Development and Evaluation of Outcome Metrics for Neuromuscular Injury Therapeutics

Neuromuscular injuries, particularly those involving volumetric muscle loss (VML) and nerve trauma, present significant challenges in functional recovery. This dissertation develops and evaluates novel outcome metrics for assessing neuromuscular injury repair and the efficacy of therapeutic interventions. A kinetic analysis of muscle contraction and force-frequency relationships was performed in both a nerve laceration model and historical neuromuscular injury datasets, revealing distinct functional consequences of varying injury severities and repair strategies. A major contribution of this work is fibcon, a morphological analysis pipeline that leverages spatial autocorrelation methods to quantify heterogeneities in myofiber size distributions. Applied to VML-injured and treated tissues, fibcon identified previously undetected differences in spatial organization of myofiber sizes, demonstrating that myofiber size distributions are not random but follow patterns that are disrupted by injury. This method was further applied to investigate the impact of concomitant nerve and muscle injuries on muscle repair. Additionally, this dissertation evaluates tissue-engineered muscle repair (TEMR) constructs in both anterior and posterior compartment injuries, assessing maximal isometric force, contraction kinetics, and motion capture gait biomechanics. Results indicate that functional recovery is not solely dependent on restoring muscle mass or myofiber size distributions but also requires neuromuscular adaptation. Notably, gait biomechanics suggested that neuromuscular compensation mechanisms differ between muscle groups, emphasizing the need for future work studying injury-specific rehabilitation strategies. This work establishes a framework for evaluating neuromuscular injuries, integrating functional, morphological, and spatial analyses. The findings provide tools that will help define more objective outcome metrics for refining regenerative neuromuscular therapies.