Hydrogels for Skeletal Muscle Regeneration: Design, Fabrication, and Future Applications

Skeletal muscle plays a crucial role in metabolic homeostasis, but severe injuries such as volumetric muscle loss (VML) compromise its regenerative capacity. Current clinical strategies have limitations, prompting the exploration of alternative therapies. Hydrogels, with their tunable properties, are promising for modulating the regenerative microenvironment and supporting muscle regeneration. While existing reviews have addressed hydrogels in muscle regeneration, this comprehensive Review offers a uniquely integrated and in-depth examination of the field. We systematically investigate design principles, advanced fabrication strategies, and critical considerations for translational application, including electroactive, immunomodulatory, and spatiotemporal delivery functionalities, alongside state-of-the-art techniques such as 3D bioprinting and electrospinning. Furthermore, this Review thoroughly assesses the multifaceted challenges in clinical translation, meticulously addressing preclinical limitations, scalability, manufacturability, regulatory pathways, and long-term safety, thereby providing a more comprehensive discourse than often encountered in existing literature. By integrating insights from muscle biology and advanced materials science, this review aims to offer a refined perspective on overcoming current barriers, informing the development of next-generation hydrogel-based therapies for severe skeletal muscle injuries.