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

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

Frontiers in Neurology ◽

10.3389/fneur.2021.658461 ◽

2021 ◽

Vol 12 ◽

Author(s):

Andrew R. Mayer ◽

Josef M. Ling ◽

Andrew B. Dodd ◽

Julie G. Rannou-Latella ◽

David D. Stephenson ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Animal Models ◽

Angular Velocity ◽

Diffuse Axonal Injury ◽

Impulsive Loading ◽

Large Animal ◽

Head Kinematics ◽

Large Animal Models ◽

Acceleration Model

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

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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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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Systematic Review of the Preclinical Technology Readiness of Orthopedic Gene Therapy and Outlook for Clinical Translation

Frontiers in Bioengineering and Biotechnology ◽

10.3389/fbioe.2021.626315 ◽

2021 ◽

Vol 9 ◽

Author(s):

Piers Wilkinson ◽

Ilya Y. Bozo ◽

Thomas Braxton ◽

Peter Just ◽

Elena Jones ◽

...

Keyword(s):

Gene Therapy ◽

Animal Models ◽

Bone Repair ◽

Safety Data ◽

Clinical Translation ◽

Model Systems ◽

Large Animal ◽

Repair Gene ◽

Public Health Burden ◽

Large Animal Models

Bone defects and improper healing of fractures are an increasing public health burden, and there is an unmet clinical need in their successful repair. Gene therapy has been proposed as a possible approach to improve or augment bone healing with the potential to provide true functional regeneration. While large numbers of studies have been performed in vitro or in vivo in small animal models that support the use of gene therapy for bone repair, these systems do not recapitulate several key features of a critical or complex fracture environment. Larger animal models are therefore a key step on the path to clinical translation of the technology. Herein, the current state of orthopedic gene therapy research in preclinical large animal models was investigated based on performed large animal studies. A summary and an outlook regarding current clinical studies in this sector are provided. It was found that the results found in the current research literature were generally positive but highly methodologically inconsistent, rendering a comparison difficult. Additionally, factors vital for translation have not been thoroughly addressed in these model systems, and the risk of bias was high in all reviewed publications. These limitations directly impact clinical translation of gene therapeutic approaches due to lack of comparability, inability to demonstrate non-inferiority or equivalence compared with current clinical standards, and lack of safety data. This review therefore aims to provide a current overview of ongoing preclinical and clinical work, potential bottlenecks in preclinical studies and for translation, and recommendations to overcome these to enable future deployment of this promising technology to the clinical setting.

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Large animals in neurointerventional research: A systematic review on models, techniques and their application in endovascular procedures for stroke, aneurysms and vascular malformations

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x19827446 ◽

2019 ◽

Vol 39 (3) ◽

pp. 375-394 ◽

Cited By ~ 17

Author(s):

Andrea M Herrmann ◽

Stephan Meckel ◽

Matthew J Gounis ◽

Leona Kringe ◽

Edith Motschall ◽

...

Keyword(s):

Systematic Review ◽

Ischemic Stroke ◽

Animal Models ◽

Translational Research ◽

Arteriovenous Malformations ◽

Vascular Malformations ◽

Large Animal ◽

Large Animal Models ◽

Large Animals ◽

Study Designs

Neuroendovascular procedures have led to breakthroughs in the treatment of ischemic stroke, intracranial aneurysms, and intracranial arteriovenous malformations. Due to these substantial successes, there is continuous development of novel and refined therapeutic approaches. Large animal models feature various conceptual advantages in translational research, which makes them appealing for the development of novel endovascular treatments. However, the availability and role of large animal models have not been systematically described so far. Based on comprehensive research in two databases, this systematic review describes current large animal models in neuroendovascular research including their primary use. It may therefore serve as a compact compendium for researchers entering the field or looking for opportunities to refine study concepts. It also describes particular applications for ischemic stroke and aneurysm therapy, as well as for the treatment of arteriovenous malformations. It focuses on most promising study designs and readout parameters, as well as on important pitfalls in endovascular translational research including ways to circumvent them.

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