Novel muscle-derived extracellular matrix hydrogel promotes angiogenesis and neurogenesis in volumetric muscle loss

•Creation and characterization of muscle-derived extracellular matrix hydrogels from TSP2 KO mice shows altered composition, assembly, and biomechanical properties when compared to WT.•TSP2 KO hydrogels allow greater myocyte spreading and invasion as well increased tube formation by endothelial cells in vitro.•In vivo study showed excellent foreign body response of TSP2 KO hydrogels associated with enhanced cell invasion, innervation, and angiogenesis.•TSP2 KO hydrogels were used to treat VML injury in mice and were found to induce greater recruitment of repair cells and enhanced tissue remodeling. Volumetric muscle loss (VML) represents a clinical challenge due to the limited regenerative capacity of skeletal muscle. Most often, it results in scar tissue formation and loss of function, which cannot be prevented by current therapies. Decellularized extracellular matrix (DEM) has emerged as a native biomaterial for the enhancement of tissue repair. Here, we report the generation and characterization of hydrogels derived from DEM prepared from WT or thrombospondin (TSP)-2 null muscle tissue. TSP2-null hydrogels, when compared to WT, displayed altered architecture, protein composition, and biomechanical properties and allowed enhanced invasion of C2C12 myocytes and chord formation by endothelial cells. They also displayed enhanced cell invasion, innervation, and angiogenesis following subcutaneous implantation. To evaluate their regenerative capacity, WT or TSP2 null hydrogels were used to treat VML injury to tibialis anterior muscles and the latter induced greater recruitment of repair cells, innervation, and blood vessel formation and reduced inflammation. Taken together, these observations indicate that TSP2-null hydrogels enhance angiogenesis and promote muscle repair in a VML model.