Barrier Systems

Two-dimensional (2D) cell-culture models on standard microplates are the most widely used method for compound and cytotoxicity screening. However, these models fail to mimic the complex interactions and communication between different cell types in physiological barrier systems, such as lung, bladder, placenta or the blood-brain barrier, which leads to a poor representation of organ and organism functions. To address this limitation, advanced in vitro 3D models that incorporate multiple cell types, complex 3D architectures and that better replicate the dynamic microenvironment of organs are needed for preclinical drug-discovery platforms.

We work on dynamic 3D cell-culture techniques of barrier tissues to overcome the limitations of conventional static cell-culture models in well-plates or transwell systems. Detection systems encompass - besides high-resolution microscopy - standard bioassays, such as adenosine triphosphate (ATP) measurements and mass spectrometry (MS).

Enlarged view: Schematic of experimental setup for culturing and imaging of transwell-insert based airway models in microfluidic platform. — Example of a dynamic microfluidic culturing and testing setup for barrier tissue. The setup enables high-resolution imaging and dynamic medium changes and exposure to drugs on both apical and basolateral side. The tissue (e.g., lung and bladder tissue) is cultured at the bottom side of the transwell insert.

Our blood-brain barrier (BBB) system, for example, features a pump-and tubing free design for parallelization of the platform, an asymmetric gravity-driven medium flow to deliver O₂ and nutrients and to expose the endothelial cell layer to shear stress, the possibility to perform high-resolution confocal imaging and real-time monitoring of the transepithelial electric resistance (TEER), as well as sampling on both sides of the cellular barrier.

Enlarged view: Microfluidic BBB model — Schematic (left) and photo (right) of a blood-brain-barrier (BBB) model, integrated with transparent indium tin oxide electrodes for continuous high-resolution microscopy and measurement of trans-endothelial electrical resistance (TEER). ECs: endothelial cells; HPs: human pericytes; HAs: human astrocytes. Eight BBB units are arranged in a well-plate format (bottom right).

We are developing microfluidic platforms for different barrier tissues and different applications that feature simple but robust operation and live-cell imaging of the cells forming the barrier. Dynamic liquid flow is realized by tilting of the platform. Current efforts include investigations of the blood-brain-barrier, also in the context of brain cancer or glioma, investigations of lung and bladder tissue in the context of bacterial infections and investigations of placental tissue with the aim to study nano- and microparticle permeation and infections.

Enlarged view: Characterization of lung tissue by means of microfluidid model systems — High-resolution real-time live-cell imaging - using our system - of a bacterial infection (pseudomonas aeruginosa) of lung tissue at 19 hours post infection when tissue breaching of the bacteria occurs. Top panel: cross-sectional view of the lung tissue and indication of the image plane of the confocal images in the lower panels (apical, intermediate, basal). Large parts of the tissue are already destroyed on the apical side, when the infection breaks through to the basal side (Collaboration with the Jenal group at the Biozentrum, University of Basel).

Relevant publications

A. Kurmashev, J. Boos, B. Laventie, L. Swart, R. Sütterlin, T. Junne, U. Jenal, A. Hierlemann, "Transwell-based microfluidic platform for high-resolution imaging of airway tissues", Adv. Mater. Technol. 2024, Article 2400326 (DOI: 10.1002/admt.202400326). external page Online

O. Nguyen, P. Misun, A. Hierlemann, C. Lohasz, "A versatile intestine-on-chip system for deciphering the immunopathogenesis of inflammatory bowel disease", Advanced Healthcare Materials 2024, 13, Article 2302454 (DOI: 10.1002/adhm.202302454). external page Online

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 page Online

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 page Online.

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