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      Investigation of drug dissolution and uptake from low-density DPI formulations in an impactor–integrated cell culture model

      , ,
      European Journal of Pharmaceutics and Biopharmaceutics
      Elsevier BV

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          Engineering an in vitro air-blood barrier by 3D bioprinting

          Intensive efforts in recent years to develop and commercialize in vitro alternatives in the field of risk assessment have yielded new promising two- and three dimensional (3D) cell culture models. Nevertheless, a realistic 3D in vitro alveolar model is not available yet. Here we report on the biofabrication of the human air-blood tissue barrier analogue composed of an endothelial cell, basement membrane and epithelial cell layer by using a bioprinting technology. In contrary to the manual method, we demonstrate that this technique enables automatized and reproducible creation of thinner and more homogeneous cell layers, which is required for an optimal air-blood tissue barrier. This bioprinting platform will offer an excellent tool to engineer an advanced 3D lung model for high-throughput screening for safety assessment and drug efficacy testing.
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            Update on macrophage clearance of inhaled micro- and nanoparticles.

            Lung macrophages, that is, the intravascular, interstitial, pleural, and surface macrophages, are part of the mononuclear phagocyte system. They are derived from the hematopoietic stem cell in the bone marrow with the monocytes as their putative precursors. Macrophages residing on the inner surfaces of the lungs and immersed within the lung lining layer, that is, the alveolar and the airway macrophages, are constantly exposed to the environment; it is those cells that are recognized as first line of cellular host defense. Phagocytic uptake of inhaled and deposited particles is the main mechanism to remove insoluble micrometer-sized particles from the lung surfaces, where mucociliary transport, cough, or sneezing fail or are absent. Phagocytosis requires an intact cytoskeleton and is most efficient when mediated by Fc-receptors, but complement and scavenger receptors like MARCO and CD206 are just as important. The main pathway for the clearance of macrophage-associated particles is by mucociliary transport; to a lesser degree and species specific, particle-containing macrophages may reenter into the interstitium and go from there to the lymphatics. Inhaled nanometer-sized particles that deposit along the entire respiratory tract, however, are not efficiently phagocytosed by surface macrophages. Uptake by spontaneous or stimulated (macro-) pinocytosis or electrokinetic's phenomena may become more important. In addition, translocation of nanometer-sized particles into the interstitium and to the blood circulation brings them into contact with other fluids; altered particle properties may influence particle uptake. Moreover, translocated particles may interact with lung macrophage populations that were previously not considered of great significance for the clearance of inhaled particles.
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              A three-dimensional cellular model of the human respiratory tract to study the interaction with particles.

              A novel triple co-culture model of the human airway barrier was designed to simulate the cellular part of the air-blood barrier of the respiratory tract represented by macrophages, epithelial cells, and dendritic cells. When epithelial cells (A549 cells) were grown on filter inserts with pores of 3.0 mum in diameter in a two-chamber system, they formed monolayers with polarization into apical and basolateral domains. The epithelial cell cultures were then supplemented with human blood monocyte-derived macrophages and dendritic cells on the apical and basal aspect, respectively. The single-cell cultures as well as the triple co-cultures were characterized in terms of a number of typical features, for example, morphology of cell types, integrity of epithelial layer, and expression of specific cell surface markers (CD14 for macrophages and CD86 for dendritic cells). The interplay of epithelial cells with macrophages and dendritic cells during the uptake of polystyrene particles (1 mum in diameter) was investigated with confocal laser scanning and conventional transmission electron microscopy. Particles were found in all three cell types, although dendritic cells were not directly exposed to the particles. More investigations are needed to understand the translocation pathway.
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                Author and article information

                Journal
                European Journal of Pharmaceutics and Biopharmaceutics
                European Journal of Pharmaceutics and Biopharmaceutics
                Elsevier BV
                09396411
                October 2020
                October 2020
                : 155
                : 12-21
                Article
                10.1016/j.ejpb.2020.07.023
                971a307f-0e4e-4fff-8734-8789682876db
                © 2020

                https://www.elsevier.com/tdm/userlicense/1.0/

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