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April 17, 2001

Penn Researchers Discover That Stretching Neurons Induces Growth

Scientists Foresee Bridging Nerve Damage with Grafts

(Philadelphia, PA) - They say that tension is bad for the nerves, but it turns out that a little applied tension might be good for nerve cells. Researchers at the University of Pennsylvania Medical Center have been able to grow nerve cells, or neurons, by stretching them - offering a new means of bridging damaged areas of the nervous system.

Using a motorized device to slowly pull connected neurons away from each other, the Penn researchers have discovered that the connecting nerve fibers, called axons, grow longer in response to the strain. In addition, the researchers have grown these elongated nerve fibers directly on a dissolvable membrane, ready-made for transplant. Their discovery is published in the April edition of Tissue Engineering.

"Most studies have examined axon growth in terms of how axons sprout from one neuron and connect to another. But there is an equally important form of axon growth that has been overlooked, the growth of axons in terms of the growth of the entire organism," said Douglas Smith, MD, lead researcher on the project and associate professor in the Penn Department of Neurosurgery. "In a way, stretching is akin to how nerve cells grow in developing children - as they get taller their axons get longer."

These findings, which have evolved from Smith's ongoing research into how neurons respond to their environment, also represent a departure from other methods of restoring neural pathways in spinal cord injuries by bridging over damaged tissue. One approach has been to transplant a synthetic scaffolding across the injured area and then use a trail of attractive chemicals to entice axons to grow out from one end of the lesion and connect with viable nervous tissue on the other side. While these attempts have had limited success in the laboratory, they have been hampered in live subjects by, among other things, the body's innate desire to stop neuron outgrowth.

"Once somebody's nervous system is already formed, further outgrowth could cause mass confusion, so the body actively produces chemicals that stop axon growth" said Smith.

But it was the inherent ability of axons that were already connected to grow during natural development that gave the researchers the idea to stretch axons in culture. Smith and his colleagues began with a group of neurons grown in a culture across two membranes. Using a motor that could function in precise increments, they separated the two membranes by a few thousandths of a centimeter every few minutes. A small distance on a human level, but a remarkably large distance on the cellular level. Eventually, as they describe in Tissue Engineering, they were able to stretch the neurons an entire centimeter. Smith, however, could find no physiological reason why they could not be stretched even further.

"We believe that, as we put pressure on the axons from either end, the axon begins to add a little to its own internal skeleton in response," said Smith. "It is sort of like the little boy who tries to get taller by having his siblings pull on his limbs, only in this case it seems to work."

During these experiments, Smith noticed another curious phenomena. "We began to see that the stretch-grown neurons could actually organize themselves into bundles, nerve fibers of composed of thousands of axons," said Smith, "and these bundles gradually consolidated into even larger tracts."

Accordingly, these large tracts could serve as the bridge across damaged tissue, connecting either side and allowing the nerve signal to cross. In fact, researchers would likely not have to modify the stretched neurons before transplanting - the body easily absorbs the membranes used in the stretching process. As with all strategies to bridge nerve damage, Smith hopes that the neuron's own innate ability to connect will allow transplantable axon bridge to rewire damaged nervous tissue.

"Axons are promiscuous little things," said Smith, "and we're counting on their innate tendency to feel around and make new connections."

In addition to spinal cord repair, Smith conceives of using the elongated axon cultures as a bridge for other types of neural injuries affecting long axon tracts, including optic nerve damage and peripheral nerve damage. "The idea itself may seem like a stretch," said Smith, "but we are only at the beginning of learning what we can do with this concept."

 

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