Details

Bioreactors


Bioreactors

Design, Operation and Novel Applications
1. Aufl.

von: Carl-Fredrik Mandenius

147,99 €

Verlag: Wiley-VCH
Format: EPUB
Veröffentl.: 16.02.2016
ISBN/EAN: 9783527683383
Sprache: englisch
Anzahl Seiten: 520

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Beschreibungen

In this expert handbook both the topics and contributors are selected so as to provide an authoritative view of possible applications for this new technology. The result is an up-to-date survey of current challenges and opportunities in the design and operation of bioreactors for high-value products in the biomedical and chemical industries. <br> Combining theory and practice, the authors explain such leading-edge technologies as single-use bioreactors, bioreactor simulators, and soft sensor monitoring, and discuss novel applications, such as stem cell production, process development, and multi-product reactors, using case studies from academia as well as from industry. A final section addresses the latest trends, including culture media design and systems biotechnology, which are expected to have an increasing impact on bioreactor design.<br> With its focus on cutting-edge technologies and discussions of future developments, this handbook will remain an invaluable reference for many years to come.<br>
<p>Preface XV</p> <p>List of Contributors XVII</p> <p><b>1 Challenges for Bioreactor Design and Operation 1</b><br /><i>Carl-Fredrik Mandenius</i></p> <p>1.1 Introduction 1</p> <p>1.2 Biotechnology Milestones with Implications on Bioreactor Design 2</p> <p>1.3 General Features of Bioreactor Design 8</p> <p>1.4 Recent Trends in Designing and Operating Bioreactors 12</p> <p>1.5 The Systems Biology Approach 17</p> <p>1.6 Using Conceptual Design Methodology 20</p> <p>1.7 An Outlook on Challenges for Bioreactor Design and Operation 29</p> <p>References 32</p> <p><b>2 Design and Operation of Microbioreactor Systems for Screening and Process Development 35</b><br /><i>Clemens Lattermann and Jochen Büchs</i></p> <p>2.1 Introduction 35</p> <p>2.2 Key Engineering Parameters and Properties in Microbioreactor Design and Operation 36</p> <p>2.2.1 Specific Power Input 37</p> <p>2.2.2 Out-of-Phase Phenomena 40</p> <p>2.2.3 Mixing in Microbioreactors 42</p> <p>2.2.4 Gas–Liquid Mass Transfer 44</p> <p>2.2.4.1 Influence of the Reactor Material 47</p> <p>2.2.4.2 Influence of the Viscosity 49</p> <p>2.2.5 Influence of Shear Rates 50</p> <p>2.2.6 Ventilation in Shaken Microbioreactors 51</p> <p>2.2.7 Hydromechanical Stress 52</p> <p>2.3 Design of Novel Stirred and Bubble Aerated Microbioreactors 53</p> <p>2.4 Robotics for Microbioreactors 54</p> <p>2.5 Fed-Batch and Continuous Operation of Microbioreactors 56</p> <p>2.5.1 Diffusion-Controlled Feeding of the Microbioreactor 56</p> <p>2.5.2 Enzyme Controlled Feeding of the Microbioreactor 58</p> <p>2.5.3 Feeding of Continuous Microbioreactors by Pumps 59</p> <p>2.6 Monitoring and Control of Microbioreactors 60</p> <p>2.6.1 DOT and pH Measurement 62</p> <p>2.6.2 Respiratory Activity 63</p> <p>2.7 Conclusion 66</p> <p>Terms 67</p> <p>Greek Letters 68</p> <p>Dimensionless Numbers 69</p> <p>List of Abbreviations 69</p> <p>References 69</p> <p><b>3 Bioreactors on a Chip 77</b><br /><i>Danny van Noort</i></p> <p>3.1 Introduction 77</p> <p>3.2 Advantages of Microsystems 79</p> <p>3.2.1 Concentration Gradients 81</p> <p>3.3 Scaling Down the Bioreactor to the Microfluidic Format 82</p> <p>3.4 Microfabrication Methods for Bioreactors-On-A-Chip 82</p> <p>3.4.1 Etching of Silicon/Glass 83</p> <p>3.4.2 Soft Lithography 83</p> <p>3.4.3 Hot Embossing 84</p> <p>3.4.4 Mechanical Fabrication Technique (Or Poor Man’s Microfluidics) 84</p> <p>3.4.5 Laser Machining 85</p> <p>3.4.6 Thin Metal Layers 86</p> <p>3.5 Fabrication Materials 86</p> <p>3.5.1 Inorganic Materials 86</p> <p>3.5.2 Elastomers and Plastics 87</p> <p>3.5.2.1 Elastomers 87</p> <p>3.5.2.2 Thermosets 87</p> <p>3.5.2.3 Thermoplastics 87</p> <p>3.5.3 Hydrogels 88</p> <p>3.5.4 Paper 88</p> <p>3.6 Integrated Sensors for Key Bioreactor Parameters 89</p> <p>3.6.1 Temperature 89</p> <p>3.6.2 pH 90</p> <p>3.6.3 O2 90</p> <p>3.6.4 CO2 90</p> <p>3.6.5 Cell Concentration (OD) 90</p> <p>3.6.6 Humidity and Environment Stability 91</p> <p>3.6.7 Oxygenation 91</p> <p>3.7 Model Organisms Applied to BRoCs 91</p> <p>3.8 Applications of Microfluidic Bioreactor Chip 92</p> <p>3.8.1 A Chemostat BRoC 92</p> <p>3.8.2 Using a BRoC as a Single-Cell Chemostat 95</p> <p>3.8.3 Mammalian Cells in the Bioreactor on a Chip 96</p> <p>3.8.4 Body-on-a-Chip Bioreactors 98</p> <p>3.8.5 Organ-on-a-Chip Bioreactor-Like Applications 99</p> <p>3.9 Scale Up 100</p> <p>3.10 Conclusion 101</p> <p>Abbreviations 102</p> <p>References 103</p> <p><b>4 Scalable Manufacture for Cell Therapy Needs 113</b><br /><i>Qasim A. Rafiq, Thomas R.J. Heathman, Karen Coopman, AlvinW. Nienow, and Christopher J. Hewitt</i></p> <p>4.1 Introduction 113</p> <p>4.2 Requirements for CellTherapy 115</p> <p>4.2.1 Quality 115</p> <p>4.2.2 Number of Cells Required 117</p> <p>4.2.3 Anchorage-Dependent Cells 118</p> <p>4.3 Stem Cell Types and Products 119</p> <p>4.4 Paradigms in Cell Therapy Manufacture 120</p> <p>4.4.1 Haplobank 121</p> <p>4.4.2 Autologous Products 121</p> <p>4.4.3 Allogeneic Products 123</p> <p>4.5 CellTherapy Manufacturing Platforms 124</p> <p>4.5.1 Scale-Out Technology 125</p> <p>4.5.2 Scale-Up Technology 127</p> <p>4.6 Microcarriers and Stirred-Tank Bioreactors 128</p> <p>4.6.1 Overview of Studies Using a Stirred-Tank Bioreactor and Microcarrier System 130</p> <p>4.7 Future Trends for Microcarrier Culture 136</p> <p>4.8 Preservation of CellTherapy Products 138</p> <p>4.9 Conclusions 139</p> <p>References 140</p> <p><b>5 Artificial Liver Bioreactor Design 147</b><br /><i>Katrin Zeilinger and Jörg C. Gerlach</i></p> <p>5.1 Need for Innovative LiverTherapies 147</p> <p>5.2 Requirements to Liver Support Systems 147</p> <p>5.3 Bioreactor Technologies Used in Clinical Trials 148</p> <p>5.3.1 Artificial Liver Support Systems 148</p> <p>5.3.2 Bioartificial Liver Support Systems 149</p> <p>5.4 Optimization of Bioartificial Liver Bioreactor Designs 152</p> <p>5.5 Improvement of Cell Biology in Bioartificial Livers 155</p> <p>5.6 Bioreactors Enabling Cell Production for Transplantation 157</p> <p>5.7 Cell Sources for Bioartificial Liver Bioreactors 158</p> <p>5.7.1 Primary Liver Cells 158</p> <p>5.7.2 Hepatic Cell Lines 161</p> <p>5.7.3 Stem Cells 161</p> <p>5.8 Outlook 163</p> <p>References 164</p> <p><b>6 Bioreactors for Expansion of Pluripotent Stem Cells and Their Differentiation to Cardiac Cells 175</b><br /><i>Robert Zweigerdt, Birgit Andree, Christina Kropp, and Henning Kempf</i></p> <p>6.1 Introduction 175</p> <p>6.1.1 Requirement for Advanced Cell Therapies for Heart Repair 175</p> <p>6.1.2 Pluripotent Stem Cell–Based Strategies for Heart Repair 176</p> <p>6.2 Culture Technologies for Pluripotent Stem Cell Expansion 179</p> <p>6.2.1 Matrix-Dependent Cultivation in 2D 179</p> <p>6.2.2 Outscaling hPSC Production in 2D 179</p> <p>6.2.3 Hydrogel-Supported Transition to 3D 182</p> <p>6.3 3D Suspension Culture 182</p> <p>6.3.1 Advantages of Using Instrumented Stirred Tank Bioreactors 182</p> <p>6.3.2 Process Inoculation and Passaging Strategies: Cell Clumps Versus Single Cells 186</p> <p>6.3.3 Microcarriers or Matrix-Free Suspension Culture: Pro and Contra 187</p> <p>6.3.4 Optimization and Current Limitations of hPSC Processing in Stirred Bioreactors 188</p> <p>6.4 Autologous Versus Allogeneic Cell Therapies: Practical and Economic Considerations for hPSC Processing 189</p> <p>6.5 Upscaling hPSC Cardiomyogenic Differentiation in Bioreactors 190</p> <p>6.6 Conclusion 192</p> <p>List of Abbreviations 193</p> <p>References 193</p> <p><b>7 Culturing Entrapped StemCells in Continuous Bioreactors 201</b><br /><i>Rui Tostoes and Paula M. Alves</i></p> <p>7.1 Introduction 201</p> <p>7.2 Materials Used in Stem Cell Entrapment 202</p> <p>7.3 Synthetic Materials 203</p> <p>7.3.1 Polymers 203</p> <p>7.3.2 Peptides 207</p> <p>7.3.3 Ceramic 208</p> <p>7.4 Natural Materials 208</p> <p>7.4.1 Proteins 208</p> <p>7.4.2 Polysaccharides 209</p> <p>7.4.3 Complex 211</p> <p>7.5 Manufacturing and Regulatory Constraints 212</p> <p>7.6 Mass Transfer in the Entrapment Material 214</p> <p>7.7 Continuous Bioreactors for Entrapped Stem Cell Culture 216</p> <p>7.8 Future Perspectives 220</p> <p>References 221</p> <p><b>8 Coping with Physiological Stress During Recombinant Protein Production by Bioreactor Design and Operation 227</b><br /><i>Pau Ferrer and Francisco Valero</i></p> <p>8.1 Major Physiological Stress Factors in Recombinant Protein Production Processes 227</p> <p>8.1.1 Physiological Constraints Imposed by High-Cell-Density Cultivation Conditions 227</p> <p>8.1.2 Metabolic and Physiologic Constraints Imposed by High-Level Expression of Recombinant Proteins 229</p> <p>8.1.3 Physiological Constraints in Large-Scale Cultures 230</p> <p>8.2 Monitoring Physiological Stress and Metabolic Load as a Tool for Bioprocess Design and Optimization 230</p> <p>8.2.1 Monitoring of Physiological Responses to Recombinant Gene Expression Using Flow Cytometry 231</p> <p>8.2.2 Monitoring of Reporter Metabolites 233</p> <p>8.2.3 Omics Analytical Tools to Assess the Impact of Recombinant Protein Production on Cell Physiology 233</p> <p>8.3 Design and Operation Strategies to Minimize/Overcome Problems Associated with Physiological Stress and Metabolic Load 241</p> <p>8.3.1 Overcoming Overflow Metabolism and Substrate Toxicity 241</p> <p>8.3.2 Improving the Energy and Building Block Supply 244</p> <p>8.3.3 Expression Strategies and Recombinant Gene Transcriptional Tuning for Stress Minimization 245</p> <p>8.4 Bioreactor Design Considerations to Minimize Shear Stress 246</p> <p>Acknowledgments 247</p> <p>References 248</p> <p><b>9 Design, Applications, and Development of Single-Use Bioreactors 261</b><br /><i>Nico M.G. Oosterhuis and Stefan Junne</i></p> <p>9.1 Introduction 261</p> <p>9.2 Design Challenges of Single-Use Bioreactors 263</p> <p>9.2.1 Material Choice and Testing 263</p> <p>9.2.2 Sterilization 267</p> <p>9.2.3 Sensors and Sampling 267</p> <p>9.2.4 Challenges for Scale-Up and Scale-Down of Single-Use Bioreactors 268</p> <p>9.2.4.1 Scalability of Stirred Single-Use Bioreactors 270</p> <p>9.2.4.2 Scalability of Orbital-Shaken Single-Use Bioreactors 273</p> <p>9.2.4.3 Scalability ofWave-Mixed Single-Use Bioreactors 275</p> <p>9.2.4.4 Recent Advances in the Description of the Mass Transfer in SUBs 276</p> <p>9.3 Cell Culture Application 277</p> <p>9.3.1 Wave-Mixed Bioreactors 277</p> <p>9.3.2 Stirred Single-Use Bioreactors 278</p> <p>9.3.3 Orbital-Shaken Single-Use Bioreactors 280</p> <p>9.3.4 Mass Transfer Requirements for Cell Culture 280</p> <p>9.3.5 Perfusion Processes in Single-Use Equipment 282</p> <p>9.3.6 Plant, Phototrophic Algae and Hairy Root Cell Cultivation in Single-Use Bioreactors 284</p> <p>9.4 Microbial Application of Single-Use Bioreactors 285</p> <p>9.5 Outlook 288</p> <p>List of Abbreviations 289</p> <p>References 290</p> <p><b>10 Computational Fluid Dynamics for Bioreactor Design 295</b><br /><i>Anurag S. Rathore, Lalita Kanwar Shekhawat, and Varun Loomba</i></p> <p>10.1 Introduction 295</p> <p>10.2 Multiphase Flows 298</p> <p>10.2.1 Eulerian–Lagrangian Approach 298</p> <p>10.2.2 Euler–Euler Approach 303</p> <p>10.2.3 Volume of Fluid Approach (VOF) 304</p> <p>10.3 Turbulent Flow 305</p> <p>10.3.1 Reynolds Stress Model 305</p> <p>10.3.2 k–𝜀 Model 306</p> <p>10.3.3 Population Balance Model 306</p> <p>10.4 CFD Simulations 308</p> <p>10.4.1 Creation of Bioreactor Geometry 308</p> <p>10.4.2 Meshing of Solution Domain 308</p> <p>10.4.3 Solver 310</p> <p>10.5 Case Studies for Application of CFD inModeling of Bioreactors 310</p> <p>10.5.1 Case Study 1:Use of CFDas a Tool for Establishing Process Design Space for Mixing in a Bioreactor 311</p> <p>10.5.2 Case Study 2: Prediction of Two-Phase Mass Transfer Coefficient in Stirred Vessel 313</p> <p>10.5.3 Case Study 3: Numerical Modeling of Gas–Liquid Flow in Stirred Tanks 315</p> <p>Summary 318</p> <p>References 319</p> <p><b>11 Scale-Up and Scale-Down Methodologies for Bioreactors 323</b><br /><i>Peter Neubauer and Stefan Junne</i></p> <p>11.1 Introduction 323</p> <p>11.2 Bioprocess Scale-Down Approaches 324</p> <p>11.2.1 A Historical View on the Development of Scale-Down Systems 324</p> <p>11.2.1.1 Phase 1: Initial Studies of Mixing Behavior and Spatial Distribution Phenomena 325</p> <p>11.2.1.2 Phase 2: Evolvement of Scale-Down Systems Based on Computational Fluid Dynamics 327</p> <p>11.2.1.3 Phase 3: Recent Approaches Considering Hybrid Models 328</p> <p>11.2.2 Scale-Up of Bioreactors 330</p> <p>11.2.2.1 Dissolved Oxygen Concentration 331</p> <p>11.2.2.2 Consideration of Similarities and Dimensionless Numbers 332</p> <p>11.2.2.3 Shear Rate 333</p> <p>11.2.2.4 Cell Physiology 333</p> <p>11.2.3 Most Severe Challenges During Scale-Up 333</p> <p>11.3 Characterization of the Large Scale 334</p> <p>11.4 Computational Methods to Describe the Large Scale 337</p> <p>11.5 Scale-Down Experiments and Physiological Responses 340</p> <p>11.5.1 Scale-Down Experiments with Escherichia coli Cultures 340</p> <p>11.5.2 Scale-Down Experiments with Corynebacterium glutamicum Cultures 343</p> <p>11.5.3 Scale-Down Experiments with Bacillus subtilis Cultures 344</p> <p>11.5.4 Scale-Down Experiments with Yeast Cultures 345</p> <p>11.5.5 Scale-Down Experiments with Cell Line Cultures 346</p> <p>11.6 Outlook 346</p> <p>Nomenclature 347</p> <p>References 347</p> <p><b>12 Integration of Bioreactors with Downstream Steps 355</b><br /><i>Ajoy Velayudhan and Nigel Titchener-Hooker</i></p> <p>12.1 Introduction 355</p> <p>12.2 Improvements in Cell-Culture 358</p> <p>12.3 Interactions with Centrifugation Steps 359</p> <p>12.4 Interactions with Filtration Steps 360</p> <p>12.5 Interactions with Chromatographic Steps 361</p> <p>12.6 Integrated Processes 364</p> <p>12.7 Integrated Models 366</p> <p>12.8 Conclusions 367</p> <p>References 368</p> <p><b>13 MultivariateModeling for Bioreactor Monitoring and Control 369</b><br /><i>Jarka Glassey</i></p> <p>13.1 Introduction 369</p> <p>13.2 Analytical Measurement Methods for Bioreactor Monitoring 370</p> <p>13.2.1 Traditional Measurement Methods 371</p> <p>13.2.2 Advanced Measurement Methods 372</p> <p>13.2.2.1 Spectral Methods 372</p> <p>13.2.2.2 Other FingerprintingMethods 374</p> <p>13.2.3 Data Characteristics and Challenges for Modeling 374</p> <p>13.3 Multivariate Modeling Approaches 376</p> <p>13.3.1 Feature Extraction and Classification 376</p> <p>13.3.2 Regression Models 378</p> <p>13.4 Case Studies 379</p> <p>13.4.1 Feature Extraction Using PCA 379</p> <p>13.4.2 Prediction of CQAs 383</p> <p>13.5 Conclusions 386</p> <p>Acknowledgments 387</p> <p>References 387</p> <p><b>14 Soft Sensor Design for Bioreactor Monitoring and Control 391</b><br /><i>Carl-Fredrik Mandenius and Robert Gustavsson</i></p> <p>14.1 Introduction 391</p> <p>14.2 The Process Analytical Technology Perspective on Soft Sensors 392</p> <p>14.3 Conceptual Design of Soft Sensors for Bioreactors 394</p> <p>14.4 "Hardware Sensor" Alternatives 395</p> <p>14.5 The Modeling Part of Soft Sensors 400</p> <p>14.6 Strategy for Using Soft Sensors 402</p> <p>14.7 Applications of Soft Sensors in Bioreactors 403</p> <p>14.7.1 Online Fluorescence Spectrometry for Estimating Media Components in a Bioreactor 404</p> <p>14.7.2 Temperature Sensors for Growth Rate Estimation of a Fed-Batch Bioreactor 405</p> <p>14.7.3 Base Titration for Estimating the Growth Rate in a Batch Bioreactor 407</p> <p>14.7.4 Online HPLC for the Estimation of Mixed-Acid Fermentation By-Products 409</p> <p>14.7.5 Electronic Nose and NIR Spectroscopy for Controlling Cholera Toxin Production 411</p> <p>14.8 Concluding Remarks and Outlook 413</p> <p>References 414</p> <p><b>15 Design-of-Experiments for Development and Optimization of Bioreactor Media 421</b><br /><i>Carl-Fredrik Mandenius</i></p> <p>15.1 Introduction 421</p> <p>15.2 Fundamentals of Design-of-Experiments Methodology 422</p> <p>15.2.1 Screening of Factors 423</p> <p>15.2.2 Evaluation of the Experimental Design 425</p> <p>15.2.3 Specific Design-of-Experiments Methods 429</p> <p>15.3 Optimization of Culture Media by Design-of-Experiments 431</p> <p>15.3.1 Media for Production of Metabolites and Proteins in Microbial Cultures 432</p> <p>15.3.2 Media for the Production of Monoclonal Antibodies and Other Proteins in Mammalian Cell Cultures 438</p> <p>15.3.3 Media for Differentiation and Production of Cells 441</p> <p>15.3.4 Other Applications to Media Design 443</p> <p>15.4 Conclusions and Outlook 447</p> <p>References 448</p> <p><b>16 Operator Training Simulators for Bioreactors 453</b><br /><i>Volker C. Hass</i></p> <p>16.1 Introduction 453</p> <p>16.2 Simulators in the Process Industry 455</p> <p>16.3 Training Simulators 456</p> <p>16.3.1 Training Simulator Types 457</p> <p>16.3.1.1 Simulators for "Standard" Processes 457</p> <p>16.3.1.2 Company-Specific Simulators (Taylor-Made Simulators) 457</p> <p>16.3.1.3 Process Automation and Control 458</p> <p>16.3.1.4 Training Simulators in Academic Education 458</p> <p>16.3.2 Training Simulator Purposes 459</p> <p>16.3.2.1 Training of Process Handling 459</p> <p>16.3.2.2 Training Simulators Supporting Engineering Tasks 461</p> <p>16.4 Requirements on Training Simulators 461</p> <p>16.4.1 Precise Simulation of the Chemical, Biological and Physical Events 462</p> <p>16.4.2 Realistic Simulation of Automation and Control Actions 462</p> <p>16.4.3 Real-Time and Accelerated Simulation 463</p> <p>16.4.4 Realistic User Interfaces 463</p> <p>16.4.5 Multipurpose Usage 463</p> <p>16.4.6 Maintainability for User-Friendly Model Updates 464</p> <p>16.4.7 Adaptability to Modified or Different Processes 464</p> <p>16.5 Architecture of Training Simulators 464</p> <p>16.6 Tools and Development Strategies 466</p> <p>16.7 Process Models and Simulation Technology 468</p> <p>16.7.1 Process Models 468</p> <p>16.7.2 Modeling Strategy 471</p> <p>16.7.3 Software Systems for Model Development 473</p> <p>16.7.4 Multiple Use of Models 473</p> <p>16.8 Training Simulator Examples 474</p> <p>16.8.1 Bioreactor Training Simulator 474</p> <p>16.8.2 Anaerobic Digestion Training Simulator 477</p> <p>16.8.3 Bioethanol Plant Simulator 479</p> <p>16.9 Concluding Remarks 482</p> <p>References 484</p> <p>Index 487</p>
Carl-Fredrik Mandenius is professor of Engineering Biology at Linkoping University (Sweden) since 1999 and head of the Division of Biotechnology. He holds a master and PhD degree in Engineering from Lund University. His main research interests are bioprocess engineering, biosensor technology and biotechnology design.

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