Preface
Part I. Historical Development of Animal Cell Bioreactors
1. An Overview of Animal Cell Biotechnology: The Conjoint Application of Science, Art, and Engineering
1.1 Shear and Bubbles
1.2 High Cell Concentration Systems
1.3 Modern Bioprocess Engineering for Animal-Cell Containing Systems
1.4 Conclusions
References
Part II. Implications of Cell Biology on Bioreactor Operation
2. Implications of Cell Biology in Animal Cell Biotechnology
2.1 Cell Status
2.2 Status of Extracellular Environment
2.3 Cell-Environment Interaction
2.4 Dynamics of Interaction of Cell and Environment
References
3. Protein Glycosylation: Function and Factors That Regulate Oligosaccharide Structure
3.1 Structure and Heterogeneity of the Protein-Bound Oligosaccharides
3.2 Factors That Influence the Structure of Protein-Bound Oligosaccharides
3.3 Conclusion
References
4. Serum-Free Media
4.1 Chemically Defined Serum-Free Media
4.2 Serum-Free Media-Containing Serum-Substitutes
4.3 Production of Biologically Active Substances by Serum-Free Cultures
4.4 Conclusion
References
5. Nuclear Magnetic Resonance Spectroscopy of Dense Cell Populations for Metabolic Studies and Bioreactor Engineering: A Synergistic Partnership
5.1 Phenomena That Can and Cannot Be Measured by NMR
5.2 Some Representative NMR Spectra
5.3 Current Limitations on Whole Cell NMR: Sensitivity and the Need for Weil-Defined Bioreactors
5.4 Bioreactor Engineering Considerations
5.5 Quantitative Measures of Diffusion and Reaction
5.6 Design Procedures Involving Weisz's Modulus
5.7 Experimental Confirmations of Reaction Rate Control: Toward Gradientless Bioreactors
5.8 Uses of NMR in Bioreactor Analysis and Design
5.9 Summary
References
6. Regulation of Animal Cell Metabolism in Bioreactors
6.1 Metabolism of Cultured Cells
6.2 Methods for Obtaining Metabolic Information in Bioreactors
6.3 Metabolic Results Obtained in Continuous Suspension Bioreactors
6.4 Models of Cell Metabolism
References
Part III. Anchorage-Dependent Cell Supports
7. Fixed Immobilized Beds for the Cultivation of Animal Cells
7.1 General Principles
7.2 Historical Developments in Animal Cell Immobilization
7.3 Fixed Beds in a Production Process
7.4 Optimization of Glass Sphere Reactors
7.5 Porous Packing Materials for High Cell Density Culture
7.6 Conclusion
References
8. Microcarriers for Animal Cell Biotechnology: An Unfulfilled Potential
8.1 Times Past
8.2 Three-Dimensional Microcarriers
8.3 The Problems Expounded
8.4 Current Manifestations of Three-Dimensional Microcarriers
8.5 Conclusions
References
9. Hydrodynamic Effects on Animal Cells in Microcarrier Bioreactors
9.1 Methods of Investigation
9.2 Hydrodynamic Effects on Cell Growth
9.3 Hydrodynamic Effects on Cell Metabolism
9.4 Fluid-Lift, Airlift, and Stirred-Tank Bioreactors
9.5 Mechanisms of Hydrodynamic Cell Death
9.6 Cell Damage from Direct Sparging
9.7 Protective Polymers
9.8 Recommendations for Future Research
9.9 Nomenclature
References
Part IV. Animal Cell Bioreactor Design, Operation, And Control
10. Scaleup of Animal Cell Suspension Culture
10.1 Scaleup Principles
10.2 Bioreactor Scaleup
10.3 Process Scaleup
10.4 Conclusions
10.5 Nomenclature
References
11. Continuous Cell Culture
11.1 Methods of Continuous Cell Culture
11.2 Automation
11.3 Assessing Cell Yield and Productivity in an Immobilized System
11.4 Maintaining Steady-State Conditions
11.5 Maintenance Media
11.6 Cell Density in Perfusion Systems
11.7 Rapid Product Isolation and Nutrient Manipulation
11.8 Scalability
References
12. Optimization of the Microenvironment for Mammalian Cell Culture in Flexible Collagen Microspheres in a Fluidized-Bed Bioreactor
12.1 Verax Microspheres and Cell Viability
12.2 The Verax Fluidized Bed Reactor
12.3 Cell-Cell and Cell-Matrix Interactions
12.4 The Microenvironment
12.5 Bioreactor Productivity and Product Quality
12.6 Summary
References
13. High Density Cell Culture
13.1 Development of a New Perfusion Culture Process
13.2 Perfusion Culture with Recycling of High Molecular Weight Components
13.3 High Density Culture Using Fluorocarbon to Supply Oxygen
References
14. Diffusion and Convection in Membrane Bioreactors
14.1 Diffusive Mass Transfer
14.2 Convective Mass Transfer
14.3 Simultaneous Diffusive and Convective Mass Transfer
14.4 Conclusions
References
15. Bioreactor Control and Optimization
15.1 Process Goals
15.2 Process Control: Direct Control of Measured Variables
15.3 Process Control from Inferred Measurements
15.4 Feed-Forward Control Using Empirically Derived Mathematical Relations
15.5 Speculative Strategies for Manipulating Cellular Metabolism to Improve Bioreactor Performance
15.6 Nomenclature
References
16. Instrumentation of Animal Cell Culture Reactors
16.1 Theoretical Approaches
16.2 State of the Art
16.3 Future Developments
16.4 Conclusions
References
17. Large-Scale Process Purification of Clinical Product from Animal Cell Cultures
17.1 Potential Product Contaminants Derived from Animal Cell Culture Processes
17.2 Discussion of a cGMP Ion Exchange Process Purification Scheme for a Monoclonal IgG
17.3 Use of Protein a Affinity Chromatography for Monoclonal IgG Purification
17.4 The Impact of Cell Culture Techniques on Product Integrity
17.5 Summary of Key Points
References
Index