A microdevice for the creation of patent, three-dimensional endothelial cell-based microcirculatory networks

Chau, L. Thieu; Rolfe, Barbara E.; Cooper-White, Justin J.

doi:10.1063/1.3609264

Cited by 22 publications

(22 citation statements)

References 28 publications

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“…Previously, the rat cell line RBE4 was studied for a similar purpose [17,36]. Biochips modeling the vascular system also widely use peripheral endothelial cells [37][38][39][40].…”

Section: 2mentioning

confidence: 99%

A versatile lab-on-a-chip tool for modeling biological barriers

Walter

Valkai

Kincses

et al. 2016

Sensors and Actuators B: Chemical

148

156

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Keywords: Microfluidics Lung and intestinal epithelial cells Endothelial cells Blood-brain barrier PermeabilityTrans-epithelial/endothelial electric resistance a b s t r a c t Models of biological barriers are important to study physiological functions, transport mechanisms, drug delivery and pathologies. However, there are only a few integrated biochips which are able to monitor several of the crucial parameters of cell-culture-based barrier models. The aim of this study was to design and manufacture a simple but versatile device, which allows a complex investigation of barrier functions. The following functions and measurements are enabled simultaneously: co-culture of 2 or 3 types of cells; flow of culture medium; visualization of the entire cell layer by microscopy; real-time transcellular electrical resistance monitoring; permeability measurements. To this end, a poly(dimethylsiloxane)-based biochip with integrated transparent gold electrodes and with a possibility to connect to a peristaltic pump was built. Unlike previous systems, the structure of the device allowed a constant visual observation of cell growth over the whole membrane surface. Morphological characterization of the layers was also accomplished by immunohistochemical staining. The chip was applied to monitor and characterize models of the intestinal and lung epithelial barriers, and the blood-brain barrier. The models were established using human Caco-2 intestinal and A549 lung epithelial cell lines, hCMEC/D3 human brain endothelial cell line and primary rat brain endothelial cells co-cultured with primary astrocytes and brain pericytes. This triple primary co-culture blood-brain barrier model was assembled on a lab-on-a-chip device and investigated under fluid flow for the first time. Such a versatile tool is expected to facilitate the kinetic investigation of various biological barriers.

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“…Previously, the rat cell line RBE4 was studied for a similar purpose [17,36]. Biochips modeling the vascular system also widely use peripheral endothelial cells [37][38][39][40].…”

Section: 2mentioning

confidence: 99%

A versatile lab-on-a-chip tool for modeling biological barriers

Walter

Valkai

Kincses

et al. 2016

Sensors and Actuators B: Chemical

148

156

View full text Add to dashboard Cite

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“…Previously developed systems relied on the use of rectangular channels with only one order of branching 9 or membrane microfluidic devices where monolayers of endothelial cells were cultivated. 5 Although more complex devices were envisioned in a mathematical modeling study focusing on designing networks that minimize vascular volume fraction, no designs were experimentally implemented and seeded with cells.…”

Section: Drug Induced Nitric Oxide Secretion and Monocyte Adhesionmentioning

confidence: 99%

“…Current microfluidic approaches either culture endothelial cells simply on the bottom of a micro-channel [5][6][7] or coat endothelial cells around a rectangular channel with sharp corners. [6][7][8][9][10] These approaches can establish a vasculature quickly in defined conditions but ignore the artifacts generated by the sharp corners on the endothelialized lumen. Although remodeling of collagen gels allows for formation of circular lumens, fragility of these gels limits the complexity of branching structures and levels of branching, enabling creation of structures that branch only to the first order, 6 in contrast to the native vasculature that follows fractal rules in branching.…”

Section: Introductionmentioning

confidence: 99%

A standalone perfusion platform for drug testing and target validation in micro-vessel networks

et al. 2013

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Studying the effects of pharmacological agents on human endothelium includes the routine use of cell monolayers cultivated in multi-well plates. This configuration fails to recapitulate the complex architecture of vascular networks in vivo and does not capture the relationship between shear stress (i.e. flow) experienced by the cells and dose of the applied pharmacological agents. Microfluidic platforms have been applied extensively to create vascular systems in vitro; however, they rely on bulky external hardware to operate, which hinders the wide application of microfluidic chips by non-microfluidic experts. Here, we have developed a standalone perfusion platform where multiple devices were perfused at a time with a single miniaturized peristaltic pump. Using the platform, multiple micro-vessel networks, that contained three levels of branching structures, were created by culturing endothelial cells within circular micro-channel networks mimicking the geometrical configuration of natural blood vessels. To demonstrate the feasibility of our platform for drug testing and validation assays, a drug induced nitric oxide assay was performed on the engineered micro-vessel network using a panel of vasoactive drugs (acetylcholine, phenylephrine, atorvastatin, and sildenafil), showing both flow and drug dose dependent responses. The interactive effects between flow and drug dose for sildenafil could not be captured by a simple straight rectangular channel coated with endothelial cells, but it was captured in a more physiological branching circular network. A monocyte adhesion assay was also demonstrated with and without stimulation by an inflammatory cytokine, tumor necrosis factor-a. V C 2013 AIP Publishing LLC. [http://dx

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“…2,16,[25][26][27] Due to its particulate nature blood exhibits unique flow dynamics at a micro-scale level. Hence, there is an increasing interest by both the microfluidic and biomedical communities to develop blood diagnostic devices as an alternative tool to the traditional diagnostic strategies.…”

Section: Introductionmentioning

confidence: 99%

Asymmetry of red blood cell motions in a microchannel with a diverging and converging bifurcation

et al. 2011

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In microcirculation, red blood cells (RBCs) flowing through bifurcations may deform considerably due to combination of different phenomena that happen at the micro-scale level, such as: attraction effect, high shear, and extensional stress, all of which may influence the rheological properties and flow behavior of blood. Thus, it is important to investigate in detail the behavior of blood flow occurring at both bifurcations and confluences. In the present paper, by using a micro-PTV system, we investigated the variations of velocity profiles of two working fluids flowing through diverging and converging bifurcations, human red blood cells suspended in dextran 40 with about 14% of hematocrit level (14 Hct) and pure water seeded with fluorescent trace particles. All the measurements were performed in the center plane of rectangular microchannels using a constant flow rate of about 3.0 Â 10 À12 m 3 /s. Moreover, the experimental data was compared with numerical results obtained for Newtonian incompressible fluid. The behavior of RBCs was asymmetric at the divergent and convergent side of the geometry, whereas the velocities of tracer particles suspended in pure water were symmetric and well described by numerical simulation. The formation of a red cell-depleted zone immediately downstream of the apex of the converging bifurcation was observed and its effect on velocity profiles of RBCs flow has been investigated. Conversely, a cell-depleted region was not formed around the apex of the diverging bifurcation and as a result the adhesion of RBCs to the wall surface was enhanced in this region.

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A microdevice for the creation of patent, three-dimensional endothelial cell-based microcirculatory networks

Cited by 22 publications

References 28 publications

A versatile lab-on-a-chip tool for modeling biological barriers

A versatile lab-on-a-chip tool for modeling biological barriers

A standalone perfusion platform for drug testing and target validation in micro-vessel networks

Asymmetry of red blood cell motions in a microchannel with a diverging and converging bifurcation

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