A Porcine Model of Traumatic Brain Injury via Head Rotational Acceleration

Abstract

Unique from other brain disorders, traumatic brain injury (TBI) generally results from a discrete biomechanical event that induces rapid head movement. The large size and high organization of the human brain makes it particularly vulnerable to traumatic injury from rotational accelerations that can cause dynamic deformation of the brain tissue. Therefore, replicating the injury biomechanics of human TBI in animal models presents a substantial challenge, particularly with regard to addressing brain size and injury parameters. Here we present the historical development and use of a porcine model of head rotational acceleration. By scaling up the rotational forces to account for difference in brain mass between swine and humans, this model has been shown to produce the same tissue deformations and identical neuropathologies found in human TBI. The parameters of scaled rapid angular accelerations applied for the model reproduce inertial forces generated when the human head suddenly accelerates or decelerates in falls, collisions, or blunt impacts. The model uses custom-built linkage assemblies and a powerful linear actuator designed to produce purely impulsive nonimpact head rotation in different angular planes at controlled rotational acceleration levels. Through a range of head rotational kinematics, this model can produce functional and neuropathological changes across the spectrum from concussion to severe TBI. Notably, however, the model is very difficult to employ, requiring a highly skilled team for medical management, biomechanics, neurological recovery, and specialized outcome measures including neuromonitoring, neurophysiology, neuroimaging, and neuropathology. Nonetheless, while challenging, this clinically relevant model has proven valuable for identifying mechanisms of acute and progressive neuropathologies as well as for the evaluation of noninvasive diagnostic techniques and potential neuroprotective treatments following TBI.

Rapid neuroinflammatory response localized to injured neurons after diffuse traumatic brain injury in swine

“…Closed-head rotational TBI was induced under anesthesia using the HYGE pneumatic actuator, a device capable of producing pure impulsive non-impact head rotation with a controlled relationship between maximum rotational acceleration and injury severity, as previously described (Browne et al, 2011; Cullen et al, 2016; Smith et al, 2000, 1997). The well-characterized model rapidly accelerates the head and induces inertial forces representative of human TBI from falls, collisions, or blunt impacts.…”

“…Briefly, the animal was randomly assigned to an injury group and the animal’s head was secured to a padded bite plate under anesthesia, and mounted to the HYGE device. In the miniature pigs, sagittal plane head accelerations (transverse to the brainstem) cause an enhancement of strain in the brainstem region compared to coronal plane accelerations (circumferential to the brainstem), therefore reduced levels of angular velocity/acceleration are required to elicit loss of consciousness and coma (Browne et al, 2011; Cullen et al, 2016; Meaney et al, 1995; Smith et al, 2000, 1997). Therefore, to induce a “mild” injury phenotype, single rapid head rotation was performed in the coronal plane (peak angular velocities of 193–299 radians/second; n=7), whereas to induce a moderate-to-severe injury phenotype rotation occurred in the sagittal plane (peak angular velocities: 80–139 rad/s; n=5).…”

“…In prior studies, it was empirically determined that head rotation at these levels of angular velocity/acceleration in the coronal plane did not induce measurable loss of consciousness or hematoma. However, head rotation at these levels of angular velocity/acceleration in the sagittal plane induced prolonged loss of consciousness and often significant hematoma (Cullen et al, 2016). In addition to the single injuries, we performed repetitive injuries on a small cohort of animals in both the sagittal and coronal planes.…”

“…Therefore, we investigated acute microglial reactivity immediately following inertial TBI using an established porcine model with biomechanical fidelity to closed-head TBI in humans (Cullen et al, 2016; Meaney et al, 1995; Smith et al, 1997). Since diffuse TBIs by definition lack a focal injury epicenter, we explored microglial activation in the context of neuronal trauma, specifically breaches in plasma membrane integrity (Cullen et al, 2011; Geddes et al, 2003; LaPlaca et al, 2009; Singleton and Povlishock, 2004).…”

“…Thus we hypothesized that microglia would be most reactive, as measured by distribution and morphology, in regions exhibiting acute neuronal damage and correlating with injury severity and number of injuries. We tested this hypothesis by subjecting swine to single or repetitive closed-head rotational TBI at levels previously established to result in an injury phenotype consistent with clinical definitions of “mild” or “severe” TBI in humans (Browne et al, 2011; Cullen et al, 2016; Smith et al, 2000). In order to assess trauma-induced alterations in membrane permeability, the cell-impermeant dye Lucifer yellow (LY) was delivered into the ventricles to diffuse throughout the interstitial tissue prior to injury.…”