Book excerpt: Volumetric muscle loss (VML), characterized by an irreversible loss of skeletal muscle due to trauma or surgery, is accompanied by severe functional impairment and long-term disability. Tissue engineering strategies combining stem cells and biomaterials hold great promise for skeletal muscle regeneration. However, scaffolds, including decellularized extracellular matrix, hydrogels, and electrospun fibers, used for VML applications generally lack macroporosity. As a result, the aforementioned scaffolds typically delay host cell infiltration, transplanted cell proliferation, and new tissue formation. In this dissertation, I will present our work on engineering macroporous hydrogel scaffolds to enhance stem cell treatment of VML. We show that scaffold macroporosity improved muscle stem cell proliferation in vitro and in vivo. In addition, scaffold macroporosity promoted early scaffold cellularization, endothelialization, and establishment of a pro-regenerative immune microenvironment in a mouse VML model. Moreover, we found that the macroporous hydrogels enhanced muscle tissue regeneration and recovery of muscle function four weeks after implantation. Finally, we demonstrated the scalability of our approach, with respect to scaffold fabrication and therapeutic efficacy, using a rat VML model. Together, our results validate macroporous hydrogels as novel scaffolds for VML treatment and skeletal muscle regeneration.