Special Issue "Advances in Micro-Bioreactor Design for Organ Cell Studies"

A special issue of Bioengineering (ISSN 2306-5354).

Deadline for manuscript submissions: closed (28 February 2018)

Special Issue Editor

Guest Editor
Prof. Dr. Carl-Fredrik Mandenius

Division of Biotechnology/IFM, Linköping University, SE-581 83 Linköping, Sweden
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Special Issue Information

Dear Colleagues,

Micro-bioreactors offer unique opportunities to study biological systems under fluidic conditions. The concept of micro-bioreactors suggests that biological reaction conditions at a large scale can be scaled down to micro-volumes while maintaining performance and functionality. Models and operation principles can be simulated at a smaller scale, either by scaling down organs in the human body, or bioreactors for the production of biologics. Dynamical models can be evaluated if space and volumes can be precisely handled and reproducibly for monitoring and molecular analysis. The gain will be lesser amounts of samples and cells, compact analytical setups, and new possibilities to run parallel and scaled-out experiments.

However, implementation and successful commercial exploitation of research results in micro-bioreactor and organ-on-chip designs have been few or slow. The reasons are numerous: Reproducibility of the biological activity in the miniaturized system is difficult to achieve, access to sensors that can be used in the devices is limited, adverse effects of scale are often difficult to avoid, and the fabrication of materials that are biocompatible and, at the same time, suitable for mass production are few.

The current Special Issue wants to highlight new engineering designs of micro-bioreactors, which present solutions that can cope with these shortcomings. In particular, new methods for monitoring of organ cells under in vivo-like conditions are welcomed. In addition, solutions that provide improvements of current methods, case studies with new prototypes for drug testing disease models. Of special interest are studies with deployment of hybrid models for multi-parametric control. The Special Issue is open for any kind of organ cell types or micro-bioreactor designs. Examples of contributions could address: 

  • Human organ cells in 3D scaffolds that mimic cell-cell interactions in vivo tissues
  • Co-cultures of combinations organ cell types
  • Online sensor methods for in situ monitoring inside the reactor
  • In situ imaging of organ cell biomarkers
  • Animal and human models of heart, liver or brain mimicked in micro-bioreactors
  • New devices for parallel or scaled-out operation

We look forward to receiving your contributions for this Special Issue.

Prof. Dr. Carl-Fredrik Mandenius
Guest Editor

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 papers will be 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. Bioengineering is an international peer-reviewed open access quarterly 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 300 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.

Published Papers (10 papers)

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Editorial

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Open AccessEditorial Advances in Micro-Bioreactor Design for Organ Cell Studies
Bioengineering 2018, 5(3), 64; https://doi.org/10.3390/bioengineering5030064
Received: 6 August 2018 / Accepted: 9 August 2018 / Published: 10 August 2018
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(This article belongs to the Special Issue Advances in Micro-Bioreactor Design for Organ Cell Studies)

Research

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Open AccessArticle A Microfluidic System for the Investigation of Tumor Cell Extravasation
Bioengineering 2018, 5(2), 40; https://doi.org/10.3390/bioengineering5020040
Received: 16 March 2018 / Revised: 17 May 2018 / Accepted: 21 May 2018 / Published: 23 May 2018
Cited by 2 | PDF Full-text (2946 KB) | HTML Full-text | XML Full-text
Abstract
Metastatic dissemination of cancer cells is a very complex process. It includes the intravasation of cells into the metastatic pathways, their passive distribution within the blood or lymph flow, and their extravasation into the surrounding tissue. Crucial steps during extravasation are the adhesion
[...] Read more.
Metastatic dissemination of cancer cells is a very complex process. It includes the intravasation of cells into the metastatic pathways, their passive distribution within the blood or lymph flow, and their extravasation into the surrounding tissue. Crucial steps during extravasation are the adhesion of the tumor cells to the endothelium and their transendothelial migration. However, the molecular mechanisms that are underlying this process are still not fully understood. Novel three dimensional (3D) models for research on the metastatic cascade include the use of microfluidic devices. Different from two dimensional (2D) models, these devices take cell–cell, structural, and mechanical interactions into account. Here we introduce a new microfluidic device in order to study tumor extravasation. The device consists of three different parts, containing two microfluidic channels and a porous membrane sandwiched in between them. A smaller channel together with the membrane represents the vessel equivalent and is seeded separately with primary endothelial cells (EC) that are isolated from the lung artery. The second channel acts as reservoir to collect the migrated tumor cells. In contrast to many other systems, this device does not need an additional coating to allow EC growth, as the primary EC that is used produces their own basement membrane. VE-Cadherin, an endothelial adherence junction protein, was expressed in regular localization, which indicates a tight barrier function and cell–cell connections of the endothelium. The EC in the device showed in vivo-like behavior under flow conditions. The GFP-transfected tumor cells that were introduced were of epithelial or mesenchymal origin and could be observed by live cell imaging, which indicates tightly adherent tumor cells to the endothelial lining under different flow conditions. These results suggest that the new device can be used for research on molecular requirements, conditions, and mechanism of extravasation and its inhibition. Full article
(This article belongs to the Special Issue Advances in Micro-Bioreactor Design for Organ Cell Studies)
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Open AccessArticle A Cardiac Cell Outgrowth Assay for Evaluating Drug Compounds Using a Cardiac Spheroid-on-a-Chip Device
Bioengineering 2018, 5(2), 36; https://doi.org/10.3390/bioengineering5020036
Received: 9 March 2018 / Revised: 23 April 2018 / Accepted: 1 May 2018 / Published: 4 May 2018
Cited by 3 | PDF Full-text (2882 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Three-dimensional (3D) models with cells arranged in clusters or spheroids have emerged as valuable tools to improve physiological relevance in drug screening. One of the challenges with cells cultured in 3D, especially for high-throughput applications, is to quickly and non-invasively assess the cellular
[...] Read more.
Three-dimensional (3D) models with cells arranged in clusters or spheroids have emerged as valuable tools to improve physiological relevance in drug screening. One of the challenges with cells cultured in 3D, especially for high-throughput applications, is to quickly and non-invasively assess the cellular state in vitro. In this article, we show that the number of cells growing out from human induced pluripotent stem cell (hiPSC)-derived cardiac spheroids can be quantified to serve as an indicator of a drug’s effect on spheroids captured in a microfluidic device. Combining this spheroid-on-a-chip with confocal high content imaging reveals easily accessible, quantitative outgrowth data. We found that effects on outgrowing cell numbers correlate to the concentrations of relevant pharmacological compounds and could thus serve as a practical readout to monitor drug effects. Here, we demonstrate the potential of this semi-high-throughput “cardiac cell outgrowth assay” with six compounds at three concentrations applied to spheroids for 48 h. The image-based readout complements end-point assays or may be used as a non-invasive assay for quality control during long-term culture. Full article
(This article belongs to the Special Issue Advances in Micro-Bioreactor Design for Organ Cell Studies)
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Open AccessArticle Efficient Computational Design of a Scaffold for Cartilage Cell Regeneration
Bioengineering 2018, 5(2), 33; https://doi.org/10.3390/bioengineering5020033
Received: 8 March 2018 / Revised: 18 April 2018 / Accepted: 20 April 2018 / Published: 24 April 2018
Cited by 2 | PDF Full-text (13549 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Due to the sensitivity of mammalian cell cultures, understanding the influence of operating conditions during a tissue generation procedure is crucial. In this regard, a detailed study of scaffold based cell culture under a perfusion flow is presented with the aid of mathematical
[...] Read more.
Due to the sensitivity of mammalian cell cultures, understanding the influence of operating conditions during a tissue generation procedure is crucial. In this regard, a detailed study of scaffold based cell culture under a perfusion flow is presented with the aid of mathematical modelling and computational fluid dynamics (CFD). With respect to the complexity of the case study, this work focuses solely on the effect of nutrient and metabolite concentrations, and the possible influence of fluid-induced shear stress on a targeted cell (cartilage) culture. The simulation set up gives the possibility of predicting the cell culture behavior under various operating conditions and scaffold designs. Thereby, the exploitation of the predictive simulation into a newly developed stochastic routine provides the opportunity of exploring improved scaffold geometry designs. This approach was applied on a common type of fibrous structure in order to increase the process efficiencies compared with the regular used formats. The suggested topology supplies a larger effective surface for cell attachment compared to the reference design while the level of shear stress is kept at the positive range of effect. Moreover, significant improvement of mass transfer is predicted for the suggested topology. Full article
(This article belongs to the Special Issue Advances in Micro-Bioreactor Design for Organ Cell Studies)
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Open AccessArticle Biocatalyst Screening with a Twist: Application of Oxygen Sensors Integrated in Microchannels for Screening Whole Cell Biocatalyst Variants
Bioengineering 2018, 5(2), 30; https://doi.org/10.3390/bioengineering5020030
Received: 28 February 2018 / Revised: 4 April 2018 / Accepted: 5 April 2018 / Published: 9 April 2018
Cited by 2 | PDF Full-text (14679 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Selective oxidative functionalization of molecules is a highly relevant and often demanding reaction in organic chemistry. The use of biocatalysts allows the stereo- and regioselective introduction of oxygen molecules in organic compounds at milder conditions and avoids the use of complex group-protection schemes
[...] Read more.
Selective oxidative functionalization of molecules is a highly relevant and often demanding reaction in organic chemistry. The use of biocatalysts allows the stereo- and regioselective introduction of oxygen molecules in organic compounds at milder conditions and avoids the use of complex group-protection schemes and toxic compounds usually applied in conventional organic chemistry. The identification of enzymes with the adequate properties for the target reaction and/or substrate requires better and faster screening strategies. In this manuscript, a microchannel with integrated oxygen sensors was applied to the screening of wild-type and site-directed mutated variants of naphthalene dioxygenase (NDO) from Pseudomonas sp. NICB 9816-4. The oxygen sensors were used to measure the oxygen consumption rate of several variants during the conversion of styrene to 1-phenylethanediol. The oxygen consumption rate allowed the distinguishing of endogenous respiration of the cell host from the oxygen consumed in the reaction. Furthermore, it was possible to identify the higher activity and different reaction rate of two variants, relative to the wild-type NDO. The meander microchannel with integrated oxygen sensors can therefore be used as a simple and fast screening platform for the selection of dioxygenase mutants, in terms of their ability to convert styrene, and potentially in terms of substrate specificity. Full article
(This article belongs to the Special Issue Advances in Micro-Bioreactor Design for Organ Cell Studies)
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Open AccessArticle A 3D Microfluidic Model to Recapitulate Cancer Cell Migration and Invasion
Bioengineering 2018, 5(2), 29; https://doi.org/10.3390/bioengineering5020029
Received: 14 March 2018 / Revised: 3 April 2018 / Accepted: 4 April 2018 / Published: 8 April 2018
Cited by 4 | PDF Full-text (46693 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
We have developed a microfluidic-based culture chip to simulate cancer cell migration and invasion across the basement membrane. In this microfluidic chip, a 3D microenvironment is engineered to culture metastatic breast cancer cells (MX1) in a 3D tumor model. A chemo-attractant was incorporated
[...] Read more.
We have developed a microfluidic-based culture chip to simulate cancer cell migration and invasion across the basement membrane. In this microfluidic chip, a 3D microenvironment is engineered to culture metastatic breast cancer cells (MX1) in a 3D tumor model. A chemo-attractant was incorporated to stimulate motility across the membrane. We validated the usefulness of the chip by tracking the motilities of the cancer cells in the system, showing them to be migrating or invading (akin to metastasis). It is shown that our system can monitor cell migration in real time, as compare to Boyden chambers, for example. Thus, the chip will be of interest to the drug-screening community as it can potentially be used to monitor the behavior of cancer cell motility, and, therefore, metastasis, in the presence of anti-cancer drugs. Full article
(This article belongs to the Special Issue Advances in Micro-Bioreactor Design for Organ Cell Studies)
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Open AccessArticle Microscale 3D Liver Bioreactor for In Vitro Hepatotoxicity Testing under Perfusion Conditions
Bioengineering 2018, 5(1), 24; https://doi.org/10.3390/bioengineering5010024
Received: 12 February 2018 / Revised: 7 March 2018 / Accepted: 12 March 2018 / Published: 15 March 2018
Cited by 2 | PDF Full-text (2487 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The accurate prediction of hepatotoxicity demands validated human in vitro models that can close the gap between preclinical animal studies and clinical trials. In this study we investigated the response of primary human liver cells to toxic drug exposure in a perfused microscale
[...] Read more.
The accurate prediction of hepatotoxicity demands validated human in vitro models that can close the gap between preclinical animal studies and clinical trials. In this study we investigated the response of primary human liver cells to toxic drug exposure in a perfused microscale 3D liver bioreactor. The cellularized bioreactors were treated with 5, 10, or 30 mM acetaminophen (APAP) used as a reference substance. Lactate production significantly decreased upon treatment with 30 mM APAP (p < 0.05) and ammonia release significantly increased in bioreactors treated with 10 or 30 mM APAP (p < 0.0001), indicating APAP-induced dose-dependent toxicity. The release of prostaglandin E2 showed a significant increase at 30 mM APAP (p < 0.05), suggesting an inflammatory reaction towards enhanced cellular stress. The expression of genes involved in drug metabolism, antioxidant reactions, urea synthesis, and apoptosis was differentially influenced by APAP exposure. Histological examinations revealed that primary human liver cells in untreated control bioreactors were reorganized in tissue-like cell aggregates. These aggregates were partly disintegrated upon APAP treatment, lacking expression of hepatocyte-specific proteins and transporters. In conclusion, our results validate the suitability of the microscale 3D liver bioreactor to detect hepatotoxic effects of drugs in vitro under perfusion conditions. Full article
(This article belongs to the Special Issue Advances in Micro-Bioreactor Design for Organ Cell Studies)
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Open AccessArticle Metabolic Reprogramming and the Recovery of Physiological Functionality in 3D Cultures in Micro-Bioreactors
Bioengineering 2018, 5(1), 22; https://doi.org/10.3390/bioengineering5010022
Received: 22 January 2018 / Revised: 21 February 2018 / Accepted: 24 February 2018 / Published: 7 March 2018
Cited by 3 | PDF Full-text (3013 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The recovery of physiological functionality, which is commonly seen in tissue mimetic three-dimensional (3D) cellular aggregates (organoids, spheroids, acini, etc.), has been observed in cells of many origins (primary tissues, embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and immortal cell lines).
[...] Read more.
The recovery of physiological functionality, which is commonly seen in tissue mimetic three-dimensional (3D) cellular aggregates (organoids, spheroids, acini, etc.), has been observed in cells of many origins (primary tissues, embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and immortal cell lines). This plurality and plasticity suggest that probably several basic principles promote this recovery process. The aim of this study was to identify these basic principles and describe how they are regulated so that they can be taken in consideration when micro-bioreactors are designed. Here, we provide evidence that one of these basic principles is hypoxia, which is a natural consequence of multicellular structures grown in microgravity cultures. Hypoxia drives a partial metabolic reprogramming to aerobic glycolysis and an increased anabolic synthesis. A second principle is the activation of cytoplasmic glutaminolysis for lipogenesis. Glutaminolysis is activated in the presence of hypo- or normo-glycaemic conditions and in turn is geared to the hexosamine pathway. The reducing power needed is produced in the pentose phosphate pathway, a prime function of glucose metabolism. Cytoskeletal reconstruction, histone modification, and the recovery of the physiological phenotype can all be traced to adaptive changes in the underlying cellular metabolism. These changes are coordinated by mTOR/Akt, p53 and non-canonical Wnt signaling pathways, while myc and NF-kB appear to be relatively inactive. Partial metabolic reprogramming to aerobic glycolysis, originally described by Warburg, is independent of the cell’s rate of proliferation, but is interwoven with the cells abilities to execute advanced functionality needed for replicating the tissues physiological performance. Full article
(This article belongs to the Special Issue Advances in Micro-Bioreactor Design for Organ Cell Studies)
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Review

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Open AccessReview Conceptual Design of Micro-Bioreactors and Organ-on-Chips for Studies of Cell Cultures
Bioengineering 2018, 5(3), 56; https://doi.org/10.3390/bioengineering5030056
Received: 9 June 2018 / Revised: 13 July 2018 / Accepted: 14 July 2018 / Published: 19 July 2018
Cited by 1 | PDF Full-text (5662 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Engineering design of microbioreactors (MBRs) and organ-on-chip (OoC) devices can take advantage of established design science theory, in which systematic evaluation of functional concepts and user requirements are analyzed. This is commonly referred to as a conceptual design. This review article compares how
[...] Read more.
Engineering design of microbioreactors (MBRs) and organ-on-chip (OoC) devices can take advantage of established design science theory, in which systematic evaluation of functional concepts and user requirements are analyzed. This is commonly referred to as a conceptual design. This review article compares how common conceptual design principles are applicable to MBR and OoC devices. The complexity of this design, which is exemplified by MBRs for scaled-down cell cultures in bioprocess development and drug testing in OoCs for heart and eye, is discussed and compared with previous design solutions of MBRs and OoCs, from the perspective of how similarities in understanding design from functionality and user purpose perspectives can more efficiently be exploited. The review can serve as a guideline and help the future design of MBR and OoC devices for cell culture studies. Full article
(This article belongs to the Special Issue Advances in Micro-Bioreactor Design for Organ Cell Studies)
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Open AccessReview Role of Bioreactor Technology in Tissue Engineering for Clinical Use and Therapeutic Target Design
Bioengineering 2018, 5(2), 32; https://doi.org/10.3390/bioengineering5020032
Received: 2 March 2018 / Revised: 17 April 2018 / Accepted: 18 April 2018 / Published: 24 April 2018
Cited by 2 | PDF Full-text (225 KB) | HTML Full-text | XML Full-text
Abstract
Micro and small bioreactors are well described for use in bioprocess development in pre-production manufacture, using ultra-scale down and microfluidic methodology. However, the use of bioreactors to understand normal and pathophysiology by definition must be very different, and the constraints of the physiological
[...] Read more.
Micro and small bioreactors are well described for use in bioprocess development in pre-production manufacture, using ultra-scale down and microfluidic methodology. However, the use of bioreactors to understand normal and pathophysiology by definition must be very different, and the constraints of the physiological environment influence such bioreactor design. This review considers the key elements necessary to enable bioreactors to address three main areas associated with biological systems. All entail recreation of the in vivo cell niche as faithfully as possible, so that they may be used to study molecular and cellular changes in normal physiology, with a view to creating tissue-engineered grafts for clinical use; understanding the pathophysiology of disease at the molecular level; defining possible therapeutic targets; and enabling appropriate pharmaceutical testing on a truly representative organoid, thus enabling better drug design, and simultaneously creating the potential to reduce the numbers of animals in research. The premise explored is that not only cellular signalling cues, but also mechano-transduction from mechanical cues, play an important role. Full article
(This article belongs to the Special Issue Advances in Micro-Bioreactor Design for Organ Cell Studies)
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