Enhanced microbubble contrast agent oscillation following 250 kHz insonation

Abstract Microbubble contrast agents are widely used in ultrasound imaging and therapy, typically with transmission center frequencies in the MHz range. Currently, an ultrasound center frequency near 250 kHz is proposed for clinical trials in which ultrasound combined with microbubble contrast agent...

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Autores principales:	Tali Ilovitsh, Asaf Ilovitsh, Josquin Foiret, Charles F. Caskey, Jiro Kusunose, Brett Z. Fite, Hua Zhang, Lisa M. Mahakian, Sarah Tam, Kim Butts-Pauly, Shengping Qin, Katherine W. Ferrara
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Microbubbles (MBs) Inertial Cavitation Stable Cavitation Marmottant Model Expansion Ratio Medicine R Science Q
Acceso en línea:	https://doaj.org/article/19ed9eca82bc4b5cb7a1622cc7c40e6a
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spelling	oai:doaj.org-article:19ed9eca82bc4b5cb7a1622cc7c40e6a2021-12-02T15:07:51ZEnhanced microbubble contrast agent oscillation following 250 kHz insonation10.1038/s41598-018-34494-52045-2322https://doaj.org/article/19ed9eca82bc4b5cb7a1622cc7c40e6a2018-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-34494-5https://doaj.org/toc/2045-2322Abstract Microbubble contrast agents are widely used in ultrasound imaging and therapy, typically with transmission center frequencies in the MHz range. Currently, an ultrasound center frequency near 250 kHz is proposed for clinical trials in which ultrasound combined with microbubble contrast agents is applied to open the blood brain barrier, since at this low frequency focusing through the human skull to a predetermined location can be performed with reduced distortion and attenuation compared to higher frequencies. However, the microbubble vibrational response has not yet been carefully evaluated at this low frequency (an order of magnitude below the resonance frequency of these contrast agents). In the past, it was assumed that encapsulated microbubble expansion is maximized near the resonance frequency and monotonically decreases with decreasing frequency. Our results indicated that microbubble expansion was enhanced for 250 kHz transmission as compared with the 1 MHz center frequency. Following 250 kHz insonation, microbubble expansion increased nonlinearly with increasing ultrasonic pressure, and was accurately predicted by either the modified Rayleigh–Plesset equation for a clean bubble or the Marmottant model of a lipid-shelled microbubble. The expansion ratio reached 30-fold with 250 kHz at a peak negative pressure of 400 kPa, as compared to a measured expansion ratio of 1.6 fold for 1 MHz transmission at a similar peak negative pressure. Further, the range of peak negative pressure yielding stable cavitation in vitro was narrow (~100 kPa) for the 250 kHz transmission frequency. Blood brain barrier opening using in vivo transcranial ultrasound in mice followed the same trend as the in vitro experiments, and the pressure range for safe and effective treatment was 75–150 kPa. For pressures above 150 kPa, inertial cavitation and hemorrhage occurred. Therefore, we conclude that (1) at this low frequency, and for the large oscillations, lipid-shelled microbubbles can be approximately modeled as clean gas microbubbles and (2) the development of safe and successful protocols for therapeutic delivery to the brain utilizing 250 kHz or a similar center frequency requires consideration of the narrow pressure window between stable and inertial cavitation.Tali IlovitshAsaf IlovitshJosquin FoiretCharles F. CaskeyJiro KusunoseBrett Z. FiteHua ZhangLisa M. MahakianSarah TamKim Butts-PaulyShengping QinKatherine W. FerraraNature PortfolioarticleMicrobubbles (MBs)Inertial CavitationStable CavitationMarmottant ModelExpansion RatioMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-15 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbubbles (MBs) Inertial Cavitation Stable Cavitation Marmottant Model Expansion Ratio Medicine R Science Q
spellingShingle	Microbubbles (MBs) Inertial Cavitation Stable Cavitation Marmottant Model Expansion Ratio Medicine R Science Q Tali Ilovitsh Asaf Ilovitsh Josquin Foiret Charles F. Caskey Jiro Kusunose Brett Z. Fite Hua Zhang Lisa M. Mahakian Sarah Tam Kim Butts-Pauly Shengping Qin Katherine W. Ferrara Enhanced microbubble contrast agent oscillation following 250 kHz insonation
description	Abstract Microbubble contrast agents are widely used in ultrasound imaging and therapy, typically with transmission center frequencies in the MHz range. Currently, an ultrasound center frequency near 250 kHz is proposed for clinical trials in which ultrasound combined with microbubble contrast agents is applied to open the blood brain barrier, since at this low frequency focusing through the human skull to a predetermined location can be performed with reduced distortion and attenuation compared to higher frequencies. However, the microbubble vibrational response has not yet been carefully evaluated at this low frequency (an order of magnitude below the resonance frequency of these contrast agents). In the past, it was assumed that encapsulated microbubble expansion is maximized near the resonance frequency and monotonically decreases with decreasing frequency. Our results indicated that microbubble expansion was enhanced for 250 kHz transmission as compared with the 1 MHz center frequency. Following 250 kHz insonation, microbubble expansion increased nonlinearly with increasing ultrasonic pressure, and was accurately predicted by either the modified Rayleigh–Plesset equation for a clean bubble or the Marmottant model of a lipid-shelled microbubble. The expansion ratio reached 30-fold with 250 kHz at a peak negative pressure of 400 kPa, as compared to a measured expansion ratio of 1.6 fold for 1 MHz transmission at a similar peak negative pressure. Further, the range of peak negative pressure yielding stable cavitation in vitro was narrow (~100 kPa) for the 250 kHz transmission frequency. Blood brain barrier opening using in vivo transcranial ultrasound in mice followed the same trend as the in vitro experiments, and the pressure range for safe and effective treatment was 75–150 kPa. For pressures above 150 kPa, inertial cavitation and hemorrhage occurred. Therefore, we conclude that (1) at this low frequency, and for the large oscillations, lipid-shelled microbubbles can be approximately modeled as clean gas microbubbles and (2) the development of safe and successful protocols for therapeutic delivery to the brain utilizing 250 kHz or a similar center frequency requires consideration of the narrow pressure window between stable and inertial cavitation.
format	article
author	Tali Ilovitsh Asaf Ilovitsh Josquin Foiret Charles F. Caskey Jiro Kusunose Brett Z. Fite Hua Zhang Lisa M. Mahakian Sarah Tam Kim Butts-Pauly Shengping Qin Katherine W. Ferrara
author_facet	Tali Ilovitsh Asaf Ilovitsh Josquin Foiret Charles F. Caskey Jiro Kusunose Brett Z. Fite Hua Zhang Lisa M. Mahakian Sarah Tam Kim Butts-Pauly Shengping Qin Katherine W. Ferrara
author_sort	Tali Ilovitsh
title	Enhanced microbubble contrast agent oscillation following 250 kHz insonation
title_short	Enhanced microbubble contrast agent oscillation following 250 kHz insonation
title_full	Enhanced microbubble contrast agent oscillation following 250 kHz insonation
title_fullStr	Enhanced microbubble contrast agent oscillation following 250 kHz insonation
title_full_unstemmed	Enhanced microbubble contrast agent oscillation following 250 kHz insonation
title_sort	enhanced microbubble contrast agent oscillation following 250 khz insonation
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/19ed9eca82bc4b5cb7a1622cc7c40e6a
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_version_	1718388368957505536

Enhanced microbubble contrast agent oscillation following 250 kHz insonation

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