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Spatio-temporal analysis of molecular delivery through the blood–brain barrier using focused ultrasound
Open accessAbstract
The deposition of gadolinium through ultrasound-induced blood-brain barrier (BBB) openings in the murine hippocampus was investigated. First, wave propagation simulations through the intact mouse skull revealed minimal beam distortion while thermal deposition simulations, at the same sonication parameters used to induce BBB opening in vivo, revealed temperature increases lower than 0.5 degrees C. The simulation results were validated experimentally in ex vivo skulls (m = 6) and in vitro tissue specimens. Then, in vivo mice (n = 9) were injected with microbubbles (Optison; 25-50 microl) and sonicated (frequency: 1.525 MHz, pressure amplitudes: 0.5-1.1 MPa, burst duration: 20 ms, duty cycle: 20%, durations: 2-4 shots, 30 s per shot, 30 s interval) at the left hippocampus, through intact skin and skull. Sequential, high-resolution, T1-weighted MRI (9.4 Tesla, in-plane resolution: 75 microm, scan time: 45-180 min) with gadolinium (Omniscan; 0.5 ml) injected intraperitoneally revealed a threshold of the BBB opening at 0.67 MPa and BBB closing within 28 h from opening. The contrast-enhancement area and gadolinium deposition path were monitored over time and the influence of vessel density, size and location was determined. Sonicated arteries, or their immediate surroundings, depicted greater contrast enhancement than sonicated homogeneous brain tissue regions. In conclusion, gadolinium was delivered through a transiently opened BBB and contained to a specific brain region (i.e., the hippocampus) using a single-element focused ultrasound transducer. It was also found that the amount of gadolinium deposited in the hippocampal region increased with the acoustic pressure and that the spatial distribution of the BBB opening was determined not only by the ultrasound beam, but also by the vasculature of the targeted brain region.
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“A more localized transient disruption of BBB is accomplished by using magnetic resonance imaging-guided focused ultrasound in combination with IV infusion of microbubbles (FUS-MB) (Fig. 4b), which induce temporary BBB opening even in NHPs [134–137].”
From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [135]
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Metadata
- Authors
- Choi, J. J., Pernot, M., Brown, T. R., Small, S. A., & Konofagou, E. E.
- Affiliations
- Columbia University (US)
- Venue
- Physics in Medicine and Biology
- Publisher
- IOP Publishing
- Published
- 2007-08-31
- Volume
- 52
- Issue
- 18
- Pages
- 5509-5530
- ISSN
- 0031-9155 (ISSN-L)
- 1361-6560
- OpenAlex
- W2105351878
- Cited by
- 141
- References
- 34
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 5 · 2023: 3 · 2022: 6 · 2021: 2 · 2020: 5 · 2019: 6 · 2018: 8 · 2017: 5 · 2016: 11 · 2015: 8 · 2014: 6 · 2013: 8 · 2012: 9
- FWCI
- 10.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Physics in Medicine and Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (P50AG008702)
- Topics
- Physical Sciences › Engineering › Biomedical Engineering › Ultrasound and Hyperthermia Applications
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Microbial Inactivation Methods
- Keywords
- focused ultrasound, blood-brain barrier opening, gadolinium deposition, hippocampus, microbubbles, acoustic pressure threshold, wave propagation simulation, T1-weighted imaging, contrast enhancement, cerebral vasculature, ultrasound-mediated drug delivery
- MeSH terms
- Albumins, Animals, Blood-Brain Barrier, Computer Simulation, Female, Fluorocarbons, Gadolinium, Hippocampus, Male, Metabolic Clearance Rate, Mice, Inbred C57BL, Models, Biological, Sonication, Tissue Distribution, Drug Delivery Systems, Mice
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