Microfluidic device for the formation of optically excitable, three-dimensional, compartmentalized motor units

Uzel, Sebastien G. M.; Platt, Randall J.; Subramanian, Vidya; Pearl, Taylor M.; Rowlands, Christopher J.; Chan, Vincent; Boyer, Laurie A.; So, Peter T. C.; Kamm, Roger D.

doi:10.1126/sciadv.1501429

Cited by 185 publications

(178 citation statements)

References 92 publications

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“…To attain MNs, we induced mESCs (HBG3 mESCs, from a transgenic mouse cell line) to directly differentiate using a protocol that recapitulates spinal MN maturation in embryonic development in vivo 13,15,22 . Temporal addition of relevant growth and signaling factors pushed cells to become neural progenitor cells and then MNs.…”

Section: Differentiation Of Ebs Containing Mnsmentioning

confidence: 99%

“…Beyond applications in regenerative medicine and therapeutics 20 , however, only a few studies have produced 3D NMJ platforms or applied neuromuscular research to living cellular systems using embryonic or neural stem cells [21][22][23] . Furthermore, there is a lack of research demonstrating the possibility of translating such an arrangement into a platform that is potentially autonomous, scalable, and forward-engineered, which are necessary characteristics of a mobile and functional cellular system or machine.…”

Section: Introductionmentioning

confidence: 99%

“…EBs containing MNs. As previously described 15,22 , to initiate differentiation, HBG3 mESCs were switched to neural differentiation medium containing…”

Section: Introductionmentioning

confidence: 99%

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A 3D-printed platform for modular neuromuscular motor units

et al. 2017

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A complex and functional living cellular system requires the interaction of one or more cell types to perform specific tasks, such as sensing, processing, or force production. Modular and flexible platforms for fabrication of such multi-cellular modules and their characterization have been lacking. Here, we present a modular cellular system, made up of multi-layered tissue rings containing integrated skeletal muscle and motor neurons (MNs) embedded in an extracellular matrix. The MNs were differentiated from mouse embryonic stem cells through the formation of embryoid bodies (EBs), which are spherical aggregations of cells grown in a suspension culture. The EBs were integrated into a tissue ring with skeletal muscle, which was differentiated in parallel, to create a co-culture amenable to both cell types. The multi-layered rings were then sequentially placed on a stationary three-dimensionalprinted hydrogel structure resembling an anatomical muscle-tendon-bone organization. We demonstrate that the site-specific innervation of a group of muscle fibers in the multi-layered tissue rings allows for muscle contraction via chemical stimulation of MNs with glutamate, a major excitatory neurotransmitter in the mammalian nervous system, with the frequency of contraction increasing with glutamate concentration. The addition of tubocurarine chloride (a nicotinic receptor antagonist) halted the contractions, indicating that muscle contraction was MN induced. With a bio-fabricated system permitting controllable mechanical and geometric attributes in a range of length scales, our novel engineered cellular system can be utilized for easier integration of other modular "building blocks" in living cellular and biological machines.

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Section: Differentiation Of Ebs Containing Mnsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A 3D-printed platform for modular neuromuscular motor units

et al. 2017

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“…This system although did not use any microfluidic platform, but proposed a method which can be easily integrated with microfluidic devices. Recently, Uzel et al 10 have designed a compartmentalized microfluidic platform for co-culture of myoblasts and motor neurons. The proposed microenvironment of the device enables physical separation of the two compartments.…”

mentioning

confidence: 99%

“…The device also exploits the use of optically excitable motor neurons, differentiated from mouse embryonic stem cells, for transmitting information to muscle strips being anchored by flexible pillars. 10 To reveal the mechanisms behind devastating neurodegenerative disease, the interaction between neuron-neuron, neuron-astrocyte and neuronmuscle should be identified distinctly. To showcase the influence of these cell types on each other Gao et al 11 has put forward an experimental setup by integrating microfluidics with micropatterning and genetically encoded calcium indicators.…”

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confidence: 99%

Microfluidic Models of Neuromuscular Junctions

Mahto¹

2017

IJBSBE

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Human Induced Pluripotent Stem Cells: Challenges and Opportunities in Developing New Therapies for Muscular Dystrophies

Paredes‐Redondo

Lin

2019

Encyclopedia of Life Sciences

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The generation of human induced pluripotent stem cells (iPSCs) has offered unparalleled opportunities for modelling human diseases and drug discovery. Muscular dystrophies are devastating inherited skeletal muscle disorders, for which there is no effective treatment. Recent breakthroughs in myogenic differentiation of iPSCs and other key technologies, including genome editing, smart biomaterials and tissue engineering, have opened new avenues to overcome the hurdles of developing therapies for previously incurable muscle diseases. The synergy between these novel technologies is increasingly transforming the fields of disease modelling, drug screening and regenerative medicine. Key Concepts Traditionally, muscular dystrophy research relies on primary human cells that have a limited expansion potential, and on animal models that do not fully recapitulate human pathophysiology. The self‐renewal and differentiation properties of human induced pluripotent stem cells (iPSCs) make them an important resource for generating a large quantity of physiology‐relevant cell types to model human diseases in vitro . In combination with genome editing and transgene‐free myogenic differentiation, human iPSCs can provide an unlimited supply of genetically corrected myogenic progenitor cells for autologous cell therapy and lay the basis for large‐scale drug screening. Safety concerns regarding iPSCs and myogenic differentiation can be addressed by integration‐free reprogramming methods and transgene‐free differentiation protocols. Recent breakthroughs in smart biomaterials and tissue engineering facilitate the transition from 2D monotypic to 3D multilineage cell cultures that resemble human tissue architecture. The synergy between human iPSCs, genome editing, transgene‐free myogenic differentiation, advanced biomaterials and tissue engineering can exploit the full potential of human iPSCs and facilitate drug discovery and cell therapies, leading towards translation of biomedical research from bench to bedside.

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Microfluidic device for the formation of optically excitable, three-dimensional, compartmentalized motor units

Abstract: Microfluidics and optogenetics enable the formation of light-excitable motor units in a compartmentalized and 3D environment.

Cited by 185 publications

References 92 publications

A 3D-printed platform for modular neuromuscular motor units

A 3D-printed platform for modular neuromuscular motor units

Microfluidic Models of Neuromuscular Junctions

Human Induced Pluripotent Stem Cells: Challenges and Opportunities in Developing New Therapies for Muscular Dystrophies

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