A microengineered Brain-Chip to model neuroinflammation in humans

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. [Display omitted] •The Brain-Chip captures complex functional interactions in the neurovascular unit•The Brain-Chip displays in vivo-like gene expression signatures•Upon TNF-α exposure, Brain-Chip reproduces key features of neuroinflammation•Key readouts include markers of glial activation and increased barrier permeability Molecular neuroscience; Cellular neuroscience; Biomedical engineering