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A special issue of Micromachines (ISSN 2072-666X). This special issue belongs to the section "B2: Biofabrication and Tissue Engineering".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 46149

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Special Issue Editors

Prof. Maria Tenje

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Guest Editor

Department of Materials Science and Engineering, Division of Microsystems Technology, Uppsala University, Uppsala, Sweden
Interests: organs-on-chip; droplet microfluidics; microfabricaton

Dr. Hannah Pohlit

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Guest Editor

Department of Materials Science and Engineering, Division of Microsystems Technology, Uppsala University, Uppsala, Sweden
Interests: polymers; hydrogels; organs-on-chip

Special Issue Information

Dear Colleagues,

Scientific discoveries in the life sciences—the study of living organisms—have decisively contributed to the improvement of human health and agriculture, but there are still many research challenges remaining. Much could be gained in these areas by utilizing miniaturization to make devices portable and reduce sample volumes. Micro- and nanofabrication are established technologies originating from the microelectronics industry used to fabricate structures on a micro- and nanometer scale. The evolution of these technologies paves the way for improvements in resolution, reproducibility, and production time and costs, all necessary for complex and detailed life science studies. Whilst many benefits are expected, there are also challenges involved with miniaturization, such as design requirements, engineering limitations, and fabrication constraints. As such, in order to rapidly advance, researchers from different areas should unite to overcome these challenges together.

This Special Issue collects research papers, technical notes, communications, and review articles that discuss the latest advancements and future perspectives in microfabrication methods applied to life science research questions and applications. It is our ambition to facilitate interdisciplinary collaboration in order to achieve progress for all involved. Contributions related to the development, design, fabrication, characterization, and especially applications of micro-fabricated devices within diverse life sciences contexts are highly welcome.

We look forward to receiving your submissions.

Prof. Maria Tenje
Dr. Hannah Pohlit
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

Micromachining (including UV lithography, dry/wet etching, thin film deposition etc.);
Additive manufacturing;
Micro- and nanofluidics;
On-chip cell cultures (prokaryotes and eukaryotes);
Organs-on-chip;
Droplet microfluidics;
Enzymatic engineering;
3D cell cultures;
BioMEMS;
Single cell analysis;
Bio/chemical sensors;
Nanosensors

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Published Papers (10 papers)

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Research

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18 pages, 3965 KiB

Open AccessArticle

Antibody-Conjugated Magnetic Beads for Sperm Sexing Using a Multi-Wall Carbon Nanotube Microfluidic Device

by Chalinee Phiphattanaphiphop, Komgrit Leksakul, Thananut Wanta, Trisadee Khamlor and Rungrueang Phattanakun

Micromachines 2022, 13(3), 426; https://doi.org/10.3390/mi13030426 - 10 Mar 2022

Cited by 2 | Viewed by 3932

Abstract

This study proposes a microfluidic device used for X-/Y-sperm separation based on monoclonal antibody-conjugated magnetic beads, which become positively charged in the flow system. Y-sperms were selectively captured via a monoclonal antibody and transferred onto the microfluidic device and were discarded, so that X-sperms can be isolated and commercially exploited for fertilization demands of female cattle in dairy industry. Therefore, the research team used monoclonal antibody-conjugated magnetic beads to increase the force that causes the Y-sperm to be pulled out of the system, leaving only the X-sperm for further use. The experimental design was divided into the following: Model 1, the microfluid system for sorting positive magnetic beads, which yielded 100% separation; Model 2, the sorting of monoclonal antibody-conjugated magnetic beads in the fluid system, yielding 98.84% microcirculation; Model 3, the sorting of monoclonal antibody-conjugated magnetic beads with sperm in the microfluid system, yielding 80.12% microcirculation. Moreover, the fabrication microfluidic system had thin film electrodes created via UV lithography and MWCNTs electrode structure capable of erecting an electrode wall 1500 µm above the floor with a flow channel width of only 100 µm. The system was tested using a constant flow rate of 2 µL/min and X-/Y-sperm were separated using carbon nanotube electrodes at 2.5 V. The structure created with the use of vertical electrodes and monoclonal antibody-conjugated magnetic beads technique produced a higher effective rejection effect and was able to remove a large number of unwanted sperm from the system with 80.12% efficiency. Full article

(This article belongs to the Special Issue Micro/Nano Fabrication for Life Sciences)

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14 pages, 11319 KiB

Open AccessArticle

Novel Quick Cell Patterning Using Light-Responsive Gas-Generating Polymer and Fluorescence Microscope

by Hidetaka Ueno, Yoshinori Akagi and Shohei Yamamura

Micromachines 2022, 13(2), 320; https://doi.org/10.3390/mi13020320 - 18 Feb 2022

Cited by 1 | Viewed by 1988

Abstract

Conventional cell patterning methods are mainly based on hydrophilic/hydrophobic differences or chemical coating for cell adhesion/non-adhesion with wavering strength as it varies with the substrate surface conditions, including the cell type and the extracellular matrix components (ECMs) coating; thus, the versatility and stability of cell patterning methods must be improved. In this study, we propose a new cell patterning method using a light-responsive gas-generating polymer (LGP) and a conventional fluorescence microscope. Herein, cells and cellular tissues are easily released from the substrate surface by the nitrogen gas bubbles generated from LGP by the excitation light for fluorescence observation without harming the cells. The LGP-implanted chip was fabricated by packing LGP into a polystyrene (PS) microarray chip with a concave pattern. HeLa cells were spread on the LGP-implanted chips coated with three different ECMs (fibronectin, collagen, and poly-D-lysine), and all HeLa cells on the three LGP patterns were released. The pattern error between the LGP pattern and the remaining HeLa cells was 8.81 ± 4.24 μm, less than single-cell size. In addition, the LGP-implanted chip method can be applied to millimeter-scale patterns, with less than 30 s required for cell patterning. Therefore, the proposed method is a simple and rapid cell patterning method with high cell patterning accuracy of less than the cell size error, high scalability, versatility, and stability unaffected by the cell type or the ECM coating. Full article

(This article belongs to the Special Issue Micro/Nano Fabrication for Life Sciences)

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19 pages, 3707 KiB

Open AccessArticle

Rapid Prototyping of Organ-on-a-Chip Devices Using Maskless Photolithography

by Dhanesh G. Kasi, Mees N. S. de Graaf, Paul A. Motreuil-Ragot, Jean-Phillipe M. S. Frimat, Michel D. Ferrari, Pasqualina M. Sarro, Massimo Mastrangeli, Arn M. J. M. van den Maagdenberg, Christine L. Mummery and Valeria V. Orlova

Micromachines 2022, 13(1), 49; https://doi.org/10.3390/mi13010049 - 29 Dec 2021

Cited by 14 | Viewed by 8409

Abstract

Organ-on-a-chip (OoC) and microfluidic devices are conventionally produced using microfabrication procedures that require cleanrooms, silicon wafers, and photomasks. The prototyping stage often requires multiple iterations of design steps. A simplified prototyping process could therefore offer major advantages. Here, we describe a rapid and cleanroom-free microfabrication method using maskless photolithography. The approach utilizes a commercial digital micromirror device (DMD)-based setup using 375 nm UV light for backside exposure of an epoxy-based negative photoresist (SU-8) on glass coverslips. We show that microstructures of various geometries and dimensions, microgrooves, and microchannels of different heights can be fabricated. New SU-8 molds and soft lithography-based polydimethylsiloxane (PDMS) chips can thus be produced within hours. We further show that backside UV exposure and grayscale photolithography allow structures of different heights or structures with height gradients to be developed using a single-step fabrication process. Using this approach: (1) digital photomasks can be designed, projected, and quickly adjusted if needed; and (2) SU-8 molds can be fabricated without cleanroom availability, which in turn (3) reduces microfabrication time and costs and (4) expedites prototyping of new OoC devices. Full article

(This article belongs to the Special Issue Micro/Nano Fabrication for Life Sciences)

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13 pages, 2753 KiB

Open AccessArticle

Wafer-Scale Patterning of Protein Templates for Hydrogel Fabrication

by Anna A. Kim, Erica A. Castillo, Kerry V. Lane, Gabriela V. Torres, Orlando Chirikian, Robin E. Wilson, Sydney A. Lance, Gaspard Pardon and Beth L. Pruitt

Micromachines 2021, 12(11), 1386; https://doi.org/10.3390/mi12111386 - 12 Nov 2021

Cited by 1 | Viewed by 3031

Abstract

Human-induced pluripotent stem cell-derived cardiomyocytes are a potentially unlimited cell source and promising patient-specific in vitro model of cardiac diseases. Yet, these cells are limited by immaturity and population heterogeneity. Current in vitro studies aiming at better understanding of the mechanical and chemical cues in the microenvironment that drive cellular maturation involve deformable materials and precise manipulation of the microenvironment with, for example, micropatterns. Such microenvironment manipulation most often involves microfabrication protocols which are time-consuming, require cleanroom facilities and photolithography expertise. Here, we present a method to increase the scale of the fabrication pipeline, thereby enabling large-batch generation of shelf-stable microenvironment protein templates on glass chips. This decreases fabrication time and allows for more flexibility in the subsequent steps, for example, in tuning the material properties and the selection of extracellular matrix or cell proteins. Further, the fabrication of deformable hydrogels has been optimized for compatibility with these templates, in addition to the templates being able to be used to acquire protein patterns directly on the glass chips. With our approach, we have successfully controlled the shapes of cardiomyocytes seeded on Matrigel-patterned hydrogels. Full article

(This article belongs to the Special Issue Micro/Nano Fabrication for Life Sciences)

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10 pages, 1311 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

A Parallelized Nanofluidic Device for High-Throughput Optical DNA Mapping of Bacterial Plasmids

by Sriram KK, Yii-Lih Lin, Tsegaye Sewunet, Marie Wrande, Linus Sandegren, Christian G. Giske and Fredrik Westerlund

Micromachines 2021, 12(10), 1234; https://doi.org/10.3390/mi12101234 - 11 Oct 2021

Cited by 5 | Viewed by 3274

Abstract

Optical DNA mapping (ODM) has developed into an important technique for DNA analysis, where single DNA molecules are sequence-specifically labeled and stretched, for example, in nanofluidic channels. We have developed an ODM assay to analyze bacterial plasmids—circular extrachromosomal DNA that often carry genes that make bacteria resistant to antibiotics. As for most techniques, the next important step is to increase throughput and automation. In this work, we designed and fabricated a nanofluidic device that, together with a simple automation routine, allows parallel analysis of up to 10 samples at the same time. Using plasmids encoding extended-spectrum beta-lactamases (ESBL), isolated from Escherichia coli and Klebsiella pneumoniae, we demonstrate the multiplexing capabilities of the device when it comes to both many samples in parallel and different resistance genes. As a final example, we combined the device with a novel protocol for rapid cultivation and extraction of plasmids from fecal samples collected from patients. This combined protocol will make it possible to analyze many patient samples in one device already on the day the sample is collected, which is an important step forward for the ODM analysis of plasmids in clinical diagnostics. Full article

(This article belongs to the Special Issue Micro/Nano Fabrication for Life Sciences)

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13 pages, 1455 KiB

Open AccessFeature PaperArticle

Low-Cost PVD Shadow Masks with Submillimeter Resolution from Laser-Cut Paper

by Farzad Elhami Nik, Isabelle Matthiesen, Anna Herland and Thomas E. Winkler

Micromachines 2020, 11(7), 676; https://doi.org/10.3390/mi11070676 - 11 Jul 2020

Cited by 13 | Viewed by 6908

Abstract

We characterize an affordable method of producing stencils for submillimeter physical vapor deposition (PVD) by using paper and a benchtop laser cutter. Patterning electrodes or similar features on top of organic or biological substrates is generally not possible using standard photolithography. Shadow masks, traditionally made of silicon-based membranes, circumvent the need for aggressive solvents but suffer from high costs. Here, we evaluate shadow masks fabricated by CO₂ laser processing from quantitative filter papers. Such papers are stiff and dimensionally stable, resilient in handling, and cut without melting or redeposition. Using two exemplary interdigitated electrode designs, we quantify the line resolution achievable with both high-quality and standard lenses, as well as the positional accuracy across multiple length scales. Additionally, we assess the gap between such laser-cut paper masks and a substrate, and quantify feature reproduction onto polycarbonate membranes. We find that ~100 µm line widths are achievable independent of lens type and that average positional accuracy is better than ±100 µm at 4”-wafer scale. Although this falls well short of the micron-size features achievable with typical shadow masks, resolution in the tenths to tens of millimeters is entirely sufficient for applications from contact pads to electrochemical cells, allowing new functionalities on fragile materials. Full article

(This article belongs to the Special Issue Micro/Nano Fabrication for Life Sciences)

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13 pages, 4610 KiB

Open AccessFeature PaperArticle

Micromirror-Embedded Coverslip Assembly for Bidirectional Microscopic Imaging

by Dongwoo Lee, Jihye Kim, Eunjoo Song, Ji-Young Jeong, Eun-chae Jeon, Pilhan Kim and Wonhee Lee

Micromachines 2020, 11(6), 582; https://doi.org/10.3390/mi11060582 - 10 Jun 2020

Cited by 2 | Viewed by 3312

Abstract

3D imaging of a biological sample provides information about cellular and subcellular structures that are important in cell biology and related diseases. However, most 3D imaging systems, such as confocal and tomographic microscopy systems, are complex and expensive. Here, we developed a quasi-3D imaging tool that is compatible with most conventional microscopes by integrating micromirrors and microchannel structures on coverslips to provide bidirectional imaging. Microfabricated micromirrors had a precisely 45° reflection angle and optically clean reflective surfaces with high reflectance over 95%. The micromirrors were embedded on coverslips that could be assembled as a microchannel structure. We demonstrated that this simple disposable device allows a conventional microscope to perform bidirectional imaging with simple control of a focal plane. Images of microbeads and cells under bright-field and fluorescent microscopy show that the device can provide a quick analysis of 3D information, such as 3D positions and subcellular structures. Full article

(This article belongs to the Special Issue Micro/Nano Fabrication for Life Sciences)

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9 pages, 2926 KiB

Open AccessArticle

Novel Fabrication Process for Integration of Microwave Sensors in Microfluidic Channels

by Juncheng Bao, Tomislav Markovic, Luigi Brancato, Dries Kil, Ilja Ocket, Robert Puers and Bart Nauwelaers

Micromachines 2020, 11(3), 320; https://doi.org/10.3390/mi11030320 - 19 Mar 2020

Cited by 9 | Viewed by 4253

Abstract

This paper presents a novel fabrication process that allows integration of polydimethylsiloxane (PDMS)-based microfluidic channels and metal electrodes on a wafer with a micrometer-range alignment accuracy. This high level of alignment accuracy enables integration of microwave and microfluidic technologies, and furthermore accurate microwave dielectric characterization of biological liquids and chemical compounds on a nanoliter scale. The microfluidic interface between the pump feed lines and the fluidic channels was obtained using magnets fluidic connection. The tube-channel interference and the fluidic channel-wafer adhesion was evaluated, and up to a pressure of 700 mBar no leakage was observed. The developed manufacturing process was tested on a design of a microwave-microfluidic capacitive sensor. An interdigital capacitor (IDC) and a microfluidic channel were manufactured with an alignment accuracy of 2.5 μm. The manufactured IDC sensor was used to demonstrate microwave dielectric sensing on deionized water and saline solutions with concentrations of 0.1, 0.5, 1, and 2.5 M. Full article

(This article belongs to the Special Issue Micro/Nano Fabrication for Life Sciences)

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Review

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30 pages, 3790 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Fabricating Silicon Resonators for Analysing Biological Samples

by Momoko Kumemura, Deniz Pekin, Vivek Anand Menon, Isabelle Van Seuningen, Dominique Collard and Mehmet Cagatay Tarhan

Micromachines 2021, 12(12), 1546; https://doi.org/10.3390/mi12121546 - 12 Dec 2021

Cited by 4 | Viewed by 2951

Abstract

The adaptability of microscale devices allows microtechnologies to be used for a wide range of applications. Biology and medicine are among those fields that, in recent decades, have applied microtechnologies to achieve new and improved functionality. However, despite their ability to achieve assay sensitivities that rival or exceed conventional standards, silicon-based microelectromechanical systems remain underutilised for biological and biomedical applications. Although microelectromechanical resonators and actuators do not always exhibit optimal performance in liquid due to electrical double layer formation and high damping, these issues have been solved with some innovative fabrication processes or alternative experimental approaches. This paper focuses on several examples of silicon-based resonating devices with a brief look at their fundamental sensing elements and key fabrication steps, as well as current and potential biological/biomedical applications. Full article

(This article belongs to the Special Issue Micro/Nano Fabrication for Life Sciences)

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22 pages, 2194 KiB

Open AccessReview

Can 3D Printing Bring Droplet Microfluidics to Every Lab?—A Systematic Review

by Nafisat Gyimah, Ott Scheler, Toomas Rang and Tamas Pardy

Micromachines 2021, 12(3), 339; https://doi.org/10.3390/mi12030339 - 22 Mar 2021

Cited by 19 | Viewed by 6521

Abstract

In recent years, additive manufacturing has steadily gained attention in both research and industry. Applications range from prototyping to small-scale production, with 3D printing offering reduced logistics overheads, better design flexibility and ease of use compared with traditional fabrication methods. In addition, printer and material costs have also decreased rapidly. These advantages make 3D printing attractive for application in microfluidic chip fabrication. However, 3D printing microfluidics is still a new area. Is the technology mature enough to print complex microchannel geometries, such as droplet microfluidics? Can 3D-printed droplet microfluidic chips be used in biological or chemical applications? Is 3D printing mature enough to be used in every research lab? These are the questions we will seek answers to in our systematic review. We will analyze (1) the key performance metrics of 3D-printed droplet microfluidics and (2) existing biological or chemical application areas. In addition, we evaluate (3) the potential of large-scale application of 3D printing microfluidics. Finally, (4) we discuss how 3D printing and digital design automation could trivialize microfluidic chip fabrication in the long term. Based on our analysis, we can conclude that today, 3D printers could already be used in every research lab. Printing droplet microfluidics is also a possibility, albeit with some challenges discussed in this review. Full article

(This article belongs to the Special Issue Micro/Nano Fabrication for Life Sciences)

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