A Single High-Intensity Shock Wave Pulse With Microbubbles Opens the Blood-Brain Barrier in Rats.
Authors: Kung Y, Huang HY, Liao WH, Huang AP, Hsiao MY, Wu CH, Liu HL, Inserra C, Chen WS
Focused extracorporeal shockwave (FSW), one kind of focused high-intensity pulsed ultrasound, has been shown to induce blood-brain barrier (BBB) opening in targeted brain areas in rat animal models with minimal detrimental effects below threshold intensity levels or iterations. In the current study, we found that the thresholds could be further reduced by the addition of microbubbles (ultrasound contrast agents or UCA; SonoVue). FSW with 2 × 10<sup>6</sup> MBs/kg of UCA (20% of clinical dosage) at an intensity level of 0.1 (peak positive pressure 5.4 MPa; peak negative pressure -4.2 MPa; energy flux density 0.03 mJ/mm<sup>2</sup>) resulting in a 100% BBB opening rate without detectable hemorrhage or apoptosis in the brain. Significantly reduced free radical production was found compared with 0.5 MHz focused ultrasound at a peak negative pressure of 0.44 MPa (1% duty cycle and 4 × 10<sup>7</sup> MBs/kg of UCA). FSW devices offer advantages of commercial availability and high safety, and thus may facilitate future research and applications of focal BBB opening for oncological and pharmacological purposes.
Introduction
Purpose
Drug delivery with BBB opening
Study Objective
To develop and test strategies—specifically adding microbubbles—to reduce the thresholds and improve the safety margin of focused extracorporeal shockwave-induced blood–brain barrier opening in the brain.
Animal model / Human subject
Rat; strain not specified; age not specified; sex not specified
Disease model
Healthy
Outcomes and Safety
Summary of Outcomes
Single-pulse FSW with intravenous microbubbles (SonoVue) at 2×10^6 MBs/kg (1/5 clinical dose) and intensity level 0.1 (P+ 5.4 MPa, P- −4.2 MPa, EFD 0.03 mJ/mm2) produced 100% focal BBB opening with minimal hemorrhage/apoptosis and an opening duration of ~1 hour; FSW without UCA required much higher intensity (intensity level 20; P+ 77.7 MPa, P- −18.7 MPa, EFD 0.82 mJ/mm2) to achieve ~60% BBB opening and caused visible bleeding. Lower UCA doses yielded intermediate success rates (1/2 CD: 100% but more bleeding; 1/10 CD: 40%; 1/100 CD: 20%), and single-pulse FSW generated fewer free radicals than 0.5 MHz HIPU, indicating reduced oxidative injury.
Duration of biological effect
1 ms
Safety-related matter
At the selected safe threshold (single FSW pulse, intensity level 0.1, with 1/5 clinical UCA dose = 2×10^6 MBs/kg) the authors achieved 100% BBB opening with no detectable hemorrhage or apoptosis and only a 0.15% chance of very slight visible bleeding or vessel breakage. Higher UCA concentrations or high-intensity FSW without UCA produced red blood cell extravasation, vessel breakage, light apoptosis and visible bleeding, but FSW induced negligible thermal injury and generated significantly fewer free radicals than HIPU.
Brain Region
Ultrasound Parameters
FUS Frequency
0.5 MHz
FUS Pressure
5.4 MPa; -4.2 MPa; 0.44 MPa
FUS Mode
pulsed
Focal Characteristics
focal depth: None; focal length: None; aperture size: None
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