Novel Experimental-Modeling Coupled Framework to Accelerate Therapeutic Development for Volumetric Muscle Loss Injuries

Volumetric muscle loss (VML) injuries, where a loss of skeletal muscle results in functional impairment, can result from traumas and combat-related extremity wounds and are challenging to repair for there is a simultaneous loss of resident cells and structures responsible for muscle regeneration. Current preclinical therapeutics for these injuries fail to completely restore functional muscle tissue, and there is a need to better understand the functional and cellular mechanisms of regeneration in VML injuries in order to improve therapeutic design. We hypothesize that a novel experiment-modeling coupled framework will elucidate the mechanisms of VML injuries and serve as a guide to improve the design of therapeutics and experiments prior to expensive in vivo testing.

My dissertation developed two computational models to investigate the functional and cellular mechanisms of regeneration in VML injuries. First, I developed a finite-element (FE) model of in situ testing in the rat latissimus dorsi that provided new biomechanical insights regarding the relationship between VML injury location and corresponding force deficits in the rat LD muscle. The FE model can also be used to inform experimental design, such as injury location, injury size, and treatment effect on force production. Then I shifted focus to better understand cellular mechanisms of VML injuries and built an agent-based model (ABM). The model predicted tissue regeneration following VML injury using the autonomous behaviors of different agents in the model, including fibroblasts, satellite stem cells (SSCs), macrophages, and extracellular matrix. We simulated the tissue response of unrepaired VML injuries and acellular and cellular treatments. The ABM was also extended to identify new strategies for VML injury treatments and found that it was a combination of factors which impaired the regeneration of new muscle fibers within the VML defect. Finally, the ABM was used to guide the design of a novel therapeutic and both computational models informed the experimental design. The ABM predicted that the addition of exogenous IL-10 to VML injuries would improve muscle regeneration, as indicated by the increased presence of fully differentiated SSCs, and this outcome was validated in vivo.

This body of work demonstrates the utility of computational models to inform functional and cellular mechanisms of VML injury regeneration and aid in therapeutic and experimental design. Experimental testing of new therapeutics is a resource-intensive and time-consuming process; however, we have demonstrated that computational tools offer a more cost-effective method to predict the effect of new therapeutics prior to in vivo testing. Moving forward, the experimental-modeling coupled framework has the ability to accelerate the development of more efficacious regenerative therapeutics to the clinic, and eventually, to guide injury specific treatment options for patients.