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

Chan Yuk Park; Hyeon Seo; Eun-Hee Lee; Mun Han; Hyojin Choi; Ki-Su Park; Sang-Youl Yoon; Sung Hyun Chang; Juyoung Park

doi:10.3390/brainsci11111429

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

Brain Sci. 2021 Oct 28;11(11):1429. doi: 10.3390/brainsci11111429.

Authors

Chan Yuk Park¹, Hyeon Seo¹, Eun-Hee Lee¹, Mun Han¹, Hyojin Choi¹, Ki-Su Park², Sang-Youl Yoon², Sung Hyun Chang², Juyoung Park^{1

3}

Affiliations

¹ Medical Device Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea.
² Department of Neurosurgery, School of medicine, Kyungpook National University, Daegu 41944, Korea.
³ Department of High-Tech Medical Device, College of Future Industry, Gachon University, Seongnam-si 13120, Korea.

Abstract

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_pp and 700 mV_pp, 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_h and SCD_u) 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.

Keywords: acoustic cavitation; blood-brain barrier; focused ultrasound; ultrasound field simulation.

Abstract

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