Engineered Skeletal Muscle Units for Repair of Volumetric Muscle Loss in the Tibialis Anterior Muscle of a Rat

VanDusen, Keith W.; Syverud, Brian C; Williams, Michael L.; Lee, Jonah D.; Larkin, Lisa M.

doi:10.1089/ten.tea.2014.0060

Cited by 105 publications

(120 citation statements)

References 35 publications

(34 reference statements)

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“…Preclinical models of extremity VML have been developed in various species, including mice [Machingal et al, 2011;Page et al, 2011;Rossi et al, 2011;Corona et al, 2012], rats [Merritt et al, 2010;Wu et al, 2012;Corona et al, 2013a, b;Willett et al, 2013;Aurora et al, 2014;Garg et al, 2014a, c;Li et al, 2014;Pilia et al, 2014;VanDusen et al, 2014;Garg et al, 2015], dogs [Turner et al, 2012], and pigs [unpubl. data] ( fig.…”

Section: Models Of Extremity Vmlmentioning

confidence: 99%

Pathophysiology of Volumetric Muscle Loss Injury

Corona

Wenke

Ward

2016

Cells Tissues Organs

125

108

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Volumetric muscle loss (VML) injuries are prevalent in civilian and military trauma patients and are known to impart chronic functional deficits. The frank loss of muscle tissue that defines VML injuries is beyond the robust reparative and regenerative capacities of mammalian skeletal muscle. Given the nature of VML injuries, there is a clear need to develop therapies that promote de novo regeneration of skeletal muscle fibers, which can integrate with the remaining musculature and restore muscle strength. However, the pathophysiology of VML injuries is not completely defined, and, therefore, there may be other opportunities to improve functional outcomes other than de novo regeneration. Herein, clinical and preclinical studies of VML were reviewed to ascertain salient manifestations of VML injury that can impair limb function and muscle strength. The limited clinical data available highlighted proliferative fibrosis secondary to VML injury as a viable target to improve limb range of motion. Selected preclinical studies that used standardized neuromuscular functional assessments broadly identified that the muscle mass remaining after VML injury is performing suboptimally, and, therefore, percent VML strength deficits are significantly worse than can be explained by the initial frank loss of contractile machinery. Potential mechanisms of suboptimal strength of the remaining muscle mass suggested within the literature include intramuscular nerve damage, muscle architectural perturbations, and diminished transmission of force. Collectively, both clinical and preclinical data indicate a complex pathophysiology after VML that presents multiple therapeutic targets. This is a work of the US Government and is not subject to copyright protection in the USA. Foreign copyrights may apply. Published by S. Karger AG, Basel

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Section: Models Of Extremity Vmlmentioning

confidence: 99%

Pathophysiology of Volumetric Muscle Loss Injury

Corona

Wenke

Ward

2016

Cells Tissues Organs

125

108

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“…Engineered tissues to date, however, have been characterized by a neonatal phenotype in terms of force production and structural maturity. 6,7 Following sufficient recovery time, engineered skeletal muscles implanted into an in vivo regenerative environment have advanced toward the adult phenotype, 8,9 and several studies have attempted to utilize key chemical and mechanical stimuli to improve the maturity of these engineered muscles in vitro. 10,11 Tissue engineers have used the influence of such growth factors on myogenesis to direct techniques for engineering skeletal muscle.…”

mentioning

confidence: 99%

“…10,11 Tissue engineers have used the influence of such growth factors on myogenesis to direct techniques for engineering skeletal muscle. Current tissue engineering techniques utilize scaffold materials, ranging from acellularized tissues 12,13 to collagen and fibrin hydrogels, 3,6,14 or opt for a scaffold-free approach 7,9,15 to support development of extracellular matrix (ECM) for subsequent muscle tissue. The ultimate success of these approaches depends on the in vitro culture of isolated primary muscle precursor cells.…”

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confidence: 99%

“…9 The articles referenced above regarding DEX activity in vitro describe its effects on the immortal C2C12 mouse myoblast cell line in two-dimensional culture, rather than the primary cell population and functional three-dimensional (3D) constructs used in our SMU experiments. We hypothesized that exposing the heterogeneous pool of satellite cells and fibroblasts used for SMU fabrication to different doses of DEX at several time points may yield an optimal combination for improving myogenesis and ultimately maximizing in vitro development of our engineered skeletal muscle.…”

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confidence: 99%

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Effects of Dexamethasone on Satellite Cells and Tissue Engineered Skeletal Muscle Units

Syverud

VanDusen

Larkin

2016

Tissue Engineering Part A

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Tissue engineered skeletal muscle has potential for application as a graft source for repairing soft tissue injuries, a model for testing pharmaceuticals, and a biomechanical actuator system for soft robots. However, engineered muscle to date has not produced forces comparable to native muscle, limiting its potential for repair and for use as an in vitro model for pharmaceutical testing. In this study, we examined the trophic effects of dexamethasone (DEX), a glucocorticoid that stimulates myoblast differentiation and fusion into myotubes, on our tissue engineered three-dimensional skeletal muscle units (SMUs). Using our established SMU fabrication protocol, muscle isolates were cultured with three experimental DEX concentrations (5, 10, and 25 nM) and compared to untreated controls. Following seeding onto a laminin-coated Sylgard substrate, the administration of DEX was initiated on day 0 or day 6 in growth medium or on day 9 after the switch to differentiation medium and was sustained until the completion of SMU fabrication. During this process, total cell proliferation was measured with a BrdU assay, and myogenesis and structural advancement of muscle cells were observed through immunostaining for MyoD, myogenin, desmin, and a-actinin. After SMU formation, isometric tetanic force production was measured to quantify function. The histological and functional assessment of the SMU showed that the administration of 10 nM DEX beginning on either day 0 or day 6 yielded optimal SMUs. These optimized SMUs exhibited formation of advanced sarcomeric structure and significant increases in myotube diameter and myotube fusion index, compared with untreated controls. Additionally, the optimized SMUs matured functionally, as indicated by a fivefold rise in force production. In conclusion, we have demonstrated that the addition of DEX to our process of engineering skeletal muscle tissue improves myogenesis, advances muscle structure, and increases force production in the resulting SMUs.

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“…Successful construction of such a muscle tissue can not only shed light on the muscle formation process 1 but can also open the door to creating organ mimics for drug screening and drug development, replacing expensive animal models, especially if the essential mechanics and biology can be recapitulated in the in vitro system. Similarly, developing in vitro methodologies for muscle formation will allow engineers to build medical implants using biological materials, 2 realize novel soft robotics and biological machines, and interface these synthetic components with other naturally occurring systems.…”

mentioning

confidence: 99%

Mechanical Characterization and Shape Optimization of Fascicle-Like 3D Skeletal Muscle Tissues Contracted with Electrical and Optical Stimuli

Neal

Sakar

Bashir

et al. 2015

Tissue Engineering Part A

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In this study, we present a quantitative approach to construct effective 3D muscle tissues through shape optimization and load impedance matching with electrical and optical stimulation. We have constructed long, thin, fascicle-like skeletal muscle tissue and optimized its form factor through mechanical characterization. A new apparatus was designed and built, which allowed us to measure force-displacement characteristics with diverse load stiffnesses. We have found that (1) there is an optimal form factor that maximizes the muscle stress, (2) the energy transmitted to the load can be maximized with matched load stiffness, and (3) optical stimulation using channelrhodopsin2 in the muscle tissue can generate a twitch force as large as its electrical counterpart for well-developed muscle tissue. Using our tissue construct method, we found that an optimal initial diameter of 500 mm outperformed tissues using 250 mm by more than 60% and tissues using 760 mm by 105%. Using optimal load stiffness, our tissues have generated 12 pJ of energy per twitch at a peak generated stress of 1.28 kPa. Additionally, the difference in optically stimulated twitch performance versus electrically stimulated is a function of how well the overall tissue performs, with average or better performing strips having less than 10% difference. The unique mechanical characterization method used is generalizable to diverse load conditions and will be used to match load impedance to muscle tissue impedance for a wide variety of applications.

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Engineered Skeletal Muscle Units for Repair of Volumetric Muscle Loss in the Tibialis Anterior Muscle of a Rat

Cited by 105 publications

References 35 publications

Pathophysiology of Volumetric Muscle Loss Injury

Pathophysiology of Volumetric Muscle Loss Injury

Effects of Dexamethasone on Satellite Cells and Tissue Engineered Skeletal Muscle Units

Mechanical Characterization and Shape Optimization of Fascicle-Like 3D Skeletal Muscle Tissues Contracted with Electrical and Optical Stimuli

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