Membrane-free culture and real-time barrier integrity assessment of perfused intestinal epithelium tubes

Trietsch, Sebastiaan J.; Naumovska, Elena; Kurek, Dorota; Setyawati, Meily C.; Vormann, Marianne K.; Wilschut, Karlijn J.; Lanz, Henriëtte L.; Nicolas, Arnaud; Ng, Chee Ping; Joore, Jos; Kustermann, Stefan; Roth, Adrian; Hankemeier, Thomas; Moisan, Annie; Vulto, Paul

doi:10.1038/s41467-017-00259-3

Cited by 218 publications

(248 citation statements)

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“…A three-lane OrganoPlate [46] (see Fig. 3a, b) was employed to establish a BBB co-culture of TY10 brain endothelial cells with hAst and hBPCT cells (see Fig.…”

Section: Resultsmentioning

confidence: 99%

A perfused human blood–brain barrier on-a-chip for high-throughput assessment of barrier function and antibody transport

Wevers

Kasi

Gray

et al. 2018

Fluids Barriers CNS

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BackgroundReceptor-mediated transcytosis is one of the major routes for drug delivery of large molecules into the brain. The aim of this study was to develop a novel model of the human blood–brain barrier (BBB) in a high-throughput microfluidic device. This model can be used to assess passage of large biopharmaceuticals, such as therapeutic antibodies, across the BBB.MethodsThe model comprises human cell lines of brain endothelial cells, astrocytes, and pericytes in a two-lane or three-lane microfluidic platform that harbors 96 or 40 chips, respectively, in a 384-well plate format. In each chip, a perfused vessel of brain endothelial cells was grown against an extracellular matrix gel, which was patterned by means of surface tension techniques. Astrocytes and pericytes were added on the other side of the gel to complete the BBB on-a-chip model. Barrier function of the model was studied using fluorescent barrier integrity assays. To test antibody transcytosis, the lumen of the model’s endothelial vessel was perfused with an anti-transferrin receptor antibody or with a control antibody. The levels of antibody that penetrated to the basal compartment were quantified using a mesoscale discovery assay.ResultsThe perfused BBB on-a-chip model shows presence of adherens and tight junctions and severely limits the passage of a 20 kDa FITC-dextran dye. Penetration of the antibody targeting the human transferrin receptor (MEM-189) was markedly higher than penetration of the control antibody (apparent permeability of 2.9 × 10−5 versus 1.6 × 10−5 cm/min, respectively).ConclusionsWe demonstrate successful integration of a human BBB microfluidic model in a high-throughput plate-based format that can be used for drug screening purposes. This in vitro model shows sufficient barrier function to study the passage of large molecules and is sensitive to differences in antibody penetration, which could support discovery and engineering of BBB-shuttle technologies.Electronic supplementary materialThe online version of this article (10.1186/s12987-018-0108-3) contains supplementary material, which is available to authorized users.

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“…A three-lane OrganoPlate [46] (see Fig. 3a, b) was employed to establish a BBB co-culture of TY10 brain endothelial cells with hAst and hBPCT cells (see Fig.…”

Section: Resultsmentioning

confidence: 99%

A perfused human blood–brain barrier on-a-chip for high-throughput assessment of barrier function and antibody transport

Wevers

Kasi

Gray

et al. 2018

Fluids Barriers CNS

Self Cite

256

255

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“…Several different geometries and designs have been developed for gut-on-a-chip devices, but two main types of designs are commonly found in the literature. The first one is based on the traditional Transwell system, where intestinal cells are grown on a circular porous membrane [9][10][11][12], and the second one is based on culturing cells on a porous membrane that separates two sides of a linear channel or tube [13][14][15][16][17]. Both types of systems contain an apical and basolateral flow of cell culture medium inducing shear forces on the cells and mimicking the luminal flow and blood flow.…”

Section: Introductionmentioning

confidence: 99%

Dynamic in vitro intestinal barrier model coupled to chip-based liquid chromatography mass spectrometry for oral bioavailability studies

et al. 2019

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In oral bioavailability studies, evaluation of the absorption and transport of drugs and food components across the intestinal barrier is crucial. Advances in the field of organ-on-a-chip technology have resulted in a dynamic gut-on-a-chip model that better mimics the in vivo microenvironment of the intestine. Despite a few recent integration attempts, ensuring a biologically relevant microenvironment while coupling with a fully online detection system still represents a major challenge. Herein, we designed an online technique to measure drug permeability and analyse unknown product formation across an intestinal epithelial layer of Caco-2 and HT29-MTX cells cultured on a flow-through Transwell system, while ensuring the quality and relevance of the biological model. Chip-based ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) was coupled to the dynamic Transwell system via a series of switching valves, thus allowing alternating measurements of the apical and basolateral sides of the in vitro model. Two trap columns were integrated for online sample pre-treatment and compatibility enhancement. Temporal analysis of the intestinal permeability was successfully demonstrated using verapamil as a model drug and ergotamine epimers as a model for natural toxins present in foods. Evidence was obtained that our newly developed dynamic system provided reliable results versus classical static in vitro models, and moreover, for the first time, epimer-specific transport is shown for ergotamine. Finally, initial experiments with the drug granisetron suggest that metabolic activity can be studied as well, thus highlighting the versatility of the bio-integrated online analysis system developed.

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“…Inspired by this landmark study, organs‐on‐chips as a new route for reverse engineering of human pathophysiology have attracted enormous attentions in both scientific and industrial fields . Different types of modular tissues/organs with simulated functions to native ones, including microvessels, cutaneous wound, intestine, kidney, liver, blood‐brain barrier, and even cancer, have been built for pathophysiologic investigations and rapid screening of drugs/therapeutic interventions in vitro.…”

Section: Biomedical Applicationsmentioning

confidence: 99%

Microfluidic Platforms toward Rational Material Fabrication for Biomedical Applications

Zhao

Cui

Wang

et al. 2019

Small

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The emergence of micro/nanomaterials in recent decades has brought promising alternative approaches in various biomedicine‐related fields such as pharmaceutics, diagnostics, and therapeutics. These micro/nanomaterials for specific biomedical applications shall possess tailored properties and functionalities that are closely correlated to their geometries, structures, and compositions, therefore placing extremely high demands for manufacturing techniques. Owing to the superior capabilities in manipulating fluids and droplets at microscale, microfluidics has offered robust and versatile platform technologies enabling rational design and fabrication of micro/nanomaterials with precisely controlled geometries, structures and compositions in high throughput manners, making them excellent candidates for a variety of biomedical applications. This review briefly summarizes the progress of microfluidics in the fabrication of various micro/nanomaterials ranging from 0D (particles), 1D (fibers) to 2D/3D (film and bulk materials) materials with controllable geometries, structures, and compositions. The applications of these microfluidic‐based materials in the fields of diagnostics, drug delivery, organs‐on‐chips, tissue engineering, and stimuli‐responsive biodevices are introduced. Finally, an outlook is discussed on the future direction of microfluidic platforms for generating materials with superior properties and on‐demand functionalities. The integration of new materials and techniques with microfluidics will pave new avenues for preparing advanced micro/nanomaterials with enhanced performance for biomedical applications.

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Membrane-free culture and real-time barrier integrity assessment of perfused intestinal epithelium tubes

Cited by 218 publications

References 20 publications

A perfused human blood–brain barrier on-a-chip for high-throughput assessment of barrier function and antibody transport

A perfused human blood–brain barrier on-a-chip for high-throughput assessment of barrier function and antibody transport

Dynamic in vitro intestinal barrier model coupled to chip-based liquid chromatography mass spectrometry for oral bioavailability studies

Microfluidic Platforms toward Rational Material Fabrication for Biomedical Applications

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