Chip-based human liver-intestine and liver-skin co-cultures--A first step toward systemic repeated dose substance testing in vitro.
Chip-based human liver-intestine and liver-skin co-cultures--A first step toward systemic repeated dose substance testing in vitro.
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DOI：
10.1016/j.ejpb.2015.03.002
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发表时间：
2015-09
期刊：
影响因子：
--
通讯作者：
Materne EM
中科院分区：
文献类型：
--
作者：
Maschmeyer I;Hasenberg T;Jaenicke A;Lindner M;Lorenz AK;Zech J;Garbe LA;Sonntag F;Hayden P;Ayehunie S;Lauster R;Marx U;Materne EM
由于缺乏预测性替代方案（例如，OECD和ICH指南），对实验动物和人类进行了系统性重复的剂量安全评估和全身性效率评估。吸入和全身性暴露途径，用于所谓的“人类对芯片”概念在该领域取得成功的小型功能性人体生物是人类屏障器官模型的生活样的结合，例如肠道，肺或皮肤，具有实质器官等效物，例如肝脏，例如最小的生物学上。使用微生物生物学系统的活检我们使用了多器官芯片（MOC）平台，该平台在低媒体与组织比的物理范围内提供了脉动流体。皮肤模型与肝脏共培养期间的液体界面分别等于1/100.000的人体体内尺度。肝脏 - 皮肤共培养的微流体通道可以成功覆盖人类内皮细胞，从而模仿人类脉管系统，首次通过施用人类的曝光路线，并通过施用人类的全身性给药。基于CHIP的共培养物的模型物质 - Troglitazone。
Systemic repeated dose safety assessment and systemic efficacy evaluation of substances are currently carried out on laboratory animals and in humans due to the lack of predictive alternatives. Relevant international regulations, such as OECD and ICH guidelines, demand long-term testing and oral, dermal, inhalation, and systemic exposure routes for such evaluations. So-called “human-on-a-chip” concepts are aiming to replace respective animals and humans in substance evaluation with miniaturized functional human organisms. The major technical hurdle toward success in this field is the life-like combination of human barrier organ models, such as intestine, lung or skin, with parenchymal organ equivalents, such as liver, at the smallest biologically acceptable scale. Here, we report on a reproducible homeostatic long-term co-culture of human liver equivalents with either a reconstructed human intestinal barrier model or a human skin biopsy applying a microphysiological system. We used a multi-organ chip (MOC) platform, which provides pulsatile fluid flow within physiological ranges at low media-to-tissue ratios. The MOC supports submerse cultivation of an intact intestinal barrier model and an air–liquid interface for the skin model during their co-culture with the liver equivalents respectively at 1/100.000 the scale of their human counterparts in vivo. To increase the degree of organismal emulation, microfluidic channels of the liver–skin co-culture could be successfully covered with human endothelial cells, thus mimicking human vasculature, for the first time. Finally, exposure routes emulating oral and systemic administration in humans have been qualified by applying a repeated dose administration of a model substance – troglitazone – to the chip-based co-cultures.
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6.2
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