01981nas a2200313   4500000000100000000000100001008004100002260001500043653002700058653002600085653002700111100002300138700002600161700002600187700002200213700002200235700002100257700002100278700001600299700001700315700002300332700002800355700001800383245007000401300001100471490000700482520116400489022001401653       2022                            d  c2022-08-1910aBiomedical Engineering10aCellular neuroscience10aMolecular neuroscience1 aIosif Pediaditakis1 aKonstantia R. Kodella1 aDimitris V. Manatakis1 aChristopher Y. Le1 aSonalee Barthakur1 aAlexander Sorets1 aAchille Gravanis1 aLorna Ewart1 aLee L. Rubin1 aElias S. Manolakos1 aChristopher D. Hinojosa1 aKatia Karalis00aA microengineered Brain-Chip to model neuroinflammation in humans  a1048130 v253 aSpecies 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.  a2589-0042