A Microfluidic Multisize Spheroid Array for Multiparametric Screening of Anticancer Drugs and Blood–Brain Barrier Transport Properties

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  • Christoph Eilenberger
    Faculty of Technical Chemistry Vienna University of Technology Getreidemarkt 9 Vienna 1060 Austria
  • Mario Rothbauer
    Faculty of Technical Chemistry Vienna University of Technology Getreidemarkt 9 Vienna 1060 Austria
  • Florian Selinger
    Faculty of Technical Chemistry Vienna University of Technology Getreidemarkt 9 Vienna 1060 Austria
  • Anna Gerhartl
    AIT Austrian Institute of Technology GmbH Center Health and Bioresources Competence Unit Molecular Diagnostics Giefinggasse 4 Vienna 1210 Austria
  • Christian Jordan
    Faculty of Technical Chemistry Vienna University of Technology Getreidemarkt 9 Vienna 1060 Austria
  • Michael Harasek
    Faculty of Technical Chemistry Vienna University of Technology Getreidemarkt 9 Vienna 1060 Austria
  • Barbara Schädl
    Ludwig‐Boltzmann‐Institute for Experimental and Clinical Traumatology Donaueschingenstraße 13 Vienna 1200 Austria
  • Johannes Grillari
    Ludwig‐Boltzmann‐Institute for Experimental and Clinical Traumatology Donaueschingenstraße 13 Vienna 1200 Austria
  • Julian Weghuber
    School of Engineering University of Applied Sciences Upper Austria Stelzhamerstraße 23 Wels 4600 Austria
  • Winfried Neuhaus
    AIT Austrian Institute of Technology GmbH Center Health and Bioresources Competence Unit Molecular Diagnostics Giefinggasse 4 Vienna 1210 Austria
  • Seta Küpcü
    Institute of Synthetic Bioarchitectures Department of Nanobiotechnology University of Natural Resources and Life Sciences Vienna, Muthgasse 11 Vienna 1190 Austria
  • Peter Ertl
    Faculty of Technical Chemistry Vienna University of Technology Getreidemarkt 9 Vienna 1060 Austria

説明

<jats:title>Abstract</jats:title><jats:p>Physiological‐relevant in vitro tissue models with their promise of better predictability have the potential to improve drug screening outcomes in preclinical studies. Despite the advances of spheroid models in pharmaceutical screening applications, variations in spheroid size and consequential altered cell responses often lead to nonreproducible and unpredictable results. Here, a microfluidic multisize spheroid array is established and characterized using liver, lung, colon, and skin cells as well as a triple‐culture model of the blood‐brain barrier (BBB) to assess the effects of spheroid size on (a) anticancer drug toxicity and (b) compound penetration across an advanced BBB model. The reproducible on‐chip generation of 360 spheroids of five dimensions on a well‐plate format using an integrated microlens technology is demonstrated. While spheroid size‐related IC<jats:sub>50</jats:sub> values vary up to 160% using the anticancer drugs cisplatin (CIS) or doxorubicin (DOX), reduced CIS:DOX drug dose combinations eliminate all lung microtumors independent of their sizes. A further application includes optimizing cell seeding ratios and size‐dependent compound uptake studies in a perfused BBB model. Generally, smaller BBB‐spheroids reveal an 80% higher compound penetration than larger spheroids while verifying the BBB opening effect of mannitol and a spheroid size‐related modulation on paracellular transport properties.</jats:p>

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