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Nervy Repair Job

Douglas Smith mechanically stretches living nerves to grow resilient transplants.

In a lab at the University of Pennsylvania, a plastic dish holds two rows of tiny black dots, pairs of them connected by dozens of thin, hairlike filaments. Each dot is a cluster of thousands of neurons, explains Douglas Smith, who is a professor of neurosurgery and the director of Penn’s Center for Brain Injury and Repair. The fibers that stretch between them actually comprise thousands of axons, long, slender projections that conduct electrical impulses away from each neuron’s central body. These bundles–each one a lab-engineered nerve–represent physical bridges that Smith hopes will help researchers like him mend previously irreparable injuries.

At the University of Pennsylvania Center for Brain Injury and Repair, professor of neurosurgery Douglas Smith uses mechanical tension to speed the growth of implants that he hopes will repair nerve damage.

When sections of nerves in the body are severed or crushed, they die. Although the nerves can regenerate, they do it at the glacial pace of about one millimeter a day. And there’s another catch: as new axons grow, they need the original nerve sheath–a protective membrane made up of several different kinds of cells–to guide them to the area that has lost function. That sheath begins to dis­integrate after about three months without a living nerve in it. “It’s a race against time,” says Smith. A nerve severed in, say, the wrist can span the short distance to the hand and heal in time to restore function. If the same nerve were cut near the shoulder, however, the person would almost certainly lose full use of that hand, since the new growth would not reach the hand before the sheath died.

Not even the most advanced experimental techniques have been able to restore nerve function to sites far from an injury. Smith thought he might facilitate fast nerve re­generation by using lab-grown nerve­s as a kind of scaffold that doctors could place where a patient’s nerve has died. Though the implanted nerve would not transmit signals itself, the presence of the living tissue could guide the body’s regenerating nerve back to the injury site while keeping the detached nerve sheath intact.

To get the engineered nerves to grow long enough to span the injured area by the time they were transplanted, he applied slight, gradually increasing physical tension; this process, he found, encouraged nerves to grow almost 100 times as fast as scientists had believed possible. And the nerves grew not just longer but also thicker, apparently because additional proteins form in response to the tension. Smith and his team introduced these engineered nerves into rats that had part of their leg nerves cut out. Within four months, as the natural nerves began to regenerate in the rats’ bodies, the transplants had helped guide those nerves across the chasms, successfully restoring function to the rats’ legs.

Stretching It
To make the long nerve transplants, Smith and his team first collect sensory neurons–­cells that transmit information to the brain–from the spinal cords of fetal rats. Research technician Kevin Browne then pipettes a gelatinous pink protein called collagen onto two adjacent films in a specially built chamber. About the size of a shoebox, it houses a stretching apparatus made up of a vertical block attached to metal rods. One of the small, clear films, called the towing membrane, is suspended at one end by the block and curves down almost to the base of the chamber, where it overlaps the second membrane. Browne places one set of neurons in the collagen on the towing membrane and another on the bottom membrane. At this point, the two groups are less than 100 micrometers–two hairs’ width–apart. He puts the whole setup into a humming incubator that runs at 37 °C, mimicking the internal temperature of a rat.

The next day, Browne drips a solution of enzymes and other proteins onto the m­embranes using a pipette; the solution encourages the neurons to sprout axons. Slowly, an axon from a single neuron reaches out and forms a synaptic connection with a neuron across the way. After about five days, the axons have securely connected to their neighboring neurons, and Browne attaches the chamber’s rods to a computer-­controlled motor. The motor pulls the towing membrane away from the bottom membrane at a varying rate that has been determined by trial and error.

After about three to five days of gradually increasing the tension, the team can begin stretching the axons as fast as one centi­meter per day (roughly 100 times the speed at which regenerating nerves grow in the body), though shorter transplants can be stretched more slowly.

Repair Work
After about a week of slow stretching, Browne takes the elongation box out of the incubator. He uses a pipette to add more collagen, which acts like a soft glue, on top of the cells. Then he rolls the nerve fibers and the attached neurons off the films. With microscopic forceps, Browne drops the new nerve, now about a centimeter long, into a strawlike tube that has been split lengthwise. The tube, made of a biodegradable material that dissolves inside the body, serves as a synthetic nerve sheath. Browne sutures or glues it securely shut with the nerve inside.

In initial experiments designed to test the transplant’s ability to repair nerve injuries, Smith removes about a centimeter of a rat’s sciatic nerve, which runs through the b­uttocks and down the back of each leg to the ankle and foot, carrying messages from the spinal cord to the various leg muscles. He then places the tube into the space where the nerve was. Using forceps, he gently pushes a stump of the rat’s sciatic nerve sheath into each end of the tube and seals it with fibrin glue. Without the implant in place, the part of the nerve sheath below the cut would degenerate, and the rat would lose movement in that leg. The lab-grown nerves provide a living pathway for regeneration, encouraging the rat’s own motor neurons to grow in the right direction and keeping the sheath alive.

Smith says that in tests performed on more than 40 rats, his group has had almost 100 percent success at restoring the animals’ ability to walk. When the researchers dissected those rats, they found that new axons had grown from their spinal cords and intertwined with the transplanted nerves. The neurons inside the tubes had also given rise to new axons that extended out of the tube in both directions and further mingled with the rats’ own regenerating axons.

Smith and his team think that longer nerve implants could help repair more extensive injuries; so far, the longest nerve they have grown is approximately 10 centi­meters. They have also shown that the stretching process works on human neurons from organ donors. Smith hopes to start testing the human-derived implants in patients with nerve injuries in the next two years.

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