Bioreactors: Design, Operation and Novel Applications

Bioreactors: Design, Operation and Novel Applications

By: Carl-Fredrik Mandenius (author)Hardback

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Description

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. 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. With its focus on cutting-edge technologies and discussions of future developments, this handbook will remain an invaluable reference for many years to come.

About Author

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.

Contents

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

Product Details

  • ISBN13: 9783527337682
  • Format: Hardback
  • Number Of Pages: 520
  • ID: 9783527337682
  • weight: 1082
  • ISBN10: 3527337687

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