Abstract 19653: Therapeutic Potential of Long Ultrasound Tone Bursts in Microbubble-Ultrasound Mediated Therapeutics: Mechanistic Insights Using High Speed Imaging

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Background: Microbubble (MB)-Ultrasound (US) assisted therapy has been shown to restore perfusion in myocardial infarction (sonothrombolysis). Due to a presumption that MBs under high acoustic pressure do not persist after long acoustic cycles, most schemes of US-assisted therapy utilize a very short US pulse (a few acoustic cycles) when a high US pressure is used. However, we have recently observed enhanced in vitro sonothrombolytic effect using MBs and very long US pulses, at high acoustic pressures. We therefore sought to explore the actual fate of MBs during a long acoustic cycle exposure by visual observation of MB acoustic behaviors at varying pulse lengths. Methods: MB behaviors were optically observed during long US tone burst excitation using an ultra-high speed imaging system that allows microscopic visualization of MB cavitation. The system is capable of capturing 128 frames at up to 25 million frames per second (Mfps). Long US tone bursts (up to 5,000 acoustic cycles) at 1 MHz and various pressures (0.25, 0.5, 1.0, and 1.5 MPa) were used to study the dynamic behavior of both lipid and polymer MBs in a 200-µm diameter cellulose tubing. Results: High speed movies of the MBs during long tone burst excitation showed that MBs first underwent inertial cavitation then formed gas-filled aggregates that continued to oscillate. The locations of the aggregates were random due to the dynamic nature of MB destruction. Figure 1 shows still frames of a high speed movie (5 Mpfs) of polymer MBs 1,000 acoustic cycles into a long tone burst at 1.5 MPa: MB aggregates continued to oscillate, break up, and new aggregates were formed. Conclusion: These data show for the first time that MBs survive as aggregates that continue to oscillate with large amplitude during a long tone burst, demonstrating the therapeutic potential for US-assisted therapy. This discovery suggests that long acoustic cycles have additional therapeutic effect for MB-US assisted therapies such as sonothrombolysis.