Agent-based model provides insight into the mechanisms behind failed regeneration following volumetric muscle loss injury

Skeletal muscle possesses a remarkable capacity for repair and regeneration following a variety of injuries. When successful, this highly orchestrated regenerative process requires the contribution of several muscle resident cell populations including satellite stem cells (SSCs), fibroblasts, macrophages and vascular cells. However, volumetric muscle loss injuries (VML) involve simultaneous destruction of multiple tissue components (e.g., as a result of battlefield injuries or vehicular accidents) and are so extensive that they exceed the intrinsic capability for scarless wound healing and result in permanent cosmetic and functional deficits. In this scenario, the regenerative process fails and is dominated by an unproductive inflammatory response and accompanying fibrosis. The failure of current regenerative therapeutics to completely restore functional muscle tissue is not surprising considering the incomplete understanding of the cellular mechanisms that drive the regeneration response in the setting of VML injury. To begin to address this profound knowledge gap, we developed an agent-based model to predict the tissue remodeling response following surgical creation of a VML injury. Once the model was able to recapitulate key aspects of the tissue remodeling response in the absence of repair, we validated the model by simulating the tissue remodeling response to VML injury following implantation of either a decellularized extracellular matrix scaffold or a minced muscle graft. The model suggested that the SSC microenvironment and absence of pro-differentiation SSC signals were the most important aspects of failed muscle regeneration in VML injuries. The major implication of this work is that agent-based models may provide a much-needed predictive tool to optimize the design of new therapies, and thereby, accelerate the clinical translation of regenerative therapeutics for VML injuries. Author summary For common muscle injuries, such as lacerations or strains, skeletal muscle has the ability to repair itself through a series of highly orchestrated cellular processes. However, in the case of volumetric muscle loss (VML) injuries, a large amount of muscle is removed and the muscle's intrinsic regenerative process fails resulting in the injury filling with fibrotic tissue. Currently there are no therapies that adequately repair muscle tissue for VML injuries, and a contributing factor is that the cellular mechanisms driving the response to these injuries are poorly understood. To aid in addressing this knowledge gap, we have developed an agent-based model to capture the cellular remodeling processes following the creation of a VML injury. We have demonstrated that our model is capable of predicting the key aspects of tissue remodeling following VML injury. Moving forward, our model can be used as a predictive tool to assess the ability of new therapies to repair VML injuries and thereby accelerate the development of improved treatments to the clinic.