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

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

doi:10.1016/j.isci.2023.106965

Cited by 13 publications

(22 citation statements)

References 68 publications

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“…There is a notably large parameter space that impacts blood-brain barrier opening, including the sonication parameters (frequency, pressure, pulse length, pulse repetition frequency, exposure duration) (McDannold et al 2008, Chopra et al 2010, Choi et al 2011, contrast agent (agent type, dose, and size distribution) (McDannold et al 2007, Samiotaki et al 2012, McMahon and Hynynen 2017, Bing et al 2018, and anesthesia administration (Itani andMattrey 2011, McDannold et al 2017). The approach is further complicated by interand intra-subject biological variability in skull transmission efficiency (Fry andBarger 1978, Pichardo et al 2011) and local target vasculature (density, diameter, flow rate) (Sassaroli and Hynynen 2005, McDannold et al 2012, Nhan et al 2013, Hosseinkhah et al 2015, Poon et al 2021, Katz et al 2023. In this study, the ultrasound parameters and microbubble dose were not varied, but were in range of previous blood-brain barrier opening preclinical studies (Baseri et al 2010, Bing et al 2018, Kovacs et al 2018, Meng et al 2019, Poon et al 2021.…”

Section: Discussionmentioning

confidence: 81%

Biaxial ultrasound driving technique for small animal blood–brain barrier opening

Pellow,

Li,

Delgado

et al. 2023

Phys. Med. Biol.

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Biaxial driving can more efficiently convert electrical power to forward acoustic power in piezoelectric materials, and the interaction between the orthogonal electric fields can produce a combination of extensional and shear deformations as a function of the phase difference between them to allow dynamic steering of the beam with a single-element. In this study, we demonstrate for the first time the application of a single-element biaxially driven ring transducer in vivo for blood–brain barrier opening in mice, and compare it to that achieved with a conventional single-element highly focused (F# = 0.7) spherical transducer operating at a similar frequency. Transcranial focused ultrasound (0.45 MPa, 10 ms pulse length, 1 Hz repetition frequency, 30 s duration) was applied bilaterally to mice with a 40 μl/kg bolus of DefinityTM microbubbles, employing either a single-element biaxial ring (1.482 MHz, 10 mm inner diameter, 13.75 mm outer diameter) or spherical (1.5 MHz, 35 mm diameter, F# = 0.7; RK50, FUS Instruments) transducer on each side. Follow-up MRI scans (T1 pre- and post- 0.2 mmol/kg Gd injection, T2) were acquired to assess blood–brain barrier opening volume and potential damage. Compared to blood–brain barrier opening achieved with a conventional single-element spherical focused transducer, the opening volume achieved with a single-element biaxial ring transducer was 35% smaller (p = 0.002) with a device of a ring diameter of 40% the aperture size. Axial refocusing was further demonstrated with the single-element biaxial ring transducer, yielding a 1.63 mm deeper, five-fold larger opening volume (p = 0.048) relative to its small-focus mode. The biaxial ring transducer achieved a more localized opening compared to the spherical focused transducer under the same parameters, and further enabled dynamic axial refocusing with a single-element transducer with a smaller fabrication footprint.

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Section: Discussionmentioning

confidence: 81%

Biaxial ultrasound driving technique for small animal blood–brain barrier opening

Pellow,

Li,

Delgado

et al. 2023

Phys. Med. Biol.

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show abstract

“…S1). Therefore, we chose parameters that were previously used 8 : A distance of 2 pixels (0.58 μm width) from the vessel wall and a perivascular area extending 10 pixels (2.93 μm width(. An analysis of 4,500 blood vessels from the NB group, 2,877 from the MB group, and 3,403 from the control group was conducted.…”

Section: Resultsmentioning

confidence: 99%

“…BBBD was induced in the treated groups through retro orbital injection of bubbles. The MB treatment group received 2 x 107 MBs in 50 µl of degassed PBS, following a protocol from previous work 8 . The NB treatment group was injected with 0.737 µl to 1 g of animal weight, diluted in a degassed PBS in a1:1 ratio, as described in other works29,43.…”

Section: In-vivo Bbbd Experimentsmentioning

confidence: 99%

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Enhanced capillary delivery with nanobubble-mediated blood-brain barrier opening and advanced high resolution vascular segmentation

Gattegno,

Arbel,

Riess

et al. 2023

Preprint

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Overcoming the blood-brain barrier (BBB) is essential to enhance brain therapy. Here, we utilized nanoscale nanobubbles with focused ultrasound for targeted and improved BBB opening in mice. A microscopy method assessed BBB opening at a single blood vessel resolution employing a dual-dye labeling technique using green fluorescent molecules to label blood vessels and Evans blue brain-permeable dye for quantifying BBB extravasation. A UNET-based deep learning architecture enabled blood vessels segmentation, delivering comparable accuracy to manual segmentation with a significant time reduction. Segmentation outcomes were applied to the Evans blue channel to quantify extravasation of each blood vessel. Results were compared to microbubble-mediated BBB opening, where reduced extravasation was observed in capillaries with 2-6μm diameter. In comparison, nanobubbles yield an improved opening in these capillaries, and equivalent efficacy to that of microbubbles in larger vessels. These results indicate the potential of nanobubbles to serve as enhanced agents for BBB opening, amplifying bioeffects in capillaries while preserving comparable opening in larger vessels.

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“…These phantoms may provide an alternative to computerized flow simulations used to evaluate localization and tracking accuracy by creating shapes that are challenging to reproduce with ULM, such as the horseshoe shape . We believe these phantoms can be used to study a wide variety of applicationssuch as the verification of contrast-enhanced harmonic imaging, resolution-improving ultrasound algorithms, and the behavior of bubble flow in therapeutic applications. – …”

Section: Discussionmentioning

confidence: 99%

Versatile Ultrasound-Compatible Microfluidic Platform for In Vitro Microvasculature Flow Research and Imaging Optimization

Mano,

Grutman,

Ilovitsh

2023

ACS Omega

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Ultrasound localization microscopy (ULM) enables the creation of super-resolved images and velocity maps by localizing and tracking microbubble contrast agents through a vascular network over thousands of frames of ultrafast plane wave images. However, a significant challenge lies in developing ultrasound-compatible microvasculature phantoms to investigate microbubble flow and distribution in controlled environments. In this study, we introduce a new class of gelatin-based microfluidic-inspired phantoms uniquely tailored for ULM studies. These devices allow for the creation of complex and reproducible microvascular networks featuring channel diameters as small as 100 μm. Our experiments focused on microbubble behavior under ULM conditions within bifurcating and converging vessel phantoms. We evaluated the impact of bifurcation angles (25, 45, and 55°) and flow rates (0.01, 0.02, and 0.03 mL/min) on the acquisition time of branching channels. Additionally, we explored the saturation time effect of narrow channels branching off larger ones. Significantly longer acquisition times were observed for the narrow vessels, with an average increase of 72% when a 100 μm channel branched off from a 300 μm channel and an average increase of 90% for a 200 μm channel branching off from a 500 μm channel. The robustness of our fabrication method is demonstrated through the creation of two trifurcating microfluidic phantoms, including one that converges back into a single channel, a configuration that cannot be achieved through traditional methods. This new class of ULM phantoms serves as a versatile platform for noninvasively studying complex flow patterns using ultrasound imaging, unlocking new possibilities for in vitro microvasculature research and imaging optimization.

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

Cited by 13 publications

References 68 publications

Biaxial ultrasound driving technique for small animal blood–brain barrier opening

Biaxial ultrasound driving technique for small animal blood–brain barrier opening

Enhanced capillary delivery with nanobubble-mediated blood-brain barrier opening and advanced high resolution vascular segmentation

Versatile Ultrasound-Compatible Microfluidic Platform for In Vitro Microvasculature Flow Research and Imaging Optimization

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