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      Microengineered human blood–brain barrier platform for understanding nanoparticle transport mechanisms

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          Abstract

          Challenges in drug development of neurological diseases remain mainly ascribed to the blood–brain barrier (BBB). Despite the valuable contribution of animal models to drug discovery, it remains difficult to conduct mechanistic studies on the barrier function and interactions with drugs at molecular and cellular levels. Here we present a microphysiological platform that recapitulates the key structure and function of the human BBB and enables 3D mapping of nanoparticle distributions in the vascular and perivascular regions. We demonstrate on-chip mimicry of the BBB structure and function by cellular interactions, key gene expressions, low permeability, and 3D astrocytic network with reduced reactive gliosis and polarized aquaporin-4 (AQP4) distribution. Moreover, our model precisely captures 3D nanoparticle distributions at cellular levels and demonstrates the distinct cellular uptakes and BBB penetrations through receptor-mediated transcytosis. Our BBB platform may present a complementary in vitro model to animal models for prescreening drug candidates for the treatment of neurological diseases.

          Abstract

          Developing an in vitro blood-brain-barrier (BBB) model that reproduces the organ’s complex structure and function is an open challenge. Here the authors present a BBB-on-a-chip that includes endothelial cells, pericytes and a 3D astrocytic network which resembles the morphology and function of astrocytes in the BBB in vivo.

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          Most cited references 68

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          Blood-brain barrier delivery.

          Neuropharmaceutics is the largest potential growth sector of the pharmaceutical industry. However, this growth is blocked by the problem of the blood-brain barrier (BBB). Essentially 100% of large-molecule drugs and >98% of small-molecule drugs do not cross the BBB. The BBB can be traversed because there are multiple endogenous transporters within this barrier. Therefore, brain drug development programs of the future need to be re-configured so that drugs are formulated to enable transport into the brain via endogenous BBB transporters.
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            Astrocyte-endothelial interactions at the blood-brain barrier.

            The blood-brain barrier, which is formed by the endothelial cells that line cerebral microvessels, has an important role in maintaining a precisely regulated microenvironment for reliable neuronal signalling. At present, there is great interest in the association of brain microvessels, astrocytes and neurons to form functional 'neurovascular units', and recent studies have highlighted the importance of brain endothelial cells in this modular organization. Here, we explore specific interactions between the brain endothelium, astrocytes and neurons that may regulate blood-brain barrier function. An understanding of how these interactions are disturbed in pathological conditions could lead to the development of new protective and restorative therapies.
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              Structure and function of the blood-brain barrier.

              Neural signalling within the central nervous system (CNS) requires a highly controlled microenvironment. Cells at three key interfaces form barriers between the blood and the CNS: the blood-brain barrier (BBB), blood-CSF barrier and the arachnoid barrier. The BBB at the level of brain microvessel endothelium is the major site of blood-CNS exchange. The structure and function of the BBB is summarised, the physical barrier formed by the endothelial tight junctions, and the transport barrier resulting from membrane transporters and vesicular mechanisms. The roles of associated cells are outlined, especially the endfeet of astrocytic glial cells, and pericytes and microglia. The embryonic development of the BBB, and changes in pathology are described. The BBB is subject to short and long-term regulation, which may be disturbed in pathology. Any programme for drug discovery or delivery, to target or avoid the CNS, needs to consider the special features of the BBB.
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                Author and article information

                Contributors
                ytkim@gatech.edu
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                10 January 2020
                10 January 2020
                2020
                : 11
                Affiliations
                [1 ]ISNI 0000 0001 2097 4943, GRID grid.213917.f, George W. Woodruff School of Mechanical Engineering, , Georgia Institute of Technology, ; Atlanta, GA 30332 USA
                [2 ]ISNI 0000 0001 2097 4943, GRID grid.213917.f, Parker H. Petit Institute for Bioengineering and Bioscience, , Georgia Institute of Technology, ; Atlanta, GA 30332 USA
                [3 ]ISNI 0000 0001 2097 4943, GRID grid.213917.f, School of Biological Sciences, , Georgia Institute of Technology, ; Atlanta, GA 30332 USA
                [4 ]ISNI 0000 0004 0470 5454, GRID grid.15444.30, Department of Medical Engineering, , Yonsei University College of Medicine, ; Seoul, 03722 Republic of Korea
                [5 ]ISNI 0000 0001 0941 6502, GRID grid.189967.8, Department of Pediatrics, , Emory University, ; Atlanta, GA 30322 USA
                [6 ]ISNI 0000 0001 0941 6502, GRID grid.189967.8, Department of Neurology, , Emory University, ; Atlanta, GA 30322 USA
                [7 ]ISNI 0000 0001 2097 4943, GRID grid.213917.f, Wallace H. Coulter Department of Biomedical Engineering, , Georgia Institute of Technology, ; Atlanta, GA 30332 USA
                [8 ]ISNI 0000 0001 2097 4943, GRID grid.213917.f, Institute for Electronics and Nanotechnology, , Georgia Institute of Technology, ; Atlanta, GA 30332 USA
                Article
                13896
                10.1038/s41467-019-13896-7
                6954233
                31924752
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: FundRef https://doi.org/10.13039/100000002, U.S. Department of Health & Human Services | National Institutes of Health (NIH);
                Award ID: 1DP2HL142050
                Award ID: R21NS091682
                Award ID: R21AG056781
                Award Recipient :
                Funded by: U.S. Department of Health & Human Services | National Institutes of Health (NIH)
                Funded by: U.S. Department of Health & Human Services | National Institutes of Health (NIH)
                Categories
                Article
                Custom metadata
                © The Author(s) 2020

                Uncategorized

                biomedical engineering, lab-on-a-chip, nanobiotechnology

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