The pig as a preclinical traumatic brain injury model: current models, functional outcome measures, and translational detection strategies

Abstract

Traumatic brain injury (TBI) is a major contributor of long-term disability and a leading cause of death worldwide. A series of secondary injury cascades can contribute to cell death, tissue loss, and ultimately to the development of functional impairments. However, there are currently no effective therapeutic interventions that improve brain outcomes following TBI. As a result, a number of experimental TBI models have been developed to recapitulate TBI injury mechanisms and to test the efficacy of potential therapeutics. The pig model has recently come to the forefront as the pig brain is closer in size, structure, and composition to the human brain compared to traditional rodent models, making it an ideal large animal model to study TBI pathophysiology and functional outcomes. This review will focus on the shared characteristics between humans and pigs that make them ideal for modeling TBI and will review the three most common pig TBI models–the diffuse axonal injury, the controlled cortical impact, and the fluid percussion models. It will also review current advances in functional outcome assessment measures and other non-invasive, translational TBI detection and measurement tools like biomarker analysis and magnetic resonance imaging. The use of pigs as TBI models and the continued development and improvement of translational assessment modalities have made significant contributions to unraveling the complex cascade of TBI sequela and provide an important means to study potential clinically relevant therapeutic interventions.

A Tilted Axis: Maladaptive Inflammation and HPA Axis Dysfunction Contribute to Consequences of TBI

“…Along with rodent models, much work has been done to better identify similarities and caveats of other animal injury models. Notably, large animal models such as pigs may offer additional insight due to the similar size, organization, and development of the brain to humans (170). Lastly, continued emphasis must be placed on translation from pre-clinical to clinical work while maintaining an appreciation for species-specific differences.…”

Alcohol Induced Brain and Liver Damage: Advantages of a Porcine Alcohol Use Disorder Model

“…As such, using an animal model with a similar WM to GM ratio will be critical in understanding alcohol induced neuropathology ( Figure 2A ). The mature rat brain is comprised of < 12% of WM while the mature human and pig brains have > 60% ( Figure 1 ; Kinder et al, 2019 ). As alcohol exhibits differential damage on these tissues, having a similar WM to GM ratio would result in a similar pattern of injury on the brain and thus similar manifestation of deficits as a result of the injury.…”

Autoregulation assessment by direct visualisation of pial arterial blood flow in the piglet brain

“…We demonstrated that the combination of vessel diameter and RBC velocity to calculate RBC flux in individual vessels remained effective in a porcine model of traumatic brain injury. Cortical impact has been demonstrated to reproducibly impair autoregulation capacity as measured by pial arteriolar diameter and LDF changes 28–30 .…”