Microtissue and Barrier Systems
In-vitro cell-based assays play a key role in the overall process of drug discovery and can provide essential information on the efficacy and toxicity of new compounds. Moreover, such advanced in-vitro systems offer the possibility of using human-based cell material and to replace animal experiments. In order to increase the predictability of such assays, 3-dimensional tissue constructs and barrier models receive more and more attention, as they better recapitulate in-vivo properties. We work with spherical microtissues, produced by the hanging drop technology, as they are comparably simple and reproducible to fabricate, and possess organotypic functionality and biomimetic morphology. Their spherical shape and compact constitution make them ideal candidates for handling in microfluidic structures. In addition, we develop a range of membrane-based barrier models, e.g., for placenta, blood-brain barrier or lung and bladder.
Microtissues of different cell types can be formed on or off-chip in hanging drops. Off-chip generated microtissues can be directly transferred into the microfluidic chips, the microtissue compartments of which are fluidically interconnected to simulate metabolite-exchange in a physiologically relevant arrangement.
As the microtissues mostly include adherent cells (liver, heart, pancreas etc.), one has to apply methods, where the spheroids do not adhere to surfaces and, thereby, remain intact over extended experimentation times. One possibility is to use the concept of "hanging-drop networks", in which the spheroids are located at the liquid-air-interface at the bottom of the hanging drops. The hanging drops are then interconnected via microfluidic channels to provide perfusion, supply of nutrients, dosage of compounds, or to interconnect them to other tissue types to realize "body-on-a-chip" arrangements.
Another possibility is to host the spheroids in microtissue compartments in well plates, which are continuously tilted in a rocking-like motion, so that the spheroids constantly perform slight motions and cannot adhere to the surface, which additionallly is coated with non-adhesive films. The tilting motion also ensures perfusion and enables metabolic tissue interaction through the connection channels.
Ultimately, both approaches allow for mimicking conditions of the human body and for predicting the impact of new compounds on multi-organ systems.
Collaborations
InSphero AG, Zurich, Switzerland; Zurich Instruments AG, Zurich, Switzerland; University Hospital Zurich, Switzerland, Department of Biomedicine University of Basel, Switzerland.
Recent publications
W. Wei, F. Cardes, A. Hierlemann, M. Modena, "3D in vitro blood-brain-barrier model for investigating barrier insults", Advanced Science 2023, Article 2205752 (DOI: 10.1002/advs.202205752). external pageOnline
C. Lohasz, J. Loretan, D. Sterker, E. Görlach, K. Renggli, P. Argast, O. Frey, M. Wiesmann, M. Wartmann, M. Rausch, A. Hierlemann, "A microphysiological cell-culturing system for pharmacokinetic drug exposure and high-resolution imaging of arrays of 3D microtissues", Frontiers in Pharmacology 2021,12:785851 (DOI: 10.3389/fphar.2021.785851). external pageOnline
J. Boos, P. Misun, G. Brunoldi, L. Furer, L. Aengenheister, M. Modena, N. Rousset, T. Buerki-Thurnherr, Andreas Hierlemann, "Microfluidic co-culture platform to recapitulate the maternal–placental–embryonic axis", Advanced Biology 2021, Article 2100609 (DOI: 10.1002/adbi.202100609). external pageOnline.
O.T. P. Nguyen, P. M. Misun, C. Lohasz, J. Lee, W. Wang, T. Schroeder, A. Hierlemann, "An immunocompetent microphysiological system to simultaneously investigate effects of anti-tumor natural killer cells on tumor and cardiac microtissues", Frontiers in Immunology 2021, Article 781337 (DOI: 10.3389/fimmu.2021.781337). external pageOnline
P. Misun, B. Yesildag, F. Forschler, A. Neelakandhan, N. Rousset, A. Biernath, A. Hierlemann, O. Frey, "In-vitro platform for studying human insulin release dynamics of single pancreatic islet microtissues at high resolution", Advanced Biosystems 2020, Article 1900291 (DOI: 10.1002/adbi.201900291). external pageOnline
C. Lohasz, F. Bonanini, L. Hoelting, K. Renggli, O. Frey, A. Hierlemann, "Predicting metabolism‐related drug–drug interactions using a microphysiological multitissue system", Advanced Biosystems 2020, Article 2000079 (DOI: 10.1002/adbi.202000079). external pageOnline
J. Boos, P. Misun, A. Michlmayr, A. Hierlemann, O. Frey, "Microfluidic multitissue platform for advanced embryotoxicity testing in vitro", Advanced Science 2019, Article 1900294 (DOI: 10.1002/advs.201900294). external pageOnline
K. Renggli, N. Rousset, C. Lohasz, O.T.P. Nguyen, A. Hierlemann, "Integrated microphysiological systems: Transferable organ models and recirculating flow", Advanced Biosystems 2019, 1900018 (DOI: 10.1002/adbi.201900018). external pageOnline