Original Contribution
High-Resolution Imaging of Intracellular Calcium Fluctuations Caused by Oscillating Microbubbles

https://doi.org/10.1016/j.ultrasmedbio.2020.03.029Get rights and content
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Abstract

Ultrasound insonification of microbubbles can locally enhance drug delivery, but the microbubble–cell interaction remains poorly understood. Because intracellular calcium (Cai2+) is a key cellular regulator, unraveling the Cai2+ 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 Cai2+ fluctuations and microbubble oscillations. Using this system, we clearly distinguished three Cai2+ 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 Cai2+ fluctuations, providing new insight into the microbubble–cell interaction to aid clinical translation.

Key Words

Drug delivery
Microbubbles
Ultrasound
Intracellular calcium
Sonoporation
Cell–cell contact opening
Confocal microscopy
High-speed imaging

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