title: BBB on chip: microfluidic platform to mechanically and biochemically modulate blood-brain barrier function.
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.cm(2) (± 0.9 Ω.cm(2)) and 28.2 Ω.cm(2) (± 1.3 Ω.cm(2)) 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.cm(2). Subsequent addition of TNF-α decreased the TEER with a factor of 10, down to 12 Ω.cm(2). 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.
authors.affiliation: BIOS, Lab on a Chip group, MESA+ Institute for Nanotechnology, University of Twente, PO Box 217, 7500 AE, Enschede, The Netherlands. l.m.griep@utwente.nl
authors.forename: L M
authors.initials: LM
authors.lastname: Griep
authors.forename: F
authors.initials: F
authors.lastname: Wolbers
authors.forename: B
authors.initials: B
authors.lastname: de Wagenaar
authors.forename: P M
authors.initials: PM
authors.lastname: ter Braak
authors.forename: B B
authors.initials: BB
authors.lastname: Weksler
authors.forename: I A
authors.initials: IA
authors.lastname: Romero
authors.forename: P O
authors.initials: PO
authors.lastname: Couraud
authors.forename: I
authors.initials: I
authors.lastname: Vermes
authors.forename: A D
authors.initials: AD
authors.lastname: van der Meer
authors.forename: A
authors.initials: A
authors.lastname: van den Berg
mesh_terms: D001696:Biomechanical Phenomena; D001812:Blood-Brain Barrier / Q000166:cytology / Q000378:metabolism*; D002460:Cell Line; D017097:Electric Impedance; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D055595:Mechanical Phenomena; D046210:Microfluidic Analytical Techniques / Q000295:instrumentation*; D018613:Microscopy, Confocal