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

Research output: Contribution to journalArticleScientificpeer-review

7 Citations (Scopus)
13 Downloads (Pure)


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
Issue number8
Publication statusPublished - 2020


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

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