Novel chip replication neuromuscular junctions help test drugs for neuromuscular disease

Release date: 2016-09-02

Engineers at the Massachusetts Institute of Technology (MIT) have developed a microfluidic device that replicates neuromuscular junctions, the critical link between nerves and muscles. The device is about 25 cents in size and contains a single muscle strip and a small group of motor neurons. Researchers can influence and observe the interaction between the two in a realistic (realistic) three-dimensional matrix.

The researchers genetically engineered the neurons in the device to respond to light. By projecting light onto these neurons, these cells can be precisely stimulated and signaled to stimulate muscle fibers. The researchers also measured the force of the muscles in the device that twitched or contracted after being stimulated.
A new microfluidic device that replicates neuromuscular junctions. The device contains a small cluster of neurons (green) and a single muscle fiber (red).
The fluorescent image below shows that motor neurons emit axons to the muscle strips over a distance of about 1 mm.
The findings, published online August 3, 2016 in the journal Science Advances, may help scientists understand and identify drugs to treat amyotrophic lateral sclerosis (ALS, Lugar's disease) and other neuromuscular-related diseases.
"Neuromuscular junctions involve many disabling diseases, some of which are cruel and deadly, and many have not yet been discovered," said Sebastien Uzel, a graduate student in the MIT Department of Mechanical Engineering who led the study. "We want to be able to form neuromuscular junctions in vitro," Help us understand certain disease activities." Sebastien Uzel is now a postdoctoral fellow at Harvard University's Wyss Institute.
Since the 1970s, scientists have proposed a number of methods to simulate neuromuscular junctions in the laboratory. Most of these experiments involve growing muscle and nerve cells on a petri dish or small glass substrate. However, such an environment is far removed from the state of the (animal) body in which muscles and nerve cells survive in a complex three-dimensional environment and are usually far away.
“Think about the giraffe,” Uzel said. “The axons from the spinal neurons need to span a very large distance to connect with the leg muscles.”
To reconstruct more realistic neuromuscular junctions in vitro, Uzel and colleagues constructed a microfluidic device that has two important characteristics: 1. a three-dimensional environment; 2. an isolation of muscle and nerve compartments to simulate two The state of natural separation in the human body. The researchers suspended muscle and neuronal cells in compartments and then filled them with gels to simulate a three-dimensional environment.
To grow muscle fibers, the team used muscle precursor cells obtained from mice and then differentiated them into muscle cells. They inject cells into a microfluidic compartment where they grow and fuse to form a single muscle strip. Similarly, they differentiated motor neurons from stem cells and placed the resulting neural cell aggregates in a second compartment. Before the differentiation of the two cells, the researchers genetically engineered the nerve cells using optogenetics.
Roger Kamm, co-author of the study, MIT Mechanical and Bioengineering Ceciland Ida Green, said: "Light allows you to precisely control the cells you want to activate." In such a small space, the electrode cannot achieve this.
Finally, the researchers added another feature to the device: force sensing. To measure muscle contraction, they construct two tiny elastic struts in the muscle cell compartment that are placed around the muscle fibers and can be wrapped by the growing muscle fibers. As the muscles contract, the struts are squeezed together to create displacement, and the researchers can measure these displacements and convert them into mechanical forces.
Microfluidic devices constructed by researchers. Muscle and neuronal cells are suspended in a hydrogel and injected into a millimeter-sized compartment (blue fine channel), followed by media (blue large channels) from both sides of the neuron/muscle tissue, simulating three-dimensional surroundings.
In an experiment to test the device, Uzel and colleagues first observed neuronal extension of axons to muscle fibers in a three-dimensional region. When axons were observed to establish a connection, they stimulated the neurons with a tiny blue lasing and immediately observed muscle contraction.
“After firing a flash, you can observe the convulsions,” Kamm said.
According to these experiments, Kamm said that this microfluidic device may be a highly effective test site for neuromuscular drug testing, and can even be customized for individual patients.
“You may get pluripotent cells from ALS patients, differentiate them into muscles and nerve cells, and make the entire system for a specific patient,” says Kamm. “Then you can replicate as many times as needed, while testing different combinations of drugs or therapies. See which treatments are most effective in improving the connection between nerves and muscles."
On the other hand, he said, the device may be useful in "modeling exercise protocols." For example, by stimulating muscle fibers at different frequencies, scientists can study how repeated stress affects muscle performance.
“Now, with the development of all these new microfluidic methods, you can begin to build more complex models of neurons and muscles,” says Kamm. “Neuromuscular junctions are another unit that can now be included in the test pattern.”
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Replicating the connection between muscles and nerves

Source: China Rare Disease Network

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