Computational and In Vitro Studies of Blast-Induced Blood-Brain Barrier Disruption

Abstract

Abstract. There is growing concern that blast-exposed individuals are at risk of developing neurological disorders later in life. Therefore, it is important to understand the dynamic properties of blast forces on brain cells, including the endothelial cells that maintain the blood-brain barrier (BBB), which regulates the passage of nutrients into the brain and protects it from toxins in the blood. To better understand the effect of shock waves on the BBB we have investigated an in vitro model in which BBB endothelial cells are grown in transwell vessels and exposed in a shock tube, confirming that BBB integrity is directly related to shock wave intensity. It is difficult to directly measure the forces acting on these cells in the transwell container during the experiments, and so a computational tool has been developed and presented in this paper.Two-dimensional axisymmetric Euler equations with the Tammann equation of state were used to model the transwell materials, and a high-resolution finite volume method based on Riemann solvers and the Clawpack software was used to solve these equations in a mixed Eulerian/Lagrangian frame. Results indicated that the geometry of the transwell plays a significant role in the observed pressure time series in these experiments. We also found that pressures can fall below vapor pressure due to the interaction of reflecting and diffracting shock waves, suggesting that cavitation bubbles could be a damage mechanism. Computations that include a simulated hydrophone inserted in the transwell suggest that the instrument itself could significantly alter blast wave properties. These findings illustrate the need for further computational modeling studies aimed at understanding possible blastinduced BBB damage.

Blast exposure elicits blood-brain barrier disruption and repair mediated by tight junction integrity and nitric oxide dependent processes

“…S2 ). Thus, as has been reported previously regarding CLD5 expression after brain injury 36 – 38 , it is more likely blast caused extant CLD5 proteins to mislocalize and diffuse within the endothelial cytoplasm, making them more difficult to detect by immunofluorescence. Taken together these results indicate that blast exposure caused brain region-specific disturbances in the expression of tight junction-localized CLD5.…”

“…Our findings of aberrant CLD5 expression 72 hours after blast, without a significant change in CLD5 protein expression as measured by immunoblotting, could suggest that CLD5 may not be degraded as a result of blast, but rather diffused within BECs. Such redistribution has been demonstrated in rodent stroke models 36 , 37 and in primary BECs after blast injury 38 . CLD5 −/− mice exhibited BBB disruption to small molecules, such as sucrose, with no effect on larger molecules such as albumin 73 .…”

Cerebral Small Vessel Disease (CSVD) – Lessons From the Animal Models

“…Recently, various in silico methods and models in the pathology of the BBB, that is, BBB computational pathology using mathematical approaches, have been used to study and predict BBB integrity up to the molecular level, and its relationship with cerebral damage (Shityakov and Förster, 2018). The majority of the computational approaches incorporate molecular dynamics (MD), molecular docking simulations, pharmacokinetics, and finite element methods, but lack details on the pathomechanism of BBB damage (Shityakov and Förster, 2014; Shityakov et al, 2015; Del Razo et al, 2016).…”

Reaction time impairments in decision-making networks as a diagnostic marker for traumatic brain injuries and neurological diseases

“…Despite the insights gained with animal studies [8,73,92] and in vitro experiments [28,29,52,51], there are still many open questions and opportunities for translational studies [33]. In particular, there have been only a modest number of theoretical and numerical works regarding blast-induced shockwaves [69], pathological effects on neuronal signaling [43,45] or network dysfunction [74]. This work aims to contribute with the latter, linking commonly found axonal injuries to a network's impaired decision-making capabilities.…”