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Review Article

Primary Blast Brain Injury Mechanisms: Current Knowledge, Limitations, and Future Directions OPEN ACCESS

[+] Author and Article Information
Elizabeth Fievisohn

Department of Biomedical Engineering
and Mechanics,
Virginia Tech,
440 Kelly Hall, 325 Stanger Street,
Blacksburg, VA 24061
e-mail: lizf87@vt.edu

Zachary Bailey

Department of Biomedical Engineering
and Mechanics,
Virginia Tech,
440 Kelly Hall, 325 Stanger Street,
Blacksburg, VA 24061
e-mail: zbailey2@vt.edu

Allison Guettler

Department of Mechanical Engineering,
Virginia Tech,
440 Kelly Hall, 325 Stanger Street,
Blacksburg, VA 24061
e-mail: aguett@vt.edu

Pamela VandeVord

Department of Biomedical Engineering
and Mechanics,
Virginia Tech,
317 Kelly Hall, 325 Stanger Street,
Blacksburg, VA 24061;
Salem Veterans Affairs Medical Center,
Salam, VA 24153
e-mail: pvord@vt.edu

1Corresponding author.

Manuscript received July 8, 2017; final manuscript received November 17, 2017; published online January 12, 2018. Editor: Beth A. Winkelstein.

J Biomech Eng 140(2), 020806 (Jan 12, 2018) (12 pages) Paper No: BIO-17-1299; doi: 10.1115/1.4038710 History: Received July 08, 2017; Revised November 17, 2017

Mild blast traumatic brain injury (bTBI) accounts for the majority of brain injury in United States service members and other military personnel worldwide. The mechanisms of primary blast brain injury continue to be disputed with little evidence to support one or a combination of theories. The main hypotheses addressed in this review are blast wave transmission through the skull orifices, direct cranial transmission, skull flexure dynamics, thoracic surge, acceleration, and cavitation. Each possible mechanism is discussed using available literature with the goal of focusing research efforts to address the limitations and challenges that exist in blast injury research. Multiple mechanisms may contribute to the pathology of bTBI and could be dependent on magnitudes and orientation to blast exposure. Further focused biomechanical investigation with cadaver, in vivo, and finite element models would advance our knowledge of bTBI mechanisms. In addition, this understanding could guide future research and contribute to the greater goal of developing relevant injury criteria and mandates to protect our soldiers on the battlefield.

FIGURES IN THIS ARTICLE
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Injury Prevalence.

United States (U.S.) soldiers have increased risk of physical and psychological injuries as they endure multiple tours of duty and are exposed to numerous blast events. In military populations, blast exposure accounts for 78% of injuries [13]. This complex environment increases the likelihood of soldiers being diagnosed with blast traumatic brain injury (bTBI) [4]. Veterans returning from combat present a wide range of cognitive symptoms without clear head injury incidents. Between 2000 and 2016, 361,092 U.S. service members were diagnosed with a traumatic brain injury (TBI), and mild TBI accounted for 82.4% of these injuries [5]. Studies conducted at the Walter Reed Medical Center indicate that 60% of blast injuries result in TBI [4]. A study by Wilk et al. [6] identified 587 (out of the 3952 surveyed) U.S. Army soldiers returning from Iraq were diagnosed with concussion. Of these, 72.2% reported a blast mechanism as the cause of injury [6]. These and other reports suggest individuals with bTBI are more likely to report long-term consequences [69]. Late-emerging behavioral deficits in mood, anxiety, impulsivity, and emotional outbursts, in addition to negative effects on cognition [1013], have taxed the annual healthcare cost and pose a major long-term societal challenge [14]. Civilian populations are also at risk for blast exposure as recent increases of terrorist events have placed bTBI on the forefront of worldwide research discussions [1520]. Despite the recent improvements in body armor technologies, the prevalence of bTBI has continued to rise.

The clinical neuropathology of bTBI is not well defined; thus, preclinical studies of primary bTBI have identified several common neuropathological outcomes. While the secondary molecular pathways triggered following blast exposure are not unique to bTBI, the diffuse and sustained injury presentation is a characteristic of blast exposure and differentiates blast from the focal injuries of impact TBI. Several groups have provided evidence that blast energy triggers an acute glial inflammatory response, which leads to chronic neurobehavioral and neuropathological outcomes [12,2131]. Although evidence suggests that cell death cascades are associated with glial activation, mechanisms that initiate these molecular cascades are currently unclear. Thus far, all blast neurotrauma animal models have shown similar diminished cognition and elevated anxiety-like behaviors following blast exposure [3235]. Many studies have related diminished cognition with hippocampal injury, although the nature of bTBI is diffusive and clinical symptom suggests there is more than one cognitive region involved in the neurotrauma. Collectively, the high incidence of bTBI and the long-term sequelae emphasize the vital need to decipher the injury mechanisms for future protective and treatment efforts.

Injury Classifications.

Blast injuries can be divided into four categories. Primary blast injury is due to the effects of blast wave propagation through tissue, also called barotrauma. Secondary injuries are caused when a person is hit by shrapnel or objects thrown by the blast wave. Tertiary injuries result from acceleration or deceleration of the body, or part of the body, as it is displaced by the blast wind, including deceleration during impact with structures in the environment. Finally, quaternary injuries are caused by thermal or chemical exposures from the explosion itself. This review focuses on the mechanisms of primary bTBI—injuries only caused by blast wave pressure.

Blast Physics.

A blast flow is complicated to define because it is compressible, time-variant, and multiphasic. In near- and mid-field blast regions, the blast dynamics are highly complex and could involve two-dimensional wave motion, projectiles, and heat from the explosive. In the far-field region, blast dynamics are largely one-dimensional and do not involve these other confounding factors. This “free-field region” is where most primary blast injury research is focused.

In a free-field blast, two parameters describe the energy of the blast wave. The first, hydrostatic pressure, is the pressure experienced by an object not obstructing the blast flow and is measured on a surface parallel to the fluid flow direction. Other terms used for this are static pressure and overpressure. The distinction of overpressure is important as all pressures considered are changes from the ambient conditions. The second is dynamic pressure—the measure of specific kinetic energy of the blast flow. To measure the dynamic pressure, the stagnation, or total, pressure must be measured. Stagnation pressure is the energy required to bring particles in the flow to rest; it is the sum of static and dynamic pressures, and is measured by a sensor normal to the fluid flow.

While not a flow-defining characteristic of a free field blast, reflected pressure represents a third classification in which the blast front interacts with the normal surface of an object or structure in its flow. Reflected pressure quantifies the force exerted on the obtrusive object and is a function of the object's size, shape, and material properties.

Static pressure and stagnation pressure can be measured with a Pitot tube sensor consisting of a pressure transducer facing the shock front and a side-on pressure transducer parallel to flow. The two pressure profiles are depicted in Fig. 1. While the Pitot tube sensor measures stagnation pressure, when the shock front initially hits the probe, the wave reflects off the transducer face, thus giving an immediate spike in the measurement, or reflected pressure.

Transient static overpressure in free-field conditions can be estimated by the Friedlander equation. First, the shock front reaches the observation point, which will increase the pressure to its maximum. The rise time to peak overpressure is nearly instantaneous. Next, the pressure decreases exponentially until it passes through zero and begins a negative pressure phase. The duration of the positive phase is typically half that of the negative phase. Finally, the pressure returns to ambient conditions. An example of the ideal Friedlander waveform is shown in Fig. 2.

The Rankine–Hugoniot equations define the conditions at the shock front. Peak static, dynamic, and reflected overpressure, as well as the temperature and density of the shocked fluid, can be determined based on the specific heat capacity of the fluid and Mach number of the blast wave (the wave speed normalized to the speed of sound in the unshocked medium). Derivations and explanations of these equations can be found in many sources [36,37].

The biomechanical mechanisms underlying primary bTBI have been a challenge for researchers to define. This lack of knowledge complicates prevention and treatment efforts. The work presented here (briefly summarized in Table 1) will identify the main theories of primary blast transmission to the brain based on historical and recent considerations, discuss them with literature that either supports or opposes the theory, and suggest directions for future research. The current theories of primary bTBI mechanisms include blast wave transmission through the skull orifices, direct cranial transmission, skull flexure dynamics, and thoracic surge. Acceleration and cavitation are also briefly discussed because they are commonly mentioned in the literature, although not considered primary mechanisms of blast brain injury.

Skull Orifices.

The skull orifice theory postulates that the blast wave can travel through the auditory canal, nasal sinuses, and/or the orbits to cause intracranial pressure (ICP) alterations, which injure the brain. ICP changes, both immediate and sustained, have been well established from blast exposure [3843]. However, ICP alterations due to blast have not been adequately attributed to a single mechanism.

Auditory Canal.

Blast injury of the ear is common and can involve both the middle and inner ear. Common injuries include tympanic membrane perforation, ossicular damage, inner and outer hair cell loss, and hemorrhage [44]. In addition, damage to both the vestibular and auditory systems has been found clinically [4547].

In vivo, postmortem human surrogate (PMHS) testing and computational modeling have investigated auditory damage due to blast exposure. An in vivo study showed tinnitus and hearing loss in unprotected rats following blast overpressure exposure [48]. Perlman [49] looked at the effects of various types of ear protection in fresh human temporal bones after being exposed to the firing of a blank 32-caliber cartridge. Ear flaps, Vaseline, wet cotton, and beeswax all reduced the amplitude of initial malleus oscillations. While the auditory canal has been shown to be subject to blast-induced pathology, little evidence exists to implicate it as a mechanism of altering ICP. In fact, a finite element investigation of blast exposure of the human head showed that overpressure can be amplified in the auditory canal when the ear faces the blast wave, but has minimal impact on the ICP [50]. The ear canal is sensitive to the orientation relative to the blast, suggesting that the auditory canal has little effect on ICP oscillations, and it is likely not a sole mechanism of bTBI.

Nasal Sinuses.

Injuries to the air-containing maxillofacial cavities, as well as olfactory dysfunction, are possible during blast wave exposure [51,52]. Xydakis et al. [53] studied 231 polytrauma inpatients acutely injured by explosions in Afghanistan or Iraq and found that only those with abnormal imaging and moderate/severe TBI had olfactory dysfunction (either hyposmia or anosmia), while patients with mild TBI did not. A simple sphere surrogate model was used to look at the effect of adding a void in the skull (as a sinus cavity) and showed that the void size and position had an effect on the intracranial response to a blast wave [54]. This shows the importance of anatomical features when using finite element models to investigate blast wave effects as they can affect the blast wave interaction with the skull and the energy transmission to the brain. Also, it is interesting to note that while many in vivo studies have investigated blast neurotrauma, none have reported sinus injuries. It is possible that these studies did not examine the sinuses or that the blast orientation was not such that would produce those injuries. Injuries to the sinus cavities should be looked at in the future to investigate the validity of this theory.

Orbits.

Eye injuries are possible due to secondary blast effects, such as debris, and can range from intraocular foreign bodies to globe rupture [55]. There have been in vivo studies that have looked at varying amounts of ocular damage due to blast. Neurodegeneration has been observed in the retina and brain visual centers after blast overpressure in rodents [5660]. A study investigating the potential blast wave transmission through orbits found changes in ICP occurred regardless of the presence of eye protection during primary blast exposure in rodents [38]. This may suggest that another mechanism is responsible for the blast energy transfer to the brain or the eye protection was not sufficient for reducing pressure [38]. Williams et al. [61] investigated eye protection and how it affects pressure at the cornea. They concluded that current eye protection works well for protecting from debris, but goggles with a better fit are necessary to reduce pressure on the cornea. Weichel et al. [62] found that TBI is frequently associated with combat ocular trauma, expressing the need for TBI screening when ocular trauma is present. Note that TBI can cause secondary injury cascades in the auditory and visual systems. Therefore, it might be difficult to find support for blast bTBI mechanisms by in vivo and clinical studies alone without more careful investigation in isolating primary injury mechanisms.

In summary, sensory organs are frequently injured following blast exposure. However, there is little evidence to support the hypothesis that these organs are involved with the blast energy transmission to the brain. In addition, blast waves are sensitive to changes in area. Therefore, the geometry of the ear canal or sinus cavities may complicate the reflected wave but this interaction remains unclear. Even if entry via the skull orifices does not cause ICP elevation, focal injuries near the orifices could lead to secondary injury responses. Damage to cranial nerves from the orifices could lead to secondary effects like neurodegeneration in the retina and brain visual centers. This theory could benefit from cadaver and in vivo studies, so the pressure changes can be identified when orifices are obstructed and the head is in different orientations. Also, in vivo research looking at the involved neurons and their signaling pathways using a combination of immunohistochemistry, diffusion tensor imaging, and the resulting sensory deficits will provide valuable insight.

Direct Cranial Transmission.

Direct cranial transmission theory, also called transosteal wave propagation, proposes that pressure is transmitted directly to the brain after passing through the skull. While the exact theory is not clearly defined in literature by proponents, it has been suggested that the pressure wave interacts with the skull, causing a compressive stress through the thickness of the skull, which transmits to the CSF and brain.

Acoustic Impedance.

Defining a system and its properties is important for understanding how it responds to a forcing function. In the case of pressure transmission, acoustic impedance is a key factor. Acoustic impedance, Z, is the product of material density and the speed of sound in that material. When two materials have similar acoustic impedances, much of the sound wave will be transmitted from one material to the other. When the two materials have a very high impedance difference (impedance mismatch), most of the waves will be reflected. The degree to which a wave is transmitted or reflected is governed by the equations below, where Λr and Λt are the reflection and transmission coefficients, material 1 is the origin of the wave, and the wave is transmitted to material 2 Display Formula

(1)Λr=Z2Z1Z2+Z1
Display Formula
(2)Λt=2Z1Z2+Z1

The structure of the head creates a complicated interface with the blast wave. While soft tissues (except lung) have characteristic impedances similar to that of water, experimentally derived values for bone can be as high as five times the acoustic impedance of water. Approximate impedance values for key materials and biological tissues are listed in Table 2. On the other hand, air has a characteristic impedance that is four orders of magnitude less than most biological materials. Theoretically, based on the high acoustic impedance mismatch, over 99% of a planar wave would reflect off any biological material. Figure 3 shows the complicated interface between a blast wave traveling through air and the head. As noted in the figure, the scalp (modeled as skin only) will cause 99.96% of the incident blast wave to be reflected, leaving only 0.04% of the blast wave to transmit to the skull.

In addition, the diploë of the cranial bones has a complex microstructure, which has been shown to scatter, and therefore attenuate, ultrasound (i.e., another type of longitudinal wave) [65]. Therefore, in addition to the reflection of the wave off the head and potential attenuation through the scalp, energy from the blast wave can also attenuate within the thickness of the skull bone. Ultimately, it is unlikely that the blast wave could directly transmit through the skull and into the brain.

Experimental Models.

In 1955, Clemedson and Pettersson measured pressure in several body regions of anesthetized rabbits while exposed to shock waves. Based on their results, they determined the skull did little to change the blast wave as it entered the brain, while regions such as the thorax varied greatly from the skull and the original blast wave [66]. Recent studies measuring ICP in swine showed a difference in the magnitude and time history between ICP and the blast wave, which would oppose this theory, but the authors still suggested a direct cranial transmission mechanism [41,67].

One study subjected pigs to the occupational shock conditions of military personnel. They noted that the magnitude of peak ICP could be as low as 40% of the magnitude of the blast overpressure. It is possible that the loss of energy during direct transmission through the skin and skull caused this pressure difference. The study also subjected pigs to underwater shock conditions, noting that different shock environments produce different responses of ICP [67]. In underwater shock conditions, the impedance mismatch with the surrounding media is much less than in air shock conditions. As a result, transmission to the brain may be enhanced and cause the different responses in ICP. Yet, the study of underwater shock conditions did not show increased transmission of blast pressure, suggesting that even with the potential transmission of the wave, another mechanism may exist [67]. Another study compared ICP response during blast in free-field and enclosed conditions and noted an approximate lag of 0.5 milliseconds in the ICP response from the overpressure profile could be due to the travel time of the pressure wave through the skull [41].

Blast TBI models utilizing rats often have different ICP responses compared to swine models. Measurement of ICP during blast testing showed that the magnitude of pressure in the brain is often similar to or higher than that of the shock wave [38,68]. Theoretically, this difference in response between swine and rats could be due to skull thickness. However, in a study with rats of different ages and skull thickness, rats with a thicker, stronger skull had higher ICP values [38]. This seems counterintuitive for the direct transmission mechanism, as it would be expected that a thicker skull would decrease the magnitude of pressure transmitted. Injury patterns observed from histological analysis led to the hypothesis that pressure was transmitted through the skull and the energy from the blast affected the brain at the CSF/brain interface due to the density boundary [69].

Blast injury experiments are complicated and expensive to setup, so physical surrogate and finite element models are frequently used to gain insight into the mechanics involved with bTBI. One study using a detailed model of the human head showed that the skull provided little protection to the brain from blast overpressure [70]. During simulations, the time history of ICP followed that of the blast wave itself. In a more simplistic model, researchers studied the pressure response within a fluid-filled cylinder in a shock tube [71]. They stated that while results show the pressure wave being transmitted through the shell, very little was transmitted directly to the brain simulant due to a high impedance mismatch between the two materials. They postulated that the same interaction would hold true for the skull and brain.

Discussion.

Current theoretical analyses and experimental efforts offer contradictory evidence of the role of direct transmission in blast wave interaction with the skull. While theory states that virtually no pressure could be transmitted through the skull, experimental evidence suggests a role for direct transmission of pressure through the skull. One possible explanation for this discrepancy is the experimental challenges of primary blast research, which can dramatically affect collection and interpretation of results. ICP measurement is often an experimental challenge as altering the cranial cavity may lead to a sacrifice of physiological relevance. Following craniotomy and implantation of the ICP pressure transducer, the skull must be properly sealed. Without a proper seal, CSF is lost, the brain is not repressurized, and the brain and skull will not be coupled. These factors can lead to an altered response of the brain.

When using in vivo or in situ models, the skull thickness and shape as well as bone quality must be considered while comparing results between studies. Differences in anatomy will change how the blast wave interacts with the specimen, and ultimately how energy is transferred to the brain. Different responses to a blast wave, whether model specific or experimentally induced, can lead to misinterpretation of data, especially while comparing to other studies. Further, several studies have used acoustic impedance mismatch to explain the interaction phenomena between the skull, CSF, and brain, but did not consider its effect on the interaction between the blast wave (in air) and the scalp or skull.

When considering impedance mismatches, the skull orifice theory can also be examined. Unless there is an opening for the blast wave to penetrate the head, the scalp will reflect a significant portion of the incoming pressure wave (Fig. 3) as will the eye (Table 2). This emphasizes that the skull orifice theory cannot be stand-alone and specific orientations relative to the blast wave may contribute to different pressures in the skull orifices.

While acoustic impedance differences suggest direct cranial transmission is an unlikely mechanism for primary blast injury, research should be done to isolate pressure transmission from other factors or potential mechanisms.

Skull Flexure.

The skull flexure dynamics theory is contradictory to the direct cranial transmission theory. In this theory, the blast wave cannot directly transmit through the skull and instead, the blast wave energy acts on the skull causing deformation and/or vibration (Fig. 4) [39,42,72,73]. The stress wave has greater velocity in skull than air, causing a complex strain profile over the entire skull as the blast wave propagates. These skull dynamics cause ICP gradients and fluctuations. Since the brain is incompressible and viscoelastic, shear forces and deformations can become injurious. This mechanism could produce diffuse injury patterns in the brain, which has been shown in several preclinical blast models with immunohistochemical staining [24,27,33,65, 74,75] and with diffusion tensor imaging both in vivo [76] and clinically [7779].

Mechanical Loading.

An object obstructing a blast flow will cause a complex response in the flow. In the case of a head, the high impedance mismatch between the air and the skull will cause almost all the blast wave to reflect off the head (Fig. 4). This transient increase in pressure is much larger in magnitude than the stagnation pressure of the blast wave. As a result, the reflected pressure at the shock front is imparting a large force on the head, which will cause the head to move or deform in response. The large mass of the rest of the body, as well as the dynamics of the flow around the head, may limit movement. The deflection and global deformation of the head caused by this force are the basis of the skull flexure theory.

Experimental Models.

This theory is supported by the presence of oscillatory ICP responses after blast exposure. To understand these oscillations, Romba and Martin [80] inserted pressure sensors into euthanized primate brains and measured ICP profiles during blast. There were distinct pressure profiles in the brain that did not match the incident pressure profile, suggesting that the blast wave was not directly transmitted, but that the complex response of the skull could have an effect.

Computational models have been devised to investigate the skull flexure caused by a blast wave acting on the human head. For example, Moss et al. [73] developed a model and observed the skull dynamically flexing inward, creating a ripple effect on the surface of the skull that propagates outward. These oscillations produce pressure gradients in the brain. Also, deflections in the skull from the shock front can lead to magnified levels of pressure within the brain, possibly resulting in substantial neurotrauma. In a computational study comparing varying levels of face shielding on helmets, a high pressure loading on the farside of the head was demonstrated. This is caused by the rejoining of the blast wave after it passes around the head. This force counteracts the initial loading on the front of the head, suggesting that the skull will not accelerate rearward, but would deform [81]. Alley et al. [82] used spherical shells, with and without apertures, and two different brain surrogates to study the effects of impedance mismatch in the human head. The results show pressure oscillations within the brain simulant and indicate regions of compression and tension, which could cause neurotrauma. Bolander et al. [42] investigated skull deformation in anaesthetized rats during blast exposure with strain gages and ICP sensors. They observed consistent oscillations in the skull strain data and in the ICP during blast exposure. Oscillations in both the strain and ICP data maintained the same pattern, but had increasing magnitudes with higher blast pressure exposures. The consistency between strain and ICP data provides strong evidence that skull deformation is associated with pressure oscillations. There was also a delay in the rise time of the ICP response relative to the incident shock wave. This was explained as the impedance mismatch of the skull preventing direct transmission and instead causing skull deformation, directing the ICP response.

Discussion.

Based on computational, surrogate, and in vivo models, skull flexure dynamics comes to the forefront as a prime contributor to blast wave energy transmission into the brain, acting as the driver for primary bTBI. In view of the impedance mismatch discussion, almost the entire blast wave is reflected before it reaches the brain. However, there is still a force acting on the skull due to this reflection. Conceivably, this force causes the skull to undergo compression and tension, affecting the internal equilibrium. Versions of this damped oscillation axisymmetric response have been observed in simplified physical models [83,84]. This response originates from the site of reflected pressure on a given surface. During this time, the region exposed to the reflected pressure and the contralateral side undergoes compression. The sides of the object undergo tension. A series of damped oscillations will occur as the response returns to baseline strains. More biomechanical testing investigating skull strain and ICP oscillations with respect to the blast wave metrics will help decipher this mechanism.

Thoracic Surge.

The thoracic theory of bTBI offers a unique mechanistic perspective on primary bTBI because it does not involve blast wave–skull interaction. Rather, the highlighted interaction is that of the blast wave with the thorax. The theory postulates that exposure of the thorax and abdomen to a blast wave leads to rapid compression and creation of a shock wave that propagates through soft tissue and vasculature. Compression of great vessels is believed to lead to a volumetric vascular surge that reaches the brain and injures the more susceptible cerebrovasculature. Under normal circumstances, the cranial compartment, which is of fixed volume, maintains homeostatic conditions through a dynamic equilibrium of blood volume, CSF volume, and cerebral perfusion pressure. Therefore, a rise in any of these is accompanied by a corresponding decrease in another such that the ICP remains unaffected. Under the thoracic theory of primary blast injury, increased thoracic pressure leads to a vascular surge and prevents cerebral blood outflow, leading to increased ICP and subsequent neuropathology.

Blast exposure typically leaves the whole-body susceptible to injury, including the thorax and abdomen. Gas-filled organs are most vulnerable because of the compressibility of air and the soft tissue-air density interface. Hemorrhage, perforation, and rupture often occur in hollow organs such as the stomach, small intestine, and large intestine [85]. Lungs are among the most commonly injured organs due to the air-filled nature and high vascularization. Typical injuries to the lungs include hemorrhage, edema, and ruptured alveoli, but can become more severe involving hemothorax and pneumothorax [86]. In fact, a four-year study of terrorist bombings in Israel showed that 52% of those injured sustained lung injuries requiring ventilation during treatment [87]. Injury to the lungs can often be fatal. The United Kingdom theatre trauma registry showed that less than 50% of patients sustaining blast lung injury survived to reach a medical facility [88]. Thoraco-abdominal injuries are not limited to gas-filled organs; reports have shown that solid organs such as the liver, spleen, and kidney are also at risk of rupture, infarction, ischemia, hemorrhage, and laceration injuries [85,89].

Due to the prevalence and severity of thoraco-abdominal injuries, the interaction of the blast wave with the thorax should not be ignored. In recent conflicts, however, the prevalence of these injuries has decreased—in part due to advancements in body armor [9092]. Wood et al. [93] has shown that ballistic vests are able to attenuate the behind-the-armor overpressure by a factor of 56.8 following blast exposure, which significantly reduces the risk of pulmonary injury. While wearing a protective vest, the acoustic impedance mismatch between the blast wave and the vest is greater than the impedance mismatch between the blast wave and soft tissue. With increased impedance mismatch, a larger fraction of the wave will be reflected rather than transmitted [94]. The decrease in transmission accounts for the reduction in behind-the-armor overpressure. However, the reflected pressure will impart a large force on the vest that can cause subsequent compression and potential injury to the thorax. Thus, even for ballistic vests, the thorax is still at risk for injury.

Anatomy.

The idea of intra-thoracic pressure rise causing compression and shock wave propagation through the great vessels seems unlikely due to the natural safeguards set in place to avoid such changes in blood flow. In considering this theory, the geometry and distribution of vessels within the brain may be important. The cerebral arteries show extensive bifurcations at near right angles as well as a radius decrease with each bifurcation. The resistance (R) to flow in a blood vessel is dependent on several factors, including radius (r), as described by the adapted Hagen–Poiseuille equation below (Eq. (3)). Here, η represents viscosity and L represents length Display Formula

(3)R=8ηLπr4

An important aspect of this equation is the influence that a small radius change can have on the resistance to flow. A decreased radius will correspond to a resistance increase equivalent to the fourth power of the change in radius. Together, the bifurcation geometry and decreased vessel size can decrease blood velocity, increase hydrostatic pressure, and increase resistance as the blood-vessel contact surface increases (Fig. 5) [95]. Thus, the hypothesis has been proposed that cerebral vessels, and especially the circle of Willis, function to prevent damage to microvasculature in the brain by reducing high systolic pressure [95]. The function and response of the circle of Willis following blast remain unknown. Under the thoracic theory, if the pressure wave is sent through the arterial systems to the circle of Willis, the magnitude and speed of the pulse are expected to overwhelm the endogenous safe measures and injure the microvasculature. However, in doing so, damage is expected to occur at the bifurcations surrounding the circle of Willis as these are areas that would absorb a large transfer of kinetic energy from the vascular surge (Fig. 5). Only one study has noted vascular disruption in the circle of Willis, but since this occurred in a body-armored setup designed to expose only the head to the blast, the damage may not result from a vascular surge [96].

Another important physiological property to consider is cerebral autoregulation. Cerebral autoregulation is an innate response that maintains proper cerebral perfusion through cerebral vessel dilation and contraction. Vascular pathology in the brain has been well established following blast exposure and often involves blood–brain barrier damage [97102]. The vascular pathology has also been shown to compromise the ability of proper vessel autoregulation leading to prolonged contraction of cerebral vessels [103,104]. This likely plays a role in the decreased cerebral blood flow that has been observed in other studies [102,105]. Under normal conditions, the ability of cerebral vessels to autoregulate blood flow is important for brain function. If a vascular surge is responsible for compromised autoregulation, it may provide evidence for a thoracic mechanism of primary blast injury; however, no current data have shown this.

Experimental Models.

One of the largest challenges to current blast injury mechanism research is the experimental difficulty in isolating thoracic exposure from head exposure. Many in vivo experimental models have been developed and used to assess the contribution of a thoracic mechanism in primary bTBI [80,106110]. Cernak et al. [107] observed neuronal injury, glial cell reactivity, oxidative stress, and cognitive impairment in rats subjected to both whole-body and thoracic blast injuries. Another study found that neuropathology following a low-level blast could be mitigated using a Kevlar protective vest [108]. However, the vest proved to be ineffective against higher-level blast exposures, which may suggest a separate mechanism of transmission to the brain or limited effect of the Kevlar protection. Other studies have noted that a thoracic mechanism may not play a role in primary blast injury. Romba and Martin [80] showed that chest-only exposure can lead to a change in thoracic pressure which had no effect on ICP. Conversely, when only the head was exposed to blast wave, the ICP was altered [80]. Goldstein et al. [110] also reported no significant contributions of a thoracic mechanism in ICP dynamics in a living mouse compared to an isolated mouse head.

These models typically use directed shock waves produced by an open-ended shock tube to achieve thoracic-only exposure. However, sufficient mitigation of blast wave interaction with the head is seldom supported with experimental evidence. Upon exiting the shock tube, the wave undergoes complex flow dynamics involving expansion and rarefaction that could reach the head of the subject [24]. Therefore, proper measurement of pressure dynamics surrounding the skull is critical for determining sufficient isolation of a thoracic blast exposure and should be considered for future studies.

Other studies aim to simplify the problem by avoiding blast exposure and using ballistic impacts with the lower body [111,112]. By avoiding blast exposure, isolation of a thoracic mechanism from a cranial mechanism is easier. These studies rationalize the model by assuming airborne blast waves and ballistic impacts with soft tissue cause similar stress wave propagations through the tissue and vasculature, conserving injury mechanisms and leading to a similar injury. It is hypothesized that ballistic impacts, especially when occurring in close proximity to major vessels, can lead to a pressure pulse that injures the brain. The relevance of this injury mechanism to bTBI has only been supported theoretically and has not been accompanied by any direct experimental support [111]. One issue is the lack of proper characterization of the intrathoracic pressure changes that occur with blast exposure. In fact, some studies have shown that blast waves are rapidly attenuated or reflected as they interact with the soft tissue and bone of the thorax walls [80,113]. The attenuation or reflection of the blast wave may create a less severe intrathoracic injury than a penetrating bullet. Therefore, prior to employing a ballistic model to study the primary bTBI mechanisms, it is vital to properly characterize the effect of the blast wave on intrathoracic pressure changes and stress waves, especially near the great vessels. This knowledge will be important to establish the relevance of two dramatically different injury models: a penetrating ballistic impact and blast exposures.

Injury Physiology.

Further support for the thoracic mechanism has been drawn from the physiological response following a lower body ballistic impact or blast exposure. In considering physiological response to injury, injury mechanisms including air embolism and systemic responses are often ignored. Either a blast exposure or ballistic impact to the lower body can lead to soft tissue damage and can lead to bubble formation in the circulatory system. This may be a result of the implosion of alveoli from blast exposure, or cavitation from bullet penetration through tissue. In either case, the resultant bubbles can cause air embolism in the brain leading to occlusion of blood flow. Previous studies have concluded that a blood surge following ballistic impact leads to ICP rise that results in immediate death of the subject [111]. However, the presence of air embolism should not be ignored as there is evidence that this is an aspect of blast injury and may explain blast fatalities [114].

Current thoracic models have shown cellular and molecular dysfunction in the brain involving glial cell reactivity, oxidative stress, and neuronal damage, which are all important aspects of the bTBI pathology [107,108]. These processes are indicative of ongoing neuropathology, but are not necessarily attributable to primary bTBI mechanisms. Rather, these processes may be initiated by secondary injury cascades that involve systemic injury. The ability of blast waves to cause injury to internal organs has been discussed previously and is well established in literature. Ballistic impact models can severely, and sometimes permanently, injure various tissues in the body. These injuries can lead to a state of systemic inflammation in which various signaling molecules, including cytokines and chemokines, are released into circulation. Once in circulation, these mediators can have distinct impacts on the brain, leading to blood–brain barrier dysfunction, edema, neuroinflammation, and neurodegeneration [115119]. Other circulating molecules, such as autacoids, can regulate cerebrovasculature changes [120]. Therefore, prior to attributing neuropathology of these models to vascular surge mechanisms, the effects of systemic inflammation need to be considered.

Discussion.

Many studies have attempted to discern the role of a thoracic mechanism in primary bTBI. As a result, some support has been generated showing that thorax-directed blast waves can cause physiologically relevant injuries in the brain. Ballistic models have also shown the ability to injure brain tissue. However, the specific mechanisms causing brain injury remain unknown. To date, no studies have adequately measured and shown the ability of blast wave to cause a volumetric surge of blood to the brain. One study aiming to determine cerebral blood pressure found a dramatic peak internal carotid artery overpressure following a thoracic blast exposure [121]. However, a large internal carotid overpressure was also noted in the head-only exposure, which may indicate improper isolation of the blast wave or a separate injury mechanism [121]. There has been much speculation on the possibility of a volumetric surge of blood to the brain during a blast exposure, but little direct experimental evidence exists. Therefore, future studies should seek to measure any volumetric surge, thoracic pressure changes, and ICP changes following blast exposure. Creation of a physiologically relevant mathematical model may be useful in understanding the feasibility of a thoracic blast exposure in creating a vascular surge and transmitting pressure to the brain. This information would be critical for properly characterizing the role of thoracic mechanism in primary bTBI.

The various studies that attempt to elucidate thoracic mechanisms of primary blast have yielded contradicting conclusions, which may be a result of the diversity of experimental setups [122]. Future efforts should properly consider designing experiments to isolate thoracic mechanisms from cranial mechanisms. It is important to conserve proper blast wave physics to maintain relevant injury responses. Adaptations of various blast models to isolate thoracic mechanisms can sacrifice important blast wave parameters and lead to injury patterns that are not accurate of bTBI pathology. For example, Simard et al. [109] observed astrocyte activation in the perivenular spaces following a thoracic exposure, which is not representative of the widespread astrocyte activation that has been well established in the bTBI pathology [22,33,75,123125] and may be attributable to the reported abnormal pressure profile [78,109]. Other studies, which avoid blast waves all together, may create injury patterns that are not relatable to those sustained from blast exposures. Therefore, future experimental efforts should utilize blast waves with proper characterization of blast–skull interaction to ensure mitigation of cranial mechanisms. Incorporation of media with differing acoustic impedances into experimental setups may be useful in isolating these mechanisms.

Acceleration.

Another mechanistic theory for primary bTBI that has been mentioned in limited discussions is the combination of rotational and translational accelerations. However, it has been shown that acceleration-induced brain injury elicits a separate injury pathology than those sustained from blast exposure [126,127]. Some blast studies have produced significant amounts of head acceleration during in vivo testing. This was done by shielding the body, but letting the head freely move during exposure inside a shock tube [110,128], or having the head exposed to the end of a shock tube where dynamic pressure is significantly elevated [129131]. It is not typical that only the head is exposed to a blast wave in theater. In addition, work by Elder and De Haas [132] (also discussed in VandeVord et al. [133]) has shown that a vortex ring develops at the end of the shock tube, creating a complex pressure profile (Fig. 6), which can explain the high head accelerations during in vivo testing [129131]. Head acceleration and/or complex pressure profile can compound the primary injury; however, it creates a different injury pattern that is not representative of the primary blast wave alone. The acceleration injuries produced in vivo, such as increased axonal injury [128], are not typically seen in studies that effectively isolate primary blast, as described by Bailey et al. [123]. In addition, experiments and simulations using a sphere provide time-course data to support acceleration as a tertiary injury mode [82]. Overall, it is possible to artificially produce brain damage from head acceleration during a blast exposure from certain experimental setups, but these experimental setups may compromise clinical applicability. Moreover, this mechanism is not supported as a primary bTBI mechanism and is more properly described as a tertiary injury mechanism that does not result from the direct effects of the static overpressure. The dynamic pressure, not static pressure, is responsible for the blast displacement of objects.

Cavitation.

Recently, cavitation has been debated as a mechanism of primary blast injury. The cavitation theory is not a stand-alone primary blast injury mechanism since it requires the creation of negative pressure. Pressure transmission, by the previously discussed mechanisms, can cause changes in ICP. Localized areas of negative pressure are subject to the formation of cavitation bubbles. According to this theory, when these bubbles collapse, they cause damage to the surrounding brain tissue. This occurrence can only exist in combination with another theory that provides a significant amount of negative pressure.

There have been finite element simulation and physical surrogate tests done to study the validity of the cavitation mechanism theory [82,134137]. Alley et al. [82] used a physical model with a plastic shell filled with a brain simulant. Their results showed pressure oscillations and speculated that the regions of compression and tension in the brain simulant would cause voids in brain tissue rather than vapor bubbles by separating the tissue. While difficult to detect the differences between tissue separation and vapor bubble tears, they did observe increases in strain that correlate with void creation, supporting a cavitation mechanism. Hong et al. [138] developed a system to control bubble formation and collapse. They measured strain in rat brain slices and found clear tissue tearing caused by high strains. Tissue tearing is not a hallmark of bTBI. Although it was shown that cavitation bubble formation and collapse is damaging to brain tissue, this phenomenon has not been shown to occur during blast exposure in an in vivo model. Thus far, only surrogate and simplified computational models have supported this theory. It is important to note that computational models cannot accurately predict the brain response to blast due to the lack of studies providing validation data. Also, the brain simulants used in physical surrogates may not be biofidelic. In addition, cavitation has been studied as a mechanism of blunt impact TBI, where negative pressures were measured by Stalhammer [139,140], Stalhammer and Olsson [141], and Nusholtz et al. [142,143]. However, the negative pressures were not considered important to the injury mechanism. Brain tissue tearing or focal damage did not occur at the locations of negative pressure. In vivo testing examining the tissue adjacent to areas that experience negative pressure will better decipher this potential injury mechanism.

In addition, negative ICP has not been frequently measured during experimental tests. Studies using physical and PMHS models exposed to blast found negative pressures with a maximum negative pressure of 150 kPa [134,136]. Using single ultrasound pulses, the thresholds necessary to cause cavitation in water, blood, kidney, and adipose tissue are above 15 MPa [144]. The presence of negative pressure in surrogate and computational studies does not prove cavitation. Goeller et al. [134] imaged cavitation bubbles in a Sylgard ellipsoid head/brain with a polycarbonate skull exposed to blast overpressure at an ICP less than −150 kPa, but this needs to be further investigated in biological tissue. Further research should focus on quantifying negative pressure and investigating the presence of cavitation in the cranial cavity following blast overpressure in vivo.

Furthermore, shock wave lithotripsy is used to break up kidney stones. This technology creates a cavitation bubble and the collapse causes the stones to break. This technology has been shown to cause local tissue damage from the collapse of the cavitation bubbles [145,146]. However, with primary bTBI, the formation and collapse of a cavitation bubble contrecoup to the blast interaction with the skull would likely cause focal damage and does not explain the diffuse brain injury seen in bTBI.

Primary bTBI mechanisms are a significant source of deliberation in the blast community since data over the years have been conflicting. Blast environments are complex and difficult to properly recreate. This lack of data limits the efficacy of prevention and treatment efforts. This problem is confounded by conclusions made from blast models that do not adequately recreate the injury and other injury models that elicit physiologically different responses. This review aims to focus the research efforts in the field by highlighting the current shortcomings, limitations, and challenges. The potential mechanisms of primary blast transmission to the brain are reviewed and discussed from physical, clinical, and physiological perspectives.

It is possible that the discussed injury mechanisms do not occur exclusively from each other. Rather, several of these mechanisms may make up the complex pathology observed following blast exposure. It is also possible that primary blast mechanisms may have different roles at various magnitudes of blast exposure. For example, low-level blasts may be attenuated through the thorax, but high-level blasts may trigger a thoracic mechanism. It will be vital for future research efforts to elucidate how blast energy levels affect various tissues.

Future Directions.

A comprehensive research endeavor is needed to identify the mechanism, or set of mechanisms, responsible for primary bTBI. The theories presented should be investigated through a series of PMHS, in vivo, and computational studies. First, a PMHS study should be conducted to investigate biomechanics during blast wave exposure. Implanting pressure transducers at multiple locations in the brain and adhering strain gages to the head will show ICP and skull strain changes during different orientations and levels of exposure. The brain should be perfused to ensure proper brain/skull coupling. Skull orifices can be closed off and sinuses filled to measure ICP in a variety of scenarios, including head orientation. This will help investigate the skull orifice theory. Measuring strain on the skull will provide insight to the skull flexure dynamics theory along with the timing of ICP changes. Strain and ICP data will also shed some light on the direct cranial transmission theory. Pressure transducers can also be inserted into other parts of the body, such as in the systemic vasculature, so a pressure surge coming from the thorax can be detected. In addition, this data can be used to validate computational models. Many questions could be answered by conducting a series of these basic studies. However, when conducting these studies, it is vital to carefully consider maintaining proper blast physics to maintain a relevant injury pattern, which is a challenge. Either a live blast environment or large advanced blast simulator would be required for these experiments.

In addition, in vivo studies can greatly benefit from this knowledge and scaling/anatomical concerns can be addressed. Animal models can be investigated so that appropriate models sharing similar biomechanical responses are identified. Depending on the responsible mechanism(s), anatomical differences of in vivo models, such as skull thickness, orbit locations and sinus cavities, will be important to consider and can be modified to match the human data. Then, brain injury could be investigated and characterized, and eventually scaled to a human to determine relevant thresholds and injury criteria. Currently, the blast wave parameter(s) most important for predicting underlying injury are unknown. Determining these will be crucial before scaling attempts are possible. Eventually, this will lead to a validated animal model that mimics the human condition and can be used to investigate neuropathology. Injury criterion were developed for blast [129,147], but these thresholds are based on brain hemorrhage from a model that induced high amounts of head acceleration on the animals. Appropriate thresholds for a primary blast environment must be determine before data are generated, which can be translated to design preventative measures. Taking the correct steps to study and replicate battlefield injuries and develop injury criteria will be immensely beneficial to our soldiers. These can lead to the implementation of scientifically relevant mandates to remove soldiers from the battlefield after a certain exposure level and can help identify prevention techniques.

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Figures

Grahic Jump Location
Fig. 1

Pressure profiles from a Pitot tube sensor in an advanced blast simulator. The stagnation, or total, pressure is measured at the tip of the sensor, and initially measures reflected pressure as the shock front reflects off it. The pressure then quickly drops to the stagnation pressure. A side-on pressure transducer is 127 mm behind the tip of the tube measuring overpressure.

Grahic Jump Location
Fig. 2

Friedlander waveform with key elements labeled. The area under the curve during the positive and negative phases of the wave is shaded to show the positive and negative impulses. It is important to note that everything is with respect to atmospheric pressure and not P = 0.

Grahic Jump Location
Fig. 3

Representation of the interface between the air and the head as a shock wave is encountered. The dashed gray and solid white lines are proportional to the amount of the wave that would either be transmitted or reflected, respectively. Here, the impedance value of skin is used for the scalp and that of water for the cerebrospinal fluid (CSF). Note that only 0.005% of the blast wave would be transmitted to the brain.

Grahic Jump Location
Fig. 4

Skull flexure theory contributes injury to a multimodal biomechanical response initiated by the incident blast wave reflected off the skull, which results in a series of compression and tension oscillations

Grahic Jump Location
Fig. 5

Schematic representation of the effects of bifurcations and vessel size on blood flow. Areas of blue indicate areas that may be subject to large stress resulting from kinetic energy associated with a volumetric surge of blood. Following bifurcations, vessel diameter decreases, causing increased resistance to flow.

Grahic Jump Location
Fig. 6

Diagram of a pressure wave exiting a shock tube. Note the dark orange areas of high pressure at the blast front, but also at the vortex rings just outside the shock tube. Over time, these vortex rings will propagate outward.

Tables

Table Grahic Jump Location
Table 1 Summary of select literature for skull orifice, direct transmission, skull flexure, and thoracic theories
Table Grahic Jump Location
Table 2 Impedance values (in 106 kg/m2s) for air, water, and various biological materials [63,64]

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