Bioinspired Hydrogel-Based Regenerative Engineering Strategies for the Structural and Functional Regeneration of Skeletal Muscles Following Volumetric Muscle Loss

Abstract

Skeletal muscle is a highly organized tissue composed of densely packed, uniaxially aligned myofibers that enable directional force generation and normal motor function. Although skeletal muscle has robust endogenous regenerative capacity, this response is overwhelmed by volumetric muscle loss (VML), which heals through fibrosis and scarring rather than functional regeneration, causing permanent structural and functional deficits. Current treatments, including autologous muscle transfer, remain limited by donor-site morbidity, restricted tissue availability, and incomplete restoration of muscle form and function. Thus, a major knowledge gap remains: the lack of an implantable, scalable construct capable of recapitulating native muscle architecture, mechanics, and function. Skeletal muscle regenerative engineering (SMRE), which integrates suitable cell sources, advanced biomaterials, and biomimetic fabrication strategies, offers a promising approach to address this gap. Hydrogels are particularly attractive for SMRE because of their high water content, muscle-like viscoelasticity, tunable properties, and compatibility with biochemical functionalization and diverse fabrication methods. Herein, we critically review hydrogel-based SMRE strategies for engineering myo-mimetic skeletal muscle constructs, including cell sources, hydrogel systems, anisotropic organization cues, and fabrication methods. We further examine key translational barriers, including vascularization, immune response, cell maturation, scalability, and manufacturing reproducibility, and outline actionable future directions for clinical translation.