BBB ON CHIP: microfluidic platform to mechanically and biochemically modulate blood-brain barrier function

Griep, L. M.; Wolbers, F.; Wagenaar, Bjorn de; Braak, Paulus Martinus ter; Weksler, Babeth B.; Romero, Ignacio A.; Couraud, P. O.; Vermes, I.; Meer, Andries D. van der; Berg, Albert van den

doi:10.1007/s10544-012-9699-7

Cited by 464 publications

(421 citation statements)

References 28 publications

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“…S1), the effect of membrane thickness on permeability coefficients cannot be excluded. In the present study we could not reproduce the intensive increase in resistance after exposing hCMEC/D3 to shear stress [31,41], but we could observe a significantly reduced tracer permeability for larger marker molecules, indicating a barrier-tightening effect. Cells in both dynamic and static cultures were elongated, formed close contacts typical for endothelial monolayers, and stained well for ZO-1 and ␤-catenin (Fig.…”

Section: 2contrasting

confidence: 88%

“…TEER values of the 5-day-old static culture were in the range of 19.0 ± 2.8 cm 2 . The resistance values measured by the device were in concert with the ones obtained on culture inserts by our group (23.7 ± 3.5 cm 2 ), and with those described in the literature [10,31]. Permeability data were also compared between the static and dynamic cultures.…”

Section: 2mentioning

confidence: 78%

“…There are several setups built for similar purposes. Most of them consist of two channels, either parallel [30] or perpendicular to each other [19,31], with a relatively small overlapping area. The arrangement of our channels enables a much larger overlapping area (ca.…”

Section: Chip Structure and Assemblymentioning

confidence: 99%

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

Walter

Valkai

Kincses

et al. 2016

Sensors and Actuators B: Chemical

146

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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Section: 2contrasting

confidence: 88%

Section: 2mentioning

confidence: 78%

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

Walter

Valkai

Kincses

et al. 2016

Sensors and Actuators B: Chemical

146

156

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“…Considerable recent advances in tissue engineering technology have helped to develop microfluidic systems (i.e. 'organ on a chip') that recapitulate the 3D complexity of the BBB, primarily to produce small vessel structures like capillaries (Prabhakarpandian et al, 2013;Herland et al, 2016;Booth and Kim, 2012;Griep et al, 2013;Cho et al, 2015). However, as CAA preferentially forms in larger arteries, we aimed to produce 3D in vitro models of functional human vessels that retain the anatomical and functional properties of native human cerebral arteries.…”

Section: Discussionmentioning

confidence: 99%

[O2–04–01]: Clearance of Beta‐amyloid Is Facilitated by Apolipoprotein E and Circulating High‐density Lipoproteins in Bioengineered Human Vessels

Robert

Button

Soo

et al. 2017

Alzheimer's & Dementia

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Amyloid plaques, consisting of deposited beta-amyloid (Ab), are a neuropathological hallmark of Alzheimer's Disease (AD). Cerebral vessels play a major role in AD, as Ab is cleared from the brain by pathways involving the cerebrovasculature, most AD patients have cerebrovascular amyloid (cerebral amyloid angiopathy (CAA), and cardiovascular risk factors increase dementia risk. Here we present a notable advance in vascular tissue engineering by generating the first functional 3-dimensioinal model of CAA in bioengineered human vessels. We show that lipoproteins including brain (apoE) and circulating (high-density lipoprotein, HDL) synergize to facilitate Ab transport across bioengineered human cerebral vessels. These lipoproteins facilitate Ab42 transport more efficiently than Ab40, consistent with Ab40 being the primary species that accumulates in CAA. Moreover, apoE4 is less effective than apoE2 in promoting Ab transport, also consistent with the well-established role of apoE4 in Ab deposition in AD.

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“…Several efforts have been initiated toward the accomplishment of this ambitious goal. For example, prototype microphysiometers have been developed for on-line measurement of glucose and lactate (19,35), oxygen (35), transepithelial electrical resistance (24,36,37), ions (38), extracellular acidification rate (pH), and protein biomarkers (39) in organ-on-a-chip systems (40)(41)(42)(43)(44)(45)(46). However, these sensing units were either built upon a single chip and limited in system-level integration and full automation (19), or were designed for measurements over relatively short periods of time in the range of minutes to hours.…”

Section: Significancementioning

confidence: 99%

Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors

Zhang

Aleman

Shin

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

638

618

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Organ-on-a-chip systems are miniaturized microfluidic 3D human tissue and organ models designed to recapitulate the important biological and physiological parameters of their in vivo counterparts. They have recently emerged as a viable platform for personalized medicine and drug screening. These in vitro models, featuring biomimetic compositions, architectures, and functions, are expected to replace the conventional planar, static cell cultures and bridge the gap between the currently used preclinical animal models and the human body. Multiple organoid models may be further connected together through the microfluidics in a similar manner in which they are arranged in vivo, providing the capability to analyze multiorgan interactions. Although a wide variety of human organ-on-a-chip models have been created, there are limited efforts on the integration of multisensor systems. However, in situ continual measuring is critical in precise assessment of the microenvironment parameters and the dynamic responses of the organs to pharmaceutical compounds over extended periods of time. In addition, automated and noninvasive capability is strongly desired for long-term monitoring. Here, we report a fully integrated modular physical, biochemical, and optical sensing platform through a fluidics-routing breadboard, which operates organ-on-a-chip units in a continual, dynamic, and automated manner. We believe that this platform technology has paved a potential avenue to promote the performance of current organ-on-a-chip models in drug screening by integrating a multitude of real-time sensors to achieve automated in situ monitoring of biophysical and biochemical parameters.organ-on-a-chip | microbioreactor | electrochemical biosensor | physical sensor | drug screening D rug discovery is a lengthy process associated with tremendous cost and high failure rate (1). On average, less than 1 in 10 drug candidates are eventually approved by the Food and Drug Administration (2), during which successful transition ratios to next phases are roughly 65, 32, and 60% for phase I, phase II, and phase III, respectively (3). Among the primary causes of failure, nonclinical/ clinical safety (>50%) and efficacy (>10%) stand out in the front, more than all other factors (e.g., strategic, commercial, operational) combined (3, 4). These two major causes not only contribute to the low success rates during the drug development but also lead to the withdrawal of approved drugs from the market. Among all of the drug attritions, it is estimated that safety liabilities related to the cardiovascular system account for 45%, whereas 32% are due to hepatotoxicity (5, 6). These high failure/attrition ratios of drugs SignificanceMonitoring human organ-on-a-chip systems presents a significant challenge, where the capability of in situ continual monitoring of organ behaviors and their responses to pharmaceutical compounds over extended periods of time is critical in understanding the dynamics of drug effects and therefore accurate prediction of human organ reacti...

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BBB ON CHIP: microfluidic platform to mechanically and biochemically modulate blood-brain barrier function

Cited by 464 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

[O2–04–01]: Clearance of Beta‐amyloid Is Facilitated by Apolipoprotein E and Circulating High‐density Lipoproteins in Bioengineered Human Vessels

Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors

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