Modeling Nanocarrier Transport across a 3D In Vitro Human Blood‐Brain–Barrier Microvasculature

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  • Sharon Wei Ling Lee
    Singapore‐MIT Alliance for Research and Technology (SMART) BioSystems and Micromechanics (BioSyM) IRG 1 Create Way, #04‐13/14 Singapore 138602 Singapore
  • Marco Campisi
    Department of Mechanical and Aerospace Engineering Politecnico di Torino Corso Duca Degli Abruzzi 24 Torino 10129 Italy
  • Tatsuya Osaki
    Institute of Industrial Science The University of Tokyo Fe412, Komaba 4‐6‐1 Meguro‐ku 153‐8505 Japan
  • Luca Possenti
    LaBS Department of Chemistry Materials and Chemical Engineering “Giulio Natta” (CMIC) Politecnico di Milano Piazza Leonardo Da Vinci 32 Milan 20133 Italy
  • Clara Mattu
    Department of Mechanical and Aerospace Engineering Politecnico di Torino Corso Duca Degli Abruzzi 24 Torino 10129 Italy
  • Giulia Adriani
    Singapore Immunology Network (SIgN) Agency for Science, Technology and Research (A*STAR) 8A Biomedical Grove, Immunos Building, Biopolis Singapore 138648 Singapore
  • Roger Dale Kamm
    Department of Mechanical Engineering Massachusetts Institute of Technology 500 Technology Square, MIT Building, Room NE47‐321 Cambridge MA 02139 USA
  • Valeria Chiono
    Department of Mechanical and Aerospace Engineering Politecnico di Torino Corso Duca Degli Abruzzi 24 Torino 10129 Italy

Abstract

<jats:title>Abstract</jats:title><jats:p>Polymer nanoparticles (NPs), due to their small size and surface functionalization potential have demonstrated effective drug transport across the blood–brain–barrier (BBB). Currently, the lack of in vitro BBB models that closely recapitulate complex human brain microenvironments contributes to high failure rates of neuropharmaceutical clinical trials. In this work, a previously established microfluidic 3D in vitro human BBB model, formed by the self‐assembly of human‐induced pluripotent stem cell‐derived endothelial cells, primary brain pericytes, and astrocytes in triculture within a 3D fibrin hydrogel is exploited to quantify polymer NP permeability, as a function of size and surface chemistry. Microvasculature are perfused with commercially available 100–400 nm fluorescent polystyrene (PS) NPs, and newly synthesized 100 nm rhodamine‐labeled polyurethane (PU) NPs. Confocal images are taken at different timepoints and computationally analyzed to quantify fluorescence intensity inside/outside the microvasculature, to determine NP spatial distribution and permeability in 3D. Results show similar permeability of PS and PU NPs, which increases after surface‐functionalization with brain‐associated ligand holo‐transferrin. Compared to conventional transwell models, the method enables rapid analysis of NP permeability in a physiologically relevant human BBB set‐up. Therefore, this work demonstrates a new methodology to preclinically assess NP ability to cross the human BBB.</jats:p>

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