TY - JOUR
T1 - High-Resolution Imaging of Intracellular Calcium Fluctuations Caused by Oscillating Microbubbles
AU - Beekers, Inés
AU - Mastik, Frits
AU - Beurskens, Robert
AU - Tang, Phoei Ying
AU - Vegter, Merel
AU - van der Steen, Antonius F.W.
AU - de Jong, Nico
AU - Verweij, Martin D.
AU - Kooiman, Klazina
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - Cell–cell contact opening
KW - Confocal microscopy
KW - Drug delivery
KW - High-speed imaging
KW - Intracellular calcium
KW - Microbubbles
KW - Sonoporation
KW - Ultrasound
UR - http://www.scopus.com/inward/record.url?scp=85084515344&partnerID=8YFLogxK
U2 - 10.1016/j.ultrasmedbio.2020.03.029
DO - 10.1016/j.ultrasmedbio.2020.03.029
M3 - Article
SN - 0301-5629
VL - 46
SP - 2017
EP - 2029
JO - Ultrasound in Medicine and Biology
JF - Ultrasound in Medicine and Biology
IS - 8
ER -