title: Mechanical stress regulates transport in a compliant 3D model of the blood-brain barrier.
abstract: Transport of fluid and solutes is tightly controlled within the brain, where vasculature exhibits a blood-brain barrier and there is no organized lymphatic network facilitating waste transport from the interstitial space. Here, using a compliant, three-dimensional co-culture model of the blood-brain barrier, we show that mechanical stimuli exerted by blood flow mediate both the permeability of the endothelial barrier and waste transport along the basement membrane. Application of both shear stress and cyclic strain facilitates tight junction formation in the endothelial monolayer, with and without the presence of astrocyte endfeet in the surrounding matrix. We use both dextran perfusion and TEER measurements to assess the initiation and maintenance of the endothelial barrier, and microparticle image velocimetry to characterize the fluid dynamics within the in vitro vessels. Application of pulsatile flow to the in vitro vessels induces pulsatile strain to the vascular wall, providing an opportunity to investigate stretch-induced transport along the basement membrane. We find that a pulsatile wave speed of approximately 1 mm/s with Womersley number of 0.004 facilitates retrograde transport of high molecular weight dextran along the basement membrane between the basal endothelium and surrounding astrocytes. Together, these findings indicate that the mechanical stress exerted by blood flow is an important regulator of transport both across and along the walls of cerebral microvasculature.
authors.affiliation: Department of Biomedical Engineering, Rowan University, United States.
authors.forename: Paul P
authors.initials: PP
authors.lastname: Partyka
authors.affiliation: School of Biomedical Sciences, Rowan University, United States.
authors.forename: George A
authors.initials: GA
authors.lastname: Godsey
authors.affiliation: Department of Physics, Camden County College, United States.
authors.forename: John R
authors.initials: JR
authors.lastname: Galie
authors.affiliation: School of Osteopathic Medicine, Rowan University, United States.
authors.forename: Mary C
authors.initials: MC
authors.lastname: Kosciuk
authors.affiliation: School of Osteopathic Medicine, Rowan University, United States.
authors.forename: Nimish K
authors.initials: NK
authors.lastname: Acharya
authors.affiliation: School of Biomedical Sciences, Rowan University, United States; School of Osteopathic Medicine, Rowan University, United States.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Nagele
authors.affiliation: Department of Biomedical Engineering, Rowan University, United States. Electronic address: galie@rowan.edu.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Galie
mesh_terms: D061249:Batch Cell Culture Techniques / Q000379:methods; D001693:Biological Transport, Active / Q000502:physiology*; D001783:Blood Flow Velocity / Q000502:physiology; D001812:Blood-Brain Barrier / Q000502:physiology*; D002199:Capillary Permeability / Q000502:physiology*; D002478:Cells, Cultured; D055119:Elastic Modulus / Q000502:physiology; D004730:Endothelium, Vascular / Q000502:physiology*; D006801:Humans; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D066330:Printing, Three-Dimensional; D011673:Pulsatile Flow / Q000502:physiology; D013314:Stress, Mechanical; D013312:Stress, Physiological / Q000502:physiology*; D019108:Tight Junctions / Q000502:physiology; D023822:Tissue Engineering / Q000379:methods*
keywords: Blood flow; Blood-brain barrier; Perivascular flow; Shear stress