Biomimetic Scaffolds and Extracellular Matrix-Based Strategies for Myofiber Regeneration in Volumetric Muscle Loss

Abstract: Volumetric Muscle Loss presents a critical challenge involving the traumatic or surgical loss of over 20% of skeletal muscle mass by overwhelming the body’s natural regenerative capacity. It causes functional decline of skeletal muscles leading to reduced quality of life. Current surgical interventions, such as autograft and allograft muscle transfers, often fall short of restoring full mobility frequently causing donor site morbidity and graft failure. The objective of this manuscript is to discuss the role of emerging regenerative strategies focusing on restoring muscle structure and regenerative microenvironment. Recent advances emphasize on extracellular matrix-based therapies that promote myogenesis and vascularization because of their ability to replicate the native structural as well as biochemical attributes leading to muscle fiber regeneration and innervation. Further, incorporation of growth factors like vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1), or stem cells in the scaffolds help to recapitulate the complex structure and signaling of extracellular matrix promoting accelerated healing and recovery as observed in pre-clinical trials. However, despite of positive outcomes, there are challenges like immunogenicity, issues with batch to batch reproducibility, which hinder scalability and translation. Interdisciplinary collaboration between biomaterials science, tissue engineering, and clinical research can serve as solution to resolve this critical issue and will be helpful to advance these technologies potentially shifting the approach of VML therapeutic management from palliative to curative. Plain Language Summary: Volumetric Muscle Loss leads to more than 20% loss of skeletal muscle fibers caused due to trauma or surgical removal. This leads to persistent weakness, impaired movement, and reduced quality of life. Traditional treatments such as muscle autografts or allografts often do not fully restore strength or coordinated function causing complications, including donor site damage, limited graft integration, or immune-related issues. Emerging regenerative approaches aim to rebuild both muscle tissue and its supportive environment. Biomaterial scaffolds designed to mimic the extracellular matrix can promote muscle fiber formation, blood vessel growth, and nerve integration. Incorporating growth factors like VEGF and IGF-1 or therapeutic cells into these scaffolds has shown encouraging results in preclinical studies. However, concerns regarding immune compatibility and manufacturing consistency must be addressed to enable reliable clinical translation. Keywords: skeletal muscle, hyaluronic acid, fibrin, laminin, natural scaffold, synthetic scaffold