Special Issue "Micro/Nano Devices for Blood Analysis"

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

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

Special Issue Editors

Guest Editor
Prof. Rui Alberto Madeira Macedo Lima Website E-Mail
Mechanical Engineering Department, Minho University, Campus de Azurem, Guimaraes, Portugal
Interests: submersible devices; renewable energy systems; microfluidics; nanofluidics
Guest Editor
Prof. Graça Minas Website E-Mail
Mechanical Engineering Department, Minho University, Campus de Azurem, Guimaraes, Portugal
Interests: lab-on-chip; microfluidics; nanofluidics
Guest Editor
Dr. Susana Catarino Website E-Mail
Microelectromechanical Systems Research Unit (CMEMS-UMinho), Universidade do Minho, Campus de Azurem, Guimarães 4800-058, Portugal
Interests: microfluidics; acoustics; sensors; actuators; numerical simulation

Special Issue Information

Dear Colleagues,

The development of micro and nanodevices for blood analysis is an interdisciplinary subject that demands an integration of several research fields such as biotechnology, medicine, chemistry, informatics, optics, electronics, mechanics, and micro/nanotechnologies.

Over the last few decades, there has been a notably fast development in the miniaturization of mechanical microdevices, later known as microelectromechanical systems (MEMS), which combine electrical and mechanical components at a micro-scale level. The integration of microflow and optical components in MEMS microdevices, as well as the development of micropumps and microvalves, have promoted the interest of several research fields dealing with fluid flow and transport phenomena happening at micro-scale devices. Microfluidic systems have many advantages over macroscale by offering the ability to work with small sample volumes, providing good manipulation and control of samples, decreasing reaction times and allowing parallel operations in one single step. As a consequence, microdevices offer a great potential to develop portable and point-of-care diagnostic devices, particularly for blood analysis. Moreover, the recent progress of nanotechnology is gaining popularity and has expanded the areas of application of the microfluidic devices including the manipulation and analysis of flows on the scale of DNA, proteins, and nanoparticles (nanoflows).

In this Special Issue, we invite contributions (original research papers, review articles, and brief communications) that focus on the latest advances and challenges in micro and nano devices for diagnostics and blood analysis, micro and nanofluidics, technologies for flows visualization, MEMS, biochips and lab-on-a-chip devices and their application to research and industry. We hope to provide an opportunity to the engineering and biomedical community to exchange knowledge and information and bring together researchers who are interested in the general field of MEMS and micro/nanofluidics, especially in its applications to biomedical areas.

Prof. Rui Lima
Prof. Graça Minas
Dr. Susana Catarino
Guest Editors

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 papers will be 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 1400 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

  • microfluidics
  • nanofluidics
  • MEMS
  • biomedical microdevices
  • micro/nano fabrication
  • blood flow
  • blood-on-chips
  • blood cells
  • biomicrofluidics
  • nanoparticles
  • blood analysis
  • point-of-care
  • spectrophotometry

Published Papers (9 papers)

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Research

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Open AccessArticle
Fabrication and Hydrodynamic Characterization of a Microfluidic Device for Cell Adhesion Tests in Polymeric Surfaces
Micromachines 2019, 10(5), 303; https://doi.org/10.3390/mi10050303 - 05 May 2019
Abstract
A fabrication method is developed to produce a microfluidic device to test cell adhesion to polymeric materials. The process is able to produce channels with walls of any spin coatable polymer. The method is a modification of the existing poly-dimethylsiloxane soft lithography method [...] Read more.
A fabrication method is developed to produce a microfluidic device to test cell adhesion to polymeric materials. The process is able to produce channels with walls of any spin coatable polymer. The method is a modification of the existing poly-dimethylsiloxane soft lithography method and, therefore, it is compatible with sealing methods and equipment of most microfluidic laboratories. The molds are produced by xurography, simplifying the fabrication in laboratories without sophisticated equipment for photolithography. The fabrication method is tested by determining the effective differences in bacterial adhesion in five different materials. These materials have different surface hydrophobicities and charges. The major drawback of the method is the location of the region of interest in a lowered surface. It is demonstrated by bacterial adhesion experiments that this drawback has a negligible effect on adhesion. The flow in the device was characterized by computational fluid dynamics and it was shown that shear stress in the region of interest can be calculated by numerical methods and by an analytical equation for rectangular channels. The device is therefore validated for adhesion tests. Full article
(This article belongs to the Special Issue Micro/Nano Devices for Blood Analysis)
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Open AccessArticle
Mechanophenotyping of B16 Melanoma Cell Variants for the Assessment of the Efficacy of (-)-Epigallocatechin Gallate Treatment Using a Tapered Microfluidic Device
Micromachines 2019, 10(3), 207; https://doi.org/10.3390/mi10030207 - 25 Mar 2019
Abstract
Metastatic cancer cells are known to have a smaller cell stiffness than healthy cells because the small stiffness is beneficial for passing through the extracellular matrix when the cancer cells instigate a metastatic process. Here we developed a simple and handy microfluidic system [...] Read more.
Metastatic cancer cells are known to have a smaller cell stiffness than healthy cells because the small stiffness is beneficial for passing through the extracellular matrix when the cancer cells instigate a metastatic process. Here we developed a simple and handy microfluidic system to assess metastatic capacity of the cancer cells from a mechanical point of view. A tapered microchannel was devised through which a cell was compressed while passing. Two metastasis B16 melanoma variants (B16-F1 and B16-F10) were examined. The shape recovery process of the cell from a compressed state was evaluated with the Kelvin–Voigt model. The results demonstrated that the B16-F10 cells showed a larger time constant of shape recovery than B16-F1 cells, although no significant difference in the initial strain was observed between B16-F1 cells and B16-F10 cells. We further investigated effects of catechin on the cell deformability and found that the deformability of B16-F10 cells was significantly decreased and became equivalent to that of untreated B16-F1 cells. These results addressed the utility of the present system to handily but roughly assess the metastatic capacity of cancer cells and to investigate drug efficacy on the metastatic capacity. Full article
(This article belongs to the Special Issue Micro/Nano Devices for Blood Analysis)
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Open AccessArticle
Deformation of a Red Blood Cell in a Narrow Rectangular Microchannel
Micromachines 2019, 10(3), 199; https://doi.org/10.3390/mi10030199 - 21 Mar 2019
Abstract
The deformability of a red blood cell (RBC) is one of the most important biological parameters affecting blood flow, both in large arteries and in the microcirculation, and hence it can be used to quantify the cell state. Despite numerous studies on the [...] Read more.
The deformability of a red blood cell (RBC) is one of the most important biological parameters affecting blood flow, both in large arteries and in the microcirculation, and hence it can be used to quantify the cell state. Despite numerous studies on the mechanical properties of RBCs, including cell rigidity, much is still unknown about the relationship between deformability and the configuration of flowing cells, especially in a confined rectangular channel. Recent computer simulation techniques have successfully been used to investigate the detailed behavior of RBCs in a channel, but the dynamics of a translating RBC in a narrow rectangular microchannel have not yet been fully understood. In this study, we numerically investigated the behavior of RBCs flowing at different velocities in a narrow rectangular microchannel that mimicked a microfluidic device. The problem is characterized by the capillary number C a , which is the ratio between the fluid viscous force and the membrane elastic force. We found that confined RBCs in a narrow rectangular microchannel maintained a nearly unchanged biconcave shape at low C a , then assumed an asymmetrical slipper shape at moderate C a , and finally attained a symmetrical parachute shape at high C a . Once a RBC deformed into one of these shapes, it was maintained as the final stable configurations. Since the slipper shape was only found at moderate C a , measuring configurations of flowing cells will be helpful to quantify the cell state. Full article
(This article belongs to the Special Issue Micro/Nano Devices for Blood Analysis)
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Open AccessArticle
Multinucleation of Incubated Cells and Their Morphological Differences Compared to Mononuclear Cells
Micromachines 2019, 10(2), 156; https://doi.org/10.3390/mi10020156 - 25 Feb 2019
Abstract
Some cells cultured in vitro have multiple nuclei. Since cultured cells are used in various fields of science, including tissue engineering, the nature of the multinucleated cells must be determined. However, multinucleated cells are not frequently observed. In this study, a method to [...] Read more.
Some cells cultured in vitro have multiple nuclei. Since cultured cells are used in various fields of science, including tissue engineering, the nature of the multinucleated cells must be determined. However, multinucleated cells are not frequently observed. In this study, a method to efficiently obtain multinucleated cells was established and their morphological properties were investigated. Initially, we established conditions to quickly and easily generate multinucleated cells by seeding a Xenopus tadpole epithelium tissue-derived cell line (XTC-YF) on less and more hydrophilic dishes, and incubating the cultures with medium supplemented with or without Y-27632—a ROCK inhibitor—to reduce cell contractility. Notably, 88% of the cells cultured on a less hydrophilic dish in medium supplemented with Y-27632 became multinucleate 48 h after seeding, whereas less than 5% of cells cultured under other conditions exhibited this morphology. Some cells showed an odd number (three and five) of cell nuclei 72 h after seeding. Multinucleated cells displayed a significantly smaller nuclear area, larger cell area, and smaller nuclear circularity. As changes in the morphology of the cells correlated with their functions, the proposed method would help researchers understand the functions of multinucleated cells. Full article
(This article belongs to the Special Issue Micro/Nano Devices for Blood Analysis)
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Open AccessArticle
Measurement of Carcinoembryonic Antigen in Clinical Serum Samples Using a Centrifugal Microfluidic Device
Micromachines 2018, 9(9), 470; https://doi.org/10.3390/mi9090470 - 17 Sep 2018
Abstract
Carcinoembryonic antigen (CEA) is a broad-spectrum tumor marker used in clinical applications. The primarily clinical method for measuring CEA is based on chemiluminescence in serum during enzyme-linked immunosorbent assays (ELISA) in 96-well plates. However, this multi-step process requires large and expensive instruments, and [...] Read more.
Carcinoembryonic antigen (CEA) is a broad-spectrum tumor marker used in clinical applications. The primarily clinical method for measuring CEA is based on chemiluminescence in serum during enzyme-linked immunosorbent assays (ELISA) in 96-well plates. However, this multi-step process requires large and expensive instruments, and takes a long time. In this study, a high-throughput centrifugal microfluidic device was developed for detecting CEA in serum without the need for cumbersome washing steps normally used in immunoreactions. This centrifugal microdevice contains 14 identical pencil-like units, and the CEA molecules are separated from the bulk serum for subsequent immunofluorescence detection using density gradient centrifugation in each unit simultaneously. To determine the optimal conditions for CEA detection in serum, the effects of the density of the medium, rotation speed, and spin duration were investigated. The measured values from 34 clinical serum samples using this high-throughput centrifugal microfluidic device showed good agreement with the known values (average relative error = 9.22%). These results indicate that the high-throughput centrifugal microfluidic device could provide an alternative approach for replacing the classical method for CEA detection in clinical serum samples. Full article
(This article belongs to the Special Issue Micro/Nano Devices for Blood Analysis)
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Open AccessArticle
Assessment of the Deformability and Velocity of Healthy and Artificially Impaired Red Blood Cells in Narrow Polydimethylsiloxane (PDMS) Microchannels
Micromachines 2018, 9(8), 384; https://doi.org/10.3390/mi9080384 - 02 Aug 2018
Cited by 8
Abstract
Malaria is one of the leading causes of death in underdeveloped regions. Thus, the development of rapid, efficient, and competitive diagnostic techniques is essential. This work reports a study of the deformability and velocity assessment of healthy and artificially impaired red blood cells [...] Read more.
Malaria is one of the leading causes of death in underdeveloped regions. Thus, the development of rapid, efficient, and competitive diagnostic techniques is essential. This work reports a study of the deformability and velocity assessment of healthy and artificially impaired red blood cells (RBCs), with the purpose of potentially mimicking malaria effects, in narrow polydimethylsiloxane microchannels. To obtain impaired RBCs, their properties were modified by adding, to the RBCs, different concentrations of glucose, glutaraldehyde, or diamide, in order to increase the cells’ rigidity. The effects of the RBCs’ artificial stiffening were evaluated by combining image analysis techniques with microchannels with a contraction width of 8 µm, making it possible to measure the cells’ deformability and velocity of both healthy and modified RBCs. The results showed that healthy RBCs naturally deform when they cross the contractions and rapidly recover their original shape. In contrast, for the modified samples with high concentration of chemicals, the same did not occur. Additionally, for all the tested modification methods, the results have shown a decrease in the RBCs’ deformability and velocity as the cells’ rigidity increases, when compared to the behavior of healthy RBCs samples. These results show the ability of the image analysis tools combined with microchannel contractions to obtain crucial information on the pathological blood phenomena in microcirculation. Particularly, it was possible to measure the deformability of the RBCs and their velocity, resulting in a velocity/deformability relation in the microchannel. This correlation shows great potential to relate the RBCs’ behavior with the various stages of malaria, helping to establish the development of new diagnostic systems towards point-of-care devices. Full article
(This article belongs to the Special Issue Micro/Nano Devices for Blood Analysis)
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Open AccessArticle
Multiple and Periodic Measurement of RBC Aggregation and ESR in Parallel Microfluidic Channels under On-Off Blood Flow Control
Micromachines 2018, 9(7), 318; https://doi.org/10.3390/mi9070318 - 24 Jun 2018
Cited by 4
Abstract
Red blood cell (RBC) aggregation causes to alter hemodynamic behaviors at low flow-rate regions of post-capillary venules. Additionally, it is significantly elevated in inflammatory or pathophysiological conditions. In this study, multiple and periodic measurements of RBC aggregation and erythrocyte sedimentation rate (ESR) are [...] Read more.
Red blood cell (RBC) aggregation causes to alter hemodynamic behaviors at low flow-rate regions of post-capillary venules. Additionally, it is significantly elevated in inflammatory or pathophysiological conditions. In this study, multiple and periodic measurements of RBC aggregation and erythrocyte sedimentation rate (ESR) are suggested by sucking blood from a pipette tip into parallel microfluidic channels, and quantifying image intensity, especially through single experiment. Here, a microfluidic device was prepared from a master mold using the xurography technique rather than micro-electro-mechanical-system fabrication techniques. In order to consider variations of RBC aggregation in microfluidic channels due to continuous ESR in the conical pipette tip, two indices (aggregation index (AI) and erythrocyte-sedimentation-rate aggregation index (EAI)) are evaluated by using temporal variations of microscopic, image-based intensity. The proposed method is employed to evaluate the effect of hematocrit and dextran solution on RBC aggregation under continuous ESR in the conical pipette tip. As a result, EAI displays a significantly linear relationship with modified conventional ESR measurement obtained by quantifying time constants. In addition, EAI varies linearly within a specific concentration of dextran solution. In conclusion, the proposed method is able to measure RBC aggregation under continuous ESR in the conical pipette tip. Furthermore, the method provides multiple data of RBC aggregation and ESR through a single experiment. A future study will involve employing the proposed method to evaluate biophysical properties of blood samples collected from cardiovascular diseases. Full article
(This article belongs to the Special Issue Micro/Nano Devices for Blood Analysis)
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Open AccessArticle
High-Precision Lens-Less Flow Cytometer on a Chip
Micromachines 2018, 9(5), 227; https://doi.org/10.3390/mi9050227 - 10 May 2018
Cited by 4
Abstract
We present a flow cytometer on a microfluidic chip that integrates an inline lens-free holographic microscope. High-speed cell analysis necessitates that cells flow through the microfluidic channel at a high velocity, but the image sensor of the in-line holographic microscope needs a long [...] Read more.
We present a flow cytometer on a microfluidic chip that integrates an inline lens-free holographic microscope. High-speed cell analysis necessitates that cells flow through the microfluidic channel at a high velocity, but the image sensor of the in-line holographic microscope needs a long exposure time. Therefore, to solve this problem, this paper proposes an S-type micro-channel and a pulse injection method. To increase the speed and accuracy of the hologram reconstruction, we improve the iterative initial constraint method and propose a background removal method. The focus images and cell concentrations can be accurately calculated by the developed method. Using whole blood cells to test the cell counting precision, we find that the cell counting error of the proposed method is less than 2%. This result shows that the on-chip flow cytometer has high precision. Due to its low price and small size, this flow cytometer is suitable for environments far away from laboratories, such as underdeveloped areas and outdoors, and it is especially suitable for point-of-care testing (POCT). Full article
(This article belongs to the Special Issue Micro/Nano Devices for Blood Analysis)
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Review

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Open AccessReview
Blood Cells Separation and Sorting Techniques of Passive Microfluidic Devices: From Fabrication to Applications
Micromachines 2019, 10(9), 593; https://doi.org/10.3390/mi10090593 - 10 Sep 2019
Abstract
Since the first microfluidic device was developed more than three decades ago, microfluidics is seen as a technology that exhibits unique features to provide a significant change in the way that modern biology is performed. Blood and blood cells are recognized as important [...] Read more.
Since the first microfluidic device was developed more than three decades ago, microfluidics is seen as a technology that exhibits unique features to provide a significant change in the way that modern biology is performed. Blood and blood cells are recognized as important biomarkers of many diseases. Taken advantage of microfluidics assets, changes on blood cell physicochemical properties can be used for fast and accurate clinical diagnosis. In this review, an overview of the microfabrication techniques is given, especially for biomedical applications, as well as a synopsis of some design considerations regarding microfluidic devices. The blood cells separation and sorting techniques were also reviewed, highlighting the main achievements and breakthroughs in the last decades. Full article
(This article belongs to the Special Issue Micro/Nano Devices for Blood Analysis)
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