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Main Title: A four-organ-chip for interconnected long-term co-culture of human intestine, liver, skin and kidney equivalents
Author(s): Maschmeyer, Ilka
Lorenz, Alexandra K.
Schimek, Katharina
Hasenberg, Tobias
Ramme, Anja P.
Hübner, Juliane
Lindner, Marcus
Drewell, Christopher
Bauer, Sophie
Thomas, Alexander
Sambo, Naomia Sisoli
Sonntag, Frank
Lauster, Roland
Marx, Uwe
Type: Article
Language Code: en
Abstract: 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 100000-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.
Issue Date: 2015
Date Available: 25-Oct-2017
DDC Class: 004 Datenverarbeitung; Informatik
570 Biowissenschaften; Biologie
540 Chemie und zugeordnete Wissenschaften
Sponsor/Funder: BMBF, 0315569, GO-Bio 3: Multi-Organ-Bioreaktoren für die prädiktive Substanztestung im Chipformat
Journal Title: Lab on a chip : miniaturisation for chemistry and biology
Publisher: Royal Society of Chemistry
Publisher Place: Cambridge
Volume: 15
Issue: 12
Publisher DOI: 10.1039/c5lc00392j
Page Start: 2688
Page End: 2699
EISSN: 1473-0189
ISSN: 1473-0197
Appears in Collections:FG Medizinische Biotechnologie » Publications

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