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      Effect of flow on targeting and penetration of angiopep-decorated nanoparticles in a microfluidic model blood-brain barrier

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          The blood-brain barrier (BBB) limits transport of nanoparticles from the circulation to the brain parenchyma. Angiopep-2, a peptide which functions as a brain transport vector, can be coupled to nanoparticles in order to facilitate binding and internalization by brain endothelial cells (ECs), and subsequent BBB penetration. This multi-step process may be affected by blood flow over brain ECs, as flow influences endothelial cell phenotype as well as interactions of nanoparticles with ECs. In the present study a microfluidic BBB model was constructed to evaluate binding and internalization by brain ECs, as well as BBB penetration of Angiopep-2 coupled liposomes (Ang2-Liposomes) in static and flow conditions. Ang2 conjugation to liposomes markedly improved binding relative to unconjugated liposomes. Ang2-Liposomes bound and were internalized efficiently by brain endothelial cells after static incubation or with 1 dyne/cm 2 of fluid shear stress (FSS), while binding was reduced at a FSS of 6 dyne/cm 2. Penetration of the model microfluidic BBB by Ang2-Liposomes was higher at a FSS of 1 dyne/cm 2 and 6 dyne/cm 2 than with static incubation. Analysis of barrier function and control experiments for receptor-mediated penetration provided insight into the magnitude of transcellular versus paracellular transport at each tested FSS. Overall, the results demonstrate that flow impacted the binding and BBB penetration of Ang2-functionalized nanoparticles. This highlights the relevance of the local flow environment for in vitro modeling of the performance of nanoparticles functionalized with BBB penetrating ligands.

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          Most cited references 75

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          Blood-brain barrier structure and function and the challenges for CNS drug delivery.

           N. Abbott (2013)
          The neurons of the central nervous system (CNS) require precise control of their bathing microenvironment for optimal function, and an important element in this control is the blood-brain barrier (BBB). The BBB is formed by the endothelial cells lining the brain microvessels, under the inductive influence of neighbouring cell types within the 'neurovascular unit' (NVU) including astrocytes and pericytes. The endothelium forms the major interface between the blood and the CNS, and by a combination of low passive permeability and presence of specific transport systems, enzymes and receptors regulates molecular and cellular traffic across the barrier layer. A number of methods and models are available for examining BBB permeation in vivo and in vitro, and can give valuable information on the mechanisms by which therapeutic agents and constructs permeate, ways to optimize permeation, and implications for drug discovery, delivery and toxicity. For treating lysosomal storage diseases (LSDs), models can be included that mimic aspects of the disease, including genetically-modified animals, and in vitro models can be used to examine the effects of cells of the NVU on the BBB under pathological conditions. For testing CNS drug delivery, several in vitro models now provide reliable prediction of penetration of drugs including large molecules and artificial constructs with promising potential in treating LSDs. For many of these diseases it is still not clear how best to deliver appropriate drugs to the CNS, and a concerted approach using a variety of models and methods can give critical insights and indicate practical solutions.
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            Characterization of a microfluidic in vitro model of the blood-brain barrier (μBBB).

            The blood-brain barrier (BBB), a unique selective barrier for the central nervous system (CNS), hinders the passage of most compounds to the CNS, complicating drug development. Innovative in vitro models of the BBB can provide useful insights into its role in CNS disease progression and drug delivery. Static transwell models lack fluidic shear stress, while the conventional dynamic in vitro BBB lacks a thin dual cell layer interface. To address both limitations, we developed a microfluidic blood-brain barrier (μBBB) which closely mimics the in vivo BBB with a dynamic environment and a comparatively thin culture membrane (10 μm). To test validity of the fabricated BBB model, μBBBs were cultured with b.End3 endothelial cells, both with and without co-cultured C8-D1A astrocytes, and their key properties were tested with optical imaging, trans-endothelial electrical resistance (TEER), and permeability assays. The resultant imaging of ZO-1 revealed clearly expressed tight junctions in b.End3 cells, Live/Dead assays indicated high cell viability, and astrocytic morphology of C8-D1A cells were confirmed by ESEM and GFAP immunostains. By day 3 of endothelial culture, TEER levels typically exceeded 250 Ω cm(2) in μBBB co-cultures, and 25 Ω cm(2) for transwell co-cultures. Instantaneous transient drop in TEER in response to histamine exposure was observed in real-time, followed by recovery, implying stability of the fabricated μBBB model. Resultant permeability coefficients were comparable to previous BBB models, and were significantly increased at higher pH (>10). These results demonstrate that the developed μBBB system is a valid model for some studies of BBB function and drug delivery.
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              The cell biology of the blood-brain barrier.

              The blood-brain barrier (BBB) is formed by brain capillary endothelial cells (ECs). In the late embryonic and early postnatal period, these cells respond to inducing factors found in the brain environment by adopting a set of defined characteristics, including high-electrical-resistance tight junctions. Although the factors have not been identified definitively, a great deal of information about brain ECs has been obtained, especially recently. This review concentrates on a cell biological analysis of the BBB, with an emphasis on regulation of the specialized intercellular junctions. The development of these junctions seems to depend on two primary processes: the appearance of high levels of the tight junction protein occludin and intracellular signaling processes that control the state of phosphorylation of junctional proteins. Recent studies have revealed that the BBB can be modulated in an ongoing way to respond to environmental stimuli.

                Author and article information

                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: MethodologyRole: ResourcesRole: Supervision
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: ResourcesRole: SupervisionRole: ValidationRole: Writing – review & editing
                Role: Editor
                PLoS One
                PLoS ONE
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                9 October 2018
                : 13
                : 10
                [1 ] Department of Mechanical Engineering, Boston University, Boston, Massachusetts, United States of America
                [2 ] Human Organ Systems, Draper Laboratory, Cambridge, Massachusetts, United States of America
                [3 ] Department of Biomedical Engineering, Boston University, Boston, Massachusetts, United States of America
                Hungarian Academy of Sciences, HUNGARY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                © 2018 Papademetriou et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 5, Tables: 0, Pages: 18
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: R01EB016102
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: R21 NS105837
                Award Recipient :
                Funding for this study was provided by the National Institutes of Health grants R01EB016102 and R21 NS105837 (TP), www.nih.gov. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Research Article
                Biology and Life Sciences
                Cell Biology
                Cellular Structures and Organelles
                Engineering and Technology
                Engineering and Technology
                Physical Sciences
                Classical Mechanics
                Continuum Mechanics
                Fluid Mechanics
                Fluid Dynamics
                Fluid Flow
                Biology and Life Sciences
                Physical Sciences
                Materials Science
                Material Properties
                Biology and Life Sciences
                Cell Biology
                Cell Physiology
                Cell Binding
                Physical Sciences
                States of Matter
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                All relevant data are within the manuscript and its Supporting Information files.



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