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Traumatic Brain Injury

Traumatic brain injury (TBI) is a universal health concern as it is has been identified as a “silent epidemic” in civilians and the “signature injury” in U.S. service members (Soldiers) in the Iraq and Afghanistan wars1,2. Each year in America, 2.53 million civilians visit the emergency department after suffering a TBI, of which 56,800 die and over 288,000 require hospitalization and long term supportive care3. In addition, 400,000 TBI diagnoses have been confirmed in the Operation Enduring Freedom and Operation Iraqi Freedom conflicts4. 80% of these Soldiers will experience comorbid psychiatric diagnoses and are >1.5x more likely to die from suicide than Soldiers without TBI5,6. These statistics correspond to civilian research where TBI has also been linked to suicide as well as mood and anxiety disorders7,8. Collectively, these consequences have major repercussions for TBI patients’ families with psychological, emotional, and financial effects.

Due to the prevalent use of improvised explosive devices, nearly 400,000 TBI diagnoses have been confirmed in the Iraq and Afghanistan conflicts. A TBI therapy that is accessible to Soldiers in combat zones is sorely needed. Photo courtesy of Michael Mahnken.

Presently, there are no neuroprotective or regenerative Food and Drug Administration (FDA)-approved TBI treatments. TBI pathologies including brain swelling and intracerebral hemorrhage are often treated with hyperosmolar fluids, decompressive craniectomy, and surgical evacuation, all of which are associated with multiple risk factors9. Consequently, a safe and neuroprotective TBI treatment is sorely needed. Preclinical evaluation of novel therapies in our TBI pig model10-13 is likely more predictive of human responses and outcomes due to the anatomical similarities between humans and pigs including brain size, gyrencephalic cytoarchitecture, and high white-to-gray matter ratios. These characteristics should be considered when evaluating the efficacy of novel therapeutics as they have a significant impact on TBI pathologies (e.g. cell death, excitotoxicity, inflammatory responses, intracerebral hemorrhage, and edema) and recovery mechanisms14,15.

  • Brain size is critically important in modeling TBI as smaller rodent brains can tolerate much greater angular acceleration forces than animals with larger brains as shearing forces and inertial loading are directly related to brain mass16.
  • Humans and pigs also have gyrencephalic brains, while rodents have lissencephalic brains. Gyrification significantly influences the movement of the brain within the cranium during TBI, as well as the maximum mechanical stress applied to neural tissues16.
  • Human and pig brains are also composed of large white matter volumes (>60%), compared to rodents (<12%)17,18. White matter composition is important when modeling TBI as white matter is more susceptible than gray matter as it possesses 3-5x less microvasculature and limited collateralization19-21.
MRI reveals post-TBI tissue (left) and white matter (right) damage in pigs closely mirrored that which is seen in humans. This is likely due to the inherent anatomical and physiological similarities in brain composition and structure. Image courtesy of Dr. Kaiser.

We believe our pig TBI model could serve as a translational platform for studying TBI sequelae across injury severities and identifying novel therapeutics.