Injectable Biomaterials for Skeletal Muscle Regeneration

Skeletal muscle injury is a leading cause of diminished quality of life and morbidity in adults, with limited therapeutic interventions. Synthetic and naturally-derived biomaterials provide a potential avenue for novel treatment modalities that address unmet clinical needs. These materials can improve delivery of biological therapeutics or serve as acellular scaffolds for stimulating endogenous tissue repair processes. The goals of this dissertation were to investigate the efficacy of a decellularized skeletal muscle matrix hydrogel in tissue specific regeneration and to design tunable enzyme-targeted nanoparticles for minimally invasive delivery to ischemic muscle. An injectable decellularized skeletal muscle matrix hydrogel has previously been developed by our lab as a therapy to improve perfusion to ischemic skeletal muscle in a preclinical peripheral artery disease model. To better understand how the skeletal muscle matrix induces beneficial effects, transcriptomic analysis of matrix or saline-injected muscle was performed in both ischemic and acute muscle regeneration models. We showed that the skeletal muscle matrix increased cell survival, neovascularization, and muscle regeneration and confirmed these pathways through histological analysis at short, medium, and long time points. In acute muscle regeneration, the skeletal muscle matrix increased the density of skeletal muscle progenitors over non-specific controls (lung matrix or saline). This suggests the tissue specific source of the decellularized matrix can have an effect on regenerative pathways. Enzyme-targeted nanoparticles are an alternative biomaterial approach for more minimally invasive therapeutic delivery as they can be injected intravenously and will target ischemic tissue due to overexpression of matrix metalloproteinases. We were the first group to show minimally invasive targeting of peptide-polymer nanoparticles to ischemic skeletal muscle. We also showed tunable nanoparticle targeting through altering the packing density of enzyme cleavable peptide and the surface charge of the nanoparticles