Safety Validation of Repeated Blood-Brain Barrier Disruption Using Focused Ultrasound.

The purpose of this study was to investigate the effects on the brain of multiple sessions of blood-brain barrier (BBB) disruption using focused ultrasound (FUS) in combination with micro-bubbles over a range of acoustic exposure levels. Six weekly sessions of FUS, using acoustical pressures between 0.66 and 0.80 MPa, were performed under magnetic resonance guidance. The success and degree of BBB disruption was estimated by signal enhancement of post-contrast T1-weighted imaging of the treated area. Histopathological analysis was performed after the last treatment. The consequences of repeated BBB disruption varied from no indications of vascular damage to signs of micro-hemorrhages, macrophage infiltration, micro-scar formations and cystic cavities. The signal enhancement on the contrast-enhanced T1-weighted imaging had limited value for predicting small-vessel damage. T2-weighted imaging corresponded well with the effects on histopathology and could be used to study treatment effects over time. This study demonstrates that repeated BBB disruption by FUS can be performed with no or limited damage to the brain tissue.

Introduction

Purpose Drug delivery with BBB opening

Study Objective To investigate the brain effects of repeated blood–brain barrier disruption using focused ultrasound with microbubbles across varying acoustic exposure levels.

Animal model / Human subject Healthy Sprague-Dawley rats, 362-490 g

Disease model Healthy

MRI or image guidance method MRI-guided

Targeted brain region(s) Hemisphere

Outcomes and Safety

Summary of Outcomes Six weekly MRI-guided FUS sessions with microbubbles successfully disrupted the BBB. While T1-weighted imaging poorly predicted small-vessel damage, T2-weighted MRI correlated well with histopathological effects, which ranged from no vascular damage to micro-hemorrhages and micro-scar formation.

Duration of biological effect 6 weeks

Safety-related matter Repeated FUS-induced BBB disruption produced variable outcomes across the tested pressures, ranging from no vascular damage to micro-hemorrhages, macrophage infiltration, micro-scar formations, and cystic cavities.

Brain Region

Ultrasound Parameters

Ultrasound instrument Single-element spherically-focused transducer

FUS Frequency 690 kHz

FUS Pressure 0.66, 0.73, and 0.80 Mpa

FUS Mode pulsed

Pulse duration 10 ms

Duration of a single FUS session 60 s

Focal Characteristics Focal length: 80 mm; Aperture size: 100 mm; Focal depth: 14 mm

Treatment frequency 6 weekly sessions

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