A small injury to a nerve outside the brain and spinal cord is relatively easy to repair just by stretching it, but a major gap in such a peripheral nerve poses problems. Usually, another nerve is taken from elsewhere in the body, and it causes an extra injury and returns only limited movement.
Now researchers at the University of Pittsburgh have found an effective way to bridge such a gap—at least in mice and monkeys—by inserting a biodegradable tube that releases a protein called a growth factor for several months. In a study published Wednesday in Science Translational Medicine, the team showed that the tube works as a guide for the nerve to grow along the proper path, and the naturally occurring protein induces the nerve to grow faster.
Kacey Marra, a professor at the university’s departments of plastic surgery and bioengineering, says she’s been working for a dozen years on the device, which she particularly hopes will help soldiers injured in combat. More than half of injured soldiers suffer nerve injuries, she says. And as the daughter and granddaughter of military men, she considers it her mission to help their successors. Combat gear does a good job of protecting a soldier’s chest and head, but arms and legs are often exposed, which is why peripheral nerve injuries are so common, Marra says. Car crashes and accidents involving machinery such as snowblowers can also damage nerves involved in hand, arm, leg and foot control.
In the U.S., there are about 600,000 nerve injuries every year, she says, though she is unsure how many are severe enough to require the relocation of a second nerve because that information is not tracked yet. When the injuries are severe, the only current treatment is to take a nerve from somewhere else on the body, Marra says. But patients recover just about 50 to 60 percent of function in the damaged nerve.
“Longer nerve grafts are always more challenging,” says Christine Schmidt, a professor and chair of the department of biomedical engineering at the University of Florida, who was not involved with the research. “It would be great to be able to tackle long-term nerve damage.” She notes that the nerve the Pittsburgh team tested is relatively small in macaques. “It will still be a challenge to scale up to larger nerves,” she says. “It would be nice to see a little bit larger nerve,” which would be more relevant to patients.
The new device restored nearly 80 percent of function, the study showed. It uses glial-cell-derived neurotrophic factor (GDNF), a protein that promotes nerve cell survival. Marra chose GDNF, she says, because “if you get a nerve injury like a paper cut, the cells in your nerves are going to express this protein at high levels. And that recruits other cells to come in and repair the nerve.” The tube is made of the same polymer as dissolvable stitches, which has already been federally approved for surgical use.
Other researchers are exploring the use of stem cells or other cells to help bridge the gap in the nerve, but Marra and her colleagues’ approach is likely to have an easier time receiving federal approval because it does not involve cells. “If they were to go adding stem cells or too many complexities,” it would be harder to win a regulatory green light, Schmidt says. It is better to make advances with small steps, as the Pittsburgh researchers have, she says. “They’re doing it in a very realistic way that can lead to a clinical outcome, and that’s really what you want,” Schmidt adds.
Nerves can regenerate at a rate of about one millimeter per day, and there are three months’ worth of GDNF in the tube, allowing for closing injuries of about 12 centimeters—or 4.7 inches.
In the eight-year-long study, the researchers trained rhesus macaques to eat with their forefinger and thumb—which they could only do if a repaired nerve was working properly. They used this finger maneuver rather than grabbing food with their fist, as they usually do when they eat. If they pinched the banana pellet, they got a second treat, Marra says. “We were able to see the recovery,” she adds. “At that point, we knew we were ready to test in humans.”
Marra says she and her colleagues have several pending proposals for the first clinical trials in humans, which are likely to start in 2021 and take at least three years. A start-up she launched, AxoMax Technologies, licensed the technology from the University of Pittsburgh to begin the experiments. Marra believes her device can be competitively priced, compared with moving a nerve from elsewhere in the body—and, potentially, even compared with existing repair approaches for small nerve gaps.
Her team is also beginning to study whether its method will work for facial nerves, but she thinks it is unlikely to be effective for spinal cord injuries, which are far more complex and involve more nerves. The researchers are looking at regenerating the muscles affected by injured nerves as well. “I think [this approach] really could revolutionize thinking about nerve repair and the different options a patient will have,” Marra says.