title: Chip-based human liver-intestine and liver-skin co-cultures--A first step toward systemic repeated dose substance testing in vitro.
abstract: 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.
authors: TissUse GmbH, Markgrafenstrasse 18, 15528 Spreenhagen, Germany; Technische Universität Berlin, Institute of Biotechnology, Department Medical Biotechnology, Gustav-Meyer-Allee 25, 13355 Berlin, Germany. Electronic address: Ilka.Maschmeyer@TissUse.com.
authors: Ilka
authors: I
authors: Maschmeyer
authors: Technische Universität Berlin, Institute of Biotechnology, Department Medical Biotechnology, Gustav-Meyer-Allee 25, 13355 Berlin, Germany. Electronic address: t.hasenberg@tu-berlin.de.
authors: Tobias
authors: T
authors: Hasenberg
authors: Technische Universität Berlin, Institute of Biotechnology, Department Medical Biotechnology, Gustav-Meyer-Allee 25, 13355 Berlin, Germany. Electronic address: a.jaenicke@tu-berlin.de.
authors: Annika
authors: A
authors: Jaenicke
authors: Technische Universität Berlin, Institute of Biotechnology, Department Medical Biotechnology, Gustav-Meyer-Allee 25, 13355 Berlin, Germany. Electronic address: marcus.lindner@mailbox.tu-berlin.de.
authors: Marcus
authors: M
authors: Lindner
authors: Technische Universität Berlin, Institute of Biotechnology, Department Medical Biotechnology, Gustav-Meyer-Allee 25, 13355 Berlin, Germany. Electronic address: lorenz@tu-berlin.de.
authors: Alexandra Katharina
authors: AK
authors: Lorenz
authors: Technische Universität Berlin, Institute of Biotechnology, Department Bioanalytics, Seestrasse 13, 13353 Berlin, Germany; Research and Teaching Institute for Brewing in Berlin (VLB), Research Institute for Special Analyses (FIS), Seestrasse 13, 13353 Berlin, Germany. Electronic address: julie.zech@vlb-berlin.org.
authors: Julie
authors: J
authors: Zech
authors: Technische Universität Berlin, Institute of Biotechnology, Department Bioanalytics, Seestrasse 13, 13353 Berlin, Germany. Electronic address: garbe@mailbox.tu-berlin.de.
authors: Leif-Alexander
authors: LA
authors: Garbe
authors: Fraunhofer Institute for Material and Beam Technology, Winterbergstr. 28, 01277 Dresden, Germany. Electronic address: Frank.Sonntag@iws.fraunhofer.de.
authors: Frank
authors: F
authors: Sonntag
authors: MatTek Corporation, Ashland, MA 01721, United States. Electronic address: phayden@mattek.com.
authors: Patrick
authors: P
authors: Hayden
authors: MatTek Corporation, Ashland, MA 01721, United States. Electronic address: sayehunie@mattek.com.
authors: Seyoum
authors: S
authors: Ayehunie
authors: Technische Universität Berlin, Institute of Biotechnology, Department Medical Biotechnology, Gustav-Meyer-Allee 25, 13355 Berlin, Germany. Electronic address: roland.lauster@tu-berlin.de.
authors: Roland
authors: R
authors: Lauster
authors: TissUse GmbH, Markgrafenstrasse 18, 15528 Spreenhagen, Germany; Technische Universität Berlin, Institute of Biotechnology, Department Medical Biotechnology, Gustav-Meyer-Allee 25, 13355 Berlin, Germany. Electronic address: uwe.marx@tu-berlin.de.
authors: Uwe
authors: U
authors: Marx
authors: Technische Universität Berlin, Institute of Biotechnology, Department Medical Biotechnology, Gustav-Meyer-Allee 25, 13355 Berlin, Germany. Electronic address: eva-maria.materne@tu-berlin.de.
authors: Eva-Maria
authors: EM
authors: Materne
mesh_terms: D045744:Cell Line, Tumor; D002839:Chromans / Q000008:administration & dosage*; D018920:Coculture Techniques / Q000379:methods; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000378:metabolism*; D056656:Lab-On-A-Chip Devices; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D012867:Skin / Q000187:drug effects / Q000378:metabolism*; D045162:Thiazolidinediones / Q000008:administration & dosage*; D000077288:Troglitazone; D055815:Young Adult
chemical_list: D002839:Chromans; D045162:Thiazolidinediones; D000077288:Troglitazone
keywords: 3D tissue culture; Alternatives to animal testing; Human barrier models; Human-on-a-chip; Intestine model; Microphysiological system; Organ-on-a-chip; Skin equivalent; Systemic drug testing; Vasculature