The Size of Blood–Brain Barrier Opening Induced by Focused Ultrasound is Dictated by the Acoustic Pressure

TLDR

Focused ultrasound combined with microbubbles has been used to deliver therapeutic agents across the blood–brain barrier. This study investigates whether the size of the BBB opening, defined by the largest permeable molecule, can be regulated by acoustic pressure through cavitation mechanisms. The authors applied FUS to the mouse hippocampus with systemically injected microbubbles, delivered fluorescent dextrans ranging from 3 to 2000 kDa, assessed ex vivo fluorescence, and monitored cavitation activity. They found that BBB opening size increased with pressure—from <3 kDa at 0.31 MPa to 70 kDa at 0.51 MPa and 2000 kDa at 0.84 MPa—stable cavitation produced smaller openings, while inertial cavitation produced larger openings, confirming pressure‑controlled opening size predicted by cavitation detection.

Abstract

Focused ultrasound (FUS) in combination with microbubbles (MBs) has been successfully used in the delivery of various-size therapeutic agents across the blood–brain barrier (BBB). This study revealed that FUS-induced BBB opening size, defined by the size of the largest molecule that can permeate through the BBB, can be controlled by the acoustic pressure as dictated by cavitational mechanisms. Focused ultrasound was applied onto the mouse hippocampus in the presence of systemically administered MBs for trans-BBB delivery of fluorescently labeled dextrans with molecular weights 3 to 2,000 kDa (hydrodynamic diameter: 2.3 to 54.4 nm). The dextran delivery outcomes were evaluated using ex vivo fluorescence imaging. Cavitation detection was employed to monitor the MB cavitation activity associated with the delivery of these agents. It was found that the BBB opening size was smaller than 3 kDa (2.3 nm) at 0.31 MPa, up to 70 kDa (10.2 nm) at 0.51 MPa, and up to 2,000 kDa (54.4 nm) at 0.84 MPa. Relatively smaller opening size (up to 70 kDa) was achieved with stable cavitation only; however, inertial cavitation was associated with relatively larger BBB opening size (above 500 kDa). These findings indicate that the BBB opening size can be controlled by the acoustic pressure and predicted using cavitation detection.