细胞培养
芯片上器官
肾
生物
生物加工
细胞生物学
微流控
器官培养
病理
化学
生物医学工程
组织工程
体外
内分泌学
生物化学
医学
纳米技术
材料科学
遗传学
作者
Ilka Maschmeyer,Alexandra Lorenz,Katharina Schimek,Tobias Hasenberg,Anja Patricia Ramme,Juliane Hübner,Marcus Lindner,Christopher Drewell,Sophie Bauer,Alexander Thomas,Naomia Sisoli Sambo,Frank Sonntag,Roland Lauster,Uwe Marx
出处
期刊:Lab on a Chip
[The Royal Society of Chemistry]
日期:2015-01-01
卷期号:15 (12): 2688-2699
被引量:639
摘要
Systemic absorption and metabolism of drugs in the small intestine, metabolism by the liver as well as excretion by the kidney are key determinants of efficacy and safety for therapeutic candidates. However, these systemic responses of applied substances lack in most in vitro assays. In this study, a microphysiological system maintaining the functionality of four organs over 28 days in co-culture has been established at a minute but standardized microsystem scale. Preformed human intestine and skin models have been integrated into the four-organ-chip on standard cell culture inserts at a size 100,000-fold smaller than their human counterpart organs. A 3D-based spheroid, equivalent to ten liver lobules, mimics liver function. Finally, a barrier segregating the media flow through the organs from fluids excreted by the kidney has been generated by a polymeric membrane covered by a monolayer of human proximal tubule epithelial cells. A peristaltic on-chip micropump ensures pulsatile media flow interconnecting the four tissue culture compartments through microfluidic channels. A second microfluidic circuit ensures drainage of the fluid excreted through the kidney epithelial cell layer. This four-organ-chip system assures near to physiological fluid-to-tissue ratios. In-depth metabolic and gene analysis revealed the establishment of reproducible homeostasis among the co-cultures within two to four days, sustainable over at least 28 days independent of the individual human cell line or tissue donor background used for each organ equivalent. Lastly, 3D imaging two-photon microscopy visualised details of spatiotemporal segregation of the two microfluidic flows by proximal tubule epithelia. To our knowledge, this study is the first approach to establish a system for in vitro microfluidic ADME profiling and repeated dose systemic toxicity testing of drug candidates over 28 days.
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