Special Issue "Organs-on-chips"

A special issue of Micromachines (ISSN 2072-666X). This special issue belongs to the section "B:Biology".

Deadline for manuscript submissions: closed (31 July 2019).

Special Issue Editors

Guest Editor
Dr. Yu-suke Torisawa Website E-Mail
1 Hakubi Center for Advanced Research, Kyoto University, Kyoto 615-8540, Japan
2 Department of Micro Engineering, Kyoto University, Kyoto 615-8540, Japan
Phone: +81-75-383-3701
Interests: microfluidics; tissue engineering; biomimetics; mechanobiology; stem cells and niches
Guest Editor
Dr. Yi-Chung Tung Website E-Mail
Research Center for Applied Sciences, Academia Sinica, Taipei 11529, Taiwan
Phone: +886-2-2787-3138
Interests: microfluidic cell culture and analysis devices; micro/nano fabrication; mechanobiology

Special Issue Information

Dear Colleagues,

Recent advances in microsystems technology and cell culture techniques have led to the development of organ-on-chip microdevices that produce tissue-level functionality, not possible with conventional culture models, by recapitulating natural tissue architecture and microenvironmental cues within microfluidic devices.  Since the physiological microenvironments in living systems are mostly microfluidic in nature, the use of microfluidic devices facilitates engineering cellular microenvironments; the microfluidic devices allow for control of local chemical gradients and dynamic mechanical forces, which play important roles in cellular viability and function.  The organ-on-chip microdevices have great potential to promote drug discovery and development, to model human physiology and disease, and to replace animal models for efficacy and toxicity testing.  Recently, induced pluripotent stem (iPS) cells have been leveraged to develop organs-on-chips, which enable various types of organ models and disease models not possible with primary cells and cell lines.  This Special Issue seeks to showcase research papers, short communications, and review articles that focus on: (1) microdevices to mimic or control cellular microenvironment; (2) microdevices to evaluate interactions between different organ models; (3) microdevices to maintain iPS cells or iPSC-derived cells; and (4) sensors and techniques to evaluate drug efficacy or toxicity.

Dr. Yu-suke Torisawa
Dr. Yi-Chung Tung
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Micromachines is an international peer-reviewed open access monthly journal published by MDPI.

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Keywords

  • Microfluidics
  • Lab on a Chip
  • Tissue Engineering
  • Cell Culture Methods
  • BioMEMS

Published Papers (7 papers)

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Research

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Open AccessArticle
The Applications of Lattice Light-sheet Microscopy for Functional Volumetric Imaging of Hippocampal Neurons in a Three-Dimensional Culture System
Micromachines 2019, 10(9), 599; https://doi.org/10.3390/mi10090599 - 11 Sep 2019
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)
Open AccessArticle
Metal and Polymeric Strain Gauges for Si-Based, Monolithically Fabricated Organs-on-Chips
Micromachines 2019, 10(8), 536; https://doi.org/10.3390/mi10080536 - 15 Aug 2019
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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Open AccessArticle
Permeability of Epithelial/Endothelial Barriers in Transwells and Microfluidic Bilayer Devices
Micromachines 2019, 10(8), 533; https://doi.org/10.3390/mi10080533 - 13 Aug 2019
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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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)
Micromachines 2019, 10(7), 487; https://doi.org/10.3390/mi10070487 - 19 Jul 2019
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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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
Micromachines 2019, 10(6), 400; https://doi.org/10.3390/mi10060400 - 16 Jun 2019
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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Open AccessReview
Microfluidic-Based 3D Engineered Microvascular Networks and Their Applications in Vascularized Microtumor Models
Micromachines 2018, 9(10), 493; https://doi.org/10.3390/mi9100493 - 27 Sep 2018
Cited by 5
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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Open AccessFeature PaperBrief Report
Competing Fluid Forces Control Endothelial Sprouting in a 3-D Microfluidic Vessel Bifurcation Model
Micromachines 2019, 10(7), 451; https://doi.org/10.3390/mi10070451 - 04 Jul 2019
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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