Ultrasound insonification of microbubbles can locally enhance drug delivery, but the microbubble–cell interaction remains poorly understood. Because intracellular calcium (Cai 2+) is a key cellular regulator, unraveling the Cai 2+ fluctuations caused by an oscillating microbubble provides crucial insight into the underlying bio-effects. Therefore, we developed an optical imaging system at nanometer and nanosecond resolution that can resolve Cai 2+ fluctuations and microbubble oscillations. Using this system, we clearly distinguished three Cai 2+ uptake profiles upon sonoporation of endothelial cells, which strongly correlated with the microbubble oscillation amplitude, severity of sonoporation and opening of cell–cell contacts. We found a narrow operating range for viable drug delivery without lethal cell damage. Moreover, adjacent cells were affected by a calcium wave propagating at 15 μm/s. With the unique optical system, we unraveled the microbubble oscillation behavior required for drug delivery and Cai 2+ fluctuations, providing new insight into the microbubble–cell interaction to aid clinical translation.

Cell–cell contact opening, Confocal microscopy, Drug delivery, High-speed imaging, Intracellular calcium, Microbubbles, Sonoporation, Ultrasound
dx.doi.org/10.1016/j.ultrasmedbio.2020.03.029, hdl.handle.net/1765/126982
Ultrasound in Medicine & Biology
Department of Biomedical Engineering

Beekers, I, Mastik, F, Beurskens, R, Tang, P.Y. (Phoei Ying), Vegter, M. (Merel), van der Steen, A.F.W, … Kooiman, K. (2020). High-Resolution Imaging of Intracellular Calcium Fluctuations Caused by Oscillating Microbubbles. Ultrasound in Medicine & Biology. doi:10.1016/j.ultrasmedbio.2020.03.029