PROJECT SUMMARY Cartilage injuries progressively degenerate if left untreated, leading to the onset of osteoarthritis. Clinical management of partial-thickness cartilage lesions via arthroscopic debridement (removal) and lavage (flushing joint with fluid) relieve pain but fail to repair or protect the tissue against further degeneration. Intraarticular stem cell injections have gained widespread adoption due to their minimally-invasive nature and the anti-inflammatory and regenerative potential of stem cells. However, systematic investigations of clinical data have demonstrated that this approach provides limited repair of the cartilage tissue and highly variable outcomes. Thus, similar to debridement and lavage, MSC injections alone is not enough to repair or halt the progression of tissue deterioration for most patients. One of the major reasons for this is failure of delivered stem cells to localize to the site of cartilage injury, which limits their therapeutic efficacy. Moreover, the lack of reinforcement at the site of tissue damage leaves the cartilage exposed to degenerative overloading, which progressively exacerbates tissue damage. We developed a hyaluronic acid (HA)-based therapeutic termed BioAdhesive that can be locally delivered to the site of cartilage damage, in a minimally-invasive manner, providing mechanical reinforcement and presenting cell-attachment peptides to enhance localization of delivered stem cells to the site of cartilage repair. Through the proposed work, we will first evaluate the material stability in a proteinaceous synovial fluid setting to determine the therapeutic window of the material and second, assess stem cell localization post intraarticular stem cell injection in a load-bearing in vivo environment using a goat model. In Aim 1, cartilage injuries created in cartilage explants will be treated with the BioAdhesive and incubated in synovial fluid with or without the addition of the inflammatory cytokine, interleukin 1β. At varying time points post treatment (up to 28 days), bone marrow-derived mesenchymal stem cells (MSCs) will be seeded on treated lesions for 24 hours, and cell attachment, material presence, and tissue reinforcement will be assessed. In Aim 2, four partial thickness cartilage lesions will be created bilaterally in the trochlear groove of goats and two of the four injuries will receive BioAdhesive treatment. After surgical closure, labeled MSCs will be delivered to each joint via intraarticular injection. After 7 days, animals will be euthanized and joint tissues will be assessed for MSC localization while cartilage tissue will be assessed for cellular and tissue matrix via histological and immunohistological staining. These studies will demonstrate the stability and cell localization potential of the BioAdhesive in a synovial, load- bearing environment, validating the feasibility of our material formulation. The completion of this SBIR Phase I would directly set the stage for progression t...