03 Apr 2017
Rubbery, multifunctional fibers could be used to study spinal cord neurons and potentially restore function.
Implantable fibers have been an enormous boon to brain research, allowing scientists to stimulate specific targets in the brain and monitor electrical responses. But similar studies in the nerves of the spinal cord, which might ultimately lead to treatments to alleviate spinal cord injuries, have been more difficult to carry out.
That’s because the spine flexes and stretches as the body moves, and the relatively stiff, brittle fibers used today could damage the delicate spinal cord tissue.
Now, researchers have developed a rubber-like fiber that can flex and stretch while simultaneously delivering both optical impulses, for optoelectronic stimulation, and electrical connections, for stimulation and monitoring. The new fibers are described in a paper in the journal Science Advances, by MIT graduate students Chi (Alice) Lu and Seongjun Park, Professor Polina Anikeeva, and eight others at MIT, the University of Washington, and Oxford University.
“I wanted to create a multimodal interface with mechanical properties compatible with tissues, for neural stimulation and recording,” as a tool for better understanding spinal cord functions, says Lu. But it was essential for the device to be stretchable, because “the spinal cord is not only bending but also stretching during movement.” The obvious choice would be some kind of elastomer, a rubber-like compound, but most of these materials are not adaptable to the process of fiber drawing, which turns a relatively large bundle of materials into a thread that can be narrower than a hair.
The spinal cord “undergoes stretches of about 12 percent during normal movement,” says Anikeeva, who is the Class of 1942 Career Development Professor in the Department of Materials Science and Engineering. “You don’t even need to get into a ‘downward dog’ [yoga position] to have such changes.” So finding a material that can match that degree of stretchiness could potentially make a big difference to research. “The goal was to mimic the stretchiness and softness and flexibility of the spinal cord,” she says. “You can match the stretchiness with a rubber. But drawing rubber is difficult — most of them just melt,” she says.
“Eventually, we’d like to be able to use something like this to combat spinal cord injury. But first, we have to have biocompatibility and to be able to withstand the stresses in the spinal cord without causing any damage,” she says.
The fibers are not only stretchable but also very flexible. “They’re so floppy, you could use them to do sutures, and do light delivery at the same time,” professor Polina Anikeeva says. (Video: Chi (Alice) Lu and Seongjun Park)
The team combined a newly developed transparent elastomer, which could act as a waveguide for optical signals, and a coating formed of a mesh of silver nanowires, producing a conductive layer for the electrical signals. To process the transparent elastomer, the material was embedded in a polymer cladding that enabled it to be drawn into a fiber that proved to be highly stretchable as well as flexible, Lu says. The cladding is dissolved away after the drawing process.
After the entire fabrication process, what’s left is the transparent fiber with electrically conductive, stretchy nanowire coatings. “It’s really just a piece of rubber, but conductive,” Anikeeva says. The fiber can stretch by at least 20 to 30 percent without affecting its properties, she says.
The fibers are not only stretchable but also very flexible. “They’re so floppy, you could use them to do sutures and deliver light at the same time,” she says.
“We’re the first to develop something that enables simultaneous electrical recording and optical stimulation in the spinal cords of freely moving mice,” Lu says. “So we hope our work opens up new avenues for neuroscience research.” Scientists doing research on spinal cord injuries or disease usually must use larger animals in their studies, because the larger nerve fibers can withstand the more rigid wires used for stimulus and recording. While mice are generally much easier to study and available in many genetically modified strains, there was previously no technology that allowed them to be used for this type of research, she says.
“There are many different types of cells in the spinal cord, and we don’t know how the different types respond to recovery, or lack of recovery, after an injury,” she says. These new fibers, the researchers hope, could help to fill in some of those blanks.
The team included Alexander Derry, Chong Hou, Siyuan Rao, Jeewoo Kang, and professor Yoel Fink at MIT; Tom Richner and professor Chet Mortiz at the University of Washington; and Imogen Brown at Oxford University. The research was supported by the National Science Foundation, the National Institute of Neurological Disorders and Stroke, the U.S. Army Research Laboratory, and the U.S. Army Research Office through the Institute for Soldier Nanotechnologies at MIT.
24 Jun 2015
The nanowires respond to an electromagnetic field generated by a separate device, which can be used to control the release of a preloaded drug. The system eliminates tubes and wires required by other implantable devices that can lead to infection and other complications, said team leader Richard Borgens, Purdue University’s Mari Hulman George Professor of Applied Neuroscience and director of Purdue’s Center for Paralysis Research.
“This tool allows us to apply drugs as needed directly to the site of injury, which could have broad medical applications,” Borgens said. “The technology is in the early stages of testing, but it is our hope that this could one day be used to deliver drugs directly to spinal cord injuries, ulcerations, deep bone injuries or tumors, and avoid the terrible side effects of systemic treatment with steroids or chemotherapy.”
The team tested the drug-delivery system in mice with compression injuries to their spinal cords and administered the corticosteroid dexamethasone. The study measured a molecular marker of inflammation and scar formation in the central nervous system and found that it was reduced after one week of treatment. A paper detailing the results will be published in an upcoming issue of the Journal of Controlled Release and is currently available online.
IMAGE: An image of a field of polypyrrole nanowires captured by a scanning electron microscope is shown. A team of Purdue University researchers developed a new implantable drug-delivery system using the… view more
Credit: (Purdue University image/courtesy of Richard Borgens)
The nanowires are made of polypyrrole, a conductive polymer material that responds to electromagnetic fields. Wen Gao, a postdoctoral researcher in the Center for Paralysis Research who worked on the project with Borgens, grew the nanowires vertically over a thin gold base, like tiny fibers making up a piece of shag carpet hundreds of times smaller than a human cell. The nanowires can be loaded with a drug and, when the correct electromagnetic field is applied, the nanowires release small amounts of the payload. This process can be started and stopped at will, like flipping a switch, by using the corresponding electromagnetic field stimulating device, Borgens said.
The researchers captured and transported a patch of the nanowire carpet on water droplets that were used used to deliver it to the site of injury. The nanowire patches adhere to the site of injury through surface tension, Gao said.
The magnitude and wave form of the electromagnetic field must be tuned to obtain the optimum release of the drug, and the precise mechanisms that release the drug are not yet well understood, she said. The team is investigating the release process.
The electromagnetic field is likely affecting the interaction between the nanomaterial and the drug molecules, Borgens said.
“We think it is a combination of charge effects and the shape change of the polymer that allows it to store and release drugs,” he said. “It is a reversible process. Once the electromagnetic field is removed, the polymer snaps back to the initial architecture and retains the remaining drug molecules.”
For each different drug the team would need to find the corresponding optimal electromagnetic field for its release, Gao said.
This study builds on previous work by Borgens and Gao. Gao first had to figure out how to grow polypyrrole in a long vertical architecture, which allows it to hold larger amounts of a drug and extends the potential treatment period. The team then demonstrated it could be manipulated to release dexamethasone on demand. A paper detailing the work, titled “Action at a Distance: Functional Drug Delivery Using Electromagnetic-Field-Responsive Polypyrrole Nanowires,” was published in the journal Langmuir.
Other team members involved in the research include John Cirillo, who designed and constructed the electromagnetic field stimulating system; Youngnam Cho, a former faculty member at Purdue’s Center for Paralysis Research; and Jianming Li, a research assistant professor at the center.
For the most recent study the team used mice that had been genetically modified such that the protein Glial Fibrillary Acidic Protein, or GFAP, is luminescent. GFAP is expressed in cells called astrocytes that gather in high numbers at central nervous system injuries. Astrocytes are a part of the inflammatory process and form a scar tissue, Borgens said.
A 1-2 millimeter patch of the nanowires doped with dexamethasone was placed onto spinal cord lesions that had been surgically exposed, Borgens said. The lesions were then closed and an electromagnetic field was applied for two hours a day for one week. By the end of the week the treated mice had a weaker GFAP signal than the control groups, which included mice that were not treated and those that received a nanowire patch but were not exposed to the electromagnetic field. In some cases, treated mice had no detectable GFAP signal.
Whether the reduction in astrocytes had any significant impact on spinal cord healing or functional outcomes was not studied. In addition, the concentration of drug maintained during treatment is not known because it is below the limits of systemic detection, Borgens said.
“This method allows a very, very small dose of a drug to effectively serve as a big dose right where you need it,” Borgens said. “By the time the drug diffuses from the site out into the rest of the body it is in amounts that are undetectable in the usual tests to monitor the concentration of drugs in the bloodstream.”
Polypyrrole is an inert and biocompatable material, but the team is working to create a biodegradeable form that would dissolve after the treatment period ended, he said.
The team also is trying to increase the depth at which the drug delivery device will work. The current system appears to be limited to a depth in tissue of less than 3 centimeters, Gao said.
- Wen Gao, Richard Ben Borgens. Remote-controlled eradication of astrogliosis in spinal cord injury via electromagnetically-induced dexamethasone release from “smart” nanowires. Journal of Controlled Release, 2015; 211: 22 DOI: 10.1016/j.jconrel.2015.05.266