Microbubble gas volume: A unifying dose parameter in blood-brain barrier disruption by focused ultrasound

Abstract

Focused ultrasound with microbubbles is being developed to transiently, locally and noninvasively disrupt the blood-brain barrier (BBB) for improved pharmaceutical delivery. Prior work has demonstrated that, for a given concentration dose, microbubble size affects both the intravascular circulation persistence and extent of BBB opening. In this study, we independently measured the effects of microbubble size (2 vs. 6 μm diameter) and concentration, covering a range of overlapping gas volume doses (1–40 μL/kg). We first demonstrated precise targeting and a linear dose-response of Evans Blue dye extravasation to the rat striatum for a set of constant microbubble and ultrasound parameters. We found that dye extravasation increased linearly with gas volume dose, with data points from both microbubble sizes collapsing to a single line. A linear trend was observed for both the initial sonication and a second sonication on the contralateral side. Based on these results, we conclude that microbubble gas volume dose, not size, determines the extent of BBB opening by focused ultrasound (1 MHz, ~0.5 MPa at the focus). Finally, using optimal parameters determined for Evan blue, we demonstrated gene delivery and expression using a viral vector one week after BBB disruption.