Controlled Cortical Impact Severity Results in Graded Cellular, Tissue, and Functional Responses in a Piglet Traumatic Brain Injury Model.

Abstract

A number of pre-clinical rodent models have been developed in an effort to recapitulate injury mechanisms and identify potential therapeutics for traumatic brain injury (TBI), which is a major cause of death and long-term disability in the United States. The lack of restorative treatments for TBI, however, has led to considerable criticism of current pre-clinical therapeutic development strategies-namely, the translatability of widely used rodent models to human patients. The use of large animal models, such as the pig, with more brain anatomy and physiology comparable to humans may enhance the translational capacity of current pre-clinical animal models. The objective of this study was to develop and characterize a graded piglet TBI model with quantitative pathological features at the cellular, tissue, and functional level that become more prominent with increasing TBI severity. A graded TBI was produced by controlled cortical impact (CCI) in "toddler-aged" Landrace piglets by increasing impact velocity and/or depth of depression to 2 m/sec; 6 mm; 4 m/sec; 6 mm; 4 m/sec; 12 mm; or 4 m/sec; 15 mm, producing a range of neural injury responses that corresponded to injury severity. Quantitative gait analysis was performed pre-TBI and one, three, and seven days post-TBI, and piglets were sacrificed seven days post-TBI. Increasing impact parameters correlated to increases in lesion size with piglets that sustained a 6 mm depth of depression exhibiting significantly smaller lesions than piglets that sustained a depth of depression of 12 mm or 15 mm. Similarly, the extent of neuronal loss, astrogliosis/astrocytosis, and white matter damage became more prominent as CCI parameters were increased. These cellular and tissue-level changes correlated with motor function deficits including swing/stance time, stride velocity, and two- versus three-limb support. The piglet TBI model described here could serve as a translational platform for studying TBI sequelae across injury severities and identifying novel therapeutics.