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Creators/Authors contains: "DeOre, Brandon J."

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  1. Abstract

    Previous in vitro studies interrogating the endothelial response to physiologically relevant flow regimes require specialized pumps to deliver time‐dependent waveforms that imitate in vivo blood flow. The aim of this study is to create a low‐cost and broadly adaptable approach to mimic physiological flow, and then use this system to characterize the effect of flow separation on velocity and shear stress profiles in a three‐dimensional (3D) topology. The flow apparatus incorporates a programmable linear actuator that superposes oscillations on a constant mean flow driven by a peristaltic pump to emulate flow in the carotid artery. The flow is perfused through a 3D in vitro model of the blood–brain barrier designed to induce separated flow. Experimental flow patterns measured by microparticle image velocimetry and modeled by computational fluid dynamics reveal periodic changes in the instantaneous shear stress along the channel wall. Moreover, the time‐dependent flow causes periodic flow separation zones, resulting in variable reattachment points during the cycle. The effects of these complex flow regimes are assessed by evaluating the integrity of the in vitro blood–brain barrier model. Permeability assays and immunostaining for proteins associated with tight junctions reveal barrier breakdown in the region of disturbed flow. In conclusion, the flow system described here creates complex, physiologically relevant flow profiles that provide deeper insight into the fluid dynamics of separated flow and pave the way for future studies interrogating the cellular response to complex flow regimes.

     
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  3. Abstract

    Cellular mechanics encompass both mechanical properties that resist forces applied by the external environment and internally generated forces applied at the location of cell–cell and cell–matrix junctions. Here, the authors demonstrate that microindentation of cellular domes formed by cell monolayers that locally lift off the substrate provides insight into both aspects of cellular mechanics in multicellular structures. Using a modified Hertz contact equation, the force–displacement curves generated by a micro‐tensiometer are used to measure an effective dome stiffness. The results indicate the domes are consistent with the Laplace–Young relationship for elastic membranes, regardless of biochemical modulation of the RhoA‐ROCK signaling axis. In contrast, activating RhoA, and inhibiting ROCK both alter the relaxation dynamics of the domes deformed by the micro‐tensiometer, revealing an approach to interrogate the role of RhoA‐ROCK signaling in multicellular mechanics. A finite element model incorporating a Mooney–Rivlin hyperelastic constitutive equation to describe monolayer mechanics predicts effective stiffness values that are consistent with the micro‐tensiometer measurements, verifying previous measurements of the response of cell monolayers to tension. Overall, these studies establish microindentation of fluid‐filled domes as an avenue to investigate the contribution of cell‐generated forces to the mechanics of multicellular structures.

     
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