PDF(Pubmed)
Abstract：
Microphysiological system (MPS), a new technology for in vitro testing platforms, have been acknowledged as a strong tool for drug development. In the central nervous system (CNS), the blood‒brain barrier (BBB) limits the permeation of circulating substances from the blood vessels to the brain, thereby protecting the CNS from circulating xenobiotic compounds. At the same time, the BBB hinders drug development by introducing challenges at various stages, such as pharmacokinetics/pharmacodynamics (PK/PD), safety assessment, and efficacy assessment. To solve these problems, efforts are being made to develop a BBB MPS, particularly of a humanized type. In this study, we suggested minimal essential benchmark items to establish the BBB-likeness of a BBB MPS; these criteria support end users in determining the appropriate range of applications for a candidate BBB MPS. Furthermore, we examined these benchmark items in a two-dimensional (2D) humanized tricellular static transwell BBB MPS, the most conventional design of BBB MPS with human cell lines. Among the benchmark items, the efflux ratios of P-gp and BCRP showed high reproducibility in two independent facilities, while the directional transports meditated through Glut1 or TfR were not confirmed. We have organized the protocols of the experiments described above as standard operating procedures (SOPs). We here provide the SOPs with the flow chart including entire procedure and how to apply each SOP. Our study is important developmental step of BBB MPS towards the social acceptance, which enable end users to check and compare the performance the BBB MPSs.
摘要：
微生理系统（MPS），一种用于体外测试平台的新技术，被认为是药物开发的有力工具。在中枢神经系统（CNS），血脑屏障（BBB）限制了循环物质从血管到大脑的渗透，从而保护CNS免受循环的异生物化合物的影响。同时,BBB通过在各个阶段引入挑战来阻碍药物开发，如药代动力学/药效学（PK/PD），安全评估,和疗效评估。为了解决这些问题,正在努力开发BBBMPS，特别是人性化类型。在这项研究中,我们建议最少的基本基准项目来建立BBBMPS的BBB相似度;这些标准支持最终用户确定候选BBBMPS的适当应用范围.此外，我们在二维（2D）人源化三细胞静态transwellBBBMPS中检查了这些基准项目，最常规的人细胞系BBBMPS设计。在基准项目中，P-gp和BCRP的外排率在两个独立的设施中显示出高重现性，而通过Glut1或TfR冥想的定向运输未得到证实。我们已经将上述实验的方案组织为标准操作程序(SOP)。我们在这里为SOP提供流程图，包括整个过程以及如何应用每个SOP。我们的研究是BBBMPS走向社会接受的重要发展步骤，它使最终用户能够检查和比较BBBMPS的性能。
