Skeletal Muscle Salvage and Repair Following Extremity Trauma

Extremity trauma may manifest in any number of ways, and can impact civilians and military service members alike. The impact of such injuries includes pain, reduced range of motion or functionality, and an overall negative impact to quality of life. While traditional treatments and current standard of care can alleviate symptoms and stop further deterioration, regenerative medicine and tissue engineered therapeutics represent a new opportunity to further improve muscle quality and function following trauma.

This dissertation focuses on two major injuries of the extremities: ischemic injury and rotator cuff tear. Clinically-relevant animal models of injury are invaluable tools for developing and evaluating therapeutics, and are a major focus of this work. We first established a rat model of hindlimb ischemia utilizing a tourniquet. This model was representative of battlefield conditions requiring extended tourniquet use, and allowed for the evaluation of muscle salvage therapeutics. Specifically, particulate oxygen generators (POGs) can provide oxygen to ischemic muscle via direct injection, making these compounds useful for field application during the time of tourniquet application. We evaluated two formulations of POGs in the rat hindlimb through a longitudinal study of muscle contractile function, as well as an evaluation of microscopic markers of muscle injury. These metrics allowed us to identify a potential therapeutic for improving muscle function following tourniquet-induced ischemic injury.

We then looked to establish a model of rotator cuff (RC) tear and atrophy development in the rat shoulder. The model involved a period of tendon detachment to allow degenerative changes in the muscle to take effect, as many clinical RC tears develop over time. The tendon was then reattached following injury to create a clinically relevant model of repair. Even after repair, injured muscles show little improvement in the degenerative changes, and are at risk for re-tear. We therefore evaluated both unrepaired and repaired muscle using functional and histological metrics, providing insight into the changes within the muscle and how those changes impact function. The insights gained from this model and the muscle evaluation can inform the development of future therapeutics and provide a biologically relevant preclinical platform for their evaluation.

Altogether, the work presented in this dissertation demonstrates the value of establishing biologically relevant animal models for development and evaluation of therapeutics for addressing some key aspects of extremity trauma. We evaluated the ability of POGs to improve function over time in a validated model of ischemic injury to the hindlimb and identified a promising formulation for further exploration. We also measured the effect of both RC injury and delayed repair using another validated animal model of RC injury that allows for evaluation of both functional and histological changes, providing insight into potential mechanisms of injury that may shed light on improved treatment options. Future work can build on this initial work to allow for rigorous assessment of therapeutics for muscle salvage and repair/regeneration in the setting of trauma to the extremities.