Development of a high throughput 3D-microfluidics-based blood-brain barrier assay system as an in vitro model for ultrasound-mediated delivery of drugs into the brain

More than 90% of the drugs that enter clinical trials fail because of lack of efficacy or unexpected toxicity. This high failure rate has been partly attributed to the use of in vitro cellular assays and animal models that do not reproduce human physiology and pathology during preclinical drug development. This gap in clinical predictability in drug development is especially severe for CNS disorders, in which many therapeutics must cross the blood-brain barrier (BBB) to be effective. There has been a steady development and evaluation of drug delivery mechanisms that bypass the BBB to reach the target site in the CNS, and ultrasound (US)-mediated therapeutics extravasation has been one of such tools. However, while there have been several in vivo animal and clinical studies done on the focused US-guided BBB disruption, there have not yet been an established in vitro model in which US has been utilized to understand the BBB tight junction disruption and penetration. This project seeks to develop a microfluidics-based BBB model in order to: (1) investigate brain endothelial cell behaviour in microenvironment when stimulated by US and microbubbles; (2) establish whether US provides a means to enhance drug delivery through the BBB using the in vitro microfluidics-based assay platform; (3) investigate the stimulation of any inflammatory responses arising from ultrasound/microbubble exposure (in collaboration with NCI, Frank Lab). The work will contribute to greater understanding of interactions between US-mediated microbubble disruption of the BBB, especially benefitting the physicians working to utilize the technique in clinical settings and the researchers developing microbubbles to establish and optimize BBB drug delivery during the drug R&D pipeline.