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Advances in Microfluidic Devices for Cell Handling and Analysis

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A special issue of Micromachines (ISSN 2072-666X).

Deadline for manuscript submissions: closed (30 June 2016) | Viewed by 66603

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Dr. Abel Martin Gonzalez Oliva

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Biomolecular Diagnostic Laboratory, Instituto de Tecnologia Quimica e Biologica Universidade Nova de Lisboa, 2780-157 Oeiras, Portugal
Interests: immune diagnostic; biosensor development; single cell analysis; microfluidics and microfabrication; tick born diseases

Special Issue Information

Dear Colleagues,

Microfluidics is a technology characterized by the engineered manipulation of fluids at the submillimeter scale, which dramatically improved diagnostics and biology research. Certain properties of microfluidic technologies, such as precise control of fluids in an assay and manipulation of particles at the microscale, made them a powerful tool for cell studies. Measurements at the level of a single cell are one of the most challenging and informative in systems biology. Advances in medicine, biotechnology, and agriculture—among other areas—are possible by these new approaches at an almost individual cell-scale.

Here, we announce a Special Issue entitled “Advances in Microfluidic Devices for Cell Handling and Analysis”, addressing recent advances in the instrumentation, fabrication, and characterization of microfluidic devices for this purpose. We invite submission of papers on developed microfluidic devices for cell handling, cell culture, cell analysis, based on imaging microscopy, metabolomics, proteomics, or genomics at the cell level.

Example topics may include: Novel system concepts and application proposals. Moreover, innovative methods in the microfabrication of chips and cell sorters, low cost disposable microdevices, microdevice characterization, novel flow cytometers, simulation of cell movement and behavior in microscale environment, cell cultivation and cell growing in microfluidic chambers, cell–cell interaction, up to date and high-throughput data collection platforms of genomics, proteomics, metabolomics, lipidomic, etc., are of interest.

Dr. Abel Oliva
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

single cell analysis
microfluidic cell handling
microfluidic cell culturing
microfluidic Cell proteomics
microfluidic Cell metabolomics
flow cytometry

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Published Papers (10 papers)

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Editorial

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154 KiB

Open AccessEditorial

Editorial for Special Issue: Advances in Microfluidic Devices for Cell Handling and Analysis

by Abel Martin Gonzalez Oliva

Micromachines 2017, 8(6), 184; https://doi.org/10.3390/mi8060184 - 9 Jun 2017

Viewed by 3137

Abstract

Microfluidics is a technology that is expanding rapidly in many areas of research, especially in the biological areas of cell handling and analysis.[...] Full article

(This article belongs to the Special Issue Advances in Microfluidic Devices for Cell Handling and Analysis)

Research

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6198 KiB

Open AccessArticle

Hybrid Microfluidic Platform for Multifactorial Analysis Based on Electrical Impedance, Refractometry, Optical Absorption and Fluorescence

by Fábio M. Pereira, Iwona Bernacka-Wojcik, Rita S. Rodrigues Ribeiro, Maria Teresa Lobato, Elvira Fortunato, Rodrigo Martins, Rui Igreja, Pedro A. S. Jorge, Hugo Águas and Abel Martin Gonzalez Oliva

Micromachines 2016, 7(10), 181; https://doi.org/10.3390/mi7100181 - 7 Oct 2016

Cited by 6 | Viewed by 5766

Abstract

This paper describes the development of a novel microfluidic platform for multifactorial analysis integrating four label-free detection methods: electrical impedance, refractometry, optical absorption and fluorescence. We present the rationale for the design and the details of the microfabrication of this multifactorial hybrid microfluidic chip. The structure of the platform consists of a three-dimensionally patterned polydimethylsiloxane top part attached to a bottom SU-8 epoxy-based negative photoresist part, where microelectrodes and optical fibers are incorporated to enable impedance and optical analysis. As a proof of concept, the chip functions have been tested and explored, enabling a diversity of applications: (i) impedance-based identification of the size of micro beads, as well as counting and distinguishing of erythrocytes by their volume or membrane properties; (ii) simultaneous determination of the refractive index and optical absorption properties of solutions; and (iii) fluorescence-based bead counting. Full article

(This article belongs to the Special Issue Advances in Microfluidic Devices for Cell Handling and Analysis)

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5507 KiB

Open AccessArticle

Study of a Microfluidic Chip Integrating Single Cell Trap and 3D Stable Rotation Manipulation

by Liang Huang, Long Tu, Xueyong Zeng, Lu Mi, Xuzhou Li and Wenhui Wang

Micromachines 2016, 7(8), 141; https://doi.org/10.3390/mi7080141 - 12 Aug 2016

Cited by 22 | Viewed by 7697

Abstract

Single cell manipulation technology has been widely applied in biological fields, such as cell injection/enucleation, cell physiological measurement, and cell imaging. Recently, a biochip platform with a novel configuration of electrodes for cell 3D rotation has been successfully developed by generating rotating electric fields. However, the rotation platform still has two major shortcomings that need to be improved. The primary problem is that there is no on-chip module to facilitate the placement of a single cell into the rotation chamber, which causes very low efficiency in experiment to manually pipette single 10-micron-scale cells into rotation position. Secondly, the cell in the chamber may suffer from unstable rotation, which includes gravity-induced sinking down to the chamber bottom or electric-force-induced on-plane movement. To solve the two problems, in this paper we propose a new microfluidic chip with manipulation capabilities of single cell trap and single cell 3D stable rotation, both on one chip. The new microfluidic chip consists of two parts. The top capture part is based on the least flow resistance principle and is used to capture a single cell and to transport it to the rotation chamber. The bottom rotation part is based on dielectrophoresis (DEP) and is used to 3D rotate the single cell in the rotation chamber with enhanced stability. The two parts are aligned and bonded together to form closed channels for microfluidic handling. Using COMSOL simulation and preliminary experiments, we have verified, in principle, the concept of on-chip single cell traps and 3D stable rotation, and identified key parameters for chip structures, microfluidic handling, and electrode configurations. The work has laid a solid foundation for on-going chip fabrication and experiment validation. Full article

(This article belongs to the Special Issue Advances in Microfluidic Devices for Cell Handling and Analysis)

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6862 KiB

Open AccessArticle

Gravity-Based Precise Cell Manipulation System Enhanced by In-Phase Mechanism

by Koji Mizoue, Manh Hao Phan, Chia-Hung Dylan Tsai, Makoto Kaneko, Junsu Kang and Wan Kyun Chung

Micromachines 2016, 7(7), 116; https://doi.org/10.3390/mi7070116 - 9 Jul 2016

Cited by 8 | Viewed by 5481

Abstract

This paper proposes a gravity-based system capable of generating high-resolution pressure for precise cell manipulation or evaluation in a microfluidic channel. While the pressure resolution of conventional pumps for microfluidic applications is usually about hundreds of pascals as the resolution of their feedback sensors, precise cell manipulation at the pascal level cannot be done. The proposed system successfully achieves a resolution of 100 millipascals using water head pressure with an in-phase noise cancelation mechanism. The in-phase mechanism aims to suppress the noises from ambient vibrations to the system. The proposed pressure system is tested with a microfluidic platform for pressure validation. The experimental results show that the in-phase mechanism effectively reduces the pressure turbulence, and the pressure-driven cell movement matches the theoretical simulations. Preliminary experiments on deformability evaluation with red blood cells under incremental pressures of one pascal are successfully performed. Different deformation patterns are observed from cell to cell under precise pressure control. Full article

(This article belongs to the Special Issue Advances in Microfluidic Devices for Cell Handling and Analysis)

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4212 KiB

Open AccessArticle

Application of Vertical Electrodes in Microfluidic Channels for Impedance Analysis

by Qiang Li and Yong J. Yuan

Micromachines 2016, 7(6), 96; https://doi.org/10.3390/mi7060096 - 25 May 2016

Cited by 11 | Viewed by 7176

Abstract

This paper presents a microfluidic device with electroplated vertical electrodes in the side walls for impedance measurement. Based on the proposed device, the impedance of NaCl solutions with different concentrations and polystyrene microspheres with different sizes was measured and analyzed. The electroplating and SU-8-PDMS (SU-8-poly(dimethylsiloxane)) bonding technologies were firstly integrated for the fabrication of the proposed microfluidic device, resulting in a tightly three-dimensional structure for practical application. The magnitude of impedance of the tested solutions in the frequency range of 1 Hz to 100 kHz was analyzed by the Zennium electrochemical workstation. The results show that the newly designed microfluidic device has potential for impedance analysis with the advantages of ease of fabrication and the integration of 3D electrodes in the side walls. The newly designed impedance sensor can distinguish different concentrations of polystyrene microspheres and may have potential for cell counting in biological areas. By integrating with other techniques such as dielectrophoresis (DEP) and biological recognition technology, the proposed device may have potential for the assay to identify foodborne pathogen bacteria. Full article

(This article belongs to the Special Issue Advances in Microfluidic Devices for Cell Handling and Analysis)

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2247 KiB

Open AccessFeature PaperArticle

Magnetophoretic Sorting of Single Cell-Containing Microdroplets

by Younggeun Jo, Fengshan Shen, Young Ki Hahn, Ji-Ho Park and Je-Kyun Park

Micromachines 2016, 7(4), 56; https://doi.org/10.3390/mi7040056 - 30 Mar 2016

Cited by 28 | Viewed by 7937

Abstract

Droplet microfluidics is a promising tool for single-cell analysis since single cell can be comparted inside a tiny volume. However, droplet encapsulation of single cells still remains a challenging issue due to the low ratio of droplets containing single cells. Here, we introduce a simple and robust single cell sorting platform based on a magnetophoretic method using monodisperse magnetic nanoparticles (MNPs) and droplet microfluidics with >94% purity. There is an approximately equal amount of MNPs in the same-sized droplet, which has the same magnetic force under the magnetic field. However, the droplets containing single cells have a reduced number of MNPs, as much as the volume of the cell inside the droplet, resulting in a low magnetic force. Based on this simple principle, this platform enables the separation of single cell-encapsulated droplets from the droplets with no cells. Additionally, this device uses only a permanent magnet without any complex additional apparatus; hence, this new platform can be integrated into a single cell analysis system considering its effectiveness and convenience. Full article

(This article belongs to the Special Issue Advances in Microfluidic Devices for Cell Handling and Analysis)

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1869 KiB

Open AccessArticle

Particulate Blood Analogues Reproducing the Erythrocytes Cell-Free Layer in a Microfluidic Device Containing a Hyperbolic Contraction

by Joana Calejo, Diana Pinho, Francisco J. Galindo-Rosales, Rui Lima and Laura Campo-Deaño

Micromachines 2016, 7(1), 4; https://doi.org/10.3390/mi7010004 - 30 Dec 2015

Cited by 35 | Viewed by 7342

Abstract

The interest in the development of blood analogues has been increasing recently as a consequence of the increment in the number of experimental hemodynamic studies and the difficulties associated with the manipulation of real blood in vitro because of ethical, economical or hazardous issues. Although one-phase Newtonian and non-Newtonian blood analogues can be found in the literature, there are very few studies related to the use of particulate solutions in which the particles mimic the behaviour of the red blood cells (RBCs) or erythrocytes. One of the most relevant effects related with the behaviour of the erythrocytes is a cell free layer (CFL) formation, which consists in the migration of the RBCs towards the center of the vessel forming a cell depleted plasma region near the vessel walls, which is known to happen in in vitro microcirculatory environments. Recent studies have shown that the CFL enhancement is possible with an insertion of contraction and expansion region in a straight microchannel. These effects are useful for cell manipulation or sorting in lab-on-chip studies. In this experimental study we present particulate Newtonian and non-Newtonian solutions which resulted in a rheological blood analogue able to form a CFL, downstream of a microfluidic hyperbolic contraction, in a similar way of the one formed by healthy RBCs. Full article

(This article belongs to the Special Issue Advances in Microfluidic Devices for Cell Handling and Analysis)

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5931 KiB

Open AccessArticle

An Inert Continuous Microreactor for the Isolation and Analysis of a Single Microbial Cell

by Katrin Rosenthal, Floris Falke, Oliver Frick, Christian Dusny and Andreas Schmid

Micromachines 2015, 6(12), 1836-1855; https://doi.org/10.3390/mi6121459 - 30 Nov 2015

Cited by 15 | Viewed by 6243

Abstract

Studying biological phenomena of individual cells is enabled by matching the scales of microbes and cultivation devices. We present a versatile, chemically inert microfluidic lab-on-a-chip (LOC) device for biological and chemical analyses of isolated microorganisms. It is based on the Envirostat concept and guarantees constant environmental conditions. A new manufacturing process for direct fusion bonding chips with functional microelectrodes for selective and gentle cell manipulation via negative dielectrophoresis (nDEP) was generated. The resulting LOC system offered a defined surface chemistry and exceptional operational stability, maintaining its structural integrity even after harsh chemical treatment. The microelectrode structures remained fully functional after thermal bonding and were proven to be efficient for single-cell trapping via nDEP. The microfluidic network consisted solely of glass, which led to enhanced chip reusability and minimized interaction of the material with chemical and biological compounds. We validated the LOC for single-cell studies with the amino acid secreting bacterium Corynebacterium glutamicum. Intracellular l-lysine production dynamics of individual bacteria were monitored based on a genetically encoded fluorescent nanosensor. The results demonstrate the applicability of the presented LOC for pioneering chemical and biological studies, where robustness and chemically inert surfaces are crucial parameters for approaching fundamental biological questions at a single-cell level. Full article

(This article belongs to the Special Issue Advances in Microfluidic Devices for Cell Handling and Analysis)

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Review

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3812 KiB

Open AccessReview

Microtechnologies for Cell Microenvironment Control and Monitoring

by Enrique Azuaje-Hualde, Maite García-Hernando, Jaione Etxebarria-Elezgarai, Marian M. De Pancorbo, Fernando Benito-Lopez and Lourdes Basabe-Desmonts

Micromachines 2017, 8(6), 166; https://doi.org/10.3390/mi8060166 - 23 May 2017

Cited by 15 | Viewed by 5861

Abstract

A great breadth of questions remains in cellular biology. Some questions cannot be answered using traditional analytical techniques and so demand the development of new tools for research. In the near future, the development of highly integrated microfluidic analytical platforms will enable the acquisition of unknown biological data. These microfluidic systems must allow cell culture under controlled microenvironment and high throughput analysis. For this purpose, the integration of a variable number of newly developed micro- and nano-technologies, which enable control of topography and surface chemistry, soluble factors, mechanical forces and cell–cell contacts, as well as technology for monitoring cell phenotype and genotype with high spatial and temporal resolution will be necessary. These multifunctional devices must be accompanied by appropriate data analysis and management of the expected large datasets generated. The knowledge gained with these platforms has the potential to improve predictive models of the behavior of cells, impacting directly in better therapies for disease treatment. In this review, we give an overview of the microtechnology toolbox available for the design of high throughput microfluidic platforms for cell analysis. We discuss current microtechnologies for cell microenvironment control, different methodologies to create large arrays of cellular systems and finally techniques for monitoring cells in microfluidic devices. Full article

(This article belongs to the Special Issue Advances in Microfluidic Devices for Cell Handling and Analysis)

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5404 KiB

Open AccessReview

Cell Monitoring and Manipulation Systems (CMMSs) based on Glass Cell-Culture Chips (GC³s)

by Sebastian M. Buehler, Marco Stubbe, Sebastian M. Bonk, Matthias Nissen, Kanokkan Titipornpun, Ernst-Dieter Klinkenberg, Werner Baumann and Jan Gimsa

Micromachines 2016, 7(7), 106; https://doi.org/10.3390/mi7070106 - 24 Jun 2016

Cited by 14 | Viewed by 8849

Abstract

We developed different types of glass cell-culture chips (GC³s) for culturing cells for microscopic observation in open media-containing troughs or in microfluidic structures. Platinum sensor and manipulation structures were used to monitor physiological parameters and to allocate and permeabilize cells. Electro-thermal micro pumps distributed chemical compounds in the microfluidic systems. The integrated temperature sensors showed a linear, Pt1000-like behavior. Cell adhesion and proliferation were monitored using interdigitated electrode structures (IDESs). The cell-doubling times of primary murine embryonic neuronal cells (PNCs) were determined based on the IDES capacitance-peak shifts. The electrical activity of PNC networks was detected using multi-electrode arrays (MEAs). During seeding, the cells were dielectrophoretically allocated to individual MEAs to improve network structures. MEA pads with diameters of 15, 20, 25, and 35 µm were tested. After 3 weeks, the magnitudes of the determined action potentials were highest for pads of 25 µm in diameter and did not differ when the inter-pad distances were 100 or 170 µm. Using 25-µm diameter circular oxygen electrodes, the signal currents in the cell-culture media were found to range from approximately −0.08 nA (0% O₂) to −2.35 nA (21% O₂). It was observed that 60-nm thick silicon nitride-sensor layers were stable potentiometric pH sensors under cell-culture conditions for periods of days. Their sensitivity between pH 5 and 9 was as high as 45 mV per pH step. We concluded that sensorized GC³s are potential animal replacement systems for purposes such as toxicity pre-screening. For example, the effect of mefloquine, a medication used to treat malaria, on the electrical activity of neuronal cells was determined in this study using a GC³ system. Full article

(This article belongs to the Special Issue Advances in Microfluidic Devices for Cell Handling and Analysis)

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