PROJECT SUMMARY/ABSTRACT Juvenile ostechondritis dissecans (OCD) is a developmental orthopaedic disease affecting children and young adults. It is characterized by formation of chondro-osseous flaps or fragments within joints which cause pain and disability and also predispose to early onset osteoarthritis. Although recent studies demonstrated that discrete areas of epiphyseal cartilage necrosis (termed osteochondrosis), caused by focal failure of vascular supply, are the clinically silent precursor lesions of juvenile OCD, it remains unclear how the extent of the inciting vascular failure, along with exposure to biomechanical trauma, determine whether these lesions heal or progress to clinically apparent disease. The overall objective of this proposal is to use porcine models to understand factors that influence the development, progression and healing of juvenile OCD lesions. To achieve this objective, we will use three specific aims to test our central hypothesis, that the degree of vascular compromise predicts the development of juvenile OCD and lesion progression is influenced by biomechanical stress. Specifically, our aims have been designed to determine (1) the relationship between the severity of vascular injury to the femoral trochlear epiphyseal cartilage and the formation and progression of juvenile OCD precursor lesions in a miniature pig model, (2) the role that low vs. high impact biomechanical stress plays in the progression of subclinical osteochondrosis to clinically apparent juvenile OCD in miniature pigs, and (3) whether oral administration of platelet inhibitors will decrease the high prevalence of naturally occurring juvenile OCD precursor lesions in domestic pigs. Our study will establish how the extent of vascular failure and exposure to biomechanical stress determine the clinical course of juvenile OCD, and will supply proof of concept evidence that platelet inhibition reduces the prevalence of subclinical osteochondrosis. Conducting these studies in a large animal model will ensure timely translation of our results to inform clinical decision making in human patients, and will also help establish controlled exercise as a component of non-operative treatment. Importantly, these findings will also have applicability to other juvenile orthopaedic disorders of vascular origin such as Legg-Calvé-Perthes disease.