Designing Biomaterials for Skeletal Muscle Tissue Engineering Following Volumetric Muscle Loss Injury

Skeletal muscle possesses an innate ability to heal and repair from most injuries that the body sustains by employing a carefully orchestrated wound healing response. However, following a significant loss of muscle tissue, volumetric muscle loss (VML) injuries trigger an aberrant wound healing response, characterized by chronic inflammation and extensive fibrosis, that results in minimal tissue regeneration and long-term functional impairment. The current standard of care for VML injuries often fails to restore functional muscle tissue and has prompted researchers to develop engineered biomaterial systems as platforms for repair. While significant advancements have shown considerable promise, many of these material systems fail to recreate key biophysical features that are essential for skeletal muscle repair. Additionally, there is a need to better understand how biophysical properties impact the dynamic cellular microenvironment following VML injury to promote regeneration and inform subsequent therapeutic design. To address this need, we have designed novel biomaterials that recapitulate features of the skeletal muscle microenvironment to elucidate fundamental cellular mechanisms responsible for functional tissue repair after VML injuries.

This thesis focuses on the development and characterization of biomaterial systems to promote skeletal muscle repair following complex VML injuries. Chapter 1 provides a review of the mechanisms governing skeletal muscle development and repair post VML, while providing an overview of the various biomaterials systems and fabrication techniques that have been used to treat traumatic injuries. In Chapter 2, we examine the role material biophysical properties play in modulating the wound healing response post-VML. We developed a photo-reactive hydrogel system with controllable mechanical properties that approximated developmental to adult muscle stiffness. We then evaluated functional recovery and de novo myogenesis in a Latissimus Dorsi (LD) injury model. In Chapter 3, we developed conductive and aligned 3D scaffolds for skeletal muscle tissue engineering. Through the addition of conductive polypyrrole (PPy) particles to an established collagen-glycosaminoglycan (CG) scaffold, we were able mimic the electrical properties of native muscle tissue and facilitate improved myogenic cell differentiation in vitro. Chapter 4 describes the use of a Tibialis Anterior (TA) VML injury model to assess the in vivo efficacy of conductive PPy-doped CG scaffolds to repair skeletal muscle tissue. Scaffolds were surgically administered to the TA VML injury and functional recovery was assessed over time. In Chapter 5, we aimed to further explore how changes in scaffold electrical properties and architecture influenced myoblast cell behavior. We synthesized scaffolds with distinct conductive polymers and pore architecture to track cell metabolic activity, organization, and differentiation. Chapter 6 concludes the thesis with a summary of the presented work and expands on potential avenues of future work to design biomaterial systems for muscle repair. Together, these studies present a framework for designing instructive biomaterials to modulate the wound healing response and support improve regenerative outcomes following VML injury.