Cavitation-induced traumatic cerebral contusion and intracerebral hemorrhage in the rat brain by using an off-the-shelf clinical shockwave device

Abstract

Traumatic cerebral contusion and intracerebral hemorrhages (ICH) commonly result from traumatic brain injury and are associated with high morbidity and mortality rates. Current animal models require craniotomy and provide less control over injury severity. This study proposes a highly reproducible and controllable traumatic contusion and ICH model using non-invasive extracorporeal shockwaves (ESWs). Rat heads were exposed to ESWs generated by an off-the-shelf clinical device plus intravenous injection of microbubbles to enhance the cavitation effect for non-invasive induction of injury. Results indicate that injury severity can be effectively adjusted by using different ESW parameters. Moreover, the location or depth of injury can be purposefully determined by changing the focus of the concave ESW probe. Traumatic contusion and ICH were confirmed by H&E staining. Interestingly, the numbers of TUNEL-positive cells (apoptotic cell death) peaked one day after ESW exposure, while Iba1-positive cells (reactive microglia) and GFAP-positive cells (astrogliosis) respectively peaked seven and fourteen days after exposure. Cytokine assay showed significantly increased expressions of IL-1β, IL-6, and TNF-α. The extent of brain edema was characterized with magnetic resonance imaging. Conclusively, the proposed non-invasive and highly reproducible preclinical model effectively simulates the mechanism of closed head injury and provides focused traumatic contusion and ICH.

Cerebrospinal Fluid Cavitation as a Mechanism of Blast-Induced Traumatic Brain Injury: A Review of Current Debates, Methods, and Findings

“…In fact, cavitation within the brain matter may be a better logical explanation of bTBI. This is because injury attributed to shearing throughout the brain would be more consistent with current damage models (29)(30)(31). Thus, the bTBI would not be limited to surfaces in contact with the CSF layer.…”

“…However, cavitation rheology (32) and research on cavitation in biological tissues (33) are newer and less well-documented nuances. As a result, this review will focus on CSF cavitation due to the paucity of literature on cavitation in the brain (31,(34)(35)(36). Additionally, the CSF is the focus of this review since the CSF is the largest and ionically simplest fluid in the brain.…”

“…Extracorporeal shock waves (ESW), similar to those used for lithotripsy, have also been used in more than one instance to generate bTBI due to cavitation (31,53). In one of those instances, bubbles were artificially injected to increase cavitation effects, suggesting likely bTBI due to bubble collapse (31).…”

A Single High-Intensity Shock Wave Pulse With Microbubbles Opens the Blood-Brain Barrier in Rats

“…The second difference is the acoustic pressure, which for the single-shot FSW is around −4 to −5 MPa (peak-negative pressure), but HIPU is −0.5 to −1 MPa. The third difference is the total duration, which for the single-shot FSW is around 1 ms, but for the HIPU is as long as 60-120 s. The last difference is the mechanical wave profile, in which FSW has a very sharp positive pulse as shown in the upper part of Figure 8C, while HIPU has regular sine waves (Bachmann et al, 2001;Kung et al, 2018;Huang et al, 2019).…”

TRPV4 promotes acoustic wave-mediated BBB opening via Ca2+/PKC-δ pathway

“…Since the concentration and quality of the gas in the blood are not homogenized and stabilized, the shockwave cannot effectively open the BBB [6] . On the other hand, when combined with microbubbles, only 1 pulse of shockwave is enough to effectively open BBB or even cause brain injury by strong cavitation effect [57] .…”