Microbubble dynamics in brain microvessels at 1 MHz and 330 kHz driving frequencies

Blood-brain barrier (BBB) disruption using ultrasound-driven microbubbles is a promising technique to deliver drugs to the brain. This study aimed to directly observe behaviours of individual microbubbles within the brain microvasculature when exposed to pulses typical in transcranial ultrasound therapy. Low centre frequencies of 1 MHz and 330 kHz were used, at mechanical indices of 0.2-1, and pulse lengths up to 10 ms. Acute brain slices were obtained from juvenile rats, transcardially perfused with SonoVue, heparin, and dye. In each slice, a suitable bubble in a microvessel (5–15 μm diameter) was observed at both microsecond and millisecond time scales during ultrasound exposure. Oscillating microbubbles cause microvessel walls to distend and invaginate at the ultrasound driving frequency and can cause micrometre-scale tissue displacements well beyond the endothelial wall. Microbubbles can also be forced out of small microvessels due to the primary radiation force; this occurred at both frequencies tested. The probability of extravasation scales approximately with mechanical index, being rare at low pressures, but much more common at MI ≥ 0.6. Microbubble extravasation due to the primary radiation force may, therefore, be a mechanism of BBB disruption or of tissue damage. These results may aid development of safer and more effective therapies.