The introduction of microbubbles in focused ultrasound therapies has enabled a diverse range of non-invasive technologies: sonoporation to deliver drugs into cells, sonothrombolysis to dissolve blood clots, and blood-brain barrier opening to deliver drugs into the brain. Current methods for passively monitoring the microbubble dynamics responsible for these therapeutic effects can identify the cavitation position by passive acoustic mapping and cavitation mode by spectral analysis. Here, we introduce a new feature that can be monitored: microbubble effective velocity. Previous studies have shown that echoes from short imaging pulses had a Doppler shift that was produced by the movement of microbubbles. Therapeutic pulses are longer (>1,000 cycles) and thus produce a larger alteration of microbubble distribution due to primary and secondary acoustic radiation force effects which cannot be monitored using pulse-echo techniques. In our experiments, we captured and analysed the Doppler shift during long therapeutic pulses using a passive cavitation detector. A population of microbubbles (5×104-5×107 microbubbles ml-1) was embedded in a vessel (inner diameter: 4mm) and sonicated using a 0.5 megahertz focused ultrasound transducer (peak-rarefactional pressure: 75-366 kPa, pulse length: 50,000 cycles or 100 milliseconds) within a water tank. Microbubble acoustic emissions were captured with a coaxially aligned 7.5 megahertz passive cavitation detector and spectrally analysed to measure the Doppler shift for multiple harmonics above the 10th harmonic (i.e., superharmonics). A Doppler shift was observed on the order of tens of kilohertz with respect to the primary superharmonic peak and is due to the axial movement of the microbubbles. The position, amplitude and width of the Doppler peaks depended on the acoustic pressure and the microbubble concentration. Higher pressures increased the effective velocity of the microbubbles up to 3m/s, prior to the onset of broadband emission, which is an indicator for high magnitude inertial cavitation. Although the microbubble redistribution was shown to persist for the entire sonication period in dense populations, it was constrained to the first few milliseconds in lower concentrations. In conclusion, superharmonic microbubble Doppler effects can provide a quantitative measure of effective velocities of a sonicated microbubble population and could be used for monitoring ultrasound therapy in real-time.
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