title: 3D spherical microtissues and microfluidic technology for multi-tissue experiments and analysis.
abstract: Rational development of more physiologic in vitro models includes the design of robust and flexible 3D-microtissue-based multi-tissue devices, which allow for tissue-tissue interactions. The developed device consists of multiple microchambers interconnected by microchannels. Pre-formed spherical microtissues are loaded into the microchambers and cultured under continuous perfusion. Gravity-driven flow is generated from on-chip reservoirs through automated chip-tilting without any need for additional tubing and external pumps. This tilting concept allows for operating up to 48 devices in parallel in order to test various drug concentrations with a sufficient number of replicates. For a proof of concept, rat liver and colorectal tumor microtissues were interconnected on the chip and cultured during 8 days in the presence of the pro-drug cyclophosphamide. Cyclophosphamide has a significant impact on tumor growth but only after bio-activation by the liver. This effect was only observed in the perfused and interconnected co-cultures of different microtissue types on-chip, whereas the discontinuous transfer of supernatant via pipetting from static liver microtissues that have been treated with cyclophosphamide did not significantly affect tumor growth. The results indicate the utility and multi-tissue functionality of this platform. The importance of continuous medium circulation and tissue interaction is highlighted.
authors.affiliation: ETH Zurich, Department of Biosystems Science and Engineering, Bio Engineering Laboratory, Mattenstrasse 26, 4058 Basel, Switzerland.
authors.forename: Jin-Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: InSphero AG, Wagistrasse 27, 8952 Schlieren, Switzerland.
authors.forename: David A
authors.initials: DA
authors.lastname: Fluri
authors.affiliation: Leibniz Research Centre for Working Environment and Human Factors (IfADo), TU Dortmund University, Ardeystrasse 67, 44139 Dortmund, Germany.
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Marchan
authors.affiliation: KU Leuven, Research Group of Functional Genomics and Proteomics, Naamsestraat 59, 3000 Leuven, Belgium.
authors.forename: Kurt
authors.initials: K
authors.lastname: Boonen
authors.affiliation: ETH Zurich, Department of Biosystems Science and Engineering, Bio Engineering Laboratory, Mattenstrasse 26, 4058 Basel, Switzerland.
authors.forename: Soumyaranjan
authors.initials: S
authors.lastname: Mohanty
authors.affiliation: ETH Zurich, Department of Biosystems Science and Engineering, Bio Engineering Laboratory, Mattenstrasse 26, 4058 Basel, Switzerland.
authors.forename: Prateek
authors.initials: P
authors.lastname: Singh
authors.affiliation: Leibniz Research Centre for Working Environment and Human Factors (IfADo), TU Dortmund University, Ardeystrasse 67, 44139 Dortmund, Germany; Department of Forensic Medicine and Veterinary Toxicology, Faculty of Veterinary Medicine, South Valley University, 83523 Qena, Egypt.
authors.forename: Seddik
authors.initials: S
authors.lastname: Hammad
authors.affiliation: KU Leuven, Research Group of Functional Genomics and Proteomics, Naamsestraat 59, 3000 Leuven, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Landuyt
authors.affiliation: Leibniz Research Centre for Working Environment and Human Factors (IfADo), TU Dortmund University, Ardeystrasse 67, 44139 Dortmund, Germany.
authors.forename: Jan G
authors.initials: JG
authors.lastname: Hengstler
authors.affiliation: InSphero AG, Wagistrasse 27, 8952 Schlieren, Switzerland.
authors.forename: Jens M
authors.initials: JM
authors.lastname: Kelm
authors.affiliation: ETH Zurich, Department of Biosystems Science and Engineering, Bio Engineering Laboratory, Mattenstrasse 26, 4058 Basel, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hierlemann
authors.affiliation: ETH Zurich, Department of Biosystems Science and Engineering, Bio Engineering Laboratory, Mattenstrasse 26, 4058 Basel, Switzerland. Electronic address: olivier.frey@bsse.ethz.ch.
authors.forename: Olivier
authors.initials: O
authors.lastname: Frey
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques / Q000295:instrumentation / Q000379:methods*; D003520:Cyclophosphamide / Q000494:pharmacology; D045325:HCT116 Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000166:cytology*; D046210:Microfluidic Analytical Techniques / Q000295:instrumentation* / Q000379:methods; D051381:Rats; D018874:Spheroids, Cellular / Q000166:cytology* / Q000187:drug effects; D046509:Tissue Culture Techniques / Q000295:instrumentation / Q000379:methods*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide
keywords: Cyclophosphamide; Liver; Pro-drug activation; Tissue engineering; “Body on a Chip”