Reconstruction of Muscle Fascicle-Like Tissues by Anisotropic 3D Patterning

Tissue engineering of skeletal muscle has been proposed as a potential regenerative treatment for extensive muscle damage. In this regard, the highly organized structure of skeletal muscles makes the alignment of cells especially indispensable in muscle tissue engineering. However, achieving the desired alignment continues to prove challenging, particularly in 3D engineered tissue constructs. In this study, a biomimetic approach for the generation of functional skeletal muscle fascicle-like tissues by recapitulating 3D muscle-like cellular and extracellular organization, is demonstrated. Anisotropic 3D alignment of muscle extracellular matrix (MEM) nanofibrils capable of providing a pro-myogenic microenvironment by regulating the kinetics of fibrillogenesis in a stretchable elastomeric chip, is achieved. Reprogrammed muscle progenitor cells develop myofibers along the aligned MEM nanofibrils in a 3D configuration, culminating in the structural and functional maturation of skeletal muscle. The resultant 3D muscle fascicle-like constructs support de novo muscle regeneration and induce functional restoration of injured muscles in animal models inflicted with volumetric muscle loss and congenital muscular dystrophy. This study not only highlights the fundamental roles of the muscle–mimetic structural guidance cues for 3D muscle tissue engineering, but also unveils the clinical potential of artificial muscle constructs in regenerative medicine.