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Hypoxia-enhanced Blood-Brain Barrier Chip recapitulates human barrier function and shuttling of drugs and antibodies

Author

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  • Tae-Eun Park

    (Wyss Institute for Biologically Inspired Engineering at Harvard University
    Ulsan National Institute of Science and Technology (UNIST))

  • Nur Mustafaoglu

    (Wyss Institute for Biologically Inspired Engineering at Harvard University)

  • Anna Herland

    (Wyss Institute for Biologically Inspired Engineering at Harvard University
    KTH Royal Institute of Technology
    Karolinska Institute)

  • Ryan Hasselkus

    (Wyss Institute for Biologically Inspired Engineering at Harvard University)

  • Robert Mannix

    (Wyss Institute for Biologically Inspired Engineering at Harvard University
    Boston Children’s Hospital and Harvard Medical School)

  • Edward A. FitzGerald

    (Wyss Institute for Biologically Inspired Engineering at Harvard University)

  • Rachelle Prantil-Baun

    (Wyss Institute for Biologically Inspired Engineering at Harvard University)

  • Alexander Watters

    (Wyss Institute for Biologically Inspired Engineering at Harvard University)

  • Olivier Henry

    (Wyss Institute for Biologically Inspired Engineering at Harvard University)

  • Maximilian Benz

    (Wyss Institute for Biologically Inspired Engineering at Harvard University)

  • Henry Sanchez

    (Wyss Institute for Biologically Inspired Engineering at Harvard University)

  • Heather J. McCrea

    (Boston Children’s Hospital and Harvard Medical School)

  • Liliana Christova Goumnerova

    (Boston Children’s Hospital and Harvard Medical School)

  • Hannah W. Song

    (University of Wisconsin-Madison)

  • Sean P. Palecek

    (University of Wisconsin-Madison)

  • Eric Shusta

    (University of Wisconsin-Madison)

  • Donald E. Ingber

    (Wyss Institute for Biologically Inspired Engineering at Harvard University
    Harvard University
    Boston Children’s Hospital and Harvard Medical School)

Abstract

The high selectivity of the human blood-brain barrier (BBB) restricts delivery of many pharmaceuticals and therapeutic antibodies to the central nervous system. Here, we describe an in vitro microfluidic organ-on-a-chip BBB model lined by induced pluripotent stem cell-derived human brain microvascular endothelium interfaced with primary human brain astrocytes and pericytes that recapitulates the high level of barrier function of the in vivo human BBB for at least one week in culture. The endothelium expresses high levels of tight junction proteins and functional efflux pumps, and it displays selective transcytosis of peptides and antibodies previously observed in vivo. Increased barrier functionality was accomplished using a developmentally-inspired induction protocol that includes a period of differentiation under hypoxic conditions. This enhanced BBB Chip may therefore represent a new in vitro tool for development and validation of delivery systems that transport drugs and therapeutic antibodies across the human BBB.

Suggested Citation

  • Tae-Eun Park & Nur Mustafaoglu & Anna Herland & Ryan Hasselkus & Robert Mannix & Edward A. FitzGerald & Rachelle Prantil-Baun & Alexander Watters & Olivier Henry & Maximilian Benz & Henry Sanchez & He, 2019. "Hypoxia-enhanced Blood-Brain Barrier Chip recapitulates human barrier function and shuttling of drugs and antibodies," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10588-0
    DOI: 10.1038/s41467-019-10588-0
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    Cited by:

    1. Vicky Chou & Richard V. Pearse & Aimee J. Aylward & Nancy Ashour & Mariko Taga & Gizem Terzioglu & Masashi Fujita & Seeley B. Fancher & Alina Sigalov & Courtney R. Benoit & Hyo Lee & Matti Lam & Nicho, 2023. "INPP5D regulates inflammasome activation in human microglia," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
    2. Iosif Pediaditakis & Konstantia R. Kodella & Dimitris V. Manatakis & Christopher Y. Le & Chris D. Hinojosa & William Tien-Street & Elias S. Manolakos & Kostas Vekrellis & Geraldine A. Hamilton & Lorna, 2021. "Modeling alpha-synuclein pathology in a human brain-chip to assess blood-brain barrier disruption," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    3. Huan Chen & Ting Li & Zhiyong Liu & Shuwan Tang & Jintao Tong & Yingfang Tao & Zinan Zhao & Nan Li & Chun Mao & Jian Shen & Mimi Wan, 2023. "A nitric-oxide driven chemotactic nanomotor for enhanced immunotherapy of glioblastoma," Nature Communications, Nature, vol. 14(1), pages 1-21, December.

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