A microengineered Brain-Chip to model neuroinflammation in humans

Iosif Pediaditakis; Konstantia R Kodella; Dimitris V Manatakis; Christopher Y Le; Sonalee Barthakur; Alexander Sorets; Achille Gravanis; Lorna Ewart; Lee L Rubin; Elias S Manolakos; Christopher D Hinojosa; Katia Karalis

doi:10.1016/j.isci.2022.104813

A microengineered Brain-Chip to model neuroinflammation in humans

iScience. 2022 Jul 21;25(8):104813. doi: 10.1016/j.isci.2022.104813. eCollection 2022 Aug 19.

Authors

Affiliations

¹ Emulate Inc., 27 Drydock Avenue, Boston, MA 02210, USA.
² University of Crete Medical School, Department of Pharmacology, Heraklion, 71110 Greece.
³ Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
⁴ Harvard Stem Cell Institute, Cambridge, MA, USA.
⁵ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
⁶ Department of Informatics and Telecommunications, National and Kapodistrian University of Athens, Greece.
⁷ Northeastern University, Bouvé College of Health Sciences, Boston, MA, USA.
⁸ Endocrine Division, Children's Hospital, Harvard Medical School, Boston, MA, USA.

Abstract

Species differences in brain and blood-brain barrier (BBB) biology hamper the translation of findings from animal models to humans, impeding the development of therapeutics for brain diseases. Here, we present a human organotypic microphysiological system (MPS) that includes endothelial-like cells, pericytes, glia, and cortical neurons and maintains BBB permeability at in vivo relevant levels. This human Brain-Chip engineered to recapitulate critical aspects of the complex interactions that mediate neuroinflammation and demonstrates significant improvements in clinical mimicry compared to previously reported similar MPS. In comparison to Transwell culture, the transcriptomic profiling of the Brain-Chip displayed significantly advanced similarity to the human adult cortex and enrichment in key neurobiological pathways. Exposure to TNF-α recreated the anticipated inflammatory environment shown by glia activation, increased release of proinflammatory cytokines, and compromised barrier permeability. We report the development of a robust brain MPS for mechanistic understanding of cell-cell interactions and BBB function during neuroinflammation.

Keywords: Biomedical engineering; Cellular neuroscience; Molecular neuroscience.

Grants and funding

UG3 TR002188/TR/NCATS NIH HHS/United States