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Mayo Clinic scientists are providing nerves with a platform for neural regeneration, using advanced biomedical technology and novel methods of tissue engineering to manipulate neural growth factors, guidance cues, and the extracellular environment.
Three integrated research initiatives are addressing regeneration in the spinal cord, the brain, and the limbs. Two of these projects—one fostering axonal extension across large-gap peripheral nerve injuries and one preventing cell death and promoting neural regeneration in the brain—are about to enter clinical trials. Work on spinal cord regeneration is being tested in animals.
In the developing nervous system, nerve growth cones (the cone-like tips of axons and dendrites) extend and retract, sniffing out the molecules needed to help the cones reach and connect with their targets. A complex array of molecular guidance cues tell them whether to continue, to keep on their path, or to turn left or right. The extracellular environment and intrinsic cell signaling are primed to help them in their search and act as a compass on their journey.
Neural growth factors and low levels of neural guidance cues also are available in the fully developed nervous system. An array of inhibitory factors, however, creates an environment that is hostile to regeneration in the CNS. In the PNS, it is the lack of a permissive pathway that prevents projection of axons across large gaps. Many of these inhibitory factors have been identified. By eliminating them in the laboratory, researchers have been able to generate nerve cell growth in vitro. Translating this success into the human nervous system has been a major challenge.
Early, but unsuccessful, efforts at human nervous system regeneration in the 1990s focused on creating antibodies to counteract inhibitory factors. Mayo Clinic took a different approach.
Led by Anthony J. Windebank, M.D., a neurologist and molecular neuroscientist, Mayo researchers pioneered ways of reengineering autologous mesenchymal stem cells to enhance their ability to produce trophic and growth factors. Dr. Windebank's theory was that after implantation, the stem cells could serve as delivery vehicles for neural growth factors, promoting nerve regeneration. What was needed was a permissive environment that could sustain growth and, equally important, enable axons to find and connect with appropriate targets.
Michael J. Yaszemski, M.D., Ph.D., a Mayo Clinic orthopedic surgeon and biomedical engineer, developed a physical structure that could house such an environment.
Single-lumen or tubule and multiple-lumen biodegradable nerve scaffolds.
Flexible nerve guidance scaffold.
Myelinated nerve fibers that have grown in synthetic polymer scaffolds.
Synthetic polymer scaffolds.
Made of a copolymer called polycaprolactone fumarate, it joins two compatible polymers never before brought together. The resulting synthetic tubing provides a biodegradable scaffold between severed axons, within which neural growth factors, signaling molecules, and guidance cues can sustain new growth and axonal projection.
It also provides physical channels through which axons can extend more readily, helping to prevent undirected peripheral nerves from forming neuromas. The scaffold degrades naturally when axons reconnect, a process that can take weeks to months.
Providing a permissive environment within the scaffold depends on overcoming inhibitory factors and directional miscues. For example, after nerve injury, soluble fragments of myelin components, such as myelin-associated glycoprotein, are released that prevent neurons from growing and can cause nerve growth cones to collapse. In addition to such growth-preventing proteins, other factors at the injury site may steer growing nerve tips in the wrong direction. Thus, even if growth is initially supported, neurons must be redirected toward their targets or they will not survive.
John R. Henley, Ph.D., a Mayo Clinic molecular neuroscientist and director of the neurodevelopment and regeneration laboratory, has devoted his career to identifying and manipulating the second messengers that regulate neurite growth and that transduce extracellular guidance signals through a cascade of intracellular events to mediate directional guidance.
These are the cues that facilitate axonal attraction or repulsion and directional turning. Dr. Henley and his colleagues have had success in altering certain second messengers to prevent misdirected axonal tip turning. For example, in an assay that elevates the intracellular second messenger cyclic adenosine monophosphate (cAMP), repulsive turning responses can be converted into attractive ones.
Dr. Henley says that this work is directed at priming nerves to grow on inhibitory substrates by altering not only the external molecular environment, but also the intrinsic state of a neuron—something previously not thought possible.
Peripheral nerve regeneration
Dr. Yaszemski, a brigadier general in the US Air Force Reserves who has served as deputy commander of the hospital at Balad Air Base north of Baghdad, has had direct experience with the extensive limb wounds of soldiers in Iraq and Afghanistan. He and Dr. Windebank serve as codirectors for nerve injury research in the Armed Forces Institute of Regenerative Medicine, a Department of Defense-funded consortium of 16 institutions to generate new treatments for war-wounded persons.
Work at Mayo Clinic focuses on nerve regeneration. Within one year, in conjunction with Robert J. Spinner, M.D., a Mayo Clinic peripheral nerve surgeon, Drs. Windebank and Yaszemski will begin the first human clinical trials of the polymer scaffold implants at Mayo Clinic.
Spinal cord nerve regeneration
The spinal cord presents a particular set of challenges. As Dr. Henley notes, neurons in the CNS face an environment that is more hostile to regeneration than do peripheral nerves. In addition, axonal growth must be bidirectional (both toward the brain and away from it), and scar tissue at the interface of the spinal cord and scaffolding exerts an extra-inhibitory environment.
Drs. Windebank and Yaszemski and their colleagues have applied the scaffolding technology to the injured spinal cord in animals. Dr. Henley's work in elevating the influence of second messengers to reprogram growth cones will help push growing nerves beyond the scaffolding and into the native spinal cord. He envisions a timed release of modulating factors and a second messenger cascade of calcium, cAMP, and other second messengers, to coordinate with the dissolving scaffolding tube as nerve tips reach the native spinal cord. This work may be 5 to 10 years away from human trials.
Neuronal regeneration in ALS
A third regeneration initiative at Mayo Clinic is focused on restoring neural function in progressive CNS disease. Using the same approach in which autologous mesenchymal stem cells supply growth factor to neurons, Dr. Windebank and colleagues are ready to conduct human safety trials. They have harvested stem cells from the adipose tissue of a patient with amyotrophic lateral sclerosis (ALS). After researchers ensured that the cells are normal, the patient has undergone stem cell injection via lumbar puncture without adverse effects. The study will now move forward to a larger safety trial to be conducted on an additional 15 patients. The next step will be to conduct a clinical trial using stem cells that have been reengineered to enhance growth factors, with the goal of generating new neuronal growth.
As Drs. Henley, Windebank, Yaszemski, and Spinner point out, regenerative medicine requires extensive collaboration among the departments of neurology, neurosurgery, orthopedic surgery, biomedical engineering, molecular neuroscience, immunology, and physiology. By integrating these areas of expertise, research teams under the investigators' direction have made substantial progress toward regenerating nerves that were once considered impossible to save.
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