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Research Center

Restoring Breathing after Spinal Cord Injury: New Hope through Nerve Regeneration

Spinal cord injury and paralysis: what do these terms mean and who is affected? While these conditions may see rare, in reality, spinal cord injury affects more people than may first be suspected.

There are 5.6 million Americans currently living with some level of paralysis, from causes including nerve diseases, autoimmune diseases, stroke and spinal cord injuries. The National Institutes of Health (NIH) estimates that 10,000 to 12,000 new cases of spinal cord trauma are added every year and nearly all of these are results of accidents that could happen to anyone. For those living with spinal cord trauma, it is often a definite, permanent diagnosis; additionally, paralysis is untreatable. Adult nerve cells, once injured, don't regenerate. However, thanks to new advances, this may not be the case forever.

What Happens In Spinal Cord Injuries?

The spinal cord is the main line of communication between the brain and body, controlling movement, feeling, and many functions of the body. It is encased by the vertebrae of the spine, which protect it. However, the vertebrae are like all bones and can break, especially in accidents. When bone fragments enter the substance of the spinal cord they become a major cause of spinal cord trauma. When nerve signals are blocked such as in an injury or the nerves are damaged, the result can be paralysis. Paralysis is total loss of muscle function in an area of the body. Damage to the spinal cord is additionally severe because the spinal cord is the main pathway to the brain allowing major life functions to occur. The amount of damage depends on what level of the spine is injured. Starting at the base of the spine, the list of functions lost gets longer as you head up the spine. An injury to the neck is the most damaging. It might result in complete loss of movement and the ability to breathe without a respirator, as well as all of the other losses that happen with injury to the lower parts of the spinal cord.

About a quarter of spinal cord injuries come from violent encounters, almost 40% from auto accidents, and the majority of the rest are due to other accidents, such as falls or sports.

A Hopeless Case?

The history of spinal cord injuries goes as far back as 1700 B.C., with the recording of paralysis from a spinal cord injury on a piece of papyrus in ancient Egypt. The case was noted as untreatable. Indeed, Greek, Roman, Hindu, Arabic, and Chinese doctors all had no solutions for spinal cord injuries. There were treatments for spinal deformities, but spinal cord injuries remained beyond help. Centuries later, the invention of the automobile and its high speeds dramatically bolstered the rate of accidents and car accidents quickly became the leading cause of spinal cord injury. In addition, there was still no cure in sight. Shortly thereafter, World War I and II added more cases of spinal cord trauma, resulting in paralysis, permanent damage, and the death of most patients within a week of injury. In 1928 Ramon y Cajal studied the spinal cord and noted that a mature central nervous system was unable to grow back after being damaged. A spinal cord injury was labeled a nearly hopeless case and premature death nearly certain. It would not be until 1981 that Sam David and Albert Aguyo would regrow the axons of nerve cells, but these could not re-enter the cord to make functional connections.

Into the Present

In the late 1980s and 90s, a new question emerged. Dr. Jerry Silver, a neuroscientist, wondered: what if there was a mystery substance that prevented nerves from growing back and healing? This went against the prevailing view and as a result the neuroscience community was skeptical. The long-held belief was that once central nerves were cut, they would never regrow. But what if that wasn't true; what if there was a mystery substance that, once removed, would free the nerves to regenerate? Perhaps the answer could be found in the field of regenerative science. Dr. Silver resolved to find out.

The Lock

During natural development of the embryo, there were places that nerves didn't grow. The body stopped nerve growth at certain stages, to be sure that the nervous system would develop with the right blueprint. This prevented nerves from crisscrossing and connecting with the wrong signals. This is important as the embryo spinal cord develops, where left and right nerves must not cross. It made sense that there was a mystery substance that prevented nerves from growing out of bounds at this stage. Once the mystery substance was found, perhaps that knowledge could be used to restore growth after spinal cord injury.

A molecule called chondroitin sulfate proteoglycan was suspected. The molecule was present in large amounts during development, preventing nerves from growing where they should not. It was possible this molecule was the one preventing nerve growth after spinal cord injury; but if it was, could it possibly be deactivated?

These suspicions were confirmed when tests showed that proteoglycans were present in nerve injuries. The damaged nerves withdraw into bulbs, trapped in a kind of net, wielding the proteoglycans.

This natural body process is intended to be helpful, limiting damage and blocking bacteria from getting in. However, the very same process prevented healing the damage from spinal cord injury.

The Key

In order to heal the nerves, the axons would need to grow fast enough, reach the specific intended target, and move through obstacles at the same time. Something was also needed to chew through the nets and proteoglycans to free the neurons. Using a nerve bridge along with a key substance, chondroitinase, might be a solution.

Chondroitinase was the key to the lock: it is an enzyme that can chew through proteoglycans and prevent them from stopping nerve growth. Chondroitinase freed the damaged nerve axon to grow and the nerve bridge provided a bypass around the spinal cord injury.

In 2006, part of an important step was made. Using the combination of neural bridges and chondroitinase, Dr. Silver and his team were able to restore some movement in the forelimbs of paralyzed rats. However, the muscles worked out of sync. To achieve the breakthrough another step was needed and the breathing system was chosen.

Breathing without a respirator is one of the things that people living with high-level spinal cord injuries want most. Without that, moment-by-moment, they are tied to a respirator to breathe. The muscle that controls breathing, the diaphragm, became the new focus in the research.

The Solution

For almost a century, it seemed certain that once injured, nerves of the spinal cord could not regrow, limiting life-giving functions throughout the body. In 2011, after decades of research, each discovery building on the next, Dr. Silver found the answer he had been looking for. 9 out of 11 previously paralyzed rats responded to the neural bridge-and- solution, and regained their breathing.

The Human Element

There are 250,000 spinal cord trauma victims living in America that add an estimated 10,000 to 12,000 to their number every year, in addition to the 5.6 million Americans living with some level of paralysis. The vast majority (80%) of these people are men, 55% ages 16-30, many living with feelings of helplessness, pain, poor sleep, and severe depression, as well as a many physical disabilities: trouble with bowel and bladder control, sexual impotence, numbness, paralysis, pain, and, in high-neck injuries, the inability to breathe without being attached to a respirator. From this breakthrough new hope exists to for research with people to restore the loss that spinal cord injuries can bring.

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Last Reviewed: Apr 01, 2013

Jerry  Silver, PhD Jerry Silver, PhD
Professor
School of Medicine
Case Western Reserve University