This proposal addresses the Topic Area of “Tissue Regeneration: Development of novel therapies for regeneration of functional skeletal muscle, particularly treatments for volumetric muscle loss.” Combat injury to the extremities commonly results in complex injuries involving both complicated bone fractures and massive loss of skeletal muscle such that the injured person may never be able to function in the same way again due to poor bone healing and permanent loss of strength and dexterity. Therefore, it is of extreme interest to develop treatments to address this type of injury that can regrow the essential components of the injured bones and muscles in the body such that strength and dexterity are sufficiently restored to enable return to duty of the wounded Warrior and ultimately a greater quality of life during and after their service.

Fortunately, clinical evidence has found that healing of complicated bone fractures can be promoted by treating the bone in a staged procedure wherein the bone is stabilized with traditional hardware and a material spacer is used to fill the space previously occupied by bone lost to the injury. A few weeks later, after any infection or heightened inflammation has subsided, the spacer is removed and bone graft is implanted to healing of the fracture. What is often overlooked in these treatment paradigms, however, is the progression the soft tissue wound healing response within adjacent muscle. When left untreated, this process results in scar tissue filling the muscle wound space rather than new muscle tissue that is capable of contracting and generating force. This results in a persistent loss of muscle strength, contributes directly to physical disability, and is a key factor driving elective amputations in patients with these types of injuries. We believe that directly addressing the muscle injury alongside and in a comparable manner to the bone treatment will decrease the disability associated with these injuries allowing the affected Service member to return to duty and function at a high level.

The overall objective of this project is to address this critical clinical need by developing and optimizing of a multi-staged regenerative approach for the muscle that can be used in conjunction with the material spacer approach to promoting bone fracture healing. The overarching hypothesis of the proposed work is that placement of a muscle void filler within injured muscle will prevent the muscle injury from filling with scar tissue and allow for the subsequent implantation of therapies capable re-growing the lost muscle tissue to promote improved whole limb healing and return of function.

This study will test this idea in animal models that mimic the severity of these combat-related injuries to bone and muscle. First, we will systematically design several varied materials to act as muscle injury spacers and test their ability to prevent filling of the muscle injury with scar tissue in a rat model of these bone and muscle injury conditions. The material that best prevents scarring of the muscle injury will be then be used to preserve the muscle injury in our rat model for a period of 4 weeks, after which several therapies intended to help the muscle regrow will be tested for their ability to promote whole limb healing and return to function. The top performer of these therapies will then be tested in a pig model of bone and muscle injury following the same multi-staged treatment strategy previously vetted in the rat. The tests in the pig are very meaningful for the purpose of eventually transitioning this treatment strategy to human use. Due to their large size and similarities to humans in biological processes of wound healing, pigs represent a more difficult challenge to the proposed treatment strategy and thus will give us a better idea of how this treatment might fair in the human.

While simple in its approach, the proposed treatment strategy is not currently a part of standard orthopaedic surgical practice. As such, this research could represent a significant advancement in the understanding of this underrepresented component of care for severe extremity trauma. If successful, the technology developed through these efforts is primed to transition quickly into clinical practice and has the potential to transform the care and quality of life of wounded Warriors.