The primary objective of this project is to develop a novel survival animal model of intra-articular fracture (IAF) in which all major pathophysiological attributes of corresponding human clinical injuries are realistically replicated, and in which post-traumatic osteoarthritis (OA) predictively develops. This animal model will facilitate translational research of orthopaedic treatment for IAFs, specifically by providing opportunities to test efficacy and safety of new treatment strategies prior to clinical trial, forward advancing orthopaedic treatment to mitigate the risk of OA following IAFs.

Post-traumatic OA is characterized by destructive joint degeneration following a traumatic injury. A leading cause of post-traumatic OA is intra-articular fracture (IAF), which typically occur in high-energy injury events, including ballistic impactions, falls from height, and vehicular accidents. Such high-energy injuries typically occur in a young, active population, including obviously soldiers on the battlefield or in training. The outcomes of reconstructive surgeries for advanced OA in relatively young, active patients have been disappointing. Since this disorder particularly affects people during their prime activity years, the financial burden is substantial, calculated at $12 billion annually (approximately 0.6% of the total U.S. healthcare outlay).

To date, clinical management for IAFs has been focused mainly on restoration of physiological joint anatomy (usually by open surgical reconstruction). However, despite evolution of orthopaedic treatments over the last several decades, the high risk of OA after IAFs has remained virtually unchanged. Post-traumatic OA following IAFs often develops quickly, presumably due to cascading cell-level damage involved in fracture-associated cartilage injury. Arguably, the most effective treatment to mitigate the risk of post-traumatic OA following IAFs would be to not only deal with the macroscopic damage (essentially, the current treatment strategy), but also attempt to preserve (or perhaps even rescue) viable metabolically effective cells by means of biological adjunct therapy. Such an approach would parallel the concept of successful early thrombolytic therapy in myocardial infarction and in ischemic stroke. Recently, laboratory research has identified several agents potentially applicable to this new treatment strategy. However, the logical next step of "paradigm shift" in IAF treatment has not proceeded, due to lack of appropriate models to test the efficacy and safety of new treatment methods prior to clinical trial. The intended end product of the proposed project is a survival animal model, for just such translational research.

In the proposed animal model, an experimental fracture will be introduced by mimicking an injury mechanism typical of clinical IAFs, replicating the pathophysiology of fracture-associated cartilage injury. The species/joint of choice is the porcine hock (analogous of the human ankle). This joint is preferable for several reasons, including a relatively large physical size that lends itself to standard-of-care fracture management (i.e., surgical reduction and fixation) similar to that in human clinical cases. The specific aims of this project are (1) to thoroughly validate the fracture insult technique/system developed for introducing pathophysiologically realistic IAFs in large animal joints, (2) to establish post-insult management methodology, and (3) to validate the capability of the animal model as a research tool for piloting new treatment methods. At the conclusion of the project, we expect to have established a definitive methodology to create a clinically realistic large animal survival model of IAF, and we expect to have demonstrated the value of the animal model as a powerful new translational research tool.