Tissue engineering involves seeding of cells on bio-mimicked scaffolds providing adhesive surfaces. Researchers though face a range of problems in generating tissue which can be circumvented by employing nanotechnology. It provides substrates for cell adhesion and proliferation and agents for cell growth and can be used to create nanostructures and nanoparticles to aid the engineering of different types of tissue. Written by renowned scientists from academia and industry, this book covers the recent developments, trends and innovations in the application of nanotechnologies in tissue engineering and regenerative medicine. It provides information on methodologies for designing and using biomaterials to regenerate tissue, on novel nano-textured surface features of materials (nano-structured polymers and metals e.g.) as well as on theranostics, immunology and nano-toxicology aspects. In the book also explained are fabrication techniques for production of scaffolds to a series of tissue-specific applications of scaffolds in tissue engineering for specific biomaterials and several types of tissue (such as skin bone, cartilage, vascular, cardiac, bladder and brain tissue). Furthermore, developments in nano drug delivery, gene therapy and cancer nanotechonology are described. The book helps readers to gain a working knowledge about the nanotechnology aspects of tissue engineering and will be of great use to those involved in building specific tissue substitutes in reaching their objective in a more efficient way. It is aimed for R&D and academic scientists, lab engineers, lecturers and PhD students engaged in the fields of tissue engineering or more generally regenerative medicine, nanomedicine, medical devices, nanofabrication, biofabrication, nano- and biomaterials and biomedical engineering.
- Provides state-of-the-art knowledge on how nanotechnology can help tackling known problems in tissue engineering
- Covers materials design, fabrication techniques for tissue-specific applications as well as immunology and toxicology aspects
- Helps scientists and lab engineers building tissue substitutes in a more efficient way
Tissue engineering involves seeding of cells on bio-mimicked scaffolds providing adhesive surfaces. Researchers though face a range of problems in generating tissue which can be circumvented by employing nanotechnology. It provides substrates for cell adhesion and proliferation and agents for cell growth and can be used to create nanostructures and nanoparticles to aid the engineering of different types of tissue. Written by renowned scientists from academia and industry, this book covers the recent developments, trends and innovations in the application of nanotechnologies in tissue engineering and regenerative medicine. It provides information on methodologies for designing and using biomaterials to regenerate tissue, on novel nano-textured surface features of materials (nano-structured polymers and metals e.g.) as well as on theranostics, immunology and nano-toxicology aspects. In the book also explained are fabrication techniques for production of scaffolds to a series of tissue-specific applications of scaffolds in tissue engineering for specific biomaterials and several types of tissue (such as skin bone, cartilage, vascular, cardiac, bladder and brain tissue). Furthermore, developments in nano drug delivery, gene therapy and cancer nanotechonology are described. The book helps readers to gain a working knowledge about the nanotechnology aspects of tissue engineering and will be of great use to those involved in building specific tissue substitutes in reaching their objective in a more efficient way. It is aimed for R&D and academic scientists, lab engineers, lecturers and PhD students engaged in the fields of tissue engineering or more generally regenerative medicine, nanomedicine, medical devices, nanofabrication, biofabrication, nano- and biomaterials and biomedical engineering. Provides state-of-the-art knowledge on how nanotechnology can help tackling known problems in tissue engineering Covers materials design, fabrication techniques for tissue-specific applications as well as immunology and toxicology aspects Helps scientists and lab engineers building tissue substitutes in a more efficient way
Front Cover 1
Nanotechnology Applications for Tissue Engineering 4
Copyright Page 5
Contents 6
List of Contributors 14
About the Editors 18
Preface 20
1 Nanomedicine and Tissue Engineering 22
1.1 Introduction 22
1.1.1 Nanomedicine 22
1.1.2 Tissue Engineering 23
1.2 Relationship of Nanomedicine and Tissue Engineering 23
1.2.1 Nanomedicine Approaches in Bone Tissue Engineering 25
1.2.2 Nanomedicine Approaches in Cardiac Tissue Engineering 26
1.2.3 Nanomedicine Approaches in Skin Tissue Engineering 27
1.2.4 Nanomedicine Approaches in Brain Tissue Engineering 28
1.2.5 Nanomedicine Approaches for Other Tissue Engineering Disciplines 28
1.3 Nanodrug Delivery Systems for Tissue Regeneration 29
1.3.1 Nanotheranostics 29
1.3.2 Nanoregeneration Medicine 30
1.3.3 Nanodrug Delivery 30
1.3.3.1 Dendrimers 30
1.3.3.2 Liposomes 31
1.3.3.3 Carbon Nanotubes 33
1.3.3.4 Nanocomposite Hydrogel 34
1.4 Medical Applications of Molecular Nanotechnology 34
1.4.1 Nanorobots 34
1.4.2 Cell Repair Machines 35
1.5 Summary and Future Directions 35
References 35
2 Biomaterials: Design, Development and Biomedical Applications 42
2.1 Overview 42
2.2 Design of Biomaterials 43
2.2.1 Polymers 44
2.2.2 Metals 44
2.2.3 Composite Materials 45
2.2.4 Ceramics 46
2.3 Basic Considerations to Design Biomaterial 46
2.4 Characteristics of Biomaterials 47
2.4.1 Nontoxicity 47
2.4.2 Biocompatible 48
2.4.3 Absence of Foreign Body Reaction 48
2.4.4 Mechanical Properties and Performance 48
2.5 Fundamental Aspects of Tissue Responses to Biomaterials 49
2.5.1 Injury 49
2.5.2 Blood–Material Interactions and Initiation of the Inflammatory Response 50
2.5.3 Provisional Matrix Formation 50
2.5.4 Acute Inflammation 50
2.5.5 Chronic Inflammation 51
2.5.6 Granulation Tissue 51
2.5.7 Foreign Body Reaction 51
2.5.8 Fibrosis and Fibrous Encapsulation 51
2.6 Evaluation of Biomaterial Behavior 52
2.6.1 Assessment of Physical Properties 52
2.6.2 In vitro Assessment 52
2.6.3 In vivo Assessment 53
2.7 Properties of Biomaterials Assessed Through In Vivo Experiments 54
2.7.1 Sensitization, Irritation, and Intracutaneous Reactivity 55
2.7.2 Systemic, Subacute, and Subchronic Toxicity 55
2.7.3 Genotoxicity 55
2.7.4 Implantation 55
2.7.5 Hemocompatibility 56
2.7.6 Chronic Toxicity 56
2.7.7 Carcinogenicity 56
2.7.8 Reproductive and Developmental Toxicity 57
2.7.9 Biodegradation 57
2.7.10 Immune Responses 57
2.8 Applications of Biomaterials 57
2.8.1 Orthopedic Applications 57
2.8.2 Ophthalmologic Applications 58
2.8.3 Cardiovascular Applications 58
2.8.4 Dental Applications 59
2.8.5 Wound Dressing Applications 60
2.8.6 Other Applications 60
2.9 Future Directions in Biomaterials 61
2.10 Conclusions 62
Acknowledgments 62
References 62
3 Electrospinning of Polymers for Tissue Engineering 66
3.1 Introduction 66
3.2 History of Electrospinning 67
3.3 Experimental Setup and Basic Principle 67
3.3.1 Theoretical Background 69
3.4 Effects of Parameters on Electrospinning 70
3.4.1 Solution Parameters 70
3.4.2 Concentration and Viscosity 70
3.4.3 Molecular Weight 70
3.4.4 Surface Tension 71
3.4.5 Conductivity of the Solution 71
3.4.6 Applied Voltage 71
3.4.7 Flow Rate of the Solution 72
3.4.8 Tip to Collector Distance 72
3.4.9 Collector Composition and Geometry 72
3.4.10 Ambient Parameters 72
3.5 Biomedical Applications of Electrospun Nanofibers 73
3.6 Conclusion 74
Acknowledgments 74
References 74
4 Biomimetic Nanofibers for Musculoskeletal Tissue Engineering 78
4.1 Structural and Functional Requirements for Musculoskeletal Tissues 78
4.1.1 Tendons and Ligaments 78
4.1.2 Knee Meniscus 79
4.1.3 Intervertebral Disc 79
4.1.4 Bone 79
4.1.5 Tissue Interfaces 80
4.2 Nanofibers as 3D Scaffolds for Tissue Regeneration 81
4.2.1 Aligned Fibers for Musculoskeletal Engineering 82
4.2.2 Braided Nanofibers for Ligament and Tendon Regeneration 83
4.2.3 Hybrids, Nanocomposites, and Surface Mineralization of Fibers for Bone Regeneration 84
4.3 Extracellular Matrix Analogs for Cartilage Regeneration 85
4.4 Bioactive Nanofibers and Methods of Immobilizing Biomolecules 86
4.5 Gene Delivery Through Nanofibers 88
4.6 Techniques to Improve Porosity and Cell Infiltration on Nanofiber Scaffolds 89
4.7 Nanofiber Scaffolds for Interface Regeneration 90
4.8 Conclusion 91
References 92
5 Hydrogels—Promising Candidates for Tissue Engineering 98
5.1 Introduction 98
5.2 Polymer 98
5.3 Hydrogel 100
5.3.1 Important Properties of Hydrogel 101
5.3.2 Classification of Hydrogels 102
5.4 Different Types of Hydrogels Used in TE 104
5.4.1 Fibroin and Silk Hydrogel 105
5.4.2 Bioresponsive Hydrogel 106
5.4.3 Thermoresponsive Hydrogel 107
5.4.4 Glucose-Responsive Hydrogels 107
5.4.5 pH-Responsive Hydrogels 107
5.4.6 Microengineering Hydrogel 108
5.4.7 Photopolymerized Hydrogels 108
5.4.8 Nanocomposite Hydrogels 109
5.5 Conclusion 110
References 110
6 3D Scaffolding for Pancreatic Islet Replacement 116
6.1 Introduction 116
6.2 Oxygenation—Prime Factor for Islet Survival 121
6.3 Conclusion 122
Acknowledgments 122
References 122
7 Scaffolds with Antibacterial Properties 124
7.1 Introduction 124
7.2 Nanoparticles Incorporated Antibacterial Scaffolds 125
7.2.1 Silver Nanoparticle-Loaded Tissue Engineering Scaffolds 126
7.2.2 ZnO Nanoparticle-Loaded Tissue Engineering Scaffolds 128
7.2.3 Nanoceria-Doped Nanoparticle-Loaded Tissue Engineering Scaffolds 131
7.3 Antibiotics-Loaded Tissue Engineering Scaffolds 135
7.4 Conclusion 141
Acknowledgments 141
References 141
8 Dermal Tissue Engineering: Current Trends 146
8.1 Introduction 146
8.2 Nanotopography-Guided Skin Tissue Engineering 147
8.3 Stem Cells for Skin Tissue Engineering 148
8.4 Scarless Fetal Skin Wound Healing 150
8.5 Conclusion 151
Acknowledgment 151
References 151
9 Chitosan and Its Application as Tissue Engineering Scaffolds 154
9.1 Introduction 154
9.2 Chitosan as Biomaterial for Tissue Engineering Scaffold 154
9.2.1 Porous Scaffold 155
9.2.2 Microsphere Scaffold 157
9.2.3 Hydrogel Scaffold 159
9.2.4 Nanofiber Scaffold 162
9.3 Biomedical Applications 162
9.3.1 Bone Tissue Engineering 162
9.3.2 Skin Tissue Engineering 163
9.4 Conclusion 164
Acknowledgment 164
References 165
10 Cell Encapsulation in Polymeric Self-Assembled Hydrogels 170
10.1 Overview 170
10.2 Preparation of Self-Assembled Hydrogels 171
10.2.1 Method (A) 171
10.2.2 Method (B) 171
10.3 Hydrogels Characteristics for Cells 172
10.3.1 Mechanical Properties of Hydrogels 173
10.3.2 Hydrogels Biodegradability 173
10.3.3 Porosity of Hydrogels 173
10.4 Self-Assembled Hydrogels 174
10.5 Significance of Natural and Synthetic Polymer for Hydrogels 175
10.5.1 Natural Polymers 175
10.5.2 Synthetic Polymers 178
10.5.3 Natural and Synthetic Polymers 181
10.6 Recent Development of Self-Assembled Hydrogels 184
10.7 Future Trends 185
10.8 Conclusions 186
Acknowledgments 186
References 187
11 Nanotechnology-Enabled Drug Delivery for Cancer Therapy 194
11.1 Cancer 194
11.2 Mutation of Gene 195
11.2.1 Oncogenes 195
11.2.2 Tumor Suppressor Genes 195
11.2.3 DNA Repair Genes 195
11.3 Nanotechnology and Its Application 196
11.4 Cancer Detection and Diagnosis 197
11.4.1 Cancer Detection Using Biomarkers 197
11.4.2 Molecular Cancer Imaging 197
11.4.3 Molecular Cancer Diagnosis 198
11.5 Pharmaceutical Nanotechnology 198
11.5.1 Carbon Nanotubes 199
11.5.2 Quantum Dots 199
11.5.3 Dendrimers 204
11.5.4 Metallic Nanoparticles 206
11.6 Conclusion 209
Acknowledgment 209
References 209
12 Nanomedicine in Theranostics 216
12.1 Introduction 216
12.2 Nanotheranostics—A New Concept of Nanomedicine 217
12.3 Design of Theranostic Agents 219
12.4 Diagnosis Through Nanoparticle Imaging 219
12.4.1 Role of QDs in Bioimaging 220
12.4.2 Gold Nanoparticles as Imaging Agents 221
12.4.3 Superparamagnetic Iron Oxide Nanoparticles for MRI 222
12.5 Therapy in Nanotheranostics—Drugs 223
12.5.1 Chemical Drugs 223
12.5.2 Genetic Drugs 224
12.6 Carriers of the Nanotheranostic System 225
12.6.1 Micelles as a Theranostic Carrier 226
12.6.2 Liposomes in Nanotheranostics 226
12.7 Theranostic Applications—the Current Situation 227
12.8 Future Perspectives of Nanotheranostics 231
12.9 Conclusion 231
References 232
13 Upconversion Nanoparticles 236
13.1 Introduction 236
13.2 Properties of UCNPs 236
13.3 Applications in Drug Delivery 237
13.4 Applications in Biological Imaging 238
13.5 Applications in Biological Detection 239
13.6 Conclusion and Future Outlook 240
Acknowledgments 240
References 241
14 Gold Nanoparticles in Cancer Drug Delivery 242
14.1 Introduction 242
14.2 Cancer Nanotechnology 242
14.2.1 Nanomaterials for Biomedical Applications 243
14.2.2 Biodistribution of Nanoparticles 244
14.2.3 Enhanced Permeation and Retention Effect 244
14.2.4 Passive Targeting by Nanoparticles 245
14.2.5 Active Targeting by Nanoparticles 245
14.2.6 Potential to Overcome Drug Resistance 246
14.3 Gold Nanoparticles 246
14.3.1 Gold Nanoparticles in Biology and Medicine 247
14.3.2 Gold Nanoparticles in Cancer Therapy 248
14.3.2.1 Targeted Drug Delivery Using Gold Nanoparticles 250
14.3.2.2 Photothermal Therapy 250
14.3.2.3 Gold Nanoparticles for Cancer Diagnosis 251
14.3.3 Biocompatibility of Gold Nanoparticle 252
14.4 Conclusion 252
References 253
15 Toxicology Considerations in Nanomedicine 260
15.1 Introduction 260
15.2 The Market Potential of Nanomedicines 260
15.3 Toxicity Associated with Nanomedicine 261
15.3.1 Dendrimers 261
15.3.2 Carbon Nanotubes 262
15.3.3 Fullerenes 264
15.3.4 Quantum Dots 267
15.3.5 Metallic NPs 269
15.4 Factors Affecting Nanomedicine Toxicity 272
15.4.1 Size 272
15.4.2 Shape 273
15.4.3 Surface Charge 273
15.4.4 Composition 273
15.4.5 Surface Coating 274
15.5 Toxicological Testing 274
15.5.1 In vitro Methods 274
15.5.2 In vivo Methods 276
15.5.3 In silico Methods 277
15.6 Conclusion 277
References 277
16 Role of Nanogenotoxicology Studies in Safety Evaluation of Nanomaterials 284
16.1 Introduction 284
16.2 Influence of the NMs’ Properties on their Biological Interactions 286
16.3 A Conceptual Framework for Toxicological Investigation in Nanomedicine 288
16.4 Nanogenotoxicology—an Essential Contribution for NMs Safety Assessment 290
16.4.1 The Standard Test Battery for Genotoxicity Assessment 290
16.4.2 Adaptation of the Standard Test Battery for Genotoxicity Assessment of NMs 295
16.5 State of the Art on Genotoxicity of NMs with Potential Interest for Scaffolds Fabrication 297
16.5.1 Polymers 298
16.5.2 Ceramics 300
16.5.3 Composites 300
16.6 Future Directions in the Genotoxicity Evaluation of NMs for Tissue Engineering 301
16.7 Conclusions 302
Acknowledgments 303
References 303
17 Future of Nanotechnology in Tissue Engineering 310
17.1 Introduction 310
17.1.1 Scaffold 311
17.1.2 Bone and Cartilage Tissue Engineering 312
17.1.3 Vascular Tissue Engineering 317
17.1.4 Nerve Regeneration 318
17.1.5 Nanomaterials in Bladder Tissue Engineering 322
17.2 Conclusion and Future Outlook 323
References 324
Index 328
Biomaterials
Design, Development and Biomedical Applications
Gownolla Malegowd Raghavendra1, Kokkarachedu Varaprasad2,3 and Tippabattini Jayaramudu1,3, 1Synthetic Polymer Laboratory, Department of Polymer Science & Technology, Sri Krishnadevaraya University, Anantapur, Andhra Pradesh, India, 2Department of Materials Engineering, Faculty of Engineering, University of Concepcion, Concepcion, Chile, 3Department of Polymer Technology, Tshwane University of Technology, Pretoria, Republic of South Africa
The explorations in medical sciences have provided innumerable biomaterials that can perform, augment, or replace the natural function of a defective organ by interacting with the biological system. These materials represent a unique class of biomedical functional materials that potentially perform broad spectrum of biological activities in the absence of the original living tissue/organ, thereby replace the problems encountered with the defective tissue/organ and support smooth functioning of the organ and the living organism. The day-to-day increased demand in the medical field for the bioalternatives that could be able to perform the living activities of bodily organs has raised the interest of the researchers to design novel biomaterials. Hence, the study of biomaterials has become crucial for the material scientists and engineers to understand more about biomaterials. In that point of view, the present chapter focuses on the design, development, and biomedical applications of biomaterials.
Keywords
Biomaterials; defective organ; biomedical functional materials; living organism; bioalternatives
2.1 Overview
Trauma, degeneration and diseases often bring the necessity of surgical repair. This usually requires replacement of the skeletal parts that include knees, hips, finger joints, elbows, vertebrae, teeth, and other bodily vital organs like kidney, heart, skin, etc. All these materials which perform the respective function of the living materials when replaced are termed as “Biomaterials.” The Clemson University Advisory Board for biomaterials has formally defined biomaterial as “a systemically and pharmacologically inert substance designed for implantation within or incorporation with living systems” [1]. Biomaterial is also defined as “a nonviable material used in a medical device, intended to interact with biological systems” [2]. Other definitions of biomaterial include “materials of synthetic as well as of natural origin in contact with tissue, blood, and biological fluids, intended for use for prosthetic, diagnostic, therapeutic, and storage applications without adversely affecting the living organism and its components” [3] and “any substance (other than drugs) or combination of substances, synthetic or natural in origin, which can be used for any period of time, as a whole or as a part of a system which treats, augments, or replaces any tissue, organ, or function of the body” [4]. As the definition for the term “biomaterial” has been difficult to formulate, the more widely accepted working definitions include: “A biomaterial is any material, natural or man-made, that comprises whole or part of a living structure or biomedical device which performs, augments, or replaces a natural function” [5]. The word “Biomaterial” should not be confusing with the word “Biological material.” In general, a biological material is a material such as skin or artery, produced by a biological system.
The study of biomaterials is called ‘Biomaterials Science’ which encompasses the elements of medicine, biology, chemistry, tissue engineering, and materials science. A number of factors, including the aging population, increasing preference by younger to middle aged candidates to undertake surgery, improvements in the technology and life style, better understanding of body functionality, improved esthetics and need for better function resulted in enormous expansion of Biomaterial Science from day to day and it is supposed to be a continuous process. As the field of biomaterials experienced steady and strong growth, many companies are investing larger amounts of money for the development of new products.
Biomaterial is not of a recent origin. The introduction of nonbiological materials into the human body was noted many centuries ago, far back in prehistory. The remains of a human found near Kennewick, WA (often referred to as the “Kennewick Man”) concluded the usage of a spear point embedded in his hip which was dated to be 9000 years old [6]. Some of the earliest biomaterial applications were found as far back in ancient Phoenicia, where loose teeth were bound together with gold wires for tying artificial ones to neighboring teeth. The Mayan people fashioned nacre teeth from sea shells in roughly 600 AD and apparently achieved what we now refer to as bone integration. Similarly, a corpse dated 200 AD with an iron dental implant found in Europe was described as properly bone integrated [7]. Though there was no materials science, biological understanding, or medicine behind the followed procedures, still their success is impressive and highlights two points: the forgiving nature of the human body and the pressing drive, even in prehistoric times, to address the loss of physiologic/anatomic function with an implant [6]. It is understood from the sources that though there were no medical device manufacturers, no formalized regulatory approval processes, no understanding of biocompatibility, and no certain academic courses on biomaterials, yet crude biomaterials have been used, generally with poor to mixed results, throughout history.
In the modern times, early in the 1900s, bone plates were introduced to aid in the fixation of long bone fractures [8]. Many of these early plates broke as a result of unsophisticated mechanical design, as they were too thin and had stress concentrating corners. Also, materials such as vanadium steel though chosen as biomaterial owing to its good mechanical properties, corroded rapidly in the body and caused adverse effects on the healing processes. Hence, better designs and materials were soon followed. With the introduction of stainless steels and cobalt chromium alloys in the 1930s, greater success was achieved in fracture fixation, and the first joint replacement surgeries were performed [9]. As for polymers, poly(methyl methacrylate) was widely used for replacements of sections of damaged skull bones. Following further advances in materials and in surgical technique, in 1950s blood vessel replacements were tried and during 1960s, heart valve replacements and cemented joint replacements came into usage. Recent years have seen many further advances [10–12]. At the dawn of the twenty-first century, biomaterials are widely used throughout medicine, dentistry, and biotechnology. Biomaterials which existed 50 years ago did not exist today as they are replaced by newer ones that give much more comfort indicating the day-to-day advances in the biomaterials field [6]. Hence, keeping all these into consideration, the chapter is aimed to describe the design and development of biomaterials. In addition to these, biomedical applications are also discussed.
2.2 Design of Biomaterials
Biomaterial is a nonviable (able to function successfully after implantation) substance intended to interact with biological systems. Their usage within a physiological medium is possible with the efficient and reliable characteristics of the biomaterials [13]. These characteristic features are provided with a suitable combination of chemical, mechanical, physical, and biological properties, to design well-established biomaterials [14]. These biomaterials are specifically designed by utilizing the classes of materials: polymers, metals, composite materials, and ceramics. Most of the biomaterials available today are developed either singly or in combination of the materials of these classes. These classes of materials have different atomic arrangement which present the diversified structural, physical, chemical, and mechanical properties and hence offer various alternative applications in the body. The classes of the materials are illustrated in the following sections.
2.2.1 Polymers
Polymers are the convenient materials for biomedical applications and are used as cardiovascular devices for replacement and proliferation of various soft tissues. There are a large number of polymeric materials that have been used as implants. The current applications of them include cardiac valves, artificial hearts, vascular grafts, breast prosthesis, dental materials [15], contact and intraocular lenses [16], fixtures of extracorporeal oxygenators, dialysis and plasmapheresis systems, coating materials for medical products, surgical materials, tissue adhesives, etc. [17]. The composition, structure, and organization of constituent macromolecules specify the properties of polymers [13]. Further, the versatility in diverse application requires the production of polymers that are prepared in different structures and compositions with appropriate physicochemical, interfacial, and biomimetic properties to meet specific purpose.
The advantages of the polymeric biomaterials over other classes of materials are (i) ease to manufacture, (ii) ease of secondary processability, (iii) availability with desired mechanical and physical properties,...
| Erscheint lt. Verlag | 3.1.2015 |
|---|---|
| Sprache | englisch |
| Themenwelt | Medizin / Pharmazie ► Pflege |
| Medizin / Pharmazie ► Physiotherapie / Ergotherapie ► Orthopädie | |
| Naturwissenschaften ► Biologie | |
| Technik ► Elektrotechnik / Energietechnik | |
| Technik ► Maschinenbau | |
| Technik ► Medizintechnik | |
| Technik ► Umwelttechnik / Biotechnologie | |
| ISBN-10 | 0-323-35303-7 / 0323353037 |
| ISBN-13 | 978-0-323-35303-8 / 9780323353038 |
| Haben Sie eine Frage zum Produkt? |
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