Danz Karin, Höcherl Tara, Wien Sascha Lars, Wien Lena, von Briesen Hagen, Wagner Sylvia
Fraunhofer Institute for Biomedical Engineering IBMT, Joseph-von-Fraunhofer-Weg 1, 66280 Sulzbach, Germany.
Pharmaceutics. 2022 Mar 29;14(4):737. doi: 10.3390/pharmaceutics14040737.
In vitro model systems of the blood-brain barrier (BBB) play an essential role in pharmacological research, specifically during the development and preclinical evaluation of new drug candidates. Within the past decade, the trend in research and further development has moved away from models based on primary cells of animal origin towards differentiated models derived from human induced pluripotent stem cells (hiPSs). However, this logical progression towards human model systems from renewable cell sources opens up questions about the transferability of results generated in the primary cell models. In this study, we have evaluated both models with identical experimental parameters and achieved a directly comparable characterisation showing no significant differences in protein expression or permeability even though the achieved transendothelial electrical resistance (TEER) values showed significant differences. In the course of this investigation, we also determined a significant deviation of both model systems from the in vivo BBB circumstances, specifically concerning the presence or absence of serum proteins in the culture media. Thus, we have further evaluated both systems when confronted with an in vivo-like distribution of serum and found a notable improvement in the differential permeability of hydrophilic and lipophilic compounds in the hiPS-derived BBB model. We then transferred this model into a microfluidic setup while maintaining the differential serum distribution and evaluated the permeability coefficients, which showed good comparability with values in the literature. Therefore, we have developed a microfluidic hiPS-based BBB model with characteristics comparable to the established primary cell-based model.
血脑屏障（BBB）的体外模型系统在药理学研究中起着至关重要的作用，特别是在新药候选物的开发和临床前评估过程中。在过去十年中，研究和进一步发展的趋势已从基于动物原代细胞的模型转向源自人类诱导多能干细胞（hiPS）的分化模型。然而，从可再生细胞来源向人类模型系统的这种逻辑进展引发了关于原代细胞模型中产生的结果的可转移性的问题。在本研究中，我们用相同的实验参数评估了这两种模型，并实现了直接可比的表征，结果表明即使所获得的跨内皮电阻（TEER）值显示出显著差异，蛋白质表达或通透性也没有显著差异。在这项研究过程中，我们还确定了这两种模型系统与体内BBB情况存在显著偏差，特别是关于培养基中血清蛋白的存在与否。因此，我们在面对血清的体内样分布时进一步评估了这两种系统，发现在hiPS衍生的BBB模型中亲水性和疏水性化合物的差异通透性有显著改善。然后，我们将该模型转移到微流控装置中，同时保持血清的差异分布，并评估了通透性系数，其与文献中的值具有良好的可比性。因此，我们开发了一种基于hiPS的微流控BBB模型，其特性与已建立的基于原代细胞的模型相当。
