Bridging the Gap
Dr. Lu and crew at UC-San Diego proved axons can regrow across complete injuries.
Severed motor axons can now be made to cross complete spinal cord injuries and connect to muscle groups below the level of injury in rats. Researchers with the University of California San Diego’s Department of Neurosciences’ Center for Neural Repair detailed their breakthrough in a June 13 article in The Journal of Neuroscience. According to Dr. Pengzhe (Paul) Lu of UCSD, there is no doubt that the axons are passing directly across the lesion, because the injuries were complete. “Most people claim axon regeneration in the incomplete lesion model but it’s very difficult to differentiate spared axons from regenerated axons,” Lu explains. Now, they know for certain it can be done and hopes are high for similar success when the procedure is finally ready for human trials.
As a T10-11 complete para of 15 years following an auto accident, Lu has a lot at stake in efforts to cure chronic SCI. Lu’s rats are newly-injured, but surgically scarred, so their injuries are similar in many respects to those seen in chronic SCI from gunshot wounds and stabbings. The tough scars associated with this type of penetrating injury make it a particular challenge in cure research. Bridging those barriers — a technique known as “scaffolding” (see Glossary) — has not been easy, and other approaches remain important elements of cure research. Other types of scaffolding, such as those under development by InVivo Technologies and techniques to maximize use of the undamaged parts of the cord in partial injuries, are also very promising and may produce earlier practical benefits (see “Related Research,” below).
Currently, UCSD’s technique requires brain surgery to inject the powerful growth regulator cAMP into the brainstem. This growth regulator prompts motor neurons to send their retracted severed axons back out toward the distant muscles (According to Lu, this surgery would most likely be replaced by injections of a cAMP-carrying drug into the bloodstream in human trials).
Prompting of motor axon growth in the brain is followed by spinal surgery, in which bone marrow stromal cells, a type of stem cell, are grafted into the one to two millimeter gap left by surgical removal of the scar. “We need to provide a substrate for the axon to attach to, to grow,” Lu says of the stem cell graft. These stem cells also are genetically modified to produce growth factors of their own, enticing the motor axons to enter the cord graft and cross over to the natural spinal cord tissue beyond.
During surgery to implant this graft in the spinal cord gap, a genetically-modified virus is injected into the tissue below the injury site, where neural connection to muscle is desired. This virus causes production of yet another growth factor, Brain Derived Neurotrophic Factor (BDNF). This growth factor draws the axons the rest of the way down to make connections with muscle groups.
Unfortunately, the rats in the UCSD study suffered functional declines, despite successful re-growth and connection of motor axons. “The anatomical result is good but we need to solve this long-term [growth factor] expression problem,” Lu says. The problem with mis-wiring resulting in degraded functional outcomes is believed to be the researchers’ current inability to turn off viral BDNF production. Better control over this element may allow for final stages of connectivity to be guided by the body’s less-intense natural mechanisms.
Other research involving scaffolding/bridging techniques is showing potential for practical application even when the exact mechanisms at play are less certain. InVivo Therapeutics reports that they are in the final stages of applying for FDA approval of human trials with their biopolymer scaffolding, which is expected to reduce bleeding and inflammation in the acute phase of SCI, sparing tissue and reducing the severity of chronic injury. They also have plans for human trials of their stem-cell-embedded scaffolding. It has shown promising results in African green monkeys with hemiparesis.
The InVivo monkeys that received human-stem-cell-embedded scaffolding recovered motor function and were running and climbing within four weeks. “Nobody had gotten a [paralyzed] monkey to walk before,” InVivo CEO Frank Reynolds says of the 2008 study that won InVivo the 2011 Apple Award. Reynolds also has personal experience with paralysis, having suffered temporary paraplegia following failed back surgery in 1992 that had lingering neural deficits.
InVivo’s success with African green monkeys is impressive, but it is uncertain whether improvements in function are due to the re-establishment of neural pathways directly across the partial lesion site itself, or strengthening of, and changes in, the connectivity around it.
Rats with incomplete injuries regained function in a recent Swiss study on neuroplasticity.
Researchers at the École Polytechnique Fédérale de Lausanne (EPFL), Switzerland, have recently proven that rats with partial injuries can be restored to a high degree of motor function by making the most of the detour effect that Lu and his fellow researchers have been so careful to prevent in order to prove that injuries can be directly bridged. By injecting rats with the chemical motor neuron stimulant MOAI, applying electrical stimulation to muscle groups, and using robotic assisted exercise to cause the animals to re-route motor signal pathways,
EPFL is able to enhance the performance of spared tissue in partial injuries. The end result demonstrates the power of neuroplasticity: restoration of voluntary ambulation without permanent use of drugs, electrical stimulation, or robotic assistance. Human trials are expected to be underway within two years.
Scaffolding: Also known as bridging, scaffolding is the addition of structural elements to an injury site to guide and support nerve tissue, and to prevent further damage. Scaffolding may be made from a wide range of biological and biocompatible materials and is often designed to release drugs or growth hormones. Scaffolding may also be pre-loaded with stem cells. Scaffolding is still in animal trials.
Neuroplasticity refers to the body’s natural ability to restructure the nervous system – including the ability to create and improve upon detours around damaged areas. This natural ability is now known to play a strong role in recovery from nerve damage, and researchers are working on ways to make the most of it in SCI cure research.
If scaffolding is the repair of a broken bridge span, then neuroplasticity is directing traffic to alternate bridges.