A Multiscale Approach to Blast Neurotrauma Modeling: Part II: Methodology for Inducing Blast Injury to in vitro Models

Abstract

Due to the prominent role of improvised explosive devices (IEDs) in wounding patterns of U.S. war-fighters in Iraq and Afghanistan, blast injury has risen to a new level of importance and is recognized to be a major cause of injuries to the brain. However, an injury risk-function for microscopic, macroscopic, behavioral, and neurological deficits has yet to be defined. While operational blast injuries can be very complex and thus difficult to analyze, a simplified blast injury model would facilitate studies correlating biological outcomes with blast biomechanics to define tolerance criteria. Blast-induced traumatic brain injury (bTBI) results from the translation of a shock wave in-air, such as that produced by an IED, into a pressure wave within the skull–brain complex. Our blast injury methodology recapitulates this phenomenon in vitro, allowing for control of the injury biomechanics via a compressed-gas shock tube used in conjunction with a custom-designed, fluid-filled receiver that contains the living culture. The receiver converts the air shock wave into a fast-rising pressure transient with minimal reflections, mimicking the intracranial pressure history in blast. We have developed an organotypic hippocampal slice culture model that exhibits cell death when exposed to a 530 ± 17.7-kPa peak overpressure with a 1.026 ± 0.017-ms duration and 190 ± 10.7 kPa-ms impulse in-air. We have also injured a simplified in vitro model of the blood–brain barrier, which exhibits disrupted integrity immediately following exposure to 581 ± 10.0 kPa peak overpressure with a 1.067 ± 0.006-ms duration and 222 ± 6.9 kPa-ms impulse in-air. To better prevent and treat bTBI, both the initiating biomechanics and the ensuing pathobiology must be understood in greater detail. A well-characterized, in vitro model of bTBI, in conjunction with animal models, will be a powerful tool for developing strategies to mitigate the risks of bTBI.

The Mechanics of Traumatic Brain Injury: A Review of What We Know and What We Need to Know for Reducing Its Societal Burden

“…), the resulting mechanical response of the brain/skull, and to integrate thresholds for damage to the brain and its coverings to identify the mechanical loading scenarios most often associated with injury. Ongoing work to study blast-induced traumatic brain injury is following a similar trajectory, although the tolerance criteria for blast loading are in the early developmental stages [21][22][23]. A defining characteristic of this research cycle is to address the most significant injuries occurring in the population, to implement new technologies for reducing the incidence of these injuries, and generate new surveys of the population for focusing future research efforts.…”

“…Because these cultures are not vascularized, however, they do not provide an estimate of the selective change in the tolerance in cases where blood flow is compromised (ischemia; relative ischemia) or vascular damage occurs (blood-brain barrier breakdown; vasospasm). The use of in vitro models to study the effects of blast exposure is in its early stages, and estimates for blood-brain barrier opening, alterations in glial signaling, and the recovery of function are starting to appear in the literature [23,203]. A key issue that will need more clarification is the correlation of these loading conditions used in vitro to the loading environment in situ during blast.…”

“…In nearly all cases of deformation-based mechanisms, the in vivo evidence matches the in vitro observations. New models to mimic only the blast wave transmission in cell cultures open up an entirely new opportunity for discovery in the blast loading regime in which several potential mechanisms of injury can be tested precisely with in vitro analogues [14,23,[203][204][205][206][207][208][209][210][211].…”

“…Perhaps the most informative and relevant in vitro model for directly coupling mechanical inputs into brain tolerance and injury mechanisms will be the organotypic, in vitro models or the reduced in vivo models [18,23,[212][213][214][215][216][217][218][219]. Organotypic brain cultures are sections of the brain isolated from the postnatal rodent brain and cultured over days to weeks.…”

Acute vitreoretinal trauma and inflammation after traumatic brain injury in mice

“…To address this heterogeneity, several preclinical models are used to study TBI that differ in mechanism and severity and allow identification of pathophysiologic changes that may be unique to a single injury type or seen across various clinical TBI phenotypes 16. While visual disturbances secondary to TBI have been documented in patients,6, 17, 18 the phenotypic changes found in the eye in mouse models of traumatic brain injury have not been routinely evaluated 19, 20, 21. Similar to the primary brain injury, however, we would expect that ocular injuries may vary with different mechanisms of TBI.…”