AWARD NUMBER: W81XWH-13-1-0393 TITLE: Prevention of the Post-traumatic Fibrotic Response in Joints PRINCIPAL INVESTIGATOR: Andrzej Fertala, Ph.D. CONTRACTING ORGANIZATION: Jefferson Medical College

The referenced project was funded through the Translational Research Partnership Award mechanism. This mechanism required research teams to conduct translational studies that would accelerate the movement of promising ideas in orthopaedic research into clinical applications to benefit soldiers with combat-relevant traumatic orthopaedic injuries. Moreover, this award mechanism required the formation of the multiinstitutional and multi-disciplinary research partnership among orthopaedic surgeons and basic researchers. Our group has fulfilled both of these requirements. Our group has been extremely successful in establishing a well-integrated partnership among orthopaedic surgeons and basic researchers focusing on research associated with post-traumatic joint stiffness. This team has grown from a group of three initial Principal Investigators into the Scientific Consortium for Arthrofibrotic Research (SCAR). At present, the scientists that form the SCAR focus on the scarring of elements of the musculoskeletal system, including tendons, joint capsules, peripheral nerves, and others. Our key accomplishment of this project is proving the efficacy of our technology to reduce posttraumatic joint stiffness in vivo. The results of our study were then published in peer-reviewed journals and at major orthopaedic conferences. In brief, posttraumatic joint contracture is a frequent orthopaedic complication that limits the movement of injured joints, thereby severely impairing affected patients. Non-surgical and surgical treatments often fail to improve the range of motion of stiff joints. The purpose of this study was to test a hypothesis that limiting the formation of collagen-rich tissue in the capsules of injured joints would reduce the consequences of the fibrotic response and improve joint mobility. To test this hypothesis, we targeted the formation of collagen fibrils, the main component of fibrotic deposits formed within the tissues of injured joints. We have employed a relevant rabbit model to test the utility of a custom-engineered antibody, delivered directly to the cavities of injured knees, to block the formation of collagen fibrils produced in response to injury. In comparison to the nontreated control, mechanical tests of the antibody-treated knees demonstrated a significant reduction of flexion contracture. Detailed microscopic and biochemical studies have verified that this reduction was a result of the antibody-mediated blocking of the assembly of collagen fibrils. The results of our study indicate that extracellular processes associated with excessive formation of fibrotic tissue represent a valid target for limiting model posttraumatic joint stiffness.