This practical book presents the modeling of dynamic biological engineering processes in a readily comprehensible manner, using the unique combination of simplified fundamental theory and direct hands-on computer simulation. The mathematics is kept to a minimum, and yet the 60 examples illustrate almost every aspect of biological engineering science, with each one described in detail, including the model equations. The programs are written in the modern user-friendly simulation language Berkeley Madonna, which can be run on both Windows PC and Power-Macintosh computers.

Madonna solves models comprising many ordinary differential equations using very simple programming, including arrays. It is so powerful that the model parameters may be defined as "sliders", which allow the effect of their change on the model behavior to be seen almost immediately. Data may be included for curve fitting, and sensitivity or multiple runs may be performed. The results can be viewed simultaneously on multiple-graph windows or by using overlays. The examples can be varied to fit any real situation, and the suggested exercises provide practical guidance.

The extensive teaching experience of the authors is reflected in this well-balanced presentation, which is suitable for the teacher, student, biochemist or the engineer.

Elmar Heinzle is Senior Professor of Biochemical Engineering at the Saarland University in Saarbrücken, Germany. Having obtained his academic degrees from the Technical University of Graz, Austria, he spent a large fraction of his career at the Chemical Engineering Department of ETH-Zurich, Switzerland, before becoming Chair of Biochemical Engineering at the Saarland University. In 2003 he was Guest Professor at the Biotechnology Institute (University of Minnesota, St. Paul) and in 2004 at the Agricultural Department (University of Kyoto, Kyoto). Professor Heinzle published well over 200 scientific publications in bioreactor design, metabolic engineering and systems biology, mammalian cell culture, on-line analysis and control and design of sustainable processes. In his teaching in Biochemical and Chemical Engineering he is extensively using modeling. He has authored several books in these fields.

Irving J. Dunn is retired from the ETH-Zurich, where he taught and did research in the area of biochemical engineering for over thirty years, within the Chemical Engineering Dept. His degrees are from the University of Washington and Princeton University.  Dr. Dunn has published widely in his field, ranging from bioreactor design, process control, animal cell culture, and specialized wastewater treatment. His teaching and research has featured the use of modeling and simulation and has resulted in the publication of three textbooks: Biological Reaction Engineering, Dynamics of Environmental Bioprocesses and Chemical Engineering Dynamics. In 1981 he founded the renowned International Modeling and Simulation Courses in Braunwald, Switzerland.

John Ingham is now retired from Chemical Engineering at Bradford University U.K. The first of a long series of courses on the Modeling and Simulation of Dynamical Chemical Engineering Systems was begun there in 1974, sponsored by the Institution of Chemical Engineers and inspired by leave of absence at the ETH Zurich. Research areas include Liquid-Liquid Column Hydrodynamics, Extraction Process Dynamics and Biochemical Engineering; the latter, being developed, during a further leave of absence at the GBF, Braunschweig. He is especially proud of this and the two other VCH-Wiley Modeling and Simulation books.

Jirí E. Prenosil was born 1939 in Prague, Czechoslovakia. Educated in Prague with PhD in Chemical Engineering, he worked in the Czechoslovak Academy of Science and various universities abroad. 1971 he moved to Switzerland with appointment at the Swiss Federal Institute of Technology (ETH) in Zürich. 1984 he was a Visiting Professor at the University of London, Canada. His life interest is in Biochemical Engineering, design and modeling of bioreactors with immobilized biocatalysts. It has resulted in over 100 publications and co-authorship of two other books in this area. He is a co-founder of the renowned International Modeling and Simulation Courses in Braunwald, Switzerland since 1981. 1997 he was granted the Swiss Technology Transfer Award. In 2006, he retired from the ETH.

Preface xiii

Acknowledgments xxi

Nomenclature for Part I xxiii

List of Simulation Examples xxviii

Part I Principles of Bioreactor Modeling 1

1 Modeling Principles 3

1.1 Fundamentals of Modeling 3

1.2 Development and Meaning of Dynamic Differential Balances 9

1.3 Formulation of Mass Balance Equations 13

1.4 Additional Relationships 29

1.5 Thermodynamics and Equilibrium Relationships 35

1.6 Energy Balancing for Bioreactors 38

1.7 Time Constants 43

2 Basic Bioreactor Concepts 47

2.1 Information for Bioreactor Modeling 47

2.2 Bioreactor Operation 48

3 Biological Kinetics 57

3.1 Enzyme Kinetics 58

3.2 Simple Microbial Kinetics 65

3.3 Interacting (Micro-)organisms 72

3.4 Structured Kinetic Models 77

4 Basic Bioreactor Modeling 91

4.1 General Balances for Tank-type Biological Reactors 91

4.2 Modeling Tubular Plug Flow Bioreactors 102

5 Mass Transfer 105

5.1 Mass Transfer in Biological Reactors 105

5.2 Interphase Gas-Liquid Mass Transfer 106

5.3 General Oxygen Balances for Gas-Liquid Transfer 109

5.4 Models for Oxygen Transfer in Large-scale Bioreactors 120

6 Diffusion and Biological Reaction in Immobilized Biocatalyst Systems 127

6.1 External Mass Transfer 128

6.2 Internal Diffusion and Reaction Within Biocatalysts 130

7 Automatic Bioprocess Control Fundamentals 143

7.1 Elements of Feedback Control 144

7.2 Measurement of Process Variables 144

7.3 Types of Controller Action 147

7.4 Controller Tuning 150

7.5 Advanced Control Strategies 153

7.6 Application Strategies of Bioprocess Control 155

8 Basic Cell and Bioreactor Models 159

8.1 Basic Cell Balances 160

8.2 The Link of the Cell Balances to a Bioreactor 162

8.3 Organism Modeling 168

References Part I and Recommended Textbooks and References for Further Reading 173

Part II Dynamic Bioprocess Modeling and Simulation

Examples Using the Berkeley Madonna Simulation Language 187

9 Dynamic Bioprocess Modeling Examples 189

9.1 Modeling a Roman Fountain 190

9.2 Modeling a Lake 191

9.3 Modeling a Mammalian Cell Recirculation Reactor with External Aeration 192

9.4 Modeling Protein Synthesis and Secretion in a Eukaryotic Cell 193

9.5 Modeling a Liver Sinusoid 194

10 Simulation Examples of Biological Reaction Processes Using Berkeley Madonna 197

10.1 Introductory Simulation Examples 199

10.2 Batch Reactors 229

10.3 Fed-batch Reactors 247

10.4 Continuous Reactors 275

10.5 Oxygen Uptake Systems 329

10.6 Diffusion Systems 361

10.7 Controlled Reactors 393

10.8 Membrane and Cell Retention Reactors 419

10.9 Multi-organism Systems 447

10.10 Structured and Metabolic Network Models 487

Appendix A Using the Berkeley Madonna Language and Accessing the Simulation Examples: A Short Guide 519

A.1. Computer Requirements 519

A.2. Downloading Simulation Examples and the Berkeley Madonna Program for this Book 519

A.3. Running Programs 520

Index 521