This proposal sets out to improve early detection and treatment of heterotopic ossification (HO): one of the major complications of extremity combat injury and civilian extremity trauma and surgery. Blast-related injuries delivered by improvised explosive devices (IEDs) and explosively formed projectiles (EFPs) have become the principal mode of injury on the modern battlefield. Of the 14,788 battle injuries suffered in Operations Iraqi Freedom/New Dawn and Enduring Freedom, over 50% of those injuries were extremity injuries; an additional 5%-20% of the injuries were burn injuries. Of these Wounded Warriors with extremity injuries, over 60% of them will go on to develop a severely debilitating disease process called heterotopic ossification. HO is characterized by the formation of mineralized bone in soft tissues such as muscle, tendon, or fascia; this disease leaves patients with severe pain, contractures, and limited range of motion. Current treatment strategies involve surgical removal of the heterotopic bone; however, this almost never restores normal form or function. Though several medications have been previously tested, these all fail to target the key pathway involved in HO and they all have detrimental side effects. In addition to Wounded Warriors, HO causes significant disability in hundreds of thousands of civilian and military Veteran patients with burn and orthopedic injuries. Over 80% of patients with open reduction and internal fixation procedures and close to 100% of patients undergoing revision joint replacements will develop HO. Thus, to target at-risk patients and prevent HO from forming would potentially benefit a large number of both civilian and military personnel. We offer a scientific revolution for HO management from one of delayed diagnosis and suboptimal treatment to that of early detection with Raman spectroscopy and prevention with novel drugs that prevent HO development.

Potential clinical applications, benefits, and risks: Clinically, we plan to address the two key barriers to improved HO treatment: (1) early diagnostic modalities that will predict which patients will develop HO and (2) drug therapies that prevent HO from forming before it has caused significant disability. We foresee using Raman spectroscopy to detect patients at risk of developing HO and then treating them with our targeted drug therapies to prevent HO formation. Treatment of civilian and military patients at risk of forming HO would be dramatically improved if we could predict which patients are at risk and then target these patients with a specific pharmacologic compound that would inhibit HO from forming. Current imaging techniques such as x-ray, CT, and MRI fail to detect HO before it is too late to intervene. Raman spectroscopy allows detection of HO several weeks before current techniques and the instrumentation is compact, portable, and cost-effective. Identification of which patients are prone to HO progression will limit therapy to those with greatest need, and thus may reduce complications by limiting unnecessary prophylactic treatments in those patients not prone to HO formation. Once we identify at-risk patients, we will employ our novel bone morphogenetic protein (BMP) pathway inhibitors to target the key mechanism behind trauma-induced HO. Whereas current treatment modalities such as non-steroidal anti-inflammatories and radiation target global inflammation, our treatment strategy targets the central pathway of HO formation. We present an innovative approach to attack HO in those high-risk patients and demonstrate a link between specific BMPs and HO. In addition, we propose the use of a military and civilian animal model that can help to elucidate the mechanism behind our pharmacologic intervention.

Projected timeline and expected patient-related outcomes: In this proposal, we plan to rapidly deploy our working Raman spectroscopic techniques as well as our optimized pharmacologic interventions. In the first 24 months, we will demonstrate the ability our novel small molecules to inhibit osteogenic differentiation of those cells responsible for HO formation in two small animal models of blast/amputation injury and burn/trauma injury. In the last 12 months, we will expand our cell populations of rodent and human HO tissues and demonstrate the efficacy of our BMP inhibitors on these cell lines. At the end of this proposal, we plan to submit an investigational new drug application to the Food and Drug Administration.

Benefit to Service Members, Veterans, and/or their family members: This proposed research will significantly improve current diagnostic and treatment strategies available to patients who are at risk of developing HO. Through this proposal, we will improve early diagnosis and provide novel targeted pharmacologic interventions to prevent HO in Service Members and Veterans.