Traumatic brain injury (TBI) contributes a major cause of death, disability, and mental health disorders. Most TBI patients suffer long-term post-traumatic stress disorder, cognitive dysfunction, and disability. The underlying molecular and cellular mechanisms of such neuropathology progression in TBI remain elusive. In part, it is due to non-standardized classification of mild, moderate, and severe injury in various animal models of TBI. Thus, a better diagnosis and treatment requires a better understanding of the injury mechanisms in a well-defined severity of mild, moderate, and severe injury in different models that may potentially reflect the various types of human brain injuries. The purpose of this review article is to highlight the classification of mild, moderate, and severe injury in various animal models of TBI with special focus on mixed injury that represents a translational concussive head injury. We will classify animal models of TBI broadly into focal injury, diffuse injury, and mixed injury. Focal injury, a localized injury, is represented by animal models of controlled cortical impact, penetrating ballistic-like brain injury, and Feeney or Shohami weight drop injury. A global diffuse injury is best represented by shock tube model of primary blast injury, and Marmarou or Maryland weight drop model. A mixed injury consists of focal and diffuse injury which reproduces the concussive clinical syndrome, and it is best studied in animal model of lateral fluid percussion injury.

Animal Models of Traumatic Brain Injury and Assessment of Injury Severity

Blast-induced traumatic brain injury (bTBI) has been recognized as the common mode of neurotrauma amongst military and civilian personnel due to an increased insurgent activity domestically and abroad. Previous studies from our laboratory have identified enhanced blood-brain barrier (BBB) permeability as a significant, sub-acute (four hours post-blast) pathological change in bTBI. We also found that NADPH oxidase (NOX)-mediated oxidative stress occurs at the same time post-blast when the BBB permeability changes. We therefore hypothesized that oxidative stress is a major causative factor in the BBB breakdown in the sub-acute stages. This work therefore examined the role of NOX1 and its downstream effects on BBB permeability in the frontal cortex (a region previously shown to be the most vulnerable) immediately and four hours post-blast exposure. Rats were injured by primary blast waves in a compressed gas-driven shock tube at 180 kPa and the BBB integrity was assessed by extravasation of Evans blue and changes in tight junction proteins (TJPs) as well as translocation of macromolecules from blood to brain and vice versa. NOX1 abundance was also assessed in neurovascular endothelial cells. Blast injury resulted in increased extravasation and reduced levels of TJPs in tissues consistent with our previous observations. NOX1 levels were significantly increased in endothelial cells followed by increased superoxide production within 4 hours of blast. Blast injury also increased the levels/activation of matrix metalloproteinase 3 and 9. To test the role of oxidative stress, rats were administered apocynin, which is known to inhibit the assembly of NOX subunits and arrests its function. We found apocynin completely inhibited dye extravasation as well as restored TJP levels to that of controls and reduced matrix metalloproteinase activation in the sub-acute stages following blast. Together these data strongly suggest that NOX-mediated oxidative stress contributes to enhanced BBB permeability in bTBI through a pathway involving increased matrix metalloproteinase activation.

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Synergistic Role of Oxidative Stress and Blood-Brain Barrier Permeability as Injury Mechanisms in the Acute Pathophysiology of Blast-induced Neurotrauma.

Blast-induced traumatic brain injury (bTBI) is a “signature wound” in soldiers during training and in combat and has also become a major cause of morbidity in civilians due to increased insurgency. This work examines the role of blood-brain barrier (BBB) disruption as a result of both primary biomechanical and secondary biochemical injury mechanisms in bTBI. Extravasation of sodium fluorescein (NaF) and Evans blue (EB) tracers were used to demonstrate that compromise of the BBB occurs immediately following shock loading, increases in intensity up to 4 hours and returns back to normal in 24 hours. This BBB compromise occurs in multiple regions of the brain in the anterior-posterior direction of the shock wave, with maximum extravasation seen in the frontal cortex. Compromise of the BBB is confirmed by (a) extravasation of tracers into the brain, (b) quantification of tight-junction proteins (TJPs) in the brain and the blood, and (c) tracking specific blood-borne molecules into the brain and brain-specific proteins into the blood. Taken together, this work demonstrates that the BBB compromise occurs as a part of initial biomechanical loading and is a function of increasing blast overpressures.

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Temporal and Spatial Effects of Blast Overpressure on Blood-Brain Barrier Permeability in Traumatic Brain Injury.

Blast-induced traumatic brain injury (bTBI) is a leading cause of morbidity in soldiers on the battlefield and in training sites with long-term neurological and psychological pathologies. ...

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A Single Primary Blast-Induced Traumatic Brain Injury in a Rodent Model Causes Cell-Type Dependent Increase in Nicotinamide Adenine Dinucleotide Phosphate Oxidase Isoforms in Vulnerable Brain Regions

Severe lung damage is a major cause of death in blast victims, but the mechanisms of pulmonary blast injury are not well understood Therefore, it is important to study the injury mechanism of pulm

Shock waves increase pulmonary vascular leakage, inflammation, oxidative stress, and apoptosis in a mouse model.

The end plate mounted at the mouth of the shock tube is a versatile and effective implement to control and mitigate the end effects. We have performed a series of measurements of incident shock wave velocities and overpressures followed by quantification of impulse values (integral of pressure in time domain) for four different end plate configurations (0.625, 2, 4 inches, and an open end). Shock wave characteristics were monitored by high response rate pressure sensors allocated in six positions along the length of 6 meters long 229 mm square cross section shock tube. Tests were performed at three shock wave intensities, which was controlled by varying the Mylar membrane thickness (0.02, 0.04 and 0.06 inch). The end reflector plate installed at the exit of the shock tube allows precise control over the intensity of reflected waves penetrating into the shock tube. At the optimized distance of the tube to end plate gap the secondary waves were entirely eliminated from the test section, which was confirmed by pressure sensor at T4 location. This is pronounced finding for implementation of pure primary blast wave animal model. These data also suggest only deep in the shock tube experimental conditions allow exposure to a single shock wave free of artifacts. Our results provide detailed insight into spatiotemporal dynamics of shock waves with Friedlander waveform generated using helium as a driver gas and propagating in the air inside medium sized tube. Diffusion of driver gas (helium) inside the shock tube was responsible for velocity increase of reflected shock waves. Numerical simulations combined with experimental data suggest the shock wave attenuation mechanism is simply the expansion of the internal pressure. In the absence of any other postulated shock wave decay mechanisms, which were not implemented in the model the agreement between theory and experimental data is excellent.

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Tailoring the Blast Exposure Conditions in the Shock Tube for Generating Pure, Primary Shock Waves: The End Plate Facilitates Elimination of Secondary Loading of the Specimen.

Dynamic loads on specimens in live-fire conditions as well as at different locations within and outside compressed-gas-driven shock tubes are determined by both static and total blast overpressure–time pressure pulses. The biomechanical loading on the specimen is determined by surface pressures that combine the effects of static, dynamic, and reflected pressures and specimen geometry. Surface pressure is both space and time dependent; it varies as a function of size, shape, and external contour of the specimens. In this work, we used two sets of specimens: (1) anthropometric dummy head and (2) a surrogate rodent headform instrumented with pressure sensors and subjected them to blast waves in the interior and at the exit of the shock tube. We demonstrate in this work that while inside the shock tube the biomechanical loading as determined by various pressure measures closely aligns with live-fire data and shock wave theory, significant deviations are found when tests are performed outside.

Dynamic loads on human and animal surrogates at different test locations in compressed-gas-driven shock tubes

This study compared the response of the wearable sensors tested against the industry-standard pressure transducers at blast overpressure (BOP) levels typically experienced in training. We systematically evaluated the effects of the sensor orientation with respect to the direction of the incident shock wave and demonstrated how the averaging methods affect the reported pressure values. The evaluated methods included averaging peak overpressure and impulse of all four sensors mounted on a helmet, taking the average of the three sensors, or isolating the incident pressure equivalent using two sensors. The experimental procedures were conducted in controlled laboratory conditions using the shock tube, and some of the findings were verified in field conditions with live fire charges during explosive breaching training. We used four different orientations (0°, 90°, 180°, and 270°) of the headform retrofitted with commonly fielded helmets (ACH, ECH, Ops-Core) with four B3 Blast Gauge sensors. We determined that averaging the peak overpressure values overestimates the actual dosage experienced by operators, which is caused by the reflected pressure contribution. This conclusion is valid despite the identified limitation of the B3 gauges that consistently underreport the peak reflected overpressure, compared to the industry-standard sensors. We also noted consistent overestimation of the impulse. These findings demonstrate that extreme caution should be exercised when interpreting occupational blast exposure results without knowing the orientation of the sensors. Pure numerical values without the geometrical, training-regime specific information such as the position of the sensors, the distance and orientation of the trainee to the source of the blast wave, and weapon system used will inevitably lead to erroneous estimation of the individual and cumulative blast overpressure (BOP) dosages. Considering that the 4 psi (~28 kPa) incident BOP is currently accepted as the threshold exposure safety value, a misinterpretation of exposure level may lead to an inaccurate estimation of BOP at the minimum standoff distance (MSD), or exclusion criteria.

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Sensor orientation and other factors which increase the blast overpressure reporting errors.

BACKGROUND
Tamping explosive charges used by breachers is an increasingly common technique. The ability to increase the directional effectiveness of the charge used, combined with the potential to reduce experienced overpressure on breachers, makes tamping a desirable tool not only from an efficacy standpoint for breachers but also from a safety standpoint for operational personnel. The long-term consequences of blast exposure are an open question and may be associated with temporary performance deficits and negative health symptomatology.


PURPOSE
This work evaluates breaches of varying charge weight, material breached, and tamping device used to determine the value of tamping during various scenarios by measuring actual breaches conducted during military and law enforcement training for efficacy and blast overpressure on Operators.


METHODS
Three data collections across 18 charges of various construction were evaluated with blast overpressure sensors at various distances and locations where breachers would be located, to assess explosive forces on human personnel engaged in breaching activities.


RESULTS AND CONCLUSIONS
Findings indicate that water tamping in general is a benefit on moderate and heavy charges but offers less benefit at a low charge with regard to mitigating blast overpressure on breachers. Reduced overpressure allows Operators to stage closer to explosives and lowers the potential for compromised reaction time. It also reduces the likelihood of negative consequences that can result from excessive overpressure exposure and allow Operators to "do more with less" in complex environments, where resource access may be limited by logistic or other limitations. However, tamping in all instances improved blast efficacy in creating successful breaches. Future studies are planned to investigate tamping mediums beyond water and environment changes, whether tamping can be used to mitigate acoustic insult, and other explosive types.

Anthony Misistia

Papers

Tailoring the Blast Exposure Conditions in the Shock Tube for Generating Pure, Primary Shock Waves: The End Plate Facilitates Elimination of Secondary Loading of the Specimen.

Dynamic loads on human and animal surrogates at different test locations in compressed-gas-driven shock tubes

Sensor orientation and other factors which increase the blast overpressure reporting errors.

An Exploratory Comparison of Water-Tamped and -Untamped Explosive Breaches: Practical Applications for the Tactical Community via a Pilot Study.