Micromachines

Editorial

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3 pages, 165 KiB

Open AccessEditorial

Editorial for the Special Issue on Organs-on-Chips

by Yu-suke Torisawa and Yi-Chung Tung

Micromachines 2020, 11(4), 369; https://doi.org/10.3390/mi11040369 - 01 Apr 2020

Cited by 5 | Viewed by 2122

Abstract

Recent advances in microsystems technology and cell culture techniques have led to the development of organ-on-chip microdevices to model functional units of organs [...] Full article

(This article belongs to the Special Issue Organs-on-chips)

Research

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10 pages, 1975 KiB

Open AccessArticle

Endothelial Cell Activation in an Embolic Ischemia-Reperfusion Injury Microfluidic Model

by Danielle Nemcovsky Amar, Mark Epshtein and Netanel Korin

Micromachines 2019, 10(12), 857; https://doi.org/10.3390/mi10120857 - 06 Dec 2019

Cited by 17 | Viewed by 3079

Abstract

Ischemia, lack of blood supply, is associated with a variety of life-threatening cardiovascular diseases, including acute ischemic stroke and myocardial infraction. While blood flow restoration is critical to prevent further damage, paradoxically, rapid reperfusion can increase tissue damage. A variety of animal models [...] Read more.

Ischemia, lack of blood supply, is associated with a variety of life-threatening cardiovascular diseases, including acute ischemic stroke and myocardial infraction. While blood flow restoration is critical to prevent further damage, paradoxically, rapid reperfusion can increase tissue damage. A variety of animal models have been developed to investigate ischemia/reperfusion injury (IRI), however they do not fully recapitulate human physiology of IRI. Here, we present a microfluidic IRI model utilizing a vascular compartment comprising human endothelial cells, which can be obstructed via a human blood clot and then re-perfused via thrombolytic treatment. Using our model, a significant increase in the expression of the endothelial cell inflammatory surface receptors E-selectin and I-CAM1 was observed in response to embolic occlusion. Following the demonstration of clot lysis and reperfusion via treatment using a thrombolytic agent, a significant decrease in the number of adherent endothelial cells and an increase in I-CAM1 levels compared to embolic occluded models, where reperfusion was not established, was observed. Altogether, the presented model can be applied to allow better understanding of human embolic based IRI and potentially serve as a platform for the development of improved and new therapeutic approaches. Full article

(This article belongs to the Special Issue Organs-on-chips)

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13 pages, 3303 KiB

Open AccessArticle

Tetrafluoroethylene-Propylene Elastomer for Fabrication of Microfluidic Organs-on-Chips Resistant to Drug Absorption

by Emi Sano, Chihiro Mori, Naoki Matsuoka, Yuka Ozaki, Keisuke Yagi, Aya Wada, Koichi Tashima, Shinsuke Yamasaki, Kana Tanabe, Kayo Yano and Yu-suke Torisawa

Micromachines 2019, 10(11), 793; https://doi.org/10.3390/mi10110793 - 19 Nov 2019

Cited by 38 | Viewed by 5337

Abstract

Organs-on-chips are microfluidic devices typically fabricated from polydimethylsiloxane (PDMS). Since PDMS has many attractive properties including high optical clarity and compliance, PDMS is very useful for cell culture applications; however, PDMS possesses a significant drawback in that small hydrophobic molecules are strongly absorbed. [...] Read more.

Organs-on-chips are microfluidic devices typically fabricated from polydimethylsiloxane (PDMS). Since PDMS has many attractive properties including high optical clarity and compliance, PDMS is very useful for cell culture applications; however, PDMS possesses a significant drawback in that small hydrophobic molecules are strongly absorbed. This drawback hinders widespread use of PDMS-based devices for drug discovery and development. Here, we describe a microfluidic cell culture system made of a tetrafluoroethylene-propylene (FEPM) elastomer. We demonstrated that FEPM does not absorb small hydrophobic compounds including rhodamine B and three types of drugs, nifedipine, coumarin, and Bay K8644, whereas PDMS absorbs them strongly. The device consists of two FEPM layers of microchannels separated by a thin collagen vitrigel membrane. Since FEPM is flexible and biocompatible, this microfluidic device can be used to culture cells while applying mechanical strain. When human umbilical vein endothelial cells (HUVECs) were subjected to cyclic strain (~10%) for 4 h in this device, HUVECs reoriented and aligned perpendicularly in response to the cyclic stretch. Moreover, we demonstrated that this device can be used to replicate the epithelial–endothelial interface as well as to provide physiological mechanical strain and fluid flow. This method offers a robust platform to produce organs-on-chips for drug discovery and development. Full article

(This article belongs to the Special Issue Organs-on-chips)

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15 pages, 4018 KiB

Open AccessArticle

A Cancer Spheroid Array Chip for Selecting Effective Drug

by Jae Won Choi, Sang-Yun Lee and Dong Woo Lee

Micromachines 2019, 10(10), 688; https://doi.org/10.3390/mi10100688 - 12 Oct 2019

Cited by 10 | Viewed by 4795

Abstract

A cancer spheroid array chip was developed by modifying a micropillar and microwell structure to improve the evaluation of drugs targeting specific mutations such as phosphor-epidermal growth factor receptor (p-EGFR). The chip encapsulated cells in alginate and allowed cancer cells to grow for [...] Read more.

A cancer spheroid array chip was developed by modifying a micropillar and microwell structure to improve the evaluation of drugs targeting specific mutations such as phosphor-epidermal growth factor receptor (p-EGFR). The chip encapsulated cells in alginate and allowed cancer cells to grow for over seven days to form cancer spheroids. However, reagents or media used to screen drugs in a high-density spheroid array had to be replaced very carefully, and this was a tedious task. Particularly, the immunostaining of cancer spheroids required numerous steps to replace many of the reagents used for drug evaluation. To solve this problem, we adapted a micropillar and microwell structure to a spheroid array. Thus, culturing cancer spheroids in alginate spots attached to the micropillar allowed us to replace the reagents in the microwell chip with a single fill of fresh medium, without damaging the cancer spheroids. In this study, a cancer spheroid array was made from a p-EGFR-overexpressing cell line (A549 lung cancer cell line). In a 12 by 36 column array chip (25 mm by 75 mm), the spheroid over 100 µm in diameter started to form at day seven and p-EGFR was also considerably overexpressed. The array was used for p-EGFR inhibition and cell viability measurement against seventy drugs, including ten EGFR-targeting drugs. By comparing drug response in the spheroid array (spheroid model) with that in the single-cell model, we demonstrated that the two models showed different responses and that the spheroid model might be more resistant to some drugs, thus narrowing the choice of drug candidates. Full article

(This article belongs to the Special Issue Organs-on-chips)

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13 pages, 1657 KiB

Open AccessArticle

Liver-on-a-Chip‒Magnetic Nanoparticle Bound Synthetic Metalloporphyrin-Catalyzed Biomimetic Oxidation of a Drug in a Magnechip Reactor

by Balázs Decsi, Réka Krammer, Kristóf Hegedűs, Ferenc Ender, Benjámin Gyarmati, András Szilágyi, Róbert Tőtős, Gabriel Katona, Csaba Paizs, György T. Balogh, László Poppe and Diána Balogh-Weiser

Micromachines 2019, 10(10), 668; https://doi.org/10.3390/mi10100668 - 01 Oct 2019

Cited by 11 | Viewed by 3919

Abstract

Biomimetic oxidation of drugs catalyzed by metalloporphyrins can be a novel and promising way for the effective and sustainable synthesis of drug metabolites. The immobilization of 5,10,15,20-tetrakis(2,3,4,5,6-pentafluorophenyl)iron(II) porphyrin (FeTPFP) and 5,10,15,20-tetrakis-(4-sulfonatophenyl)iron(II) porphyrin (FeTSPP) via stable covalent or rapid ionic binding on aminopropyl-functionalized magnetic [...] Read more.

Biomimetic oxidation of drugs catalyzed by metalloporphyrins can be a novel and promising way for the effective and sustainable synthesis of drug metabolites. The immobilization of 5,10,15,20-tetrakis(2,3,4,5,6-pentafluorophenyl)iron(II) porphyrin (FeTPFP) and 5,10,15,20-tetrakis-(4-sulfonatophenyl)iron(II) porphyrin (FeTSPP) via stable covalent or rapid ionic binding on aminopropyl-functionalized magnetic nanoparticles (MNPs-NH₂) were developed. These immobilized catalysts could be efficiently applied for the synthesis of new pharmaceutically active derivatives and liver related phase I oxidative major metabolite of an antiarrhythmic drug, amiodarone integrated in a continuous-flow magnetic chip reactor (Magnechip). Full article

(This article belongs to the Special Issue Organs-on-chips)

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17 pages, 16101 KiB

Open AccessFeature PaperArticle

Nanogroove-Enhanced Hydrogel Scaffolds for 3D Neuronal Cell Culture: An Easy Access Brain-on-Chip Model

by Alex Bastiaens, Sijia Xie and Regina Luttge

Micromachines 2019, 10(10), 638; https://doi.org/10.3390/mi10100638 - 23 Sep 2019

Cited by 16 | Viewed by 4383

Abstract

In order to better understand the brain and brain diseases, in vitro human brain models need to include not only a chemically and physically relevant microenvironment, but also structural network complexity. This complexity reflects the hierarchical architecture in brain tissue. Here, a method [...] Read more.

In order to better understand the brain and brain diseases, in vitro human brain models need to include not only a chemically and physically relevant microenvironment, but also structural network complexity. This complexity reflects the hierarchical architecture in brain tissue. Here, a method has been developed that adds complexity to a 3D cell culture by means of nanogrooved substrates. SH-SY5Y cells were grown on these nanogrooved substrates and covered with Matrigel, a hydrogel. To quantitatively analyze network behavior in 2D neuronal cell cultures, we previously developed an automated image-based screening method. We first investigated if this method was applicable to 3D primary rat brain cortical (CTX) cell cultures. Since the method was successfully applied to these pilot data, a proof of principle in a reductionist human brain cell model was attempted, using the SH-SY5Y cell line. The results showed that these cells also create an aligned network in the 3D microenvironment by maintaining a certain degree of guidance by the nanogrooved topography in the z-direction. These results indicate that nanogrooves enhance the structural complexity of 3D neuronal cell cultures for both CTX and human SH-SY5Y cultures, providing a basis for further development of an easy access brain-on-chip model. Full article

(This article belongs to the Special Issue Organs-on-chips)

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15 pages, 2022 KiB

Open AccessFeature PaperArticle

The Applications of Lattice Light-Sheet Microscopy for Functional Volumetric Imaging of Hippocampal Neurons in a Three-Dimensional Culture System

by Chin-Yi Chen, Yen-Ting Liu, Chieh-Han Lu, Po-Yi Lee, Yun-Chi Tsai, Jyun-Sian Wu, Peilin Chen and Bi-Chang Chen

Micromachines 2019, 10(9), 599; https://doi.org/10.3390/mi10090599 - 11 Sep 2019

Cited by 9 | Viewed by 4206

Abstract

The characterization of individual cells in three-dimensions (3D) with very high spatiotemporal resolution is crucial for the development of organs-on-chips, in which 3D cell cultures are integrated with microfluidic systems. In this study, we report the applications of lattice light-sheet microscopy (LLSM) for [...] Read more.

The characterization of individual cells in three-dimensions (3D) with very high spatiotemporal resolution is crucial for the development of organs-on-chips, in which 3D cell cultures are integrated with microfluidic systems. In this study, we report the applications of lattice light-sheet microscopy (LLSM) for monitoring neuronal activity in three-dimensional cell culture. We first established a 3D environment for culturing primary hippocampal neurons by applying a scaffold-based 3D tissue engineering technique. Fully differentiated and mature hippocampal neurons were observed in our system. With LLSM, we were able to monitor the behavior of individual cells in a 3D cell culture, which was very difficult under a conventional microscope due to strong light scattering from thick samples. We demonstrated that our system could study the membrane voltage and intracellular calcium dynamics at subcellular resolution in 3D under both chemical and electrical stimulation. From the volumetric images, it was found that the voltage indicators mainly resided in the cytosol instead of the membrane, which cannot be distinguished using conventional microscopy. Neuronal volumetric images were sheet scanned along the axial direction and recorded at a laser exposure of 6 ms, which covered an area up to 4800 μm², with an image pixel size of 0.102 μm. When we analyzed the time-lapse volumetric images, we could quantify the voltage responses in different neurites in 3D extensions. Full article

(This article belongs to the Special Issue Organs-on-chips)

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15 pages, 22299 KiB

Open AccessArticle

Metal and Polymeric Strain Gauges for Si-Based, Monolithically Fabricated Organs-on-Chips

by William F. Quirós-Solano, Nikolas Gaio, Cinzia Silvestri, Gregory Pandraud, Ronald Dekker and Pasqualina M. Sarro

Micromachines 2019, 10(8), 536; https://doi.org/10.3390/mi10080536 - 15 Aug 2019

Cited by 7 | Viewed by 4046

Abstract

Organ-on-chip (OOC) is becoming the alternative tool to conventional in vitro screening. Heart-on-chip devices including microstructures for mechanical and electrical stimulation have been demonstrated to be advantageous to study structural organization and maturation of heart cells. This paper presents the development of metal [...] Read more.

Organ-on-chip (OOC) is becoming the alternative tool to conventional in vitro screening. Heart-on-chip devices including microstructures for mechanical and electrical stimulation have been demonstrated to be advantageous to study structural organization and maturation of heart cells. This paper presents the development of metal and polymeric strain gauges for in situ monitoring of mechanical strain in the Cytostretch platform for heart-on-chip application. Specifically, the optimization of the fabrication process of metal titanium (Ti) strain gauges and the investigation on an alternative material to improve the robustness and performance of the devices are presented. The transduction behavior and functionality of the devices are successfully proven using a custom-made set-up. The devices showed resistance changes for the pressure range (0–3 kPa) used to stretch the membranes on which heart cells can be cultured. Relative resistance changes of approximately 0.008% and 1.2% for titanium and polymeric strain gauges are respectively reported for membrane deformations up to 5%. The results demonstrate that both conventional IC metals and polymeric materials can be implemented for sensing mechanical strain using robust microfabricated organ-on-chip devices. Full article

(This article belongs to the Special Issue Organs-on-chips)

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18 pages, 4765 KiB

Open AccessArticle

Permeability of Epithelial/Endothelial Barriers in Transwells and Microfluidic Bilayer Devices

by Timothy S. Frost, Linan Jiang, Ronald M. Lynch and Yitshak Zohar

Micromachines 2019, 10(8), 533; https://doi.org/10.3390/mi10080533 - 13 Aug 2019

Cited by 59 | Viewed by 10408

Abstract

Lung-on-a-chip (LoC) models hold the potential to rapidly change the landscape for pulmonary drug screening and therapy, giving patients more advanced and less invasive treatment options. Understanding the drug absorption in these microphysiological systems, modeling the lung-blood barrier is essential for increasing the [...] Read more.

Lung-on-a-chip (LoC) models hold the potential to rapidly change the landscape for pulmonary drug screening and therapy, giving patients more advanced and less invasive treatment options. Understanding the drug absorption in these microphysiological systems, modeling the lung-blood barrier is essential for increasing the role of the organ-on-a-chip technology in drug development. In this work, epithelial/endothelial barrier tissue interfaces were established in microfluidic bilayer devices and transwells, with porous membranes, for permeability characterization. The effect of shear stress on the molecular transport was assessed using known paracellular and transcellular biomarkers. The permeability of porous membranes without cells, in both models, is inversely proportional to the molecular size due to its diffusivity. Paracellular transport, between epithelial/endothelial cell junctions, of large molecules such as transferrin, as well as transcellular transport, through cell lacking required active transporters, of molecules such as dextrans, is negligible. When subjected to shear stress, paracellular transport of intermediate-size molecules such as dextran was enhanced in microfluidic devices when compared to transwells. Similarly, shear stress enhances paracellular transport of small molecules such as Lucifer yellow, but its effect on transcellular transport is not clear. The results highlight the important role that LoC can play in drug absorption studies to accelerate pulmonary drug development. Full article

(This article belongs to the Special Issue Organs-on-chips)

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17 pages, 3478 KiB

Open AccessFeature PaperArticle

Micro Vacuum Chuck and Tensile Test System for Bio-Mechanical Evaluation of 3D Tissue Constructed of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes (hiPS-CM)

by Kaoru Uesugi, Fumiaki Shima, Ken Fukumoto, Ayami Hiura, Yoshinari Tsukamoto, Shigeru Miyagawa, Yoshiki Sawa, Takami Akagi, Mitsuru Akashi and Keisuke Morishima

Micromachines 2019, 10(7), 487; https://doi.org/10.3390/mi10070487 - 19 Jul 2019

Cited by 12 | Viewed by 4424

Abstract

In this report, we propose a micro vacuum chuck (MVC) which can connect three-dimensional (3D) tissues to a tensile test system by vacuum pressure. Because the MVC fixes the 3D tissue by vacuum pressure generated on multiple vacuum holes, it is expected that [...] Read more.

In this report, we propose a micro vacuum chuck (MVC) which can connect three-dimensional (3D) tissues to a tensile test system by vacuum pressure. Because the MVC fixes the 3D tissue by vacuum pressure generated on multiple vacuum holes, it is expected that the MVC can fix 3D tissue to the system easily and mitigate the damage which can happen by handling during fixing. In order to decide optimum conditions for the size of the vacuum holes and the vacuum pressure, various sized vacuum holes and vacuum pressures were applied to a normal human cardiac fibroblast 3D tissue. From the results, we confirmed that a square shape with 100 µm sides was better for fixing the 3D tissue. Then we mounted our developed MVCs on a specially developed tensile test system and measured the bio-mechanical property (beating force) of cardiac 3D tissue which was constructed of human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CM); the 3D tissue had been assembled by the layer-by-layer (LbL) method. We measured the beating force of the cardiac 3D tissue and confirmed the measured force followed the Frank-Starling relationship. This indicates that the beating property of cardiac 3D tissue obtained by the LbL method was close to that of native cardiac tissue. Full article

(This article belongs to the Special Issue Organs-on-chips)

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13 pages, 4637 KiB

Open AccessFeature PaperArticle

Study Effects of Drug Treatment and Physiological Physical Stimulation on Surfactant Protein Expression of Lung Epithelial Cells Using a Biomimetic Microfluidic Cell Culture Device

by Ting-Ru Lin, Sih-Ling Yeh, Chien-Chung Peng, Wei-Hao Liao and Yi-Chung Tung

Micromachines 2019, 10(6), 400; https://doi.org/10.3390/mi10060400 - 16 Jun 2019

Cited by 4 | Viewed by 3976

Abstract

This paper reports a biomimetic microfluidic device capable of reconstituting physiological physical microenvironments in lungs during fetal development for cell culture. The device integrates controllability of both hydrostatic pressure and cyclic substrate deformation within a single chip to better mimic the in vivo [...] Read more.

This paper reports a biomimetic microfluidic device capable of reconstituting physiological physical microenvironments in lungs during fetal development for cell culture. The device integrates controllability of both hydrostatic pressure and cyclic substrate deformation within a single chip to better mimic the in vivo microenvironments. For demonstration, the effects of drug treatment and physical stimulations on surfactant protein C (SPC) expression of lung epithelial cells (A549) are studied using the device. The experimental results confirm the device’s capability of mimicking in vivo microenvironments with multiple physical stimulations for cell culture applications. Furthermore, the results indicate the critical roles of physical stimulations in regulating cellular behaviors. With the demonstrated functionalities and performance, the device is expected to provide a powerful tool for further lung development studies that can be translated to clinical observation in a more straightforward manner. Consequently, the device is promising for construction of more in vitro physiological microenvironments integrating multiple physical stimulations to better study organ development and its functions. Full article

(This article belongs to the Special Issue Organs-on-chips)

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Review

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22 pages, 6302 KiB

Open AccessReview

Methods of Delivering Mechanical Stimuli to Organ-on-a-Chip

by Kattika Kaarj and Jeong-Yeol Yoon

Micromachines 2019, 10(10), 700; https://doi.org/10.3390/mi10100700 - 14 Oct 2019

Cited by 94 | Viewed by 8983

Abstract

Recent advances in integrating microengineering and tissue engineering have enabled the creation of promising microengineered physiological models, known as organ-on-a-chip (OOC), for experimental medicine and pharmaceutical research. OOCs have been used to recapitulate the physiologically critical features of specific human tissues and organs [...] Read more.

Recent advances in integrating microengineering and tissue engineering have enabled the creation of promising microengineered physiological models, known as organ-on-a-chip (OOC), for experimental medicine and pharmaceutical research. OOCs have been used to recapitulate the physiologically critical features of specific human tissues and organs and their interactions. Application of chemical and mechanical stimuli is critical for tissue development and behavior, and they were also applied to OOC systems. Mechanical stimuli applied to tissues and organs are quite complex in vivo, which have not adequately recapitulated in OOCs. Due to the recent advancement of microengineering, more complicated and physiologically relevant mechanical stimuli are being introduced to OOC systems, and this is the right time to assess the published literature on this topic, especially focusing on the technical details of device design and equipment used. We first discuss the different types of mechanical stimuli applied to OOC systems: shear flow, compression, and stretch/strain. This is followed by the examples of mechanical stimuli-incorporated OOC systems. Finally, we discuss the potential OOC systems where various types of mechanical stimuli can be applied to a single OOC device, as a better, physiologically relevant recapitulation model, towards studying and evaluating experimental medicine, human disease modeling, drug development, and toxicology. Full article

(This article belongs to the Special Issue Organs-on-chips)

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26 pages, 3863 KiB

Open AccessFeature PaperReview

Engineered Liver-On-A-Chip Platform to Mimic Liver Functions and Its Biomedical Applications: A Review

by Jiu Deng, Wenbo Wei, Zongzheng Chen, Bingcheng Lin, Weijie Zhao, Yong Luo and Xiuli Zhang

Micromachines 2019, 10(10), 676; https://doi.org/10.3390/mi10100676 - 07 Oct 2019

Cited by 152 | Viewed by 12525

Abstract

Hepatology and drug development for liver diseases require in vitro liver models. Typical models include 2D planar primary hepatocytes, hepatocyte spheroids, hepatocyte organoids, and liver-on-a-chip. Liver-on-a-chip has emerged as the mainstream model for drug development because it recapitulates the liver microenvironment and has [...] Read more.

Hepatology and drug development for liver diseases require in vitro liver models. Typical models include 2D planar primary hepatocytes, hepatocyte spheroids, hepatocyte organoids, and liver-on-a-chip. Liver-on-a-chip has emerged as the mainstream model for drug development because it recapitulates the liver microenvironment and has good assay robustness such as reproducibility. Liver-on-a-chip with human primary cells can potentially correlate clinical testing. Liver-on-a-chip can not only predict drug hepatotoxicity and drug metabolism, but also connect other artificial organs on the chip for a human-on-a-chip, which can reflect the overall effect of a drug. Engineering an effective liver-on-a-chip device requires knowledge of multiple disciplines including chemistry, fluidic mechanics, cell biology, electrics, and optics. This review first introduces the physiological microenvironments in the liver, especially the cell composition and its specialized roles, and then summarizes the strategies to build a liver-on-a-chip via microfluidic technologies and its biomedical applications. In addition, the latest advancements of liver-on-a-chip technologies are discussed, which serve as a basis for further liver-on-a-chip research. Full article

(This article belongs to the Special Issue Organs-on-chips)

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26 pages, 3940 KiB

Open AccessReview

Microfluidic-Based 3D Engineered Microvascular Networks and Their Applications in Vascularized Microtumor Models

by Xiaolin Wang, Qiyue Sun and Jianghua Pei

Micromachines 2018, 9(10), 493; https://doi.org/10.3390/mi9100493 - 27 Sep 2018

Cited by 72 | Viewed by 9420

Abstract

The microvasculature plays a critical role in human physiology and is closely associated to various human diseases. By combining advanced microfluidic-based techniques, the engineered 3D microvascular network model provides a precise and reproducible platform to study the microvasculature in vitro, which is an [...] Read more.

The microvasculature plays a critical role in human physiology and is closely associated to various human diseases. By combining advanced microfluidic-based techniques, the engineered 3D microvascular network model provides a precise and reproducible platform to study the microvasculature in vitro, which is an essential and primary component to engineer organ-on-chips and achieve greater biological relevance. In this review, we discuss current strategies to engineer microvessels in vitro, which can be broadly classified into endothelial cell lining-based methods, vasculogenesis and angiogenesis-based methods, and hybrid methods. By closely simulating relevant factors found in vivo such as biomechanical, biochemical, and biological microenvironment, it is possible to create more accurate organ-specific models, including both healthy and pathological vascularized microtissue with their respective vascular barrier properties. We further discuss the integration of tumor cells/spheroids into the engineered microvascular to model the vascularized microtumor tissue, and their potential application in the study of cancer metastasis and anti-cancer drug screening. Finally, we conclude with our commentaries on current progress and future perspective of on-chip vascularization techniques for fundamental and clinical/translational research. Full article

(This article belongs to the Special Issue Organs-on-chips)

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Other

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10 pages, 3011 KiB

Open AccessBrief Report

Prototyping a Versatile Two-Layer Multi-Channel Microfluidic Device for Direct-Contact Cell-Vessel Co-Culture

by Li-Jiun Chen, Bibek Raut, Nobuhiro Nagai, Toshiaki Abe and Hirokazu Kaji

Micromachines 2020, 11(1), 79; https://doi.org/10.3390/mi11010079 - 10 Jan 2020

Cited by 16 | Viewed by 4940

Abstract

Microfluidic devices are gaining increasing popularity due to their wide applications in various research areas. Herein, we propose a two-layer multi-channel microfluidic device allowing for direct-contact cell-vessel co-culture. Using the device, we built a co-culture model of the outer blood-retina barrier (oBRB), mimicking [...] Read more.

Microfluidic devices are gaining increasing popularity due to their wide applications in various research areas. Herein, we propose a two-layer multi-channel microfluidic device allowing for direct-contact cell-vessel co-culture. Using the device, we built a co-culture model of the outer blood-retina barrier (oBRB), mimicking the in vivo retinal pigment epithelial cells-Bruch membrane-fenestrated choroids. To demonstrate the versatility of the design, we further modified the device by inserting platinum electrodes for trans-epithelial electrical resistance (TEER) measurement, demonstrating the feasibility of on-chip assessment of the epithelial barrier integrity. Our proposed design allows for direct-contact co-culture of cell–cell or cell–vessel, modifiable for real-time evaluation of the state of the epithelial monolayers. Full article

(This article belongs to the Special Issue Organs-on-chips)

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10 pages, 2624 KiB

Open AccessFeature PaperBrief Report

Competing Fluid Forces Control Endothelial Sprouting in a 3-D Microfluidic Vessel Bifurcation Model

by Ehsan Akbari, Griffin B. Spychalski, Kaushik K. Rangharajan, Shaurya Prakash and Jonathan W. Song

Micromachines 2019, 10(7), 451; https://doi.org/10.3390/mi10070451 - 04 Jul 2019

Cited by 25 | Viewed by 3516

Abstract

Sprouting angiogenesis—the infiltration and extension of endothelial cells from pre-existing blood vessels—helps orchestrate vascular growth and remodeling. It is now agreed that fluid forces, such as laminar shear stress due to unidirectional flow in straight vessel segments, are important regulators of angiogenesis. However, [...] Read more.

Sprouting angiogenesis—the infiltration and extension of endothelial cells from pre-existing blood vessels—helps orchestrate vascular growth and remodeling. It is now agreed that fluid forces, such as laminar shear stress due to unidirectional flow in straight vessel segments, are important regulators of angiogenesis. However, regulation of angiogenesis by the different flow dynamics that arise due to vessel branching, such as impinging flow stagnation at the base of a bifurcating vessel, are not well understood. Here we used a recently developed 3-D microfluidic model to investigate the role of the flow conditions that occur due to vessel bifurcations on endothelial sprouting. We observed that bifurcating fluid flow located at the vessel bifurcation point suppresses the formation of angiogenic sprouts. Similarly, laminar shear stress at a magnitude of ~3 dyn/cm² applied in the branched vessels downstream of the bifurcation point, inhibited the formation of angiogenic sprouts. In contrast, co-application of ~1 µm/s average transvascular flow across the endothelial monolayer with laminar shear stress induced the formation of angiogenic sprouts. These results suggest that transvascular flow imparts a competing effect against bifurcating fluid flow and laminar shear stress in regulating endothelial sprouting. To our knowledge, these findings are the first report on the stabilizing role of bifurcating fluid flow on endothelial sprouting. These results also demonstrate the importance of local flow dynamics due to branched vessel geometry in determining the location of sprouting angiogenesis. Full article

(This article belongs to the Special Issue Organs-on-chips)

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