Nerve regeneration restores bladder function in rats

In what they are calling a breakthrough study, researchers from Case Western Reserve University School of Medicine and Cleveland Clinic have restored significant bladder function through nerve regeneration in rats with the most severe spinal cord injuries.

Their approach paired a traditional nerve bridge graft with a novel combination of scar degrading and growth factor treatments to grow new nerve cells from the thoracic level to the lower spinal cord region.

The authors built a regeneration bridge across a lesion in animals with complete gap transections of their spinal cords. Although the animals did not regain the ability to walk, the procedure did allow them to recover a strong level of bladder control.

Senior author Jerry Silver, PhD, of Case Western Reserve, and first author Yu-Shang Lee, PhD, of Cleveland Clinic, created the bridge using a scaffold of multiple segments of the animals’ own peripheral nerves. Key to the regeneration was surrounding the graft and both spinal cord stumps with a stimulating growth factor and an enzyme to dissolve scar tissue, which inhibits the nerve fibers from crossing over the bridge and traveling down the spinal cord.

“While urinary control is complex and recovery took several months, it was clear that this primitive function lost to spinal cord injury does possess the capacity to rewire itself, even when a relatively small number of axons are regenerated,” Dr. Silver said.

The creation of the neural bridge, which spans the open cavity between the severed ends of the spinal cord, kills the axons that normally reside within the nerve. However, the glial cells of the bridge, called Schwann cells, remain alive in the nerve and encourage the severed nearby axons in the spinal cord to enter the bridge and regrow.

To establish functional regeneration across the gap and down the rats’ spinal cord, the authors had to coax the regenerating axons to enter and transcend the bridge. Then the axons had to grow well beyond the bridge and form connections capable of relaying nerve signals once they arrived at their destination-approximately 2 cm down the spinal cord.

To achieve these results, Dr. Silver and Dr. Lee added fibroblast growth factor to help align the Schwann cells in the graft with the scar tissue cells at the bridge’s interfaces. Next, they injected chondroitinase to break down inhibitory molecules that often form in scar tissue and curtail regeneration at both ends of the bridge.

“We were especially surprised and excited to discover that once a permissive environment was created, a subset of neurons situated largely within the brainstem, which play important roles in bladder function, slowly re-grew lengthy axons far down the cord,” said Dr. Silver.

Dr. Silver and Dr. Lee are planning on testing the technique in larger animal models before moving to human clinical trials in the U.S.

Results from the study were published in the Journal of Neuroscience (2013; 33:10591-606).

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