ORIGINAL RESEARCH Hydrogels for Skeletal Muscle Regeneration Kristin M. Fischer 1 & Tracy E. Scott 2 & Daniel P. Browe 2 & Tyler A. McGaughey 1 & Caroline Wood 2 & Michael J. Wolyniak 1 & Joseph W. Freeman 2 Received: 9 August 2019 /Revised: 2 November 2019 /Accepted: 24 December 2019 /Published online: 9 January 2020 # The Regenerative Engineering Society 2020 Abstract Skeletal muscle is made up of hundreds of multinucleated, aligned fibers that work together during contraction. While smaller injuries are typically able to be repaired by the body, large volumetric muscle loss (VML) typically results in loss of function. Tissue engineering (TE) applications that use cells seeded onto hydrogels are one potential option for regenerating the lost tissue. Hydrogels are described as soft crosslinked polymeric networks with high water content that simulates the body’s natural aqueous environment. They can be formulated from many different starting materials into biocompatible, biodegradable systems. Fabrication methods such as electrospinning, freeze-drying, molding, and 3D printing can be used with the hydrogel solution to form 3D structures. In this review, natural, semi-synthetic, synthetic, and composite hydrogels for skeletal muscle regeneration are discussed. It was ascertained that the majority of the current research focused on natural polymeric hydrogels including collagen, gelatin, agarose, alginate, fibrin, chitosan, keratin, and combinations of the aforementioned. This category was followed by a discussion of composite hydrogels, defined in this review as at least one synthetic and one natural polymer combined to form a hydrogel, and these are the next most favored materials. Synthetic polymer hydrogels came in third with semi-synthetic polymers, chemically modified natural polymers, being the least common. While many of the hydrogels show promise for skeletal muscle regeneration, continued investigation is needed in order to regenerate a functional muscle tissue replacement. Lay Summary Skeletal muscle tissue engineering focuses on regenerating large amounts of skeletal muscle tissue lost due to tumor removal, traumatic injuries, and/or disease. Neither natural repair processes by the body nor current medical interventions are able to completely restore function after volumetric muscle loss. Thus, scientists are investigating alternative approaches to regenerate the lost muscle, restore function, and increase patient quality of life. This review paper summarizes the research from 2013 to early 2018 using hydrogels, a soft material with a high water content, as a tool to regenerate muscle. The review is categorized into hydrogels made from natural materials, semi-synthetic materials, synthetic materials, and composite materials (at least one natural and one synthetic material combined). Keywords Volumetric muscle loss . Tissue engineering . Scaffold . Skeletal muscle . Myogenesis . Biomaterials Introduction Skeletal muscle accounts for 30–40% of a human’s total body mass, and its functions include stabilization and movement of the skeleton, guarding entrances/exits to the digestive, respiratory, and urinary systems, generating heat, and protecting internal organs [1–5]. It consists of hundreds of multinucleated, unidirectional fibers that work together with the nervous system to coordinate movement of the entire mus- culoskeletal system [2–4]. After injury, adult skeletal muscle stem cells called satellite cells proliferate, differentiate, and fuse at the site of the injury to fill in and close the gap created by the injury. Satellite cells only account for about 1–5% of muscle cells, and if not enough are not able to accumulate at the injury site, scar tissue may form. In the case of smaller injuries, scar tissue formation may not interfere with the func- tion of the muscle tissue [5–9]. However, traumatic injuries, congenital abnormalities, tumor ablation, and/or denervation lead to larger muscle loss termed volumetric muscle loss * Kristin M. Fischer kfischer@hsc.edu 1 Biology Department, Hampden-Sydney College, Hampden Sydney, VA, USA 2 Biomedical Engineering Department, Rutgers University, Piscataway, NJ, USA Regenerative Engineering and Translational Medicine (2021) 7:353–361 https://doi.org/10.1007/s40883-019-00146-x