Park Chan Yuk, Seo Hyeon, Lee Eun-Hee, Han Mun, Choi Hyojin, Park Ki-Su, Yoon Sang-Youl, Chang Sung Hyun, Park Juyoung
Medical Device Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea.
Department of Neurosurgery, School of medicine, Kyungpook National University, Daegu 41944, Korea.
Brain Sci. 2021 Oct 28;11(11):1429. doi: 10.3390/brainsci11111429.
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 and 700 mV, 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 and SCD) 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.
基于微泡和聚焦超声（FUS）通过破坏血脑屏障（BBBD）来提高药物递送效率的方法正在不断研究中。然而，大多数研究是在使用小动物的临床前试验环境中进行的。人体颅骨的使用显示出临床试验和临床前试验之间的差异。临床前试验的BBBD结果难以在临床试验中体现，因为人体颅骨对超声的各种畸变在前一种试验中被排除了。因此，在我们的研究中，开发了一个基于临床前试验环境的临床验证平台，使用人体颅骨碎片和大鼠模型，以在类似于临床试验的条件下诱导BBBD。为此，将一块人体颅骨碎片插入大鼠头部和一个250 kHz的FUS换能器之间，分别通过300 mV和700 mV得出自由场（无人体颅骨碎片）和人体颅骨（有人体颅骨碎片）的最佳超声参数。根据每种情况，使用磁共振图像、伊文思蓝染料、空化和组织学分析BBBD。尽管使用磁共振图像和伊文思蓝染料证实每种情况下都诱导了血脑屏障开放，但在脑组织中观察到了多个血脑屏障开放。通过数值模拟分析了这种现象，证实这是由于大鼠模型颅骨尺寸小导致的驻波。与自由场相比，人体颅骨中的稳定空化剂量（SCD和SCD）分别降低了13.6倍和5.3倍。此外，人体颅骨中的惯性空化剂量比自由场降低了1.05倍。对于组织学分析，尽管每种情况下都观察到了一些外渗的红细胞，但根据我们之前的研究结果，将其评估为可恢复的。因此，我们提出的平台可以帮助在小动物临床前试验中推导用于临床试验的最佳超声参数和BBBD结果，因为它考虑了与人体颅骨相关的变量。
