- Improving the Care of Individuals with SCI/TBI Dual Injury
- Advanced Development of a Therapeutic, Humanized, Anti-Inflammatory Antibody: A Novel Neuroprotective Treatment that Improves Outcomes after Spinal Cord Injury
- Schwann Cell Implantation for SCI Repair: Optimization of Dosing, Long-Term Cell Persistence, and the Evaluation of Toxicity and Tumorigenicity
- Brain-Controlled Intrafascicular Nerve Stimulation with High-Count Electrode Arrays for Producing Coordinated Hand Movements
Improving the Care of Individuals with SCI/TBI Dual Injury
Posted October 5, 2012
Drs. Michael Beattie and Geoffrey Manley, University of California, San Francisco
Dr. Graham Creasey, VA Health Care System, Palo Alto
Spinal cord injury (SCI) is often accompanied by traumatic brain injury (TBI), which complicates treatment in both the critical care and rehabilitation settings. Validated treatment approaches for this dual diagnosis, however, are lacking. Drs. Beattie, Manley, and Creasey received a FY09 Translational Research Partnership Award to initiate a bedside to bench to bedside strategy for improving the clinical care of individuals with SCI/TBI dual injury. They queried the clinical community, including participants at the Santa Clara Valley Brain Injury Conference, to gather information on the current treatment strategies for SCI/TBI dual injury, and to determine what they feel are the greatest needs for this population. Survey responses revealed that a majority of clinicians feel that there is a strong need for more research to improve the care of individuals with SCI/TBI dual injury, and that animal models of hand function may motivate changes in clinical practice. Additional clinical information is being gathered from several national and local databases of SCI and TBI clinical care and patient outcomes to identify factors that may affect recovery, including type and extent of injury, medical complications, Functional Independence Measure, and other factors that affect recovery. All of this information will help to inform the development and characterization of SCI/TBI animal models. To establish a baseline for future models, the investigators utilized currently available protocols to create rat models of incomplete SCI plus mild-complicated and moderate TBI. The development of additional models will be based on the needs of the clinical community, and will be used to evaluate clinic-driven hypotheses for new critical care and rehabilitation strategies for SCI/TBI dual injury. To bring the project full circle, data derived from the animal studies will be used to propose improved guidelines clinical treatment. This partnership has developed a community of researchers and clinicians working together to improve the care and treatment of individuals with SCI and TBI.
Advanced Development of a Therapeutic, Humanized, Anti-Inflammatory Antibody: A Novel Neuroprotective Treatment that Improves Outcomes after Spinal Cord Injury
Posted August 21, 2012
Gregory Dekaban, Ph.D., and Arthur Brown, Ph.D., University of Western Ontario
Trauma to the central nervous system (CNS) initiates tissue responses that include swelling and inflammation. Inflammation, in turn, causes damage to surrounding tissues, resulting in secondary injury and increased loss of neurological function. It is critical, therefore, to treat for inflammation as soon as possible following SCI in order to protect undamaged neurological tissues and improve recovery and long-term functionality. Previous studies in animal models have shown that treatment with a monoclonal antibody against the immune cell protein CD11d reduces systemic inflammatory response after CNS trauma, and improves recovery. Drs. Dekaban and Brown received an FY09 Advanced Technology/Therapeutic Development Award to advance a humanized anti-CD11d antibody into clinical trials. In the first year of this award, the team has developed assays to measure the serum concentration of anti-CD11d after treatment, to characterize the antibody's activity, and to determine the subject's biological response to this treatment. The team also compared the effectiveness of several anti-CD11d antibodies of increasing affinity in a rat model and identified the most effective antibody for reducing inflammation and improving neurological recovery. Experiments are in progress to optimize the dosing schedule for this antibody treatment in the rat SCI model. To aid in further analysis of this antibody, Drs. Dekaban and Brown are developing additional animal models for testing in different types and degrees of SCI and are developing new functional measurements, including behavioral scales for locomotion and treadmill training in a larger animal model of SCI. These preclinical studies of anti-CD11d antibodies in animal models of SCI will pave the way to translating this promising therapeutic for human use.
Schwann Cell Implantation for SCI Repair: Optimization of Dosing, Long-Term Cell Persistence, and the Evaluation of Toxicity and Tumorigenicity
Posted August 7, 2012
Damien D. Pearse, Ph.D., Mary Bartlett Bunge, Ph.D., and James Guest, M.D., Ph.D., University of Miami School of Medicine
Individuals with spinal cord injury (SCI) endure lifelong complications from their injury. New strategies to repair the injured spinal cord and effectively restore function following SCI are greatly needed. Schwann cells, a key component of the peripheral nervous system, have been shown to be effective in promoting axon growth, remyelination, and functional recovery in many SCI models, and may serve as effective cell therapy in humans. To avoid the need for immune suppression, Schwann cells can be derived in large numbers from an individual with SCI, expanded and purified in culture, and then implanted in the same individual. Drs. Pearse, Bunge, and Guest received an FY09 Advanced Technology/Therapeutic Development Award to perform dosage, safety, and toxicity studies of Schwann cell implantation in animal models of SCI in preparation for human clinical trials. Optimal dose was obtained in a thoracic contusion (T8) rat model based on functional recovery over a course of 12 weeks after implantation. The investigators demonstrated that transplanted human Schwann cells survived for up to 6 months, the longest time examined, and were not associated with tumor formation, additional tissue damage, scarring, or adverse immune responses. The extent of axon growth into the spinal cord lesion correlated with the number of persisting human Schwann cells present in the animals. Importantly, locomotor function was significantly improved in injured rats treated with Schwann cells compared to injured controls. These promising results allowed the team to submit an application to the Food and Drug Administration to begin a clinical safety trial in humans.
Brain-Controlled Intrafascicular Nerve Stimulation with High-Count Electrode Arrays for Producing Coordinated Hand Movements
Posted July 18, 2012
Gregory A. Clark, Ph.D., University of Utah, Salt Lake City, Utah
Lee E. Miller, Ph.D., Northwestern University, Chicago, Illinois
The single most difficult injury to surmount for many individuals with spinal cord injury is the loss of hand function. Although some restoration of hand use has been obtained through functional electrical stimulation techniques, the resulting movements are limited, difficult to control, and fatigue muscles easily. In Fiscal Year 2009, Dr. Gregory Clark received an Investigator-Initiated Research Award through the Spinal Cord Injury Research Program to develop an improved approach to restoring coordinated hand function following paralysis. In collaboration with Dr. Lee Miller at Northwestern University School of Medicine, Dr. Clark will implant high-channel-count Utah Slanted Electrode Arrays (USEAs) into the peripheral forearm nerves of an animal model to activate paralyzed muscles. The intrafasicular implantation of USEAs will facilitate the activation of motor units of multiple forearm, wrist, and hand muscles selectively and independently, leading to more coordinated and graded movements with a reduced risk of fatigue. Drs. Clark and Miller have performed the first-ever chronic implantation of USEAs in the median nerve of two animal preparations, with little initial adverse reaction. Three months following USEA implantation, compound action potentials were evoked in arm muscles following nerve stimulation by USEA electrodes. In future planned experiments, signals recorded directly from motor cortex with Utah Electrode Arrays will be used to drive the stimulation of the USEA to produce movement despite a temporary, nerve-block-induced paralysis of the forearm and hand. The performance on trained motor behaviors, such as individual digit flexions and grasp-and-placement tasks, will be used to evaluate performance of cortical control of the implanted USEA, and will provide feedback for the researchers to fine-tune the system. If successful, this novel brain-machine interface will provide a means of restoring voluntary control of paralyzed muscles following spinal cord injury.