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Micro/Nano Devices for Blood Analysis

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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 (31 May 2019) | Viewed by 53800

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Special Issue Editors

Dr. Rui A. Lima

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Guest Editor

Mechanical Engineering Department, Minho University, Campus de Azurém, 4800-058 Guimarães, Portugal
Interests: microfluidics; nanofluids; bio-microfluidics; heat transfer
Special Issues, Collections and Topics in MDPI journals

Dr. Graça Minas

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Guest Editor

Department of Industrial Electronics, University of Minho, Campus de Azurém, 4800-058 Guimarães, Portugal
Interests: lab-on-a-chip; organ-on-a-chip; microsensors and microactuators
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Dr. Susana Catarino

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Guest Editor

Center for MicroElectroMechanical Systems (CMEMS), University of Minho, Campus Azurém, 4800-058 Guimarães, Portugal
Interests: lab-on-a-chip; microfluidics; microdevices; sensors and actuators
Special Issues, Collections and Topics in MDPI journals

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 A. 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 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

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 (12 papers)

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Editorial

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4 pages, 171 KiB

Open AccessEditorial

Editorial for the Special Issue on Micro/Nano Devices for Blood Analysis

by Susana O. Catarino, Graça Minas and Rui Lima

Micromachines 2019, 10(10), 708; https://doi.org/10.3390/mi10100708 - 18 Oct 2019

Cited by 1 | Viewed by 2133

Abstract

The development of microdevices 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 [...] Full article

(This article belongs to the Special Issue Micro/Nano Devices for Blood Analysis)

Research

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13 pages, 2410 KiB

Open AccessArticle

Viscosity Estimation of a Suspension with Rigid Spheres in Circular Microchannels Using Particle Tracking Velocimetry

by Misa Kawaguchi, Tomohiro Fukui, Kenichi Funamoto, Miho Tanaka, Mitsuru Tanaka, Shigeru Murata, Suguru Miyauchi and Toshiyuki Hayase

Micromachines 2019, 10(10), 675; https://doi.org/10.3390/mi10100675 - 04 Oct 2019

Cited by 10 | Viewed by 3214

Abstract

Suspension flows are ubiquitous in industry and nature. Therefore, it is important to understand the rheological properties of a suspension. The key to understanding the mechanism of suspension rheology is considering changes in its microstructure. It is difficult to evaluate the influence of change in the microstructure on the rheological properties affected by the macroscopic flow field for non-colloidal particles. In this study, we propose a new method to evaluate the changes in both the microstructure and rheological properties of a suspension using particle tracking velocimetry (PTV) and a power-law fluid model. Dilute suspension (0.38%) flows with fluorescent particles in a microchannel with a circular cross section were measured under low Reynolds number conditions (Re ≈ 10⁻⁴). Furthermore, the distribution of suspended particles in the radial direction was obtained from the measured images. Based on the power-law index and dependence of relative viscosity on the shear rate, we observed that the non-Newtonian properties of the suspension showed shear-thinning. This method will be useful in revealing the relationship between microstructural changes in a suspension and its rheology. Full article

(This article belongs to the Special Issue Micro/Nano Devices for Blood Analysis)

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15 pages, 2181 KiB

Open AccessArticle

A Microfluidic Deformability Assessment of Pathological Red Blood Cells Flowing in a Hyperbolic Converging Microchannel

by Vera Faustino, Raquel O. Rodrigues, Diana Pinho, Elísio Costa, Alice Santos-Silva, Vasco Miranda, Joana S. Amaral and Rui Lima

Micromachines 2019, 10(10), 645; https://doi.org/10.3390/mi10100645 - 25 Sep 2019

Cited by 45 | Viewed by 3912

Abstract

The loss of the red blood cells (RBCs) deformability is related with many human diseases, such as malaria, hereditary spherocytosis, sickle cell disease, or renal diseases. Hence, during the last years, a variety of technologies have been proposed to gain insights into the factors affecting the RBCs deformability and their possible direct association with several blood pathologies. In this work, we present a simple microfluidic tool that provides the assessment of motions and deformations of RBCs of end-stage kidney disease (ESKD) patients, under a well-controlled microenvironment. All of the flow studies were performed within a hyperbolic converging microchannels where single-cell deformability was assessed under a controlled homogeneous extensional flow field. By using a passive microfluidic device, RBCs passing through a hyperbolic-shaped contraction were measured by a high-speed video microscopy system, and the velocities and deformability ratios (DR) calculated. Blood samples from 27 individuals, including seven healthy controls and 20 having ESKD with or without diabetes, were analysed. The obtained data indicates that the proposed device is able to detect changes in DR of the RBCs, allowing for distinguishing the samples from the healthy controls and the patients. Overall, the deformability of ESKD patients with and without diabetes type II is lower in comparison with the RBCs from the healthy controls, with this difference being more evident for the group of ESKD patients with diabetes. RBCs from ESKD patients without diabetes elongate on average 8% less, within the hyperbolic contraction, as compared to healthy controls; whereas, RBCs from ESKD patients with diabetes elongate on average 14% less than the healthy controls. The proposed strategy can be easily transformed into a simple and inexpensive diagnostic microfluidic system to assess blood cells deformability due to the huge progress in image processing and high-speed microvisualization technology. Full article

(This article belongs to the Special Issue Micro/Nano Devices for Blood Analysis)

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16 pages, 3610 KiB

Open AccessArticle

Fabrication and Hydrodynamic Characterization of a Microfluidic Device for Cell Adhesion Tests in Polymeric Surfaces

by J. Ponmozhi, J. M. R. Moreira, F. J. Mergulhão, J. B. L. M. Campos and J. M. Miranda

Micromachines 2019, 10(5), 303; https://doi.org/10.3390/mi10050303 - 05 May 2019

Cited by 8 | Viewed by 2696

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 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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14 pages, 5214 KiB

Open AccessArticle

Mechanophenotyping of B16 Melanoma Cell Variants for the Assessment of the Efficacy of (-)-Epigallocatechin Gallate Treatment Using a Tapered Microfluidic Device

by Masanori Nakamura, Daichi Ono and Shukei Sugita

Micromachines 2019, 10(3), 207; https://doi.org/10.3390/mi10030207 - 25 Mar 2019

Cited by 12 | Viewed by 3802

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 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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15 pages, 2262 KiB

Open AccessArticle

Deformation of a Red Blood Cell in a Narrow Rectangular Microchannel

by Naoki Takeishi, Hiroaki Ito, Makoto Kaneko and Shigeo Wada

Micromachines 2019, 10(3), 199; https://doi.org/10.3390/mi10030199 - 21 Mar 2019

Cited by 21 | Viewed by 6420

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 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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10 pages, 2414 KiB

Open AccessArticle

Multinucleation of Incubated Cells and Their Morphological Differences Compared to Mononuclear Cells

by Shukei Sugita, Risa Munechika and Masanori Nakamura

Micromachines 2019, 10(2), 156; https://doi.org/10.3390/mi10020156 - 25 Feb 2019

Cited by 3 | Viewed by 3750

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 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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10 pages, 2238 KiB

Open AccessArticle

Measurement of Carcinoembryonic Antigen in Clinical Serum Samples Using a Centrifugal Microfluidic Device

by Zhigang Gao, Zongzheng Chen, Jiu Deng, Xiaorui Li, Yueyang Qu, Lingling Xu, Yong Luo, Yao Lu, Tingjiao Liu, Weijie Zhao and Bingcheng Lin

Micromachines 2018, 9(9), 470; https://doi.org/10.3390/mi9090470 - 17 Sep 2018

Cited by 15 | Viewed by 5311

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 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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16 pages, 4466 KiB

Open AccessArticle

Assessment of the Deformability and Velocity of Healthy and Artificially Impaired Red Blood Cells in Narrow Polydimethylsiloxane (PDMS) Microchannels

by Liliana Vilas Boas, Vera Faustino, Rui Lima, João Mário Miranda, Graça Minas, Carla Sofia Veiga Fernandes and Susana Oliveira Catarino

Micromachines 2018, 9(8), 384; https://doi.org/10.3390/mi9080384 - 02 Aug 2018

Cited by 38 | Viewed by 3844

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 (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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17 pages, 2868 KiB

Open AccessArticle

Multiple and Periodic Measurement of RBC Aggregation and ESR in Parallel Microfluidic Channels under On-Off Blood Flow Control

by Yang Jun Kang and Byung Jun Kim

Micromachines 2018, 9(7), 318; https://doi.org/10.3390/mi9070318 - 24 Jun 2018

Cited by 19 | Viewed by 4047

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 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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13 pages, 2537 KiB

Open AccessArticle

High-Precision Lens-Less Flow Cytometer on a Chip

by Yuan Fang, Ningmei Yu, Yuquan Jiang and Chaoliang Dang

Micromachines 2018, 9(5), 227; https://doi.org/10.3390/mi9050227 - 10 May 2018

Cited by 19 | Viewed by 4155

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 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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20 pages, 3529 KiB

Open AccessReview

Blood Cells Separation and Sorting Techniques of Passive Microfluidic Devices: From Fabrication to Applications

by Susana O. Catarino, Raquel O. Rodrigues, Diana Pinho, João M. Miranda, Graça Minas and Rui Lima

Micromachines 2019, 10(9), 593; https://doi.org/10.3390/mi10090593 - 10 Sep 2019

Cited by 98 | Viewed by 9128

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 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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