Mechanical stress regulates transport in a compliant 3D model of the blood-brain barrier

Partyka, Paul P.; Godsey, George; Galie, John R.; Kosciuk, Mary C.; Acharya, Nimish K.; Nagele, Robert G.; Galie, Peter A.

doi:10.1016/j.biomaterials.2016.11.012

Cited by 153 publications

(153 citation statements)

References 51 publications

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“…Three-dimensional models of the blood-brain barrier (3D BBB) were fabricated by polymerizing hydrogels composed of 5 mg/mL type I collagen, 1 mg/mL hyaluronan, and 1 mg/mL Matrigel within microfabricated devices. The full method for this approach is described in a previous study 33 . Briefly, hydrogels were injected into the reservoir of the device and 180-µm needles coated in 0.1% BSA were inserted prior to polymerization to create two, parallel, and cylindrical voids within the gel.…”

Section: D Bbb Modelmentioning

confidence: 99%

The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in vitro models of the human blood–brain barrier

Buzhdygan

DeOre

Baldwin‐Leclair

et al. 2020

Preprint

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As researchers across the globe have focused their attention on understanding SARS-CoV-2, the picture that is emerging is that of a virus that has serious effects on the vasculature in multiple organ systems including the cerebral vasculature. Observed effects on the central nervous system includes neurological symptoms (headache, nausea, dizziness), fatal microclot formation and in rare cases encephalitis. However, our understanding of how the virus causes these mild to severe neurological symptoms and how the cerebral vasculature is impacted remains unclear. Thus, the results presented in this report explored whether deleterious outcomes from the SARS-COV-2 viral spike protein on primary human brain microvascular endothelial cells (hBMVECs) could be observed. First, using postmortem brain tissue, we show that the angiotensin converting enzyme 2 or ACE2 (a known binding target for the SARS-CoV-2 spike protein), is expressed throughout various caliber vessels in the frontal cortex. Additionally, ACE2 was also detectable in primary human brain microvascular endothelial (hBMVEC) maintained under cell culture conditions. Analysis for cell viability revealed that neither the S1, S2 or a truncated form of the S1 containing only the RBD had minimal effects on hBMVEC viability within a 48hr exposure window. However, when the viral spike proteins were introduced into model systems that recapitulate the essential features of the Blood-Brain Barrier (BBB), breach to the barrier was evident in various degrees depending on the spike protein subunit tested. Key to our findings is the demonstration that S1 promotes loss of barrier integrity in an advanced 3D microfluid model of the human BBB, a platform that most closely resembles the human physiological conditions at this CNS interface. Subsequent analysis also showed the ability for SARS-CoV-2 spike proteins to trigger a pro-inflammatory response on brain endothelial cells that may contribute to an altered state of BBB function. Together, these results are the first to show the direct impact that the SARS-CoV-2 spike protein could have on brain endothelial cells; thereby offering a plausible explanation for the neurological consequences seen in COVID-19 patients.

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Section: D Bbb Modelmentioning

confidence: 99%

The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in vitro models of the human blood–brain barrier

Buzhdygan

DeOre

Baldwin‐Leclair

et al. 2020

Preprint

Self Cite

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“…Therefore, alternative ways to employ shear stress are required to introduce flow of the medium in perfusion culture dishes during or after differentiation, potentially through use of microfluidic systems. For example, flow might be employed through inlet and outlet channels that push liquid through a hydrogel reservoir in which the cells are cultured [118]. Alternatively, cells might be grown on a membrane within a microfluidic device with a flow channel on top of the cells, as described by Booth and Kim in 2014 [119].…”

Section: Future Considerations For Improving Bbb Production In Vitromentioning

confidence: 99%

Paving the Way Toward Complex Blood-Brain Barrier Models Using Pluripotent Stem Cells

Lauschke

Frederiksen

Hall

2017

Stem Cells and Development

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“…This was clearly demonstrated by Placone et al [37], who manipulated the type and ratio of ECM including HA, and analyzed astrocyte morphology and active states under each ECM condition. To recapitulate the distinct star-shaped astrocyte morphology in the 3D in vitro model, we tuned the 3D ECM base using previously developed protocols [37, 49]. In our microfluidic devices, astrocytes exhibited a star-shaped morphology in the presence of HA when mixed with fibrin hydrogel (Fig.…”

Section: Discussionmentioning

confidence: 99%

3D brain angiogenesis model to reconstitute maturation of functional human blood-brain barrier in vitro

Lee

Chung

Jeon

2018

Preprint

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The human central nervous system (CNS) vasculature expresses a distinctive barrier phenotype, the blood–brain barrier (BBB). As the BBB contributes to low efficiency in CNS pharmacotherapy by restricting drug transport, the development of an in vitro human BBB model has been in demand. Here, we present a microfluidic model of CNS angiogenesis having three‐dimensional (3D) lumenized vasculature in concert with perivascular cells. We confirmed the necessity of the angiogenic tri‐culture system (brain endothelium in direct interaction with pericytes and astrocytes) to attain essential phenotypes of BBB vasculature, such as minimized vessel diameter and maximized junction expression. In addition, lower vascular permeability is achieved in the tri‐culture condition compared to the monoculture condition. Notably, we focussed on reconstituting the functional efflux transporter system, including p‐glycoprotein (p‐gp), which is highly responsible for restrictive drug transport. By conducting the calcein‐AM efflux assay on our 3D perfusable vasculature after treatment of efflux transporter inhibitors, we confirmed the higher efflux property and prominent effect of inhibitors in the tri‐culture model. Taken together, we designed a 3D human BBB model with functional barrier properties based on a developmentally inspired CNS angiogenesis protocol. We expect the model to contribute to a deeper understanding of pathological CNS angiogenesis and the development of effective CNS medications.

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Mechanical stress regulates transport in a compliant 3D model of the blood-brain barrier

Cited by 153 publications

References 51 publications

The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in vitro models of the human blood–brain barrier

The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in vitro models of the human blood–brain barrier

Paving the Way Toward Complex Blood-Brain Barrier Models Using Pluripotent Stem Cells

3D brain angiogenesis model to reconstitute maturation of functional human blood-brain barrier in vitro

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