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.
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).
This is a preview of subscription content, log in to check access.
Buy single article
Instant unlimited access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Bettadapur A, Suh GC, Geisse NA, Wang ER, Hua C, Huber HA, et al. Prolonged culture of aligned skeletal myotubes on micromolded gelatin hydrogels. Sci Rep. 2016;6:1–14. https://doi.org/10.1038/srep28855.
Guyton AC, Hall JE. Textbook of medical physiology. 11th ed. Philadelphia: Elsevier Saunders; 2006.
Martini F, Nath J, Batholomew E. Fundamentals of anatomy and physiology. 10th ed. San Francisco: Pearson/Benjamin Cummings; 2015.
Marieb EN, Hoehn K. Human anatomy & physiology. 8th ed. San Francisco: Benjamin Cummings; 2010.
Scott JB, Ward CL, Corona BT, Deschenes MR, Harrison BS, Saul JM, et al. Achieving acetylcholine receptor clustering in tissue-engineered skeletal muscle constructs in vitro through a materials-directed Agrin delivery approach. Front Pharmacol. 2017;7. https://doi.org/10.3389/fphar.2016.00508.
Fan C, Jiang P, Fu L, Cai P, Sun L, Zeng B. Functional reconstruction of traumatic loss of flexors in forearm with gastrocnemius myocutaneous flap transfer. Microsurgery. 2008;28(1):71–5. https://doi.org/10.1002/micr.20449.
Vekris MD, Beris AE, Lykissas MG, Korompilias AV, Vekris AD, Soucacos PN. Restoration of elbow function in severe brachial plexus paralysis via muscle transfers. Injury. 2008;39:S15–22. https://doi.org/10.1016/j.injury.2008.06.008.
Baniasadi H, Mashayekhan S, Fadaoddini S, Haghirsharifzamini Y. Design, fabrication and characterization of oxidized alginate-gelatin hydrogels for muscle tissue engineering applications. J Biomater Appl. 2016;31(1):152–61. https://doi.org/10.1177/0885328216634057.
Bach AD, Beier JP, Stern-Staeter J, Horch RE. Skeletal muscle tissue engineering. J Cell Mol Med. 2004;8(4):413–22.
Pollot BE, Rathbone CR, Wenke JC, Guda T. Natural polymeric hydrogel evaluation for skeletal muscle tissue engineering. J Biomed Mater Res B Appl Biomater. 2018;106(2):672–9. https://doi.org/10.1002/jbm.b.33859.
Corona BT, Rivera JC, Owens JG, Wenke JC, Rathbone CR. Volumetric muscle loss leads to permanent disability following extremity trauma. J Rehabil Res Dev. 2015;52(7):785–92. https://doi.org/10.1682/jrrd.2014.07.0165.
Garg K, Ward CL, Hurtgen BJ, Wilken JM, Stinner DJ, Wenke JC, et al. Volumetric muscle loss: persistent functional deficits beyond frank loss of tissue. J Orthop Res. 2015;33(1):40–6. https://doi.org/10.1002/jor.22730.
Grogan BF, Hsu JR. Skeletal trauma Res C. Volumetric muscle loss. J Am Acad Orthop Surg. 2011;19:S35–S7.
Goldman SM, Henderson BEP, Walters TJ, Corona BT. Co-delivery of a laminin-111 supplemented hyaluronic acid based hydrogel with minced muscle graft in the treatment of volumetric muscle loss injury. PLoS One. 2018;13(1). https://doi.org/10.1371/journal.pone.0191245.
Kim JT, Kasukonis BM, Brown LA, Washington TA, Wolchok JC. Recovery from volumetric muscle loss injury: a comparison between young and aged rats. Exp Gerontol. 2016;83:37–46. https://doi.org/10.1016/j.exger.2016.07.008.
Baker HB, Passipieri JA, Siriwardane M, Ellenburg MD, Vadhavkar M, Bergman CR, et al. Cell and growth factor-loaded keratin hydrogels for treatment of volumetric muscle loss in a mouse model. Tissue Eng A. 2017;23(11–12):572−+. https://doi.org/10.1089/ten.tea.2016.0457.
Bootsma K, Fitzgerald MM, Free B, Dimbath E, Conjerti J, Reese G, et al. 3D printing of an interpenetrating network hydrogel material with tunable viscoelastic properties. J Mech Behav Biomed Mater. 2017;70:84–94. https://doi.org/10.1016/j.jmbbm.2016.07.020.
Heher P, Maleiner B, Pruller J, Teuschl AH, Kollmitzer J, Monforte X, et al. A novel bioreactor for the generation of highly aligned 3D skeletal muscle-like constructs through orientation of fibrin via application of static strain. Acta Biomater. 2015;24:251–65. https://doi.org/10.1016/j.actbio.2015.06.033.
Hwang JH, Kim IG, Piao S, Jung AR, Lee JY, Park KD, et al. Combination therapy of human adipose-derived stem cells and basic fibroblast growth factor hydrogel in muscle regeneration. Biomaterials. 2013;34(25):6037–45. https://doi.org/10.1016/j.biomaterials.2013.04.049.
De France KJ, Yager KG, Chan KJW, Corbett B, Cranston ED, Hoare T. Injectable anisotropic nanocomposite hydrogels direct in situ growth and alignment of myotubes. Nano Lett. 2017;17(10):6487–95. https://doi.org/10.1021/acs.nanolett.7b03600.
Costantini M, Testa S, Fornetti E, Barbetta A, Trombetta M, Cannata SM, et al. Engineering muscle networks in 3D gelatin methacryloyl hydrogels: influence of mechanical stiffness and geometrical confinement. Front Bioeng Biotechnol. 2017;5:22. https://doi.org/10.3389/fbioe.2017.00022.
Villa C, Martello F, Erratico S, Tocchio A, Belicchi M, Lenardi C, et al. P(NIPAAM-co-HEMA) thermoresponsive hydrogels: an alternative approach for muscle cell sheet engineering. J Tissue Eng Regen Med. 2017;11(1):187–96. https://doi.org/10.1002/term.1898.
Jo H, Sim M, Kim S, Yang S, Yoo Y, Park JH, et al. Electrically conductive graphene/polyacrylamide hydrogels produced by mild chemical reduction for enhanced myoblast growth and differentiation. Acta Biomater. 2017;48:100–9. https://doi.org/10.1016/j.actbio.2016.10.035.
Rich MH, Lee MK, Marshall N, Clay N, Chen JR, Mahmassani Z, et al. Water hydrogel binding affinity modulates freeze-drying-induced micropore architecture and skeletal myotube formation. Biomacromolecules. 2015;16(8):2255–64. https://doi.org/10.1021/acs.biomac.5b00652.
McKeon-Fischer KD, Rossmeisl JH, Whittington AR, Freeman JW. In vivo skeletal muscle biocompatibility of composite, coaxial electrospun, and microfibrous scaffolds. Tissue Eng A. 2014;20(13–14):1961–70. https://doi.org/10.1089/ten.tea.2013.0283.
Wang L, Wu YB, Guo BL, Ma PX. Nanofiber yarn/hydrogel core-shell scaffolds mimicking native skeletal muscle tissue for guiding 3D myoblast alignment, elongation, and differentiation. ACS Nano. 2015;9(9):9167–79. https://doi.org/10.1021/acsnano.5b03644.
Browe DP, Wood C, Sze MT, White KA, Scott T, Olabisi RM, et al. Characterization and optimization of actuating poly(ethylene glycol) diacrylate/acrylic acid hydrogels as artificial muscles. Polymer. 2017;117:331–41. https://doi.org/10.1016/j.polymer.2017.04.044.
Neal D, Sakar MS, Ong L-LS, Asada HH. Formation of elongated fascicle-inspired 3D tissues consisting of high-density, aligned cells using sacrificial outer molding. Lab Chip. 2014;14(11):1907–16. https://doi.org/10.1039/c4lc00023d.
Matthias N, Hunt SD, Wu JB, Lo J, Callahan LAS, Li Y, et al. Volumetric muscle loss injury repair using in situ fibrin gel cast seeded with muscle-derived stem cells (MDSCs). Stem Cell Res. 2018;27:65–73. https://doi.org/10.1016/j.scr.2018.01.008.
Marcinczyk M, Elmashhady H, Talovic M, Dunn A, Bugis F, Garg K. Laminin-111 enriched fibrin hydrogels for skeletal muscle regeneration. Biomaterials. 2017;141:233–42. https://doi.org/10.1016/j.biomaterials.2017.07.003.
Ansari S, Chen C, Xu XT, Annabi N, Zadeh HH, Wu BM, et al. Muscle tissue engineering using gingival mesenchymal stem cells encapsulated in alginate hydrogels containing multiple growth factors. Ann Biomed Eng. 2016;44(6):1908–20. https://doi.org/10.1007/s10439-016-1594-6.
Chen P-Y, Yang K-C, Wu C-C, Yu J-H, Lin F-H, Sun J-S. Fabrication of large perfusable macroporous cell-laden hydrogel scaffolds using microbial transglutaminase. Acta Biomater. 2014;10(2):912–20.
Paguirigan AL, Beebe DJ. Protocol for the fabrication of enzymatically crosslinked gelatin microchannels for microfluidic cell culture. Nat Protoc. 2007;2(7):1782–8.
Ma J, Baker AR, Calabro A, Derwin KA. Exploratory study on the effect of osteoactivin on muscle regeneration in a rat volumetric muscle loss model. PLoS One. 2017;12(4). https://doi.org/10.1371/journal.pone.0175853.
Hagiwara K, Chen G, Kawazoe N, Tabata Y, Komuro H. Promotion of muscle regeneration by myoblast transplantation combined with the controlled and sustained release of bFGFcpr. J Tissue Eng Regen Med. 2016;10(4):325–33. https://doi.org/10.1002/term.1732.
Tomblyn S, Kneller ELP, Walker SJ, Ellenburg MD, Kowalczewski CJ, Van Dyke M, et al. Keratin hydrogel carrier system for simultaneous delivery of exogenous growth factors and muscle progenitor cells. J Biomed Mat Res B. 2016;104(5):864–79. https://doi.org/10.1002/jbm.b.33438.
Passipieri JA, Baker HB, Siriwardane M, Ellenburg MD, Vadhavkar M, Saul JM, et al. Keratin hydrogel enhances in vivo skeletal muscle function in a rat model of volumetric muscle loss. Tissue Eng A. 2017;23(11–12):556−+. https://doi.org/10.1089/ten.tea.2016.0458.
Yi HL, Forsythe S, He YY, Liu Q, Xiong G, Wei SC, et al. Tissue-specific extracellular matrix promotes myogenic differentiation of human muscle progenitor cells on gelatin and heparin conjugated alginate hydrogels. Acta Biomater. 2017;62:222–33. https://doi.org/10.1016/j.actbio.2017.08.022.
Ding K, Yang Z, Zhang YL, Xu JZ. Injectable thermosensitive chitosan/−glycerophosphate/collagen hydrogel maintains the plasticity of skeletal muscle satellite cells and supports their in vivo viability. Cell Biol Int. 2013;37(9):977–87. https://doi.org/10.1002/cbin.10123.
Pepelanova I, Kruppa K, Scheper T, Lavrentieva A. Gelatin-Methacryloyl (GelMA) hydrogels with defined degree of functionalization as a versatile toolkit for 3D cell culture and extrusion bioprinting. Bioengineering. 2018;5(3):55.
Kim MJ, Shin YC, Lee JH, Jun SW, Kim C-S, Lee Y, et al. Multiphoton imaging of myogenic differentiation in gelatin-based hydrogels as tissue engineering scaffolds. Biomater Res. 2016;20:2. https://doi.org/10.1186/s40824-016-0050-x.
Ramon-Azcon J, Ahadian S, Estili M, Liang X, Ostrovidov S, Kaji H, et al. Dielectrophoretically aligned carbon nanotubes to control electrical and mechanical properties of hydrogels to fabricate contractile muscle myofibers. Adv Mater. 2013;25(29):4028–34. https://doi.org/10.1002/adma.201301300.
Hong Y, Yao Y, Wong S, Bian L, Mak AFT. Change in viability of C2C12 myoblasts under compression, shear and oxidative challenges. J Biomech. 2016;49(8):1305–10. https://doi.org/10.1016/j.jbiomech.2016.03.014.
Agrawal G, Aung A, Varghese S. Skeletal muscle-on-a-chip: an in vitro model to evaluate tissue formation and injury. Lab Chip. 2017;17(20):3447–61. https://doi.org/10.1039/c7lc00512a.
Davoudi S, Chin C-Y, Cooke MJ, Tam RY, Shoichet MS, Gilbert PM. Muscle stem cell intramuscular delivery within hyaluronan methylcellulose improves engraftment efficiency and dispersion. Biomaterials. 2018;173:34–46. https://doi.org/10.1016/j.biomaterials.2018.04.048.
Cha SH, Lee HJ, Koh W-G. Study of myoblast differentiation using multi-dimensional scaffolds consisting of nano and micropatterns. Biomater Res. 2017;21(1):1. https://doi.org/10.1186/s40824-016-0087-x.
Vannozzi L, Yasa IC, Ceylan H, Menciassi A, Ricotti L, Sitti M. Self-folded hydrogel tubes for implantable muscular tissue scaffolds. Macromol Biosci. 2018;18(4):1700377. https://doi.org/10.1002/mabi.201700377.
Xu Y, Li Z, Li X, Fan Z, Liu Z, Xie X, et al. Regulating myogenic differentiation of mesenchymal stem cells using thermosensitive hydrogels. Acta Biomater. 2015;26:23–33. https://doi.org/10.1016/j.actbio.2015.08.010.
Hosseinzadeh S, Rezayat SM, Giaseddin A, Aliyan A, Soleimani M. Microfluidic system for synthesis of nanofibrous conductive hydrogel and muscle differentiation. J Biomater Appl. 2018;32(7):853–61. https://doi.org/10.1177/0885328217744377.
McKeon-Fischer KD, Flagg DH, Freeman JW. Coaxial electrospun poly(epsilon-caprolactone), multiwalled carbon nanotubes, and polyacrylic acid/polyvinyl alcohol scaffold for skeletal muscle tissue engineering. J Biomed Mater Res A. 2011;99A(3):493–9. https://doi.org/10.1002/jbm.a.33116.
Mulyasasmita W, Cai L, Dewi RE, Jha A, Ullmann SD, Luong RH, et al. Avidity-controlled hydrogels for injectable co-delivery of induced pluripotent stem cell-derived endothelial cells and growth factors. J Control Release. 2014;191:71–81. https://doi.org/10.1016/j.jconrel.2014.05.015.
Salimath AS, García AJ. Biofunctional hydrogels for skeletal muscle constructs. J Tissue Eng Regen Med. 2016;10(11):967–76. https://doi.org/10.1002/term.1881.
Fuoco C, Sangalli E, Vono R, Testa S, Sacchetti B, Latronico MV, et al. 3D hydrogel environment rejuvenates aged pericytes for skeletal muscle tissue engineering. Front Physiol. 2014;5:203. https://doi.org/10.3389/fphys.2014.00203.
Fuoco C, Rizzi R, Biondo A, Longa E, Mascaro A, Shapira-Schweitzer K, et al. In vivo generation of a mature and functional artificial skeletal muscle. Embo Mol Med. 2015;7(4):411–22. https://doi.org/10.15252/emmm.201404062.
Costantini M, Testa S, Mozetic P, Barbetta A, Fuoco C, Fornetti E, et al. Microfluidic-enhanced 3D bioprinting of aligned myoblast-laden hydrogels leads to functionally organized myofibers in vitro and in vivo. Biomaterials. 2017;131:98–110. https://doi.org/10.1016/j.biomaterials.2017.03.026.
Mozetic P, Giannitelli SM, Gori M, Trombetta M, Rainer A. Engineering muscle cell alignment through 3D bioprinting. J Biomed Mater Res A. 2017;105(9):2582–8. https://doi.org/10.1002/jbm.a.36117.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Fischer, K.M., Scott, T.E., Browe, D.P. et al. Hydrogels for Skeletal Muscle Regeneration. Regen. Eng. Transl. Med. (2020) doi:10.1007/s40883-019-00146-x
- Volumetric muscle loss
- Tissue engineering
- Skeletal muscle