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The Blood-brain Barrier00:49

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Generation of a Human iPSC-Based Blood-Brain Barrier Chip
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An isogenic hiPSC-derived BBB-on-a-chip.

Pedram Motallebnejad1, Andrew Thomas2, Sarah L Swisher2

  • 1Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, Minnesota 55455, USA.

Biomicrofluidics
|November 27, 2019
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Summary

This study presents a novel human induced pluripotent stem cell (hiPSC)-based blood-brain barrier (BBB) model on a chip. This advanced in vitro model accurately recapitulates BBB physiology and disease for drug screening and mechanistic studies.

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Area of Science:

  • Neuroscience
  • Biotechnology
  • Biomedical Engineering

Background:

  • The blood-brain barrier (BBB) is crucial for brain homeostasis, regulated by brain microvascular endothelial cells (BMECs) and astrocytes.
  • Conventional in vitro BBB models often lack the physiological complexity and functional integrity of the in vivo barrier.
  • Modeling the BBB, especially in disease states, presents significant challenges due to its intricate structure.

Purpose of the Study:

  • To develop and validate a sophisticated in vitro blood-brain barrier model using human induced pluripotent stem cells (hiPSCs).
  • To create a BBB-on-a-chip device that incorporates physiological flow and astrocyte co-culture for enhanced modeling capabilities.
  • To demonstrate the utility of the model for studying BBB transport, genetic diseases, and disease-induced BBB disruption.

Main Methods:

  • Utilized hiPSC-derived BMECs and astrocytes in a microfluidic BBB-on-a-chip device with varying pore sizes (0.4 μm and 8.0 μm).
  • Co-cultured BMECs with astrocytes in a 3D hydrogel, separated by a porous membrane, to mimic the BBB microenvironment.
  • Assessed barrier formation and integrity using immunocytochemistry for tight junction proteins, fluorescein permeability assays, and impedance spectroscopy.

Main Results:

  • Successfully formed a confluent BMEC barrier with demonstrated integrity, confirmed by tight junction protein expression and low fluorescein permeability.
  • The BBB-on-a-chip device effectively modeled BBB disruption upon TGF-β1 stimulation, showing reduced electrical resistance and astrocyte activation.
  • The device's design allows for studying molecular and cellular transport across the BBB.

Conclusions:

  • The developed hiPSC-based BBB-on-a-chip model offers a physiologically relevant platform for studying BBB function and dysfunction.
  • This model system is suitable for drug screening, rare disease modeling, and investigating mechanisms of BBB disruption.
  • The device facilitates advanced research into neurological disorders and therapeutic interventions targeting the BBB.