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

Inés Beekers*, Frits Mastik, Robert Beurskens, Phoei Ying Tang, Merel Vegter, Antonius F.W. van der Steen, Nico de Jong, Martin D. Verweij, Klazina Kooiman

*Corresponding author for this work

Research output: Contribution to journalArticleScientificpeer-review

22 Citations (Scopus)
68 Downloads (Pure)

Abstract

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.

Original languageEnglish
Pages (from-to)2017-2029
Number of pages13
JournalUltrasound in Medicine and Biology
Volume46
Issue number8
DOIs
Publication statusPublished - 2020

Keywords

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

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