or more months) disease-modifying effects. Anterior cruciate ligament (ACL) injuries in U.S. Military Service members have a 10-fold higher incidence than that of the general population due to the physically demanding aspects of military duties. More than 50% of Service members have activity limitations or are unable to return to duty following ACL reconstructive surgery. The proposal addresses the well-established link between ACL injury and development of PTOA by proposing a novel strategy for primary repair of an ACL tear. Our approach involves a collagen (vitrigel) membrane wrap that serves (1) as a vehicle for local low-dose (therapeutic) drug delivery of dexamethasone, a corticosteroid, in the synovial joint that reduces inflammation, promotes cartilage protection and supports ligament repair, and (2) enhances primary ACL repair by providing a surrogate synovial sheath as a barrier to synovial fluid solutes (such as hyaluronan) that may inhibit ligament healing while permitting nutrient access, thereby restoring ligament function and joint stability.