Cell-scale porosity in microporous annealed particle (MAP) scaffolds modulates immune response and promotes formation of innervated muscle fibers in volumetric muscle loss injuries

Volumetric muscle loss (VML) is caused by severe traumatic injuries to skeletal muscle and is characterized by the irreversible loss of contractile tissue and permanent functional deficits. VML injuries cannot be healed by endogenous mechanisms and are exceptionally difficult to treat in the clinic due to the excessive upregulation of the inflammatory response, which leads to fibrosis, denervation of muscle fibers, and impaired regeneration. These injuries lead to long-term disability. Using a rodent model of VML in the tibialis anterior, this study presents microporous annealed particle (MAP) hydrogel scaffolds as a biomaterial platform for improved muscle regeneration in VML injuries, specifically highlighting the benefits of cell-scale porosity. In contrast to bulk (i.e., nanoporous) hydrogel scaffolds, MAP scaffolds promote integration by avoiding the foreign body response, decreasing the rate of implant degradation, and shifting macrophage polarization to favor regeneration. In addition, cell migration and angiogenesis throughout the implant precede the degradation of MAP scaffolds, including the formation of muscle fibers and neuromuscular junctions within MAP scaffolds prior to degradation. These fibers and junctions continue to develop as the implant degrades, indicating that MAP hydrogel scaffolds are a promising therapeutic approach for VML injuries.