In-vitro approaches for studying blast-induced traumatic brain injury

Abstract

Traumatic brain injury caused by explosive or blast events is currently divided into four phases: primary, secondary, tertiary, and quaternary blast injury. These phases of blast-induced traumatic brain injury (bTBI) are biomechanically distinct, and can be modeled in both in-vivo and in-vitro systems. The purpose of this review is to consider the mechanical phases of bTBI, how these phases are reproduced with in-vitro models, and to review findings from these models to assess how each phase of bTBI can be examined in more detail. Highlighted are some important gaps in the literature that may be addressed in the future to better identify the exact contributing mechanisms for bTBI. These in-vitro models, viewed in combination with in-vivo models and clinical studies, can be used to assess both the mechanisms and possible treatments for this type of trauma.

FIG. 1.

Models of tertiary bTBI. (A and B) For two-dimensional monolayer cultures, the cells are typically plated on a transparent flexible membrane and the membrane is either deformed using an air pressure pule (P, ΔP) to strain the cells in both directions (biaxial), or primarily only in one direction (uniaxial). Shown are illustrations of both techniques, with highlights of how the cells in a region of the membrane (the dark objects) are deformed from their initial shape (dashed lines), and then returned rapidly to their initial shape. (C) A less commonly used technique on monolayer cultures is using hydrodynamic shear (λ), which is applied to the surface of the cell monolayer, to induce a deformation in the cells. (D) A new three-dimensional technique to study the response of cells embedded within a three-dimensional structure is also shown. The cells (the dark spots) are within a three-dimensional hydrogel that is deformed in shear by applying a force (F(t), ΔF) to the top of the gel.

FIG. 2.

Models of secondary bTBI. (A and B) The most simple models used on tissue slices and aggregates involve using either a dropped weight (W) or rotating spinner (ω) bottle to induce the primary injury. (C) More recent techniques use a stylus to induce a primary injury, which can be designed to injure several regions of the culture simultaneously. (D) A less commonly used approach is to use a laser (energy hv) to precisely injure local regions of the cell to study the regenerative or repair response.

FIG. 3.

Models of primary bTBI. (A) In the barotrauma chamber, even pressure (ΔP) is applied to all cells and slices to induce pressure-mediated injury. In a hydrostatic chamber, the pressure is quasistatic; in a fluid percussion chamber, the pressure is transient. (B) In the rapid acceleration injury (RAI) model, a flask containing the cells is swung on a pendulum from specified heights. A pressure transient (P(x)) is induced by the fluid upon impact of the pendulum/flask against a stationary object at the lowest point of the trajectory. The resulting injury is from a combination of acceleration (a(t)) and pressure forces. (C) In lithotripsy, shockwaves are generated and reflected off the ellipsoidal reflector.