Wolff Anette, Antfolk Maria, Brodin Birger, Tenje Maria
Lund University, Department of Biomedical Engineering, Lund, Sweden.
University of Copenhagen, Department of Pharmacy, Copenhagen, Denmark.
J Pharm Sci. 2015 Sep;104(9):2727-46. doi: 10.1002/jps.24329. Epub 2015 Jan 28.
The societal need for new central nervous system (CNS) medicines is substantial, because of the global increase in life expectancy and the accompanying increase in age-related CNS diseases. Low blood-brain barrier (BBB) permeability has been one of the major causes of failure for new CNS drug candidates. There has therefore been a great interest in cell models, which mimic BBB permeation properties. In this review, we present an overview of the performance of monocultured, cocultured, and triple-cultured primary cells and immortalized cell lines, including key parameters such as transendothelial electrical resistance values, permeabilities of paracellular flux markers, and expression of BBB-specific marker proteins. Microfluidic systems are gaining ground as a new automated technical platform for cell culture and systematic analysis. The performance of these systems was compared with current state-of-the-art models and it was noted that, although they show great promise, these systems have not yet reached beyond the proof-of-concept stage. In general, it was found that there were large variations in experimental protocols, BBB phenotype markers, and paracellular flux markers used. It is the author's opinion that the field may benefit greatly from developing standardized methodologies and initiating collaborative efforts on optimizing culture protocols.
由于全球预期寿命的增加以及随之而来的与年龄相关的中枢神经系统疾病的增多，社会对新型中枢神经系统（CNS）药物的需求巨大。血脑屏障（BBB）通透性低一直是新型中枢神经系统候选药物研发失败的主要原因之一。因此，人们对模拟血脑屏障渗透特性的细胞模型产生了浓厚兴趣。在本综述中，我们概述了单培养、共培养和三培养原代细胞以及永生化细胞系的性能，包括跨内皮电阻值、细胞旁通量标记物的通透性以及血脑屏障特异性标记蛋白的表达等关键参数。微流控系统作为一种用于细胞培养和系统分析的新型自动化技术平台正在逐渐兴起。将这些系统的性能与当前最先进的模型进行了比较，结果发现，尽管它们显示出巨大的潜力，但这些系统尚未超越概念验证阶段。总体而言，发现所使用的实验方案、血脑屏障表型标记物和细胞旁通量标记物存在很大差异。作者认为，该领域可能会从开发标准化方法以及开展优化培养方案的合作努力中受益匪浅。
