Do damaged nerves ever heal?

When a nerve is injured, it's often hard to get it to regrow fast enough to restore function.

But now researchers say they can speed up that process, so that damaged nerves can be healed in days instead of months — at least in rats.

The scientists say they've developed a technique that reconnects the severed ends of a nerve, allowing it to begin carrying messages again very quickly. Usually, severed nerves must regrow from the point of injury — a process that can take months, if it ever happens.

This might eventually help the more than 50,000 people a year in the U.S. who suffer nerve injuries that leave them unable to use a particular muscle or without feeling in part of their body.

"It's exciting," says Wesley Thayer, a plastic surgeon at Vanderbilt University Medical Center and a co-author of the study.

Thayer says these peripheral nerve injuries are caused by everything from car crashes to gunshot wounds. But he says many of them happen when somebody does something careless in the kitchen.

"Unfortunately, a lot of people with granite countertops will place their hand down hard on a wine glass and actually sever nerves in their hand or forearm just because the glass shatters on these very hard surfaces," he says.

A slip while slicing a bagel can also cut a nerve. And nerves don't heal the way other body parts do, Thayer says.

"What happens after a nerve is transected is that between the brain and the injury, the nerve mechanism stays alive, but [the tissue] beyond that, it actually dies," he says.

The nerve on the side connected to the brain usually starts to regenerate, but very slowly — only about 1 or 2 millimeters a day. That's bad news if you cut a nerve in your shoulder that controls, say, one of your fingers, Thayer says.

"It will take, in an adult, over a year for that nerve to grow out and reach the hand," he says. "And over the course of that year, the muscle really develops a permanent atrophy and is no longer functional, even if the nerve reaches its target."

And it may not.

So for decades, scientists have been trying to find better ways to repair damaged or severed nerves.

George Bittner of the University of Texas, Austin, has been studying the problem since he was a graduate student in the 1960s.

He says a damaged nerve is a bit like a bridge with a missing section. "What you'd want to do is put some sort of patch in there and rejoin the two halves," he says.

Bittner worked with Thayer and other researchers to come up with a multistep process that appears to do just that.

First they expose the severed nerve. Then they use chemical compounds to reverse a process that normally seals the nerve ends shut. At that point, they draw the two nerve ends together with tiny sutures and apply more chemicals that cause the nerve ends to fuse. This work is reported in a study published online in the Journal of Neuroscience Research.

The technique can be done entirely with chemicals that are already approved for use in people, Bittner says. And it produced very good results in a study of rats that had their sciatic nerve cut, he says.

That nerve controls the entire leg, paw and toes, and without it rats are badly disabled. But rats treated with his technique got better as soon as they began to recover from the surgery, Bittner says.

"You'd be hard-pressed to know which rats after several weeks had their entire sciatic nerve cut and which had a sham operation, never had it cut," he says

Bittner isn't the only one working on this technique. Researchers at Harvard are also involved. And Thayer at Vanderbilt hopes to try the approach on people within a year.

Meanwhile, researchers at Purdue University have reported success fusing nerves a different way — using a substance made from the shells of crustaceans.

The new technique may eventually have a broader application in people, Bittner says. "If you could get it to work on peripheral nerves, it might then be applied to spinal nerves," he says

Another person thinking that way is Doug English. He was a defensive tackle for the Detroit Lions back in the 1970s and '80s.

"My football career was ended with a neck injury," English says. "I'm very fortunate it wasn't nearly as severe as so many of the neck injuries are."

English is president of the Lone Star Paralysis Foundation in Austin, which has helped support Bittner's research.

The foundation has just started funding efforts to use Bittner's technique on rats with spinal injuries.

To determine whether you have nerve damage, your doctor will take a history and do an exam. He or she will ask about what you are experiencing and how long you have had symptoms. If your doctor is concerned you havenerve damage, they may order a Nerve Conduction Study (NCS) or Electromyography (EMG). These tests are done by a neurologist and help determine if your nerves are working abnormally.

Treatment

Some nerve injuries get better on their own, but more severe injuries can require nerve repair or other interventions. A nerve repair is not like an artery or vein repair, where blood starts flowing immediately. A nerve repair only recreates the tunnel for the nerve. Then, the nerve fibers have to grow back through that tunnel. This is why nerve repairs are described as “like planting a tree”. Until the nerve re-grows from the point of injury to the target muscle or skin, the nerve will not function normally.

In the case of a sharp nerve injury involving only a short segment of nerve, a direct repair may be possible. In this case, a surgeon will bring the two ends of the nerve together and use small stitches to hold the nerve ends together (Figure 1).

If it has been a long time since your nerve damage, nerve repair may not be possible. If a muscle does not receive a signal from a nerve for a long time, it can stop responding altogether. This usually happens after 18 months without a signal but depends on the kind of nerve damage, the age of the patient, and other factors. If the nerve is not repairable, your doctor may discuss other options such as nerve or tendon transfers to help you regain function.

News Release

Tuesday, March 3, 2020

NIH-funded project in mice provides insights into why nerves fail to regrow following injury.

When the spinal cord is injured, the damaged nerve fibers — called axons — are normally incapable of regrowth, leading to permanent loss of function. Considerable research has been done to find ways to promote the regeneration of axons following injury. Results of a study performed in mice and published in Cell Metabolism suggests that increasing energy supply within these injured spinal cord nerves could help promote axon regrowth and restore some motor functions. The study was a collaboration between the National Institutes of Health and the Indiana University School of Medicine in Indianapolis.

“We are the first to show that spinal cord injury results in an energy crisis that is intrinsically linked to the limited ability of damaged axons to regenerate,” said Zu-Hang Sheng, Ph.D., senior principal investigator at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and a co-senior author of the study.

Like gasoline for a car engine, the cells of the body use a chemical compound called adenosine triphosphate (ATP) for fuel. Much of this ATP is made by cellular power plants called mitochondria. In spinal cord nerves, mitochondria can be found along the axons. When axons are injured, the nearby mitochondria are often damaged as well, impairing ATP production in injured nerves.

“Nerve repair requires a significant amount of energy,” said Dr. Sheng. “Our hypothesis is that damage to mitochondria following injury severely limits the available ATP, and this energy crisis is what prevents the regrowth and repair of injured axons.”

Adding to the problem is the fact that, in adult nerves, mitochondria are anchored in place within axons. This forces damaged mitochondria to remain in place while making it difficult to replace them, thus accelerating a local energy crisis in injured axons.

The Sheng lab, one of the leading groups studying mitochondrial transport, previously created genetic mice that lack the protein—called Syntaphilin—that tethers mitochondria in axons. In these “knockout mice” the mitochondria are free to move throughout axons.

“We proposed that enhancing transport would help remove damaged mitochondria from injured axons and replenish undamaged ones to rescue the energy crisis” said Dr. Sheng.

To test whether this has an impact on spinal cord nerve regeneration, the Sheng lab collaborated with Xiao-Ming Xu, M.D., Ph.D. and colleagues from the Indiana University School of Medicine, who are experts in modeling multiple types of spinal cord injury.

“Spinal cord injury is devastating, affecting patients, their families, and our society,” said Dr. Xu. “Although tremendous progress has been made in our scientific community, no effective treatments are available. There is definitely an urgent need for the development of new strategies for patients with spinal cord injury.”

When the researchers looked in three injury models in the spinal cord and brain, they observed that Syntaphilin knockout mice had significantly more axon regrowth across the injury site compared to control animals. The newly grown axons also made appropriate connections beyond the injury site.

When the researchers looked at whether this regrowth led to functional recovery, they saw some promising improvement in fine motor tasks in mouse forelimbs and fingers. This suggested that increasing mitochondrial transport and thus the available energy to the injury site could be key to repairing damaged nerve fibers.

To test the energy crisis model further, mice were given creatine, a bioenergetic compound that enhances the formation of ATP. Both control and knockout mice that were fed creatine showed increased axon regrowth following injury compared to mice fed saline instead. More robust nerve regrowth was seen in the knockout mice that got the creatine.

“We were very encouraged by these results,” said Dr. Sheng. “The regeneration that we see in our knockout mice is very significant, and these findings support our hypothesis that an energy deficiency is holding back the ability of both central and peripheral nervous systems to repair after injury.”

Dr. Sheng also points out that these findings, while promising, are limited by the need to genetically manipulate mice. Mice that lack Syntaphilin show long-term effects on regeneration, while creatine alone produces only modest regeneration. Future research is required to develop therapeutic compounds that are more effective in entering the nervous system and increasing energy production for possible treatment of traumatic brain and spinal cord injury.

This study was supported by the NINDS Intramural Research Program (ZIA NS003029, ZIA NS002946), NINDS (NS100531, NS103481), U.S. Department of Veterans Affairs, Indiana Spinal Cord and Brain Injury Research Foundation, and the Mari Hulman George Endowment Funds.

NINDS is the nation’s leading funder of research on the brain and nervous system. The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

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