Micro-beads and Nano-Nerve Rewiring

Posted by Sam Maddox in Research News on September 13, 2016 # Research, Technology

I came across a news article a few weeks ago about how a scientist created a miniaturized spinal cord in a tubular mold. The idea, says inventor Margaret Magdesian, a Brazilian working at McGill University in Montreal, was to keep nerve cells alive in a petri dish and to grow them they way they grow naturally. Turns out the tubular molds, shaped like the spinal cord, worked great; Magdesian left academia to start Ananda Devices to commercialize the molds.

OK, cool new tool, sure. Here’s Magdesian:

“Our spinal cord is a cable of nerves inside the vertebral column, and it has a precise shape, and when you remove this cable and you put it on a petri dish, it just get all entangled and mixed. So it’s impossible to reproducibly cause a lesion and to evaluate if this lesion is cured or not,” she said. “When we make a mold exactly like the vertebral column, and add the cells, they grow inside precisely like they grow in the body.”

Looking further, I discovered a paper by lead author Madgesian and a group at McGill published earlier this year. They used her molds and nanoscale technology to rewire nerve circuits. It’s a bold-new-world example of the blurred boundaries between biology and physics, engineering and chemistry.

The paper, from the Journal of Neuroscience, is called Rapid Mechanically Controlled Rewiring of Neuronal Circuits. The authors, including physicist Peter Grutter, attached microbeads coated with a protein to growing neurons in a dish; they used a special microscope visualizing a tiny pointer to physically tug the bead ahead. The neuron sticks to the bead, and stretches. The elongation is 60 times faster than it would normally occur, and it can be precisely directed, according to the research group, to make a functional circuit with another neuron.

In this study, the distance the neuron can be manipulated is less than a millimeter, limited by the size of the dish. Magdesian says the distance could be much greater as the tools and technique improve.

This is quite a feat, but it’s in a dish. Madgesian et al think this nano-nerve approach has clinical potential. From the paper, citing the granddaddy of neuroscience, Cajal, quoted from 1928.

"... the capacity to regenerate long axons to distant targets and to form appropriate functional synapses remains severely limited. Santiago Ramon y Cajal's statement from 90 years ago remains essentially true today: “once the development was ended, the founts of growth and regeneration of the axons and dendrites dried up irrevocably. In the adult centers the nerve paths are something fixed, ended and immutable. Everything may die, nothing may be regenerated. It is for the science of the future to change, if possible, this harsh decree.”

In the present work, we use microbeads, atomic force microscopy (AFM), micromanipulation, and microfabrication techniques to rapidly initiate, elongate, and precisely connect new functional neuronal circuits over long distances.

Our results show, unexpectedly, that the intrinsic capacity of these neurites for elongation is much faster than previously thought. Our proposed mechanical approach bypasses slow chemical strategies and enables controlled connection to a specific target. This technique opens new avenues for the in vitro study of novel therapies to restore neuronal connectivity after injury. It also enables the manipulation and rewiring of neuronal networks to investigate fundamental aspects of neuronal signal processing and neuronal function in vitro.

This work shows for the first time that it is possible to create new neurites, elongate them for hundreds of micrometers in <1 hour, and functionally connect the new neurites to any desired target to (re)wire neuronal networks. The great advantage of the current technique is that it is not necessary to wait for neurites to naturally grow, eventually interact with chemical cues, possibly turn toward a target, and maybe form functional connections.

... these results unequivocally indicate that functional connections were established by the direct micromanipulation of new synaptic connections.

Our findings reveal that the newly created CNS neurites contain the main structural components of naturally grown neurites and are able to transmit electrical signals. To the best of our knowledge these measurements are the first micromanipulated neuronal connections.

Possible uses: lots of R&D potential, a great tool to better understand nerve signaling and message processing; may offer a way, in vivo, to rapidly bridge gaps formed by spinal cord scar tissue; may facilitate better brain–machine interfaces by hooking up functional nerve wiring to inorganic interfaces.

Magdesian was happy as scientist, working on a spinal cord injury model. Once other labs started asking her for molds, and were willing to pay for them, she got caught up in the start-up world. She is now CEO of ANANDA (Advanced Nano Design Applications). Here’s why she thinks her venture into microfluidics could work:

“The main advantage is that our products can help you organize your cell cultures to achieve reproducible and impactful results faster. Today, scientists lack control over the reproducibility of cell cultures, and cell culture variability is a main source of experimental error. Our devices are the first ones to be able to hold the organized cells alive for weeks. This is very important for neurons because before two weeks, neurons do not communicate. In our devices they can survive up to a month, and it’s long enough to make different tests.”