SPINE Volume 30, Number 17S, pp S3–S13 ©2005, Lippincott Williams & Wilkins, Inc. Strategies to Promote Neural Repair and Regeneration After Spinal Cord Injury Brian K. Kwon, MD, PhD, FRCSC, Charles G. Fisher, MD, MPH, FRCSC, Marcel F. Dvorak, MD, FRCSC, and Wolfram Tetzlaff, MD, PhD Study Design. Retrospective review of current litera- ture regarding neuroprotection and axonal regeneration therapies for acute spinal cord injury. Objectives. To provide an update for spine clinicians of the emerging therapeutic strategies for promoting neu- ral repair and regeneration after spinal cord injury. Summary of Background Data. The neuroscientific community has generated a number of novel potential treatments for spinal injuries, some of which have en- tered clinical trials. Clinicians who manage spinal cord trauma are likely to encounter patients and their families who have questions or wish to be involved in these emerging treatments. Methods. Literature review, with particular focus on currently used medications that may have neuroprotec- tive potential in spinal cord injury, and axonal regenera- tion strategies that are emerging in preliminary human clinical trials. Results. A number of medications such as erythropoi- etin and minocycline have demonstrated neuroprotective properties in animal models of spinal cord injury, and their long-established safety in humans make them ap- pealing candidates for clinical trials. Human experience with novel neuroprotective and axonal regeneration strat- egies is growing around the world, and the peer-reviewed reporting of this is anxiously awaited. Conclusions. The initiation of human clinical trials for spinal cord-injured patients heralds great hope that effec- tive therapies will be forthcoming, although a great deal remains to be learned. Clinicians must provide leadership in the epidemiologic design and rigor of these initial for- ays into human evaluation. Key words: spinal cord injury, neuroprotection, axonal regeneration, minocycline, erythropoietin, clinical trials, neurotrophic factors, olfactory ensheathing cells. Spine 2005;30:S3–S13 The permanence and irreversibility of the paralysis asso- ciated with spinal cord injury have been recognized and accepted for thousands of years, 1 with hope emerging in only the latter part of the 20 th century that advances in our scientific understanding of the neurobiology of spi- nal cord injury might produce therapies for this devas- tating condition. 2 The sequelae of spinal cord paralysis are most profoundly manifested in the loss of voluntary motor, sensory, urologic, and sexual function, but signif- icant abnormalities of the respiratory, cardiovascular, gastrointestinal, and musculoskeletal systems are com- mon. 3 In adult patients, mechanical failure of the spinal column in association with nonpenetrating spinal cord injury can lead to progressive kyphotic, and less com- monly, scoliotic deformity. 4 In skeletally immature pa- tients, spinal cord injuries are associated with a high inci- dence of progressive deformity, with chronic spinal column instability, asymmetric growth arrest, and neuromuscular imbalance contributing to the paralytic collapse of the spine. The role of neuromuscular imbalance is demon- strated by the near 100% incidence of scoliosis in children paralyzed before the age of 10 years or before the adoles- cent growth spurt, 5,6 a statistic that in itself represents the relevance of emerging therapies for spinal cord injury in the discussion of spinal deformity and its management. Current Areas of Focus in Spinal Cord Research The mechanical forces imparted to the spinal cord during fractures and dislocations of the spine disrupt the cord’s local neuroglial architecture (the “primary” damage) and initiate a complex pattern of acute pathophysiologic processes that are thought to exacerbate the derange- ment at and around the epicenter of injury (the “second- ary” damage) (reviewed by Kwon et al 7 ). It is well rec- ognized that such nonpenetrating injuries to the spinal column rarely result in complete transection of the spinal cord. Even in individuals who are deemed to have func- tionally “complete” spinal cord injuries graded as “A” by the American Spinal Injury Association (ASIA), the chronically injured spinal cord remains anatomically in- continuity and is often characterized by a peripheral rim of intact tissue encircling a cystic cavity, 8,9 a gross mor- phology that can be reasonably reproduced in animal models of a dorsal contusion spinal cord injury (Figure 1). The implications of this observation of the cord his- tomorphology are numerous. One is that if the entire spinal cord at the site of impact does not completely succumb to the initial mechanical injury and subsequent secondary pathophysiologic processes, then an interven- tion that attenuates these processes and maximizes the extent of this spared tissue could potentially result in improved neurologic function. Cautious optimism for such a strategy is derived from the observation in both From the Combined Neurosurgical and Orthopaedic Spine Program, Division of Spine, Department of Orthopaedics, International Collab- oration on Repair Discoveries, University of British Columbia, Van- couver, British Columbia, Canada. Acknowledgment date: February 16, 2005. Acceptance date: May 31, 2005. Supported by the Vancouver Coastal Health Research Institute in it for life Mentored Clinician Scientist Award (to. B.K.K.). The device(s)/drug(s) that is/are the subject of this manuscript is/are not FDA-approved for this indication and is/are not commercially avail- able in the United States. No funds were received to support this work. No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript. Address correspondence and reprint requests to Brian K. Kwon, MD, PhD, FRCSC, D6 Heather Pavilion, Vancouver General Hospital, Department of Orthopaedics, University of British Columbia, 2733 Heather Street, Vancouver, British Columbia V5Z 3J5, Canada; E-mail: bkwon@vanhosp.bc.ca S3