Ultrasound Triggered Bubble-Induced Blood-Brain Barrier Opening: A Monodisperse Microbubble and Organ-On-Chip Study

Neurological diseases such as multiple sclerosis, Alzheimer's, and Parkinson's are associated with impaired blood-brain barrier (BBB) function. The presence of the BBB significantly restricts the passage of drug molecules thus limiting the treatment of brain diseases. Ultrasound-mediated bubble-induced BBB disruption is a promising non-invasive approach that can be used to temporally increase the permeability of the BBB and thereby the transport of intravascularly injected drugs. However, clinical translation of this promising method is hindered by safety and standardization concerns that are largely due to the acoustic non-uniformity of the currently used microbubbles (MBs). Recent advances in microfluidics allow the production of highly uniform monodisperse MBs. However, there is no knowledge of ideal bubble properties for BBB permeabilization because bubble-BBB interactions remain elusive.In this work, we present a novel experimental approach allowing bubble-induced BBB opening studies at the sub-μs time and μm length scale. An optically transparent organ-on-chip (OOC) model of the BBB is used in combination with both ultra-high-speed imaging at 10 million frames per second and confocal imaging. On top of that, we uniquely use monodisperse MBs to ensure a uniform acoustic response of all bubbles inducing BBB permeabilization, which allows direct correlation of optically resolved bubble dynamics and their induced bioeffect both on a single cell level and across the entire BBB model. Here we studied the effect of two different acoustic driving pressures on BBB opening. Preliminary results indicate that 7-μm bubbles induce tight junctions (TJs) disruption when driven at an acoustic pressure amplitude of 500 kPa (1 MHz, 10 cycles) whereas they induce membrane poration when the acoustic pressure amplitude is increased to 1 MPa.