Objective
The ultrasound-mediated blood–brain barrier (BBB) opening with microbubbles has been
widely employed, while recent studies also indicate the possibility that ultrasound
alone can open the BBB through a direct mechanical effect. However, the exact mechanisms
through which ultrasound interacts with the BBB and whether it can directly trigger
intracellular signaling and a permeability change in the BBB endothelium remain unclear.
Methods
Vertically deployed surface acoustic waves (VD-SAWs) were applied on a human cerebral
microvascular endothelial cell line (hCMEC/D3) monolayer using a 33-MHz interdigital
transducer that exerts shear stress-predominant stimulation. The intracellular calcium
response was measured by fluorescence imaging, and the permeability of the hCMEC/D3
monolayer was assessed by transendothelial electrical resistance (TEER).
Discussion
At a certain intensity threshold, VD-SAWs induced an intracellular calcium surge that
propagated to adjacent cells as intercellular calcium waves. VD-SAWs induced a TEER
decrease in a pulse repetition frequency-dependent manner, thereby suggesting possible
involvement of the mechanosensitive ion channels.
Conclusion
The unique VD-SAW system enables more physiological mechanical stimulation of the
endothelium monolayer. Moreover, it can be easily combined with other measurement
devices, providing a useful platform for further mechanistic studies on ultrasound-mediated
BBB opening.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Ultrasound in Medicine and BiologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Ultrasound neuromodulation: a review of results, mechanisms and safety.Ultrasound Med Biol. 2019; 45: 1509-1536
- Targeted delivery of doxorubicin to the rat brain at therapeutic levels using MRI-guided focused ultrasound.Int J Cancer. 2007; 121: 901-907
- Noninvasive MR imaging-guided focal opening of the blood–brain barrier in rabbits.Radiology. 2001; 220: 640-646
- Blood–brain barrier disruption induced by focused ultrasound and circulating preformed microbubbles appears to be characterized by the mechanical index.Ultrasound Med Biol. 2008; 34: 834-840
- Concurrent blood–brain barrier opening and local drug delivery using drug-carrying microbubbles and focused ultrasound for brain glioma treatment.Biomaterials. 2012; 33: 704-712
- Novel focused ultrasound gene therapy approach noninvasively restores dopaminergic neuron function in a rat Parkinson's disease model.Nano Lett. 2017; 17: 3533-3542
- Focused ultrasound-induced blood–brain barrier opening enhanced vascular permeability for GDNF delivery in Huntington's disease mouse model.Brain Stimul. 2019; 12: 1143-1150
- Non-invasive, neuron-specific gene therapy by focused ultrasound-induced blood–brain barrier opening in Parkinson's disease mouse model.J Control Release. 2016; 235: 72-81
- Cellular mechanisms of the blood–brain barrier opening induced by ultrasound in presence of microbubbles.Ultrasound Med Biol. 2004; 30: 979-989
- Local and reversible blood–brain barrier disruption by noninvasive focused ultrasound at frequencies suitable for trans-skull sonications.Neuroimage. 2005; 24: 12-20
- Brain arterioles show more active vesicular transport of blood-borne tracer molecules than capillaries and venules after focused ultrasound-evoked opening of the blood–brain barrier.Ultrasound Med Biol. 2006; 32: 1399-1409
- Effect of focused ultrasound applied with an ultrasound contrast agent on the tight junctional integrity of the brain microvascular endothelium.Ultrasound Med Biol. 2008; 34: 1093-1104
- Blood–neural barrier: its diversity and coordinated cell-to-cell communication.BMB Rep. 2008; 41: 345-352
- Looking at the blood–brain barrier: molecular anatomy and possible investigation approaches.Brain Res Rev. 2010; 64: 328-363
- Mechanism of low-frequency ultrasound in opening blood–tumor barrier by tight junction.J Mol Neurosci. 2011; 43: 364-369
- Focused ultrasound-mediated BBB disruption is associated with an increase in activation of AKT: experimental study in rats.BMC Neurol. 2010; 10: 114
- A role for Ca(2+)-conducting ion channels in mechanically-induced signal transduction of airway epithelial cells.J Cell Sci. 1994; 107: 3037-3044
- Mechanical stimulation induces intercellular calcium signaling in bovine aortic endothelial cells.Am J Physiol. 1993; 264: H2094-H2102
- Mechanically induced intercellular calcium communication in confined endothelial structures.Biomaterials. 2013; 34: 2049-2056
- Intercellular propagation of calcium waves mediated by inositol trisphosphate.Science. 1992; 258: 292-295
- Thrombin inhibits intercellular calcium wave propagation in corneal endothelial cells by modulation of hemichannels and gap junctions.Invest Ophthalmol Vis Sci. 2007; 48: 120-133
- An intercellular regenerative calcium wave in porcine coronary artery endothelial cells in primary culture.J Physiol. 1998; 513: 103-116
- Investigating contactless high frequency ultrasound microbeam stimulation for determination of invasion potential of breast cancer cells.Biotechnol Bioeng. 2013; 110: 2697-2705
- Ca2+ signaling, TRP channels, and endothelial permeability.Microcirculation. 2006; 13: 693-708
- Dual regulation of endothelial junctional permeability.Sci STKE. 2007; 2007: re8
- Regulation of endothelial junctional permeability.Ann NY Acad Sci. 2008; 1123: 134-145
- Protein kinase signaling in the modulation of microvascular permeability.Vascul Pharmacol. 2002; 39: 213-223
- Utilizing ultrasound to transiently increase blood–brain barrier permeability, modulate of the tight junction proteins, and alter cytoskeletal structure.Curr Neurovasc Res. 2015; 12: 375-383
- Focused shockwave induced blood–brain barrier opening and transfection.Sci Rep. 2018; 8: 2218
- Mechanically activated ion channels.Neuron. 2015; 87: 1162-1179
- Mechanosensitive channels: what can they do and how do they do it?.Structure. 2011; 19: 1356-1369
- Sonothermogenetics for noninvasive and cell-type specific deep brain neuromodulation.Brain Stimul. 2021; 14: 790-800
- The mechanosensitive ion channel piezo1 significantly mediates in vitro ultrasonic stimulation of neurons.iScience. 2019; 21: 448-457
- Optimal pulse length of insonification for Piezo1 activation and intracellular calcium response.Sci Rep. 2021; 11: 709
- Activation of Piezo1 mechanosensitive ion channel in HEK293T cells by 30MHz vertically deployed surface acoustic waves.Biochem Biophys Res Commun. 2019; 518: 541-547
- Potential adverse ultrasound-related biological effects: a critical review.Anesthesiology. 2011; 115: 1109-1124
- Cell membrane deformation and bioeffects produced by tandem bubble-induced jetting flow.Proc Natl Acad Sci USA. 2015; 112: E7039-E7047
- Mechanically induced integrin ligation mediates intracellular calcium signaling with single pulsating cavitation bubbles.Theranostics. 2021; 11: 6090-6104
- TEER measurement techniques for in vitro barrier model systems.J Lab Autom. 2015; 20: 107-126
- The human brain endothelial cell line hCMEC/D3 as a human blood–brain barrier model for drug transport studies.J Neurochem. 2008; 107: 1358-1368
- Immortalized human brain endothelial cell line HCMEC/D3 as a model of the blood–brain barrier facilitates in vitro studies of central nervous system infection by Cryptococcus neoformans.Eukaryot Cell. 2009; 8: 1803-1807
- The hCMEC/D3 cell line as a model of the human blood brain barrier.Fluids Barriers CNS. 2013; 10: 16
- Blood–brain barrier-specific properties of a human adult brain endothelial cell line.FASEB J. 2005; 19: 1872-1874
- Intercellular Ca2+ waves: mechanisms and function.Physiol Rev. 2012; 92: 1359-1392
- Calcium signalling: dynamics, homeostasis and remodelling.Nat Rev Mol Cell Biol. 2003; 4: 517-529
- Intercellular calcium signaling mediated by point-source burst release of ATP.Proc Natl Acad Sci USA. 2002; 99: 9840-9845
- Volume flow and wall shear stress quantification in the human conjunctival capillaries and post-capillary venules in vivo.Biorheology. 2007; 44: 375-386
- Characterization of the dynamic activities of a population of microbubbles driven by pulsed ultrasound exposure in sonoporation.Ultrasound Med Biol. 2014; 40: 1260-1272
- Cavitation microstreaming and stress fields created by microbubbles.Ultrasonics. 2010; 50: 273-279
- Acoustic cavitation.Phys Rep. 1980; 61: 159-251
- Dynamics and mechanisms of intracellular calcium waves elicited by tandem bubble-induced jetting flow.Proc Natl Acad Sci USA. 2018; 115: E353-E362
- Calcium-induced calcium release.Curr Biol. 2003; 13: R425
- Ion channels in endothelial responses to fluid shear stress.Physiology (Bethesda). 2016; 31: 359-369
- Endothelial cation channel PIEZO1 controls blood pressure by mediating flow-induced ATP release.J Clin Invest. 2016; 126: 4527-4536
- Calcium signaling.Cell. 2007; 131: 1047-1058
- Transduction of repetitive mechanical stimuli by Piezo1 and Piezo2 ion channels.Cell Rep. 2017; 19: 2572-2585
- The role of thermosensitive ion channels in mammalian thermoregulation.Adv Exp Med Biol. 2021; 1349: 355-370
- Ion channels and thermosensitivity: TRP, TREK, or both?.Int J Mol Sci. 2019; 20: 2371
- Barrier function of epithelia.Am J Physiol. 1981; 241: G275-G288
Article info
Publication history
Published online: February 08, 2023
Accepted:
December 29,
2022
Received in revised form:
November 28,
2022
Received:
August 12,
2022
Identification
Copyright
© 2022 World Federation for Ultrasound in Medicine & Biology. All rights reserved.
