Targeting Heterotopic Ossification Induced Joint Contractures Before They Occur Through Early Detection and Angiogenic Inhibition

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

? DESCRIPTION (provided by applicant): Heterotopic ossification (HO) is the ectopic formation of bone within soft tissue structures that commonly occurs as a complication of trauma, burn injury, spinal cord damage, and joint arthroplasty. Few effective options for treatment exist, and patients with peri-articular HO rarely regain complete range of motion due to the persistent and recurrent nature of the disease. Furthermore, given the limited ability of imaging modalities to detect HO early in the disease process, patients often develop debilitating joint contractures before the diagnosis is even suspected. Given the rising burden of HO as a result of the increasing number of joint arthroplasties performed annually and improved survival after trauma, there is substantial need for improvement in our ability to diagnosis and prevent HO by targeting its causative processes. Several studies as well as our preliminary data have demonstrated the role of hypoxia-inducible factor-1a (HIF-1a) in HO; increased vasculogenesis in the setting of hypoxia leads to osteogenesis in the form of endochondral ossification. Therefore, the use of HIF-1a inhibitors in the treatment and prophylaxis of HO is an important mechanism to target. Given the inability to detect HO at early time points, however, it is important to first develop novel imaging strategies to allow for the prompt recognition of HO. In this proposal, we will use our validated tenotomy-burn mouse model to evaluate the use of Raman spectroscopy and Near-infrared imaging in the detection of HO. We will then assess the degree of HO formation in the setting of HIF-1a inhibition. Current treatment algorithms are limited by delayed diagnosis and unreliable treatment efficacy. Successful and prompt recognition of HO using novel imaging modalities and treatments specific to inhibition of the vascular signaling pathways leading to HO will revolutionize patient outcomes.