A Three-Dimensional Arrayed Microfluidic Blood–Brain Barrier Model With Integrated Electrical Sensor Array

Jeong, Sehoon; Kim, Sun-Ja; Buonocore, John; Park, Jaewon; Welsh, C. Jane; Lǐ, Jiànróng; Han, Arum

doi:10.1109/tbme.2017.2773463

Cited by 104 publications

(96 citation statements)

References 31 publications

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“…While the measured electrical properties -in particular the resting potential -suggest that neurons in our model were not fully mature, they are comparable to electrical function previously measured in brain organoids 13 . The endothelial barrier represents an important feature of the NVU, and most previous studies use either FITC-dextran or trans endothelial electrical resistance (TEER) measurement to assess BBB integrity 38,39 .…”

Section: Discussionmentioning

confidence: 99%

An in vitro bioengineered model of the human arterial neurovascular unit to study neurodegenerative diseases

Robert

Weilinger

Zao

et al. 2020

Preprint

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Introduction: The neurovascular unit (NVU) – the interaction between the neurons and the cerebrovasculature – is increasingly important to interrogate through human-based experimental models. Although advanced models of cerebral capillaries have been developed in the last decade, there is currently noin vitro3-dimensional (3D) perfusible model of the human cortical arterial NVU. Method: We used a tissue-engineering technique to develop a scaffold-directed, perfusible, 3D human NVU that is cultured in native-like flow conditions that mimics the anatomy and physiology of cortical penetrating arteries. Results: This system, composed of primary human vascular cells (endothelial cells, smooth muscle cells and astrocytes) and induced pluripotent stem cell (iPSC) derived neurons, demonstrates a physiological multilayer organization of the involved cell types. It also reproduces key characteristics of cortical neurons and astrocytes, as well as the formation of a selective and functional endothelial barrier. We further provide proof-of-principle that our in vitro human arterial NVU may be suitable to study neurodegenerative diseases such as Alzheimer’s disease (AD), as we report both phosphorylated tau and beta-amyloid accumulation in our model over time. Finally, we show that our arterial NVU model enables the study of neuronal and glial fluid biomarkers. Conclusion: This model is a suitable tool to investigate arterial NVU functions such as neuronal electrophysiology in health and disease. Further the design of platform allows culture under native-like flow conditions for extended periods of time and yields sufficient tissue and media for downstream immunohistochemistry and biochemistry analyses.

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Section: Discussionmentioning

confidence: 99%

An in vitro bioengineered model of the human arterial neurovascular unit to study neurodegenerative diseases

Robert

Weilinger

Zao

et al. 2020

Preprint

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“…represents an important feature of the NVU, and most previous studies use either FITC-dextran or trans endothelial electrical resistance (TEER) measurement to assess BBB integrity 41,42 . Here we confirmed the integrity of the endothelium barrier using 4 kDa FITC-dextran.…”

Section: Discussionmentioning

confidence: 99%

An in vitro bioengineered model of the human arterial neurovascular unit to study neurodegenerative diseases

Robert

Weilinger

Zao

et al. 2020

Preprint

View full text Add to dashboard Cite

Introduction: The neurovascular unit (NVU) – the interaction between the neurons and the cerebrovasculature – is increasingly important to interrogate through human-based experimental models. Although advanced models of cerebral capillaries have been developed in the last decade, there is currently no in vitro 3-dimensional (3D) perfusible model of the human cortical arterial NVU.Method: We used a tissue-engineering technique to develop a scaffold-directed, perfusible, 3D human NVU that is cultured in native-like flow conditions that mimics the anatomy and physiology of cortical penetrating arteries.Results: This system, composed of primary human vascular cells (endothelial cells, smooth muscle cells and astrocytes) and induced pluripotent stem cell (iPSC) derived neurons, demonstrates a physiological multilayer organization of the involved cell types. It reproduces key characteristics of cortical neurons and astrocytes and enables formation of a selective and functional endothelial barrier. We provide proof-of-principle data showing that this in vitro human arterial NVU may be suitable to study neurovascular components of neurodegenerative diseases such as Alzheimer’s disease (AD), as endogenously produced phosphorylated tau and beta-amyloid accumulate in the model over time. Finally, neuronal and glial fluid biomarkers relevant to neurodegenerative diseases are measurable in our arterial NVU model.Conclusion: This model is a suitable research tool to investigate arterial NVU functions in healthy and disease states. Further, the design of the platform allows culture under native-like flow conditions for extended periods of time and yields sufficient tissue and media for downstream immunohistochemistry and biochemistry analyses.

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“…Recently, Jeong et al [50] devised a PDMS bilayer chip design wherein neural endothelial cells and astrocytes were co-cultured in a polycarbonate membrane. With this configuration, the endothelial cells and astrocytes are physically separated and grow in two separate microenvironments, being allowed however to establish localized interactions through the pores of the membrane, which is important for the development of a realistic brain-capillary interface.…”

Section: D Microfluidic Systemsmentioning

confidence: 99%

Recent Developments in Microfluidic Technologies for Central Nervous System Targeted Studies

et al. 2020

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Neurodegenerative diseases (NDs) bear a lot of weight in public health. By studying the properties of the blood-brain barrier (BBB) and its fundamental interactions with the central nervous system (CNS), it is possible to improve the understanding of the pathological mechanisms behind these disorders and create new and better strategies to improve bioavailability and therapeutic efficiency, such as nanocarriers. Microfluidics is an intersectional field with many applications. Microfluidic systems can be an invaluable tool to accurately simulate the BBB microenvironment, as well as develop, in a reproducible manner, drug delivery systems with well-defined physicochemical characteristics. This review provides an overview of the most recent advances on microfluidic devices for CNS-targeted studies. Firstly, the importance of the BBB will be addressed, and different experimental BBB models will be briefly discussed. Subsequently, microfluidic-integrated BBB models (BBB/brain-on-a-chip) are introduced and the state of the art reviewed, with special emphasis on their use to study NDs. Additionally, the microfluidic preparation of nanocarriers and other compounds for CNS delivery has been covered. The last section focuses on current challenges and future perspectives of microfluidic experimentation.

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A Three-Dimensional Arrayed Microfluidic Blood–Brain Barrier Model With Integrated Electrical Sensor Array

Abstract: The developed multisite BBB chip is expected to be used for screening drug by more accurately predicting their permeability through BBB as well as their toxicity.

Cited by 104 publications

References 31 publications

An in vitro bioengineered model of the human arterial neurovascular unit to study neurodegenerative diseases

An in vitro bioengineered model of the human arterial neurovascular unit to study neurodegenerative diseases

An in vitro bioengineered model of the human arterial neurovascular unit to study neurodegenerative diseases

Recent Developments in Microfluidic Technologies for Central Nervous System Targeted Studies

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