Non-invasive opening of BBB by focused ultrasound
Abstract
Blood brain barrier (BBB) is a major barrier for delivering therapeutic agents in the brain. In this study we investigated the feasibility of open the BBB by using focused ultrasound. Rabbit brains were exposed to pulsed focused ultrasound while injecting ultrasound contrast agent containg microbubbles intravenously. The BBB opening was measured after the sonications by injecting MRI contrast agent i.v. and evaluating the local enhancement in the brain. Low ultrasound powers and pressure amplitudes were found to cause focal enhancement. Before sacrificing the animals trypan blue was also injected i.v.. After the sacrifice of the animals blue spots were found in the brain in the sonicated locations. This method may have potential for targeted delivery of macromolecules in the brain.
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Animal studies have demonstrated reduction of amyloid-beta plaque, neurogenesis, and improvement of memory with focused ultrasound.
“Animal studies have demonstrated safe and reversible BBB opening (4, 6, 7) as well as reduction of amyloid-beta plaque, neurogenesis, and improvement of memory.”
From Noninvasive hippocampal blood-brain barrier opening in Alzheimer's disease with focused ultrasound. (2020) · cites this paper as [7]
Animal studies have demonstrated safe and reversible blood-brain barrier opening with focused ultrasound.
“Animal studies have demonstrated safe and reversible BBB opening (4, 6, 7) as well as reduction of amyloid-beta plaque, neurogenesis, and improvement of memory.”
From Noninvasive hippocampal blood-brain barrier opening in Alzheimer's disease with focused ultrasound. (2020) · cites this paper as [7]
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“Trypan blue injected before animals were sacrificed indicated blue spots in the areas of the sonicated locations [61].”
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“In addition, it presents a potential limitation if and when there will be a need for a repeated tcMRgFUS in the cases of BBB opening [25-27] that should be synced to chemotherapy administration or when ‘time to treat’ may be limited, as could be the case in stroke clot lysis [28,29].”
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“parenchyma after FUS-BBB opening procedure was considered to be a hazardous complication [3], [4], [37].”
BackgroundQuantification of blood-brain barrier permeability by dynamic contrast-enhanced NIRS
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Ultrasound-assisted brain delivery of nanomedicines for brain tumor therapy: advance and prospect
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“discovered that ultrasound combined with microbubbles (USCM) can safely and effectively open the BBB, thereby establishing a new field of transcranial ultrasound treatment for brain diseases [15].”
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“To confirm BBB opening, Gdperfluorocarbon-filled albumin–gadolinium-diethylene-triamine penta-acetic acid (Gd-DTPA) contrast-enhanced T1-weighted MR imaging has been regarded as a gold standard to detect the positive contrast change at the BBB-opening locations (Hynynen et al 2001, 2003, 2005).”
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“applied either through a cranial window or completely transcranially, to reversibly open the blood–brain barrier in rats [33,46–51].”
BackgroundMethodRecent Trend of Ultrasound-Mediated Nanoparticle Delivery for Brain Imaging and Treatment
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Current status of clinical high-intensity focused ultrasound
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“Neurologic applications Neurologic applications of HIFU include disrupting the blood-brain barrier to permit delivery of therapeutic molecules into the brain [24-27], focal ablation of brain lesions for the treatment of hyperkinetic disorders or epilepsy [28], and ablation of brain tumors [29].”
BackgroundLiu, H.-L., Chen, P.-Y., Yang, H.-W., Wu, J.-S., Tseng, I.-C., Ma, Y.-J., Huang, C.-Y., Tsai, H.-C., Chen, S.-M., Lu, Y.-J., et al. (2011) · Journal of Magnetic Resonance Imaging · doi:10.1002/jmri.22697 · Cited by 32 · see citing works
Odéen, H., DeBever, J., Almquist, S., Farrer, A. I., Todd, N., Payne, A., Snell, J., Christensen, D., & Parker, D. (2014) · Journal of Therapeutic Ultrasound · doi:10.1186/2050-5736-2-19 · Cited by 30 · see citing works
“Irreversible surgical procedures utilizing high US intensities for tissue ablation [24,29,30] as well as reversible neuro-modulation and blood-brain barrier disruption procedures utilizing lower US intensities [31-35] have been investigated.”
BackgroundRecent advances in gene delivery with ultrasound and microbubbles
Pichon, C., Kaddur, K., Midoux, P., Tranquart, F., & Bouakaz, A. (2008) · doi:10.1080/17458080801993422 · Cited by 30
“There are several reports concerning in vitro gene delivery into neural cells and the use of US to breach the blood brain barrier [10,38,39].”
BackgroundCharacterization of bioeffects on endothelial cells under acoustic droplet vaporization
Seda, R., Li, D. S., Fowlkes, J., & Bull, J. L. (2015) · Ultrasound in Medicine and Biology · doi:10.1016/j.ultrasmedbio.2015.07.019 · Cited by 29
“where the endothelial wall is highly impermeable, such as the blood brain barrier [32, 33, 34, 35].”
BackgroundZhang, Y.-R., Wang, J., Ghobadi, S. N., Zhou, H.-Y., Huang, A.-W., Gerosa, M., Hou, Q., Keunen, O., Gołȩbiewska, A., Habte, F., et al. (2023) · Ultrasound in Medicine and Biology · doi:10.1016/j.ultrasmedbio.2022.12.006 · Cited by 28 · see citing works
In vivo targeted delivery of large payloads with an ultrasound clinical scanner.
Couture, O., Urban, A., Bretagne, A., Martinez, L., Tanter, M., & Tabeling, P. (2012) · Medical Physics (Lancaster) · doi:10.1118/1.4736822 · Cited by 28
Applications of Ultrasound to Stimulate Therapeutic Revascularization
Gorick, C. M., Chappell, J. C., & Price, R. J. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20123081 · Cited by 23 · see citing works
Sorace, A., Korb, M., Warram, J., Umphrey, H., Zinn, K., Rosenthal, E., & Hoyt, K. (2014) · Ultrasound in Medicine and Biology · doi:10.1016/j.ultrasmedbio.2013.11.002 · Cited by 26
“This strategy was first introduced to augment delivery of molecules through the blood-brain barrier (Hynynen et al. 2003; Marty et al. 2012; McDannold et al. 2012; Schlachetzki et al. 2002), and has since been investigated for multiple other purposes.”
BackgroundFan, L., Liu, Y., Ying, H., Xue, Y., Zhang, Z., Wang, P., Liu, L., & Zhang, H. (2010) · Journal of Molecular Neuroscience · doi:10.1007/s12031-010-9479-x · Cited by 29 · see citing works
“Smart” liposomal nanocontainers in biology and medicine
Tarahovsky, Y. S. (2010) · Biochemistry (Moscow) · doi:10.1134/s0006297910070023 · Cited by 25
Suzuki, R., & Klibanov, A. (2016) · Advances in Experimental Medicine and Biology · doi:10.1007/978-3-319-22536-4_12 · Cited by 25
Hartman, R. K., Hallam, K. A., Donnelly, E., & Emelianov, S. (2019) · Laser Physics Letters · doi:10.1088/1612-202x/aaf89e · Cited by 24 · see citing works
Laser-activated perfluorocarbon nanodroplets: a new tool for blood brain barrier opening
Hallam, K. A., Donnelly, E. M., Karpiouk, A. B., Hartman, R. K., & Emelianov, S. (2018) · Biomedical Optics Express · doi:10.1364/boe.9.004527 · Cited by 28 · see citing works
Drug-Loaded Microbubbles Combined with Ultrasound for Thrombolysis and Malignant Tumor Therapy
Gong, Q., Gao, X.-X., Liu, W.-F., Hong, T., & Chen, C. (2019) · BioMed Research International · doi:10.1155/2019/6792465 · Cited by 23 · see citing works
“Ultrasound can instantly open BBB without damage to nerve cells [83, 84].”
BackgroundDelivery of hydroxycamptothecin via sonoporation: An effective therapy for liver fibrosis
Chen, Q., Huang, J., Ye, Y., Hu, A., Xu, B., Hu, D., Wang, L., Xing, L., Chen, S., Gui, X., et al. (2023) · Journal of Controlled Release · doi:10.1016/j.jconrel.2023.05.002 · Cited by 24 · see citing works
Valdez, M., Fernández, E., Matsunaga, T., Erickson, R., & Trouard, T. (2019) · Ultrasound in Medicine and Biology · doi:10.1016/j.ultrasmedbio.2019.08.024 · Cited by 20 · see citing works
“This method is often carried out in conjunction with magnetic resonance imaging (MRI) to guide and assess BBB opening and has been referred to as MRI guided FUS (MRgFUS) (Chen et al. 2013; Choi et al. 2007; Hynynen et al. 2001; Hynynen et al. 2003; Hynynen et al. 2005; Kinoshita et al. 2006a).”
MethodCarradori, D., Chen, H., Werner, B., Shah, A., Leonardi, C., Usuelli, M., Mezzenga, R., Platt, F., & Leroux, J. (2020) · Small · doi:10.1002/smll.202004735 · Cited by 19 · see citing works
Magnetic Resonance Methods for Focused Ultrasound-Induced Blood-Brain Barrier Opening
Conti, A., Kamimura, H. A. S., Novell, A., Duggento, A., & Toschi, N. (2020) · Frontiers in Physics · doi:10.3389/fphy.2020.547674 · Cited by 22 · see citing works
“This includes the potential use of magnetic resonance (MR) contrast agents (CA) [11, 14, 21, 22] to control the safety of the permeabilization protocol [23, 24], as well as putative changes induced in brain function [25–27].”
BackgroundIntracranial Applications of MR Imaging–Guided Focused Ultrasound
Khanna, N., Gandhi, D., Steven, A., Frenkel, V., & Melhem, E. R. (2016) · American Journal of Neuroradiology · doi:10.3174/ajnr.a4902 · Cited by 19 · see citing works
“Rather, mechanical effects will predominate, which may be used to enhance drug and gene delivery(9) via reversible localized enhanced permeability of the BBB (Fig 3).(15) Early investigations into FUS-induced BBB permeability enhancement were inconsistent and required acoustic energy levels that resulted in localized…”
BackgroundLiu, J., Li, M., Huang, Y., Zhang, L., Li, W., Cao, P., Min, W., Li, J., & Jing, W. (2021) · Journal of Nanomaterials · doi:10.1155/2021/6623031 · Cited by 25 · see citing works
Liu, H.-L., Chen, H.-W., Kuo, Z.-H., & Huang, W.-C. (2008) · IEEE Transactions on Biomedical Engineering · doi:10.1109/tbme.2008.925697 · Cited by 18
Jungehulsing, G. J., Brunecker, P., Nolte, C. H., Fiebach, J. B., Kunze, C., Doepp, F., Villringer, A., & Schreiber, S. J. (2007) · Ultrasound in Medicine & Biology · doi:10.1016/j.ultrasmedbio.2007.07.006 · Cited by 21 · see citing works
Kong, C., Park, S. H., Shin, J., Baek, H. G., Park, J., Na, Y. C., Chang, W., & Chang, J. W. (2021) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2021.783048 · Cited by 17 · see citing works
“Meanwhile, research on non-thermal FUS for blood brain barrier (BBB) opening and neuromodulation has also been widely expanded (Hynynen et al., 2003; Treat et al., 2007; Vykhodtseva et al., 2008) (Tufail et al., 2010).”
BackgroundMaimbourg, G., Houdouin, A., Santin, M., Lehéricy, S., Tanter, M., & Aubry, J. (2018) · Physics in Medicine and Biology · doi:10.1088/1361-6560/aaca21 · Cited by 17 · see citing works
“For these reasons, an alternative method, combining the injection of encapsulated microbubbles with transcranial focused ultrasound, has been developed to open the BBB [19, 20].”
MethodLiu, H.-L., Wai, Y., Hsu, P.-H., Lyu, L.-A., Wu, J.-S., Shen, C.-R., Chen, J.-C., Yen, T., & Wang, J.-J. (2010) · Journal of Cerebral Blood Flow and Metabolism · doi:10.1038/jcbfm.2009.179 · Cited by 17 · see citing works
“If microbubbles are combined with ultrasound exposure, the effects of ultrasound can be focused to reduce the acoustic intensity required to produce BBB opening (Hynynen et al, 2003, 2005, 2006; Kinoshita et al, 2006; McDannold et al, 2005).”
Background
- Authors
- Hynynen, K., McDannold, N., Vykhodtseva, N., & Jolesz, F. A.
- Affiliations
- Brigham and Women's Hospital (US)
- Venue
- Brain Edema XII
- Publisher
- Springer Vienna
- Published
- 2003
- Volume
- 86
- Pages
- 555-558
- OpenAlex
- W1801991441
- Cited by
- 156
- References
- 12
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 9 · 2022: 8 · 2021: 6 · 2020: 6 · 2019: 15 · 2018: 7 · 2017: 7 · 2016: 6 · 2015: 7 · 2014: 9 · 2013: 9 · 2012: 10
- FWCI
- 15.03
- Type
- book chapter
- Language
- en
- Open access
- closed
- Locations
- Springer eBooks (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Public Health Service (46627)
- 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
- blood-brain barrier opening, focused ultrasound, ultrasound contrast agents, microbubbles, brain drug delivery, MRI contrast enhancement, rabbit brain
- MeSH terms
- Animals, Blood-Brain Barrier, Brain, Coloring Agents, Feasibility Studies, Injections, Intravenous, Rabbits, Sonication, Trypan Blue, Drug Delivery Systems, Microbubbles
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