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

Department of Biomedical Engineering, Columbia University New York, NY, USA.
Frontiers in Neurology 01/2012; 3:23. DOI: 10.3389/fneur.2012.00023
Source: PubMed

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.

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    ABSTRACT: Recent studies have demonstrated increased susceptibility to breakdown of the cerebral vasculature associated with repetitive traumatic brain injury. We hypothesized that exposure to two consecutive blast injuries would result in exacerbated damage to an in vitro model of the blood-brain barrier (BBB) compared to exposure to a single blast of the same severity. However, contrary to our hypothesis, repeated mild or moderate primary blast delivered within 24 or 72 hours did not significantly exacerbate reductions in trans-endothelial electrical resistance (TEER) across a brain endothelial monolayer compared to sister cultures receiving a single exposure of the same intensity. Permeability of the barrier to a range of different-sized solutes remained unaltered after single and repeated blast, supporting that the effects of repeated blast on BBB integrity were not additive. Single blast exposure significantly reduced immunostaining of ZO-1 and claudin-5 tight junction proteins, but subsequent exposure did not cause additional damage to tight junctions. Although repeated blast did not further reduce TEER, the second exposure delayed TEER recovery in BBB cultures. Similarly, recovery of hydraulic conductivity through the BBB was delayed by a second exposure. Extending the inter-injury interval to 72 hours, the effects of multiple injuries on the BBB were found to be independent given sufficient recovery time between consecutive exposures. Careful investigation of the effects of repeated blast on the BBB will help identify injury levels and a temporal window of vulnerability associated with BBB dysfunction, ultimately leading to improved strategies for protecting warfighters against repeated blast-induced disruption of the cerebral vasculature.
    Journal of neurotrauma 12/2013; · 4.25 Impact Factor
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    Frontiers in neurology. 01/2014; 5:128.
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    ABSTRACT: An increasing number of U.S. soldiers are diagnosed with traumatic brain injury (TBI) following exposure to blast. In the field, blast injury biomechanics are highly complex and multiphasic. The pathobiology caused by exposure to some of these phases in isolation, such as penetrating or inertially-driven injuries, has been investigated extensively. However, it is unclear whether the primary component of blast, a shock wave, is capable of causing pathology on its own. Previous in vivo studies in the rodent and pig have demonstrated that it is difficult to deliver a primary blast (i.e. shock wave only) without rapid head accelerations and potentially confounding effects of inertially-driven TBI. We have previously developed a well-characterized shock tube and custom in vitro receiver for exposing organotypic hippocampal slice cultures (OHSC) to pure primary blast. In this study, isolated primary blast induced minimal hippocampal cell death (on average below 14% in any region of interest), even for the most severe blasts tested (424 kPa peak pressure, 2.3 ms overpressure duration, and 248 kPa-ms impulse). In contrast, measures of electrophysiological function were significantly altered at much lower exposures (336 kPa, 0.84 ms, 86.5 kPa-ms), indicating that functional changes occur at exposures below the threshold for cell death. This is the first study to investigate a tolerance for primary blast-induced brain cell death in response to a range of blast parameters and to demonstrate functional deficits at sub-threshold exposures for cell death.
    Journal of neurotrauma 02/2014; · 4.25 Impact Factor

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