SUMMARY ABSTRACT Meniscal tearing is a significant risk factor for the development of posttraumatic osteoarthritis (PTOA). The long- term goal of this project is to develop an innovative biologic therapy to improve meniscus tear healing for the prevention of PTOA. Our laboratory has demonstrated the efficacy of utilizing cartilage-derived progenitor cells (CPCs) to stimulate healing of meniscal tears in a small animal model. In efforts to translate our success in small animals to a clinically relevant large animal model, we will optimize and implement a bioactive tear interfacing fibrin hydrogel (FibroGel) that is laden with CPCs and infused with the chemokine Stromal Cell Derived Factor- 1 (SDF-1) and the small molecule Kartogenin (KGN), which collectively increases CPC retention at the tear site and increases their chondrogenic matrix synthesis, respectively. The objectives of the proposed study are: To optimize FibroGel as a novel biologic therapy for meniscus tear repair; (2) To determine its efficacy for stimulating tear reunification and reduction of PTOA severity; and (3) To collect biocompatibility data throughout the study to aid in clinical translation of this technology. There are three independent specific aims: (I) Optimize cellular and bioactive components of FibroGel to produce robust fibrocartilage matrix re-synthesis to bridge and reunify meniscus tears; (II) Evaluate the efficacy of using FibroGel for improving meniscal fibrocartilage healing in a preclinical large animal model; and (III) Determine the efficacy of FibroGel-augmented meniscus repair in attenuating PTOA in the knee. The research design will employ a meniscus tissue explant model to optimize FibroGel in order to maximize cell retention and chondrogenic matrix re-synthesis at the tear site, as well as increase the strength of tissue reintegration/reunion at the tear site. A porcine model of meniscal injury will be used to examine the short- and long-term efficacy and biocompatibility of FibroGel. Outcome assessments will include evaluation of meniscus tear healing, evaluation of PTOA severity as determined by biomarker analysis, gait asymmetry analysis, and macroscopic/microscopic assessment of the articular cartilage and synovium following FibroGel treatment. Successful completion will have a positive impact by facilitating the development and translation of a new strategy to stimulate meniscus injury repair through the use of cellular biologics. This project is relevant to the mission of NIAMS because it seeks to find innovative ways to treat musculoskeletal injuries and prevent arthritis.

PROJECT NARRATIVE The proposed research is relevant to public health because it will fill knowledge gaps that can help lay the groundwork for the development of innovative and effective biologic therapies for meniscus injury repair in order to delay/prevent degenerative joint disease. This research is aligned with the NIH’s mission that pertains to seeking fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to reduce illness and disability.