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    A BIOMIMETIC MICROFLUIDIC DEVICE FOR MODELING THE LEUKOCYTE ADHESION/MIGRATION CASCADE

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    Genre
    Thesis/Dissertation
    Date
    2014
    Author
    Lamberti, Giuseppina
    Advisor
    Kiani, Mohammad F.
    Committee member
    Wang, Bin
    Prabhakarpandian, Balabhaskar
    Achary, Mohan P.
    Pillapakkam, Shriram
    Krynska, Barbara
    Department
    Mechanical Engineering
    Subject
    Engineering
    Engineering, Mechanical
    Inflammation
    Leukocyte
    Microfluidic Device
    Permanent link to this record
    http://hdl.handle.net/20.500.12613/3161
    
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    DOI
    http://dx.doi.org/10.34944/dspace/3143
    Abstract
    There is a clear need for testing targeted drug carrier systems in a more realistic microenvironment where both biochemical interactions and shear forces are present. This is critical both for understanding of the molecular mechanisms involved in this process and during the drug discovery process. Current in vitro models of the leukocyte adhesion cascade cannot be used for real-time studies of the entire leukocyte adhesion cascade including rolling, adhesion and migration in a single assay. In this study, we have developed and validated a novel bioinspired microfluidic device (bMFD) and used it to test the hypothesis that blocking of specific steps in the adhesion/migration cascade significantly affects other steps of the cascade. The bMFD consists of an endothelialized microvascular network in communication with a tissue compartment via a 3 µm porous barrier. Human neutrophils in bMFD preferentially adhered to activated human endothelial cells near bifurcations with rolling and adhesion patterns in close agreement with in vivo observations. Treating endothelial cells with monoclonal antibodies to E-selectin or ICAM-1 or treating neutrophils with wortmannin reduced rolling, adhesion, and migration of neutrophils to 60%, 20% and 18% of their respective control values. Antibody blocking of specific steps in the adhesion/migration cascade (e.g. mAb to E-selectin) significantly downregulated other steps of the cascade (e.g. migration). This novel in vitro assay provides a realistic human cell based model for basic science studies, identification of new treatment targets, selection of pathways to target validation, and rapid screening of candidate agents.
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