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 ...
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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 B???chs 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 J???rg 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
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