Real-Time Optical and Acoustic Characterization of Phase-Shift Droplets for Drug-Delivery Applications

Phase-shift droplets undergoing acoustic droplet vaporization (ADV) offer a promising approach for ultrasound-mediated drug delivery, enabling the spatiotemporally controlled release of therapeutic payloads. A comprehensive understanding of their behavior, through both optical and acoustic methods, is essential for optimizing the therapeutic efficacy. In this study, we investigated the effects of driving pressure, pulse duration, and bulk boiling point of perfluorocarbon droplets on ADV dynamics, payload release, and acoustic emissions. We employed ultra-high-speed brightfield [10 million frames per second (Mfps)], fluorescence (2 Mfps), and confocal microscopy (1 fps) to capture ADV and real-time payload release in fibrin-based hydrogels. During ADV, payload release velocities reached 2-4 m/s, slowing to 0.6-2.7 μm/s post ultrasound. While the cycle number and pressure affected early bubble expansion and acoustic output, long-term bubble behavior and release kinetics were governed by the droplet's thermophysical properties. Ultra-high-speed imaging revealed a direct coupling between bubble dynamics and payload release during ultrasound exposure, with release continuing via diffusion after ultrasound. Notably, payload release rates post-ultrasound exceeded bubble growth rates. Additionally, acoustic emissions, recorded via passive cavitation detection, increased with both pressure and pulse number but decreased in droplets with higher bulk boiling points. These findings underscore the importance of integrating multimodal imaging methods to elucidate ADV mechanisms and design effective hydrogel-based drug-delivery systems.