Biomechatronic Design in Biotechnology

PREFACE xiii

1 Introduction 1

1.1 Scope of Design / 1

1.2 Definition of Biomechatronic Products / 3

1.3 Principles of Biomechatronics / 4

1.4 Brief History of the Development of Biomechatronic Products and Engineering / 7

1.5 Aim of This Book / 9

References / 10

PART I FUNDAMENTALS 13

2 Conceptual Design Theory 15

2.1 Systematic Design / 15

2.1.1 Design for Products / 15

2.1.2 Origin of the Design Task / 18

2.1.3 Development of Design Thinking / 18

2.1.4 Recent Methods / 20

2.2 Basics of Technical Systems / 21

2.2.1 Energy, Material, and Signals and Their Conversion / 22

2.2.2 Interrelationships of Functions / 22

2.2.3 Interrelationship of Constructions / 25

2.2.4 Interrelationship of Systems / 25

2.3 Psychology in the Systematic Approach / 25

2.4 A General Working Methodology / 26

2.4.1 Analysis for Resolving Technical Problems / 27

2.4.2 Abstraction of Interrelationships of Systems / 28

2.4.3 Synthesis of the Technical System / 28

2.5 Conceptual Design / 28

2.6 Abstraction inOrder to Identify Essential Problems / 29

2.7 Developing the Concepts / 31

2.7.1 Organizing the Development Process / 33

2.8 Concluding Remarks / 34

References / 35

3 Biotechnology and Mechatronic Design 37

3.1 Transduction of the Biological Science into Biotechnology / 37

3.2 Biological Sciences and Their Applications / 39

3.3 Biotechnology and Bioengineering / 42

3.4 Applying Mechatronic Theory to Biotechnology: Biomechatronics / 44

3.5 Conclusions / 47

References / 48

4 Methodology for Utilization of Mechatronic Design Tools 49

4.1 Idea of Applying the Mechatronic Design Tools / 49

4.2 Table of User Needs / 51

4.3 List of Target Specifications / 52

4.4 Concept Generation Chart / 52

4.4.1 Basic Concept Component Chart / 53

4.4.2 Permutation Chart / 54

4.5 Concept Screening Matrix / 55

4.6 Concept Scoring Matrix / 56

4.7 Hubka-Eder Mapping / 57

4.7.1 Overview Hubka-Eder Map / 57

4.7.2 Zoom-in Hubka-Eder Mapping / 59

4.8 Functions Interaction Matrix / 60

4.8.1 Functions Interaction Matrix for Systems and Subsystems / 60

4.8.2 Functions Interaction Matrix for Systems and Transformation Process / 61

4.8.3 Design Structure Matrix / 61

4.9 Anatomical Blueprint / 62

4.10 Conclusions / 63

References / 63

PART II APPLICATIONS 65

5 Blood Glucose Sensors 67

5.1 Background of Blood Glucose Analysis / 67

5.2 Specification of Needs for Blood Glucose Analysis / 70

5.3 Design of Blood Glucose Sensors / 71

5.3.1 Generation of Sensor Concepts / 71

5.4 Description of the Systems Involved in the Design Concepts for Glucose Blood Sensors / 76

5.4.1 Biological Systems / 77

5.4.2 Technical Systems / 77

5.4.3 Information Systems / 78

5.4.4 Management and Goal Systems / 78

5.4.5 Human Systems / 79

5.4.6 Active Environment / 79

5.4.7 Interactions Between the Systems and Functions of the Design / 79

5.4.8 Anatomical Blueprints from the Functions Interaction Matrix Analysis / 81

5.5 Conclusions / 82

References / 82

6 Surface Plasmon Resonance Biosensor Devices 85

6.1 Introduction / 85

6.2 Design Requirements on SPR Systems / 88

6.2.1 Needs and Specifications of an SPR Design / 88

6.3 Mechatronic Design Approach of SPR Systems / 89

6.3.1 Generation of Design Alternatives / 89

6.3.2 Hubka-Eder Mapping of the Design Alternatives / 92

6.4 Detailed Design of Critical SPR Subsystems / 99

6.4.1 Design of the Sensor Surface / 100

6.4.2 Design of the Fluidic System / 103

6.5 Conclusions / 109

References / 109

7 A Diagnostic Device for Helicobacter pylori Infection 113

7.1 Diagnostic Principle of Helicobacter Infection / 113

7.2 Mechatronic Analysis of Urea Breath Test Systems / 117

7.2.1 Mission and Specification for a Urea Breath Tests / 117

7.2.2 Generation of UBT Design Concepts / 118

7.2.3 Screening and Scoring of UBT Design Concepts / 119

7.3 Description of the Systems Involved in the Design Concepts for the Urea Breath Tests / 124

7.3.1 Biological Systems Involved / 124

7.3.2 Technical Systems Alternatives / 126

7.3.3 Information Systems (SIS) Required / 127

7.3.4 Management and Goal Systems Required / 127

7.3.5 Human Systems Involved in the Testing / 127

7.3.6 Active Environment That Can Influence / 128

7.4 Aspects of the Design for Efficient Manufacture / 128

7.5 Conclusions / 131

References / 131

8 Microarray Devices 135

8.1 Principles, Methods, and Applications of Microarrays / 135

8.1.1 Principles and Technology / 135

8.1.2 Fabrication Methods / 136

8.1.3 Companies Developing Microarrays / 138

8.1.4 Applications of DNA Microarrays / 139

8.2 Specification of Needs / 141

8.3 Design of Microarrays / 142

8.3.1 Generation of cDNA Microarray Concepts / 142

8.4 Description of the Systems Involved in the Design Concepts / 145

8.4.1 Biological Systems / 146

8.4.2 Technical Systems / 147

8.4.3 Information System / 147

8.4.4 Management and Goal Systems and the Human Systems / 147

8.4.5 Active Environment / 147

8.4.6 Interaction Analysis / 148

8.5 Conclusions / 149

References / 149

9 Microbial and Cellular Bioreactors 153

9.1 Bioreactor Development During the 1970s-1990s / 153

9.2 Missions, User Needs, and Specifications for Bioreactors / 158

9.2.1 Design Mission and User Needs / 158

9.2.2 Target Specifications / 158

9.3 Analysis of Systems for Conventional Bioreactors / 161

9.3.1 Biological Systems in the Bioreactor / 161

9.3.2 Technical Systems / 164

9.3.3 Studying the Interactions of the Systems / 166

9.3.4 Penicillin Production in a Metabolically Engineered Penicillium strain (Case 1) / 168

9.3.5 A Bioreactor System Producing a Recombinant Protein in CHO Cell Culture (Case 2) / 171

9.3.6 Information Systems / 173

9.3.7 Management and Goal Systems / 177

9.3.8 Human Systems / 179

9.3.9 Active Environment / 179

9.4 Novel Bioreactor Designs / 180

9.4.1 Microbioreactors / 180

9.4.2 Bioreactors with Immobilized Cells / 183

9.4.3 Bioreactors for Tissue and Stem Cell Cultures / 185

9.4.4 Bioreactors for Plant Cell Cultures / 186

9.5 Conclusions / 187

References / 187

10 Chromatographic Protein Purification 193

10.1 Background of Chromatographic Protein Purification / 193

10.2 Specification of Needs for Protein Purification Systems / 197

10.3 Design of Purification Systems / 199

10.3.1 Generation of Design Alternatives / 199

10.3.2 Screening the Design Alternatives / 201

10.3.3 Analysis of the Generated Alternatives for a Chromatography System / 202

10.3.4 Interactions Between Key Systems and the Transformation Process / 206

10.4 Unit Operation Purification in a FVIII Production Process (Case 1) / 208

10.5 Micropurification System Based on a Multichip Device (Case 2) / 209

10.6 Conclusions / 211

References / 212

11 Stem Cell Manufacturing 215

11.1 State of the Art of Stem Cell Manufacturing / 215

11.2 Needs and Target Specifications for Scaled-Up Stem Cell Manufacturing / 218

11.3 Setting Up an Efficient Manufacturing System by Using Biomechatronic Conceptual Design / 220

11.3.1 Generating Process Alternatives / 220

11.3.2 Hubka-Eder Map for a Human Embryonic Stem Cell Process / 220

11.4 Conclusions / 225

References / 226

12 Bioartificial Organ-Simulating Devices 229

12.1 Introduction / 229

12.2 Design of Bioartificial Organ-Simulation Devices / 232

12.2.1 Needs and Specifications / 232

12.2.2 Evaluation of the Design Concepts / 236

12.3 Analysis of Bioartificial Liver Systems / 239

12.3.1 Biological Systems / 239

12.3.2 Technical Systems / 241

12.3.3 Information Systems / 242

12.3.4 Management and Goals Systems / 243

12.3.5 Human Systems / 243

12.4 Conclusions / 244

References / 244

13 Applications to Process Analytical Technology and Quality by Design 249

13.1 PAT and QbD Concepts / 249

13.2 Needs of the PAT/QbD Players and Resulting Specifications / 253

13.3 Application of Design Methodology to PAT/QbD / 255

13.3.1 Concept Generation for a PAT/QbD System Structure / 255

13.3.2 Hubka-Eder Mapping of the PAT/QbD Transformation Process for a Pharmaceutical

Process / 257

13.3.3 Analysis of Effects / 259

13.4 Applying Mechatronic Design on a PAT System for Online Software Sensing in a Bioprocess (Case) / 260

13.5 Conclusions / 263

References / 263

GLOSSARY 267

INDEX 275

"Over the past few years the field of biotechnological products, with roots in the fields of both mechanics and electronics, has achieved rapid advances in systematic design principles and methodology. The Swedish authors Carl-Fredrik Mendenius and Mats Björkman?s book Biomechatronic Design in Biotechnology aims to link aspects of biotechnology with mechanical and electrical engineering.

The content of the book is structured into two parts. The first part containing four chapters outlines the fundamentals of biomechatronic design dealing with the theory of conceptual design, biotechnology, mech atronic design, and the methodology for the use of mechatronic design tools. This concise and well-structured introduction of the basic terms and concepts shows the reader how to develop a conclusive approach to identify interrelationships between these fields, as well as how to analyze and abstract them. This is then followed by the identification of the essential biomechatronic design problems together with the organization of the development process of biotechnological products. Furthermore the first part of the book also covers the structuring of different methods of mechatronic design tools such as Hubka-Eder mapping, the use of function interaction matrices, design structure matrices as well as the anatomical blueprint. Consequently the authors briefly describe how electronics, mechanics and biotechnology overlap and why it is necessary to synthesize all three fields into biomechatronics.

The second part, applications, composed of nine chapters provides hands-on examples for the development of biotechnological devices and methods. The first chapter, dedicated to blood glucose sensors, is a perfect basic example of the development process. The chapter starts with background information and a list of specifications such as analytical devices the reader should possess. The chapter goes on to outline various conceptual designs, different systems and environments involved, and the required user specifications. This chapter is followed by the highly interesting topic of the construction of a surface plasmon resonance (SPR) biosensor device. Every part of this detection system is analyzed from a design perspective during the development pro cess of the system, meanwhile potential strategies for improvement are proposed. While the SPR technologies are well described and thoroughly analyzed, the processes described only take the BiacoreTM system from GE Healthcare and the SPREETATM system from Texas Instruments into account. The book would have benefitted from a comparison with other systems.

The next chapter in the second part addresses the very specific topic of the development process of a diagnostic device for Helicobacter pylori infection, a gastrointestinal infection that can cause gastritis with abdominal pain (stomach ache) or nausea. Several available testing methods are described in this chapter and their advantages are also compared. This chapter is followed by a mechatronic analysis of the urea breath test system in order to generate a collection of design alternatives. Once again, the various systems required are described and aspects of the design for efficient manufacturing are discussed. Similarly structured to other chapters, Chapter 8 discusses the design of microarray devices and concentrates on the needs and target specifications for DNA microarrays. Consequently the tools presented in the fundamentals sections are applied towards this conceptual design problem.

In chapter 9, on microbial and cellular bioreactors, a more intensive and detailed example is given that includes not only a distinctive system analysis but also a study of the interactions of the systems ordered by the different types of bioreactors and their application ranges from stem cell bioreactors to novel bioreactor systems. This must-read chapter contains lots of interesting insights and clever conclusions. For those interested in the topic, the research article by the same authors may also be relevant.

The next chapter is dedicated to chromatographic protein purification. In this chapter three different processes are explained: batch, membrane and chromatography configurations. The whole design process of stem cell manufacturing is outlined in chapter 11, which focuses on scale-up problems and the setup of a biomechatronic conceptual design. Bio-artificial organ-simulating devices is the topic of chapter 12 and mimics a living human or animal organ by recreating its essential functions. These devices can be used for the testing of new pharmaceuticals in vitro. In contrast to bioreactor systems described in earlier chapters, this is a far more advanced technology and its needs and specifications are more diverse. The authors conclude that for such a specific device the formulation of a clear mission is most important during the design process and outline the strategy. While this chapter is fairly short it is well written and points out the direction of research in terms of drug testing method development.

The book finishes with a chapter on process analytical technology (PAT) and quality-by-design (QbD) approaches. In this very interesting section of the book, the authors describe the different perspectives for an appropriate PAT process such as inter- scientific understanding and knowledge management. QbD and PAT approaches are synthesized into the conceptual design methodology (e.g. Hubka-Eder mapping).

This book effectively presents the methodology and most of the necessary tools for a design process in biotechnology. I thus recommend this book to students who want to learn the fundamentals and basic applications of a product design process quickly. It is also a good read for professors, researchers and professionals from both engineering and biology in order to get helpful input for their own device or method developments. In conclusion, this book is a must-read for all modern bio-scientists and engineers working in the field of biotechnology. "

- Biotechnology Journal, 2012, 7

Professor Carl-Fredrik Mandenius is head of the Division of Biotechnology at Linkoping University in Sweden. His main research interests include biochemical and bio-production engineering, bioprocess monitoring and control, stem cell technology, and biosensor technology. He was a director for process R&D at Pharmacia AB and has coordinated several EU networks on hESC-derived models for drug testing.

Professor Mats Björkman is head of the Division of Assembly Technology at Linkoping University in Sweden. His main research interests include design and operation of flexible manufacturing systems and equipment. He has also been involved in research that has developed from traditional mechanical industries to include areas such as electronic manufacturing and manufacturing of biotech equipment, as well as pharmaceutical products.