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 02/2012; 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: Throughout current military actions, explosive devices have become more powerful, their detonation systems more creative, and their additives more devastating. As a continuing threat to both military troops and civilians, blast injuries, especially blast-induced neurotrauma (BINT), are called the “signature wound” of the wars in Iraq and Afghanistan. In both civilian and military environments, exposure to a blast may cause instant death, injuries with immediate manifestation of symptoms, and latent injuries that are initiated at the time of exposure and may manifest over a period of hours, months, or even years. The improved interceptive properties of body armor, providing better protection from penetrating injuries and prompt evacuation of the wounded, increased the number of surviving soldiers. Nevertheless, in parallel with this increased survival-rate, the number of victims with severe debilitating long-term consequences, not seen before, is also increased. BINT is a traumatic brain injury (TBI) caused by a blast that is generated during an explosion. It is a unique clinical entity in which the functional and morphological impairments in the brain are coupled with considerable systemic and/or local changes. This chapter provides a basic explanation of blast physics and the types of interaction between blast effects and the body/brain. Moreover, the essential mechanisms of blast injuries and BINT are reviewed including cerebral, systemic, and local responses to blast and their intricate interactions that can lead to debilitating chronic deficits.
    Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects, 1st edited by Kobeissy F, 03/2015: chapter 45: Blast Injuries and Blast-Induced Neurotrauma: Overview of Pathophysiology and Experimental Knowledge - Models and Findings: pages 631-644; CRC Press., ISBN: 978-1-4665-6599-9
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    ABSTRACT: Finite element (FE) models of traumatic brain injury (TBI) are capable of predicting injury-induced brain tissue deformation. However, current FE models are not equipped to predict the biological consequences of tissue deformation, which requires the determination of tolerance criteria relating the effects of mechanical stimuli to biologically relevant functional responses. To address this deficiency, we present functional tolerance criteria for the cortex for alterations in neuronal network electrophysiological function in response to controlled mechanical stimuli. Organotypic cortical slice cultures were mechanically injured via equibiaxial stretch with a well-characterized in vitro model of TBI at tissue strains and strain rates relevant to TBI (up to Lagrangian strain of 0.59 and strain rates up to 29 [Formula: see text]. At 4-6 days post-injury, electrophysiological function was assessed simultaneously throughout the cortex using microelectrode arrays. Electrophysiological parameters associated with unstimulated spontaneous network activity (neural event rate, duration, and magnitude), stimulated evoked responses (the maximum response [Formula: see text], the stimulus current necessary for a half-maximal response [Formula: see text], and the electrophysiological parameter [Formula: see text] that is representative of firing uniformity), and evoked paired-pulse ratios at varying interstimulus intervals were quantified for each cortical slice culture. Nonlinear regression was performed between mechanical injury parameters as independent variables (tissue strain and strain rate) and each electrophysiological parameter as output. Parsimonious best-fit equations were determined from a large pool of candidate equations with tenfold cross-validation. Changes in electrophysiological parameters were dependent on strain and strain rate in a complex manner. Compared to the hippocampus, the cortex was less spontaneously active, less excitable, and less prone to significant changes in electrophysiological function in response to controlled deformation (strain or strain rate). Our study provides functional data that can be incorporated into FE models to improve their predictive capabilities of the in vivo consequences of TBI.
    Biomechanics and Modeling in Mechanobiology 01/2015; DOI:10.1007/s10237-015-0652-6 · 3.25 Impact Factor
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    ABSTRACT: Due to recent involvement in military conflicts, and an increase in the use of explosives, there has been an escalation in the incidence of blast-induced traumatic brain injury (bTBI) among US military personnel. Having a better understanding of the cellular and molecular cascade of events in bTBI is prerequisite for the development of an effective therapy that currently is unavailable. The present study utilized organotypic hippocampal slice cultures (OHCs) exposed to blast overpressures of 150 kPa (low) and 280 kPa (high) as an in vitro bTBI model. Using this model, we further characterized the cellular effects of the blast injury. Blast-evoked cell death was visualized by a propidium iodide (PI) uptake assay as early as 2 h post-injury. Quantification of PI staining in the cornu Ammonis 1 and 3 (CA1 and CA3) and the dentate gyrus regions of the hippocampus at 2, 24, 48, and 72 h following blast exposure revealed significant time dependent effects. OHCs exposed to 150 kPa demonstrated a slow increase in cell death plateauing between 24 and 48 h, while OHCs from the high-blast group exhibited a rapid increase in cell death already at 2 h, peaking at ~24 h post-injury. Measurements of lactate dehydrogenase release into the culture medium also revealed a significant increase in cell lysis in both low- and high-blast groups compared to sham controls. OHCs were fixed at 72 h post-injury and immunostained for markers against neurons, astrocytes, and microglia. Labeling OHCs with PI, neuronal, and glial markers revealed that the blast-evoked extensive neuronal death and to a lesser extent loss of glial cells. Furthermore, our data demonstrated activation of astrocytes and microglial cells in low- and high-blasted OHCs, which reached a statistically significant difference in the high-blast group. These data confirmed that our in vitro bTBI model is a useful tool for studying cellular and molecular changes after blast exposure.
    Frontiers in Neurology 02/2015; 6:20. DOI:10.3389/fneur.2015.00020