Ultrafast Microscopy Imaging of Acoustic Cluster Therapy Bubbles: Activation and Oscillation.

Acoustic Cluster Therapy (ACT®) is a platform for improving drug delivery and has had promising pre-clinical results. A clinical trial is ongoing. ACT® is based on microclusters of microbubbles-microdroplets that, when sonicated, form a large ACT® bubble. The aim of this study was to obtain new knowledge on the dynamic formation and oscillations of ACT® bubbles by ultrafast optical imaging in a microchannel. The high-speed recordings revealed the microbubble-microdroplet fusion, and the gas in the microbubble acted as a vaporization seed for the microdroplet. Subsequently, the bubble grew by gas diffusion from the surrounding medium and became a large ACT® bubble with a diameter of 5-50 μm. A second ultrasound exposure at lower frequency caused the ACT® bubble to oscillate. The recorded oscillations were compared with simulations using the modified Rayleigh-Plesset equation. A term accounting for the physical boundary imposed by the microchannel wall was included. The recorded oscillation amplitudes were approximately 1-2 µm, hence similar to oscillations of smaller contrast agent microbubbles. These findings, together with our previously reported promising pre-clinical therapeutic results, suggest that these oscillations covering a large part of the vessel wall because of the large bubble volume can substantially improve therapeutic outcome.