Mechanical Design and Analysis of a Unilateral Cervical Spinal Cord Contusion Injury Model in Non-Human Primates

Abstract

Non-human primate (NHP) models of spinal cord injury better reflect human injury and provide a better foundation to evaluate potential treatments and functional outcomes. We combined finite element (FE) and surrogate models with impact data derived from in vivo experiments to define the impact mechanics needed to generate a moderate severity unilateral cervical contusion injury in NHPs (Macaca mulatta). Three independent variables (impactor displacement, alignment, and pre-load) were examined to determine their effects on tissue level stresses and strains. Mechanical measures of peak force, peak displacement, peak energy, and tissue stiffness were analyzed as potential determinants of injury severity. Data generated from FE simulations predicted a lateral shift of the spinal cord at high levels of compression (>64%) during impact. Submillimeter changes in mediolateral impactor position over the midline increased peak impact forces (>50%). Surrogate cords established a 0.5 N pre-load protocol for positioning the impactor tip onto the dural surface to define a consistent dorsoventral baseline position before impact, which corresponded with cerebrospinal fluid displacement and entrapment of the spinal cord against the vertebral canal. Based on our simulations, impactor alignment and pre-load were strong contributors to the variable mechanical and functional outcomes observed in in vivo experiments. Peak displacement of 4 mm after a 0.5N pre-load aligned 0.5-1.0 mm over the midline should result in a moderate severity injury; however, the observed peak force and calculated peak energy and tissue stiffness are required to properly characterize the severity and variability of in vivo NHP contusion injuries.

Advanced oxidation protein products induce microglia-mediated neuroinflammation via MAPKs-NF-κB signaling pathway and pyroptosis after secondary spinal cord injury

“…In our study, the rats in the SCI + apocynin group were intraperitoneally administered with apocynin each day at a dose of 100 mg/kg after SCI. Rats underwent a C5 hemicontusion as previously described [22]. Briefly, a custom-designed clamp was mounted onto the lateral C4-C6 column after a unilateral C5 laminectomy was performed.…”

A Unilateral Cervical Spinal Cord Contusion Injury Model in Non-Human Primates (Macaca mulatta)

“…These force increments indicated the spatial location of the impactor, reflecting (in order): 1) dural contact, 2) cord surface contact, and 3) cord contact with the base of the canal. 17 As illustrated in Figure 1D and 1E , the initial contact of the impactor with the dural surface generated a slight negative shift in the force readout from baseline ( Fig. 1D , step 1; Fig.…”

“…There is a complex relationship between displacement, peak force, and the other measured biomechanical parameters that depends in part on tissue stiffness, cord and spinal column morphology, and perhaps unknown factors, as well. 17 To examine the relationships between mechanics, lesion size, and behavioral outcome at the end of the experiment, we performed both bivariate correlations and a multivariate analysis. Lesion size, including volume, length, and area at the epicenter, are best predicted by peak force (e.g., r = − 0.932 for lesion volume) and force at maximum displacement (r = − 0.621 for lesion volume).…”

“…Thus, accurate and consistent force and displacement readouts prior to the actual in vivo impact were confirmed. 17 …”

“…We used a pre-planning approach based on engineering considerations from prior rat injuries and scaled up using computational and surrogate cord modeling approaches. 17 We now report the design of the primate contusion device, the parameters of injury, sustainability of functional deficits as a function of varying lesion severities, and a multivariate syndromic analysis of the resulting dataset. 14 , 18 The ability to pre-set the injury level and predict outcomes from the resultant biomechanical parameters provides a potential means of efficiently testing candidate therapies in a NHP model that more closely approximates the human condition.…”