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

• Type of Material: Article
• Authors: Song Ih Ahn, Georgia Institute of Technology; Yoshitaka J. Sei, Georgia Institute of Technology; Hyun-Ji Park, Georgia Institute of Technology; Jinhwan Kim, Georgia Institute of Technology; Yujung Ryu, Georgia Institute of Technology; Jeongmoon J. Choi, Georgia Institute of Technology; Hak-Joon Sung, Yonsei University College of Medicine; Tobey MacDonald, Emory University; Allan I Levey, Emory University; Yong Tae Kim, Georgia Institute of Technology
• Language: English
• Date: 2020-12-01
• Publisher: Nature Research (part of Springer Nature): Fully open access journals
• Publication Version: Final Published Version
• Copyright Statement: © 2020, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-019-13896-7
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 11
• Issue: 1
• Start Page: 175
• End Page: 175
• Grant/Funding Information: This work was supported by the National Institutes of Health Director’s New Innovator Award 1DP2HL142050 (Y.K.); National Institute of Neurological Disorders and Stroke (NINDS) R21NS091682 (Y.K.); and the National Institutes on Aging R21AG056781 (Y.K.).; We thank the core facilities at the Parker H. Petit Institute for Bioengineering and Bioscience; and the Institute for Electronics and Nanotechnology at Georgia Institute of Technology; a member of the National Nanotechnology Coordinated Infrastructure, which is supported by the National Science Foundation (ECCS­1542174).
• Keywords: Permeability; Drug Delivery Systems; Transcytosis; Lab-On-A-Chip Devices; Blood-Brain Barrier; Gene Expression; Animals; Flow Cytometry; Drug Discovery; Models, Animal; Astrocytes; Nanotechnology; Biological Transport; Cell Culture Techniques; Gliosis; Aquaporin 4; Humans; Nanoparticles; Biomedical Engineering
• Research Categories: Engineering, Biomedical; Biology, Neuroscience

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.