Project 459019

Skeletal muscle's oft-noted capacity for regeneration is severely diminished in cases of traumatic injury that result in volumetric muscle loss (VML). This type of injury commonly affects people involved in motor vehicle accidents and military conflicts but a more illustrative example is that of the surfer who has suffered a shark attack bite. At the core of VML pathophysiology is the loss of two critical muscle tissue components: the pro-regenerative muscle stem cells (MuSCs) and the complex network of supporting tissues and ancillary cells that exist to provide the structural and trophic support necessary to re-build and maintain healthy muscle. To address these deficits, the best therapeutic approaches have aimed to reconstitute both the ablated MuSC population and the supportive environment in which they thrive. Though many experimental therapies have been successful in generating de novo muscle tissue in areas affected by VML, few have demonstrated long-term functional regeneration that matches that of healthy undamaged muscle tissue. Even then, efficient scalability of such therapies often limits their translational applicability. Our work aims to generate cellularized scaffolds using cross-linkable natural polymers combined with novel synthetic compounds. We have demonstrated that these synthetic muscle fibers mimic muscle's physical properties by encouraging MuSCs to align into functional muscle fibers. The next steps of this work will involve the delivery of pro-regenerative growth factors precisely within the area of damaged muscle using target-specific techniques made possible by the introduction of synthetic gene circuits to cells used in the proposed therapy. Ultimately, our goal with this approach is to deliver edited iPSC-derived MuSCs within an environment that supports both the immediate repair of VML injuries and the long-term maintenance of this de novo muscle tissue through preservation of a MuSC population in vivo.