Special Issue "Bioreactor System: Design, Modeling and Continuous Production Process"

A special issue of Processes (ISSN 2227-9717). This special issue belongs to the section "Biological Processes and Systems".

Deadline for manuscript submissions: closed (31 July 2021).

Special Issue Editors

Dr. Francesca Raganati
E-Mail Website
Guest Editor
Dipartimento di Ingegneria Chimica, dei Materiali e della Produzione Industriale, Università degli Studi di Napoli Federico II, Piazzale Tecchio 80, 80125 Napoli, Italy
Interests: fermentation; bioreactors; bioprocesse engineering; biomass conversion
Special Issues, Collections and Topics in MDPI journals
Dr. Alessandra Procentese
E-Mail Website
Guest Editor
Department of Biotechnology and Biomedicine, Technical University of Denmark, Søltofts Plads 2800 Kgs. Lyngby, Denmark
Interests: fermentation; bioreactors; bioprocess engineering; biomass conversion
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The Special Issue, “Bioreactor System: Design, Modeling and Continuous Production Process”, will address experimental/theoretical research and latest progress in the field of bioreactor systems.

Bioreactors play an important role in many industries, including fermentation, food, pharmaceuticals, and wastewater treatment. Bioreactor is the heart of any biochemical process in which enzymes, microbial, mammalian, or plant cell systems are used for the manufacture of a wide range of useful biological products.

Each bioconversion process is dependent on many factors, including growth conditions, homogeneity of fermentation medium, cell density, etc. The decisions made in the design of the bioreactor might have a significant impact on overall process performance; in fact, bioreactor design/operation-mode is an important key factor to achieve optimum conditions for maximum yield/productivity in fermentation; the main function of a properly designed bioreactor is to provide a controlled environment to achieve optimal growth and/or product formation in the particular cell system employed. In this regard, knowledge of reaction kinetics is essential for an understanding of the working of a biological reactor. Other areas of bioprocess engineering such as mass and energy balances, mixing, mass transfer, and heat transfer are also required.

Moreover, qualitative and quantitative descriptions of a production process through the analysis of various parameters by automatic or manual methods are necessary for process control and optimization. The objects of process monitoring can be the environmental status or the varied values of operational variables. Through analysis, the cellular or engineering problems of a bioreactor on different scales can be identified. Interscale observation and operation is crucial in bioprocess optimization.

Therefore, the objective of this issue is to showcase the diversity and advances in research that contributes to developing effective systems for the microorganism culture and biochemical production.

Original papers are solicited on experimental/theoretical studies on bioreactor systems. We are particularly interested in receiving manuscripts that integrate biology and engineering research and/or experimental and theoretical studies. We invite researchers from all areas of bioengineering to submit manuscripts for this important Special Issue of Processes.

Dr. Francesca Raganati
Dr. Alessandra Procentese
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 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. Processes 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 2000 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

  • cell culture
  • fermentation
  • bioprocessing
  • scale-up
  • bioreactor design
  • mathematical models
  • monitoring and control

Published Papers (11 papers)

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Research

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Article
Automated Compartment Model Development Based on Data from Flow-Following Sensor Devices
Processes 2021, 9(9), 1651; https://0-doi-org.brum.beds.ac.uk/10.3390/pr9091651 - 13 Sep 2021
Viewed by 482
Abstract
Due to the heterogeneous nature of large-scale fermentation processes they cannot be modelled as ideally mixed reactors, and therefore flow models are necessary to accurately represent the processes. Computational fluid dynamics (CFD) is used more and more to derive flow fields for the [...] Read more.
Due to the heterogeneous nature of large-scale fermentation processes they cannot be modelled as ideally mixed reactors, and therefore flow models are necessary to accurately represent the processes. Computational fluid dynamics (CFD) is used more and more to derive flow fields for the modelling of bioprocesses, but the computational demands associated with simulation of multiphase systems with biokinetics still limits their wide applicability. Hence, a demand for simpler flow models persists. In this study, an approach to develop data-based flow models in the form of compartment models is presented, which utilizes axial-flow rates obtained from flow-following sensor devices in combination with a proposed procedure for automatic zoning of volume. The approach requires little experimental effort and eliminates the necessity for computational determination of inter-compartmental flow rates and manual zoning. The concept has been demonstrated in a 580 L stirred vessel, of which models have been developed for two types of impellers with varying agitation intensities. The sensor device measurements were corroborated by CFD simulations, and the performance of the developed compartment models was evaluated by comparing predicted mixing times with experimentally determined mixing times. The data-based compartment models predicted the mixing times for all examined conditions with relative errors in the range of 3–27%. The deviations were ascribed to limitations in the flow-following behavior of the sensor devices, whose sizes were relatively large compared to the examined system. The approach provides a versatile and automated flow modelling platform which can be applied to large-scale bioreactors. Full article
(This article belongs to the Special Issue Bioreactor System: Design, Modeling and Continuous Production Process)
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Article
Designing of an Advanced Compression Bioreactor with an Implementation of a Low-Cost Controlling System Connected to a Mobile Application
Processes 2021, 9(6), 915; https://0-doi-org.brum.beds.ac.uk/10.3390/pr9060915 - 23 May 2021
Viewed by 539
Abstract
(1) Background: Bioreactors mimic the natural environment of cells and tissues by providing a controlled micro-environment. However, their design is often expensive and complex. Herein, we have introduced the development of a low-cost compression bioreactor which enables the application of different mechanical stimulation [...] Read more.
(1) Background: Bioreactors mimic the natural environment of cells and tissues by providing a controlled micro-environment. However, their design is often expensive and complex. Herein, we have introduced the development of a low-cost compression bioreactor which enables the application of different mechanical stimulation regimes to in vitro tissue models and provides the information of applied stress and strain in real-time. (2) Methods: The compression bioreactor is designed using a mini-computer called Raspberry Pi, which is programmed to apply compressive deformation at various strains and frequencies, as well as to measure the force applied to the tissue constructs. Besides this, we have developed a mobile application connected to the bioreactor software to monitor, command, and control experiments via mobile devices. (3) Results: Cell viability results indicate that the newly designed compression bioreactor supports cell cultivation in a sterile environment without any contamination. The developed bioreactor software plots the experimental data of dynamic mechanical loading in a long-term manner, as well as stores them for further data processing. Following in vitro uniaxial compression conditioning of 3D in vitro cartilage models, chondrocyte cell migration was altered positively compared to static cultures. (4) Conclusion: The developed compression bioreactor can support the in vitro tissue model cultivation and monitor the experimental information with a low-cost controlling system and via mobile application. The highly customizable mold inside the cultivation chamber is a significant approach to solve the limited customization capability of the traditional bioreactors. Most importantly, the compression bioreactor prevents operator- and system-dependent variability between experiments by enabling a dynamic culture in a large volume for multiple numbers of in vitro tissue constructs. Full article
(This article belongs to the Special Issue Bioreactor System: Design, Modeling and Continuous Production Process)
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Article
Novel Strategy for the Calorimetry-Based Control of Fed-Batch Cultivations of Saccharomyces cerevisiae
Processes 2021, 9(4), 723; https://0-doi-org.brum.beds.ac.uk/10.3390/pr9040723 - 20 Apr 2021
Viewed by 638
Abstract
Typical controllers for fed-batch cultivations are based on the estimation and control of the specific growth rate in real time. Biocalorimetry allows one to measure a heat signal proportional to the substrate consumed by cells. The derivative of this heat signal is usually [...] Read more.
Typical controllers for fed-batch cultivations are based on the estimation and control of the specific growth rate in real time. Biocalorimetry allows one to measure a heat signal proportional to the substrate consumed by cells. The derivative of this heat signal is usually used to evaluate the specific growth rate, introducing noise to the resulting estimate. To avoid this, this study investigated a novel controller based directly on the heat signal. Time trajectories of the heat signal setpoint were modelled for different specific growth rates, and the controller was set to follow this dynamic setpoint. The developed controller successfully followed the setpoint during aerobic cultivations of Saccharomyces cerevisiae, preventing the Crabtree effect by maintaining low glucose concentrations. With this new method, fed-batch cultivations of S. cerevisiae could be reliably controlled at specific growth rates between 0.075 h−1 and 0.20 h−1, with average root mean square errors of 15 ± 3%. Full article
(This article belongs to the Special Issue Bioreactor System: Design, Modeling and Continuous Production Process)
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Article
A Bioreactor Designed for Restricting Oversize of Aerobic Granular Sludge
Processes 2021, 9(2), 374; https://0-doi-org.brum.beds.ac.uk/10.3390/pr9020374 - 18 Feb 2021
Viewed by 1187
Abstract
Aerobic granular sludge (AGS) with oversized diameter commonly affects its stability and pollutant removal. In order to effectively restrict the particle size of AGS, a sequencing batch reactor (SBR) with a spiny aeration device was put forward. A conventional SBR (R1) and an [...] Read more.
Aerobic granular sludge (AGS) with oversized diameter commonly affects its stability and pollutant removal. In order to effectively restrict the particle size of AGS, a sequencing batch reactor (SBR) with a spiny aeration device was put forward. A conventional SBR (R1) and an SBR (R2) with the spiny aeration device treating tannery wastewater were compared in the laboratory. The result indicates that the size of the granular sludge from R2 was smaller than that from R1 with sludge granulation. The spines and air bubbles could effectively restrict the particle size of AGS by collision and abrasion. Nevertheless, there was no significant change in mixed liquor suspended solids (MLSS) and the sludge volume index (SVI) in either bioreactors. The removal (%) of chemical oxygen demand (COD) and ammonia nitrogen (NH4+-N) in these two bioreactors did not differ from each other greatly. The analysis of biological composition displays that the proportion of Proteobacteria decreased slightly in R2. The X-ray fluorescence (XRF) analysis revealed less accumulation of Fe and Ca in smaller granules. Furthermore, a pilot-scale SBR with a spiny aeration device was successfully utilized to restrict the diameter of granules at about 300 μm. Full article
(This article belongs to the Special Issue Bioreactor System: Design, Modeling and Continuous Production Process)
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Article
Batch Syngas Fermentation by Clostridium carboxidivorans for Production of Acids and Alcohols
Processes 2020, 8(9), 1075; https://0-doi-org.brum.beds.ac.uk/10.3390/pr8091075 - 01 Sep 2020
Cited by 5 | Viewed by 1118
Abstract
Syngas (CO, CO2, and H2) has attracted special attention due to the double benefit of syngas fermentation for carbon sequestration (pollution reduction), while generating energy. Syngas can be either produced by gasification of biomasses or as a by-product of [...] Read more.
Syngas (CO, CO2, and H2) has attracted special attention due to the double benefit of syngas fermentation for carbon sequestration (pollution reduction), while generating energy. Syngas can be either produced by gasification of biomasses or as a by-product of industrial processes. Only few microorganisms, mainly clostridia, were identified as capable of using syngas as a substrate to produce medium chain acids, or alcohols (such as butyric acid, butanol, hexanoic acid, and hexanol). Since CO plays a critical role in the availability of reducing equivalents and carbon conversion, this work assessed the effects of constant CO partial pressure (PCO), ranging from 0.5 to 2.5 atm, on cell growth, acid production, and solvent production, using Clostridium carboxidivorans. Moreover, this work focused on the effect of the liquid to gas volume ratio (VL/VG) on fermentation performances; in particular, two VL/VG were considered (0.28 and 0.92). The main results included—(a) PCO affected the growth kinetics of the microorganism; indeed, C. carboxidivorans growth rate was characterized by CO inhibition within the investigated range of CO concentration, and the optimal PCO was 1.1 atm (corresponding to a dissolved CO concentration of about 25 mg/L) for both VL/VG used; (b) growth differences were observed when the gas-to-liquid volume ratio changed; mass transport phenomena did not control the CO uptake for VL/VG = 0.28; on the contrary, the experimental CO depletion rate was about equal to the transport rate in the case of VL/VG = 0.92. Full article
(This article belongs to the Special Issue Bioreactor System: Design, Modeling and Continuous Production Process)
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Article
Propagation and Molecular Characterization of Fowl Adenovirus Serotype 8b Isolates in Chicken Embryo Liver Cells Adapted on Cytodex™ 1 Microcarrier Using Stirred Tank Bioreactor
Processes 2020, 8(9), 1065; https://0-doi-org.brum.beds.ac.uk/10.3390/pr8091065 - 01 Sep 2020
Cited by 1 | Viewed by 802
Abstract
Large volume production of vaccine virus is essential for prevention and control of viral diseases. The objectives of this study were to propagate Fowl adenovirus (FAdV) isolate (UPM08136) in chicken embryo liver (CEL) cells adapted to Cytodex™ 1 microcarriers using stirred tank bioreactor [...] Read more.
Large volume production of vaccine virus is essential for prevention and control of viral diseases. The objectives of this study were to propagate Fowl adenovirus (FAdV) isolate (UPM08136) in chicken embryo liver (CEL) cells adapted to Cytodex™ 1 microcarriers using stirred tank bioreactor (STB) and molecularly characterize the virus. CEL cells were prepared and seeded onto prepared Cytodex™ 1 microcarriers and incubated first in stationary phase for 3 h and in STB at 37 °C, 5% CO2, and 20 rpm for 24 h. The CEL cells were infected with FAdV isolate (UPM08136) passage 5 (UPM08136CELP5) or passage 20 (UPM08136CELP20) and monitored until cell detachment. Immunofluorescence, TCID50, sequencing, alignment of hexon and fiber genes, and phylogenetic analysis were carried out. CEL cells were adapted well to Cytodex™ 1 microcarriers and successfully propagated the FAdV isolates in STB with virus titer of 107.5 (UPM08136CELP5B1) and 106.5 (UPM08136CELP20B1) TCID50/mL. These isolates clustered with the reference FAdV serotype 8b in the same evolutionary clade. The molecular characteristics remained unchanged, except for a point substitution at position 4 of the hexon gene of UPM08136CELP20B1, suggesting that propagation of the FAdV isolate in STB is stable and suitable for large volume production and could be a breakthrough in the scale-up process. Full article
(This article belongs to the Special Issue Bioreactor System: Design, Modeling and Continuous Production Process)
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Article
Bio-Methane Production via Anaerobic Co-Digestion by Optimizing the Mixing Ratios of River Tamarind (Leucaena leucocephala) and Dolphin Fish (Coryphaena hippurus) Offal
Processes 2020, 8(8), 934; https://0-doi-org.brum.beds.ac.uk/10.3390/pr8080934 - 03 Aug 2020
Cited by 2 | Viewed by 858
Abstract
Fish offal and other high protein substrates are generally not suitable for anaerobic digestion because of the high levels of ammonia produced as a result of their biodegradation. In order to efficiently use these types of substrates to produce methane, co-digestion is used [...] Read more.
Fish offal and other high protein substrates are generally not suitable for anaerobic digestion because of the high levels of ammonia produced as a result of their biodegradation. In order to efficiently use these types of substrates to produce methane, co-digestion is used to balance the amounts of carbon and nitrogen in the feedstock. In this experiment an optimization procedure for maximizing the methane potential of fish offal, using river tamarind as the co-substrates was developed. Our experimental design tested the effects of substrate to substrate mixtures, as well as overall substrate to inoculum combinations, on the methane potentials. This was performed using batch style biochemical methane potential assays, which employed a methodology developed in our laboratory. The optimum of the 25 combinations tested was 50% fish offal to 50% river tamarind at a substrate to inoculum ratio of 0.03, with a specific methane yield of 144 ± 6 NmL/gFM (330 ± 14 NmL/goDM). This gave much improvement when compared with the fish offal alone, which reached 63 ± 4 NmL/gFM (317 ± 20 NmL/goDM) at maximum. These results indicate that with the correct mixture, rivertamarind is a suitable co-substrate for anaerobic co-digestion of fish offal. Full article
(This article belongs to the Special Issue Bioreactor System: Design, Modeling and Continuous Production Process)
Article
CFD and Experimental Characterization of a Bioreactor: Analysis via Power Curve, Flow Patterns and k L a
Processes 2020, 8(7), 878; https://0-doi-org.brum.beds.ac.uk/10.3390/pr8070878 - 20 Jul 2020
Cited by 1 | Viewed by 1701
Abstract
Mixing operations in biological processes is of utmost importance due to its effect on scaling-up and heat and mass transfer. This paper presents the characterization of a bench-top bioreactor with different impeller configurations, agitation and oxygen transfer rates, using CFD simulations and experimental [...] Read more.
Mixing operations in biological processes is of utmost importance due to its effect on scaling-up and heat and mass transfer. This paper presents the characterization of a bench-top bioreactor with different impeller configurations, agitation and oxygen transfer rates, using CFD simulations and experimental procedures. Here, it is demonstrated that factors such as the type of impeller and the flow regime can drastically vary the operation as in the preparation of cultures. It was observed that the bioreactor equipped with a Rushton generates a k L a of 0.0056 s−1 for an agitation velocity and airflow rate of 250 RPM and 5 L/min, respectively. It is suitable result for the dissolved oxygen (DO) but requires a considerable amount of power consumption. It is here where the importance of the agitator’s diameter can be observed, since, in the case of the two propeller types studied, lower energy consumption can be achieved with a smaller diameter, as well as a much smaller shear cup 2.376 against 0.723 s−1 by decreasing by 4 cm the standard diameter of an agitated tank (10 cm). Finally, the k L a values obtained for the different configurations are compared with the maximum shear rate values of different cell cultures to highlight the impact of this study and its applicability to different industries that use agitation processes for cell growth. Full article
(This article belongs to the Special Issue Bioreactor System: Design, Modeling and Continuous Production Process)
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Article
Self-Synchronized Oscillatory Metabolism of Clostridium pasteurianum in Continuous Culture
Processes 2020, 8(2), 137; https://0-doi-org.brum.beds.ac.uk/10.3390/pr8020137 - 21 Jan 2020
Cited by 2 | Viewed by 1064
Abstract
By monitoring the real-time gas production (CO2 and H2) and redox potential at high sampling frequency in continuous culture of Clostridium pasteurianum on glycerol as sole carbohydrate, the self-synchronized oscillatory metabolism was revealed and studied. The oscillations in CO2 [...] Read more.
By monitoring the real-time gas production (CO2 and H2) and redox potential at high sampling frequency in continuous culture of Clostridium pasteurianum on glycerol as sole carbohydrate, the self-synchronized oscillatory metabolism was revealed and studied. The oscillations in CO2 and H2 production were in sync with each other and with both redox potential and glycerol in the continuous stirred tank reactor (CSTR). There is strong evidence that the mechanism for this is in the regulation of the oxidative pathway of glycerol metabolism, including glycolysis, and points toward complex, concerted cycles of enzyme inhibition and activation by pathway intermediates and/or redox equivalents. The importance of understanding such an “oscillatory metabolism” is for developing a stable and highly productive industrial fermentation process for butanol production, as unstable oscillations are unproductive. It is shown that the oscillatory metabolism can be eradicated and reinstated and that the period of oscillations can be altered by modification of the operating parameters. Synchronized oscillatory metabolism impacted the product profile such that it lowered the selectivity for butanol and increased the selectivity for ethanol. This elucidates a possible cause for the variability in the product profile of C. pasteurianum that has been reported in many previous studies. Full article
(This article belongs to the Special Issue Bioreactor System: Design, Modeling and Continuous Production Process)
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Review

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Review
Cell Factories for Industrial Production Processes: Current Issues and Emerging Solutions
Processes 2020, 8(7), 768; https://0-doi-org.brum.beds.ac.uk/10.3390/pr8070768 - 30 Jun 2020
Cited by 7 | Viewed by 1790
Abstract
Despite all the progresses made by metabolic engineering, still only a few biotechnological processes are running at an industrial level. In order to boost the biotechnological sector, integration strategies as well as long-term views are needed. The aim of the present review is [...] Read more.
Despite all the progresses made by metabolic engineering, still only a few biotechnological processes are running at an industrial level. In order to boost the biotechnological sector, integration strategies as well as long-term views are needed. The aim of the present review is to identify the main drawbacks in biotechnological processes, and to propose possible solutions to overcome the issues in question. Novel cell factories and bioreactor design are discussed as possible solutions. In particular, the following microorganisms: Yarrowia lipolytica, Trichosporon oleaginosus, Ustilago cynodontis, Debaryomyces hansenii along with sequential bioreactor configurations are presented as possible cell factories and bioreactor design solutions, respectively. Full article
(This article belongs to the Special Issue Bioreactor System: Design, Modeling and Continuous Production Process)
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Review
Industrial Production of Poly-β-hydroxybutyrate from CO2: Can Cyanobacteria Meet this Challenge?
Processes 2020, 8(3), 323; https://0-doi-org.brum.beds.ac.uk/10.3390/pr8030323 - 10 Mar 2020
Cited by 16 | Viewed by 2167
Abstract
The increasing impact of plastic materials on the environment is a growing global concern. In regards to this circumstance, it is a major challenge to find new sources for the production of bioplastics. Poly-β-hydroxybutyrate (PHB) is characterized by interesting features that draw attention [...] Read more.
The increasing impact of plastic materials on the environment is a growing global concern. In regards to this circumstance, it is a major challenge to find new sources for the production of bioplastics. Poly-β-hydroxybutyrate (PHB) is characterized by interesting features that draw attention for research and commercial ventures. Indeed, PHB is eco-friendly, biodegradable, and biocompatible. Bacterial fermentation processes are a known route to produce PHB. However, the production of PHB through the chemoheterotrophic bacterial system is very expensive due to the high costs of the carbon source for the growth of the organism. On the contrary, the production of PHB through the photoautotrophic cyanobacterium system is considered an attractive alternative for a low-cost PHB production because of the inexpensive feedstock (CO2 and light). This paper regards the evaluation of four independent strategies to improve the PHB production by cyanobacteria: (i) the design of the medium; (ii) the genetic engineering to improve the PHB accumulation; (iii) the development of robust models as a tool to identify the bottleneck(s) of the PHB production to maximize the production; and (iv) the continuous operation mode in a photobioreactor for PHB production. The synergic effect of these strategies could address the design of the optimal PHB production process by cyanobacteria. A further limitation for the commercial production of PHB via the biotechnological route are the high costs related to the recovery of PHB granules. Therefore, a further challenge is to select a low-cost and environmentally friendly process to recover PHB from cyanobacteria. Full article
(This article belongs to the Special Issue Bioreactor System: Design, Modeling and Continuous Production Process)
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