Verification of Blood-Brain Barrier Disruption Based on the Clinical Validation Platform Using a Rat Model with Human Skull

Methods to improve drug delivery efficiency through blood-brain barrier disruption (BBBD) based on microbubbles and focused ultrasound (FUS) are continuously being studied. However, most studies are being conducted in preclinical trial environments using small animals. The use of the human skull sho...

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Autores principales:	Chan Yuk Park, Hyeon Seo, Eun-Hee Lee, Mun Han, Hyojin Choi, Ki-Su Park, Sang-Youl Yoon, Sung Hyun Chang, Juyoung Park
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	focused ultrasound blood-brain barrier acoustic cavitation ultrasound field simulation Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/2b9815b9186f40c5ad65c1c13db64ad8
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spelling	oai:doaj.org-article:2b9815b9186f40c5ad65c1c13db64ad82021-11-25T16:57:01ZVerification of Blood-Brain Barrier Disruption Based on the Clinical Validation Platform Using a Rat Model with Human Skull10.3390/brainsci111114292076-3425https://doaj.org/article/2b9815b9186f40c5ad65c1c13db64ad82021-10-01T00:00:00Zhttps://www.mdpi.com/2076-3425/11/11/1429https://doaj.org/toc/2076-3425Methods to improve drug delivery efficiency through blood-brain barrier disruption (BBBD) based on microbubbles and focused ultrasound (FUS) are continuously being studied. However, most studies are being conducted in preclinical trial environments using small animals. The use of the human skull shows differences between the clinical and preclinical trials. BBBD results from preclinical trials are difficult to represent in clinical trials because various distortions of ultrasound by the human skull are excluded in the former. Therefore, in our study, a clinical validation platform based on a preclinical trial environment, using a human skull fragment and a rat model, was developed to induce BBBD under conditions similar to clinical trials. For this, a human skull fragment was inserted between the rat head and a 250 kHz FUS transducer, and optimal ultrasound parameters for the free field (without human skull fragment) and human skull (with human skull fragment) were derived by 300 mV<sub>pp</sub> and 700 mV<sub>pp</sub>, respectively. BBBD was analyzed according to each case using magnetic resonance images, Evans blue dye, cavitation, and histology. Although it was confirmed using magnetic resonance images and Evans blue dye that a BBB opening was induced in each case, multiple BBB openings were observed in the brain tissues. This phenomenon was analyzed by numerical simulation, and it was confirmed to be due to standing waves owing to the small skull size of the rat model. The stable cavitation doses (SCD<sub>h</sub> and SCD<sub>u</sub>) in the human skull decreased by 13.6- and 5.3-fold, respectively, compared to those in the free field. Additionally, the inertial cavitation dose in the human skull decreased by 1.05-fold compared to that of the free field. For the histological analysis, although some extravasated red blood cells were observed in each case, it was evaluated as recoverable based on our previous study results. Therefore, our proposed platform can help deduct optimal ultrasound parameters and BBBD results for clinical trials in the preclinical trials with small animals because it considers variables relevant to the human skull.Chan Yuk ParkHyeon SeoEun-Hee LeeMun HanHyojin ChoiKi-Su ParkSang-Youl YoonSung Hyun ChangJuyoung ParkMDPI AGarticlefocused ultrasoundblood-brain barrieracoustic cavitationultrasound field simulationNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENBrain Sciences, Vol 11, Iss 1429, p 1429 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	focused ultrasound blood-brain barrier acoustic cavitation ultrasound field simulation Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	focused ultrasound blood-brain barrier acoustic cavitation ultrasound field simulation Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Chan Yuk Park Hyeon Seo Eun-Hee Lee Mun Han Hyojin Choi Ki-Su Park Sang-Youl Yoon Sung Hyun Chang Juyoung Park Verification of Blood-Brain Barrier Disruption Based on the Clinical Validation Platform Using a Rat Model with Human Skull
description	Methods to improve drug delivery efficiency through blood-brain barrier disruption (BBBD) based on microbubbles and focused ultrasound (FUS) are continuously being studied. However, most studies are being conducted in preclinical trial environments using small animals. The use of the human skull shows differences between the clinical and preclinical trials. BBBD results from preclinical trials are difficult to represent in clinical trials because various distortions of ultrasound by the human skull are excluded in the former. Therefore, in our study, a clinical validation platform based on a preclinical trial environment, using a human skull fragment and a rat model, was developed to induce BBBD under conditions similar to clinical trials. For this, a human skull fragment was inserted between the rat head and a 250 kHz FUS transducer, and optimal ultrasound parameters for the free field (without human skull fragment) and human skull (with human skull fragment) were derived by 300 mV<sub>pp</sub> and 700 mV<sub>pp</sub>, respectively. BBBD was analyzed according to each case using magnetic resonance images, Evans blue dye, cavitation, and histology. Although it was confirmed using magnetic resonance images and Evans blue dye that a BBB opening was induced in each case, multiple BBB openings were observed in the brain tissues. This phenomenon was analyzed by numerical simulation, and it was confirmed to be due to standing waves owing to the small skull size of the rat model. The stable cavitation doses (SCD<sub>h</sub> and SCD<sub>u</sub>) in the human skull decreased by 13.6- and 5.3-fold, respectively, compared to those in the free field. Additionally, the inertial cavitation dose in the human skull decreased by 1.05-fold compared to that of the free field. For the histological analysis, although some extravasated red blood cells were observed in each case, it was evaluated as recoverable based on our previous study results. Therefore, our proposed platform can help deduct optimal ultrasound parameters and BBBD results for clinical trials in the preclinical trials with small animals because it considers variables relevant to the human skull.
format	article
author	Chan Yuk Park Hyeon Seo Eun-Hee Lee Mun Han Hyojin Choi Ki-Su Park Sang-Youl Yoon Sung Hyun Chang Juyoung Park
author_facet	Chan Yuk Park Hyeon Seo Eun-Hee Lee Mun Han Hyojin Choi Ki-Su Park Sang-Youl Yoon Sung Hyun Chang Juyoung Park
author_sort	Chan Yuk Park
title	Verification of Blood-Brain Barrier Disruption Based on the Clinical Validation Platform Using a Rat Model with Human Skull
title_short	Verification of Blood-Brain Barrier Disruption Based on the Clinical Validation Platform Using a Rat Model with Human Skull
title_full	Verification of Blood-Brain Barrier Disruption Based on the Clinical Validation Platform Using a Rat Model with Human Skull
title_fullStr	Verification of Blood-Brain Barrier Disruption Based on the Clinical Validation Platform Using a Rat Model with Human Skull
title_full_unstemmed	Verification of Blood-Brain Barrier Disruption Based on the Clinical Validation Platform Using a Rat Model with Human Skull
title_sort	verification of blood-brain barrier disruption based on the clinical validation platform using a rat model with human skull
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/2b9815b9186f40c5ad65c1c13db64ad8
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Verification of Blood-Brain Barrier Disruption Based on the Clinical Validation Platform Using a Rat Model with Human Skull

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