A Multi-Factorial Therapeutic Delivery System to Attenuate Post-Traumatic Osteoarthritis

Post-traumatic osteoarthritis (PTOA) is a phenotype of osteoarthritis (OA) that is temporally linked to acute joint injuries, such as intra-articular ligament rupture or meniscus tear (1). Service members and veterans are disproportionally affected by extremity injuries that can lead to PTOA due to heavy load carriage, high activity rates, insufficient recovery time, and combat trauma (10–14). Absent early intervention, acute knee injuries induce diverse pathogenic cascades including hemarthrosis, inflammation, necrosis, apoptosis, and matrix degradation (2). Targeting only a single aspect of these pathogenic mechanisms has proven insufficient for joint- level chondroprotection and attenuation of PTOA. Due to the lack of regenerative capacity of cartilage and the paucity of early intervention therapeutics, OA and PTOA have remained the leading cause of service member disability and medical discharge over the past decade (11, 13). Current reliance on non-steroidal anti- inflammatory drugs, analgesics, and physical therapy highlights an unmet need for novel solutions that attenuate, delay, or altogether prevent PTOA following an acute knee injury. Without these solutions, the young cohort of veterans suffering from career-ending and life-altering joint injuries will continue to grow. Therefore, our goal is to develop an intra-articular therapeutic to control the spatial and temporal release of bioactive factors in an early intervention setting following an acute joint injury. By establishing an early intervention therapeutic, we hope to reduce the number of service members who develop PTOA and alleviate the physical, medical, financial, and psychosocial burden on the veteran population (8, 9). In Aim 1, we will establish a biologic profile of the post- injury joint microenvironment using human clinical data from veteran patients enrolled at the Corporal Michael J. Crescenz Veterans Affairs Medical Center (CMCVAMC) with traumatic ACL and/or meniscus tears. Through our understanding of the pro-inflammatory biomarkers and synovial transcriptome gained from this data, we will develop a state-of-the-art large animal model of PTOA that resembles the phenotype observed in our veteran patients. We will extend our existing porcine model of PTOA to combine arthroscopically assisted ACL transection (ACLT) and destabilization of the medial meniscus (DMM) to recapitulate an acute knee injury for evaluation of novel, early intervention therapeutics. In Aim 2, we will develop a multi-factorial therapeutic that addresses the spatial and temporal pathology of PTOA by precisely delivering multiple bioactive factors within mechanically activated microcapsules (MAMCs) in a hyaluronic acid (HA) carrier. We will employ a 3D model of PTOA using porcine osteochondral explants exposed to mechanical overload to recapitulate the aberrant cartilage loading observed in our in vivo ACLT/DMM model. By early delivery of anti-inflammatory, anti-apoptotic, and antioxidant factors, we will achieve superior chondroprotection compared to delayed treatment or delivery of a single factor. Upon completion of the proposed Aims, we will have defined and validated a bioactive, multi- factorial, injectable therapy to attenuate the effects of an acute knee injury and establish a clinically relevant animal model for the future translational evaluation of this novel therapeutic approach.