Diameter-dependent assessment of microvascular leakage following ultrasound-mediated blood-brain barrier opening

Sharon Katz; Roni Gattegno; Lea Peko; Romario Zarik; Yulie Hagani; Tali Ilovitsh

doi:10.1016/j.isci.2023.106965

Diameter-dependent assessment of microvascular leakage following ultrasound-mediated blood-brain barrier opening

Sharon Katz, Roni Gattegno, Lea Peko, Romario Zarik, Yulie Hagani, Tali Ilovitsh

Tel Aviv University

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

Blood brain barrier disruption (BBBD) using focused ultrasound (FUS) and microbubbles (MB) is an effective tool for therapeutic delivery to the brain. BBBD depends to a great extent on MB oscillations. Because the brain vasculature is heterogenic in diameter, reduced MB oscillations in smaller blood vessels, together with a lower number of MBs in capillaries, can lead to variations in BBBD. Therefore, evaluating the impact of microvasculature diameter on BBBD is of great importance. We present a method to characterize molecules extravasation following FUS-mediated BBBD, at a single blood vessel resolution. Evans blue (EB) leakage was used as marker for BBBD, whereas blood vessels localization was done using FITC labeled Dextran. Automated image processing pipeline was developed to quantify the extent of extravasation as function of microvasculature diameter, including a wide range of vascular morphological parameters. Variations in MB vibrational response were observed in blood vessel mimicking fibers with varied diameters. Higher peak negative pressures (PNP) were required to initiate stable cavitation in fibers with smaller diameters. In vivo in the treated brains, EB extravasation increased as a function of blood vessel diameter. The percentage of strong BBBD blood vessels increased from 9.75% for 2–3 μm blood vessels to 91.67% for 9–10 μm. Using this method, it is possible to conduct a diameter-dependent analysis that measures vascular leakage resulting from FUS-mediated BBBD at a single blood vessel resolution.

Original language	English
Article number	106965
Journal	iScience
Volume	26
Issue number	6
DOIs	https://doi.org/10.1016/j.isci.2023.106965
State	Published - 16 Jun 2023
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2023 The Author(s)

Funding

This work was supported by funding from Insightec Ltd ., the Israel Science Foundation (grant numbers 192/22 and 3450/20 ), the Israel Ministry of Science & Technology (grant number 101716 ), an ERC StG grant no. 101041118 (NanoBubbleBrain), a Zimin Institute grant, and was partially supported by a grant from the Nicholas and Elizabeth Slezak Super Center for Cardiac Research and Biomedical Engineering at Tel Aviv University . This work was supported by funding from Insightec Ltd. the Israel Science Foundation (grant numbers 192/22 and 3450/20), the Israel Ministry of Science & Technology (grant number 101716), an ERC StG grant no. 101041118 (NanoBubbleBrain), a Zimin Institute grant, and was partially supported by a grant from the Nicholas and Elizabeth Slezak Super Center for Cardiac Research and Biomedical Engineering at Tel Aviv University. S.K. designed and performed all the research and wrote the paper. R.G. L.P. R.Z. and Y.H. assisted with the in vivo experiments, microscopy, and image processing. T.I. advised and designed the research and wrote the paper. All authors have approved the final version of this manuscript. The authors have declared that no competing interest exists.

Funders	Funder number
Insightec Ltd
Insightec Ltd. the Israel Science Foundation
European Commission	101041118
Israel Science Foundation	3450/20, 192/22
Tel Aviv University
Ministry of science and technology, Israel	101716
Nicholas and Elizabeth Slezak Super Center for Cardiac Research and Biomedical Engineering

Keywords

Biomaterials
Biomedical engineering
Engineering
Materials science

Access to Document

10.1016/j.isci.2023.106965

Cite this

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abstract = "Blood brain barrier disruption (BBBD) using focused ultrasound (FUS) and microbubbles (MB) is an effective tool for therapeutic delivery to the brain. BBBD depends to a great extent on MB oscillations. Because the brain vasculature is heterogenic in diameter, reduced MB oscillations in smaller blood vessels, together with a lower number of MBs in capillaries, can lead to variations in BBBD. Therefore, evaluating the impact of microvasculature diameter on BBBD is of great importance. We present a method to characterize molecules extravasation following FUS-mediated BBBD, at a single blood vessel resolution. Evans blue (EB) leakage was used as marker for BBBD, whereas blood vessels localization was done using FITC labeled Dextran. Automated image processing pipeline was developed to quantify the extent of extravasation as function of microvasculature diameter, including a wide range of vascular morphological parameters. Variations in MB vibrational response were observed in blood vessel mimicking fibers with varied diameters. Higher peak negative pressures (PNP) were required to initiate stable cavitation in fibers with smaller diameters. In vivo in the treated brains, EB extravasation increased as a function of blood vessel diameter. The percentage of strong BBBD blood vessels increased from 9.75% for 2–3 μm blood vessels to 91.67% for 9–10 μm. Using this method, it is possible to conduct a diameter-dependent analysis that measures vascular leakage resulting from FUS-mediated BBBD at a single blood vessel resolution.",

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Diameter-dependent assessment of microvascular leakage following ultrasound-mediated blood-brain barrier opening

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Keywords

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