Exploiting flow to control the in vitro spatiotemporal distribution of microbubble-seeded acoustic cavitation activity in ultrasound therapy

Focused ultrasound and microbubbles have been extensively used to generate therapeutic bioeffects. Despite encouraging in vivo results, there remains poor control of the magnitude and spatial distribution of these bioeffects due to the limited ability of conventional pulse shapes and sequences to control cavitation dynamics. Thus current techniques are restricted by an efficacy-safety trade-off. The primary aim of the present study was to incorporate the presence of flow in the design of new short pulse sequences, which can more uniformly distribute the cavitation activity. Microbubbles flowing (fluid velocity: 10 mm s(-1)) through a 300 μm tube were sonicated with a focused 0.5 MHz transducer while acoustic emissions were captured with an inserted focused 7.5 MHz passive cavitation detector. The two foci were co-axially aligned and their focal points were overlapped. Whereas conventional sequences are composed of a long burst (>10,000 cycles) emitted at a low burst repetition frequency (<10 Hz), we decomposed this burst into short pulses by adding intervals to facilitate inter-pulse microbubble movement. To evaluate how this sequence influenced cavitation distribution, we emitted short pulses (peak-rarefactional pressure (PRP): 40-366 kPa, pulse length (PL): 5-25 cycles) at high pulse repetition frequencies (PRF: 0.625-10 kHz) for a burst length of 100 ms. Increased cavitation persistence, implied by the duration of the microbubble acoustic emissions, was a measure of improved distribution due to the presence of flow. Sonication at lower acoustic pressures, longer pulse intervals and lower PLs improved the spatial distribution of cavitation. Furthermore, spectral analysis of the microbubble emissions revealed that the improvement at low pressures is due to persisting stable cavitation. In conclusion, new short-pulse sequences were shown to improve spatiotemporal control of acoustic cavitation dynamics during physiologically relevant flow. This could lead to adjustable distribution of the generated in vivo bioeffect and therefore efficient and safe treatment of a wide range of pathologies.