Applied Bioengineering E-Book
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- Herausgeber: Wiley-VCH Verlag GmbH & Co. KGaA
- Kategorie: Fachliteratur
- Serie: Advanced Biotechnology
- Sprache: Englisch
A comprehensive overview of the topic, highlighting recent developments, ongoing research trends and future directions.
Experts from Europe, Asia and the US cover five core areas of imminent importance to the food, feed, pharmaceutical and water treatment industries in terms of sustainable and innovative processing and production. In the field of enzyme engineering, they summarize historic developments and provide an overview of molecular enzyme engineering, while also discussing key principles of microbial process engineering, including chapters on process development and control. Further sections deal with animal and plant cell culture engineering. The final section of the book deals with environmental topics and highlights the application of bioengineering principles in waste treatment and the recovery of valuable resources.
With its cutting-edge visions, extensive discussions and unique perspectives, this is a ready reference for biotechnologists, bioengineers, bioengineers, biotechnological institutes, and environmental chemists.
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Veröffentlichungsjahr: 2017
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Table of Contents
Cover
Related Titles
Title Page
Copyright
List of Contributors
1: Introduction
1.1 Introduction
1.2 Enzyme Technology
1.3 Microbial Process Engineering
1.4 Plant Cell Culture
1.5 Animal Cell Culture
1.6 Environmental Bioengineering
1.7 Composition of the Volume
References
Part I: Enzyme Technology
2: Enzyme Technology: History and Current Trends
2.1 The Early Period up to 1890
2.2 The Period from 1890 to 1940
2.3 A New Biocatalyst Concept – Immobilized Enzymes
2.4 Expanding Enzyme Application after the 1950s
2.5 Recombinant Technology – A New Era in Biocatalysis and Enzyme Technology
2.6 Current Strategies for Biocatalyst Search and Tailor Design
2.7 Summary and Conclusions
Acknowledgment
Abbreviations
References
3: Molecular Engineering of Enzymes
3.1 Introduction
3.2 Protein Engineering: An Expanding Toolbox
3.3 High-Throughput Screening Systems
3.4 Engineered Enzymes for Improved Stability and Asymmetric Catalysis
3.5
De Novo
Design of Catalysts: Novel Activities within Common Scaffolds
3.6 Conclusions
References
4: Biocatalytic Process Development
4.1 A Structured Approach to Biocatalytic Process Development
4.2 Process Metrics
4.3 Technologies for Implementation of Biocatalytic Processes
4.4 Industrial Development Examples
4.5 Future Outlook
4.6 Concluding Remarks
References
5: Development of Enzymatic Reactions in Miniaturized Reactors
5.1 Introduction
5.2 Fundamental Techniques for Enzyme Immobilization
5.3 Novel Techniques for Enzyme Immobilization
5.4 Conclusions and Future Perspectives
Abbreviations
References
Part II: Microbial Process Engineering
6: Bioreactor Development and Process Analytical Technology
6.1 Introduction
6.2 Bioreactor Development
6.3 Monitoring and Process Analytical Technology
6.4 Conclusion
Abbreviations
References
7: Omics-Integrated Approach for Metabolic State Analysis of Microbial Processes
7.1 General Introduction
7.2 Transcriptome Analysis of Microbial Status in Bioprocesses
7.3 Analysis of Metabolic State Based on Simulation in a Genome-Scale Model
7.4
13
C-Based Metabolic Flux Analysis of Microbial Processes
7.5 Comprehensive Phenotypic Analysis of Genes Associated with Stress Tolerance
7.6 Multi-Omics Analysis and Data Integration
7.7 Future Aspects for Developing the Field
Acknowledgments
References
8: Control of Microbial Processes
8.1 Introduction
8.2 Monitoring
8.3 Bioprocess Control
8.4 Recent Trends in Monitoring and Control Technologies
8.5 Concluding Remarks
Abbreviations
References
Part III: Plant Cell Culture and Engineering
9: Contained Molecular Farming Using Plant Cell and Tissue Cultures
9.1 Molecular Farming – Whole Plants and Cell/Tissue Cultures
9.2 Plant Cell and Tissue Culture Platforms
9.3 Comparison of Whole Plants and
In Vitro
Culture Platforms
9.4 Technical Advances on the Road to Commercialization
9.5 Regulatory and Industry Barriers on the Road to Commercialization
9.6 Outlook
Acknowledgments
References
10: Bioprocess Engineering of Plant Cell Suspension Cultures
10.1 Introduction
10.2 Culture Development and Maintenance
10.3 Choice of Culture System
10.4 Engineering Considerations
10.5 Bioprocess Parameters
10.6 Operational Modes
10.7 Bioreactors for Plant Cell Suspensions
10.8 Downstream Processing
10.9 Yield Improvement Strategies
10.10 Case Studies
10.11 Conclusion
References
11: The Role of Bacteria in Phytoremediation
11.1 The Problem
11.2 Defining Phytoremediation and Its Components
11.3 Role of Bacteria in Phytoremediation
11.4 Examples of Phytoremediation in Action
11.5 Summary and Perspectives
References
Part IV: Animal Cell Cultures
12: Cell Line Development for Biomanufacturing Processes
12.1 Introduction
12.2 Host Cell
12.3 Vector Components
12.4 Transfection
12.5 Integration of Foreign DNA into Host Chromosome
12.6 Amplification
12.7 Single-Cell Cloning
12.8 Selecting the Production Clone
12.9 Clone Stability
12.10 Conclusion
Acknowledgments
References
13: Medium Design, Culture Management, and the PAT Initiative
13.1 Historical Perspective on Culture Medium
13.2 Cell Growth Environment
13.3 Media Types
13.4 Medium Components
13.5 High Molecular Weight and Complex Supplements
13.6 Medium for Industrial Production
13.7 Conclusions
References
Further Reading/Resources
14: Advanced Bioprocess Engineering: Fed-Batch and Perfusion Processes
14.1 Primary Modes of Bioreactor Operation
14.2 Fed-Batch Mode of Operation
14.3 Perfusion Mode of Bioreactor Operation
14.4 Use of Disposables in Cell Culture Bioprocesses
14.5 Analytical Methods to Monitor Key Metabolites and Parameters
14.6 Concluding Remarks
References
Further Reading/Resources
Part V: Environmental Bioengineering
15: Treatment of Industrial and Municipal Wastewater: An Overview about Basic and Advanced Concepts
15.1 Types of Wastewater
15.2 Biological Treatment
15.3 Wastewater Regulations
15.4 Biological Treatment Processes
15.5 Aerobic Techniques
15.6 Anaerobic Techniques
15.7 Aerobic–Anaerobic Processes
15.8 Modified Biological Processes
15.9 Overall Conclusions
List of Acronyms/Abbreviations
References
16: Treatment of Solid Waste
16.1 Biological Treatment of Source Segregated Bio-Waste
16.2 Mechanical–Biological Treatment of Mixed Municipal Solid Waste
16.3 Biological Treatment of Agricultural Waste
16.4 Conclusion
References
17: Energy Recovery from Organic Waste
17.1 Advantage of Methane Fermentation for Energy Recovery from Organic Matter
17.2 Basic Knowledge of Methane Fermentation of Organic Wastes
17.3 Conventional Methane Fermentation Process
17.4 Advanced Methane Fermentation Processes
17.5 Hydrogen Production from Organic Wastes
17.6 Upgrading of Biogas from Organic Wastes Based on Biological Syngas Platform
17.7 Conclusions
References
18: Microbial Removal and Recovery of Metals from Wastewater
18.1 Microbial Reactions Available for Metal Removal/Recovery
18.2 Selenium Recovery by
Pseudomonas stutzeri
NT-I
18.3 Future Prospects
18.4 Conclusions
References
19: Sustainable Use of Phosphorus Through Bio-Based Recycling
19.1 Introduction
19.2 Microbiological Basis
19.3 Bio-Based P Recycling
19.4 Other Options for P Recycling
19.5 Conclusions
References
Index
End User License Agreement
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Guide
Table of Contents
Part I
Begin Reading
List of Illustrations
2: Enzyme Technology: History and Current Trends
Figure 2.1 Process for dextrin production, with reaction vessel for starch hydrolysis (a), filtration unit (b), reservoir for intermediate storage (c), concentration unit where water is evaporated to give a concentrated syrup of dextrin solution (d) [11].
Figure 2.2 Acetic acid fermentation using immobilized bacteria. The vessel was equipped with sieve plates in positions D and B. Space A was filled with beech wood chips (on which the bacteria were immobilized). A 6–10% alcohol solution was added from the top to a solution containing 20% acetic acid and beer (containing nutrients). Air for oxidation was introduced through holes in a position above B, and the temperature was maintained at 20–25 °C. The product containing 4–10% acetic acid was continuously removed via position E [15].
Scheme 2.1 Enzymatic and chemical production of semisynthetic penicillins and cephalosporins from the hydrolysis products (6-APA, 7-ACA, 7-ADCA) of β-lactam antibiotics. The by-products phenylacetate and adipate can be recycled in the fermentations. The amounts produced are estimated from literature data [45].
Figure 2.3 Market for enzymes used as biocatalysts for different purposes 2010 (a), and the increase in the application of enzymes reflected in the number of employees in the industry producing enzymes for biocatalytic purposes and their worldwide sales since 1970 (b). Number of Novozymes employees that has about 50% of the world market for such enzymes (squares) and value of their worldwide sales (filled circles) are shown (Novozymes yearly reports, last one from 2010). The value of the world production of technical enzymes is much larger than shown in (a), as many companies that use enzymes as biocatalysts produce them in-house in order to have a safe and stable enzyme supply and/or protect their proprietary knowledge.
Scheme 2.2 An engineered amine transaminase could replace the earlier chemical process in the large-scale production of the drug sitagliptin [102, 103].
Scheme 2.3 An enzyme cascade reaction to convert unsaturated fatty acids such as oleic acid into ω-hydroxycarboxylic acids or dicarboxylic acids. Cofactors are not shown for clarity [111, 112].
Scheme 2.4 Enzyme cascade reactions to afford
ε
-caprolactone oligomers (top right, [115]) or 6-amino-hexanoic acid (bottom right, [116]), a Nylon 6 precursor, starting from cyclohexanol. In all cases, the required enzymes were recombinantly expressed in
E. coli
and whole cell extracts or lyophilized cells were used. ADH: alcohol dehydrogenase, CHMO: cyclohexanone monooxygenase, CAL-A: lipase A from
C. antarctica
, HLE: horse liver esterase, ATA: amine transaminase.
Scheme 2.5 Artemisinic acid (box) production pathway in an engineered
S. cerevisiae
strain [123]. The last step to the final product artemisinin is performed chemically. IPP, isopentyl diphosphate; DMAPP, dimethylallyl diphosphate; FPP, farnesyl diphosphate.
3: Molecular Engineering of Enzymes
Figure 3.1 The CASCO approach for designing enantioselective enzymes. Two rounds of
in silico
screening HTMI-MD simulations are included to reduce the occurrence of variants with low-energy structures that allow undesired substrate orientations (see also [76]).
Figure 3.2 Directed evolution in biomimetic gel-shell beads (GSBs). Single
E. coli
cells expressing the phosphotriesterase (a) are trapped into water-in-oil emulsion droplets that contain the phosphotriesterase substrate and a lysis agent (b). The enzyme reacts (if active) with the substrate at 30 °C, releasing a fluorescent product (c). After de-emulsification, the GBSs are formed retaining the enzyme, its encoding plasmid, and the reaction product (d). GBSs are sorted by fluorescence based on the variants' activity (e), and the phosphotriesterase encoding plasmid is recovered after removal of the polyelectrolyte shell by raising the pH (f). Isolated variants are characterized or subjected to further rounds of evolution.
Figure 3.3 CalB residues selected for iterative saturation mutagenesis (ISM).
Scheme 3.1 (a) P450-BM3 hydroxylation of cyclohexene-1-carboxylic acid methyl ester. (b) P450pyr hydroxylation of
N
-benzyl pyrrolidine. (c) P450pyr regio- and enantio-selective subterminal hydroxylation of alkanes. (d) P450-BM3 (A74G/L188Q) llylic hydroxylation of ω-alkenoic acids and esters.
Figure 3.4 General scheme for computational enzyme design using Rosetta. (a) A target reaction and its reaction mechanism are chosen; (b) key intermediates and the transition state (TS) are modeled in the context of a given binding pocket; (c) models are overlaid based on the protein functional group positions to create an idealized active site that can accommodate each state (namely substrates, TS and product); (d) active site models (theozymes) are computed with catalytic residues placed around the optimal geometry for the composite TS. Large ensembles of different conformations of these composite active sites are generated by varying the degrees of freedom of the composite TS, the orientation of the catalytic side chains regarding the composite TS, and the internal conformation of the catalytic side chains; (e) protein backbone positions able to hold such an idealized active site are searched among high-resolution crystal structures with ligand-binding pockets. Matches are optimized, including neighbor residues shaping the binding pocket; (f) best ranked designs are chosen for experimental validation [171, 172, 178, 179].
Scheme 3.2 Kemp elimination.
Scheme 3.3 Retro-aldol reaction. The retro-aldol reaction is initiated by a nucleophilic lysine, which forms with the substrate
16
a covalent enzyme–substrate imine complex. Fragmentation is followed by deprotonation of the hydroxyl group with a base, and the imine is then hydrolyzed to yield
17
.
Scheme 3.4 Diels–Alder reaction. Diene (
18
) and dienophile (
19
) undergo a pericyclic [4 + 2] cycloaddition to form a chiral cyclohexene ring (
20
).
Scheme 3.5 Chemical structures of the G-type nerve agents.
4: Biocatalytic Process Development
Figure 4.1 General biocatalytic process using (immobilized) enzymes for the production of chemicals.
Figure 4.2 Proposed methodology for the systematic development of biocatalytic processes.
Figure 4.3 Concept for ISPR in a biocatalytic process with recycle stream.
Scheme 4.1 Biocatalytic synthesis of atorvastatin.
Scheme 4.2 Biocatalytic synthesis of sitagliptin.
5: Development of Enzymatic Reactions in Miniaturized Reactors
Figure 5.1 Enzyme immobilization techniques.
Figure 5.2 (a) Schematic representation of the double microreactor μPAD. The Figure shows an eight-channel double microreactor μPAD. Diaphorase (DI), lactate dehydrogenase (LDH), and the sample are spotted on the μPAD prior to analysis. (b) Photograph of the double microreactor μPAD using a range (0.0, 0.5, 0.8, 1.2, 1.6, and 2.0 mM) of concentrations of resazurin. Running buffer is 0.2 mM Tris at pH 7.4. (From [30] with permission ©2008 American Chemical Society.)
Figure 5.3 Schematic representation of the immobilized capillary enzyme reactor prepared by the layer-by-layer assembly. (From [16] with permission ©2013 Elsevier.)
Figure 5.4 Process of functional PMMA surface modification followed by enzyme immobilization using silica sol-gel entrapment. (From [41] with permission ©2004 American Chemical Society.)
Figure 5.5 Process of forming enzyme-encapsulated sol–gel inside microchannel of PDMS functionalized by oxidation in oxygen plasma. (From [44] with permission ©2004 American Chemical Society.)
Figure 5.6 SEM images of bulk freeze-dried foams. (a) Specimen prepared in copper sample holder, slow cooling. (b) Copper sample holder, rapid cooling. (c) PTFE sample holder, slow cooling. (d) PTFE sample holder, rapid cooling. (From [54] with permission ©2014 Elsevier B.V.)
Figure 5.7 Schematic diagram of the photoimmobilization process. Enzyme patches are formed on the top and bottom of a microchannel using the following procedure. (1) Passivation of the surface with a fibrinogen monolayer is followed by (2) biotin-4-fluorescein surface attachment. This is accomplished by photobleaching with 488-nm laser light. (3) Next, the binding of streptavidin-linked enzymes can be exploited to immobilize catalysts and (4) to monitor reaction processes on-chip. (From [64] with permission ©2004, American Chemical Society.)
Figure 5.8 Scheme for the preparation of enzyme reactors with two proteases. (a) Empty Teflon-coated capillary (100 µm id/365 µm od). (b) Fabrication of the monolith column. (c) One section of monolith photografted with glycidyl methacrylate (GMA) by masking the other section during exposure. (d) Trypsin immobilized onto the GMA grafted monolith. (e) The second section of monolith photografted with GMA. (f) V-8 protease (Glu-C) immobilized onto the second GMA grafted monolith. (From [106] with permission ©2009, John Wiley and Sons.)
Figure 5.9 Scheme of β-galactosidase immobilization on a microchannel surface. (a) Glutaraldehyde (GA)-microreactor. (b) MWNTs-microreactor. (c) SWNTs-DNA-microreactor. (From [113] with permission ©2012 Elsevier B.V.)
Figure 5.10 Morphology of silicon dioxide nanosprings before (top) and after (bottom) vapor-phase silanization with APTES. (From [97] with permission ©2010 John Wiley and Sons.)
Figure 5.11 Functional silanization techniques.
Figure 5.12 (a) Schematic setup of the flow-through silica microstructured optical fiber (SMOF) microreactor. (b) SEM image of a cross-section of the SMOF microreactor. (c) Micrograph of the SMOF microreactor. (From [80] with permission ©2010 Elsevier B.V.)
Figure 5.13 Preparation of enzyme-membrane on the inner wall of a PTFE tube. (a) Enzyme and aldehyde solutions were each charged into a 1-ml syringe, and the solutions were supplied to a PTFE tube using a syringe pump. (b) Cylindrical enzyme-membrane (dry state) exposed from PTFE tube, which forms on the inner wall of the tube. (c) Possible mechanism of polymerization process of enzyme and cross-linker reagent in a microchannel. (From [121] with permission ©2005 Royal Society of Chemistry.)
Figure 5.14 Schematic illustration of the procedure used to prepare an acylase-CEM (top). The cross-linking polymerization was performed in a concentric laminar flow. A silica capillary was fitted to the outer diameter of the T-shaped connector by attaching to a PTFE tube using heat-shrink tubing. The capillary was set in the connector located at the concentric position of the CEM tube. The cross-linker solution was supplied to the substrate PTFE tube through the silica capillary, corresponding to a central stream in the concentric laminar flow. A solution of acylase-poly-Lys mixture was poured from the other inlet of the T-shaped connector, and formed an outer stream of the laminar flow. Charge-coupled device (CCD) images (bottom) of cylindrical enzyme-membrane (dry state) exposed from the PTFE tube, which forms on the inner wall of the tube and a sectional view of the obtained CEM. (From [122] with permission ©2006, John Wiley and Sons.)
Scheme 5.1 Simultaneous esterification and peptide synthesis using a two-enzyme, one-pot approach.
Scheme 5.2 Synthesis of
L
-DOPA from
L
-tyrosine by tyrosinase-CLEA.
Scheme 5.3 Synthesis of CAPE using lipase-catalyzed esterification of caffeic acid and 2-phenylethanol.
6: Bioreactor Development and Process Analytical Technology
Figure 6.1 Development of micro-/miniature bioreactors in parallel use for high-throughput processing.
Figure 6.2 Measurement principle of the microtiter plate fermentation via back scattering of light from cells and fluorescence emission of molecules in a microtiter plate platform.
Figure 6.3 Micro-bioreactor array and agitation scheme. The bubbles comprising the headspace traverse the perimeter of each reactor as the array is rotated at 20 rpm. CFD calculations predict that the average shear stress on cells ranges from 0.11 to 0.34 dyne cm
−2
.
Figure 6.4 Cuvette-based micro-bioreactor. At the left wall, blue and UV LEDs with 530 nm photodetector are used to measure pH; at the right wall, blue LED, oxygen sensing patch, and a 590-nm photodetector are used to measure DO; red LED and 600-nm photodetector are used to measure OD through the front and back wall.
Figure 6.5 Microbioreactor built of three layers of PDMS on top of a layer of glass. (a) Solid model drawn to scale. (b) Photograph of microbioreactor at the end of a run.
Figure 6.6 Bioreactor monitoring systems advancing toward the automation for real-time information acquisition. (1) Manual sampling and analysis in a separated chemical laboratory, (2) at-line monitoring with manual sampling, (3) iline monitoring with continuous sampling, (4) inline monitoring in a culture circulation path, and (5) online monitoring with an invasive probe, and (6) online monitoring with a noninvasive probe through a window or indirect detection.
7: Omics-Integrated Approach for Metabolic State Analysis of Microbial Processes
Figure 7.1 Schematic of the integration method, with
in silico
and experimental approaches, for the creation of cell factories.
Figure 7.2 Typical patterns of gene expression among 29 clusters. Each chart (i–iii) indicates the expression pattern of genes in individual clusters. The horizontal axes indicate time points of the data, and vertical axes indicate log
2
expression ratios. The left panel represents the gene expression pattern of the laboratory strain, and the right panel represents that of the brewing strain. In each chart, the distance between the two red lines represents a twofold expression change. (i) The genes significantly expressed only in the brewing strain (Cluster 10). (ii) The genes expressed in both laboratory and brewing strains following the addition of ethanol; the expression ratios of these genes were higher in the brewing strain than in the laboratory strain (Cluster 27). (iii) Genes were significantly expressed more in the laboratory strain than in the brewing strain (Cluster 7).
Figure 7.3 Experimental evolution of
E. coli
under 5% ethanol stress condition. (a) The time course of specific growth rates in six parallel evolution experiments. The cells obtained after 2500 h of cultivation under ethanol stress were named “strain A–strain F,” in descending order corresponding to the final growth rate. (b) PCA score plot of the first and second principle components (PC1 and PC2). P0 and A0–F0 represent the expression profiles of strain P (parental strain) and tolerant strains A–F, respectively, obtained without addition of ethanol. P5 and A5–F5 indicate data obtained in the 5% ethanol condition.
Figure 7.4 Schematic representation of the constraint-based flux balance analysis. The axes represent metabolic fluxes. (a) By applying the steady-state assumption, we obtained the feasible solution space. (b) When the biomass production flux was used for the objective function, optimal solutions that maximize the objective function could be calculated by linear programming (LP).
Figure 7.5 Changes in yield of organic acids, biomass, and carbon dioxide when the OUR/GUR ratio was altered. (a) Experimental results obtained from different OUR/GUR ratios. GUR, OUR, and the production rates of CO
2
, lactate, acetate, succinate, and biomass are represented in mmol gDW
−1
h
−1
. (b) Predictions by FBA simulations. The simulation results were obtained using the GUR and OUR values from the experimental data. (c) A scatter plot of carbon yield. The
x
-axis corresponds to the result of FBA simulation, while the
y
-axis shows the experimentally observed carbon yield. The carbon yield in five sets of experimental and simulation results are presented. The diagonal line corresponds to
y
=
x
.
Figure 7.6 Overview of flux estimation using
13
C-metabolic flux analysis.
Figure 7.7 In
C. glutamicum
, metabolic fluxes in growth and production phases of two different glutamate production activities. Dotted arrows indicate fluxes for biomass. Left, middle, and right values in boxes indicate fluxes in the growth phase, low production phase, and high production phase, respectively, of two different activities caused by two levels of Tween 40 addition, where glutamate fluxes were 0, 20, and 68, respectively. In this study, the fluxes with backward (exchange) reactions, that is, those in glycolysis, the pentose phosphate pathway, the latter steps of the TCA cycle (succinate to oxaloacetate), and C1 metabolisms, are shown as net values. Abbreviations: Gly, glycine; Ser, serine; Glu, glutamate; G6P, glucose-6-phosphate; F6P, fructose-6-phosphate; FBP, fructose-1,6-bisphosphate; GAP, glyceraldehyde-3-phosphate; PEP, phosphoenolpyruvate; Pyr, pyruvate; Ru5P, ribulose-5-phosphate; R5P, ribose-5-phosphate; Xu5P, xylulose-5-phosphate; S7P, sedoheptulose-7-phosphate; E4P, erythrose-4-phosphate; DHAP, dihydroxyacetone phosphate; PGA, phosphoglycerate; AcCoA, acetyl-CoA; IsoCit, isocitrate; aKG, 2-oxoglutarate; Suc, succinate; Fum, fumarate; Mal, malate; Oxa, oxaloacetate.
Figure 7.8 Sensitivity analysis of ethanol and osmotic stress conditions. Red plots indicate specific growth rate of standard strain; dark blue plots indicate specific growth rate of gene deletion strain, which does not show sensitivity under non-stress condition; light blue plots indicate specific growth rate of gene deletion strain, which shows sensitivity even under non-stress condition. Blue line denotes the threshold value of growth sensitivity under stress conditions, and the red line the threshold value of growth tolerance under stress conditions.
Figure 7.9 Interactions between omics technologies and future aspects for developing the field.
8: Control of Microbial Processes
Figure 8.1 Estimation of specific rates using the extended Kalman filter (EKF).
Figure 8.2 Estimates using a modification of the extended Kalman filter. (a) Cell concentration and specific growth rate. (b) Glucose concentration and specific glucose consumption rate. The bottom sections show the directly calculated values (the differences between the current and the last data).
Figure 8.3 Block diagram for the online optimizing control.
Figure 8.4 Process scheme for the cell recycle system with cross-flow filtration for lactic acid fermentation.
Figure 8.5 Application of the optimizing control to lactic acid fermentation.
Figure 8.6 Concept of microbial interaction control.
Figure 8.7 Schematic diagram of the cascade control in the co-culture system.
Figure 8.8 Experimental result for the cascade control of pH and DO in the co-culture system.
Figure 8.9 Cascade control results of pH and DO in the mixed culture of
L. lactis
and
K. marxianus
. The pH was stabilized at 6.0 by the cascade controller [59].
Figure 8.10 Stability test for uncertainty in inoculum size for cascade control results of pH and DO in the mixed culture [59].
10: Bioprocess Engineering of Plant Cell Suspension Cultures
Figure 10.1 Initiation and propagation of plant cell suspension cultures. Cell image is from [11].
Figure 10.2 Impellers typically used for plant cell suspensions. (a) Rushton turbine, (b) rushton turbine (curved-blade), (c) marine impeller, (d) pitched-blade impeller, (e) Intermig® impeller, (f) helical-ribbon impeller.
Figure 10.3 Disposable bioreactors developed specifically for plant cell suspensions. (a) Slug-Bubble bioreactor. (b) wave and undertow (WU) bioreactor.
Figure 10.4 Disposable pneumatic bioreactors that lie at the center of the ProCellEx® platform. Structures assembled around each reactor provide structurally integrity, allowing for cultivation at 400-l volumes [7].
Figure 10.5 (a) Bioreactor facility at Phyton Biotech® [11]. (b) Paclitaxel (note the 4 rings and 11 chiral centers as well as the 6/8/6-membered ring system common to all taxanes). (c) Cost comparison of different paclitaxel production strategies.
11: The Role of Bacteria in Phytoremediation
Figure 11.1 Categorization of pollutants in the environment.
Figure 11.2 Categorization of nitrogen-fixing microorganisms.
12: Cell Line Development for Biomanufacturing Processes
Figure 12.1 Steps involved in stable cell line development. Options available at each step are described in brief. The amplification step, when implemented, may be carried out either on a bulk selected pool or on expanded single-cell clones, as discussed in text.
14: Advanced Bioprocess Engineering: Fed-Batch and Perfusion Processes
Figure 14.1 Schematic of the different modes of a bioreactor operation.
Figure 14.2 Comparison of the different modes of a bioreactor operation: (a) Growth profile for batch, fed-batch, continuous, and perfusion cultures. For perfusion, cell density data is plotted only till day 16. The culture actually lasts for 2–3 months. (b) Antibody profiles for batch, fed-batch, continuous, and perfusion cultures. For perfusion, data has been shown only till day 13. Note that while titers (mg l
−1
) of antibody are lower in the perfusion culture, cumulative product amounts (mg) are much higher [3].
Figure 14.3 Overview of fed-batch process development.
Figure 14.4 Different modes of feeding. (a) Bolus, (b) continuous, and (c) dynamic.
Figure 14.5 Sedimentation- and filtration-based retention devices for perfusion process. (a) Principle of gravity settlers. (b) Compact inclined settler ([211] with permission from Wiley ©Wiley 2003). (c) Principle of cross-flow filtration. (d) Repligen ATF system [108]. (e) Schematic of ATF system [108]. (f) Schematic of experimental laboratory-scale CSF ([114] with permission from Gesellschaft für Biotechnologische Forschung mbH, Braunschweig, Germany). (g) Schematic of the vortex flow filter [211]. (h) Schematic of a spin filter bioreactor.
Figure 14.6 Centrifugation-based retention devices for perfusion bioreactor. (a) Schematic of separation cycle. (b) Centritech Lab III. (c) Centritech Cell II [212].
Figure 14.7 Hydrocyclones. (a) Sartorius hydroclone [140]. (b) Scheme and working principle of the hydroclone [211].
Figure 14.8 Acoustic settler-based perfusion device. (a) Biosep 10 l. (b) Biosep 200 l. (c) Typical configuration of the 50-l Biosep acoustic cell retention system [213].
Figure 14.9 Schematic of wave bioreactor.
15: Treatment of Industrial and Municipal Wastewater: An Overview about Basic and Advanced Concepts
Figure 15.1 Conventional wastewater treatment.
Figure 15.2 Activated sludge process (ASP).
Figure 15.3 Sequencing batch reactor (one cycle).
Figure 15.4 Oxidation ditch.
Figure 15.5 Trickling filter.
Figure 15.6 Rotating biological contactors.
Figure 15.7 Submerged biological contactors.
Figure 15.8 ASP combined with powdered activated carbon treatment (PACT).
Figure 15.9 Membrane bioreactors for aerobic wastewater treatment.
Figure 15.10 (a,b) Biological aerated filters (BAFs).
Figure 15.11 Upflow anaerobic sludge basket (UASB).
Figure 15.12 Anaerobic baffled reactors.
Figure 15.13 Anaerobic fluidized bed reactors.
Figure 15.14 Expanded granule sludge blanket reactor.
Figure 15.15 Anaerobic membrane bioreactor.
Figure 15.16 Schematic representations of different sonochemical reactor configurations.
Figure 15.17 Schematic representation of hydrodynamic cavitation setup based on a flow loop housing a cavitation chamber.
Figure 15.18 Treatment flow sheet for Fenton oxidation.
Figure 15.19 Schematic representation of equipments used for ozonation.
16: Treatment of Solid Waste
Figure 16.1 Simplified layout of a composting facility.
Figure 16.2 (a) BACHKUS windrow turner [10], (b) BACKHUS Lane turner [10]. (With permission from BACKHUS EcoEngineers.)
Figure 16.3 Schema of tunnel composting from STRABAG [11]. (With permission from STRABAG Umwelttechnik GMBH.)
Figure 16.4 Simplified layout of an anaerobic digestion facility.
Figure 16.5 Schema of a percolation digester from BEKON [22]. (With permission from BEKON Energy Technologies GmbH & Co. KG.)
Figure 16.6 Schema of a plug flow digester from STABAG [11]. (With permission from STRABAG Umwelttechnik GMBH.)
Figure 16.7 Simplified layout of the different MBT technologies.
17: Energy Recovery from Organic Waste
Figure 17.1 Production of various fuels by biological processes of methane fermentation.
Figure 17.2 Methane production from biomass wastes by multistep reactions. LCFA, long-chain fatty acid; VFA, volatile fatty acid (such as propionate and butyrate).
Figure 17.3 (a) Schematic diagram of the two-stage reactor system for methane fermentation of marine mud sediments. (b) Profiles of methane production and acetic acid in acidogenic reactor effluent (closed triangle) and in methanogenic reactor effluent (closed square) during batch treatment of mud sediment in a two-stage UASB reactor system. (Adapted from [45]; with permission ©2001, Springer-Verlag.)
Figure 17.4 Ammonia–methane fermentation process for anaerobic digestion of nitrogen-rich organic wastes.
Figure 17.5 Methane fermentation of raw chicken manure by the one-stage reactor process with biogas recycle and ammonia capturing.
Figure 17.6 Anaerobic catabolism of
Enterobacter aerogenes
HU-101 and screening method applied for increasing hydrogen yield. AA, metabolite reduced by allyl-alcohol method; PS, metabolite reduced by proton-suicide method; VP, metabolite reduced by Voges–Proskauer (VP) test.
Figure 17.7 The relationship between H
2
yield and
C
ave
in
E. aerogenes
HU-101. Symbols: closed square, hydrogen; open diamond, ethanol. (Adapted from [98]; with permission ©2002 International Association for Hydrogen Energy. Published by Elsevier Ltd.)
Figure 17.8 Schematic drawing of (a) packed reactor system for self-immobilized cells of
E. aerogens
and (b) continuous H
2
production from glucose. (Adapted from [101]; with permission ©1998, Springer-Verlag, Berlin, Heidelberg.).
Figure 17.9 Process flow of biodiesel fuel production combined with H
2
and ethanol production from BDF waste containing glycerol. (Adapted from experimental data by Ito
et al
. [102].)
Figure 17.10 Production of biofuels and materials based on a syngas platform.
18: Microbial Removal and Recovery of Metals from Wastewater
Figure 18.1 Microbial processes available for metal removal/recovery from wastewater: (a) bioprecipitation/biomineralization, (b) biovolatilization, (c) biosorption, and (d) bioleaching.
Figure 18.2 Selenium species in the environment. Roman numerals in parentheses indicate oxidation numbers.
Figure 18.3 Typical time courses of selenate reduction by the strain NT-I [4]. (a) Reduction under aerobic conditions, and (b) reduction under anaerobic conditions. Symbols: open squares, selenate; open circles, selenite; open triangles, elemental selenium. Vertical bars represent the standard deviation of three independent experiments.
Figure 18.4 Scanning electron microscopy image of strain NT-I [4]. The arrow indicates a particle of elemental selenium.
Figure 18.5 Recovery of Se through biovolatilization by strain NT-I [6]. (a) Time course of Se during cultivation. The vertical axis indicates the amount of Se in the culture and trapping solution. (b) Material balance of Se at 48 h. The ratio of Se in its respective phases to total Se in the jar fermenter at 0 h is indicated as a percentage.
19: Sustainable Use of Phosphorus Through Bio-Based Recycling
Figure 19.1 P acquisition in bacteria [12].
Figure 19.2 Settleability, filterability, and dewaterability of P recovered by A-CSHs, CaCl
2
, and Ca(OH)
2
[42]. The settleability (a), filterability (b), and dewaterability (c) of recovered P were assessed by the method described previously [42]. Symbols are A-CSHs (circles), Ca(OH)
2
(squares), and CaCl
2
(triangles).
Figure 19.3 P
i
refinery technology.
List of Tables
2: Enzyme Technology: History and Current Trends
Table 2.1 Ferments (enzyme activities) known until 1880
Table 2.2 Industrial applications of enzymes: major selected areas [37, Chapter 7] – Additional sector: diagnostic enzymes
a
4: Biocatalytic Process Development
Table 4.1 Rationale for introduction of biocatalytic processes.
Table 4.2 Examples of appropriate biocatalyst yield and product concentration for scalable processes in different industrial sectors
Table 4.3 Process metrics for biocatalytic atorvastatin process
Table 4.4 Example process metrics for biocatalytic sitagliptin process
5: Development of Enzymatic Reactions in Miniaturized Reactors
Table 5.1 Adsorption techniques for enzyme-immobilized microreactor preparation.
Table 5.2 Entrapment techniques for enzyme-immobilized microreactor preparation
Table 5.3 Affinity labeling techniques for enzyme immobilized microreactor preparation
Table 5.4 Covalent linking techniques for enzyme immobilized microreactor preparation
Table 5.5 Enzyme polymerization techniques for enzyme-immobilized microreactor preparation
6: Bioreactor Development and Process Analytical Technology
Table 6.1 Development of microtiter-plate (MTP) bioreactors for high-throughput processing
Table 6.2 Development of stirred-tank bioreactors for high-throughput processing (HTP)
Table 6.3 Development of microfluidic bioreactors (MFLBR) for high-throughput processing
Table 6.4 Overview of various mini/micro bioreactors for high-throughput processing – key technologies and performance specifications
10: Bioprocess Engineering of Plant Cell Suspension Cultures
Table 10.1 Products produced commercially via plant cell suspension culture [5–7]
Table 10.2 Properties of recombinant proteins from various expression systems
Table 10.3 Comparison of characteristics of plant, mammalian, and bacterial cells [41, 42]
Table 10.4 Comparison of bioreactors for plant cell suspension culture
11: The Role of Bacteria in Phytoremediation
Table 11.1 Examples of contributions of degradative bacteria to phytoremediation of organic contaminants
Table 11.2 Rhizobial strains resistant to heavy metals and producing plant-growth-promoting substances
12: Cell Line Development for Biomanufacturing Processes
Table 12.1 High-throughput clone selection methods and criterion for clone selection
13: Medium Design, Culture Management, and the PAT Initiative
Table 13.1 Examples of commonly employed media
Table 13.2 Approximate concentrations in the cellular environment
Table 13.3 Main constituents and physical characteristics of extracellular fluid
Table 13.4 Quality standards for purified water (PW) and water for injection (WFI) for pharmaceutical use
Table 13.5 Essential and nonessential amino acids
Table 13.6 Vitamins for cells in culture
Table 13.7 Approximate lipid content of bovine serum [47]
Table 13.8 Concentration of bulk ions in basal medium
Table 13.9 Synthetic protective agents and surfactants used in cell culture
Table 13.10 Antibiotics for cell culture
Table 13.11 Iron chelators used as transferrin replacements
Table 13.12 Transport and carrier proteins
Table 13.13 Adhesion molecules used for cell culture
14: Advanced Bioprocess Engineering: Fed-Batch and Perfusion Processes
Table 14.1 Different fed batch strategies in cell culture bioprocesses.
Table 14.2 Cell retention devices and their application in perfusion bioprocess
Table 14.3 Comparison of perfusion devices.
Table 14.4 Examples of disposable bioreactors in cell culture bioprocessing
Table 14.5 Overview of methods for quantification of metabolites and process parameters
15: Treatment of Industrial and Municipal Wastewater: An Overview about Basic and Advanced Concepts
Table 15.1 Characteristics of complex wastewater (biomethanated distillery wastewater) used in the experimental work [122]
Table 15.2 Effect of cavitation pretreatment on biodegradability index of biomethanated distillery wastewater [122]
17: Energy Recovery from Organic Waste
Table 17.1 Mean composition and specific yields of biogas in relation to the kind of substances degraded.
Table 17.2 Schematic overview of anaerobic digestion process classified by IEA
18: Microbial Removal and Recovery of Metals from Wastewater
Table 18.1 Examples of bioprecipitation.
Table 18.2 Examples of biovolatilization.
Table 18.3 Examples of reported biosorbents for metal removal/recovery.
Table 18.4 Examples of reported microbes for bioleaching.
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Coming soon:
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Print ISBN: 978-3-527-34075-0
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Print ISBN: 978-3-527-34181-8
Planned:
Systems Biology
J. Nielsen & S. Hohmann (Chalmers University, Sweden)
Emerging Areas in Bioengineering
H. N. Chang (KAIST, South Korea)
Edited by Toshiomi Yoshida
Applied Bioengineering
Innovations and Future Directions
Volume Editor
Toshiomi Yoshida
Osaka University
International Center for Biotechnology
2-1 Yamada-oka
Suita-shi
565-0871 Osaka
Japan
Series Editors
Sang Yup Lee
KAIST
373-1; Guseong-Dong
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305-701 Daejon
South Korea
Jens Nielsen
Chalmers University
Department of Chemical and Biological
Engineering
Kemivägen 10
412 96 Göteborg
Sweden
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Massachusetts Instituts of Technology
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Cambridge MA 02139
USA
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List of Contributors
Gregory R. Andrews
Worcester Polytechnic
Institute Goddard Hall
Department of Chemical Engineering
100 Institute Road
Worcester
MA 01609
USA
Uwe T. Bornscheuer
University of Greifswald
Institute of Biochemistry
Felix‐Hausdorff‐Str. 4
17487 Greifswald
Germany
Klaus Buchholz
University of Braunschweig
Institute for Technical Chemistry
Hans‐Sommer‐Strasse 10
38106 Braunschweig
Germany
Vikas Chandrawanshi
Indian Institute of Technology Bombay
Department of Chemical Engineering
Powai
Mumbai 400076
India
Ayman El Naas
University of Rostock
Faculty of Agricultural and Environmental Sciences
Department of Waste Management and Material Flow
Justus‐von‐Liebig‐Weg 6
18059 Rostock
Germany
Rainer Fischer
Fraunhofer Institute for Molecular Biology and Applied Ecology IME
Forckenbeckstrasse 6
52074 Aachen
Germany
and
RWTH Aachen University
Institute for Molecular Biotechnology
Worringerweg 1
52074 Aachen
Germany
Chikara Furusawa
Osaka University
Graduate School of Information Science and Technology
Department of BioinformaticEngineering
1‐5 Yamadaoka
Suita
Osaka 565‐0871
Japan
and
RIKEN
Quantitative Biology Center
6‐2‐3 Furuedai
Suita
Osaka 565‐0874
Japan
Mugdha Gadgil
CSIR‐National Chemical Laboratory
Chemical Engineering and Process Development Division
Dr Homi Bhabha Road
Pune
Maharashtra 411008
India
Ziomara P. Gerdtzen
University of Chile
Centre for Biotechnology and Bioengineering (CeBiB)
Department of Chemical Engineering and Biotechnology
Beauchef 850
Santiago 8370448
Chile
Bernard R. Glick
University of Waterloo
Department of Biology
200 University Avenue
West Waterloo
ON N2L 3G1
Canada
Parag R. Gogate
Institute of Chemical Technology (Deemed University)
Chemical Engineering Department
N. P. Road Matunga (East)
Mumbai
Maharashtra 400019
India
Takashi Hirasawa
Osaka University
Graduate School ofInformation Science and Technology
Department of BioinformaticEngineering
1‐5 Yamadaoka
Suita
Osaka 565‐0871
Japan
and
Tokyo Institute of Technology
Department of Bioengineering
4259 Nagatsuta‐cho
Midori‐ku
Yokohama 226‐8501
Japan
Takeshi Honda
National Institute of Advanced Industrial Science and Technology
Advanced Manufacture Research Institute
807‐1 Shuku
Tosu
Saga 841‐0052
Japan
and
Yamaguchi University Graduate School of Medicine
Department of Pharmacology
1-1-1 Minamikogushi
Ube
Yamaguchi 755-8505
Japan
Wei‐Shou Hu
University of Minnesota
Department of Chemical Engineering and Materials Science
421 Washington Ave SE Minneapolis
MN 55455
USA
Michihiko Ike
Osaka University
Graduate School of Engineering
Division of Sustainable Energy and EnvironmentalEngineering
2‐1 Yamadaoka
Suita
Osaka 565‐0871
Japan
Zhaoyu Kong
Nanchang University
School of Life Science
999 Xuefu Avenue Nanchang 330031
China
Jyoti K. Kumar
Institute of Chemical Technology(Deemed University)
Chemical Engineering Department
N. P. Road Matunga (East)
Mumbai
Maharashtra 400019
India
Masashi Kuroda
Osaka University
Graduate School of Engineering
Division of Sustainable Energy and EnvironmentalEngineering
2‐1 Yamadaoka
Suita
Osaka 565‐0871
Japan
Astrid Lemke
University of Rostock
Faculty of Agricultural and Environmental Sciences
Department of Waste Management and Material Flow
Justus‐von‐Liebig‐Weg 6
18059 Rostock
Germany
Fumio Matsuda
Osaka University
Graduate School of Information Science and Technology
Department of BioinformaticEngineering
1‐5 Yamadaoka
Suita
Osaka 565‐0871
Japan
Sarika Mehra
Indian Institute of Bombay
Department of Chemical Engineering
Powai
Mumbai 400076
India
Masaya Miyazaki
National Institute of Advanced Industrial Science and Technology
Advanced Manufacture Research Institute
807‐1 Shuku
Tosu
Saga 841‐0052
Japan
and
Kyushu University
Interdisciplinary Graduate School of Engineering Science
Department of Molecular and Material Sciences
6-1 Kasuga-koen
Kasuga
Fukuoka 816-8580
Japan
Gert Morscheck
University of Rostock
Faculty of Agricultural and Environmental Sciences
Department of Waste Management and Material Flow
Justus‐von‐Liebig‐Weg 6
18059 Rostock
Germany
Yutaka Nakashimada
Hiroshima University
Graduate School of
Advanced Sciences of Matter
Department of Molecular Biotechnology
1‐3‐1 Kagamiyama Higashi‐Hiroshima 7398530
Japan
Michael Nelles
University of Rostock
Faculty of Agricultural and Environmental Sciences
Department of Waste Management and Material Flow
Justus‐von‐Liebig‐Weg 6
18059 Rostock
Germany
Naomichi Nishio
Hiroshima University
Graduate School of
Advanced Sciences of Matter
Department of Molecular Biotechnology
1‐3‐1 Kagamiyama
Higashi‐Hiroshima 7398530
Japan
Hisao Ohtake
Waseda University
Phosphorus Atlas Research Institute
2-2 Wakamatsu
Shinjuku
Tokyo 162-0056
Japan
Maria Elena Ortiz‐Soto
Julius‐Maximilians‐UniversitätWürzburg
Institut für Organische Chemie
Am Hubland
97074 Würzburg
Germany
Aniruddha B. Pandit
Institute of Chemical Technology (Deemed University)
Chemical Engineering Department
N. P. Road Matunga (East)
Mumbai
Maharashtra 400019
India
Kamal Prashad
Indian Institute of Technology Bombay
Department of Chemical Engineering
Powai
Mumbai 400076
India
Nicole Raven
Fraunhofer Institute for Molecular Biology and Applied Ecology IME
Forckenbeckstrasse 6
52074 Aachen
Germany
Susan C. Roberts
Worcester Polytechnic Institute Goddard Hall
Department of Chemical Engineering
100 Institute Road
Worcester MA 01609
USA
Andreas Schiermeyer
Fraunhofer Institute for Molecular Biology and Applied Ecology IME
Forckenbeckstrasse 6
52074 Aachen
Germany
Stefan Schillberg
Fraunhofer Institute for Molecular Biology and Applied Ecology IME
Forckenbeckstrasse 6
52074 Aachen
Germany
and
Justus‐Liebig University Giessen
Phytopathology Department
Institute for Phytopathologyand Applied Zoology
Heinrich‐Buff‐Ring 26‐32
35392 Giessen
Germany
Jürgen Seibel
Julius‐Maximilians‐UniversitätWürzburg
Institut für Organische Chemie
Am Hubland
97074 Würzburg
Germany
Hiroshi Shimizu
Osaka University
Graduate School of Information Science and Technology
Department of BioinformaticEngineering
1‐5 Yamadaoka
Suita
Osaka 565‐0871
Japan
Kazuyuki Shimizu
Kyushu Institute of Technology
680-4, Kawazu Iizuka
Fukuoka 820‐8502
Japan
and
Keio University
Institute of Advanced Bioscience
246_2 Mizukami
Kakuganji
Tsuruoka
Yamagata 997-0017
Japan
Tomokazu Shirai
RIKEN
Center for Sustainable Resource Science
1‐7‐22 Suehiro
Tsurumi
Yokohama
Kanagawa 230‐0045
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Yoshihiro Toya
Osaka University
Graduate School of Information Science and Technology
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Osaka 565‐0871
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Richard M. Twyman
TRM Ltd.
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John M. Woodley
Technical University of Denmark (DTU)
Department of Chemical and Biochemical Engineering
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Hiroshi Yamaguchi
National Institute of Advanced Industrial Science and Technology
Advanced Manufacture Research Institute
807‐1 Shuku
Tosu
Saga 841‐0052
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and
Tokai University
Liberal Arts Education Center
Kawayo
Minamiaso
Kumamoto 869‐1404
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Mitsuo Yamashita
Shibaura Institute of Technology
Faculty of Engineering
Department of Applied Chemistry
3-7-5 Toyosu Koto-ku
Tokoyo 135-8548
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Toshiomi Yoshida
Osaka University
International Center for Biotechnology
2‐1 Yamadaoka
Suita
Osaka 565‐0871
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Katsunori Yoshikawa
Osaka University
Graduate School ofInformation Science and Technology
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1Introduction
Toshiomi Yoshida
1.1 Introduction
The European Federation of Biotechnology proposed a definition of biotechnology as “The integration of natural science and organisms, cells, parts thereof and molecular analogs for products and services.” The Concise Oxford English Dictionary states “biotechnology is the exploitation of biological processes for industrial and other purposes especially the genetic manipulation of microorganisms for the production of antibiotics, hormone, and so on” [1].
Biochemical engineering has developed as a branch of chemical engineering, and deals with the design and construction of unit processes that involve biological molecules or organisms. Biochemical engineering is often taught as a supplementary option to students of chemical engineering or biological engineering courses because of the overlap in the curriculum and similarities in problem-solving techniques used in both professions. Its contribution is widely found in the food, feed, pharmaceutical, and biotechnological industries, and in water treatment plants.
Biological engineering or bioengineering is the application of the concepts, principles, and methods of biology to solve real-world problems using engineering methodologies and also its traditional sensitivity to the cost advantage and practicality. In this context, while traditional engineering applies physical and mathematical sciences to analyze, design, and manufacture inanimate tools, structures, and processes, biological engineering primarily utilizes knowledge of molecular biology to study, investigate, and develop applications of living organisms. In summary, biological engineers principally focus on applying engineering principles and the knowledge of molecular biology to study and enhance biological systems for varied applications.
Referring to the above review and brief discussion, it is proposed to have a section titled “Applied Bioengineering” be included in the Wiley Biotechnology Series. This section will deal with recent progress in all subjects closely related to “engineering and technologies” in the field of biotechnology; widening the coverage beyond conventional biochemical engineering and bioprocess engineering to include other biology-based engineering disciplines. The topics involved were selected specifically from the perspective of practical applications.
The volume “Applied Bioengineering” comprises five topics: enzyme technology, microbial process engineering, plant cell culture, animal cell culture, and environmental bioengineering. Each topic is figured in several chapters, though with more chapters pertaining to environmental bioengineering. This field has seen an increase in active research as mentioned below because of growing awareness and concern about conservation, remediation, and improvement of the environment.
The later part of this chapter provides a brief overview on the developments in bioengineering, referring to recent highly cited research.
1.2 Enzyme Technology
Recently, several attempts have been made to screen organic-solvent-tolerant enzymes from various microorganisms [2]. The ligninolytic oxidoreductases are being improved utilizing protein engineering by the application of different “omics” technologies. Enzymatic delignification will soon come into practical use in pulp mills [3]. Enzyme stabilization has been attempted using various approaches such as protein engineering, chemical modification, and immobilization [4].
Microbial glucose oxidase has garnered considerable interest because of its wide applications in chemical, pharmaceutical, food, beverage, clinical chemistry, biotechnology, and other industries. Novel applications of glucose oxidase in biosensors have further increased its demand [5]. Numerous oxidative biotransformation studies have demonstrated that enzymes have diverse characteristics and wide range of potential, and established applications [6]. Multienzymatic cascade reactions used in the asymmetric synthesis of chiral alcohols, amines, and amino acids, as well as for C–C bond formation, have been extensively studied [7].
1.3 Microbial Process Engineering
1.3.1 Bioreactor Development
Stirred-tank bioreactors are used in a large variety of bioprocesses because of their high rates of mass and heat transfer and excellent mixing. Theoretical predictions of the volumetric mass transfer coefficient have been recently proposed, and different criteria for bioreactor scale-up have been reported [8].
Miniaturized bioreactor (MBR) systems have made great advances both in function and in performance. The dissolved oxygen transfer performance of submilliliter microbioreactors and 1–10 ml mini-bioreactors has been well examined. MBRs have achieved considerably high kLa values and offer flexible instrumentation and functionality comparable to that of production systems at high-throughput screening volumes; furthermore, the superior integration of these bioreactors with automated fluid handling systems demonstrates that they allow efficient scale-up [9].
The pharmaceutical and biotechnology industries face constant pressure to reduce development costs and accelerate process development. A small scale bioreactor system enabling multiple reactions in parallel (n ≥ 20) with automated sampling would provide significant improvement in development timelines. State-of-the-art equipment that facilitates high-throughput process developments includes shake flasks, microfluidic reactors, microtiter plates, and small-scale stirred reactors [10].
An expert panel organized by the M3C Working Group of the European Section of Biochemical Engineering Science (ESBES) reviewed the prevailing methods of monitoring of MBRs and identified the need for further development [11]. Their recommendations includes combining online analytics such as chromatography or mass spectrometry with bioreactors, preferably using noninvasive sensors such as optical or electronic ones. The sensors to be used online in these bioreactors should be selected on the basis of three criteria: (i) detection limits in relation to analytes, (ii) stability in relation to the testing period, and (iii) the possibility for miniaturization to the volume ranges and dimensions of the microfluidic system applied in the bioreactors. In addition, mathematical models based on soft sensor principles should be exploited to reduce the number of sensors.
1.3.2 Measurement and Monitoring
Biosensors for detection of cellobiose, lactose, and glucose based on various cellobiose dehydrogenases from different fungal producers, which differ with respect to their substrate specificity, optimum pH, electron transfer efficiency, and surface-binding affinity; therefore, promising a wide range of new applications [12].
Infrared sensors are ideal tools for bioprocess monitoring, because they are noninvasive, of no-time-delay, and harmless on the bioprocess itself, and furthermore, simultaneous analyses of several components are possible. Therefore, directly monitoring of substrates, products, metabolites, and the biomass itself is possible [13]. The panel of the M3C Working Group of ESBES recommended the use of soft sensors in bioprocess engineering [14]. In the Food and Drug Administration's (FDA) proposed and promoted process analytical technology (PAT) initiative, intending to collaborate with industry to promote the integration of new manufacturing technologies with pharmaceutical production [15]. The program aimed to design, develop, and operate processes consistently ensuring a predefined quality at the end of the manufacturing process [15]. An advanced monitoring and control system has been developed, based on different inline, online and at-line measurements for substrates and products. Observation of cell viability by inline measurement of radio frequency impedance and online determination of intracellular recombinant target protein using the reporter protein T-sapphire green fluorescent protein (GFP) could allow real-time monitoring of critical process states [16].
1.3.3 Modeling and Control
Stoichiometric models of cell metabolism have been developed with the use of information about reaction stoichiometry embedded in metabolic networks and the assumption of a pseudo-steady state. Stoichiometric models have been used to estimate the metabolic flux distribution under given circumstances in the cell at some given moment (metabolic flux analysis) and to predict it on the basis of some optimality hypothesis (flux balance analysis). Mechanistic models based on deterministic principles, recently, have been interested in substantially. Gernaey et al
