Hypoxia-enhanced Blood-Brain Barrier Chip recapitulates human barrier function, drug penetration, and antibody shuttling properties

The highly specialized human brain microvascular endothelium forms a selective blood-brain barrier (BBB) with adjacent pericytes and astrocytes that restricts delivery of many pharmaceuticals and therapeutic antibodies to the central nervous system. Here, we describe an in vitro microfluidic 'o...

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Bibliographic Details
Published inbioRxiv
Main Authors Park, Tae-Eun, Mustafaoglu, Nur, Herland, Anna, Hasselkus, Ryan M, Mannix, Robert, Fitzgerald, Edward A, Prantil-Baun, Rachelle, Watters, Alexander, Henry, Olivier, Benz, Maximilian, Sanchez, Henry, Mccrea, Heather J, Goumnerova, Liliana Christova, Song, Hannah W, Palecek, Sean P, Shusta, Eric, Ingber, Donald E
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 29.11.2018
Subjects
Antibodies
Astrocytes
Biochips
Blood-brain barrier
Brain
Brain stem
Cell culture
Central nervous system
Drug delivery
Drug development
Endothelium
Hypoxia
Immunoglobulins
Microfluidics
Microvasculature
Pericytes
Pluripotency
Stem cells
Transferrins
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Summary:The highly specialized human brain microvascular endothelium forms a selective blood-brain barrier (BBB) with adjacent pericytes and astrocytes that restricts delivery of many pharmaceuticals and therapeutic antibodies to the central nervous system. Here, we describe an in vitro microfluidic 'organ-on-a-chip' (Organ Chip) model of the BBB lined by induced pluripotent stem cell-derived human brain microvascular endothelium (iPS-BMVEC) 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, multiple functional efflux pumps, and displays selective transcytosis of peptides and anti-transferrin receptor antibodies previously observed in vivo. This increased level of 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.
DOI:10.1101/482463