Biomimetic engineered muscle with capacity for vascular integration and functional maturation in vivo
Edited by Robert Langer, Massachusetts Institute of Technology, Cambridge, MA, and approved March 7, 2014 (received for review February 14, 2014)
Significance
Engineering of highly functional skeletal muscle tissues can provide accurate models of muscle physiology and disease and aid treatment of various muscle disorders. Previous tissue-engineering efforts have fallen short of recreating structural and contractile properties of native muscle in vitro. Here, we describe the creation of biomimetic skeletal muscle tissues with structural, functional, and myogenic properties characteristic of native muscle and contractile stress values that surpass those of neonatal rat muscle. When implanted and real-time imaged in live animals, engineered muscle grafts undergo robust vascularization and perfusion, exhibit continued myogenesis, and show further improvements in intracellular calcium handling and contractile function. This process is significantly enhanced by myogenic predifferentiation and formation of aligned muscle architecture in vitro.
Abstract
Tissue-engineered skeletal muscle can serve as a physiological model of natural muscle and a potential therapeutic vehicle for rapid repair of severe muscle loss and injury. Here, we describe a platform for engineering and testing highly functional biomimetic muscle tissues with a resident satellite cell niche and capacity for robust myogenesis and self-regeneration in vitro. Using a mouse dorsal window implantation model and transduction with fluorescent intracellular calcium indicator, GCaMP3, we nondestructively monitored, in real time, vascular integration and the functional state of engineered muscle in vivo. During a 2-wk period, implanted engineered muscle exhibited a steady ingrowth of blood-perfused microvasculature along with an increase in amplitude of calcium transients and force of contraction. We also demonstrated superior structural organization, vascularization, and contractile function of fully differentiated vs. undifferentiated engineered muscle implants. The described in vitro and in vivo models of biomimetic engineered muscle represent enabling technology for novel studies of skeletal muscle function and regeneration.
Acknowledgments
We acknowledge R. Kirkton, W. Bian, S. Hinds, E. Krol, A. Ganapathi, and L. Li for technical support. This study was supported by a National Science Foundation Graduate Research Fellowship (to M.J.) and National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant AR055226 (to N.B.).
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Published online: March 31, 2014
Published in issue: April 15, 2014
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Acknowledgments
We acknowledge R. Kirkton, W. Bian, S. Hinds, E. Krol, A. Ganapathi, and L. Li for technical support. This study was supported by a National Science Foundation Graduate Research Fellowship (to M.J.) and National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant AR055226 (to N.B.).
Notes
This article is a PNAS Direct Submission.
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The authors declare no conflict of interest.
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