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Micromachines
Special Issues
Viscoelastic Microfluidics and Cell Sorting
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Viscoelastic Microfluidics and Cell Sorting

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

Deadline for manuscript submissions: 31 July 2024 | Viewed by 10882

Special Issue Editors

Prof. Dr. Abraham Lee

E-Mail Website
Guest Editor
Department of Biomedical Engineering, University of California, Irvine, CA 92697, USA
Interests: microfluidics; lab on a chip technology; droplet emulsions
Prof. Dr. Ian Papautsky

E-Mail Website
Guest Editor
Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, IL 60607, USA
Interests: microfluidics; lab-on-a-chip; point-of-care biosensors
Special Issues, Collections and Topics in MDPI journals
Dr. Jian Zhou

E-Mail Website
Guest Editor
Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, IL 60607, USA
Interests: microfluidics; cancer; hemodynamics; circulating tumor cells

Special Issue Information

Dear Colleague,

Cell sorting is indispensable in biomedical research and clinical applications, such as blood sorting for diagnosis and therapeutics. In the past decades, numerous microfluidic platforms including both active and passive approaches have been developed for improving the cell-sorting performance as well as for enabling unprecedented applications of cell sorting, including the isolation of circulating tumor cells (CTCs) and exosomes for cancer disease management.

While these platforms are highly efficient and/or high throughput, most of them are designed to work with samples exhibiting properties of Newtonian fluid. However, most of the unmodified biological samples such as blood, saliva, and cytoplasma are non-Newtonian and viscoelastic in nature. The pretreatment to render a sample into Newtonian fluid is required in these platforms before cell sorting. However, such pretreatment is not preferred for processing real-world samples, as it can be time-consuming and lead to added risks which could compromise the end results. Therefore, microfluidic methods which leverage the inherent nature of the biosamples and thus eliminate sample pretreatment are the ongoing direction of the field of cell sorting.

The emerging viscoelastic microfluidics, shear-induced diffusion (SID) devices as well as the active method based on lateral cavity acoustic transducers (LCAT) are the few examples of the ongoing research toward the elimination of sample pretreatments for cell sorting. Meanwhile, synthetic microparticles are continuously used for prototyping microfluidic devices, and numerical simulation is increasingly employed for improving the fundamental understanding of the physics behind microfluidic focusing and sorting phenomena.

As such, this Special Issue seeks to showcase research papers, communications, and review articles that focus on novel microfluidic approaches that utilize the properties of biological samples for high-performance cell sorting, and that investigate the fundamental physics of the cell focusing phenomena in microflows, with special emphasis on the utilization of fluid viscoelasticity for cell focusing and sorting. This Special Issue welcomes manuscripts with topics including, but not limited to, the following:

  1. Viscoelastic and elasto-inertial flows;
  2. Particle migration, focusing, and/or separation;
  3. Numerical simulation in particle migration;
  4. Blood sorting (e.g., plasma, leukocytes, CTCs);
  5. Hybrid methods for cell sorting;
  6. Bacteria, exosome, or nanoparticle separation. 

Prof. Dr. Abraham Lee
Prof. Dr. Ian Papautsky
Dr. Jian Zhou
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 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
  • viscoelastic focusing
  • blood sorting
  • bacteria separation
  • exosomes
  • circulating tumor cells
  • saliva
  • leukocyte separation
  • cell sorting
  • elasto-inertial migration
  • microparticles
  • nanoparticles
  • acoustics
  • numerical simulation

Published Papers (7 papers)

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Research

17 pages, 3785 KiB  
Article
A High-Throughput Microfluidic Cell Sorter Using a Three-Dimensional Coupled Hydrodynamic-Dielectrophoretic Pre-Focusing Module
by Mohammad Aghaamoo, Braulio Cardenas-Benitez and Abraham P. Lee
Micromachines 2023, 14(10), 1813; https://doi.org/10.3390/mi14101813 - 22 Sep 2023
Cited by 1 | Viewed by 1074
Abstract
Dielectrophoresis (DEP) is a powerful tool for label-free sorting of cells, even those with subtle differences in morphological and dielectric properties. Nevertheless, a major limitation is that most existing DEP techniques can efficiently sort cells only at low throughputs (<1 mL h−1 [...] Read more.
Dielectrophoresis (DEP) is a powerful tool for label-free sorting of cells, even those with subtle differences in morphological and dielectric properties. Nevertheless, a major limitation is that most existing DEP techniques can efficiently sort cells only at low throughputs (<1 mL h−1). Here, we demonstrate that the integration of a three-dimensional (3D) coupled hydrodynamic-DEP cell pre-focusing module upstream of the main DEP sorting region enables cell sorting with a 10-fold increase in throughput compared to conventional DEP approaches. To better understand the key principles and requirements for high-throughput cell separation, we present a comprehensive theoretical model to study the scaling of hydrodynamic and electrostatic forces on cells at high flow rate regimes. Based on the model, we show that the critical cell-to-electrode distance needs to be ≤10 µm for efficient cell sorting in our proposed microfluidic platform, especially at flow rates ≥ 1 mL h−1. Based on those findings, a computational fluid dynamics model and particle tracking analysis were developed to find optimum operation parameters (e.g., flow rate ratios and electric fields) of the coupled hydrodynamic-DEP 3D focusing module. Using these optimum parameters, we experimentally demonstrate live/dead K562 cell sorting at rates as high as 10 mL h−1 (>150,000 cells min−1) with 90% separation purity, 85% cell recovery, and no negative impact on cell viability. Full article
(This article belongs to the Special Issue Viscoelastic Microfluidics and Cell Sorting)
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11 pages, 2895 KiB  
Article
Continuous On-Chip Cell Washing Using Viscoelastic Microfluidics
by Hyunjung Lim, Minji Kim, Yeongmu Kim, Seunghee Choo, Tae Eun Kim, Jaesung Han, Byoung Joe Han, Chae Seung Lim and Jeonghun Nam
Micromachines 2023, 14(9), 1658; https://doi.org/10.3390/mi14091658 - 25 Aug 2023
Viewed by 874
Abstract
Medium exchange of particles/cells to a clean buffer with a low background is essential for biological, chemical, and clinical research, which has been conventionally conducted using centrifugation. However, owing to critical limitations, such as possible cell loss and physical stimulation of cells, microfluidic [...] Read more.
Medium exchange of particles/cells to a clean buffer with a low background is essential for biological, chemical, and clinical research, which has been conventionally conducted using centrifugation. However, owing to critical limitations, such as possible cell loss and physical stimulation of cells, microfluidic techniques have been adopted for medium exchange. This study demonstrates a continuous on-chip washing process in a co-flow system using viscoelastic and Newtonian fluids. The co-flow system was constructed by adding a small amount of biocompatible polymer (xanthan gum, XG) to a sample containing particles or cells and introducing Newtonian fluids as sheath flows. Polymer concentration-dependent and particle size-dependent lateral migration of particles in the co-flow system were examined, and then the optimal concentration and the critical particle size for medium exchange were determined at the fixed total flow rate of 100 μL/min. For clinical applications, the continuous on-chip washing of white blood cells (WBCs) in lysed blood samples was demonstrated, and the washing performance was evaluated using a scanning spectrophotometer. Full article
(This article belongs to the Special Issue Viscoelastic Microfluidics and Cell Sorting)
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15 pages, 4410 KiB  
Article
Numerical Study of Viscoelastic Microfluidic Particle Manipulation in a Microchannel with Asymmetrical Expansions
by Tiao Wang, Dan Yuan, Wuyi Wan and Boran Zhang
Micromachines 2023, 14(5), 915; https://doi.org/10.3390/mi14050915 - 23 Apr 2023
Cited by 3 | Viewed by 2070
Abstract
Microfluidic microparticle manipulation is currently widely used in environmental, bio-chemical, and medical applications. Previously we proposed a straight microchannel with additional triangular cavity arrays to manipulate microparticles with inertial microfluidic forces, and experimentally explored the performances within different viscoelastic fluids. However, the mechanism [...] Read more.
Microfluidic microparticle manipulation is currently widely used in environmental, bio-chemical, and medical applications. Previously we proposed a straight microchannel with additional triangular cavity arrays to manipulate microparticles with inertial microfluidic forces, and experimentally explored the performances within different viscoelastic fluids. However, the mechanism remained poorly understood, which limited the exploration of the optimal design and standard operation strategies. In this study, we built a simple but robust numerical model to reveal the mechanisms of microparticle lateral migration in such microchannels. The numerical model was validated by our experimental results with good agreement. Furthermore, the force fields under different viscoelastic fluids and flow rates were carried out for quantitative analysis. The mechanism of microparticle lateral migration was revealed and is discussed regarding the dominant microfluidic forces, including drag force, inertial lift force, and elastic force. The findings of this study can help to better understand the different performances of microparticle migration under different fluid environments and complex boundary conditions. Full article
(This article belongs to the Special Issue Viscoelastic Microfluidics and Cell Sorting)
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14 pages, 3371 KiB  
Article
Single Cell Analysis of Inertial Migration by Circulating Tumor Cells and Clusters
by Jian Zhou, Alexandra Vorobyeva, Qiyue Luan and Ian Papautsky
Micromachines 2023, 14(4), 787; https://doi.org/10.3390/mi14040787 - 31 Mar 2023
Cited by 2 | Viewed by 1337
Abstract
Single-cell analysis provides a wealth of information regarding the molecular landscape of the tumor cells responding to extracellular stimulations, which has greatly advanced the research in cancer biology. In this work, we adapt such a concept for the analysis of inertial migration of [...] Read more.
Single-cell analysis provides a wealth of information regarding the molecular landscape of the tumor cells responding to extracellular stimulations, which has greatly advanced the research in cancer biology. In this work, we adapt such a concept for the analysis of inertial migration of cells and clusters, which is promising for cancer liquid biopsy, by isolation and detection of circulating tumor cells (CTCs) and CTC clusters. Using high-speed camera tracking live individual tumor cells and cell clusters, the behavior of inertial migration was profiled in unprecedented detail. We found that inertial migration is heterogeneous spatially, depending on the initial cross-sectional location. The lateral migration velocity peaks at about 25% of the channel width away from the sidewalls for both single cells and clusters. More importantly, while the doublets of the cell clusters migrate significantly faster than single cells (~two times faster), cell triplets unexpectedly have similar migration velocities to doublets, which seemingly disagrees with the size-dependent nature of inertial migration. Further analysis indicates that the cluster shape or format (for example, triplets can be in string format or triangle format) plays a significant role in the migration of more complex cell clusters. We found that the migration velocity of a string triplet is statistically comparable to that of a single cell while the triangle triplets can migrate slightly faster than doublets, suggesting that size-based sorting of cells and clusters can be challenging depending on the cluster format. Undoubtedly, these new findings need to be considered in the translation of inertial microfluidic technology for CTC cluster detection. Full article
(This article belongs to the Special Issue Viscoelastic Microfluidics and Cell Sorting)
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16 pages, 4005 KiB  
Article
A Method for Rapid, Quantitative Evaluation of Particle Sorting in Microfluidics Using Basic Cytometry Equipment
by Robert Salomon, Sajad Razavi Bazaz, Wenyan Li, David Gallego-Ortega, Dayong Jin and Majid Ebrahimi Warkiani
Micromachines 2023, 14(4), 751; https://doi.org/10.3390/mi14040751 - 29 Mar 2023
Cited by 1 | Viewed by 1419
Abstract
This paper describes, in detail, a method that uses flow cytometry to quantitatively characterise the performance of continuous-flow microfluidic devices designed to separate particles. Whilst simple, this approach overcomes many of the issues with the current commonly utilised methods (high-speed fluorescent imaging, or [...] Read more.
This paper describes, in detail, a method that uses flow cytometry to quantitatively characterise the performance of continuous-flow microfluidic devices designed to separate particles. Whilst simple, this approach overcomes many of the issues with the current commonly utilised methods (high-speed fluorescent imaging, or cell counting via either a hemocytometer or a cell counter), as it can accurately assess device performance even in complex, high concentration mixtures in a way that was previously not possible. Uniquely, this approach takes advantage of pulse processing in flow cytometry to allow quantitation of cell separation efficiencies and resulting sample purities on both single cells as well as cell clusters (such as circulating tumour cell (CTC) clusters). Furthermore, it can readily be combined with cell surface phenotyping to measure separation efficiencies and purities in complex cell mixtures. This method will facilitate the rapid development of a raft of continuous flow microfluidic devices, will be helpful in testing novel separation devices for biologically relevant clusters of cells such as CTC clusters, and will provide a quantitative assessment of device performance in complex samples, which was previously impossible. Full article
(This article belongs to the Special Issue Viscoelastic Microfluidics and Cell Sorting)
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12 pages, 2212 KiB  
Article
Separation and Washing of Candida Cells from White Blood Cells Using Viscoelastic Microfluidics
by Hyunjung Lim, Jae Young Kim, Seunghee Choo, Changseok Lee, Byoung Joe Han, Chae Seung Lim and Jeonghun Nam
Micromachines 2023, 14(4), 712; https://doi.org/10.3390/mi14040712 - 23 Mar 2023
Cited by 2 | Viewed by 1202
Abstract
An early and accurate diagnosis of Candida albicans is critical for the rapid antifungal treatment of candidemia, a mortal bloodstream infection. This study demonstrates viscoelastic microfluidic techniques for continuous separation, concentration, and subsequent washing of Candida cells in the blood. The total sample [...] Read more.
An early and accurate diagnosis of Candida albicans is critical for the rapid antifungal treatment of candidemia, a mortal bloodstream infection. This study demonstrates viscoelastic microfluidic techniques for continuous separation, concentration, and subsequent washing of Candida cells in the blood. The total sample preparation system contains two-step microfluidic devices: a closed-loop separation and concentration device and a co-flow cell-washing device. To determine the flow conditions of the closed-loop device, such as the flow rate factor, a mixture of 4 and 13 μm particles was used. Candida cells were successfully separated from the white blood cells (WBCs) and concentrated by 74.6-fold in the sample reservoir of the closed-loop system at 800 μL/min with a flow rate factor of 3.3. In addition, the collected Candida cells were washed with washing buffer (deionized water) in the microchannels with an aspect ratio of 2 at a total flow rate of 100 μL/min. Finally, Candida cells at extremely low concentrations (Ct > 35) became detectable after the removal of WBCs, the additional buffer solution in the closed-loop system (Ct = 30.3 ± 1.3), and further removal of blood lysate and washing (Ct = 23.3 ± 1.6). Full article
(This article belongs to the Special Issue Viscoelastic Microfluidics and Cell Sorting)
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20 pages, 4138 KiB  
Article
Elasto-Inertial Focusing Mechanisms of Particles in Shear-Thinning Viscoelastic Fluid in Rectangular Microchannels
by Mohammad Moein Naderi, Ludovica Barilla, Jian Zhou, Ian Papautsky and Zhangli Peng
Micromachines 2022, 13(12), 2131; https://doi.org/10.3390/mi13122131 - 01 Dec 2022
Cited by 4 | Viewed by 2080
Abstract
Growth of the microfluidics field has triggered numerous advances in focusing and separating microparticles, with such systems rapidly finding applications in biomedical, chemical, and environmental fields. The use of shear-thinning viscoelastic fluids in microfluidic channels is leading to evolution of elasto-inertial focusing. Herein, [...] Read more.
Growth of the microfluidics field has triggered numerous advances in focusing and separating microparticles, with such systems rapidly finding applications in biomedical, chemical, and environmental fields. The use of shear-thinning viscoelastic fluids in microfluidic channels is leading to evolution of elasto-inertial focusing. Herein, we showed that the interplay between the elastic and shear-gradient lift forces, as well as the secondary flow transversal drag force that is caused by the non-zero second normal stress difference, lead to different particle focusing patterns in the elasto-inertial regime. Experiments and 3D simulations were performed to study the effects of flowrate, particle size, and the shear-thinning extent of the fluid on the focusing patterns. The Giesekus constitutive equation was used in the simulations to capture the shear-thinning and viscoelastic behaviors of the solution used in the experiments. At low flowrate, with Weissenberg number Wi ~ O(1), both the elastic force and secondary flow effects push particles towards the channel center. However, at a high flowrate, Wi ~ O(10), the elastic force direction is reversed in the central regions. This remarkable behavior of the elastic force, combined with the enhanced shear-gradient lift at the high flowrate, pushes particles away from the channel center. Additionally, a precise prediction of the focusing position can only be made when the shear-thinning extent of the fluid is correctly estimated in the modeling. The shear-thinning also gives rise to the unique behavior of the inertial forces near the channel walls which is linked with the ‘warped’ velocity profile in such fluids. Full article
(This article belongs to the Special Issue Viscoelastic Microfluidics and Cell Sorting)
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