A mechanical way to stimulate neurons.

In addition to responding to electrical and chemical stimuli, many of the body’s neural cells can also respond to mechanical effects, such as pressure or vibration. But these responses have been more difficult for researchers to study because there has been no easily controllable method of inducing such mechanical stimulation of cells. Now researchers at MIT and elsewhere have found a new way to do it.

The finding could offer a step toward new types of therapeutic treatments, similar to electrically based neurostimulation that has been used to treat Parkinson’s disease and other conditions. Unlike those systems, which require an external cable connection, the new system would be completely free of contact after an initial injection of particles, and could be reactivated at will through an externally applied magnetic field.

The finding is reported in the journal. ACS Nano, in an article by ex-MIT postdoc Danijela Gregurec, Alexander Senko PhD ’19, associate professor Polina Anikeeva and nine others at MIT, at Brigham and Women’s Hospital in Boston, and in Spain.

The new method opens up a new avenue for stimulating nerve cells within the body, which until now has relied almost entirely on chemical pathways, using pharmaceuticals or electrical pathways, which require invasive cables to supply voltage to the Body. . According to the researchers, this mechanical stimulation, which activates completely different signaling pathways within the neurons themselves, could provide a significant study area.

“An interesting thing about the nervous system is that neurons can really detect forces,” says Senko. “This is how your sense of touch works, and also your sense of hearing and balance.” The team targeted a particular group of neurons within a structure known as the dorsal root ganglion, which forms an interface between the central and peripheral nervous systems, because these cells are particularly sensitive to mechanical forces.

The applications of the technique could be similar to those being developed in the field of bioelectronic drugs, Senko says, but they require electrodes that are usually much larger and more rigid than stimulated neurons, which limits their precision and sometimes damages the cells.

The key to the new process was developing tiny discs with an unusual magnetic property, which can cause them to start to shake when subjected to a certain type of variable magnetic field. Although the particles themselves are only about 100 nanometers in diameter, about a hundredth of the size of the neurons they are trying to stimulate, they can be made and injected in large numbers, so that their collective effect is strong enough to activate cell pressure. receptors “We made nanoparticles that actually produce forces that cells can detect and respond to,” says Senko.

Anikeeva says that conventional magnetic nanoparticles would have required the activation of impractically large magnetic fields, so finding materials that could provide enough force with moderate magnetic activation was “a very difficult problem.” The solution turned out to be a new type of magnetic nanodisc.

These disks, which are hundreds of nanometers in diameter, contain an atomic spin vortex configuration when external magnetic fields are not applied. This makes the particles behave as if they are not magnetic, making them exceptionally stable in solutions. When these disks are subjected to a very weak variable magnetic field of a few millitesla, with a low frequency of only several hertz, they change to a state where all the internal spins are aligned in the plane of the disk. This allows these nanodiscs to act as levers, moving up and down with the direction of the field.

Anikeeva, who is an associate professor in the Materials Science and Engineering and Brain and Cognitive Sciences departments, says this work combines several disciplines, including the new chemistry that led to the development of these nanodiscs, along with electromagnetic effects and work on the biology of neurostimulation. .

The team first considered the use of magnetic metal alloy particles that could provide the necessary forces, but these were not biocompatible materials, and were prohibitively expensive. The researchers found a way to use particles made of hematite, a benign iron oxide, that can form the required disc shapes. Hematite was converted to magnetite, which has the magnetic properties they needed and is known to be benign in the body. This chemical transformation from hematite to magnetite dramatically turns a tube of blood-red particles into jet black.

“We had to confirm that these particles actually supported this really unusual spinning state, this vortex,” says Gregurec. They first tested the newly developed nanoparticles and demonstrated, using holographic imaging systems provided by colleagues in Spain, that the particles actually reacted as expected, providing the forces necessary to elicit responses from neurons. The results came in late December and “everyone thought it was a Christmas present,” Anikeeva recalls, “when we got our first holograms, and we really got to see that what we had theoretically predicted and chemically suspected was really true.”

Work is still in its infancy, she says. “This is a first demonstration that it is possible to use these particles to transduce great forces into neuron membranes to stimulate them.”

She adds “that it opens up a whole field of possibilities. … This means that anywhere in the nervous system where cells are sensitive to mechanical forces, and which is essentially any organ, we can now modulate the function of that organ.” That takes science one step closer, he says, to the goal of bioelectronic medicine that can provide stimulation at the level of individual organs or body parts, without the need for drugs or electrodes.

The work was supported by the U.S. Defense Advanced Research Projects Agency, the National Institute of Mental Health, the Department of Defense, the Office of Scientific Research of the Air Force and the Science Graduate Scholarship e National Defense Engineering.