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

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, Heather J. McCrea, Liliana Christova Goumnerova, Hannah W. Song, Sean P. Palecek, Eric Shusta and Donald E. Ingber ()
Additional contact information
Tae-Eun Park: Wyss Institute for Biologically Inspired Engineering at Harvard University
Nur Mustafaoglu: Wyss Institute for Biologically Inspired Engineering at Harvard University
Anna Herland: Wyss Institute for Biologically Inspired Engineering at Harvard University
Ryan Hasselkus: Wyss Institute for Biologically Inspired Engineering at Harvard University
Robert Mannix: Wyss Institute for Biologically Inspired Engineering at Harvard University
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

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10588-0

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