Neuro-Regeneration and Spinal Cord Injury
“Can the spinal cord be rebuilt?” is the question that drives basic research in spinal cord injuries. Mayo investigators are striving to understand the underlying biological mechanisms that either inhibit or promote new growth in the spinal cord. They are making surprising discoveries, not just about how neurons and their axons grow in the central nervous system (CNS) but also about why they fail to regenerate after injury in the adult CNS. Understanding the cellular and molecular mechanisms involved in both the working and the damaged spinal cord could lead to therapies and secondary damage, encourage axons to grow past injured areas, and reconnect vital neural circuits within the spinal cord and CNS. Successful research in a number of fields has provided insight into spinal cord injuries. Genetic studies have revealed a number of molecules that encourage axon growth in the developing CNS but prevent it in the adult. Research into embryonic and adult stem cell biology has furthered knowledge about how cells communicate with each other. Basic research has helped describe the mechanisms involved in the process of apoptosis, in which large groups of seemingly healthy cells self-destruct. New rehabilitation therapies that retrain neural circuits through forced motion and electrical stimulation of muscle groups are helping injured patients regain lost function.
Mayo researchers are advancing our understanding of the four key principles of spinal cord repair:
A spinal cord injury is complex. Repairing it has to take into account all of the different kinds of damage that occur during and after the injury. Because the molecular and cellular environment of the spinal cord is constantly changing from the moment of injury until several weeks or even months later, combination therapies will have to be designed to address specific types of damage at different points in time.
The following are some of the projects Mayo Clinic neurologists are pursuing in spinal cord and neuro-regeneration.
Mayo investigators have completed animal studies that are the first steps in showing that nerve connections can regenerate in the spinal cord. Anthony Windebank, M.D., and Michael Yaszemski, M.D., have assembled a multi-disciplinary team for this project with remarkable breadth. Areas involved include:
Dr. Windebank and his team have simulated spinal cord injury (SCI) by excising a small section of the spine of an anesthetized rat. It is replaced with a trellis-like, biodegradable, polymer scaffold designed to anchor nerve cells, deliver drugs that promote nerve regeneration, and dissolve after a predetermined time to make room for more nerve growth. The goal is to produce a permissive environment that encourages the nerve cells to grow in a determined small section of a spine surgically excised from an anesthetized rat. Schwann cells are one type of cell that can promote nerve growth. They can be harvested from the peripheral nervous system and loaded into the polymer scaffold. Then neurotrophins—protein growth factors that promote nerve growth by blocking natural cell death—are introduced.
Three months after injecting Schwann cells into rat spinal cords, the research team observed as many as 5,000 nerve fibers growing throughout the length of the polymer scaffolds. Other cell types being used to promote regeneration in these animal models are embryonic and adult stem cells. Other basic scientists at Mayo are conducting research that may help when the team is ready to begin the complex process of restoring function.
Biodegradable polymer conduits for peripheral nerve repair
Dr. Windebank and Dr. Yaszemski, along with Robert Spinner, M.D., and Bradford Currier, M.D., are studying peripheral nerve injuries that occur with accidental trauma or during the course of surgery. The latter often occurs when nerves are sacrificed during removal of tumors. Direct surgical repair of severed nerve ends provides the best opportunity for regeneration. If that is not possible, a bridge must be provided involving the sacrifice of another nerve such as the sural nerve. The amount of tissue available from this source is limited in both length and diameter. Several brands of synthetic nerve tubes are marketed but have not met with great success. We have assembled a multidisciplinary team of clinicians, surgeons, cell biologists, engineers, and neuroscientists who have developed a series of novel biodegradable polymers that support regeneration in the central and peripheral nervous system of animals. We have demonstrated that these conduits may be used as drug delivery vehicles, the surfaces can be modified to enhance biocompatibility, and conduits can be loaded with cells that support regeneration. Computer-aided design has enabled design of complex microarchitecture that enhances fidelity of regeneration. We are now studying the most promising polymers (polycaprolactone fumarate/polypropylene fumarate co-polymer; PCL-PPF and oligo (polyethylene glycol) fumarate (OPF) hydrogel) to develop specific conditions (micro-architecture and surfaces) that will translate into patient therapies and treatments.
Targeting antibodies to repair the myelin sheath and to promote nerve regeneration
Moses Rodriguez, M.D., has developed antibodies that may play a critical role in repair of the myelin sheath—the fatty insulation that surrounds most nerves in the brain and spinal cord. He is optimistic that a greater understanding of the mechanisms that promote remyelination will one day result in non-invasive treatments that promote nerve repair.
Dr. Rodriguez directs the Demyelinating Laboratory and has dedicated twenty years to researching ways to promote nervous system repair. Though his primary interest is multiple sclerosis, much of what he has learned is applicable to SCI. Multiple sclerosis results from injury to the myelin sheath, and we have developed a series of assays by which researchers can examine how various antibodies directly stimulate its repair. There is strong pathological evidence that demyelination is the cause of dysfunction in many SCI cases. Some antibodies that promote remyelination will also promote functional recovery. In addition to the myelination projects, Dr. Rodriguez's lab is now developing a whole new set of antibodies that are specifically targeted at nerve regeneration.
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