Journal ArticleDOI
BBB ON CHIP: microfluidic platform to mechanically and biochemically modulate blood-brain barrier function
L. M. Griep,Floor Wolbers,B. de Wagenaar,P.M. ter Braak,Babette B. Weksler,Babette B. Weksler,Ignacio A. Romero,P.O. Couraud,I. Vermes,A. D. van der Meer,A. van den Berg +10 more
TLDR
The smallest model of the blood-brain barrier yet is presented, using a microfluidic chip, and the immortalized human brain endothelial cell line hCMEC/D3, which is very well suited to study barrier function and evaluate drug passage to finally gain more insight into the treatment of neurodegenerative diseases.Abstract:
The blood-brain barrier (BBB) is a unique feature of the human body, preserving brain homeostasis and preventing toxic substances to enter the brain. However, in various neurodegenerative diseases, the function of the BBB is disturbed. Mechanisms of the breakdown of the BBB are incompletely understood and therefore a realistic model of the BBB is essential. We present here the smallest model of the BBB yet, using a microfluidic chip, and the immortalized human brain endothelial cell line hCMEC/D3. Barrier function is modulated both mechanically, by exposure to fluid shear stress, and biochemically, by stimulation with tumor necrosis factor alpha (TNF-α), in one single device. The device has integrated electrodes to analyze barrier tightness by measuring the transendothelial electrical resistance (TEER). We demonstrate that hCMEC/D3 cells could be cultured in the microfluidic device up to 7 days, and that these cultures showed comparable TEER values with the well-established Transwell assay, with an average (± SEM) of 36.9 Ω.cm2 (± 0.9 Ω.cm2) and 28.2 Ω.cm2 (± 1.3 Ω.cm2) respectively. Moreover, hCMEC/D3 cells on chip expressed the tight junction protein Zonula Occludens-1 (ZO-1) at day 4. Furthermore, shear stress positively influenced barrier tightness and increased TEER values with a factor 3, up to 120 Ω.cm2. Subsequent addition of TNF-α decreased the TEER with a factor of 10, down to 12 Ω.cm2. This realistic microfluidic platform of the BBB is very well suited to study barrier function in detail and evaluate drug passage to finally gain more insight into the treatment of neurodegenerative diseases.read more
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Journal ArticleDOI
Microfluidic organs-on-chips
TL;DR: A microfluidic cell culture device created with microchip manufacturing methods that contains continuously perfused chambers inhabited by living cells arranged to simulate tissue- and organ-level physiology has great potential to advance the study of tissue development, organ physiology and disease etiology.
Journal ArticleDOI
TEER Measurement Techniques for In Vitro Barrier Model Systems
Balaji Srinivasan,Aditya Reddy Kolli,Mandy B. Esch,Hasan E. Abaci,Michael L. Shuler,James J. Hickman +5 more
TL;DR: The aim of this article is to review the different TEER measurement techniques and analyze their strengths and weaknesses, determine the significance of TEER in drug toxicity studies, and examine the various in vitro models and microfluidic organs-on-chips implementations using TEER measurements in some widely studied barrier models.
Journal ArticleDOI
Organs-on-chips at the frontiers of drug discovery
TL;DR: The new opportunities for the application of organ-on-chip technologies in a range of areas in preclinical drug discovery, such as target identification and validation, target-based screening, and phenotypic screening are examined.
Journal ArticleDOI
Microfabrication of human organs-on-chips
Dongeun Huh,Hyun-Jung Kim,Jacob P. Fraser,Daniel E Shea,Mohammed Khan,Anthony Bahinski,Geraldine A. Hamilton,Donald E. Ingber,Donald E. Ingber,Donald E. Ingber +9 more
TL;DR: A protocol for the fabrication, microengineering and operation of microfluidic organ-on-chip systems that replicate key functional units of living organs to reconstitute integrated human organ-level pathophysiology in vitro is described and can be easily adapted to develop other human organ chips.
Journal ArticleDOI
In vitro models of the blood-brain barrier: An overview of commonly used brain endothelial cell culture models and guidelines for their use
Hans Christian Cederberg Helms,N. Joan Abbott,Malgorzata Burek,Roméo Cecchelli,Pierre Olivier Couraud,Mária A. Deli,Carola Förster,H.-J. Galla,Ignacio A. Romero,Eric V. Shusta,Matthew J. Stebbins,Elodie Vandenhaute,Babette B. Weksler,Birger Brodin +13 more
TL;DR: A review of established in vitro blood-brain barrier models with a focus on their validation regarding a set of well-established bloodbrain barrier characteristics is given in this paper, with an overview of the advantages and drawbacks of the different models described.
References
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Journal ArticleDOI
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Babette B. Weksler,E. A. Subileau,N. Perrière,Pierre Charneau,Karen Holloway,Mathilde Leveque,H. Tricoire-Leignel,A. Nicotra,Sandrine Bourdoulous,Patric Turowski,David Male,Françoise Roux,John Greenwood,Ignacio A. Romero,P.O. Couraud +14 more
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Journal ArticleDOI
Hemodynamic shear stress and the endothelium in cardiovascular pathophysiology
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Journal ArticleDOI
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Journal ArticleDOI
Characterization of a microfluidic in vitro model of the blood-brain barrier (μBBB)
Ross Booth,Hanseup Kim +1 more
TL;DR: A microfluidic blood-brain barrier (μBBB) is developed which closely mimics the in vivo BBB with a dynamic environment and a comparatively thin culture membrane, demonstrating stability of the fabricated μBBB model.
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