Immunotolerant Oligomer scaffolds promote regenerative remodeling and improved muscle structure and function after volumetric muscle loss.

Volumetric muscle loss (VML) overwhelms endogenous repair mechanisms, leading to defect contraction, fibrosis, and persistent aesthetic and functional deficits. Restorative biomaterials capable of re-establishing muscle structure and function represent promising strategies for treating severe injuries where conventional surgical repair is inadequate. Using a rat full-thickness VML model, we evaluated Oligomer, an engineered collagen polymeric biomaterial, in three prototype scaffold configurations that differed in application format and microstructure, with untreated defects serving as controls. Muscle structure, function, and tissue response were assessed longitudinally, including spatial transcriptomic profiling. Oligomer scaffolds supported regeneration of organized muscle architecture, including aligned myofibers, vascular networks, and integrated neurovascular structures. Higher-density scaffolds preserved defect geometry and yielded greater recovery of muscle mass and contractile function. Spatial transcriptomic analyses defined a regenerative remodeling mechanism distinct from reparative or constructive remodeling, characterized by an immunotolerant environment that enabled infiltration of diverse progenitor populations, including pro-regenerative mesenchymal cells, pericytes, satellite cells, and endothelial and neural stem cells. This cellular niche supported coordinated activation of myogenic, vascular, and neural pathways, recapitulating key aspects of developmental myogenesis. Collectively, these findings establish the mechanistic foundation for Oligomer scaffold-mediated regenerative remodeling and demonstrate its potential as a restorative biomaterial for treatment of VML.