Abstract
Blood-brain barrier (BBB) disruption mediated by ultrasound and microbubbles (US-BBBD) is a promising strategy for non-invasive and targeted delivery of therapeutics to the brain. In US-BBBD, treatment control is achieved by externally monitoring acoustic emissions (AE) and adjusting ultrasound parameters in real-time to avoid AE associated with damage. Recent work suggests that AE may also provide insight regarding the extent of BBB opening and BBB recovery time. The mechanisms underlying BBB opening and recovery, however, are largely not understood. To investigate US-BBBD mechanisms with regard to AE, we developed an in vitro platform for monitoring both BBB integrity and AE during US-BBBD. Temporally resolved BBB integrity monitoring was achieved using a microfluidic BBB-on-a-chip device with integrated trans-endothelial electrical resistance (TEER) measurements. Well-characterized ultrasound exposure and AE monitoring were achieved using a focally aligned high-intensity focused ultrasound transducer and passive cavitation detector. In addition to recording TEER and AE data, our platform is compatible with fluorescence microscopy during ultrasound exposure, providing further insight into US-BBBD mechanisms. This work further demonstrates potential for in vitro screening of cavitation agents and/or therapeutics for novel US-BBBD applications and strategies.
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