Microbubble dynamics in brain microvessels

Abstract

ABSTRACTBackgroundFocused ultrasound stimulation of microbubbles is being tested in clinical trials for its ability to deliver drugs across the blood-brain barrier (BBB). This technique has the potential to treat neurological diseases by preferentially delivering drugs to targeted regions. Yet despite its potential, the physical mechanisms by which microbubbles alter the BBB permeability remain unclear, as direct observations of microbubbles oscillating in cerebral capillaries have never been previously recorded.The purpose of this study was to reveal how microbubbles respond to ultrasound when within the microvessels of living brain tissue.MethodsMicrobubbles in acute brain slices acquired from juvenile rats perfused with a concentrated solution of SonoVue® and dye were exposed to ultrasound pulses typically used in BBB disruption (center frequency: 1 MHz, peak-negative pressure: 0.2–1 MPa, pulse length: up to 10 ms) and observed using high-speed microscopy at up to 10 million frames per second.ResultsWe observed that microbubbles can exert mechanical stresses on a wide region of tissue beyond their initial location and immediate surroundings. A single microbubble can apply mechanical stress to parenchymal tissues several micrometers away from the vessel. Microbubbles can travel at high velocities within the microvessels, extending their influence across tens of micrometers during a single pulse. With longer pulses and higher pressures, microbubbles could penetrate the vessel wall and move through the parenchyma, refuting a previous assumption that microbubbles are confined to vessels. The probability of extravasation scales approximately with mechanical index, being rare at low pressures, but much more common at a mechanical index ≥ 0.6.ConclusionsThese observations provide important insight into microbubble dynamics in microvessels, and are critical leads into ultimately identifying the microbubble activities that lead to both safe drug delivery and into activities we seek to avoid, such as petechiae and other bioeffects.