Biomaterials Science: An Introduction to Materials in Medicine

Biomaterials Science
Copyright
List of Contributors
Preface
How to Use this Book
1.1.1  - Introduction to Biomaterials Science: An Evolving, Multidisciplinary Endeavor
	Biomaterials and Biomaterials Science
	Key Definitions
	The Expansion of the Biomaterials Field
	Examples of Today’s Biomaterials Applications
		Heart Valve Prostheses
		Total Hip Replacement Prostheses
		Dental Implants
	Intraocular Lenses
		Ventricular Assist Devices
	Characteristics of Biomaterials Science
		Multidisciplinary
		Diverse Materials Are Used
		Biomaterials to Devices to Markets and Medicine
		Magnitude of the Field
			Success and Failure
		Subjects Integral to Biomaterials Science
			Toxicology
			Biocompatibility
			Inflammation and Healing
			Functional Tissue Structure and Pathobiology
			Dependence on Specific Anatomical Sites of Implantation
			Mechanical Requirements and Physical Performance Requirements
			Industrial Involvement
			Risk/Benefit and Corporate Realities
			Ethics
			Regulation
	Biomaterials Literature
	Biomaterials Societies
	Summary
1.1.2 - A History of Biomaterials
	Biomaterials Before World War II
		Before Civilization
		Dental Implants in Early Civilizations
		Sutures Dating Back Thousands of Years
		Artificial Hearts and Organ Perfusion
		Contact Lenses
		Basic Concepts of Biocompatibility
	World War II to the Modern Era: The Surgeon/Physician-Hero
		Intraocular Lenses
		Hip and Knee Prostheses
		Dental Implants
		The Artificial Kidney
		The Artificial Heart
		Breast Implants
		Vascular Grafts
		Stents
		Pacemakers
		Heart Valves
		Pyrolytic Carbon
		Drug Delivery and Controlled Release
	Designed Biomaterials
		Silicones
		Polyurethanes
		Teflon
		Hydrogels
		Poly(Ethylene Glycol)
		Poly(Lactic-Glycolic Acid)
		Hydroxyapatite
		Titanium
		Bioglass
	The Contemporary Era (Modern Biology and Modern Materials)
	Conclusions
1.2.1 - Introduction: Properties of Materials—the Palette of the Biomaterials Engineer
1.2.2 - The Nature of Matter and Materials
	Introduction
	Atoms and Molecules
	Molecular Assemblies
	Surfaces
	Conclusion
1.2.3 - Bulk Properties of Materials
	Introduction
	Mechanical Variables and Mechanical Properties
		Five Types of Mechanical Loading
		From External Loads to Internal Loads and Stresses
		Linear and Nonlinear Relationship, Elastic and Plastic Behavior
		Pseudoelastic, Hyperelastic, and Viscoelastic Materials
		Common Mechanical Properties of Isotropic Materials
			Elastic Properties
			Yield Strength and Ductility
			Strength and Failure
			Hardness
			Resilience
			Toughness
			Fracture Toughness and Fatigue Strength
		Generalized Hooke's Law and Anisotropy of Materials
		Loading Modes, Stress States, and Mohr's Circle
		Plane-Stress and Plane-Strain Simplification
		Trajectories of Tensile and Compressive Stress Lines
	Other Bulk Properties
		Thermal Properties
		Optical Properties
		Piezoelectric Properties
		Electrochemical Properties
	Chapter Questions
		Solution
		Solution
		Solution
		Solution
		Solution
		Solution
		Solution
		Solution
		Solution
1.2.4  - Surface Properties and Surface Characterization of Biomaterials
	Introduction
		General Surface Considerations and Definitions
		What Surface Properties Are We Interested in?
	Surface Analysis Techniques: Principles and Methods
		Sample Preparation
		Surface Analysis General Comments
		Contact Angle Methods
		Electron Spectroscopy for Chemical Analysis
		Secondary Ion Mass Spectrometry
		Scanning Electron Microscopy
		Infrared Spectroscopy
		Scanning Tunneling Microscopy (STM), Atomic Force Microscopy (AFM), and the Scanning Probe Microscopies (SPMs)
		Newer Methods
	Studies With Surface Methods
		Platelet Consumption and Surface Composition
		Contact-Angle Correlations
		Contamination of Intraocular Lenses
		Titanium
		SIMS for Adsorbed Protein Identification and Quantification
		Poly(Glycolic Acid) Degradation Studied by SIMS
		MultiTechnique Characterization of Adsorbed Peptides and Proteins
	Conclusions
	Chapter Questions
1.2.5  - Role of Water in Biomaterials
	Water: The Special Molecule
		Melting Point and Boiling Point
		Density and Surface Tension
		Specific Heat and Latent Heats of Fusion and Evaporation
		Water as a Solvent
	Water: Structure
	Water: Significance for Biomaterials
		Hydrophobic Effect, Liposomes, and Micelles
		Hydrogels
			Protein Adsorption
	Life
	Chapter Exercises
	Suggested External Reading
1.3.1  - The Materials Side of the Biomaterials Relationship
1.3.2  - Polymers: Basic Principles
	Introduction
	The Polymer Molecule
		Molecular Structure of Single Polymer Molecules
		Chemical Structure of Single Polymer Molecules
		Copolymers
		Determination of Chemical Composition
		Tacticity
		Molecular Mass
			The Molecular Mass Distribution and Its Averages
		Characterizing the Molecular Mass Distribution
		Connecting Physical Behavior With Chemical Characteristics
			Physical States of Linear Polymers
			The Rubbery State
			The Glassy State
			The Semicrystalline State
		The Physical Behavior of Linear and Amorphous Polymers
		The Physical Behavior of Other Physical States
		Characterizing a Polymer's Physical State and Behavior
		Measuring the Transition Temperatures Between States
	Interactions With Water
		Measuring the Hydrophilicity of Polymer Materials
		Degradation Characteristics
	Polymer Synthesis
		Polymerization Mechanisms
		Using Synthesis Conditions to Build the Desired Polymer
	Case Studies
	The Present and the Future
	Further Reading
1.3.2A - Polyurethanes
	Introduction
	Anatomy of a Polyurethane Molecule
	The Physical Properties of Polyurethanes
		Thermosets
		Thermoplastic Elastomers
	Polyurethane Synthesis
		Precursors
		Synthesis Reactions
		Tailoring Polyurethane Behavior
	Concluding Remarks
	Chapter Exercises
1.3.2B - Silicones
	Chemical Structure and Nomenclature
	Preparation
		Silicone Polymers
		Polymerization and Polycondensation
	Physicochemical Properties
	Types, Properties, and Preparation of Silicone Materials
		Silicone Elastomers
			Elastomer Filler
			Processing of Silicone Elastomers
		Silicone Gels
		Silicone Adhesives
		Silicone Film-in-Place, Fast-Cure Elastomers
	Biocompatibility of Silicones
	Biodurability of Silicones
	Medical Applications
		Siliconization
		Extracorporeal Equipment
		Medical Inserts and Implants
			Catheters, Drains, and Shunts
			Aesthetic Implants
	Conclusion
	Chapter Questions
	Chapter Answers
		Question 1
		Question 2
		Question 3
		Question 4
		Question 5
		Question 6
		Question 7
1.3.2C.  - Fluorinated Biomaterials
	Introduction
	Distinguishing the Different Fluoropolymers
		Polytetrafluoroethylene
		Fluorinated Ethylene Propylene
		Polyvinylidene Fluoride
		Fluoropolymer Melt Processing
		Original Gore-Tex and Generic Equivalents
		Surfaces Modified by Fluorination Treatments (Grainger and Stewart, 2001)
	Biomedical Applications
		Fluorinated Material Biological Response
		PTFE (Teflon) Mesh and Fabric Vascular Implants
		ePTFE and Teflon Soft Tissue Repair Meshes
		ePTFE Vascular Implants
		Arteriovenous ePTFE Grafts for Dialysis Access
		Multilumen Catheters
		Guiding Catheters
		PTFE Catheter Introducers
		Perfluorocarbon Liquids and Emulsions as Oxygen-Carrying Blood Substitutes
		Fluorinated Liquids in the Eye as Experimental Vitreous Substitutes
		Fluorinated (Meth)Acrylates and (Meth)Acrylated Perfluoroalkyl Silicones as Cross-Linked Polymer Cores for Soft Contact Lenses
		Fluorinated Materials as Antifouling Coatings for Intraocular Lenses
		PTFE Paste Injectable Bulking Agent
		Ligament Replacement
		Sutures
	Summary
	Glossary
	References
	Chapter Exercises
1.3.2D - The Organic Matrix of Restorative Composites and Adhesives
	Introduction—Historical Perspective
	The Monomer Matrix—Conventional Systems
		Dimethacrylates (Base and Diluent Monomers) Used in Commercial Composites
		Adhesive Monomers
	The Monomer Matrix—Novel Systems
		Lower Stress Resin Systems
			Low-Shrinkage Materials
			Network Modulation
		Fast Polymerizing Monomers
		Antimicrobial Resins
		Enhanced Chemical Stability
		Enhanced Toughness
		Hydrophobic Resins
	Silane Coupling Agents
	Chapter Exercises
1.3.2E - Hydrogels
	Introduction
	Classification and Basic Structures of Hydrogels
	Synthesis of Hydrogels
	Swelling Behavior of Hydrogels
	Determination of Structural Characteristics
	Biomedical Hydrogels
		Acrylic Hydrogels
		Poly(Vinyl Alcohol) (PVA) Hydrogels
		Poly(Ethylene Glycol) (PEG) Hydrogels
		Degradable Hydrogels
		Star Polymer and Dendrimer Hydrogels
		Self-Assembled Hydrogel Structures
	“Smart” or “Intelligent,” Stimuli-Responsive Hydrogels and Their Applications
		pH-Sensitive Hydrogels
		pH-Responsive Complexation Hydrogels
		Temperature-Sensitive Hydrogels
		Affinity Hydrogels
	Biomedical Applications of Hydrogels
		Contact Lenses
		Blood-Contacting Hydrogels
		Drug Delivery From Hydrogels
		Targeted Drug Delivery From Hydrogels
		Tissue Engineering Scaffolds From Hydrogels
		Miscellaneous Biomedical Applications of Hydrogels
1.3.2F - Degradable and Resorbable Polymers
	Introduction
		Brief History of Degradable Polymers
		Definition of Degradation, Erosion, Bulk, and Surface Processes
	Degradable Polymer Properties
		Polymer Backbone Functionality
			Polyanhydrides
			Poly(Ortho Esters)
			Polyesters and Polycarbonates
		Polymer Architecture
			Polymerization Routes
			Molecular Weight
			Morphology
			Relative Hydrophobicity versus Hydrophilicity
	Degradation Routes and Kinetics
		Hydrolytic Degradation
			Surface Erosion
			Bulk Degradation
		Photodegradation
		Enzymatic Degradation
	Polymer Design and Processing
		Lifetime—How Long Does the Biomaterial Need to Function?
		Location—Where Will the Biomaterial Perform Its Task?
		Mechanical Properties—What Mechanical Properties Are Required for the Task?
		Delivery—How Will the Biomaterial Reach the Required Site?
		Composites—When Should a Composite Be Used and How Will Additives Affect Degradation?
		Shape—How Will the Material Be Shaped and How Does Shape Affect Degradation Kinetics?
		Sterilization—Will Degradation Properties Be the Same After Sterilization?
	Performance Metrics
	Worked Examples
		Question
		Solution
		Question
		Solution
		Question
		Solution
	Case Studies on Degradable Polymers Used in Medicine
	Chapter Exercises
1.3.2G  - Applications of “Smart Polymers” as Biomaterials
	Introduction
	Smart Polymers in Solution
	Smart Polymer–Protein Bioconjugates
	Site-Specific Smart Polymer Bioconjugates
	Smart Polymers on Surfaces
	Smart Polymer Hydrogels
	Stimuli-Responsive Polymer Micelles and Carriers
	Conclusions
	References
1.3.3 - Metals: Basic Principles
	Introduction
		Medical Devices and Metals in the Body
		The Major Alloy Systems (Ti, NiTi, CoCrMo, SS, Pt, Au, Mg, Ag)
	Metal Processing
	Processing–Structure–Properties–Performance Paradigm
	Structure of Metals and Alloys
		Electronic and Atomic Structure: Crystal Structures
		Alloying, Microstructure, and Phase Diagrams
	Defects in Crystals
		Point Defects
		Line Defects
		Area Defects
		Volume Defects
	Bulk Mechanical Properties of Metallic Biomaterials
		Elastic and Plastic Deformation of Metals
		Strength of Metals and Strengthening Mechanisms
		Strengthening Mechanisms: Alloying
		Strengthening Mechanisms: Cold Working
		Strengthening Mechanisms: Grain Size
		Strengthening Mechanisms: Precipitation Strengthening
	Fracture of Metals
	Fatigue of Metals
	Surfaces of Metals: Oxide Films and Passivity
		High-Field, Low-Temperature Oxide Film Growth
	Introduction to Metallic Corrosion
		Electrochemical Reactions (Oxidation and Reduction) and the Nernst Equation
		The Principal Reduction Reaction in Biomaterials (Oxygen Reduction)
		Polarizable and Nonpolarizable Electrodes
		Pourbaix Diagrams (Electrode Potentials vs. pH)
		Electrochemical Currents (Evans Diagrams)
	Electrochemical Impedance Spectroscopy (an Introduction)
		Resistive (Faradaic) and Capacitive (Non-Faradaic) Behavior
		Basic Impedance Concepts
		Semiconducting Oxide Impedance (Mott–Schottky Analysis)
	References
	Questions
1.3.3A  - Titanium Alloys, Including Nitinol
	Introduction
	Biocompatibility
	Biocompatible Titanium Alloys
	Recent Efforts in Fabrication Processes
	Mechanical Properties of Titanium Alloys
		Elastic Modulus
		Wear Resistance
		Fatigue Behavior
		Effects of Interstitial Atoms on Mechanical Properties
	Surface Modification of Titanium Alloys
		Recent Efforts in the Anodization Process
		Effects of Anodization on Corrosion and Surface Mechanical Properties
		Coloring Methods for Titanium Alloys
	Conclusions
	Chapter Exercise 1
	Chapter Exercise 2
	Chapter Exercise 3
1.3.3B  - Stainless Steels
	Overview
	History
	Composition and Types
	Structure
	Structure, Composition, and Processing Effects on Mechanical Properties
	Corrosion
	Summary
1.3.3C - CoCr Alloys
	Introduction
	Microstructure, Mechanical Properties, and Manufacturing of CoCr Alloys
	3D Printing of CoCr Alloys
	Bio-Tribocorrosion of CoCr Alloys
	Application of CoCr Alloys in Biomedical Devices
	Properties Leading to Biocompatibility of CoCr Alloys and Their Applications
		Corrosion Resistance
		CoCr Alloys in Biological Environments
	Clinical Concerns Related to Metal Ion Release From CoCr Alloys
	Conclusions
	Questions
1.3.3D - Biodegradable Metals
	Introduction
	General Considerations of Corrosion Design of Biodegradable Metals
	General Ideas on the Influence of Alloying Elements, Corrosion Behavior, and the Biocompatibility of Zn and Mg
	Iron-Based Biodegradable Metals
		Introduction to Fe-Based Implants
		Modifications to Accelerate the Corrosion Rate of Fe-Based Biodegradable Metals
		The Proposed Degradation Process of Fe-Based Biodegradable Metals
		Biocompatibility Evaluations
		Current Perspective on Fe-Based Degradable Implants
	Zinc-Based Biodegradable Metals
		Introduction to Zn-Based Implants
		Zn-Based Materials Under Investigation
		The Proposed Degradation Process of Zn-Based Biodegradable Metals
		Biocompatibility of Dissolved Zn Corrosion Products
		Current Perspective on Zn-Based Degradable Implants
	Magnesium-Based Biodegradable Metals
		Introduction to Mg-Based Implants
			Impact of Alloying Elements on Mg Processing and Microstructure
			Current Models of the Corrosion Process In Vitro
			Situation In Vivo: Tissue Perfusion, pH, and the Issue of Gas Formation
			Methods to Measure Mg-Based Implant Corrosion In Vitro and In Vivo
			Preclinical and Clinical Observations for Mg-Based Biodegradable Metals
		Orthopedic Devices Based on MgYREZr Alloy (Magnezix)
			Orthopedic Devices Based on MgCaZn Alloy (Resomet)
			Orthopedic Devices Based on Pure Mg
		Current Perspective on Mg-Based Degradable Implants
	Summary
	Acknowledgment
	References
1.3.4 - Ceramics, Glasses, and Glass-Ceramics: Basic Principles
	Introduction
	Nearly-Bioinert Ceramics
		Alumina and Zirconia Ceramics
	Bioactive Ceramics and Glasses
		Bioactive Ceramics
		Porous Calcium Phosphate Ceramics
		Calcium Phosphate Cements
		Bioglass and Bioactive Glass
		Bioglass Granules
		Bioactive Glass Composites and Putties for Bone Repair
		Porous Bioactive Glasses
		Wound Healing
		Bioactive Glass in Toothpaste
		Glasses for Cancer Therapy
	Glass-Ceramics
	Summary
	Chapter Questions
	Questions with answers
1.3.4A - Natural and Synthetic Hydroxyapatites
	Introduction
	Synthesis of Hydroxyapatite Ceramics
	Characterization of Hydroxyapatite Ceramics
		Physicochemical Characterization
		In Vitro and In Vivo Characterization
	Clinical Use of Hydroxyapatite Ceramics
1.3.4B  - Structural Ceramic Oxides
	Introduction
	Structural Ceramic Oxides
		Aluminum Oxide (Alumina)
		Zirconia
		Yttria and Magnesia-Stabilized Zirconias
		Zirconia-Toughened Alumina
	A History of These Structural Materials in Medical Devices
	Properties in General
	Questions
1.3.5 - Carbon Biomaterials
	Introduction
		Carbon Biomaterials
			Diamond and Diamond-Like Carbon
				Diamond
				Diamond-Like Carbon
			Pyrolytic Carbon
			Hexagonally Bonded Carbon
				Graphite
				Fullerenes
				Carbon Nanotubes
				Graphene-Based Materials
				Other Hexagonally Bonded Carbons
					.Graphene quantum dots (GQD) are 0D materials (2–20nm) with a crystalline form of carbon containing sp2 hybridized atoms. These ...
					.Carbon fibers (CF) are a 3D material (diameter: 5–10μm) with a crystalline form of carbon containing sp2 hybridized atoms. Thes...
					.Carbon nanofibers (CNF) are noncontinuous 1D materials with a crystalline form of carbon containing sp2 hybridized atoms. CNF c...
					.Graphene nanoribbons (GNR) are 1D materials with a crystalline form of carbon containing sp2 hybridized atoms. GNR are commonly...
			Other Carbon Biomaterials
				Carbon Dots
				Glassy Carbon
				Activated Charcoal
	Biomedical Applications of Carbon Biomaterials
		Drug Delivery
		Phototherapy and Imaging
		Biosensors
		Antimicrobial Therapy
		Cardiovascular Applications
			Long-Term Implants
				Mechanical Heart Valves
				Vascular Stents
				Ventricular Assist Devices
			Tissue-Engineering Approaches
		Orthopedic Applications
			Long-Term Implants
			Tissue-Engineering Approaches
		Dental Applications
		Neurological Applications
		Ophthalmologic Applications
			Contact Lenses
		Catheters
		Guidewires
		Other Biomedical Applications
	Safety of Carbon Biomaterials: Short Considerations
	Summary
	Chapter Questions and Answers
1.3.6 - Natural Materials
	Introduction to Natural Materials
	Natural Based-Biomaterials Exploring Structural Molecules
		Extracellular Matrix-Based Biomaterials
			Proteins
			Glycosaminoglycans
		Blood Derivatives as a Source of Bioinstructive Materials
		Multifunctional Biomaterials Based on DNA
	Dynamic Hydrogels Exploring Supramolecular Chemistry
		Reversible Hydrogels Based on Supramolecular Cross-Linking of Polymeric Precursors
		Hydrogels Based on Natural Supramolecular Self-Assembly
	Soft Nanocomposite Smart Materials
		Stimuli-Responsive Soft Nanocomposites
	Future Perspectives
	Questions
1.3.6A - Processed Tissues
	Introduction
	Cryopreservation and Vitrification
	Tissue Cross-Linking
	Decellularization
		Decellularization Methods
		Quality of Decellularization
	Post-decellularization Processing and Modifications
		Milling for ECM Powder and Partial Enzymatic Digestion for Hydrogel Formation
		Cross-Linking
	Applications of Decellularized ECM
		Scaffold-Based Therapies
		Whole Organ Recellularization
		Powder and Injectable Decellularized ECM Therapies
		Tissue-Specific In Vitro Models of the Native Microenvironment
	Current Challenges and Future Directions for Decellularized Tissues
	Conclusion
	Acknowledgments
	Questions
1.3.6B - Use of Extracellular Matrix Proteins and Natural Materials in Bioengineering
	Introduction
	Collagens
	Elastin, Elastic Fibers, and Elastin-Like Peptides
	Proteoglycans and Glycosaminoglycans
	Alginates
	Chitosan
	Fibrin
	Manufacturing Approaches Utilizing Natural Materials
		Human Recombinant ECM Protein Production
		Purification of Recombinant ECM Proteins
		3D Bioprinting
		Electrospinning of ECM Proteins and Natural Materials
	Summary
1.3.7  - Composites
	Introduction
	Matrix and Reinforcement in Composites
		Matrix Materials
		Reinforcements
		Nonporous and Porous Composites
	Properties of Composites
		Major Influencing Factors
		Geometry and Size of the Dispersed Phase and Its Distribution in Composite
		Fiber Arrangement
		Interfaces in Composites
	Mechanical Properties of Composites
		Tensile Properties of Fibrous Composites
		Compressive Properties of Fibrous (CF/PEEK) Composites: A New Perspective
			Rosen’s Microbuckling Model and the Contradictions
			A First-Principles-Based Compressive Microbuckling Model
			Selected Results
	Medical Applications of Composites
		Biomedical Composites in Orthopedic Applications
		Biomedical Composites in Dental Applications
		Biomedical Composites for Tissue Engineering
	Chapter Questions
1.3.8A  - Microparticles
	Introduction
		Why Size Matters
	Materials for the Synthesis of Microparticles
		Natural Polymers
		Synthetic Polymers
		Nonpolymeric Materials
	Microparticle Preparation
	Characterization of Microparticles
	Drug Release Mechanisms
	Biomedical Applications of Microparticles
		Drug Delivery
		Radiotherapy
		Other Applications
	Concluding Remarks
	Chapter Exercises
1.3.8B - Nanoparticles
	Chapter Objectives
	Introduction
	Categories of NPs
		Polymeric NPs
		Lipid-Based NPs
		Inorganic NPs
		Bio-Inspired NPs
		Hybrid NPs
	Characterization of NPs
		Size
		Surface Charge
		Morphology
		Biocompatibility
			In Vitro Toxicity
			Hemocompatibility
			In Vivo Toxicity
	Drug Delivery Applications of NPs
		Drug Loading
			Covalent Bonding (Prodrug)
			Noncovalent Encapsulation
		Systemic Barriers Against Drug Delivery
		Approaches to Overcome Systemic Barriers
			Long-Circulating NPs
			Targeted Drug Delivery
			Tumor Penetration
			Stimuli-Responsive Drug Delivery
		Clinical Development
	Nucleic Acid Delivery Applications of NPs
		Intracellular Barriers Against Nucleic Acid Delivery
		Strategies to Overcome Intracellular Barriers
			Nucleic Acid Condensation and Cellular Internalization
			Endosomal Escape
			Stimuli-Responsive NPs for Intracellular Gene Release
			Nuclear Transport
		Clinical Development
	Diagnostic/Theranostic Applications of NPs
		In Vitro Diagnosis
		In Vivo Imaging
		Theranostics
		Imaging-Guided Surgery
	Conclusion
	Chapter Assessment Questions
1.4.1 - Introduction to Materials Processing for Biomaterials
1.4.2 - Physicochemical Surface Modification of Materials Used in Medicine
	Introduction
	General Principles
		Thin Surface Modifications
		Delamination Resistance
		Surface Rearrangement
		Surface Analysis
		Manufacturability and Commercializability
	Methods for Modifying the Surfaces of Materials
		Chemical Reaction
		Surface Grafting: Radiation Grafting, Photografting, and Newer Methods
		RFGD Plasma Deposition and Other Plasma Gas Processes
		The Nature of the Plasma Environment
		The Apparatus to Generate Plasmas for Surface Modification
		RFGD Plasmas for the Immobilization of Molecules
		High-Temperature and High-Energy Plasma Treatments
		Specific Chemical Reactions for Forming Surface Grafts
		Silanization
		Ion Beam Implantation
		Langmuir–Blodgett Deposition
		Self-Assembled Monolayers
	Layer-By-Layer Deposition and Multilayer Polyelectrolyte Deposition
		Surface-Modifying Additives
		Conversion Coatings
		Parylene Coating
		Laser Methods
		Patterning
	References
	Conclusions
1.4.3A - Nonfouling Surfaces
	Introduction
	Background and Mechanism
	Nonfouling Materials and Methods
	Conclusions and Perspectives
1.4.3B - Nonthrombogenic Treatments and Strategies
	Introduction
	Historical
	Criteria for Nonthrombogenicity
	Inert Materials
		Hydrogels
		Polyethylene Glycol (PEG) Immobilization
		Albumin Coating and Alkylation
		Zwitterionic Group/Phospholipid-Mimicking Surfaces
		Surface-Modifying Additives (SMAs)
		Fluorination
		Heparin-Like Materials
		Self-Assembled Surface Layers
	Active Materials
		Heparinization
			Ionically Bound Heparin and Controlled-Release Systems
			Covalently Bound Heparin
		Thrombin Inhibition Without Heparin
		Immobilization of Antiplatelet Agents
		Immobilization of Fibrinolytic Agents
	Use of Endothelial Cells and RGD Peptides
	Strategies to Lower the Thrombogenicity of Metals
	Summary
1.4.4 - Surface-Immobilized Biomolecules
	Introduction
	Patterned Surface Compositions
	Immobilized Biomolecules and Their Uses
	Immobilized Cell Ligands and Cells
	Immobilization Methods
	Conclusions
	References
1.4.5 - Surface Patterning
	Introduction
	Common Concerns In Biomolecular Surface Patterning
		Resolution
		Throughput
		Contrast
		Bioactivity
		Shelf-Life and Durability
	Patterning Techniques
		Direct-Write Patterning
			Writing With A Stylus
				Printing With Inkjets, Quills, and Pins
				Dip-Pen Nanolithography
				Nanoshaving and Nanografting
			Writing With Beams
				Direct-Write Photolithography
				Electron Beam Lithography
				Focused Ion Beam Lithography
			Writing With Fields
				Electric Field
				Magnetic Field
		Patterning With Masks
			Photolithography With Masks
			Deposition/Etching With Masks
		Patterning With Masters
			Imprinting With a Master
			Printing With a Stamp
				Microcontact Printing: Use of Protruding Features of a Stamp
				Microfluidic Patterning: Use of Void Features of a Stamp
		Patterning by Self-Assembly of Polymers and Colloids
			Block Copolymer Self-Assembly
			Nanosphere Lithography
			Magnetic Self-Assembly
		Dynamic Patterning
		Three-Dimensional Printing
	Conclusions
1.4.6 - Medical Fibers and Biotextiles
	Introduction
	Fiber-Forming Polymers
		Characteristics of Fiber-Forming Polymers
		Natural and Synthetic Polymers for Biotextile Production
	Medical Fibers and Production Methods
		Introduction to Textile Fibers
		Melt Extrusion
		Wet/Gel Spinning
		Electrospinning
			Electrospinning Process and Spinning Parameter Optimization
			Materials Selection for Electrospinning
			Coelectrospinning
			Centrifugal Electrospinning
		Hydrogel Fiber Spinning
		Surface Functionalization
	Textile Structures
		Woven Textiles
		Knitted Textiles
		Braided Textiles
		Nonwoven Textiles
		Finishing and Surface Coating
	Applications of Medical Fibers and Biotextiles
		Biotextiles of General Surgery
			Meshes and Sutures: Design and Materials
			Barbed and Drug-Eluting Sutures
		Cardiovascular Applications of Biotextiles
			Design Criteria for Vascular Prostheses
			Woven Versus Knitted Structure
			Examples of Cardiovascular Biotextiles
			Endovascular Stent Grafts
			Knitted Textile Structures as Sewing Rings
		Orthopedic Applications of Biotextiles
			Ligament and Tendon Replacement With Woven and Braided Biotextiles
			Fiber Reinforcement in Bone Graft Cement
		Biotextiles as Wound Dressings and Skin Grafts
			Wound Dressings and Hemostats
			Skin Grafting for Burn Injuries
		Applications of Electrospun Fibers
			Wound Dressing
			Musculoskeletal Tissue Engineering
			Neural Tissue Engineering
			Nanofibers for Cardiovascular Repair
			Nanofibers for Local Drug Delivery
	Future Directions
	Chapter Study Questions
1.4.7 - Textured and Porous Biomaterials
	Introduction
	Importance of Texture and Porosity in Facilitating Biomaterial Integration
		Textured Devices Promote Healing and Restore Organ Function
		Porosity to Promote Tissue Ingrowth
		Biomaterials for Tissue Engineering
	Fabrication Methods for Biomimetic Nanoscale Texture
		Electrospinning
		Self-Assembly of Nanoscale Features
		Thermally Induced Phase Separation
		Grooves and Micropatterns
	Fabrication Methods for Micro- and Macroscale Architectural Features
		Interconnected Spherical Macropores by Porogen Methods
		Nonspherical Architectural Patterning
	Combining Multiple Fabrication Methods
		Macroporous, Nanofibrous Tissue-Engineering Scaffolds
		Multiphasic Scaffolds
		3D Printed Scaffolds
		Injectable Tissue-Engineering Scaffolds
		Surface Modification of Biomaterial Constructs
	Summary and Future Perspectives
	Chapter Exercises
1.4.8 - Biomedical Applications of Additive Manufacturing
	Introduction
	3D Printing Modalities
		Vat Photolithography
		Material Jetting
		Material Extrusion
		Powder Bed Fusion
		Binder Jetting
		Sheet Lamination
		Directed Deposition
	Bioprinting
		Bioprinting Approaches
		Bioink Design Parameters
		Biofabrication Window
		Biomaterials for Bioprinting
	Medical Applications of 3D Printing
		Surgical Planning and Medical Training
		Fabrication of Complex Implants
	Personalized Drug Delivery Systems
	Summary
	Chapter Review Questions
2.1.1 - Introduction to Biology and Medicine—Key Concepts in the Use of Biomaterials in Surgery and Medical Devices
2.1.2  - Adsorbed Proteins on Biomaterials
	Introduction
	Examples of the Effects of Adhesion Proteins on Cellular Interactions With Materials
		The Effects of Preadsorption With Purified Adhesion Proteins
		Depletion Studies
		Inhibition of Receptor Activity With Antibodies
	The Adsorption Behavior of Proteins at Solid–Liquid Interfaces
		Adsorption Transforms the Interface
		Rapid Adsorption Kinetics and Irreversibility
		The Monolayer Model
		Competitive Adsorption of Proteins to Surfaces From Protein Mixtures
	Molecular Spreading Events: Conformational and Biological Changes in Adsorbed Proteins
		Physicochemical Studies of Conformational Changes
		Changes in Biological Properties of Adsorbed Proteins
	The Importance of Adsorbed Proteins in Biomaterials
	Surface Chemistries Highly Resistant to Protein Adsorption
	Concluding Remarks
	Chapter Solutions to Problems
	Chapter Solutions to Problems
		Protein Monolayer Calculation
2.1.3 - Cells and Surfaces in Vitro
	Introduction
	A Basic Overview of Cell Culture
		Primary Culture
		Cell Lines
		Characteristics of Cultured Cells
	Understanding Cell–Substrate Interactions
		Surfaces for Cell Culture
		Process of Cell Attachment in Vitro
		Commercial and Experimental Modifications of Culture Surfaces
		Dynamic Control of Cell Culture Surfaces
		Investigating Cell–Substrate Interactions
	Cell Response to Substrate Chemistry
		Micrometer-Scale Chemical Patterns
		Nonfouling Surfaces in Cell Culture
		Chemical Patterning for the Coculture of Cells
		High-Throughput Screening
		Nanometer-Scale Chemical Patterning
	Cell Response to Substrate Topography
		Micrometer-Scale Topography
		Nanometer-Scale Topography
		High-Throughput Screening of Surface Topography
	Cell Response to Substrate Elasticity
	Cell Response to Mechanical Deformation (Strain)
	Comparison and Evaluation of Substrate Cues
		Chemistry and Topography
		Chemistry and Strain
		Topography and Strain
	Organ-on-a-Chip 3D culture
	Summary
2.1.4 - Functional Tissue Architecture, Homeostasis, and Responses to Injury
	Tissue Constituents, Organization, and Integration
		The Essential Role of Cells
		Parenchyma and Stroma
			Vascular Supply: Tissue Perfusion
			Extracellular Matrix (See also Chapter 2.1.5)
		Organ Structure
	Cell and Tissue Differentiation, Phenotype, and Maintenance
		Structure–Function Correlation
		Stem Cells
		Cellular Differentiation and Gene Expression
		Tissue Homeostasis
			Cell Turnover
			Matrix Remodeling
	Cell and Tissue Injury, Adaptation, and Other Responses (Fig. 2.1.4.12)
		Cell Regeneration and Proliferation
		Reversible versus Irreversible Injury
		Adaptation
			Hyperplasia Can Be Physiologic or Pathologic
			Atrophy, Proteasomes, and Autophagy
			Metaplasia
			Neoplasia
		Causes of Cell Injury
			Hypoxia and Ischemia
			Toxic Injury and Trauma
			Infection and Inflammation
		Pathogenesis of Cell Injury
			Ischemia-Reperfusion Injury
		Cell Death
			Necrosis
			Apoptosis
	Response to Tissue Injury and Biomaterials
		Inflammation and Innate Immunity
			Macrophage Recruitment and Polarization
		Regeneration Versus Fibrosis (Scar)
			Growth Factors
		Vascular Response
	Wound Healing in the Presence of Biomaterials
		Complications and Defective Wound Healing
2.1.5 - The Extracellular Matrix and Cell–Biomaterial Interactions
	Introduction
	Extracellular Matrices
	Properties of the Extracellular Matrix
	Collagens and Elastin
	Fibronectin
	Laminins
	Proteoglycans, Glycosaminoglycans, and Hyaluronic Acid
	Growth Factor Sequestering Proteins and Motifs
	ECM Remodeling and Proteolysis
	Integrins and Adhesion Receptors
	Cell–Biomaterial Interactions
	Cell Interactions With Adsorbed Proteins on Biomaterials
	Engineered Receptor-Targeting Peptide Sequences for Cell Adhesion
	Engineered MMP-Sensitive Peptide Sequences for ECM Remodeling and Proteolysis
	Engineered Peptide Fibers That Mimic the ECM Structure
	Summary
	Chapter Exercises
2.1.6 - Effects of Mechanical Forces on Cells and Tissues
	Introduction
	Molecular Mechanisms of Cellular Mechanotransduction
		Focal Adhesion and Mechanosensing at the ECM–Biomaterial Interface
		Cytoskeletal Mechanotransduction
		Nuclear Mechanotransduction
	Techniques for Studying Mechanical Interactions of Cells
		Shear Stress
		Mechanical Stretch
		Substrate Stiffness
		Micro- and Nanopatterning
	Mechanical Forces in the Vascular System
		Effect of Shear Stress on Blood Vessels
		Effect of Cyclic Strain on Blood Vessels
	Bone and Cartilage
	Summary
2.2.1 - Introduction to Biological Responses to Materials
2.2.2  - Inflammation, Wound Healing, the Foreign-Body Response, and Alternative Tissue Responses
	Biocompatibility and Implantation
	Sequence of the Host Response Following Implantation of Medical Devices
	Wound Healing
	Host Response to Implanted Biomaterials
	Tissue Remodeling and Biomaterial Integration—Alternative Tissue Responses
	Cellular and Molecular Mediators of Constructive Remodeling and Tissue Restoration
	Strategies to Control Host Responses
2.2.3 - Innate and Adaptive Immunity: The Immune Response to Foreign Materials
	Overview
	Innate Immunity
		First Barriers Against Danger
		Complement System
		Pattern Recognition by the Innate Immune System
		Cells of the Innate Immune System
		Antigen Uptake, Processing, and Presentation
		Costimulatory Molecules
		Chemokines and Cytokines
	Adaptive Immunity
		Components of Adaptive Immunity
		Humoral Immunity
		Cell-Mediated Immunity
		Cytotoxic T Cells
		Helper T Cells
		Recognition in Adaptive Immunity
		B Cell and Antibody Recognition
		T Cell Recognition
		Effector Pathways in Adaptive Immunity
		Immunological Memory
		Overview of the Immune Response to Pathogens
		Overview of Immune Regulation and Tolerance
		Intersection of Biomaterials and Immunology
	Chapter Exercises
		Innate Immunity
		Adaptive Immunity
2.2.4 - The Complement System
	Introduction
	Classical Pathway
	Lectin Pathway
	Alternative Pathway
	Membrane Attack Complex
	Control Mechanisms
	Complement Receptors
	Measurement of Complement Activation
	Complement–Coagulation System Interactions
	Clinical Correlates
	Summary and Future Directions
	Chapter Questions
2.2.5 - Systemic and Immune Toxicity of Implanted Materials
	Basic Principles of Systemic Distribution and Toxicity of Biomaterial Constituents
	Metals and Metal Alloy Toxicity
	Hypersensitivity and Immunotoxicity
	Organ Localization of Inflammatory and Immune Responses to Device Materials
	Summary and Conclusions
	Chapter Exercises
2.2.6 - Blood Coagulation and Blood–Material Interactions
	Introduction
	Platelet Adhesion and the Blood Coagulation Cascade—An Overview
		Cellular Composition of Blood
			Erythrocytes (Red Cells)
			Leukocytes (White Cells)
			Platelets
		Platelet Adhesion
		Platelet Aggregation
		Platelet Release Reaction
		Platelet Coagulant Activity
		Platelet Consumption
		Coagulation
		Mechanisms of Coagulation
		Control Mechanisms
		Fibrinolysis
		Complement
	Blood–Material Interactions
		Overview
		Platelet–Material Interactions
		Contact Activation of the Blood Coagulation Cascade
		Approaches to Improve the Blood Compatibility of Artificial Materials
	Conclusions
	Chapter Exercise Questions
		Question 1
		Question 2
		Question 3
2.2.7 - Tumorigenesis and Biomaterials
	General Concepts
	Association of Implants With Human and Animal Tumors
	Pathobiology of Foreign Body Tumorigenesis
	Stem Cell Therapies and Tumorigenesis
	Conclusions
	References
2.2.8 - Biofilms, Biomaterials, and Device-Related Infections
	Introduction
	Bacterial Biofilms
		What Are Biofilms and Why Are They Problematic?
		The Biofilm Microenvironment
		Antibiotic and Antimicrobial Tolerance of Bacteria in Biofilms
		Biofilms and the Immune Response
	Bacterial Adhesion
		The Process of Bacterial Adhesion to Surfaces
			DLVO Theory
			Thermodynamic Model
		Influence of Material Properties on Bacterial Adhesion
			Surface Free Energy (Wettability)
			Roughness
		Environment Factors Influence Bacterial Adhesion
	Device-Related Infection
		Major Medical Devices, Materials, and Pathogens
	Evidence for Biofilms on Devices
	Control of Biofilm Formation
		Antimicrobial Approaches: Biomaterials With Antimicrobial Properties
			Biomaterials Releasing Bioactive Molecules
				Antibiotics
				Silver
				Low-Dose Nitric Oxide
			Intrinsically Bioactive Biomaterials: Cationic Materials
				Natural Cationic Polymers
					.Chitosan is a polysaccharide composed of randomly distributed N-acetylglucosamine and d-glucosamine having low toxicity toward ...
					.Antimicrobial peptides (AMPs) are produced as part of the first line of defense in innate immunity system. Typical AMPs are sma...
				Synthetic Cationic Polymers
		Antifouling Approaches: Biomaterials That Repel Microbes
			Hydrophilic Materials Based on Polyethylene Glycol
			Superhydrophobic Materials
			Materials With Nano/Microscale Surface Texture
		Biomaterials Affecting Biofilm Architecture
			Biomaterials Modified With QS-Quenching Enzymes
			Biofilm Matrix-Degrading Enzymes
	Methods for Testing Antibacterial and Antifouling Properties of Biomaterials
	Conclusions
	Chapter Questions
2.3.1 - How Well Will It Work Introduction to Testing Biomaterials
2.3.2 - The Concept and Assessment of Biocompatibility
	Biocompatibility Today
	Toxicology
	The Products of Extrinsic Organisms Colonizing the Biomaterial
	Mechanical Effects
	Cell–Biomaterial Interactions
	Summary of Ideas to This Point
	New Developments Are Changing the Paradigm of Biocompatibility
	Clinical Significance of Biocompatibility
	Conclusions
2.3.3 - In Vitro Assessment of Cell and Tissue Compatibility
	Introduction
	Background Concepts
	Use of Medical Device/Biomaterial Chemical Composition and Their Extracts for Toxicological Risk Assessment and In Vitro Testing...
	In Vitro Assays to Assess Cell and Tissue Compatibility in Medical Device/Biomaterial Evaluation for Regulatory Purposes
	In Vitro Tests for Genotoxicity, Carcinogenicity, and Reproductive Toxicity: ISO 10993-3
	In Vitro Tests for Interactions with Blood: ISO 10993-4
	In Vitro Tests for Cytotoxicity: ISO 10993-5
	Application-Specific In Vitro Assays Considered in Proof-of-Concept Testing
	Future Challenges in In Vitro Assessment of Cell and Tissue Compatibility
	Summary Remarks
	Chapter Questions
2.3.4 - In Vivo Assessment of Tissue Compatibility
	Introduction
	Selection of in Vivo Tests According to Intended Use
	Biomaterial and Device Perspectives in In Vivo Testing
	Specific Biological Properties Assessed by In Vivo Tests
		Sensitization, Irritation, and Intracutaneous (Intradermal) Reactivity
		Systemic Toxicity: Acute, Subacute, and Subchronic Toxicity
		Genotoxicity
		Implantation
		Hemocompatibility
		Chronic Toxicity
		Carcinogenicity
		Reproductive and Developmental Toxicity
		Biodegradation
		Immune Responses
	Selection of Animal Models for In Vivo Tests
	Future Perspectives on In Vivo Medical Device Testing
2.3.5 - Evaluation of Blood–Materials Interactions
	Introduction
	Background and Principles of Blood–Materials Interactions Assessment
		What Is Blood Compatibility?
		Why Measure Blood Compatibility?
		What Is Thrombogenicity?
		Key Considerations for BMI Assessment
			Blood: A Fragile Fluid That Is Readily Compromised
			Flow: Blood Interactions Dictated by Shear and Mass Transport
			Surfaces: Actively Studied, but Least Well Defined, of the BMI Variables
			Blood Interaction Times With Materials and Devices
	Evaluation of BMI
		In Vitro Tests
		In Vivo Tests of BMI
		In Vivo Evaluation of Devices
		Contemporary Concepts in BMI Evaluation
		Examples of BMI Evaluation
		What Materials Are Blood Compatible?
	Conclusions
	References
2.3.6 - Animal Surgery and Care of Animals
	Introduction
	Ethical and Regulatory Overview
		Governmental Regulations
			United States Department of Agriculture
			Public Health Service
			Food and Drug Administration
		Institutional Responsibilities
			Institutional Animal Care and Use Committee
			Attending Veterinarian
			Principal Investigator
	Surgical Facility Design
	Model Selection
		Cardiovascular Devices
			Heart Valve Replacement
			Ventricular Assist Devices
		Orthopedic Devices
			Bone Defect Models
		Vascular
		Ophthalmology
		Skin
	Animal Management and Care of Animals
		Rodent
			Animal Selection and Preoperative Preparation
			General Anesthesia
			Analgesia
		Ruminants (Sheep, Goats, Calves)
			Animal Selection and Preoperative Preparation
			Brief Restraint
			General Anesthesia
			Analgesia
		Rabbit
			Animal Selection and Preoperative Preparation
			Brief Procedures
			General Anesthesia
			Analgesia
		Swine
			Animal Selection and Preoperative Preparation
			Brief Restraint
			General Anesthesia
			Analgesia
	Chapter Study Questions
2.4.1 - Introduction: The Body Fights Back–Degradation of Materials in the Biological Environment
2.4.2- Chemical and Biochemical Degradation of Polymers Intended to Be Biostable
	Introduction
	Polymer Degradation Processes
		Preimplant Degradation
		Postimplant Degradation Forces
	Hydrolytic Biodegradation
		Structures of Hydrolyzable Polymers
		Host-Induced Hydrolytic Processes
		Hydrolysis: Preclinical and Clinical Experience
		Polymers Containing Hydrolyzable Pendant Groups
	Oxidative Biodegradation
		Oxidation Reaction Mechanisms and Polymer Structures
		Direct Oxidation by Host
		Stress Cracking
		Device- or Environment-Mediated Oxidation
		Chemical Structure Strategies to Combat Oxidation
		Oxidative Degradation Induced by External Environment
	Emerging Long-Term Elastomer Applications
		Polyurethanes
		Hydrocarbon Elastomers
	Conclusions
	Chapter Questions
2.4.3 - Metallic Degradation and the Biological Environment
	Introduction
	The Severe Biological Environment (Fatigue, Tribology, Corrosion, and Biology)
	Basic Corrosion of Passive Oxide-Covered Alloys
	Tribological Aspects of Metal-Hard Contact Degradation
	Metal-on-Metal (Hard) Surface Mechanics
	Clinically Observed Mechanically Assisted Crevice Corrosion (Fretting Crevice Corrosion) In Vivo
	Mechanically Assisted Corrosion Basics for CoCrMo and Ti–6Al–4V Alloys
		Tribocorrosion Layer and Surface Damage on Metallic Biomaterials Surfaces
	Biology and Corrosion: Additional Insights
	Reduction Reactions Affect Cells
	Reactive Oxygen Species May Enhance Corrosion Reactions
	Summary
	Acknowledgments
	References
2.4.4 - Degradative Effects of the Biological Environment on Ceramic Biomaterials
	Introduction
	Reactivity of Bioceramics
	Factors Influencing the Degradation of Bioceramics
	Reactivity and Degradation of Natural Apatites
	Evolution in the Use of Bioceramics for Bone Repair
	Bioceramic Interactions With the Biological Environment
		Inert Ceramics: First-Generation Bioceramics
		Resorbable and Bioactive Ceramics: Second-Generation Bioceramics
		Third-Generation Ceramics
	Summary and Future Perspectives
2.4.5 - Pathological Calcification of Biomaterials
	The Spectrum of Pathologic Biomaterial and Medical Device Calcification
		Bioprosthetic Heart Valves
		Transcatheter (or Percutaneous) Cardiac Valve Replacements
		Polymeric Heart Valves and Blood Pump Bladders
		Breast Implants
		Intrauterine Contraceptive Devices
		Urinary Stents and Prostheses
		Intraocular and Soft Contact Lenses and Scleral Buckles
	Assessment of Biomaterial Calcification
		Morphologic Evaluation
		Chemical Assessment
	Mechanisms of Biomaterial Calcification
		Regulation of Pathologic Calcification
		Role of Biological Factors
		Role of Biomaterial Factors
		Role of Biomechanical Factors
		Experimental Models for Biomaterial Calcification
		Role of Cells
		Role of Collagen and Elastin
		Role of Glutaraldehyde
		Role of Immunologic Factors
	Prevention of Calcification
		Inhibitors of Hydroxyapatite Formation
			Bisphosphonates
		Trivalent Metal Ions
		Calcium Diffusion Inhibitor
		Removal/Modification of Calcifiable Material
			Surfactants
			Alcohol Treatments
			Glutaraldehyde Neutralization
			Decellularization
		Modification of Glutaraldehyde Fixation and Other Tissue Fixatives
		Alternative Materials
	Design Considerations and Selection of Materials to Avoid Calcification
	Conclusions
	References
2.5.1 - Introduction to Applications of Biomaterials
2.5.2A - Cardiovascular Medical Devices: Heart Valves, Pacemakers and Defibrillators, Mechanical Circulatory Support, and Other Intracardiac Devices
	Introduction
	Heart Valve Function and Valvular Heart Disease
		Surgical Bioprosthetic and Mechanical Heart Valves
		Percutaneous Transcatheter Valves and Other Devices
	Cardiac Arrhythmias
		Cardiac Pacemakers
		Implantable Cardioverter-Defibrillators
		Complications of Pacemakers and ICDs
	Congestive Heart Failure
		Cardiopulmonary Bypass
		Percutaneous Mechanical Circulatory Support Devices
		Durable Ventricular Assist Devices and Total Artificial Hearts
	Atrial Septal Defects and Other Intracardiac Defects
		Closure Devices
	Atrial Fibrillation
		Left Atrial Appendage Occlusion Devices
2.5.2B - Cardiovascular Medical Devices: Stents, Grafts, Stent-Grafts and Other Endovascular Devices
	Key Concepts in Vascular Structure and Function
		Architecture of the Circulation
		Vascular Pathology
			Vascular Injury and Healing
			Thrombosis
			Atherosclerosis
			Aneurysms and Dissections
	Vascular Devices and Biomaterials
		Angioplasty and Endovascular Stents
		Vascular Grafts
		Endovascular Stent-Grafts
		Other Vascular Devices
			Endovascular Catheters
			Diagnostic Catheters
			Therapeutic Catheters
			Endovascular Coils
			Vascular Filters
			Vascular Closure Devices (VCDs)
	Unintended Embolic Biomaterials
	Ex Vivo Evaluation
	Conclusions
2.5.3 - Extracorporeal Artificial Organs and Therapeutic Devices
	Introduction
	Extracorporeal Respiratory Support
		Pulmonary Disease—Incidence, Causes, and Mortality
		Extracorporeal Membrane Oxygenation (ECMO)
		Alternative Extracorporeal Gas Exchange Devices
		Oxygenator Biocompatibility Challenges: Coagulation and Inflammation
		Surface Coatings
		Nitric Oxide Surface Flux
	Renal Replacement Therapies and Therapeutic Apheresis
		Introduction
		Renal Replacement Therapy
			Function of the Kidney
			Treatment of Renal Failure
				Peritoneal Dialysis
				Hemodialysis
				Dialyzer Materials and Coatings
				Coagulation and Inflammation During Hemodialysis
				Extracorporeal Hemofiltration
		Hemoperfusion
		Therapeutic Apheresis
			Plasmapheresis
			Plasma Separation
			Plasma Exchange
			Plasma Treatment
		Sorbent Dialysis
		Blood Pumps in Extracorporeal Circulation
			Roller Pumps
	Summary
	Chapter Exercises
2.5.4 - Orthopedic Applications
	Biomaterials Development: A History of Total Hip Arthroplasty
	Current Biomaterials in Total Arthroplasty
	Orthopedic Biomaterials: Clinical Concerns
		Orthopedic Biomaterial Wear
		Orthopedic Biomaterial Corrosion
			Fretting Corrosion or Mechanically Assisted Crevice Corrosion (MACC)
		Implant Debris Types: Particles and Ions
		Particulate Debris
		Metal Ions (Soluble Debris)
		Local Tissue Effects of Wear and Corrosion
		Remote and Systemic Effects of Wear and Corrosion
		Hypersensitivity
		Carcinogenesis
		Preventive Strategies and Future Directions
	Chapter Study Questions
2.5.5 - Dental Applications
	Overview
	Unique Needs in Developing Biomaterials for DOC Procedures
	Restorative Materials
	Dental Implants
		Criteria for Successful Implant Function
		Osseointegration and Accelerating Healing and Attachment to Tissue
		Surface Topology and Chemistry
		Mechanical Parameters and Implant Design
	Materials Used in Dental Implants
		Metals
		Ceramics
		Future Directions
	Tissue Engineering in Dentistry
		Need for Tissue Engineering in Dentistry
		Materials for Engineering DOC Tissue Structure and Function
		DOC Tissue-Engineering Applications
			Teeth
			Temporomandibular Joint
			Oral Mucosa
			Salivary Glands
			Bone and Periodontium
	Summary and How Experience From Dental Biomaterials has Brought Value to Other Areas of Biomaterials
	Chapter Exercises
2.5.6 - Ophthalmologic Applications: Introduction
	Overview of the Anatomy of the Eye
	Eye-related Conditions and Statistics
	Considerations for Ophthalmic Materials
	Biomaterials: Contact Lenses
	Contact Lens Materials
		Hard Contact Lenses
		Soft Hydrogel Contact Lenses
		Silicone Hydrogel Contact Lenses
	Surface Modification
	Contact Lens Solutions
	Intraocular Lens Implants
		Introduction to Intraocular Lens Implants, the Optics of the Eye, and Cataracts
		IOL Biomaterials and Design
		IOLs With Variations of Optical Function
		Multifocal IOLs
		Accommodative IOLs
		Adjustable-Power IOLs
		Summary and Future of IOLs
		Glaucoma Drainage Devices
		Aqueous Humor Production and Drainage
	New-generation Microinvasive Glaucoma Surgery (MIGS) Implantation Devices
		The Glaukos iStent Series
	Summary
	Retinal Implants
	Epiretinal Devices
		Argus II
	The Intelligent Retinal Implant System II (IRIS II)
	EPI-RET3 Retinal Implant System
	Subretinal Devices
		Alpha IMS/AMS
	Photovoltaic Retinal Implant (PRIMA) Bionic Vision System
	Suprachoroidal Devices
		Bionic Vision Australia (BVA) Team
	Suprachoroidal–Transretinal Stimulation (STS)
	Conclusions and Future Directions
2.5.7  - Bioelectronic Neural Implants
	Introduction
	Bioelectronic Devices
		Electrode Materials
			Factors That Influence Materials Selection
				Conducting/Capacitive Materials
				Insulating Materials
		Equivalent Circuit Models
	Technologies
		Battery, IPG
		Leads and Interconnects
		Electrode Contacts
	Applications
		Research
		Rehabilitation
			Sensory Restoration
				Visual
				Tactile
				Auditory
			Genitourinary, Bladder Dysfunction
			Motor Function
			Brain–Computer Interface
		Bioelectronic Medicine, “Electroceuticals”
		Regeneration
	Failure Modes
		Mechanical
		Materials
		Biological
	Biomaterial-Based Strategies to Enable Neural Implants
		Micromotion and Tissue Mechanics
		Antioxidative Strategies
	Conclusions and Future Directions
2.5.8 - Burn Dressings and Skin Substitutes
	Burn Wounds
	Surgical Planning for Wound Care
	Ideal Properties of Dressings and Skin Substitutes
	Topical Microbial Management
	Negative-Pressure Dressings
	Degradable Polymers
	Temporary Skin Substitutes
	Permanent Skin Substitutes
	Cost Considerations
	Regulatory Considerations
	Conclusions and Future Directions
	Chapter Exercises
2.5.9 - Description and Definition of Adhesives, and Related Terminology
	Introduction
		Description and Definition of Adhesives, and Related Terminology
	The Logic of Adhesion Procedures
	Hard-Tissue Adhesives: Bone and Tooth Cements
		Autopolymerizing PMMA Bone Cement
			Historical Background
			Mechanism of Setting of PMMA/MMA Dough
			Mechanism of “Bonding” or Grouting
			Alternative Bone Cements: Calcium Phosphate
			Classical and Modern Dental-Bonding Cements: Conventional Acid–Base Cements
			Polyelectrolyte Cements: Zinc Polycarboxylates and Glass Ionomers
		Acid-Etch Bonding to Enamel
		Chemistry of Etchants, Primers, and Bonding Agents
		Hybrid-Layer Creation Via A Three-Stage Approach: Etch, Prime, Bond
		Aging and Stability of the Bonded Interface
	Inhibitors for the Preservation of the Hybrid Interfacial Zone Between Adhesives and Human Dentin
		Soft-Tissue Adhesives and Sealants
			Performance Requirements
			Historical Overview
	The Relationship Between Soft-Tissue Adhesion and Drug Delivery
		Cyanoacrylate Esters
			Chemistry
			Performance
		Fibrin Sealants
			Formulation, Presentation, and Setting Processes
			Advantages and Applications
		Bioadhesives
		Hydrogel Sealants
		New Research Directions: Biomimetic Approaches
	Sutures
		Genesis and Common Uses
		Description of Surgical Sutures
		Surgical Gut Sutures
		Silk Sutures
		Polyester Sutures
		Nylon Sutures
		Polypropylene Sutures
		Ultrahigh-Molecular-Weight Polyethylene (UHMWPE) Sutures
		Stainless Steel Sutures
		Synthetic Absorbable Sutures
			Monomers and Preparation of Polymers
		Poly(Glycolic Acid) (PGA)
		Poly(Dioxanone) (PDO) Sutures
		High-Glycolide Copolymeric Sutures
		Dyes
		Coatings
		Needles and Attachment
		Packaging
		Physical Properties
		In Vitro and In Vivo Performance
	Newer Trends and Future Developments
2.5.10 - Biomaterials for Immunoengineering
	Use of Biomaterials in Vaccine Development
		Introduction
		Biomaterials for Improving Vaccine Efficacy
			Use of Biomaterials to Adjuvant the Immune System
			Use of Biomaterials to Improve Delivery of Antigen to APCs
			Activation of B Cells and Humoral Immunity
				Overview of the B Cell Activation Process
				Biomaterial Design for Enhancing the Humoral Response
		Biomaterials for Alternative Vaccine Administration Routes
		Biomaterials for Improved Vaccine Manufacturing and Accessibility
		Conclusion/Future Directions
	Use of Biomaterials in T Cell Modulation
		Introduction
		Biomaterials for Targeting and Modulation of T Cell Therapies
		Biomaterials for Enhanced T Cell Manufacturing
		Conclusions/Future Directions
	Use of Biomaterials to Induce Tolerance
		Introduction
		Induction of Tolerance in Autoimmune Disorders
			T Cell Anergy and Deletion Through Incomplete Dendritic Cell Activation
			Elevation of Treg Activity to Induce Tolerance
			Suppression of B Cell Activation
		Concluding Remarks
	Exercises
2.5.11 - Biomaterials-Based Model Systems to Study Tumor–Microenvironment Interactions
	Introduction
	Biological Design Considerations
		Tissue Dimensionality
		Transport Phenomena and Interstitial Pressure
		ECM Physicochemical Properties
		Immunological Changes
	Biomaterials to Study the Tumor Microenvironment
		Natural Biomaterials
			Protein-Based Materials
			Carbohydrate-Based Materials
			Cell- and Tissue-Derived Materials
		Synthetic Biomaterials
			Synthetic Hydrogels
			Polyesters
		Composite Materials
	Applications of Biomaterials-Based Tumor Models
		Analyzing the Effect of Tissue Dimensionality
		Modeling Tumor–Stroma Interactions
		Platforms to Interrogate Cell–ECM Interactions
		Dynamic Materials Systems for Studies of Mechanical Memory
		Analyzing the Effect of Local and Systemic Transport Phenomena
	Metastasis
	Conclusions
	Chapter Exercises With (Guided) Solutions
2.5.12 - Drug Delivery Systems
	History of DDS Development
	General Considerations in DDS Design
		Routes of Drug Delivery
		DDS Biomaterials Design Considerations
		Biomaterials Used in DDSs
		DDS Biomaterial Properties
			Degradation
			Surface Properties
			Mechanics
	DDSs to Improve Drug Pharmacokinetics
		Pharmacokinetics
		Dosage and Distribution Control
		Controlling Drug Release Kinetics
	DDSs to Improve Drug Solubility
		Colloidal DDSs
		Noncolloidal DDSs
	Biomaterial DDSs Can Enhance Drug Stability
		Small Molecule Drugs
		Protein/Peptide Drugs
		Nucleic Acid Drugs
	DDS Design to Overcome Biological Barriers
		Epithelial Barriers
			Parenteral Administration
			Transdermal DDSs
			Mucosal DDSs
			Oral DDSs
		Endothelial Barriers
	Biomaterial DDSs for Drug Targeting
		Passive Targeting
		Active Targeting
			Antibodies
			Proteins
			Peptides
			Aptamers
			Carbohydrates
			Small Molecules
	Regulatory and Intellectual Property Considerations for DDSs
		Regulation
		Intellectual Property
	Final Remarks
	Chapter Review Questions
2.5.13 - Responsive Polymers in the Fabrication of Enzyme-Based Biosensors
	Introduction
		Classic Biosensor System
			Bioreceptor (Recognition Layer)
			Physicochemical Transducers
			Computer Processing
		Types of Enzymatic Glucose Biosensors
			Electrochemical Biosensors
			Amperometric Biosensors
			Conductometric Biosensors
			Impedimetric Biosensors
			Potentiometric Biosensors
			Optical Biosensors
			Piezoelectric Biosensors
			Thermal Biosensors
	Roles of Responsive Polymers in Enzymatic Biosensors
		Passive Roles (Physical Support)
			Covalent Linkage
			Cross-Linking
			Entrapment
			Encapsulation
		Active Roles
			Redox Mediators
			Chromogenic Agents
			Fast Ion Conductors
			Fluorescence Probes
	Integrating Responsive Polymers With Enzymes
		Physicochemical Conjugation With CNTs
		Active Site Conjugation Using Boric Acid
		Molecular Wiring
		Covalent Conjugation
	Integrating Responsive Polymers With Transducers
		Interface Engineering
	Systems Integration
		Microfabrication
		Three-Dimensional (3-D) Bioprinting
	Future Outlook
2.6.1 - Rebuilding Humans Using Biology and Biomaterials
2.6.2 - Overview of Tissue Engineering Concepts and Applications
	General Introduction
		History of Tissue Engineering
	Goals of Tissue Engineering and Classification
		Goals of Tissue Engineering
		Classification of Tissue-Engineering Approaches
	Components of Tissue Engineering
		The Cell
		Materials
		Biological Factors
		Scaffold Design
		Integration of Multiple Factors
	Models for Tissue Engineering
		Bioreactors
		Organoids
		In Vivo Models
	Applications of Tissue Engineering
		Transplantation
		Replacing/Regenerating Target Organs
		Drug Delivery
		Disease Models and Therapy
		Organ-On-a-Chip Systems
	Current Challenges and Opportunities
		Cell Source
		Vascularization
		Tissue Maturation
		In Vivo Integration
		FDA Regulations for Clinical Translation
		Gene Editing and CRISPR
	Future Perspectives
2.6.3 - Tissue Engineering Scaffolds
	Introduction
	Scaffold Design Criteria
	Scaffold Applications
		Cell Delivery
		Drug and Biomolecule Delivery
	Scaffold Materials
		Polycondensation Polymers
			Ring-Opening Polymerization
			Click Reactions
		Polyaddition Polymers
			Ionic Polymerization
			Free Radical Polymerization
		Biological Polymers
		Composites and Additives
	Scaffold Fabrication Techniques
		Rapid Prototyping
		Electrospinning/Electrospraying
		Superstructure Engineering
		Solvent Casting, Particulate/Porogen Leaching
		Freeze-Drying
		Phase Separation
		Gas Foaming/Supercritical Fluid Processing
	Scaffold Characterization Techniques
	Cell-Incorporated Scaffolds
	Conclusions
	Chapter Exercises
	Chapter Exercise Answers
2.6.4 - Micromechanical Design Criteria for Tissue-Engineering Biomaterials
	Introduction
	Cell–Matrix Interactions and Mechanotransduction
		Focal Adhesion
		Roles of Focal Adhesion Maturation and Stress Fiber Formation in Mechanotransduction
		Important Mechanotransduction Molecular Pathways for Design of Scaffolds
		Direct Transmission of Forces to the Nucleus
	Design Considerations for Scaffolds to Regulate Tissue Development
		Local Stiffness
		Surface Topography
		Fibrous Scaffolds
		Multicellular Interactions
		Mechanical Stimulation
		Effects of Combined Mechanical Stimuli
	Implications for Future Materials Design
	Conclusion
2.6.5 - Tendon Tissue-Engineering Scaffolds
	Introduction
	Native Adult Tendon Properties
		Mechanical Properties
		Extracellular Matrix Composition and Molecular Arrangement
		Tendon Cells
	Scaffold Design Goals
		Immediate or Early Return to Load-Bearing Function
		Guidance Cues to Induce Tenogenic Cell Behaviors
	Fabrication Methods
		Spinning
		Textile Technologies
		Gelation
		Freeze Drying
		Decellularization
	Postfabrication Modifications
	Delivery of Bioactive Molecules (e.g., Drugs and Growth Factors)
	Polymer Selection and Scaffold Designs
		Natural Plant- and Animal-Derived Polymers
			Alginates
			Chitin/Chitosan
			Collagen
			Gelatin
			Silk
		Synthetic Polymers
			Poly(Glycolic Acid) and Poly(Lactic Acid)
			Poly(ε-Caprolactone)
			Other Synthetic Polymers
	Future Directions: Developmental Biology-Inspired Strategies
	Summary
2.6.6  - Bone Tissue Engineering
	Introduction
	Bone Biology
	Types of Bone Tissue
	Cells Involved
		Osteoblasts
		Bone Lining Cells
		Osteocytes
		Osteoclasts
	Bone Tissue Development
		Intramembranous Ossification
		Endochondral Ossification
	Bone Tissue Engineering
	Bone Grafts
		Autograft
		Allograft
	Bone Graft Substitutes
		Allograft-Based Substitutes
		Natural Polymer-Based Substitutes
		Synthetic Polymer-Based Substitutes
		Ceramic-Based Substitutes
		Cell-Based Substitutes
		Growth Factor-Based Substitutes
		Composite Substitutes
	Porosity in Bone Graft Substitutes
	Dimension in Bone Graft Substitutes
		Sintered Microspheres
		Nanofibers
	In Vitro Culture Techniques for Bone Graft Substitutes
	Conclusion
2.6.7 - Biomaterials for Cardiovascular Tissue Engineering
	Introduction
	Endothelial Cells
	Cardiac Muscle
	Heart Valves
	Blood Vessels
	Scaffold Materials
		Protein Hydrogels
		Decellularized Tissues
		Synthetic Polymers
		Synthetic Hydrogels
	Conclusions
2.6.8 - Soft Tissue Engineering
	Introduction
	Properties of Soft Tissues
	Common Biomaterials Used for Soft Tissue Engineering
		Synthetic Polymers
		Natural Polymers
		Decellularized Tissues
	Soft Tissue Engineering Applications: Adipose, Gastrointestinal, and Skin
		Adipose Tissue Engineering
			Anatomy and Physiology
			Design Criteria for Adipose Tissue Engineering
			Commercially Available and Clinically Tested Biomaterials
			Novel Materials and Technologies
				Challenges
		Gastrointestinal Tissue Engineering
			Anatomy and Physiology
			Gastrointestinal Disorders and the Need for Tissue Engineering
			Design Criteria for Engineered Gastrointestinal Tissues
			Gastrointestinal Soft Tissue-Engineering Strategies
			Challenges and Future Goals
		Tissue-Engineered Skin: Future Goals of Skin Substitutes
			Anatomy and Physiology
			Design Criteria
			Skin Substitute Technology
			Challenges
	Conclusions
	Chapter Exercises
3.1.1 - Introduction: Biomaterials in Medical Devices
3.1.2 - Total Product Lifecycle for Biomaterial-Based Medical Devices
	Chapter Questions for the Student
3.1.3  - Safety and Risk Considerations in Medical Device Development
	Introduction
	Absence of Toxicity Is Not Evidence of Safety
	Assessing the Continuum of Biological Risk in Performance
	Assessing the Contribution of Secondary Processes to Biological Risk
	Assessing Biological Risk of Aging Biomaterials in the Aging Patient
	Summary and Study Guide
	Chapter Study Guide
3.1.4 - Sterilization and Disinfection of Biomaterials for Medical Devices
	Introduction
	Radiation-Based Techniques
		Safety Considerations
		Principles of Action and Efficacy
		Gamma Sterilization
		Electron Beam Sterilization
		X-Ray Sterilization
		Application Considerations
			R&D, Pilot, and Low-Volume Technologies
			Material Considerations for Radiation Sterilization
			Biologics and Human-Based Tissue: Compatibility With Radiation Sterilization
	Chemical Techniques
		Safety Considerations
		Principles of Action and Efficacy
		Ethylene Oxide Sterilization
		Sterilization by Oxidation: Hydrogen Peroxide or Ozone
		Physicochemical Methods: Gas Plasma
		Material Considerations for Chemical Sterilization
			R&D, Pilot, and Low-Volume Technologies
			Pharmaceuticals and Biologics: Compatibility With EO Sterilization
	Thermal Techniques
		Safety Considerations
		Principles of Action and Efficacy
		Dry Heat Sterilization
		Steam Sterilization and Disinfection
		Application Considerations
	Materials Development Considerations for Sterility
	Safety Testing and Validation After Sterilization
	Patient Safety: FDA Recall Classifications: Class I, Class II, and Class III
		Biological Safety Verification
		Maintaining Sterility: Packaging and Shelf Life
		Sourcing, Quality Systems, and Manufacturing Controls
		Sterilization Standards
	Summary and Future Challenges
	Chapter Exercises
3.1.5 - Verification and Validation: From Bench to Human Studies
	Introduction: Focusing on Commercial Medical Device Development
	Starting a Medical Device Project
	Design Controls for Medical Device Development
	Verification of Medical Device Design
	Types of Verification Testing
	Validation of Medical Device Design
	Verification Versus Validation
	Concluding Remarks: Design Transfer Beyond Human Studies
	Chapter Study Questions
3.1.6 - Commercial Considerations in Medical Device Development
	Introduction
	Traditional Model of Product Development
	Determining Market Opportunity
	Medical Device Reimbursement
	Securing Intellectual Property and Funding
		Intellectual Property
		Securing Funding
	Commercial Operations: Sales and Marketing
	Summary
	Student Questions
3.1.7 - Regulatory Constraints for Medical Products Using Biomaterials
	Introduction and History in the United States
	Global Premarket Assessment Methods
	Premarket Assessment Requirements
	Premarket Clearance and Approvals
	Manufacturing and Material Supplier Controls
	Postmarketing Management of Risk and Product Performance
	Registration, Device Listing, Licenses
	Summary and Study Guide
	Chapter Questions: True or False
3.1.8 - Role of Standards for Testing and Performance Requirements of Biomaterials
	Introduction: What Is a Standard
	Reference Materials
	Reference Data
	Documentary Standards
		Documentary Standards: Voluntary, Consensus
		Who Writes Documentary Standards?
		How Are Documentary Standards Developed?
		Applications of Documentary Standards
			Accelerating the Regulatory Process
				Specificity versus Universality
				A Standard Test Method Does Not Necessarily Define the Best Measurement
			Clinical Relevance
	Measurement Assurance
		Interlaboratory Comparison Studies
	Looking Ahead
	Conclusion
	Homework Questions
	Answer Key for Homework Questions
3.1.9 - Medical Device Failure—Implant Retrieval, Evaluation, and Failure Analysis
	Overview and Definitions
		Medical Implants
		Implant Retrieval
		Postmarket Surveillance
	Goals for Implant Retrieval and Evaluation and Failure Mode Analysis
	Medical Surveillance and the Role of Retrieval Analysis in Device Development
	Chapter Exercises (With Answers)
3.1.10 - Legal Concepts for Biomaterials Engineers
	Introduction
	Employment Agreements
	Confidentiality and Materials Use Agreements
	Intellectual Property: Patents, Trade Secrets, and Freedom to Operate
	Contract Negotiation, Performance, and Compliance
	Sponsored Research Agreements
	License Agreements
	Litigation
	Conclusion
3.1.11 - Moral and Ethical Issues in the Development of Biomaterials and Medical Products
	Introduction
	Selected Approaches to Ethical Reasoning
		The Utilitarian Approach
		The Rights Approach
		The Justice Approach
		The Virtue Approach
	Safety
	Animal Testing
	Human Testing
	Research Integrity
	Conflict of Interest
	Emerging Ethical Issues in Medical Product Development
		Ethical Issues in Stem Cell Research
		Gene Editing
	Cost and Access to Medical Products
	Conclusions
A -  Properties of Biological Fluids
B - Properties of Soft Materials
C - Chemical Composition of Metals and Ceramics Used for Implants
D - The Biomaterials Literature
E - Assessment of Cell and Matrix Components in Tissues
	Light Microscopy
	Special Staining
	Immunohistochemical Staining
	In Situ Hybridization
	Electron Microscopy
	Special Techniques
Index
	A
	B
	C
	D
	E
	F
	G
	H
	I
	J
	K
	L
	M
	N
	O
	P
	Q
	R
	S
	T
	U
	V
	W
	X
	Y
	Z