UBC Theses and Dissertations
Clinically relevant mechanisms of spinal cord injury : contusion, dislocation, and distraction Choo, Anthony Min-Te
There remains no cure for traumatic spinal cord injury (SCI). Pre-clinical research typically models spinal cord transection, contusion, and compression, although in humans, other injury mechanisms such cord shearing from vertebral dislocation, and stretching from distraction occur frequently. This creates a potentially important disparity between experimental paradigms and clinical injuries. The objective of this thesis was to develop and compare three biomechanically distinct, yet clinically relevant SCI animal models. A multi-mechanism SCI system was developed to deliver high-speed (~100cm/s) injuries along any direction vector. A new vertebral clamping strategy with enhanced clamping strength (64.7±10.2N) and stiffness (83.6±18.9N/mm) was designed for modelling cervical vertebral dislocation (2.Smm), distraction (4.1mm), as well as contusion (1.1mm) injuries. The pattern of primary mechanical injury (n=36 rats) was found to differ between the three injury models. Contusion and dislocation produced intramedullary hemorrhage whereas overt vascular damage was not detected following distraction injury. Vertebral dislocation consistently sheared axons in the lateral columns. Plasma membrane disruption was detected by assessing the intracellular penetration of 10kDa dextran. Following contusion, membrane compromise of neuronal somata and axons was localized near the lesion epicentre whereas following dislocation and distraction, membrane damage extended several vertebral segments rostrally. At 3 hours post-trauma (n= 39 rats), damaged cell membranes were found to reseal especially in the white matter. In spite of this recovery, extensive loss of neurofilaments and accumulation of β-amyloid precursor protein was observed following dislocation injury. In the gray matter, staining for cytochrome c and the oxidative stress marker 3-nitrotyrosine was similar following contusion and dislocation but less pronounced after distraction. Reactive astrocytes and activated microglia extended over a greater rostro-caudal zone only in the dislocation model. These rostro-caudal patterns demarcate disparate populations of primary and secondary injury suggesting that therapies developed in contusion paradigms may not translate to other SCIs. Neuroprotection and repair strategies might favour contusion and distraction injuries, whereas axonal regeneration across a lengthy lesion may inevitably be required for restoring function following dislocation. This interaction between the primary mechanism of injury and secondary neuropathology suggests treatment paradigms may be guided in a mechanism-specific manner.
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