02159nas a2200253   4500000000100000000000100001008004100002653003300043653002800076653004000104653002300144100001800167700001800185700001600203700001700219700001600236700001700252245011300269856006700382300001100449490000800460520142300468022001401891                                       d10abrain microvascular networks10aendothelial dysfunction10aflavivirus non-structural protein 110amicrofluidic chips1 aMonika Rajput1 aYen-Ting Tung1 aYu-Chi Chen1 aMin Jae Song1 aMarc Ferrer1 aEmily M. Lee00aPerfusable Brain Microvascular Network-On-Chip Model to Study Flavivirus NS1-Induced Endothelial Dysfunction  uhttps://onlinelibrary.wiley.com/doi/abs/10.1002/adfm.202504476  ae044760 vn/a3 aFlaviviruses can lead to severe neurotropic-encephalitic pathology, for which the viral nonstructural protein 1 (NS1) plays a major role. 2D in vitro cellular systems and animal models are currently used to investigate the effects of flavivirus NS1 in the brain-blood barrier do not fully capture pathogenesis and drug responses seen in humans. Here is reported the development of a perfusable human brain microvascular network-on-a-chip (BMVasChip) model which incorporates brain endothelial cells and pericytes and recapitulates the cellular organization and expression of brain blood barrier-specific markers, including intracellular junction proteins. This BMVasChip model is used to investigate vasculopathy caused by exposure to a panel of flavivirus NS1 proteins, including Japanese encephalitis (JEV), West Nile (WNV), and dengue virus (DENV) NS1 proteins. The BMVasChip platform is able to demonstrate flavivirus NS1-induced pathophysiological phenotypes in the BMVasChip, including early and late endothelial activation and dysfunction features such as loss of barrier integrity, morphological features, and production of pro-inflammatory markers in a virus, dose, and time-dependent manner. In summary, the BMVasChip model recapitulates key features of endothelial dysfunction, potentially reflecting NS1's role in viral pathogenesis and providing targets for antiviral therapeutics and vaccine development.  a1616-3028