Effects on Neurons and Hippocampal Slices by Single and Multiple Primary Blast Pressure Waves From Detonating Spherical Cyclotrimethylenetrinitramine (RDX) Explosive Charges

Abstract

Threshold shock-impulse levels required to induce cellular injury and cumulative effects upon single and/or multiple exposures are not well characterized. Currently, there are few in vitro experimental models with blast pressure waves generated by using real explosives in the laboratory for investigating the effects of primary blast-induced traumatic brain injury. An in vitro indoor experimental platform is developed using real military explosive charges to accurately represent battlefield blast exposure and to probe the effects of primary explosive blast on dissociated neurons and tissue slices. Preliminary results indicate that physical insults altered membrane permeability, impacted cellular viability, created axonal beadings, and led to synaptic protein loss in hippocampal slice cultures. Injuries from blast under the conditions that were examined did not appear to cause immediate or sustained damage to the cells. Three consecutive primary blasts failed to disrupt the overall cellular integrity in the hippocampal slice cultures and produced a unique type of pathology comprised with distinct reduction in synaptic proteins before cellular deterioration set in. These observed changes might add to the challenges in regard to enhancing our understanding of the complex biochemical and molecular mechanisms caused by primary blast-induced injury.

Axonopathy precedes cell death in ocular damage mediated by blast exposure

“…Dysfunction in synaptic transmission and reduction in the expression of synaptic proteins have been reported in other models of blast-induced TBI in the brain [82][83][84][85] , the retina 86 and the auditory system 87 . Nevertheless, information about the molecular changes that occur at synapses after exposure to blast is scant.…”

Understanding Primary Blast Injury: High Frequency Pressure Acutely Disrupts Neuronal Network Dynamics in Cerebral Organoids

“… 28 Additionally, in ex vivo hippocampal slices exposed to mild TBI overpressures have also shown axon beading, which suggests isolated neurons and reduced circuit preparations respond to mild pressure changes. 27 However, in both studies, tissue shear stress could not be eliminated, was not quantifiable, and the pressure waveform was more complex and multi-modal. 27 , 28 An additional advancement with our organoid approach is that the complex cytoarchitecture of a complex neural circuit is maintained without introducing confounding slice injury necessary to assess in rodent brain slice cultures.…”

“… 27 However, in both studies, tissue shear stress could not be eliminated, was not quantifiable, and the pressure waveform was more complex and multi-modal. 27 , 28 An additional advancement with our organoid approach is that the complex cytoarchitecture of a complex neural circuit is maintained without introducing confounding slice injury necessary to assess in rodent brain slice cultures. These lower amplitude exposures do not appear to injure cells and together with the acute changes in neurophysiology suggest that 250 kPa amplitude waveforms across 500 Hz-5000 Hz frequencies induce a disruption in brain function.…”

“…To isolate physiologic changes from pure quasi-hydrostatic pressure, a unique approach should be taken to address two key challenges: 1) the generation of controlled pressure exposures, and 2) a relevant human-based in vitro brain tissue model. Current in vivo 25 , 26 and in vitro 27 , 28 blast models utilize spatially and spectrally heterogeneous pressure exposures systems that are not tunable across a range of pressure and frequency parameters. In this study, we utilize a previously developed computer-controlled pressure chamber 29 to expose human cerebral organoids to varied frequencies of idealized pressure waves that are representative of those experienced intracranially during blast exposure.…”

Localizing Clinical Patterns of Blast Traumatic Brain Injury Through Computational Modeling and Simulation

“…Currently it is unclear if transient high pressures themselves alter cell behavior or can cause neuronal dysfunction, however there is older experimental data from blast lung that imply the high frequency components of pressure waves found in blasts (>3,000 Hz) may preferentially cause tissue injury over pressure waves with larger overpressures but slower frequencies ( 46 ). Additionally, blast overpressures onto cell cultures can reduce neuron viability ( 47 ), alter membrane permeability, increase synaptic protein loss ( 48 ), and lead to changes in long term potentiation ( 49 ). All these changes could result in clinical deficits, but direct evidence of these changes to clinical injury is lacking.…”