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Microfluidic Bioreactors and Organ-on-Chip Devices for Drug Screening and Disease Modeling

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A special issue of Micromachines (ISSN 2072-666X).

Deadline for manuscript submissions: closed (25 April 2016) | Viewed by 102584

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Special Issue Editors

Prof. Dr. Nam-Trung Nguyen

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Guest Editor

Queensland Micro- and Nanotechnology Centre, Griffith University, West Creek Road, Nathan, QLD 4111, Australia
Interests: microfluidics; nanofluidics; micro/nanomachining technologies; micro/nanoscale science; instrumentation for biomedical applications
Special Issues, Collections and Topics in MDPI journals

Dr. Seyed Ali Mousavi Shaegh

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Harvard-MIT Division of Health Sciences and Technology Center for Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School 65 Landsdowne Street, Rm. 252, Cambridge, MA, USA 02139, USA
Interests: microfluidics, nanofluidics, microfluidic organs-on-chip, microscale 3D printing, electrochemical sensors

Special Issue Information

Dear Colleagues,

Microfluidic organs-on-chip devices are for culturing living cells in continuously perfused, micrometer-sized chambers in order to model the physiological functions of tissues and organs. The devices can mimic the in vivo microenvironment of cells and organ constructs at in vitro conditions to model and analyse organ-specific responses in reaction to drugs, toxins, or other environmental stimulations. Taking advantage of micro/nanofluidics and nanotechnology, organs-on-chip attempt to produce the complexity of living tissues by incorporating physical forces, spatial diffusive gradients, multiple cell types, and creating interfaces between different tissues. Consequently, such devices provide an enabling platform for high-resolution, real-time imaging and in vitro analysis of biochemical, genetic, and metabolic activities of living cells required for drug screening and disease modelling purposes.

Hereby, we announce a Special Issue addressing advances in fabrication and operation of microfluidic organs-on-chip. We invite submissions of papers on various topics, including novel designs of bioreactors and organ-on-chip devices to mimic single or multi-organ constructs, and also employing of additive manufacturing techniques, 3D printing and 3D bioprinting, for making complex designs of organ-on-chip devices.

Moreover, manuscripts on developing sensors for long-term monitoring of cells microenvironment, such as pH and dissolved oxygen, as well as for detection of secreted biomarkers or trace concentration of drugs are great contributions. Investigations about instrumentation and control of integrated complex organ-on-chip devices are of great interest as well. In addition, submissions associated with the scale effect for multi-organ devices and human-on-chip platforms to understand organ-organ interactions during drug screening studies are highly encouraged.

Prof. Dr. Nam-Trung Nguyen
Dr. Seyed Ali Mousavi Shaegh
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

microfluidic organ-on-chip
human-on-chip
disease modeling
drug screening
scale effect
sensor
bioreactor
Micro/nano-scale additive manufacturing techniques

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Published Papers (9 papers)

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Research

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2149 KiB

Open AccessArticle

Human Liver Sinusoid on a Chip for Hepatitis B Virus Replication Study

by Young Bok (Abraham) Kang, Siddhartha Rawat, Nicholas Duchemin, Michael Bouchard and Moses Noh

Micromachines 2017, 8(1), 27; https://doi.org/10.3390/mi8010027 - 20 Jan 2017

Cited by 39 | Viewed by 7325

Abstract

We have developed a miniature human liver (liver-sinusoid-on-a-chip) model using a dual microchannel separated by a porous membrane. Primary human hepatocytes and immortalized bovine aortic endothelial cells were co-cultured on opposite sides of a microporous membrane in a dual microchannel with continuous perfusion. Primary human hepatocytes in this system retained their polygonal morphology for up to 26 days, while hepatocytes cultured in the absence of bovine aortic endothelial cells lost their morphology within a week. In order to demonstrate the utility of our human-liver-sinusoid-on-a-chip, human hepatocytes in this system were directly infected by Hepatitis B Virus (HBV). Expression of the HBV core antigen was detected in human hepatocytes in the microchannel system. HBV replication, measured by the presence of cell-secreted HBV DNA, was also detected. Importantly, HBV is hepatotropic, and expression of HBV RNA transcripts is dependent upon expression of hepatocyte-specific factors. Moreover, HBV infection requires expression of the human-hepatocyte-specific HBV cell surface receptor. Therefore, the ability to detect HBV replication and Hepatitis B core Antigen (HBcAg) expression in our microfluidic platform confirmed that hepatocyte differentiation and functions were retained throughout the time course of our studies. We believe that our human-liver-sinusoid-on-a-chip could have many applications in liver-related research and drug development. Full article

(This article belongs to the Special Issue Microfluidic Bioreactors and Organ-on-Chip Devices for Drug Screening and Disease Modeling)

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1933 KiB

Open AccessArticle

High-Throughput Assessment of Drug Cardiac Safety Using a High-Speed Impedance Detection Technology-Based Heart-on-a-Chip

by Xi Zhang, Tianxing Wang, Ping Wang and Ning Hu

Micromachines 2016, 7(7), 122; https://doi.org/10.3390/mi7070122 - 19 Jul 2016

Cited by 42 | Viewed by 6892

Abstract

Drug cardiac safety assessments play a significant role in drug discovery. Drug-induced cardiotoxicity is one of the main reasons for drug attrition, even when antiarrhythmic drugs can otherwise effectively treat the arrhythmias. Consequently, efficient drug preclinical assessments are needed in the drug industry. However, most drug efficacy assessments are performed based on electrophysiological tests of cardiomyocytes in vitro and cannot effectively provide information on drug-induced dysfunction of cardiomyocyte beating. Here we present a heart-on-a-chip device for evaluating the drug cardiac efficacy using a high-speed impedance detection technology. Verapamil and doxorubicin were utilized to test this heart-on-a-chip, and multiple parameters of cardiomyocyte beating status are used to reveal the effects of drugs. The results show that drug efficacy or cardiotoxicity can be determined by this heart-on-a-chip. We believe this heart-on-a-chip will be a promising tool for the preclinical assessment of drug cardiac efficacy. Full article

(This article belongs to the Special Issue Microfluidic Bioreactors and Organ-on-Chip Devices for Drug Screening and Disease Modeling)

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8270 KiB

Open AccessArticle

Cytostretch, an Organ-on-Chip Platform

by Nikolas Gaio, Berend Van Meer, William Quirós Solano, Lambert Bergers, Anja Van de Stolpe, Christine Mummery, Pasqualina M. Sarro and Ronald Dekker

Micromachines 2016, 7(7), 120; https://doi.org/10.3390/mi7070120 - 14 Jul 2016

Cited by 37 | Viewed by 8495

Abstract

Organ-on-Chips (OOCs) are micro-fabricated devices which are used to culture cells in order to mimic functional units of human organs. The devices are designed to simulate the physiological environment of tissues in vivo. Cells in some types of OOCs can be stimulated in situ by electrical and/or mechanical actuators. These actuations can mimic physiological conditions in real tissue and may include fluid or air flow, or cyclic stretch and strain as they occur in the lung and heart. These conditions similarly affect cultured cells and may influence their ability to respond appropriately to physiological or pathological stimuli. To date, most focus has been on devices specifically designed to culture just one functional unit of a specific organ: lung alveoli, kidney nephrons or blood vessels, for example. In contrast, the modular Cytostretch membrane platform described here allows OOCs to be customized to different OOC applications. The platform utilizes silicon-based micro-fabrication techniques that allow low-cost, high-volume manufacturing. We describe the platform concept and its modules developed to date. Membrane variants include membranes with (i) through-membrane pores that allow biological signaling molecules to pass between two different tissue compartments; (ii) a stretchable micro-electrode array for electrical monitoring and stimulation; (iii) micro-patterning to promote cell alignment; and (iv) strain gauges to measure changes in substrate stress. This paper presents the fabrication and the proof of functionality for each module of the Cytostretch membrane. The assessment of each additional module demonstrate that a wide range of OOCs can be achieved. Full article

(This article belongs to the Special Issue Microfluidic Bioreactors and Organ-on-Chip Devices for Drug Screening and Disease Modeling)

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7860 KiB

Open AccessFeature PaperArticle

A Microchip for High-Throughput Axon Growth Drug Screening

by Hyun Soo Kim, Sehoon Jeong, Chiwan Koo, Arum Han and Jaewon Park

Micromachines 2016, 7(7), 114; https://doi.org/10.3390/mi7070114 - 7 Jul 2016

Cited by 14 | Viewed by 8120

Abstract

It has been recently known that not only the presence of inhibitory molecules associated with myelin but also the reduced growth capability of the axons limit mature central nervous system (CNS) axonal regeneration after injury. Conventional axon growth studies are typically conducted using multi-well cell culture plates that are very difficult to use for investigating localized effects of drugs and limited to low throughput. Unfortunately, there is currently no other in vitro tool that allows investigating localized axonal responses to biomolecules in high-throughput for screening potential drugs that might promote axonal growth. We have developed a compartmentalized neuron culture platform enabling localized biomolecular treatments in parallel to axons that are physically and fluidically isolated from their neuronal somata. The 24 axon compartments in the developed platform are designed to perform four sets of six different localized biomolecular treatments simultaneously on a single device. In addition, the novel microfluidic configuration allows culture medium of 24 axon compartments to be replenished altogether by a single aspiration process, making high-throughput drug screening a reality. Full article

(This article belongs to the Special Issue Microfluidic Bioreactors and Organ-on-Chip Devices for Drug Screening and Disease Modeling)

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2121 KiB

Open AccessReview

Review of Microfluidic Photobioreactor Technology for Metabolic Engineering and Synthetic Biology of Cyanobacteria and Microalgae

by Ya-Tang Yang and Chun Ying Wang

Micromachines 2016, 7(10), 185; https://doi.org/10.3390/mi7100185 - 11 Oct 2016

Cited by 17 | Viewed by 11069

Abstract

One goal of metabolic engineering and synthetic biology for cyanobacteria and microalgae is to engineer strains that can optimally produce biofuels and commodity chemicals. However, the current workflow is slow and labor intensive with respect to assembly of genetic parts and characterization of production yields because of the slow growth rates of these organisms. Here, we review recent progress in the microfluidic photobioreactors and identify opportunities and unmet needs in metabolic engineering and synthetic biology. Because of the unprecedented experimental resolution down to the single cell level, long-term real-time monitoring capability, and high throughput with low cost, microfluidic photobioreactor technology will be an indispensible tool to speed up the development process, advance fundamental knowledge, and realize the full potential of metabolic engineering and synthetic biology for cyanobacteria and microalgae. Full article

(This article belongs to the Special Issue Microfluidic Bioreactors and Organ-on-Chip Devices for Drug Screening and Disease Modeling)

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2089 KiB

Open AccessReview

Microfluidic-Based Multi-Organ Platforms for Drug Discovery

by Ahmad Rezaei Kolahchi, Nima Khadem Mohtaram, Hassan Pezeshgi Modarres, Mohammad Hossein Mohammadi, Armin Geraili, Parya Jafari, Mohsen Akbari and Amir Sanati-Nezhad

Micromachines 2016, 7(9), 162; https://doi.org/10.3390/mi7090162 - 8 Sep 2016

Cited by 36 | Viewed by 12219

Abstract

Development of predictive multi-organ models before implementing costly clinical trials is central for screening the toxicity, efficacy, and side effects of new therapeutic agents. Despite significant efforts that have been recently made to develop biomimetic in vitro tissue models, the clinical application of such platforms is still far from reality. Recent advances in physiologically-based pharmacokinetic and pharmacodynamic (PBPK-PD) modeling, micro- and nanotechnology, and in silico modeling have enabled single- and multi-organ platforms for investigation of new chemical agents and tissue-tissue interactions. This review provides an overview of the principles of designing microfluidic-based organ-on-chip models for drug testing and highlights current state-of-the-art in developing predictive multi-organ models for studying the cross-talk of interconnected organs. We further discuss the challenges associated with establishing a predictive body-on-chip (BOC) model such as the scaling, cell types, the common medium, and principles of the study design for characterizing the interaction of drugs with multiple targets. Full article

(This article belongs to the Special Issue Microfluidic Bioreactors and Organ-on-Chip Devices for Drug Screening and Disease Modeling)

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4096 KiB

Open AccessReview

Organ-Tumor-on-a-Chip for Chemosensitivity Assay: A Critical Review

by Navid Kashaninejad, Mohammad Reza Nikmaneshi, Hajar Moghadas, Amir Kiyoumarsi Oskouei, Milad Rismanian, Maryam Barisam, Mohammad Said Saidi and Bahar Firoozabadi

Micromachines 2016, 7(8), 130; https://doi.org/10.3390/mi7080130 - 28 Jul 2016

Cited by 70 | Viewed by 13739

Abstract

With a mortality rate over 580,000 per year, cancer is still one of the leading causes of death worldwide. However, the emerging field of microfluidics can potentially shed light on this puzzling disease. Unique characteristics of microfluidic chips (also known as micro-total analysis system) make them excellent candidates for biological applications. The ex vivo approach of tumor-on-a-chip is becoming an indispensable part of personalized medicine and can replace in vivo animal testing as well as conventional in vitro methods. In tumor-on-a-chip, the complex three-dimensional (3D) nature of malignant tumor is co-cultured on a microfluidic chip and high throughput screening tools to evaluate the efficacy of anticancer drugs are integrated on the same chip. In this article, we critically review the cutting edge advances in this field and mainly categorize each tumor-on-a-chip work based on its primary organ. Specifically, design, fabrication and characterization of tumor microenvironment; cell culture technique; transferring mechanism of cultured cells into the microchip; concentration gradient generators for drug delivery; in vitro screening assays of drug efficacy; and pros and cons of each microfluidic platform used in the recent literature will be discussed separately for the tumor of following organs: (1) Lung; (2) Bone marrow; (3) Brain; (4) Breast; (5) Urinary system (kidney, bladder and prostate); (6) Intestine; and (7) Liver. By comparing these microchips, we intend to demonstrate the unique design considerations of each tumor-on-a-chip based on primary organ, e.g., how microfluidic platform of lung-tumor-on-a-chip may differ from liver-tumor-on-a-chip. In addition, the importance of heart–liver–intestine co-culture with microvasculature in tumor-on-a-chip devices for in vitro chemosensitivity assay will be discussed. Such system would be able to completely evaluate the absorption, distribution, metabolism, excretion and toxicity (ADMET) of anticancer drugs and more realistically recapitulate tumor in vivo-like microenvironment. Full article

(This article belongs to the Special Issue Microfluidic Bioreactors and Organ-on-Chip Devices for Drug Screening and Disease Modeling)

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3508 KiB

Open AccessReview

Mimicking the Kidney: A Key Role in Organ-on-Chip Development

by Roberto Paoli and Josep Samitier

Micromachines 2016, 7(7), 126; https://doi.org/10.3390/mi7070126 - 20 Jul 2016

Cited by 35 | Viewed by 20881

Abstract

Pharmaceutical drug screening and research into diseases call for significant improvement in the effectiveness of current in vitro models. Better models would reduce the likelihood of costly failures at later drug development stages, while limiting or possibly even avoiding the use of animal models. In this regard, promising advances have recently been made by the so-called “organ-on-chip” (OOC) technology. By combining cell culture with microfluidics, biomedical researchers have started to develop microengineered models of the functional units of human organs. With the capacity to mimic physiological microenvironments and vascular perfusion, OOC devices allow the reproduction of tissue- and organ-level functions. When considering drug testing, nephrotoxicity is a major cause of attrition during pre-clinical, clinical, and post-approval stages. Renal toxicity accounts for 19% of total dropouts during phase III drug evaluation—more than half the drugs abandoned because of safety concerns. Mimicking the functional unit of the kidney, namely the nephron, is therefore a crucial objective. Here we provide an extensive review of the studies focused on the development of a nephron-on-chip device. Full article

(This article belongs to the Special Issue Microfluidic Bioreactors and Organ-on-Chip Devices for Drug Screening and Disease Modeling)

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1769 KiB

Open AccessReview

Farewell to Animal Testing: Innovations on Human Intestinal Microphysiological Systems

by Tae Hyun Kang and Hyun Jung Kim

Micromachines 2016, 7(7), 107; https://doi.org/10.3390/mi7070107 - 27 Jun 2016

Cited by 29 | Viewed by 11820

Abstract

The human intestine is a dynamic organ where the complex host-microbe interactions that orchestrate intestinal homeostasis occur. Major contributing factors associated with intestinal health and diseases include metabolically-active gut microbiota, intestinal epithelium, immune components, and rhythmical bowel movement known as peristalsis. Human intestinal disease models have been developed; however, a considerable number of existing models often fail to reproducibly predict human intestinal pathophysiology in response to biological and chemical perturbations or clinical interventions. Intestinal organoid models have provided promising cytodifferentiation and regeneration, but the lack of luminal flow and physical bowel movements seriously hamper mimicking complex host-microbe crosstalk. Here, we discuss recent advances of human intestinal microphysiological systems, such as the biomimetic human “Gut-on-a-Chip” that can employ key intestinal components, such as villus epithelium, gut microbiota, and immune components under peristalsis-like motions and flow, to reconstitute the transmural 3D lumen-capillary tissue interface. By encompassing cutting-edge tools in microfluidics, tissue engineering, and clinical microbiology, gut-on-a-chip has been leveraged not only to recapitulate organ-level intestinal functions, but also emulate the pathophysiology of intestinal disorders, such as chronic inflammation. Finally, we provide potential perspectives of the next generation microphysiological systems as a personalized platform to validate the efficacy, safety, metabolism, and therapeutic responses of new drug compounds in the preclinical stage. Full article

(This article belongs to the Special Issue Microfluidic Bioreactors and Organ-on-Chip Devices for Drug Screening and Disease Modeling)

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