From mouse to man, traumatic injuries to the joint cause inflammation and, when the instigating injury remains uncorrected, persistent inflammation culminates in irreversible degradation of all joint structures. In companion animals, such as dogs, cranial cruciate ligament (CCL) disease is one of the most common causes of lameness and is the leading cause of degenerative changes in the stifle joint. A number of therapies have been developed to treat inflammation associated with persistent joint pain, including direct joint injections of non-steroidal anti- inflammatories and intra-articular (IA) glucocorticoid and systemically delivered biologic therapies, among others. However, most IA therapeutics are rapidly cleared from the joint via the synovium within 24-48 hours. To sustain drug delivery in the mechanically loaded joint, our team recently developed a novel delivery system based on PLGA microparticles that are designed to rupture under specific mechanical loading parameters (MAMCs). Our data show that biologic therapies (including receptor antagonists such as IL-1Ra) can be encapsulated at high efficiency and release active factors through both mechanically induced rupture and/or passive degradation of the MAMCs. When injected into a minipig synovial joint, empty MAMCs are well tolerated, and progressively release their contents over a two-week period. While promising, this technology has not yet been extensively evaluated in a naturally occurring spontaneous injury model. In this proposal, we will first (Aim 1) develop MAMCs delivering the clinical formulation of IL-1Ra (AnakinraTM) and test their efficacy in attenuating inflammatory signaling in canine synovial tissue organ culture. Next, we will assess this technology in client owned canines subsequent to presentation of CCL injury and compare the safety and efficacy of IA IL-1Ra MAMCs to both systemic and IA delivery of unencapsulated soluble IL-1Ra . In these dogs, as well as humans with ACL injuries, several weeks generally pass between the timing of knee injury and the surgical repair, during which time inflammatory factors are present in the joint. Aim 2 will test the hypothesis that sustained release of anti-inflammatory therapeutics after injury, but before surgical repair, will better limit joint inflammation and improve patient recovery after surgical repair when compared to systemic or IA delivery of unencapsulated soluble IL-1Ra. Successful completion of this study will advance a new technology towards human clinical implementation and validate, for the first time, the safety and therapeutic efficacy of MAMC-delivered IL-1Ra in a pilot clinical trial (executed through the PennVet Veterinary Clinical Investigation Center) in client owned canines. These pilot data will set the stage for subsequent larger and longer lasting clinical trials, as well as application of this novel drug delivery platform to other injury scenarios in which quelling inflammation improves long term outco...