PROJECT SUMMARY Total joint arthroplasty (TJA) procedures are estimated to rise by over 300% by the year 2030. Periprosthetic joint infection (PJI) is the most significant complication following TJA with healthcare costs exceeding $1.6 billion annually. Treatment of PJI generally requires surgical intervention combined with a prolonged course of antibiotics costing $50,000 per patient. Despite this aggressive treatment, treatment is only successful in half of patients. The leading cause of treatment failure in PJI is the formation of protective bacterial biofilms or communities of bacteria encased within an extracellular matrix which are tolerant to commercially available antibiotics. We have discovered that platelet-rich plasma (PRP) displays both antibacterial and antibiofilm properties. Nevertheless, there is tremendous variability in the literature on the clinical efficacy of PRP. To overcome this variability, we have developed a PRP-derived biologic that is specifically formulated with high antimicrobial and anti-inflammatory activity with little to no lot-to-lot variability, termed BIO-PLY™. In an equine model of native joint infection, BIO-PLY™ not only decreased intraarticular bacterial load but also dampened inflammation and protected venerable cartilage from damage. In this proposal, we will capitalize on the equine model of native joint infection to manufacture a human equivalent and evaluate the safety and efficacy of human BIO-PLY™ using established in vitro and in vivo models of PJI. The goal of this proposal is to generate the key data necessary for a go/no-go decision to advance BIO-PLY™ toward a Phase II pre-clinical animal model and an Investigational New Drug (IND) application with the Federal Drug Administration.