Reproducibility and Characterization of Head Kinematics During a Large Animal Acceleration Model of Traumatic Brain Injury

Acceleration parameters have been utilized for the last six decades to investigate pathology in both human and animal models of traumatic brain injury (TBI), design safety equipment, and develop injury thresholds. Previous large animal models have quantified acceleration from impulsive loading forces (i.e., machine/object kinematics) rather than directly measuring head kinematics. No study has evaluated the reproducibility of head kinematics in large animal models. Nine (five males) sexually mature Yucatan swine were exposed to head rotation at a targeted peak angular velocity of 250 rad/s in the coronal plane. The results indicated that the measured peak angular velocity of the skull was 51% of the impulsive load, was experienced over 91% longer duration, and was multi- rather than uni-planar. These findings were replicated in a second experiment with a smaller cohort (N = 4). The reproducibility of skull kinematics data was mostly within acceptable ranges based on published industry standards, although the coefficients of variation (8.9% for peak angular velocity or 12.3% for duration) were higher than the impulsive loading parameters produced by the machine (1.1 vs. 2.5%, respectively). Immunohistochemical markers of diffuse axonal injury and blood–brain barrier breach were not associated with variation in either skull or machine kinematics, suggesting that the observed levels of variance in skull kinematics may not be biologically meaningful with the current sample sizes. The findings highlight the reproducibility of a large animal acceleration model of TBI and the importance of direct measurements of skull kinematics to determine the magnitude of angular velocity, refine injury criteria, and determine critical thresholds.

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Large animal models of traumatic brain injury

Journal of Neuroscience Research ◽

10.1002/jnr.24079 ◽

2017 ◽

Vol 96 (4) ◽

pp. 527-535 ◽

Cited By ~ 33

Author(s):

Robert Vink

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Animal Models ◽

Large Animal ◽

Large Animal Models

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Large animal models of stroke and traumatic brain injury as translational tools

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00163.2017 ◽

2018 ◽

Vol 315 (2) ◽

pp. R165-R190 ◽

Cited By ~ 24

Author(s):

Annabel J. Sorby-Adams ◽

Robert Vink ◽

Renée J. Turner

Keyword(s):

Traumatic Brain Injury ◽

Ischemic Stroke ◽

Brain Injury ◽

Animal Models ◽

Animal Species ◽

Experimental Models ◽

Clinical Translation ◽

Large Animal ◽

Large Animal Models ◽

Significant Burden

Acute central nervous system injury, encompassing traumatic brain injury (TBI) and stroke, accounts for a significant burden of morbidity and mortality worldwide. Studies in animal models have greatly enhanced our understanding of the complex pathophysiology that underlies TBI and stroke and enabled the preclinical screening of over 1,000 novel therapeutic agents. Despite this, the translation of novel therapeutics from experimental models to clinical therapies has been extremely poor. One potential explanation for this poor clinical translation is the choice of experimental model, given that the majority of preclinical TBI and ischemic stroke studies have been conducted in small animals, such as rodents, which have small lissencephalic brains. However, the use of large animal species such as nonhuman primates, sheep, and pigs, which have large gyrencephalic human-like brains, may provide an avenue to improve clinical translation due to similarities in neuroanatomical structure when compared with widely adopted rodent models. This purpose of this review is to provide an overview of large animal models of TBI and ischemic stroke, including the surgical considerations, key benefits, and limitations of each approach.

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A systematic review of large animal models of combined traumatic brain injury and hemorrhagic shock

Neuroscience & Biobehavioral Reviews ◽

10.1016/j.neubiorev.2019.06.024 ◽

2019 ◽

Vol 104 ◽

pp. 160-177 ◽

Cited By ~ 2

Author(s):

Andrew R. Mayer ◽

Andrew B. Dodd ◽

Meghan S. Vermillion ◽

David D. Stephenson ◽

Irshad H. Chaudry ◽

...

Keyword(s):

Systematic Review ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Animal Models ◽

Hemorrhagic Shock ◽

Large Animal ◽

Large Animal Models

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Large animal models of traumatic brain injury

International Journal of Neuroscience ◽

10.1080/00207454.2017.1380008 ◽

2017 ◽

Vol 128 (3) ◽

pp. 243-254 ◽

Cited By ~ 16

Author(s):

Jun-Xi Dai ◽

Yan-Bin Ma ◽

Nan-Yang Le ◽

Jun Cao ◽

Yang Wang

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Animal Models ◽

Large Animal ◽

Large Animal Models

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17α-Ethinyl estradiol-3-sulfate increases survival and hemodynamic functioning in a large animal model of combined traumatic brain injury and hemorrhagic shock: a randomized control trial

Critical Care ◽

10.1186/s13054-021-03844-7 ◽

2021 ◽

Vol 25 (1) ◽

Author(s):

Andrew R. Mayer ◽

Andrew B. Dodd ◽

Julie G. Rannou-Latella ◽

David D. Stephenson ◽

Rebecca J. Dodd ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Hemorrhagic Shock ◽

Ethinyl Estradiol ◽

Axonal Injury ◽

Diffuse Axonal Injury ◽

Large Animal Model ◽

Large Animal ◽

Circulating Blood Volume ◽

Blood Brain

Abstract Background Traumatic brain injury (TBI) and severe blood loss resulting in hemorrhagic shock (HS) represent leading causes of trauma-induced mortality, especially when co-occurring in pre-hospital settings where standard therapies are not readily available. The primary objective of this study was to determine if 17α-ethinyl estradiol-3-sulfate (EE-3-SO4) increases survival, promotes more rapid cardiovascular recovery, or confers neuroprotection relative to Placebo following TBI + HS. Methods All methods were approved by required regulatory agencies prior to study initiation. In this fully randomized, blinded preclinical study, eighty (50% females) sexually mature (190.64 ± 21.04 days old; 28.18 ± 2.72 kg) Yucatan swine were used. Sixty-eight animals received a closed-head, accelerative TBI followed by removal of approximately 40% of circulating blood volume. Animals were then intravenously administered EE-3-SO4 formulated in the vehicle at 5.0 mg/mL (dosed at 0.2 mL/kg) or Placebo (0.45% sodium chloride solution) via a continuous pump (0.2 mL/kg over 5 min). Twelve swine were included as uninjured Shams to further characterize model pathology and replicate previous findings. All animals were monitored for up to 5 h in the absence of any other life-saving measures (e.g., mechanical ventilation, fluid resuscitation). Results A comparison of Placebo-treated relative to Sham animals indicated evidence of acidosis, decreased arterial pressure, increased heart rate, diffuse axonal injury and blood–brain barrier breach. The percentage of animals surviving to 295 min post-injury was significantly higher for the EE-3-SO4 (28/31; 90.3%) relative to Placebo (24/33; 72.7%) cohort. EE-3-SO4 also restored pulse pressure more rapidly post-drug administration, but did not confer any benefits in terms of shock index. Primary blood-based measurements of neuroinflammation and blood brain breach were also null, whereas secondary measurements of diffuse axonal injury suggested a more rapid return to baseline for the EE-3-SO4 group. Survival status was associated with biological sex (female > male), as well as evidence of increased acidosis and neurotrauma independent of EE-3-SO4 or Placebo administration. Conclusions EE-3-SO4 is efficacious in promoting survival and more rapidly restoring cardiovascular homeostasis following polytraumatic injuries in pre-hospital environments (rural and military) in the absence of standard therapies. Poly-therapeutic approaches targeting additional mechanisms (increased hemostasis, oxygen-carrying capacity, etc.) should be considered in future studies.

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Perinatal hypoxic-ischemic brain injury in large animal models: Relevance to human neonatal encephalopathy

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x18797328 ◽

2018 ◽

Vol 38 (12) ◽

pp. 2092-2111 ◽

Cited By ~ 17

Author(s):

Raymond C Koehler ◽

Zeng-Jin Yang ◽

Jennifer K Lee ◽

Lee J Martin

Keyword(s):

Brain Injury ◽

Animal Models ◽

Cerebral Hypoperfusion ◽

Large Animal ◽

Perinatal Hypoxia ◽

Cellular Mechanisms ◽

Fetal Sheep ◽

Newborn Piglets ◽

Large Animal Models ◽

Hypoxia Ischemia

Perinatal hypoxia-ischemia resulting in death or lifelong disabilities remains a major clinical disorder. Neonatal models of hypoxia-ischemia in rodents have enhanced our understanding of cellular mechanisms of neural injury in developing brain, but have limitations in simulating the range, accuracy, and physiology of clinical hypoxia-ischemia and the relevant systems neuropathology that contribute to the human brain injury pattern. Large animal models of perinatal hypoxia-ischemia, such as partial or complete asphyxia at the time of delivery of fetal monkeys, umbilical cord occlusion and cerebral hypoperfusion at different stages of gestation in fetal sheep, and severe hypoxia and hypoperfusion in newborn piglets, have largely overcome these limitations. In monkey, complete asphyxia produces preferential injury to cerebellum and primary sensory nuclei in brainstem and thalamus, whereas partial asphyxia produces preferential injury to somatosensory and motor cortex, basal ganglia, and thalamus. Mid-gestational fetal sheep provide a valuable model for studying vulnerability of progenitor oligodendrocytes. Hypoxia followed by asphyxia in newborn piglets replicates the systems injury seen in term newborns. Efficacy of post-insult hypothermia in animal models led to the success of clinical trials in term human neonates. Large animal models are now being used to explore adjunct therapy to augment hypothermic neuroprotection.

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