Current interventions offer little hope of functional recovery for patients after a spinal cord injury (SCI). In the United States, the incidence of SCI is 32 injuries per million population, approximately 11,000 new injuries per year, affecting a young group of people of median age 26, that is predominately male (82%). Road traffic accidents, acts of violence, falls, and sports injuries account for the majority of injuries. The average inpatient stay is 9 months, during and following which the patient’s life, in virtually all aspects, is profoundly changed (Lali et al., 2001
). 45.7% of the 253,000 persons living in the United States with the residual of spinal cord injury have permanent and complete paraplegia or tetraplegia, irreversible loss of neurologic function below the level of the injury (National Spinal Cord Injury Association, 2009
The majority of patients die from respiratory complications. Injury at any level of the spinal cord will impair respiratory function, through the destruction of motor nuclei and descending motor tracts innervating diaphragmatic, thoracic, intercostal and abdominal accessory muscles. Equally impaired are ascending sensory signals for muscle control via stretch reflexes, for cough, vomit and secretion clearance and from peripheral respiratory chemoreceptors. These axons project through the spinal cord to and from a neural network in the brainstem comprising three interconnected centers, the pontine group, and the medullary dorsal and ventral respiratory group. The pontine group (parabrachial/Kölliker-Fuse complex) controls respiratory timing, receives input from lung stretch receptors, and links respiration to behavioural cues; the dorsal group receives afferents from respiratory chemo and mechanoreceptors, and coordinates respiratory-cardiac reflexes; the ventral group (Bötzinger complex) projects inspiratory neurons, expiratory motor neurons rostrally, and includes a pre-complex generating the respiratory rhythm. Axons descend in the spinal cord in the anterolateral white matter to phrenic, intercostal and abdominal motor neurons, laterally in the high cervical cord near the spinothalamic tract for autonomic function and with the corticospinal tracts for voluntary respiratory control (Nogues and Benarroch, 2008
Accordingly, respiratory failure with spinal cord injury occurs as a consequence of alternations in tidal volume, ventilation and its pattern, diminished responses to hypercapnia, reduced lung and chest wall compliance, and progressive respiratory muscle fatigue due to compensatory breathing rates. Hypoxia from respiratory compromise can further the neurologic injury. Common secondary pathology includes (aspiration) pneumonia, atelectasis and the complications of mechanical ventilation (Lane et al., 2008
). Injury to the cord can also induce paralytic ileus worsening aspiration. More severe respiratory compromise occurs with higher levels of injury with risk to phrenic motor nuclei located in cervical spinal cord segments C3-C5 (occasionally as low as C7) (Zimmer et al., 2007
Pathological (Quencer and Bunge, 1996
) and imaging studies (Bodley, 2002
) demonstrate tissue destruction with cysts and gliosis in the area of injury, along with atrophy in adjacent segments of cord. Strategies aimed at preventing immediate and delayed secondary damage need to be administered within minutes or hours of injury. Even if ideal protective agents were available, many patients would not be in circumstances where this would be available or successful. The area of cysts and glial scarring does not contain cells or tissue that contribute to regeneration and is consequently both a gap and a barrier to regeneration. There are, therefore, only two ways to re-establish neurologic function below the block: bypassing the area or rebuilding functional tissue within the cyst/scar. A functional bypass might be established by nerve autograft connections from areas above the lesion to distal effectors (cord or muscle) (Tadie et al., 2002
). The second approach is to replace the cyst/scar with functional tissue, promoting the development of neural tissue bridges to carry regenerating axons from above to roots or muscles below the lesion (Friedman et al., 2002
). For future use in patients, replacement of a segment of cord would be suitable for those with massive damage to the cord with no evidence of residual functional tissue in the area. Unfortunately, this accounts for a significant number of patients.
Animal models of spinal cord injury include complete transection (thoracic), hemisection (dorsal or unilateral), and contusion injuries (forceps and computer-controlled weight impact). These models approximate common human pathology, open cord laceration (1/4 of injuries) and closed compression/contusion injuries (3/4). Biomaterial polymers may be delivered as gels, suitable for contusion and small tears, as devices designed to fill larger defects (sponges) or to bridge large gaps and traverse the glial scar (tubes and multichannel scaffolds (Hiroshi et al., 2006
). While deep tears or transections are rare in human injury, complete or partial transections in animal models are useful as proof of concept, and for the controlled study of axonal regeneration (Talac et al., 2004
). Animal models of respiratory dysfunction focus on high cervical injury producing diaphragm hemiplegia, but no studies to date have employed polymer-based tissue engineering strategies specifically in this context. Given the severity of patient morbidity and the rates of mortality associated with respiratory compromise, neurologic repair is an important therapeutic goal. A relatively short distance, from the medulla to phrenic C3-C5 or within the phrenic segments for example, needs be bridged by new neuronal tissue. Equally, respiratory innervation associates with discrete tracts, corticospinal and spinothalamic, and repair may often be unilateral given a lateral injury and diaphragmic hemiplegia. Such tracts represent ideal targets for polymer scaffold implantation given their limited scope and clinical importance.