Diagnostic and Therapeutic Strategy to Prevent Trauma-Induced Upper-Extremity Muscle Fibrosis and Heterotopic Ossification

Patients This Proposal Will Help: This proposal will develop portable, cost-effective, translatable solutions for early management of combat-related and trauma-induced injury to minimize morbidity and improve recovery in prolonged field care settings. This proposal leverages data from a productive collaboration between military (Uniformed Services University of the Health Sciences) and civilian (University of Michigan) laboratories that have published over 60 publications individually and 10 publications in collaboration that were focused on heterotopic ossification (HO) and muscle fibrosis. Specifically, we will improve early detection and prevention of trauma-induced muscle fibrosis (scar tissue between muscle fibers) and HO (bony tissue formation within muscle and soft tissues surrounding joints), both of which are two of the major complications of extremity, spinal cord, and traumatic brain combat injury and civilian trauma and orthopedic surgery.

Of the 14,788 battle injuries suffered in Operations Iraqi Freedom/New Dawn and Enduring Freedom, over 50% were extremity injuries; an additional 5-20% of the injuries were burn injuries. Of these wounded Soldiers with extremity injuries, over 60% will go on to develop severely debilitating HO and muscle fibrosis, leaving them with pain and a limited range of motion. An additional subset of patients at significant risk of HO-induced joint contractures and fibrosis is patients with traumatic amputations that limit their daily living activities. There are currently no effective early diagnostic or timed preventive strategies for traumatic fibrosis or HO. The overall goal of this proposal is to target a central pathway to prevent trauma-induced HO and fibrosis while minimizing treatment duration using a portable, point-of-care spectral ultrasound (SUSI) to detect HO and guide treatment initiation and duration. Current treatment strategies once fibrosis and HO develops involve surgical removal; however, this fails to restore normal form or function in 75% of patients. Though several medications have been previously trialed, all have negative side effects and all fail to target the early changes that precede HO and fibrosis.

In addition to wounded Soldiers, HO causes significant disability in hundreds of thousands of civilian and military Veteran patients with burn and orthopaedic injuries. Over 80% of patients with fracture repair and close to 100% of patients undergoing revision joint replacements (20% of primary joint replacements) develop HO. Thus, targeting at-risk patients to prevent HO would benefit a large number of both civilian and military personnel. We offer a paradigm shift in the detection and management of HO and fibrosis from delayed diagnosis and surgery to early detection and image-guided therapy to minimize its duration and improve precise patient selection.

Potential Clinical Applications, Benefits, and Risks: Clinically, we plan to address the three key barriers to improved treatment: (1) early diagnostic modalities, (2) timing of therapy to minimize toxicity and maximize efficacy, and (3) therapeutics that prevent fibrosis and HO from forming before it has caused significant tissue and joint destruction and disability. Once we identify at-risk patients, we will employ our inhibitors to target the key mechanism behind traumatic HO and fibrosis. Whereas current non-selective treatment, such as non-steroidal anti-inflammatories and radiation, target global inflammation, our treatment strategy targets the early signals and responsive cells that support and lead to the development of pathologic scar formation and the bony lesions embedded in soft tissues outside of the skeletal structure. We present an innovative approach to target fibrosis and HO in those high-risk patients and demonstrate a link between early hypoxic signaling (low level of oxygen in tissues), fibrosis, and HO. The combination of these techniques makes this proposal an important preclinical study that lends itself to establishing the key data necessary to push forward definitive clinical trials.

Projected Timeline/Expected Patient-Related Outcomes: We will rapidly deploy our treatment interventions. In the first 12 months, we will demonstrate the ability of our therapeutics to block HO in our proven animal models and validate a portable point-of-care diagnostic (SUSI) and timed treatment strategy. In the last 12 months, we will demonstrate that Rapamycin and Amphotericin will prevent fibrosis in our animal extremity trauma models. Upon completion, the Uniformed Services University of the Health Sciences will test these therapies on human cell lines and file a request for Institutional Review Board approval for a clinical trial.

Benefit to Service Members, Veterans, and/or Their Family Members: This proposed research will significantly improve the current diagnostic and treatment strategies that are available to all patients who are at risk of deve .......