Therapeutic Small-Molecule and Timed Limb Stabilization Strategies to Prevent Complications of Extremity Trauma and Enhance Return to Duty

This project aligns with the PRORP focus area for (1) Retention on Duty Strategies: development and/or optimization of battlefield-feasible interventions and/or rehabilitation strategies that can facilitate retention on duty for common combat-related musculoskeletal injuries and (2) Limb Stabilization and Protection: development of rapid limb stabilization and novel wound protectants for severely wounded limbs to enable transport at the point of need. Specifically, we propose to validate an early stabilization protocol and therapeutic intervention to prevent two of the most common complications of extremity trauma that limit return to duty: ischemia-reperfusion injury (IRI) and heterotopic ossification (HO). IRI from tourniquet use leads to muscle fibrosis, acute kidney injury, and liver damage and increases the risk of HO. HO is the pathologic formation of extra-skeletal bone within soft tissues, which occurs in patients with severe trauma and significantly limits return to duty, given its cause of chronic pain and limitation of prosthetic use. This proposal has been developed to specifically address IRI and HO prevention after tourniquet use and extremity trauma and treatment. The goal of this proposal is to validate a new Standard Practice Guideline for a mobilization protocol and a pharmacologic intervention to prevent post-traumatic IRI and HO in patients with severe trauma such as is seen with orthopaedic and blast-related injuries.

With dramatic improvements in survival from combat-related blast injuries due to tourniquet use, we have witnessed a concomitant increase in patients with debilitating injuries that drastically diminish quality of life. Of the nearly 15,000 battle injuries suffered in Operations Iraqi Freedom/New Dawn and Enduring Freedom, over 50% of those injuries were extremity injuries. Of these wounded Soldiers with extremity injuries, over 60% of them will go on to develop HO. HO also causes significant disability in hundreds of thousands of civilians and Veterans with joint arthroplasties, amputations, and orthopaedic injuries. For example, over 80% of patients with fractures and revision joint replacements will develop HO. As a result of forming bone outside of the skeleton, HO causes severe chronic pain, open wounds, and limited range of motion.

Current treatment strategies address HO after its development with surgical excision. However, surgery is unable to restore range of motion, which has often been chronically limited due to HO, cannot address chronic pain, and causes prolonged wounds with poor healing. After excision, patients often develop recurrence within the original tissue bed, which necessitates re-excision, or continues to cause the original signs and symptoms. Though several prophylactic medications have been previously trialed, all have negative side effects and all fail to target the causative signaling mediators that lead to HO. We offer a paradigm shift in the prevention and management of HO through an easily deployed mobilization protocol and pharmacologic targeting mechanotransduction to improve our precision treatment of combat casualties with extremity trauma in a prolonged field care (PFC) scenario.

Potential Clinical Applications, Benefits, and Risks: This proposal is designed to be translatable and simulates the real-world PFC trauma and management that patients may expect to receive. First, we use clinically relevant models of trauma-induced IRI and HO, which are broadly applicable to combat-wounded military personnel and to civilians with significant trauma. Second, we utilize a near clinical pharmacotherapy and mobilization strategy targeting mechanotransduction in the bone formation pathway; this method is highly translatable, cost-effective, and easily implemented. Third, this proposal addresses duration of treatment by selecting a short-time period of treatment to minimize cost, improve adherence, and avoid adverse consequences. The combination of these techniques make this proposal an important preclinical study that lends itself to establishing key data necessary to push forward definitive clinical trials.

Projected Timeline and Expected Patient-Related Outcomes: In this proposal, we plan to rapidly deploy our optimized mobilization protocol and pharmacologic treatment interventions. In the first 12 months, we will validate our therapeutic strategy to prevent HO in our proven extremity trauma models. In the last 12 months, we will determine the precise mobilization protocol and demonstrate the duration timed of immobilization needed to inhibit HO. Upon completion of this proposal's aims, we will test these pharmacotherapies on human HO cell lines in three-dimensional cultures exposed to strain and begin a clinical trial with collaborators at San Antonio Military Medical Center Burn Unit to validate our mobilization protocol.

Short- and/or Long-Term Impact on Patient Care and/or Restoration of Function: This proposed research will significantly improve current occupational therapy and pharmacologic treatment strategies available to all patients who are at risk of developing HO. Through this proposal, we will improve our understanding of the role of mechanotransduction, which stimulates heterotopic ossification. This proposal will lead to a novel, targeted therapy and a mobilization Standard Practice Guideline to prevent HO.