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Author: S. Krisztian Kovacs
Explosive blast–related traumatic brain injury (TBI), specifically primary blast- or shockwave-related TBI, is highly prevalent among military personnel. The majority of battlefield wounds in 21st century military conflicts are due to explosive devices—in the recent wars in Iraq and Afghanistan, almost 80 percent of injury was due to explosion. It is estimated that 20 percent of US military personnel had TBI between 2001 and 2008; and in just the first quarter of 2015, according to the Department of Defense, almost 6,000 US military servicemembers suffered some degree of TBI (83 percent being mild TBI, which may elude diagnosis and thus go untreated) (DOD 2015).
One of the distinct features of recent military conflicts is the high survival rate of victims of TBI. This is a result of improved body armor, which has decreased the rate of fatal chest and lung injury, and advanced medical care, both of which have contributed to a killed-to-wounded ratio of 1:10, the lowest in modern history. As a result, however, doctors see more brain trauma in surviving soldiers (Bandak et al. 2015).
This paper reviews the basic biomechanics of blast injuries, experimental animal blast models, and some relevant pathology discovered through our research group’s blast experiments conducted on rats (other animal models are mice, swine, and monkeys).
What Happens During a Blast?
Traumatic brain injury occurs in multiple ways: it can be caused by nonpenetrating projectile hits, indirect acceleration/deceleration forces, blasts, or penetrating trauma to the head. Primary, nonpenetrating blast injury is the effect of the shockwave propagating through the body and the head, and is the focus of the research in my laboratory. Other explosion-induced injuries can be caused by being struck by material propelled by the explosive blast, by the body’s being thrown by the blast, and by radiation, toxic fumes, or burns.
Primary and Secondary Effects
In terms of tissue response, injury may be primary and secondary. Acute (primary) injury may directly damage the structural elements of the brain and trigger secondary pathophysiological processes such as inflammation, ischemic and hypoxic damage due to diminished blood flow or lack of oxygen, reactive oxygen species formation, or excitatory amino acid release and iron-mediated cell death. These secondary injuries involve biochemical and cellular changes that occur days and even years after the traumatic event and result in symptoms such as cognitive and personality changes as well as modulated gene expression and/or protein regulation (CDC, NIH, DOD, VA Leadership Panel 2013).
Specific Effects of Shockwaves
Our studies are designed to examine damage due to shockwaves, the leading elements of pressure disturbance in a blast. The compressibility of air causes the front of this pressure disturbance to steepen, reaching and surpassing the speed of sound.
Shockwaves can injure the brain both directly and indirectly. Direct mechanisms include spallation, which occurs between tissues with different densities and different acoustic impedance and may result in direct tissue disruption. Rapid rise in intracranial pressure after a blast can lead to bubble formation at the boundary of the cerebrospinal fluid and brain tissue, and may cause cavitation with axonal stretching and blood vessel disruption. Direct mechanisms also include skull deformation with elastic rebound, intracranial wave reflection off the inner surface of the skull, and acceleration/deceleration forces resulting in axonal injury from shear stress and strains (Rosenfeld et al. 2013).
One of the most important indirect mechanisms is kinetic energy transfer through large blood vessels from the abdomen and chest. Hypothetically, waves oscillating through large blood vessels after the blast can cause brain damage. Air embolism from lung injury is another indirect mechanism (Bandak et al. 2015; Cernak and Noble-Haeusslein 2009; Rosenfeld et al. 2013).
Another consideration is the effect of multiple blast events. Ongoing studies suggest that chronic traumatic encephalopathy may occur in soldiers exposed to multiple blast events, with neuropathological changes similar to those with previous sport concussion, but more research is needed (Goldstein et al. 2012; McKee et al. 2009).
How Do We Study Blast Injuries?
The limited availability of human tissues and lack of specific clinical signs, especially at the beginning of the disease, make clinical blast TBI research challenging. Animal models of blast TBI are therefore essential to characterize injuries and disorders, and should imitate real-life human blast conditions.
The most frequently used animal models are tube and open-field models. The former may be blast or shock tube experiments with explosives or with compressed air and gas explosions. Open-field experiments and blast tubes (“blast wave generators”) closely mimic real-life blast events.
Irrespective of the species and method used, the neuropathological changes are very similar and axonal injury/degeneration is the principal outcome. Micro-glia activation, astrocyte activation, and occasional cell death have also been reported in the central nervous system. Numerous blast models describe injuries to the optic pathways, the auditory system, and long white matter fiber tracts of the brain. Reports of intracranial hemorrhages or petechial bleedings are less common in blast models, but are a prevalent finding in human injuries from blunt trauma caused by vehicle, projectile, and sports collisions. The evidence of blast brain injury is usually best seen microscopically 7–14 days after the event (de Lanerolle et al. 2015; Kovacs et al. 2014; Needham et al. 2015).
Blast experiments on rats conducted by our research group were carried out using a 6-foot diameter, 70-foot long blast tube (or blast wave generator, BWG) (figure 1). We studied only primary blasts, using uncased explosives, with the body protected by an insulated aluminum holder that left only the animal’s head and neck exposed. To ensure that there was no movement of the head during the blast, we restrained it using a rigid sling support.
Pressure changes in several locations near the animal were measured during the blast (figure 2). According to our data the BWG was able to produce an almost ideal Friedlander wave that is typical of free-field blasts.
In animals that died during or shortly after the blast, with peak overpressures beyond 45–50 psi, we detected brain edema, subarachnoid hemorrhage, and frank tissue disruption with parenchymal microhemorrhages. We assessed effects in the animals 24 hours, 7 days, and 28 days after the blast. In animals that survived the blast, exposed to approximately 30 psi overpressure or less, we observed limited evidence of gross abnormalities in the brain; for example, subdural hemorrhages and microhemorrhages were seen after 24 hours.
The most significant pathology, as in other blast models (e.g., Bauman et al. 2009), was multifocal axonal injury (detected by FD Neurotech silver stain kit; figure 3). Axonal damage more frequently involved the optic pathway, but cerebellar structures and brainstem areas also showed axonal pathology, mostly after 7 and 28 days. Astrocyte activation was present in the optic pathways after 7 and 28 days. Activated microglial cells appeared as early as 24 hours after the blast and remained visible after 28 days in brain areas that showed signs of axonal injury.
In our blast tube animal model we observed axonal injury that showed blast-intensity- and time-dependent changes. With increased intervals between blast exposure and pathological examinations, there was an increase in the number of brain regions with evidence of axonal injury. Axons were the most vulnerable structures to primary explosive blast, and direct forces from the shockwave may have been transmitted through weak areas (e.g., eyes) on the skull.
We also compared the results of our blast model to another nonpenetrating blunt head trauma model (fluid percussion injury; Dixon et al. 1987) and a penetrating ballistic brain injury model (Williams et al. 2005). In identifying axonal injuries using common procedures—hematoxylin and eosin (H&E)–stained standard slides, amyloid precursor protein (APP) immunohistochemistry, FD Neurotech silver staining, and Fluoro-Jade B (FJB) staining—we noted that silver staining and FJB clearly showed evidence of axonal injury in some cases where APP showed little or none. We conclude that H&E and APP staining underestimated the extent of injury caused by the shockwave, and that blasts may have a different and unique biomechanical effect on axonal fibers.
Animal models are excellent research tools to study blasts, but because of the variety of methods used and the lack of basic data reporting, such as pressure changes and physical properties of the blasts, results have been controversial. Moreover, rodent brains are different from those with grey-to-white-matter ratios and architectures closer to those of primates, and this is an important factor to consider as the biomechanical parameters of brain tissues are significant in injury models. Scaling animal models to humans is a key consideration, as discussed by Radovitzky and colleagues (2015) in this issue.
Research suggests that axons are the brain structure most vulnerable to explosive blast. Controlled, reproducible interdisciplinary research is critical to improved understanding of the mechanics of blast injuries and the identification of neuropathological structural changes.
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