Effect of Impact Parameters on a Unilateral Contusion Model of Spinal Cord Injury in a Virtual Population of Non-Human Primates.

Non-human primate (NHP) spinal cord injury experiments exhibit high intersubject variability in biomechanical parameters even when a consistent impact protocol is applied to each subject. Optimizing impact parameters to reduce this variability through experiments is logistically challenging in NHP studies. Finite element models provide a complimentary tool to inform experimental design without the cost and complexity of live animal studies. A morphologically variable virtual population (N = 10) of NHPs quantified the interaction of morphological variability and different impact conditions in a unilateral cervical contusion, including impactor size (4 and 5 mm) and mediolateral alignment over the cord midline (0.5 and 1 mm). We explored the effect of these conditions on the magnitude and intersubject variability of impact force and cord lateral slippage. The study demonstrated that a 1-mm mediolateral alignment maximized peak forces and minimized lateral slippage. A 5-mm impactor was beneficial in increasing peak forces, whereas a 4-mm impactor reduced lateral slippage. Comparatively, intersubject variability in peak forces and lateral slippage were minimized with a 0.5-mm mediolateral alignment. The study highlights that impact parameters selected based on peak forces may not be beneficial in reducing variability. The study also showed that morphology was an important contributor to variability. Integrating morphology variability through a virtual population in an injury simulation to investigate mechanistic research questions will more effectively capture the heterogeneity of experiments and provide better insights for effective experimental design.

Correlating Tissue Mechanics and Spinal Cord Injury: Patient-Specific Finite Element Models of Unilateral Cervical Contusion Spinal Cord Injury in Non-Human Primates.

Non-human primate (NHP) models are the closest approximation of human spinal cord injury (SCI) available for pre-clinical trials. The NHP models, however, include broader morphological variability that can confound experimental outcomes. We developed subject-specific finite element (FE) models to quantify the relationship between impact mechanics and SCI, including the correlations between FE outcomes and tissue damage. Subject-specific models of cervical unilateral contusion SCI were generated from pre-injury MRIs of six NHPs. Stress and strain outcomes were compared with lesion histology using logit analysis. A parallel generic model was constructed to compare the outcomes of subject-specific and generic models. The FE outcomes were correlated more strongly with gray matter damage (0.29 < R2 < 0.76) than white matter (0.18 < R2 < 0.58). Maximum/minimum principal strain, Von-Mises and Tresca stresses showed the strongest correlations (0.31 < R2 < 0.76) with tissue damage in the gray matter while minimum principal strain, Von-Mises stress, and Tresca stress best predicted white matter damage (0.23 < R2 < 0.58). Tissue damage thresholds varied for each subject. The generic FE model captured the impact biomechanics in two of the four models; however, the correlations between FE outcomes and tissue damage were weaker than the subject-specific models (gray matter [0.25 < R2 < 0.69] and white matter [R2 < 0.06] except for one subject [0.26 < R2 < 0.48]). The FE mechanical outputs correlated with tissue damage in spinal cord white and gray matters, and the subject-specific models accurately mimicked the biomechanics of NHP cervical contusion impacts.

Compressive mechanical characterization of non-human primate spinal cord white matter.

The goal of developing computational models of spinal cord injury (SCI) is to better understand the human injury condition. However, finite element models of human SCI have used rodent spinal cord tissue properties due to a lack of experimental data. Central nervous system tissues in non human primates (NHP) closely resemble that of humans and therefore, it is expected that material constitutive models obtained from NHPs will increase the fidelity and the accuracy of human SCI models. Human SCI most often results from compressive loading and spinal cord white matter properties affect FE predicted patterns of injury; therefore, the objectives of this study were to characterize the unconfined compressive response of NHP spinal cord white matter and present an experimentally derived, finite element tractable constitutive model for the tissue. Cervical spinal cords were harvested from nine male adult NHPs (Macaca mulatta). White matter biopsy samples (3 mm in diameter) were taken from both lateral columns of the spinal cord and were divided into four strain rate groups for unconfined dynamic compression and stress relaxation (post-mortem <1-hour). The NHP spinal cord white matter compressive response was sensitive to strain rate and showed substantial stress relaxation confirming the viscoelastic behavior of the material. An Ogden 1st order model best captured the non-linear behavior of NHP white matter in a quasi-linear viscoelastic material model with 4-term Prony series. This study is the first to characterize NHP spinal cord white matter at high (>10/sec) strain rates typical of traumatic injury. The finite element derived material constitutive model of this study will increase the fidelity of SCI computational models and provide important insights for transferring pre-clinical findings to clinical treatments. STATEMENT OF SIGNIFICANCE: Spinal cord injury (SCI) finite element (FE) models provide an important tool to bridge the gap between animal studies and human injury, assess injury prevention technologies (e.g. helmets, seatbelts), and provide insight into the mechanisms of injury. Although, FE model outcomes depend on the assumed material constitutive model, there is limited experimental data for fresh spinal cords and all was obtained from rodent, porcine or bovine tissues. Central nervous system tissues in non human primates (NHP) more closely resemble humans. This study characterizes fresh NHP spinal cord material properties at high strains rates and large deformations typical of SCI for the first time. A constitutive model was defined that can be readily implemented in finite strain FE analysis of SCI.

The Transverse Isotropy of Spinal Cord White Matter Under Dynamic Load.

The rostral-caudally aligned fiber-reinforced structure of spinal cord white matter (WM) gives rise to transverse isotropy in the material. Stress and strain patterns generated in the spinal cord parenchyma following spinal cord injury (SCI) are multidirectional and dependent on the mechanism of the injury. Our objective was to develop a WM constitutive model that captures the material transverse isotropy under dynamic loading. The WM mechanical behavior was extracted from the published tensile and compressive experiments. Combinations of isotropic and fiber-reinforcing models were examined in a conditional quasi-linear viscoelastic (QLV) formulation to capture the WM mechanical behavior. The effect of WM transverse isotropy on SCI model outcomes was evaluated by simulating a nonhuman primate (NHP) contusion injury experiment. A second-order reduced polynomial hyperelastic energy potential conditionally combined with a quadratic reinforcing function in a four-term Prony series QLV model best captured the WM mechanical behavior (0.89 < R2 < 0.99). WM isotropic and transversely isotropic material models combined with discrete modeling of the pia mater resulted in peak impact forces that matched the experimental outcomes. The transversely isotropic WM with discrete pia mater resulted in maximum principal strain (MPS) distributions which effectively captured the combination of ipsilateral peripheral WM sparing, ipsilateral injury and contralateral sparing, and the rostral/caudal spread of damage observed in in vivo injuries. The results suggest that the WM transverse isotropy could have an important role in correlating tissue damage with mechanical measures and explaining the directional sensitivity of the spinal cord to injury.