PROJECT SUMMARY: Osteonecrosis of the femoral head [ONFH] is a serious hip disorder affecting both children and adults that can lead to collapse of the femoral head and osteoarthritis. ONFH is the cause for approximately 10% of total hip replacements in the United States (25,000/year). Clinical management of ONFH focuses on preventing femoral head collapse, but the primary treatment for ONFH, core decompression surgery, fails to prevent disease progression in 30-50% of patients. This can be attributed in part to delayed diagnosis and limited ability to predict clinical outcome, monitor disease progression, and evaluate response to treatment using current clinical imaging methods (radiographs and traditional T1- and T2-weighted magnetic resonance imaging [MRI]). Our long-term goal is to improve clinical outcomes for patients with or at risk for ONFH by advancing imaging techniques to enable earlier detection and more precise treatment. The objective of this R01 proposal is to characterize quantitative, non-contrast-enhanced MRI techniques to detect ischemic injury to the femoral head, monitor disease progression, and assess treatment response. Our central hypothesis is that quantitative MRI can detect disease earlier than traditional MRI techniques, at a potentially reversible stage, and better predict and monitor treatment response. We will build upon our promising work using a pig model of ischemic ONFH, which demonstrated that quantitative relaxation time mapping and diffusion imaging techniques are very sensitive in detecting acute ischemic injury to the femoral head. In Aim 1, we will identify the cellular changes driving the sensitivity of the quantitative MRI methods using the pig model of ischemic ONFH. Animals will be imaged in vivo at 3T MRI, and the femoral heads will subsequently be studied ex vivo using high-resolution 9.4T MRI and histology. In Aim 2, we will characterize the response of the quantitative MRI methods to progression and repair of steroid-induced ONFH, which is the most common cause of ONFH (30% of cases). For this aim, we will use a rabbit model of steroid-induced ONFH, which has a different pathogenesis than the pig model used in Aim 1. Animals will be longitudinally imaged in vivo at 3T MRI, and the imaging findings will be validated by ex vivo analysis of the proximal femurs using histology. In Aim 3, we will take the first step toward clinically translating the quantitative MRI techniques by conducting an exploratory study to detect early-stage injury and monitor response to treatment in patients with ONFH undergoing core decompression surgery. Patients will be imaged before surgery and serially after surgery, for up to two years, to study how the quantitative MRI measures respond in patients whose treatment fails to prevent femoral head collapse versus patients who do not have disease progression. The contralateral femoral head will also be evaluated for early-stage ONFH. Collectively, our project has the potentia...