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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 (30 April 2021) | Viewed by 36325

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Special Issue Editors

Prof. Dr. András Dér

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Guest Editor

Biological Research Centre, Szeged, Hungary
Interests: bioelectronics; protein dynamics
Special Issues, Collections and Topics in MDPI journals

Dr. Sándor Valkai

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Co-Guest Editor

Institute of Biophysics, Biological Research Centre of Hungarian Research Network, Temesvári krt. 62, 6726 Szeged, Hungary
Interests: microfluidics; integrated optics; all optical biosensors; photolythography; optical waveguide
Special Issues, Collections and Topics in MDPI journals

Dr. Fruzsina Walter

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Co-Guest Editor

Institute of Biophysics, Biological Research Centre, Temesvari krt 62, H-6726 Szeged, Hungary
Interests: biological barriers, brain pathologies, drug delivery, permeability studies, organoid and lab-on-a-chip devices; animal and human vascular endothelial cell culture models; co-culture models of the blood–brain barrier; protection of the biological barriers in pathologies; natural compounds as barrier-protecting agents; surface glycocalyx, surface potential measurements
Special Issues, Collections and Topics in MDPI journals

Dr. András Kincses

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Co-Guest Editor

Institute of Biophysics, Biological Research Centre, 6726 Szeged, Hungary
Interests: lab-on-a-chip technologies
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is our pleasure to announce a forthcoming Special Issue of the MDPI journal Micromachines, entitled “Versatile Organ-on-a-Chip Devices.”

The tremendous success of microelectronics at the end of the 20th century, often symbolized by “Moore’s law,” is based on miniaturization of the active and passive elements of electronic circuits. Improving the methods of the underlying micro- and nanofabrication technique, lithography actually paved the way to the development of various “lab-on-a-chip” (LOC) applications, which complement microelectronics by miniature fluidic, mechanical, and/or optical elements. Since biological cells and their 2-D or 3-D cultures, organoids (miniature organ models), can be easily accommodated by LOC structures, it was only a question of time when this trend reached biological and medical science. Miniature organ models of brain, heart, lung, muscle, blood vessels, liver, and skin have been created during the past 10 years to model and study cellular and molecular interactions and pathological conditions of these organs. Predictably such “organs-on-a-chip” will increasingly represent a cornerstone of translational medicine in the forthcoming decades, and may complement, or in many cases substitute, animal studies in modeling diseases. Given the complexity of the human body, however, such disease models should also include the interaction of organs with each other (e.g., gut epithelium, microbiome, blood-brain barrier, brain for the “gut-brain axis,” etc.). The goal of this Special Issue is to facilitate the solution of this task by giving an overview of various existing approaches for versatile organ-on-a-chip models, and stimulating cooperation among experts of different areas.

Accordingly, we invite regular research papers and review articles that focus on novel methodological developments related to organ-on-a-chip technologies, and/or their utilizations in basic or applied sciences.

We are looking forward to receiving your submissions!

With best wishes,

Prof. Dr. András Dér
Dr. Sándor Valkai
Dr. Fruzsina Walter
Dr. András Kincses
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

Cells
Tissues
Spheroids/Organoids
Self-Assembly
Microfluidics
Microelectrodes
Optics
Microscopy

Published Papers (9 papers)

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Editorial

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3 pages, 190 KiB

Open AccessEditorial

Special Issue on Versatile Organ-on-a-Chip Devices

by András Dér

Micromachines 2021, 12(12), 1444; https://doi.org/10.3390/mi12121444 - 25 Nov 2021

Cited by 2 | Viewed by 1297

Abstract

The tremendous success of microelectronics at the end of the 20th century, often symbolized by “Moore’s law”, is based on miniaturization of the active and passive elements of electronic circuits [...] Full article

(This article belongs to the Special Issue Versatile Organ-on-a-Chip Devices)

Research

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17 pages, 3267 KiB

Open AccessArticle

Design of a Hybrid Inertial and Magnetophoretic Microfluidic Device for CTCs Separation from Blood

by Rohollah Nasiri, Amir Shamloo and Javad Akbari

Micromachines 2021, 12(8), 877; https://doi.org/10.3390/mi12080877 - 26 Jul 2021

Cited by 37 | Viewed by 3654

Abstract

Circulating tumor cells (CTCs) isolation from a blood sample plays an important role in cancer diagnosis and treatment. Microfluidics offers a great potential for cancer cell separation from the blood. Among the microfluidic-based methods for CTC separation, the inertial method as a passive method and magnetic method as an active method are two efficient well-established methods. Here, we investigated the combination of these two methods to separate CTCs from a blood sample in a single chip. Firstly, numerical simulations were performed to analyze the fluid flow within the proposed channel, and the particle trajectories within the inertial cell separation unit were investigated to determine/predict the particle trajectories within the inertial channel in the presence of fluid dynamic forces. Then, the designed device was fabricated using the soft-lithography technique. Later, the CTCs were conjugated with magnetic nanoparticles and Ep-CAM antibodies to improve the magnetic susceptibility of the cells in the presence of a magnetic field by using neodymium permanent magnets of 0.51 T. A diluted blood sample containing nanoparticle-conjugated CTCs was injected into the device at different flow rates to analyze its performance. It was found that the flow rate of 1000 µL/min resulted in the highest recovery rate and purity of ~95% and ~93% for CTCs, respectively. Full article

(This article belongs to the Special Issue Versatile Organ-on-a-Chip Devices)

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14 pages, 2403 KiB

Open AccessArticle

Breaking the Third Wall: Implementing 3D-Printing Techniques to Expand the Complexity and Abilities of Multi-Organ-on-a-Chip Devices

by Yoel Goldstein, Sarah Spitz, Keren Turjeman, Florian Selinger, Yechezkel Barenholz, Peter Ertl, Ofra Benny and Danny Bavli

Micromachines 2021, 12(6), 627; https://doi.org/10.3390/mi12060627 - 28 May 2021

Cited by 20 | Viewed by 4547

Abstract

The understanding that systemic context and tissue crosstalk are essential keys for bridging the gap between in vitro models and in vivo conditions led to a growing effort in the last decade to develop advanced multi-organ-on-a-chip devices. However, many of the proposed devices have failed to implement the means to allow for conditions tailored to each organ individually, a crucial aspect in cell functionality. Here, we present two 3D-print-based fabrication methods for a generic multi-organ-on-a-chip device: One with a PDMS microfluidic core unit and one based on 3D-printed units. The device was designed for culturing different tissues in separate compartments by integrating individual pairs of inlets and outlets, thus enabling tissue-specific perfusion rates that facilitate the generation of individual tissue-adapted perfusion profiles. The device allowed tissue crosstalk using microchannel configuration and permeable membranes used as barriers between individual cell culture compartments. Computational fluid dynamics (CFD) simulation confirmed the capability to generate significant differences in shear stress between the two individual culture compartments, each with a selective shear force. In addition, we provide preliminary findings that indicate the feasibility for biological compatibility for cell culture and long-term incubation in 3D-printed wells. Finally, we offer a cost-effective, accessible protocol enabling the design and fabrication of advanced multi-organ-on-a-chip devices. Full article

(This article belongs to the Special Issue Versatile Organ-on-a-Chip Devices)

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17 pages, 3540 KiB

Open AccessArticle

3D Bioprinting of Model Tissues That Mimic the Tumor Microenvironment

by Florina Bojin, Andreea Robu, Maria Iulia Bejenariu, Valentin Ordodi, Emilian Olteanu, Ada Cean, Roxana Popescu, Monica Neagu, Oana Gavriliuc, Adrian Neagu, Stelian Arjoca and Virgil Păunescu

Micromachines 2021, 12(5), 535; https://doi.org/10.3390/mi12050535 - 09 May 2021

Cited by 12 | Viewed by 3435

Abstract

The tumor microenvironment (TME) influences cancer progression. Therefore, engineered TME models are being developed for fundamental research and anti-cancer drug screening. This paper reports the biofabrication of 3D-printed avascular structures that recapitulate several features of the TME. The tumor is represented by a hydrogel droplet uniformly loaded with breast cancer cells (10⁶ cells/mL); it is embedded in the same type of hydrogel containing primary cells—tumor-associated fibroblasts isolated from the peritumoral environment and peripheral blood mononuclear cells. Hoechst staining of cryosectioned tissue constructs demonstrated that cells remodeled the hydrogel and remained viable for weeks. Histological sections revealed heterotypic aggregates of malignant and peritumoral cells; moreover, the constituent cells proliferated in vitro. To investigate the interactions responsible for the experimentally observed cellular rearrangements, we built lattice models of the bioprinted constructs and simulated their evolution using Metropolis Monte Carlo methods. Although unable to replicate the complexity of the TME, the approach presented here enables the self-assembly and co-culture of several cell types of the TME. Further studies will evaluate whether the bioprinted constructs can evolve in vivo in animal models. If they become connected to the host vasculature, they may turn into a fully organized TME. Full article

(This article belongs to the Special Issue Versatile Organ-on-a-Chip Devices)

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13 pages, 5614 KiB

Open AccessArticle

Rapid Fabrication of Microfluidic Devices for Biological Mimicking: A Survey of Materials and Biocompatibility

by Hui Ling Ma, Ana Carolina Urbaczek, Fayene Zeferino Ribeiro de Souza, Paulo Augusto Gomes Garrido Carneiro Leão, Janice Rodrigues Perussi and Emanuel Carrilho

Micromachines 2021, 12(3), 346; https://doi.org/10.3390/mi12030346 - 23 Mar 2021

Cited by 5 | Viewed by 3618

Abstract

Microfluidics is an essential technique used in the development of in vitro models for mimicking complex biological systems. The microchip with microfluidic flows offers the precise control of the microenvironment where the cells can grow and structure inside channels to resemble in vivo conditions allowing a proper cellular response investigation. Hence, this study aimed to develop low-cost, simple microchips to simulate the shear stress effect on the human umbilical vein endothelial cells (HUVEC). Differentially from other biological microfluidic devices described in the literature, we used readily available tools like heat-lamination, toner printer, laser cutter and biocompatible double-sided adhesive tapes to bind different layers of materials together, forming a designed composite with a microchannel. In addition, we screened alternative substrates, including polyester-toner, polyester-vinyl, glass, Permanox^® and polystyrene to compose the microchips for optimizing cell adhesion, then enabling these microdevices when coupled to a syringe pump, the cells can withstand the fluid shear stress range from 1 to 4 dyne cm². The cell viability was monitored by acridine orange/ethidium bromide (AO/EB) staining to detect live and dead cells. As a result, our fabrication processes were cost-effective and straightforward. The materials investigated in the assembling of the microchips exhibited good cell viability and biocompatibility, providing a dynamic microenvironment for cell proliferation. Therefore, we suggest that these microchips could be available everywhere, allowing in vitro assays for daily laboratory experiments and further developing the organ-on-a-chip concept. Full article

(This article belongs to the Special Issue Versatile Organ-on-a-Chip Devices)

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19 pages, 23462 KiB

Open AccessArticle

Generation of Photopolymerized Microparticles Based on PEGDA Using Microfluidic Devices. Part 1. Initial Gelation Time and Mechanical Properties of the Material

by José M. Acosta-Cuevas, José González-García, Mario García-Ramírez, Víctor H. Pérez-Luna, Erick Omar Cisneros-López, Rubén González-Nuñez and Orfil González-Reynoso

Micromachines 2021, 12(3), 293; https://doi.org/10.3390/mi12030293 - 10 Mar 2021

Cited by 8 | Viewed by 2949

Abstract

Photopolymerized microparticles are made of biocompatible hydrogels like Polyethylene Glycol Diacrylate (PEGDA) by using microfluidic devices are a good option for encapsulation, transport and retention of biological or toxic agents. Due to the different applications of these microparticles, it is important to investigate the formulation and the mechanical properties of the material of which they are made of. Therefore, in the present study, mechanical tests were carried out to determine the swelling, drying, soluble fraction, compression, cross-linking density (

M_{c}

) and mesh size (

ξ

) properties of different hydrogel formulations. Tests provided sufficient data to select the best formulation for the future generation of microparticles using microfluidic devices. The initial gelation times of the hydrogels formulations were estimated for their use in the photopolymerization process inside a microfluidic device. Obtained results showed a close relationship between the amount of PEGDA used in the hydrogel and its mechanical properties as well as its initial gelation time. Consequently, it is of considerable importance to know the mechanical properties of the hydrogels made in this research for their proper manipulation and application. On the other hand, the initial gelation time is crucial in photopolymerizable hydrogels and their use in continuous systems such as microfluidic devices. Full article

(This article belongs to the Special Issue Versatile Organ-on-a-Chip Devices)

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9 pages, 3317 KiB

Open AccessArticle

An Improved Transwell Design for Microelectrode Ion-Flux Measurements

by Boris Buchroithner, Pavel Spurný, Sandra Mayr, Johannes Heitz, Dmitry Sivun, Jaroslaw Jacak and Jost Ludwig

Micromachines 2021, 12(3), 273; https://doi.org/10.3390/mi12030273 - 06 Mar 2021

Cited by 3 | Viewed by 3633

Abstract

The microelectrode ion flux estimation (MIFE) is a powerful, non-invasive electrophysiological method for cellular membrane transport studies. Usually, the MIFE measurements are performed in a tissue culture dish or directly with tissues (roots, parts of the plants, and cell tissues). Here, we present a transwell system that allows for MIFE measurements on a cell monolayer. We introduce a measurement window in the transwell insert membrane, which provides direct access for the cells to the media in the upper and lower compartment of the transwell system and allows direct cell-to-cell contact coculture. Three-dimensional multiphoton lithography (MPL) was used to construct a 3D grid structure for cell support in the measurement window. The optimal polymer grid constant was found for implementation in transwell MIFE measurements. We showed that human umbilical vein endothelial cells (HUVECs) efficiently grow and maintain their physiological response on top of the polymer structures. Full article

(This article belongs to the Special Issue Versatile Organ-on-a-Chip Devices)

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Review

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18 pages, 2130 KiB

Open AccessReview

Transendothelial Electrical Resistance Measurement across the Blood–Brain Barrier: A Critical Review of Methods

by Judit P. Vigh, András Kincses, Burak Ozgür, Fruzsina R. Walter, Ana Raquel Santa-Maria, Sándor Valkai, Mónika Vastag, Winfried Neuhaus, Birger Brodin, András Dér and Mária A. Deli

Micromachines 2021, 12(6), 685; https://doi.org/10.3390/mi12060685 - 11 Jun 2021

Cited by 54 | Viewed by 6298

Abstract

The blood–brain barrier (BBB) represents the tightest endothelial barrier within the cardiovascular system characterized by very low ionic permeability. Our aim was to describe the setups, electrodes, and instruments to measure electrical resistance across brain microvessels and culture models of the BBB, as well as critically assess the influence of often neglected physical and technical parameters such as temperature, viscosity, current density generated by different electrode types, surface size, circumference, and porosity of the culture insert membrane. We demonstrate that these physical and technical parameters greatly influence the measurement of transendothelial electrical resistance/resistivity (TEER) across BBB culture models resulting in severalfold differences in TEER values of the same biological model, especially in the low-TEER range. We show that elevated culture medium viscosity significantly increases, while higher membrane porosity decreases TEER values. TEER data measured by chopstick electrodes can be threefold higher than values measured by chamber electrodes due to different electrode size and geometry, resulting in current distribution inhomogeneity. An additional shunt resistance at the circumference of culture inserts results in lower TEER values. A detailed description of setups and technical parameters is crucial for the correct interpretation and comparison of TEER values of BBB models. Full article

(This article belongs to the Special Issue Versatile Organ-on-a-Chip Devices)

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25 pages, 5380 KiB

Open AccessReview

Development of Skin-On-A-Chip Platforms for Different Utilizations: Factors to Be Considered

by J. Ponmozhi, S. Dhinakaran, Zsófia Varga-Medveczky, Katalin Fónagy, Luca Anna Bors, Kristóf Iván and Franciska Erdő

Micromachines 2021, 12(3), 294; https://doi.org/10.3390/mi12030294 - 10 Mar 2021

Cited by 26 | Viewed by 5582

Abstract

There is increasing interest in miniaturized technologies in diagnostics, therapeutic testing, and biomedicinal fundamental research. The same is true for the dermal studies in topical drug development, dermatological disease pathology testing, and cosmetic science. This review aims to collect the recent scientific literature and knowledge about the application of skin-on-a-chip technology in drug diffusion studies, in pharmacological and toxicological experiments, in wound healing, and in fields of cosmetic science (ageing or repair). The basic mathematical models are also presented in the article to predict physical phenomena, such as fluid movement, drug diffusion, and heat transfer taking place across the dermal layers in the chip using Computational Fluid Dynamics techniques. Soon, it can be envisioned that animal studies might be at least in part replaced with skin-on-a-chip technology leading to more reliable results close to study on humans. The new technology is a cost-effective alternative to traditional methods used in research institutes, university labs, and industry. With this article, the authors would like to call attention to a new investigational family of platforms to refresh the researchers’ theranostics and preclinical, experimental toolbox. Full article

(This article belongs to the Special Issue Versatile Organ-on-a-Chip Devices)

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