AnIntroductiontoTissue-BiomaterialInteractions KayCDee,DavidA.Puleo,RenaBizios. Copyright(2002JohnWiley&Sons,Inc. ISBNs:0-471-25394-4(Hardback);0-471-27059-8(Electronic) An Introduction To Tissue- Biomaterial Interactions An Introduction To Tissue- Biomaterial Interactions Kay C Dee, Ph.D. Tulane University Department of Biomedical Engineering New Orleans, Louisiana David A. Puleo, Ph.D. University of Kentucky Center for Biomedical Engineering Lexington, Kentucky Rena Bizios, Ph.D. Rensselaer Polytechnic Institute Department of Biomedical Engineering Troy, New York AJohnWiley&Sons,Inc.,Publication Copyright62002byJohnWiley&Sons,Inc.Allrightsreserved. PublishedbyJohnWiley&Sons,Inc.,Hoboken,NewJersey. PublishedsimultaneouslyinCanada. 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LibraryofCongressCataloging-in-PublicationData: Bizios,Rena. Anintroductiontotissue-biomaterialinteractions/RenaBizios,Kay C.Dee,DavidA.Puleo. p. cm. ISBN0-471-25394-4 1. Biomedicalmaterials. 2. Biocompatibility. I. Dee,KayC. II. Puleo,DavidA. III. Title. R857.M3B595 2003 6100.28—dc21 2002005591 PrintedintheUnitedStatesofAmerica 10 9 8 7 6 5 4 3 2 1 To students —of the past, present and future— who have shared our fascination with the tissues, cells, and molecules of the human body. Contents Preface xiii Acknowledgments xv Introduction xvii 1 Biomaterials 1 1.1 Introduction 1 1.1.1 Definition 1 1.2 Metallic Biomaterials 2 1.2.1 Basis of Structure-Property Relationships 3 1.2.2 Corrosion 4 1.2.3 Mechanical Properties 4 1.3 Ceramic and Glass Biomaterials 6 1.3.1 Basis of Structure-Property Relationships 6 1.3.2 Degradation 6 1.3.3 Mechanical Properties 7 1.4 Polymeric Biomaterials 8 1.4.1 Basis of Structure-Property Relationships 8 1.4.2 Degradation 9 1.4.3 Mechanical Properties 9 1.5 Choice of Materials for Biomedical Applications 10 1.6 Biomaterials for Implantable Devices: Present and Future Directions 11 1.7 Summary 11 1.8 Bibliography/Suggested Reading 12 1.9 Quiz Questions 12 1.10 Study Questions 13 2 Proteins 15 2.1 Introduction 15 vii viii AnIntroductionToTissue-BiomaterialInteractions 2.2 Primary Structure 15 2.3 Secondary Structure 19 2.4 Tertiary Structure 22 2.5 Quaternary Structure 25 2.6 Importance of Conformation 25 2.7 Examples 26 2.7.1 Collagen 26 2.7.2 Elastin 29 2.7.3 Fibronectin 31 2.7.4 Fibrinogen 32 2.8 Summary 34 2.9 Bibliography/Suggested Reading 34 2.10 Quiz Questions 35 2.11 Study Questions/Discovery Activities 35 3 Protein-Surface Interactions 37 3.1 Introduction 37 3.2 Important Protein and Surface Properties 37 3.2.1 Protein Properties 37 3.2.2 Surface Properties 40 3.3 Adsorption and Desorption 41 3.4 Conformational Changes 45 3.5 Multicomponent Solutions 45 3.5.1 Example—Blood-Surface Interactions 49 3.6 Summary 51 3.7 Bibliography/Suggested Reading 51 3.8 Quiz Questions 51 3.9 Study Questions/Discovery Activities 52 4 Blood-Biomaterial Interactions and Coagulation 53 4.1 Introduction 53 4.2 The Blood Cell Source: Marrow and Stem Cells 53 4.3 Red Blood Cells 55 4.3.1 Formation and Function 55 4.3.2 Deformation and Blood Flow 59 4.4 Platelets 64 4.4.1 Formation and Function 64 4.4.2 Platelet Aggregation and the Process of Coagulation 68 4.5 The Coagulation Cascades 73 4.5.1 Mechanisms 73 Contents ix 4.5.2 Control Points 79 4.6 Anticoagulants and Fibrinolysis 80 4.7 Biomaterials, Devices, and Thrombosis 81 4.8 Summary 85 4.9 Bibliography/Suggested Reading 86 4.10 Study Questions 87 4.11 Discovery Activities 87 5 Inflammation and Infection 89 5.1 Introduction 89 5.2 Historical Observations: Inflammation and Infection 89 5.3 Nonlymphatic Leukocytes 90 5.4 Inflammation and Leukocyte Functions 94 5.4.1 Chemotaxis and Cell Migration 94 5.4.2 Phagocytosis 97 5.4.3 Diapedesis 100 5.5 Physiological Explanations for the Cardinal Signs 102 5.6 Infection 103 5.7 Summary 105 5.8 References 106 5.9 Bibliography/Suggested Reading 106 5.10 Study Questions 106 5.11 Discovery Activities 107 6 The Immune System and Inflammation 109 6.1 Introduction 109 6.2 Lymphocytes 110 6.3 Immunogens, Antigens, and Antibodies 111 6.4 Cell-Mediated Immunity 114 6.4.1 T Cell Subpopulations and Functions 114 6.4.2 Antigen-Presenting Cells 116 6.5 Humoral Immunity 117 6.5.1 B Cell Subpopulations and Functions 117 6.5.2 The Complement System 119 6.6 Generating Specificity 120 6.6.1 Clonal Selection Theory 120 6.6.2 ‘‘Self’’ Versus ‘‘Non-self’’? 121 6.7 Summary 123 6.8 Bibliography/Suggested Reading 125 6.9 Study Questions 125 6.10 Discovery Activities 126 x AnIntroductionToTissue-BiomaterialInteractions 7 Wound Healing 127 7.1 Introduction 127 7.2 Tissues 127 7.3 The Biology of Wound Healing of Vascularized Connective Tissue in Adults 128 7.3.1 Pertinent Aspects of Hemostasis and Inflammation 128 7.3.2 Proliferative and Repair Phase 129 7.3.3 Remodeling Phase 135 7.3.4 Scar Tissue 136 7.3.5 Timing Aspects 136 7.3.6 Factors that Affect the Wound Healing Outcome 137 7.3.7 An Example of Wound Healing Tissue: Skin 137 7.4 Chronic Nonhealing Wounds 137 7.5 Wound Healing Around Implants in Adults 138 7.6 Complications Related to Wound Healing Around Implants 142 7.7 Closing Remarks 145 7.8 Summary 145 7.9 Bibliography/Suggested Reading 146 7.10 Quiz Questions 146 7.11 Study Questions 147 8 Biomaterial Surfaces and the Physiological Environment 149 8.1 Introduction 149 8.2 Surface Characterization Methods 149 8.2.1 Contact Angle Analysis 150 8.2.2 X-Ray Photoelectron Spectroscopy (XPS) 151 8.2.3 Fourier Transform Infrared (FTIR) Spectroscopy 153 8.2.4 Secondary Ion Mass Spectroscopy (SIMS) 155 8.2.5 Scanning Electron Microscopy (SEM) 159 8.2.6 Atomic Force Microscopy (AFM) 160 8.3 Surface Responses to the Wound Healing Process 161 8.3.1 Protein Fouling 161 8.3.2 Degradation and Dissolution 163 8.3.3 Calcification 165 8.4 Engineering Biomaterial Surfaces 166 8.4.1 Morphologic Modifications 166 8.4.2 Physicochemical Modifications 167 Contents xi 8.4.3 Biological Modifications 169 8.5 Summary 171 8.6 Bibliography/Suggested Reading 172 8.7 Quiz Questions 172 8.8 Study Questions/Discovery Activities 172 9 Biocompatibility 173 9.1 Introduction 173 9.1.1 Differences between Biological and Synthetic Materials 173 9.2 Tests Prerequisite to Evaluation of Biocompatibility 174 9.3 Methods for Testing and Evaluating Biocompatibility 175 9.3.1 In Vitro Testing 175 9.3.2 Animal Models 176 9.3.3 Clinical Trials 180 9.4 Attempting to Define Biocompatibility 181 9.5 Concluding Remarks 182 9.6 Summary 182 9.7 Bibliography/Suggested Reading 182 9.8 Quiz Questions 183 9.9 Study Questions 184 10 Example 1. Opening Occluded Vessels: Vascular Grafts, Intimal Hyperplasia 185 Example 2. Replacing Joints and Teeth 191 Answers to Quiz Questions 197 Glossary 205 Index 219 Preface Undergraduatebiomedicalengineeringprogramsandcurriculaarebeingrapidly developed across the United States. We perceive a correspondingly increasing need for biomedical engineering textbooks specifically designed for under- graduate readers. Many educators have come to appreciate that physiology and biology are not narrow, specialized applications to be ‘‘tacked onto’’ an en- gineering curriculum, but are instead rich subjects that can naturally elicit and benefit from the kinds of creative problem-solving and quantitative analyses that are hallmarks of engineering. However, integrating life sciences within the structured and rigorous framework of fundamental knowledge required for an undergraduate engineering degree—especially early in the undergraduate curriculum, before the senior year or a ‘‘capstone’’ course—is still a challenge for educators. We believe that providing undergraduates with an opportunity to learn bio- medically oriented material early in their academic careers establishes a vivid framework of ‘‘vocational relevance’’ (i.e., showing students that the basic science and engineering skills they are learning are crucially important to bio- medical science) that is often otherwise lacking. We also believe that helping students see connections between seemingly disparate course materials—fluid mechanics and cell biology, for example, connected by understanding both how red blood cells flow through capillaries and why altered flow characteristics may be of clinical importance—can help students develop creative thinking and problem-solving skills. The fields of biomaterials and cell/tissue engineering present excellent opportunities to integrate life sciences and engineering, by capitalizing on the inherently interdisciplinary interface between cells/tissues and biomaterials (whether man-made or biologically-derived). In accordance with the principles and needs described above, we have de- signed this textbook, which focuses on the wound healing process and inter- actions between the human body and implanted biomaterials or devices. This book is short, accessible, and we hope a¤ordable, because it is intended for use in a one-semester, undergraduate-level course by students who have com- pleted some science/engineering course work (introduction to materials, statics, and perhaps mechanics of materials or a fundamental fluid mechanics course) with minimal chemistry or biology (general chemistry and one semester of cell xiii