Project summary Post-traumatic osteoarthritis (PTOA) is a painful, debilitating and expensive joint disease that conservatively impacts 5.6 million people at any time in the United States. Currently available clinical treatments are mostly palliative and fail to suppress cartilage degeneration or synovial inflammation or to promote tissue regeneration. Consequently, osteoarthritis progresses to an end-stage disease where total joint replacement is the only answer. Our aim is to provide an injectable solution for the treatment of PTOA, through the fabrication of super- lubricious microspheres loaded with platelet-rich plasma (PRP), which is blood plasma that has been spun down to concentrate the platelet component. These platelets contain more than 300 bioactive molecules that play critical roles in controlling and resolving inflammation, while also stimulating cells within the joint to proliferate and regenerate tissues such as articular cartilage. Unfortunately, direct injection of PRP into the knee joint has shown inconsistent efficacy in the clinic, mainly because the harsh environment within the osteoarthritic knee rapidly breaks down and destroys the bioactive molecules rendering them useless for therapeutic effect. Therefore, we propose to fabricate lubricious injectable polyethylene glycol (PEG) microspheres for injection into the intra-articular knee space that cannot be cleared by the body with the synovial fluid turnover. We will evaluate the incorporation and release as well as bioactivity and immunotoxicity of PRP from the hydrogel system, through both quantification of specific proteins released over time and in vitro cellular response studies, respectively. Finally, PRP-loaded microspheres will be used in a mouse model of knee injury and osteoarthritis to determine the ability for our system to i) modify the intracapsular inflammatory state, ii) stop cartilage degeneration, iii) promote new cartilage formation and, iii) restore joint homeostasis.