By Sam Maddox
One of the major obstacles to recovery of function in chronic spinal cord injury is the failure of nerve axons to cross the lesion site, an area characterized by a scar-lined cyst filled with substances that repel axons. Several experimental models have found ways to detoxify the cyst by neutralizing specific molecular inhibitors, thereby promoting axon growth.
But it’s going to take more than that: the growing axons need some sort of scaffold or structure to guide them to make an appropriate connection. Enter the realm of bioengineering.
An interesting paper just came out (in ACS Nano: Transplantation of Nanostructured Composite Scaffolds Results in the Regeneration of Chronically Injured Spinal Cords
) from a group in Italy working with engineers from MIT; they transplanted designer nanostructures to form a sort of 3-dimensional tubular neuroprosthesis six months after SCI in an animal model. Treated rats got a set of nanofibers (very, very tiny inorganic structures) transplanted into the lesion area, along with some unspecified cytokines to promote axon growth. The nerves reportedly grew and made functional connections.
Fabrizio Gelain, lead author for the paper noted, “Where usually in the damaged spinal cord there is scar tissue or a fluid filled cyst, nervous tissue regenerated and followed the direction given by our guidance channels. Histological results were also supported by significant functional recovery of the treated animals.”
What Gelain and his group found is that the implanted tubular channels to guided regenerating axons across across the cysts. The scaffold eventually was bio-degraded and there was negligible inflammatory response, said Gelain. “The nanostructured scaffolds led to the cyst being replaced by newly formed tissue, composed of both neural, vascular and stromal (support) cell types, that provided the appropriate environment for axonal regeneration and myelination, electrophysiological improvement and significant neurological recovery."
Gelain, working with stem cell researcher Angelo Vescovi, plans to add neural stem cells to the implant.
Meanwhile, the scaffold model is the focus of several other laboratory efforts. In 2007 a group in Hong Kong working with a spinal cord injury model transplanted a self-assembled nanofiber scaffold along with neural progenitor cells and Schwann cells. They reported “robust migration of host cells, growth of blood vessels, and axons into the scaffolds, indicating that the nanofiber scaffold provides a true three-dimensional environment for the migration of living cells.” They are also working on a brain procedure. A group in mainland China reported last fall that a co-transplantation of neural stem cells and Schwann cells along a polymer (poly lactide-co-glycolide acid) scaffold also promoted recovery in an animal model of SCI.
Boston-area biotech start up InVivo Therapeutics has based its entire business model on scaffolds for sub-acute (first few days) SCI. The company has applied for approval to transplant a biodegradable guidance structure invented by polymer guru Robert Langer of MIT. InVivo says it has successfully tested its device in nonhuman primates and hopes eventually to market polymer devices that also deliver drugs.
Scaffolds themselves will not be enough for significant recovery. It’s going to take a combination of treatments. Charles H. Tator, from the Toronto Western Hospital Research Institute, funded in part by the Reeve Foundation, has begun testing a novel four-part strategy to treat chronic SCI in animals. He starts with a transplanted guidance channel made of chitosan (naturally occurring and well tolerated by the cord) directly into the lesion cyst. The channel, 6 mm long and about 1.5 mm in diameter, features a scaffold made of fibrin – this allows axons nerve fibers to enter and grow along its course without inflammation or inhibition. The scientists are also adding spinal cord-derived neural stem cells to help guide fiber growth in and out of the channels. Finally, chondroitinase-ABC is injected at the ends of the channels; this enzyme dissolves chemicals that block axon growth.
Clearly, scaffold engineering and axon guidance are going to remain hot areas of research as biologists continue to find ways to spur growth or replace cells.