How Shockwaves Open Tight Junctions of Blood-Brain Barrier: Comparison of Three Biomechanical Effects

Revealing how blast shockwaves open the tight junction of the blood-brain barrier (BBB) is very important for understanding blast-induced traumatic brain injury (bTBI) and shockwave-assisted drug delivery; however, the underlying mechanism remains unresolved. Here, we used multiscale molecular dynamics simulations to reveal the disruption mechanism of claudin-5 protein in a relatively complex BBB model by comparing three typical effects from blast loads. The results showed that the opening of claudin-5 did not result from the direct compressive loading of the single shockwave but from indirect cavitation and stretching effects induced by shockwaves. Importantly, stretch-mediated mechanical opening from the asymmetric distribution of overpressure in temporal and spatial dimensions is a novel damage mode. In detail, the nanojet from the cavitation pushed away two adjacent endothelial cell membranes and the embedded claudin-5 was rapidly stretched. Even α-helix showed a drastic conformational breakdown and its content was only 15.9%. Structural changes of this magnitude are difficult to repair in a short time, which may be related to chronic BBB dysfunction and persistent neurological deficits. This is a more common injury, since the tensile response of membranes to blast loads is relatively common. Taken together, we provided a biomechanical underpinning for acute disruption of tight junction proteins in BBB from exposure to blast shockwaves, and this may be helpful as a therapeutic strategy for bTBI.