In Situ Surface Modification of Microfluidic Blood-Brain-Barriers for Improved Screening of Small Molecules and Nanoparticles

Bo Peng, Ziqiu Tong, Wing Yin Tong, Paul J. Pasic, Arianna Oddo, Yitian Dai, Meihua Luo, Juliette Frescene, Nicholas G. Welch, Christopher D. Easton, Helmut Thissen, Nicolas H. Voelcker

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1 Citation (Scopus)

Abstract

Here, we have developed and evaluated a microfluidic-based human blood-brain-barrier (μBBB) platform that models and predicts brain tissue uptake of small molecule drugs and nanoparticles (NPs) targeting the central nervous system. By using a photocrosslinkable copolymer that was prepared from monomers containing benzophenone and N-hydroxysuccinimide ester functional groups, we were able to evenly coat and functionalize μBBB chip channels in situ, providing a covalently attached homogenous layer of extracellular matrix proteins. This novel approach allowed the coculture of human endothelial cells, pericytes, and astrocytes and resulted in the formation of a mimic of cerebral endothelium expressing tight junction markers and efflux proteins, resembling the native BBB. The permeability coefficients of a number of compounds, including caffeine, nitrofurantoin, dextran, sucrose, glucose, and alanine, were measured on our μBBB platform and were found to agree with reported values. In addition, we successfully visualized the receptor-mediated uptake and transcytosis of transferrin-functionalized NPs. The BBB-penetrating NPs were able to target glioma cells cultured in 3D in the brain compartment of our μBBB. In conclusion, our μBBB was able to accurately predict the BBB permeability of both small molecule pharmaceuticals and nanovectors and allowed time-resolved visualization of transcytosis. Our versatile chip design accommodates different brain disease models and is expected to be exploited in further BBB studies, aiming at replacing animal experiments.

Original languageEnglish
Pages (from-to)56753–56766
Number of pages14
JournalACS Applied Materials & Interfaces
Volume12
Issue number51
DOIs
Publication statusPublished - 23 Nov 2020

Keywords

  • blood-brain-barrier
  • brain-specific nanoparticles
  • organ-on-a-chip
  • photo-crosslinkable copolymer
  • surface functionalization

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