Ultrasound-mediated blood-brain barrier disruption: Correlation with acoustic emissions

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.

The Role of Ultrasound-Driven Microbubble Dynamics in Drug Delivery: From Microbubble Fundamentals to Clinical Translation

“…MRI has been widely used to monitor blood-brain barrier opening, with the aid of MR contrast agents 97,165,[168][169][170] . This has proven that even the tight-junctions that make up the blood-brain barrier can be opened by microbubble-assisted ultrasound treatment, giving this approach a unique opportunity to channel drugs into the cerebral fluids across this otherwise impermeable barrier 68,161,[171][172][173] . A more detailed analysis of the physiological effects and drug uptake in different organs can be obtained via histology and immunohistochemistry.…”

“…To increase the knowledge of microbubble-assisted drug delivery in vivo, methods to estimate the tissue distribution of the drug in small animals have been described, either on the entire animal using near-infrared fluorescence imaging , or by harvesting the organs and extracting the drug separately . MRI has been widely used to monitor the blood–brain barrier opening, with the aid of MR contrast agents. ,,− This has proven that even the tight junctions that make up the blood–brain barrier can be opened by microbubble-assisted ultrasound treatment, giving this approach a unique opportunity to channel drugs into the cerebral fluids across this otherwise impermeable barrier. ,,− A more detailed analysis of the physiological effects and drug uptake in different organs can be obtained via histology and immunohistochemistry. Using this approach, positive results have been obtained for numerous microbubble–drug formulations and ultrasound in comparison to the delivery of drugs or nanoparticles alone. ,,,− Nevertheless, a number of adverse effects have also been reported, including hemorrhage, ,, local burns, necrosis due to vascular shut down, the formation of thrombi, , and drug accumulation in the lungs, liver, and kidneys.…”

Opening doors with ultrasound and microbubbles: Beating biological barriers to promote drug delivery

“…Ultrasound has shown tremendous potential for the temporal opening of the BBB and allows the extravasation of (chemo)therapeutics leading to significantly enhancing the bioavailability of therapeutics in the brain [6,152,[240][241][242]. The concept is very appealing as it can stimulate drug delivery to the brain in a noninvasive, non-surgical way [243].…”