The Use of Tissue Engineering to Fabricate Perfusable 3D Brain Microvessels in vitro

Dona, Kalpani N. U. Galpayage; Hale, Jonathan F; Salako, Tobi; Anandanatarajan, Akanksha; Tran, Kiet A.; DeOre, Brandon J.; Galie, Peter A.; Ramirez, Servio H.; Andrews, Allison M.

doi:10.3389/fphys.2021.715431

Cited by 9 publications

(9 citation statements)

References 79 publications

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“…One limitation of this study is that the applied flow rates are selected to induce disturbed flow within the specific geometry of the 3D blood–brain barrier model, and not to mimic physiological flow. Therefore, further studies can take advantage of recent advances in bioprinting to mimic specific vascular topologies [ 35 ] to determine whether similar genes are differentially regulated in cells adjacent to the bifurcation and whether the shear gradient applied to cells in vitro cause barrier breakdown of in vivo vasculature. Still, in steady flow, five of the eight most downregulated genes in cells exposed to disturbed compared to fully developed flow are associated with cell–matrix interactions: either isoforms of matrix metalloproteinases or lumican, a small leucine-rich proteoglycan.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic analysis of a 3D blood–brain barrier model exposed to disturbed fluid flow

Bouhrira

DeOre

Tran

et al. 2022

Fluids Barriers CNS

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Cerebral aneurysms are more likely to form at bifurcations in the vasculature, where disturbed fluid is prevalent due to flow separation at sufficiently high Reynolds numbers. While previous studies have demonstrated that altered shear stress exerted by disturbed flow disrupts endothelial tight junctions, less is known about how these flow regimes alter gene expression in endothelial cells lining the blood–brain barrier. Specifically, the effect of disturbed flow on expression of genes associated with cell–cell and cell–matrix interaction, which likely mediate aneurysm formation, remains unclear. RNA sequencing of immortalized cerebral endothelial cells isolated from the lumen of a 3D blood–brain barrier model reveals distinct transcriptional changes in vessels exposed to fully developed and disturbed flow profiles applied by both steady and physiological waveforms. Differential gene expression, validated by qRT-PCR and western blotting, reveals that lumican, a small leucine-rich proteoglycan, is the most significantly downregulated gene in endothelial cells exposed to steady, disturbed flow. Knocking down lumican expression reduces barrier function in the presence of steady, fully developed flow. Moreover, adding purified lumican into the hydrogel of the 3D blood–brain barrier model recovers barrier function in the region exposed to fully developed flow. Overall, these findings emphasize the importance of flow regimes exhibiting spatial and temporal heterogeneous shear stress profiles on cell–matrix interaction in endothelial cells lining the blood–brain barrier, while also identifying lumican as a contributor to the formation and maintenance of an intact barrier.

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Section: Discussionmentioning

confidence: 99%

Transcriptomic analysis of a 3D blood–brain barrier model exposed to disturbed fluid flow

Bouhrira

DeOre

Tran

et al. 2022

Fluids Barriers CNS

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“…Images were captured using an EVOS M7000 fluorescence microscope at T = 0 min and 10 min at 10× magnification. Permeability was quantified using Aivia imaging software (Leica) and determined by calculating the percent permeability from the fluorescent intensity by pixel of the gel divided by that of the lumen [6]. The permeability values were compared to scaffolds not treated with TNFα.…”

Section: Permeability Assaymentioning

confidence: 99%

“…Our understanding of BBB biology has improved over the decades thanks to animal studies and 2D models [4,5]. Although instructive, in vivo studies are time consuming, and species differences have reduced the translatability of results [6][7][8]. Conventional in vitro models of the BBB have been useful for exploring BBB function and CNS drug penetrability [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

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A Next-Generation 3D Tissue-Engineered Model of the Human Brain Microvasculature to Study the Blood-Brain Barrier

2023

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More than a billion people are affected by neurological disorders, and few have effective therapeutic options. A key challenge that has prevented promising preclinically proven strategies is the translation gap to the clinic. Humanized tissue engineering models that recreate the brain environment may aid in bridging this translational gap. Here, we showcase the methodology that allows for the practical fabrication of a comprehensive microphysicological system (MPS) of the blood-brain barrier (BBB). Compared to other existing 2D and 3D models of the BBB, this model features relevant cytoarchitecture and multicellular arrangement, with branching and network topologies of the vascular bed. This process utilizes 3D bioprinting with digital light processing to generate a vasculature lumen network surrounded by embedded human astrocytes. The lumens are then cellularized with primary human brain microvascular endothelial cells and pericytes. To initiate mechanotransduction pathways and complete maturation, vascular structures are continuously perfused for 7 days. Constructs are validated for complete endothelialization with viability dyes prior to functional assessments that include barrier integrity (permeability) and immune-endothelial interactions. This MPS has applications for the study of novel therapeutics, toxins, and elucidating mechanisms of pathophysiology.

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“…Cylindrical channels lined with BMECs are surrounded by a cell-containing hydrogel, thus reflecting the ECM. The microvessel structure can either be achieved artificially or with self-assembled microvessels in hydrogels [ 149 ]. Campisi et al [ 150 ] combined an iBMEC network with human brain pericytes and astrocytes within a single fibrin hydrogel.…”

Section: In Vitro Modelingmentioning

confidence: 99%

Blood–Brain Barrier Breakdown in Neuroinflammation: Current In Vitro Models

Brandl,

Reindl

2023

IJMS

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The blood–brain barrier, which is formed by tightly interconnected microvascular endothelial cells, separates the brain from the peripheral circulation. Together with other central nervous system-resident cell types, including pericytes and astrocytes, the blood–brain barrier forms the neurovascular unit. Upon neuroinflammation, this barrier becomes leaky, allowing molecules and cells to enter the brain and to potentially harm the tissue of the central nervous system. Despite the significance of animal models in research, they may not always adequately reflect human pathophysiology. Therefore, human models are needed. This review will provide an overview of the blood–brain barrier in terms of both health and disease. It will describe all key elements of the in vitro models and will explore how different compositions can be utilized to effectively model a variety of neuroinflammatory conditions. Furthermore, it will explore the existing types of models that are used in basic research to study the respective pathologies thus far.

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The Use of Tissue Engineering to Fabricate Perfusable 3D Brain Microvessels in vitro

Cited by 9 publications

References 79 publications

Transcriptomic analysis of a 3D blood–brain barrier model exposed to disturbed fluid flow

Transcriptomic analysis of a 3D blood–brain barrier model exposed to disturbed fluid flow

A Next-Generation 3D Tissue-Engineered Model of the Human Brain Microvasculature to Study the Blood-Brain Barrier

Blood–Brain Barrier Breakdown in Neuroinflammation: Current In Vitro Models

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