The engineering of three-dimensional (3D) bioartificial skeletal muscle holds promise for the treatment of a variety of muscle diseases and injuries, including muscular dystrophy, traumatic muscle damage, prolonged denervation, and cardiac infarction. To improve impaired muscle function, bioartificial skeletal muscle should survive and rapidly vascularize and innervate in vivo while containing sufficient numbers of aligned muscle fibers to generate the necessary contractile force. However, state-of-the-art engineered skeletal muscle tissues consist of only a few hundred ?m thick sheets or muscle bundles that generate active forces too small to be clinically used for direct repair of muscle damage. Therefore, we propose to develop a novel, reproducible tissue engineering approach to fabricate relatively large skeletal muscle tissues made of aligned and differentiated muscle fibers that generate forces comparable to those of native muscle. To achieve this goal, we will integrate expertise in 3D tissue microfabrication and muscle mechanotransduction with non-invasive imaging of tissue growth and function in vitro and vascularization in vivo. Specifically, we will: 1) fabricate porous aligned skeletal myoblast networks using a cell/hydrogel micromolding approach and by stacking multiple networks create thicker skeletal muscle constructs, 2) enhance the functional properties of the muscle constructs using optimized regimens of electromechanical stimulation, and 3) endothelialize the muscle constructs with different pore sizes to optimize for construct survival and force production after implantation in a rat dorsal skinfold chamber. The obtained knowledge and technologies developed in this proposal can be applied in the future to create other tissues with complex architecture.

Public Health Relevance

A variety of muscular diseases and injuries, including muscular dystrophy, craniofacial defects, traumatic injury and cardiac infarction would benefit from the implantation of a functional bioartificial muscle. This proposal describes a novel tissue engineering approach to fabricate relatively large bioartificial muscle tissues made of aligned and differentiated muscle fibers with potential to be used for experimental studies and tissue replacement therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR055226-05
Application #
8308566
Study Section
Special Emphasis Panel (ZRG1-MOSS-L (03))
Program Officer
Nuckolls, Glen H
Project Start
2008-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$326,177
Indirect Cost
$117,089
Name
Duke University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Cheng, Cindy S; Ran, Lydia; Bursac, Nenad et al. (2016) Cell Density and Joint microRNA-133a and microRNA-696 Inhibition Enhance Differentiation and Contractile Function of Engineered Human Skeletal Muscle Tissues. Tissue Eng Part A 22:573-83
Juhas, Mark; Ye, Jean; Bursac, Nenad (2016) Design, evaluation, and application of engineered skeletal muscle. Methods 99:81-90
Shadrin, I Y; Khodabukus, A; Bursac, N (2016) Striated muscle function, regeneration, and repair. Cell Mol Life Sci 73:4175-4202
Bursac, Nenad; Juhas, Mark; Rando, Thomas A (2015) Synergizing Engineering and Biology to Treat and Model Skeletal Muscle Injury and Disease. Annu Rev Biomed Eng 17:217-42
Madden, Lauran; Juhas, Mark; Kraus, William E et al. (2015) Bioengineered human myobundles mimic clinical responses of skeletal muscle to drugs. Elife 4:e04885
Rangarajan, Swathi; Madden, Lauran; Bursac, Nenad (2014) Use of flow, electrical, and mechanical stimulation to promote engineering of striated muscles. Ann Biomed Eng 42:1391-405
Cheng, Cindy S; Davis, Brittany N J; Madden, Lauran et al. (2014) Physiology and metabolism of tissue-engineered skeletal muscle. Exp Biol Med (Maywood) 239:1203-14
Juhas, Mark; Engelmayr Jr, George C; Fontanella, Andrew N et al. (2014) Biomimetic engineered muscle with capacity for vascular integration and functional maturation in vivo. Proc Natl Acad Sci U S A 111:5508-13
Juhas, Mark; Bursac, Nenad (2014) Roles of adherent myogenic cells and dynamic culture in engineered muscle function and maintenance of satellite cells. Biomaterials 35:9438-46
Juhas, Mark; Bursac, Nenad (2013) Engineering skeletal muscle repair. Curr Opin Biotechnol 24:880-6

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