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Micro/Nanofluidic Devices for Single Cell Analysis, Volume II

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

Deadline for manuscript submissions: closed (15 November 2020) | Viewed by 40139

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Dr. Tuhin Subhra Santra

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Guest Editor

Department of Engineering Design, Indian Institute of Technology Madras, Chennai, India
Interests: MEMS; Bio-NEMS; single- cell technology; biomedical micro/nano devices; micro/nanofluidics; nanomedicine
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Prof. Dr. Fan-Gang Tseng

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Guest Editor

Distinguished Professor, Department of Engineering and System Science, National Tsing Hua University (NTHU), Affiliated Research Fellow, Academia Sinica, Hsinchu, Taiwan
Interests: organ on a chip; microfluidic systems; biosensors; CTCs/CTM diagnosis; single cell analysis
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Special Issue Information

Dear Colleagues,

Cells are the most fundamental building blocks for most of life forms, and always play a significant role in coordinating with one another to perform systematic functions in living creatures. However the behaviors of cell to cell or cell to the environment with their organelles and their intracellular physical/biochemical/biological effects are still unknown. To insight this interaction, ensemble measurement for millions of cells together cannot provide the proper information, such as stem cell proliferation and differentiation, neural network coordination, and cardiomyocytes synchronization. Thus single cells analysis has come into frontier research since last few decades. To analyze the cellular function, single cells analysis (SCA) can be conducted by employing miniaturized devices, whose dimension is similar to that of single cells. Micro/nanofludic device with the power to manipulate and detect biosamples, reagents, or biomolecules in micro/nano scale can well fulfill this requirement for single cells analysis. The analysis can be performed by combining capillary electrophoresis (CE) with laser induced fluorescence (LIF) detection methods, electrochemical detection (ED), flow cytometry, mass spectrometer etc. However this powerful technology can provide specific information about cell interactions with high spatial and temporal resolution. Micro-nanofludic device is not only useful for cell manipulation, cell lysis, cell separation but also it can easily control biochemical, electrical, mechanical parameters for SCA analysis.

This special issue will invite manuscripts conducting researches on integrated micro or nano systems dealing with single cell manipulation, injection, separation, lysis of single cell, dynamics of single cell with the use of micro/nanofluidic devices combined with various detection schemes. The role of single cell analysis is recognized as one of the important pathways for system biology, proteomics, genomics, metabolomics and fluxomics and potentially leads to paradigm shift. The discussion of application of single cell analysis for biocatalysis, metabolic, bioprocess engineering and the future challenge for single cell analysis with their advantages and limitations are also welcome to be included in the manuscripts.

Dr. Tuhin Subhra Santra
Prof. Fan-Gang Tseng
Guest Editors

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Keywords

lab on a chip
life on a chip
organ on a chip
lab in a cell
cell chip
micro total analysis (µTAS)
microfluidics
nanofluidics
single-cell perturbation
single-cell cultivation
single-cell proteomics
single-cell interactions
dielectrophoresis
electrophoresis
optical trapping
capillary electrophoresis
electroporation
flow cytometry
heterogeneity
mechanical characterization
optical characterization
biochemical characterization
system biology

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Published Papers (10 papers)

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Editorial

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5 pages, 512 KiB

Open AccessEditorial

Editorial for the Special Issue on Micro/Nanofluidic Devices for Single Cell Analysis, Volume II

by Tuhin Subhra Santra and Fan-Gang Tseng

Micromachines 2021, 12(8), 875; https://doi.org/10.3390/mi12080875 - 26 Jul 2021

Cited by 1 | Viewed by 1599

Abstract

The functional, genetic, or compositional heterogeneity of healthy and diseased tissues promotes significant challenges to drug discovery and development [...] Full article

(This article belongs to the Special Issue Micro/Nanofluidic Devices for Single Cell Analysis, Volume II)

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Research

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12 pages, 1627 KiB

Open AccessArticle

Design and Clinical Application of an Integrated Microfluidic Device for Circulating Tumor Cells Isolation and Single-Cell Analysis

by Mingxin Xu, Wenwen Liu, Kun Zou, Song Wei, Xinri Zhang, Encheng Li and Qi Wang

Micromachines 2021, 12(1), 49; https://doi.org/10.3390/mi12010049 - 2 Jan 2021

Cited by 9 | Viewed by 3697

Abstract

Circulating tumor cells (CTCs) have been considered as an alternative to tissue biopsy for providing both germline-specific and tumor-derived genetic variations. Single-cell analysis of CTCs enables in-depth investigation of tumor heterogeneity and individualized clinical assessment. However, common CTC enrichment techniques generally have limitations of low throughput and cell damage. Herein, based on micropore-arrayed filtration membrane and microfluidic chip, we established an integrated CTC isolation platform with high-throughput, high-efficiency, and less cell damage. We observed a capture rate of around 85% and a purity of 60.4% by spiking tumor cells (PC-9) into healthy blood samples. Detection of CTCs from lung cancer patients demonstrated a positive detectable rate of 87.5%. Additionally, single CTCs, ctDNA and liver biopsy tissue of a representative advanced lung cancer patient were collected and sequenced, which revealed comprehensive genetic information of CTCs while reflected the differences in genetic profiles between different biological samples. This work provides a promising tool for CTCs isolation and further analysis at single-cell resolution with potential clinical value. Full article

(This article belongs to the Special Issue Micro/Nanofluidic Devices for Single Cell Analysis, Volume II)

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15 pages, 1603 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

On-Chip Multiple Particle Velocity and Size Measurement Using Single-Shot Two-Wavelength Differential Image Analysis

by Shuya Sawa, Mitsuru Sentoku and Kenji Yasuda

Micromachines 2020, 11(11), 1011; https://doi.org/10.3390/mi11111011 - 17 Nov 2020

Cited by 1 | Viewed by 2694

Abstract

Precise and quick measurement of samples’ flow velocities is essential for cell sorting timing control and reconstruction of acquired image-analyzed data. We developed a simple technique for the single-shot measurement of flow velocities of particles simultaneously in a microfluidic pathway. The speed was calculated from the difference in the particles’ elongation in an acquired image that appeared when two wavelengths of light with different irradiation times were applied. We ran microparticles through an imaging flow cytometer and irradiated two wavelengths of light with different irradiation times simultaneously to those particles. The mixture of the two wavelength transmitted lights was divided into two wavelengths, and the images of the same microparticles for each wavelength were acquired in a single shot. We estimated the velocity from the difference of its elongation divided by the difference of irradiation time by comparing these two images. The distribution of polystyrene beads’ velocity was parabolic and highest at the center of the flow channel, consistent with the expected velocity distribution of the laminar flow. Applying the calculated velocity, we also restored the accurate shapes and cross-sectional areas of particles in the images, indicating this simple method for improving of imaging flow cytometry and cell sorter for diagnostic screening of circulating tumor cells. Full article

(This article belongs to the Special Issue Micro/Nanofluidic Devices for Single Cell Analysis, Volume II)

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14 pages, 8218 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Single-Cell Mechanophenotyping in Microfluidics to Evaluate Behavior of U87 Glioma Cells

by Esra Sengul and Meltem Elitas

Micromachines 2020, 11(9), 845; https://doi.org/10.3390/mi11090845 - 11 Sep 2020

Cited by 10 | Viewed by 4349

Abstract

Integration of microfabricated, single-cell resolution and traditional, population-level biological assays will be the future of modern techniques in biology that will enroll in the evolution of biology into a precision scientific discipline. In this study, we developed a microfabricated cell culture platform to investigate the indirect influence of macrophages on glioma cell behavior. We quantified proliferation, morphology, motility, migration, and deformation properties of glioma cells at single-cell level and compared these results with population-level data. Our results showed that glioma cells obtained slightly slower proliferation, higher motility, and extremely significant deformation capability when cultured with 50% regular growth medium and 50% macrophage-depleted medium. When the expression levels of E-cadherin and Vimentin proteins were measured, it was verified that observed mechanophenotypic alterations in glioma cells were not due to epithelium to mesenchymal transition. Our results were consistent with previously reported enormous heterogeneity of U87 glioma cell line. Herein, for the first time, we quantified the change of deformation indexes of U87 glioma cells using microfluidic devices for single-cells analysis. Full article

(This article belongs to the Special Issue Micro/Nanofluidic Devices for Single Cell Analysis, Volume II)

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15 pages, 2268 KiB

Open AccessArticle

Quantifying Heterogeneity According to Deformation of the U937 Monocytes and U937-Differentiated Macrophages Using 3D Carbon Dielectrophoresis in Microfluidics

by Meltem Elitas and Esra Sengul

Micromachines 2020, 11(6), 576; https://doi.org/10.3390/mi11060576 - 8 Jun 2020

Cited by 8 | Viewed by 3192

Abstract

A variety of force fields have thus far been demonstrated to investigate electromechanical properties of cells in a microfluidic platform which, however, are mostly based on fluid shear stress and may potentially cause irreversible cell damage. This work presents dielectric movement and deformation measurements of U937 monocytes and U937-differentiated macrophages in a low conductive medium inside a 3D carbon electrode array. Here, monocytes exhibited a crossover frequency around 150 kHz and presented maximum deformation index at 400 kHz and minimum deformation index at 1 MHz frequencies at 20 V_peak-peak. Although macrophages were differentiated from monocytes, their crossover frequency was lower than 50 kHz at 10 V_peak-peak. The change of the deformation index for macrophages was more constant and lower than the monocyte cells. Both dielectric mobility and deformation spectra revealed significant differences between the dielectric responses of U937 monocytes and U937-differentiated macrophages, which share the same origin. This method can be used for label-free, specific, and sensitive single-cell characterization. Besides, damage of the cells by aggressive shear forces can, hence, be eliminated and cells can be used for downstream analysis. Our results showed that dielectric mobility and deformation have a great potential as an electromechanical biomarker to reliably characterize and distinguish differentiated cell populations from their progenitors. Full article

(This article belongs to the Special Issue Micro/Nanofluidic Devices for Single Cell Analysis, Volume II)

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13 pages, 2496 KiB

Open AccessArticle

Single Cell Hydrodynamic Stretching and Microsieve Filtration Reveal Genetic, Phenotypic and Treatment-Related Links to Cellular Deformability

by Fenfang Li, Igor Cima, Jess Honganh Vo, Min-Han Tan and Claus Dieter Ohl

Micromachines 2020, 11(5), 486; https://doi.org/10.3390/mi11050486 - 9 May 2020

Cited by 10 | Viewed by 4734

Abstract

Deformability is shown to correlate with the invasiveness and metastasis of cancer cells. Recent studies suggest epithelial-to-mesenchymal transition (EMT) might enable cancer metastasis. However, the correlation of EMT with cancer cell deformability has not been well elucidated. Cellular deformability could also help evaluate the drug response of cancer cells. Here, we combine hydrodynamic stretching and microsieve filtration to study cellular deformability in several cellular models. Hydrodynamic stretching uses extensional flow to rapidly quantify cellular deformability and size with high throughput at the single cell level. Microsieve filtration can rapidly estimate relative deformability in cellular populations. We show that colorectal cancer cell line RKO with the mesenchymal-like feature is more flexible than the epithelial-like HCT116. In another model, the breast epithelial cells MCF10A with deletion of the TP53 gene are also significantly more deformable compared to their isogenic wildtype counterpart, indicating a potential genetic link to cellular deformability. We also find that the drug docetaxel leads to an increase in the size of A549 lung cancer cells. The ability to associate mechanical properties of cancer cells with their phenotypes and genetics using single cell hydrodynamic stretching or the microsieve may help to deepen our understanding of the basic properties of cancer progression. Full article

(This article belongs to the Special Issue Micro/Nanofluidic Devices for Single Cell Analysis, Volume II)

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13 pages, 2857 KiB

Open AccessArticle

Scalable Parallel Manipulation of Single Cells Using Micronozzle Array Integrated with Bidirectional Electrokinetic Pumps

by Moeto Nagai, Keita Kato, Satoshi Soga, Tuhin Subhra Santra and Takayuki Shibata

Micromachines 2020, 11(4), 442; https://doi.org/10.3390/mi11040442 - 22 Apr 2020

Cited by 7 | Viewed by 2930

Abstract

High throughput reconstruction of in vivo cellular environments allows for efficient investigation of cellular functions. If one-side-open multi-channel microdevices are integrated with micropumps, the devices will achieve higher throughput in the manipulation of single cells while maintaining flexibility and open accessibility. This paper reports on the integration of a polydimethylsiloxane (PDMS) micronozzle array and bidirectional electrokinetic pumps driven by DC-biased AC voltages. Pt/Ti and indium tin oxide (ITO) electrodes were used to study the effect of DC bias and peak-to-peak voltage and electrodes in a low conductivity isotonic solution. The flow was bidirectionally controlled by changing the DC bias. A pump integrated with a micronozzle array was used to transport single HeLa cells into nozzle holes. The application of DC-biased AC voltage (100 kHz, 10 V_pp, and V_DC: −4 V) provided a sufficient electroosmotic flow outside the nozzle array. This integration method of nozzle and pumps is anticipated to be a standard integration method. The operating conditions of DC-biased AC electrokinetic pumps in a biological buffer was clarified and found useful for cell manipulation. Full article

(This article belongs to the Special Issue Micro/Nanofluidic Devices for Single Cell Analysis, Volume II)

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10 pages, 1690 KiB

Open AccessArticle

Real-Time Monitoring and Detection of Single-Cell Level Cytokine Secretion Using LSPR Technology

by Chen Zhu, Xi Luo, Wilfred Villariza Espulgar, Shohei Koyama, Atsushi Kumanogoh, Masato Saito, Hyota Takamatsu and Eiichi Tamiya

Micromachines 2020, 11(1), 107; https://doi.org/10.3390/mi11010107 - 19 Jan 2020

Cited by 18 | Viewed by 4957

Abstract

Cytokine secretion researches have been a main focus of studies among the scientists in the recent decades for its outstanding contribution to clinical diagnostics. Localized surface plasmon resonance (LSPR) technology is one of the conventional methods utilized to analyze these issues, as it could provide fast, label-free and real-time monitoring of biomolecule binding events. However, numerous LSPR-based biosensors in the past are usually utilized to monitor the average performance of cell groups rather than single cells. Meanwhile, the complicated sensor structures will lead to the fabrication and economic budget problems. Thus, in this paper, we report a simple synergistic integration of the cell trapping of microwell chip and gold-capped nanopillar-structured cyclo-olefin-polymer (COP) film for single cell level Interleukin 6 (IL-6) detection. Here, in-situ cytokine secreted from the trapped cell can be directly observed and analyzed through the peak red-shift in the transmittance spectrum. The fabricated device also shows the potential to conduct the real-time monitoring which would greatly help us identify the viability and biological variation of the tested single cell. Full article

(This article belongs to the Special Issue Micro/Nanofluidic Devices for Single Cell Analysis, Volume II)

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11 pages, 2143 KiB

Open AccessArticle

Characterization of Single-Nucleus Electrical Properties by Microfluidic Constriction Channel

by Hongyan Liang, Yi Zhang, Deyong Chen, Huiwen Tan, Yu Zheng, Junbo Wang and Jian Chen

Micromachines 2019, 10(11), 740; https://doi.org/10.3390/mi10110740 - 31 Oct 2019

Cited by 10 | Viewed by 3854

Abstract

As key bioelectrical markers, equivalent capacitance (C_ne, i.e., capacitance per unit area) and resistance (R_ne, i.e., resistivity multiply thickness) of nuclear envelopes have emerged as promising electrical indicators, which cannot be effectively measured by conventional approaches. In this study, single nuclei were isolated from whole cells and trapped at the entrances of microfluidic constriction channels, and then corresponding impedance profiles were sampled and translated into single-nucleus C_ne and R_ne based on a home-developed equivalent electrical model. C_ne and R_ne of A549 nuclei were first quantified as 3.43 ± 1.81 μF/cm² and 2.03 ± 1.40 Ω·cm² (N_n = 35), which were shown not to be affected by variations of key parameters in nuclear isolation and measurement. The developed approach in this study was also used to measure a second type of nuclei, producing C_ne and R_ne of 3.75 ± 3.17 μF/cm² and 1.01 ± 0.70 Ω·cm² for SW620 (N_n = 17). This study may provide a new perspective in single-cell electrical characterization, enabling cell type classification and cell status evaluation based on bioelectrical markers of nuclei. Full article

(This article belongs to the Special Issue Micro/Nanofluidic Devices for Single Cell Analysis, Volume II)

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Review

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33 pages, 4883 KiB

Open AccessReview

Lab-on-a-Chip Technologies for the Single Cell Level: Separation, Analysis, and Diagnostics

by Axel Hochstetter

Micromachines 2020, 11(5), 468; https://doi.org/10.3390/mi11050468 - 29 Apr 2020

Cited by 28 | Viewed by 7145

Abstract

In the last three decades, microfluidics and its applications have been on an exponential rise, including approaches to isolate rare cells and diagnose diseases on the single-cell level. The techniques mentioned herein have already had significant impacts in our lives, from in-the-field diagnosis of disease and parasitic infections, through home fertility tests, to uncovering the interactions between SARS-CoV-2 and their host cells. This review gives an overview of the field in general and the most notable developments of the last five years, in three parts: 1. What can we detect? 2. Which detection technologies are used in which setting? 3. How do these techniques work? Finally, this review discusses potentials, shortfalls, and an outlook on future developments, especially in respect to the funding landscape and the field-application of these chips. Full article

(This article belongs to the Special Issue Micro/Nanofluidic Devices for Single Cell Analysis, Volume II)

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