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A Microengineered Brain-Chip to Model Neuroinflammation in Humans

View ORCID ProfileI. Pediaditakis, View ORCID ProfileK. R. Kodella, View ORCID ProfileD. V. Manatakis, C. Y. Le, S. Barthakur, A. Sorets, A. Gravanis, L. Ewart, L. L. Rubin, E. S. Manolakos, C. D. Hinojosa, View ORCID ProfileK. Karalis
doi: https://doi.org/10.1101/2022.03.11.484005
I. Pediaditakis
1Emulate Inc., 27 Drydock Avenue, Boston, MA 02210, USA
9Vesalius Therapeutics Inc., 100 Binney St, Cambridge, MA, 02142, USA
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  • For correspondence: spediaditakis@vesaliustx.com katia.karalis@regeneron.com
K. R. Kodella
1Emulate Inc., 27 Drydock Avenue, Boston, MA 02210, USA
2University of Crete Medical School, Department of Pharmacology, Heraklion, 71110 Greece
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D. V. Manatakis
1Emulate Inc., 27 Drydock Avenue, Boston, MA 02210, USA
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C. Y. Le
1Emulate Inc., 27 Drydock Avenue, Boston, MA 02210, USA
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S. Barthakur
1Emulate Inc., 27 Drydock Avenue, Boston, MA 02210, USA
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A. Sorets
1Emulate Inc., 27 Drydock Avenue, Boston, MA 02210, USA
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A. Gravanis
2University of Crete Medical School, Department of Pharmacology, Heraklion, 71110 Greece
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L. Ewart
1Emulate Inc., 27 Drydock Avenue, Boston, MA 02210, USA
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L. L. Rubin
3Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
4Harvard Stem Cell Institute, Cambridge, MA, USA
5Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
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E. S. Manolakos
6Department of Informatics and Telecommunications, National and Kapodistrian University of Athens, Greece
7Northeastern University, Bouvé College of Health Sciences, Boston, MA, USA
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C. D. Hinojosa
1Emulate Inc., 27 Drydock Avenue, Boston, MA 02210, USA
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K. Karalis
1Emulate Inc., 27 Drydock Avenue, Boston, MA 02210, USA
8Endocrine Division, Children’s Hospital, Harvard Medical School, Boston, MA, USA
10Regeneron Pharmaceuticals, 777 Old Saw Mill River Rd, Tarrytown, NY, 10591, USA
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  • For correspondence: spediaditakis@vesaliustx.com katia.karalis@regeneron.com
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SUMMARY

Species differences in the brain and the blood-brain barrier (BBB) biology hamper the translation from animal models to humans and impede the development of specific therapeutics for brain diseases. Here we present a human Brain-Chip engineered to recapitulate critical aspects of the complex brain cell-cell interactions that mediate neuroinflammation development. Our human organotypic microphysiological system (MPS) includes endothelial-like cells, pericytes, glia, and cortical neurons and maintains BBB permeability at in vivo relevant levels, providing a significant improvement in complexity and clinical mimicry compared to previous MPS models. This is the first report of a Brain-Chip with an RNA expression profile close to that of the adult human cortex and that demonstrates advantages over Transwell culture. Through perfusion of TNF-α, we recreated key inflammatory features, such as glia activation, the release of proinflammatory cytokines, and increased barrier permeability. Our model may provide a reliable tool for mechanistic studies in neuron-glial interactions and dysregulation of BBB function during neuroinflammation.

Competing Interest Statement

I.P., K.R.K., D.V.M., C.Y.L, S.B., A.S., L.E., C.D.H., and K.K. are current or former employees of Emulate, Inc and may hold equity interests in Emulate, Inc. All other authors declare no competing interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 14, 2022.
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A Microengineered Brain-Chip to Model Neuroinflammation in Humans
I. Pediaditakis, K. R. Kodella, D. V. Manatakis, C. Y. Le, S. Barthakur, A. Sorets, A. Gravanis, L. Ewart, L. L. Rubin, E. S. Manolakos, C. D. Hinojosa, K. Karalis
bioRxiv 2022.03.11.484005; doi: https://doi.org/10.1101/2022.03.11.484005
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A Microengineered Brain-Chip to Model Neuroinflammation in Humans
I. Pediaditakis, K. R. Kodella, D. V. Manatakis, C. Y. Le, S. Barthakur, A. Sorets, A. Gravanis, L. Ewart, L. L. Rubin, E. S. Manolakos, C. D. Hinojosa, K. Karalis
bioRxiv 2022.03.11.484005; doi: https://doi.org/10.1101/2022.03.11.484005

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