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Interstitial Flow Promotes the Formation of Functional Microvascular Networks In Vitro through Upregulation of Matrix Metalloproteinase-2

机译:Interstitial Flow Promotes the Formation of Functional Microvascular Networks In Vitro through Upregulation of Matrix Metalloproteinase-2

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摘要

Self-organized microvascular networks (MVNs) have become key to the developmentof many microphysiological models. However, the self-organizingnature of this process combined with variations between types or batches ofendothelial cells (ECs) often lead to inconsistency or failure to form functionalMVNs. Because interstitial flow (IF) has been reported to play a beneficial rolein angiogenesis, vasculogenesis, and 3D capillary morphogenesis, the roleIF plays during neovessel formation in a customized single-channel microfluidicchip for which IF has been fully characterized is systematically investigated.Compared to static conditions, MVNs formed under IF have highervessel density and diameters and greater network perfusability. Through aseries of inhibitory experiments, this study demonstrates that IF treatmentimproves vasculogenesis by ECs through upregulation of matrix metalloproteinase-2 (MMP-2). This study then successfully implements a novel strategyinvolving the interplay between IF and MMP-2 inhibitor to regulate morphologicalparameters of the self-organized MVNs, with vascular permeabilityand perfusability well maintained. The revealed mechanism and proposedmethodology are further validated with a brain MVN model. The findings andmethods have the potential to be widely utilized to boost the developmentof various organotypic MVNs and can be incorporated into related bioengineeringapplications where perfusable vasculature is desired.

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