Cell-scale porosity minimizes foreign body reaction and promotes innervated myofiber formation after volumetric muscle loss

Volumetric muscle loss (VML) from severe traumatic injuries results in irreversible loss of contractile tissue and permanent functional deficits. These injuries resist endogenous healing and clinical treatment due to excessive inflammation, leading to fibrosis, muscle fiber denervation, and impaired regeneration. Using a rodent tibialis anterior VML model, this study demonstrates microporous annealed particle (MAP) hydrogel scaffolds as a biomaterial platform for improved muscle regeneration. Unlike bulk (nanoporous) hydrogel scaffolds, MAP scaffolds enhance integration by preventing a foreign body reaction, slowing implant degradation, and promoting regenerative macrophage polarization. Cell migration and angiogenesis occur throughout the implant before MAP scaffold degradation, with muscle fibers and neuromuscular junctions forming within the scaffolds. These structures continue developing as the implant degrades, suggesting MAP hydrogel scaffolds offer a promising therapeutic approach for VML injuries.