For release: Monday, May 19, 2008
Several experimental treatments for spinal cord injury involve a relatively simple idea: implant a "scaffold" at the site of the injury to support the regrowth of severed connections. Unfortunately, many kinds of scaffolds – from pieces of living nerve tissue to artificial polymers – have been tested in animal models of spinal cord injury, and they tend to produce disappointing results. Typically, damaged nerve cells will grow into a scaffold, but then fail to extend through it and beyond, where new connections could truly improve functional outcomes.
In a study reported in the Journal of Neuroscience*, scientists describe a new kind of polymer scaffold, designed using nanotechnology. They show that the polymer stimulates axons – the nerve cell extensions that run up and down the spinal cord – to regrow all the way across a spinal injury. In mice, a single injection of the polymer given one day after a spinal cord injury led to functional improvements that would be "life-changing" in humans, said John Kessler, M.D., the study's senior investigator and the chairman of neurology at Northwestern University in Chicago.
"This is not a magic bullet, but it's a promising advance," said Dr. Kessler, who is supported by the National Institute of Neurological Disorders and Stroke (NINDS).
Long after an injury, the damaged part of the spinal cord remains an inhospitable place for axons. The injured spinal cord lacks the signals that guide axons during embryonic development, and it becomes filled with scar tissue formed by cells called glia. The new polymer, produced through a collaboration between Dr. Kessler and Samuel Stupp, Ph.D., a biomaterials engineer at Northwestern, is an attempt to solve those problems.
The polymer consists of a carbon-based molecule that forms nanofibers (10,000 times finer than a human hair), and ultimately assembles into a nanogel, upon contact with bodily tissues or fluids. That means the polymer can be injected into the spinal cord in liquid form, which carries less risk of additional damage compared to implanting a pre-formed scaffold, Dr. Kessler said.
The polymer also contains fragments of laminin – a protein that stimulates axon growth. Perhaps most importantly, once the gelatinous scaffold forms, it lasts for about two weeks and then disintegrates. This apparently gives axons the extra nudge they need to keep growing until they cross the lesion. Previously tested scaffolds "seem to create such a favorable environment that the axons don't want to leave," Dr. Kessler explained.
Dr. Kessler has spent the better part of his career studying regenerative medicine, particularly the biology of the stem cells that make neurons and glia. He began to focus on spinal cord regeneration in 2001, when his teenage daughter Allison was in a skiing accident that left her paralyzed from the waist down. (Now in her early 20s, she is a Harvard alum and a graduate student at the London School of Economics and Political Science.)
Drs. Kessler and Stupp originally developed the nanogel thinking it could serve as a delivery vehicle for stem cells and a niche where the cells – stimulated by laminin and shielded from negative cues in the spinal cord – would morph into neurons. But in an earlier study, they found that the nanogel not only stimulated cultured stem cells to turn into neurons, it also suppressed them from becoming astrocytes – the glia that produce scar tissue.
"We reasoned that if the nanogel had the same effect inside the spinal cord, it would limit the amount of glial scarring," Dr. Kessler said.
In their current study, Dr. Kessler and his colleagues injected the polymer into mice 24 hours after a spinal cord injury that caused hindlimb paralysis. By nine weeks, the treated mice were using their hindlimbs to take coordinated, weight-bearing steps.
Inside the spinal cords of the mice, even those that were not treated, axons appeared to grow into the damaged area over several weeks. However, in the treated mice, axons were more likely to enter the lesion, and they also tended to penetrate into it more deeply. By 11 weeks, about 35 percent of descending axons (those that extend downward from the brain) had grown all the way across the lesion in treated mice, while none grew across the lesion in untreated mice. As expected, the treated mice also had less glial scarring than the untreated mice, which may have made it easier for the regrowing axons to leave the scaffold area and make new functional connections within the spinal cord.
Additional data from animal models will be necessary before the nanogel can be tested in humans with spinal cord injury, Dr. Kessler said. The researchers are investigating the long-term effects of the treatment in mice, as well as its mode of action. They have evidence that the nanogel not only inhibits stem cells from becoming astrocytes, but also encourages them to become oligodendrocytes, the cells that form a protective myelin sheath around spinal axons.
NINDS is a component of the National Institutes of Health (NIH) within the Department of Health and Human Services. The NIH — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research. It investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.
-By Daniel Stimson, Ph.D.
*Tysseling-Mattiace VM et al. "Self-Assembling Nanofibers Inhibit Glial Scar Formation and Promote Axon Elongation after Spinal Cord Injury." Journal of Neuroscience, April 2, 2008, Vol. 28(14), pp. 3814-3823.
Last Modified May 19, 2008