02694nas a2200373   4500000000100000000000100001008004100002653001700043653002300060653002300083653002400106100001600130700002400146700002400170700002200194700002100216700002100237700001700258700001700275700001600292700002200308700001800330700002300348700002100371700002200392700002100414700002100435245015700456856006700613300001100680490000800691520160700699022001402306                                       d10aastrogliosis10abarrier resilience10afluid shear stress10ahuman BBB-on-a-chip1 aKaihua Chen1 aIsabelle M. Linares1 aMichelle A. Trempel1 aAlexis M. Feidler1 aDinindu De Silva1 aSami Farajollahi1 aJordan Jones1 aJulia Kuebel1 aPelin Kasap1 aBritta Engelhardt1 aJonathan Flax1 aVinay V. Abhyankar1 aRichard E. Waugh1 aHarris A. Gelbard1 aNiccolo Terrando1 aJames L. McGrath00aShear Conditioning Promotes Microvascular Endothelial Barrier Resilience in a Human BBB-on-a-Chip Model of Systemic Inflammation Leading to Astrogliosis  uhttps://onlinelibrary.wiley.com/doi/abs/10.1002/advs.202508271  ae082710 vn/a3 aThe blood–brain barrier (BBB) maintains cerebral homeostasis and protects the central nervous system (CNS) during systemic inflammation. Advanced in vitro models integrating circulation, a functional BBB, and reactive glial cells are essential for studying the link between peripheral inflammation and neuroinflammation. Fluid shear stress, a key hemodynamic parameter, strengthens microvascular barriers. This study examines endothelial shear conditioning on barrier function in a fluidic µSiM-BBB (Microphysiological System featuring a Silicon Membrane –BBB). hiPSC-derived brain microvascular endothelial cell monocultures are conditioned with 0.5 Pa shear stress for 48 h. Shear conditioning lowers baseline permeability, increases glycocalyx production, and reduces responses to inflammatory challenges, including barrier breakdown, ICAM-1 upregulation, and neutrophil transmigration. Shear conditioning produces a resilient barrier function against a low-dose inflammatory challenge (10 pg mL−1 TNF-α/IL1-β/INF-γ) but a high-dose challenge (50 pg mL−1) disrupts the barrier. Adding astrocytes as neuroinflammatory “sensors” reveals that a high-dose inflammatory challenge activates astrocytes but only in combination with fibrinogen—a plasma protein known to trigger astrogliosis in multiple neurological conditions. This study highlights the utility of fluidic-enabled µSiM-BBB for investigating acute peripheral inflammation and brain injury relationships, serving as a foundation for more advanced models, including more cells of the neurovascular unit and brain parenchyma.  a2198-3844