Integrated Safety and Risk Assessment for Medical Devices and Combination Products

Contents
Chapter 1: Introduction: History and Where We Are Headed
	1.1 Biocompatibility
		1.1.1 Fundamentals of Biocompatibility Tests
	1.2 Scope of Devices and the Medical Device Market
	1.3 History
	1.4 Nonspecific Regulatory Considerations
		1.4.1 Good Laboratory Practices
		1.4.2 Animal Welfare Act (AWA)
		1.4.3 Regulations Versus Law
		1.4.4 Organizations Regulating Drug and Device Safety in the United States
	1.5 Potential Patient Exposure Parameters (Routes, Regimens, Quantities, and Durations) as a Principal Determinant of Risk
		1.5.1 What Is the Type or Route of Patient Exposure?
		1.5.2 How Much of the Device Contacts Patient Tissues?
		1.5.3 What Is the Cumulative Duration of Contact of a Device with a Patient?
	References
Chapter 2: Regulatory Aspects and Strategy in Medical Device and Biomaterials Safety Evaluation
	2.1 Regulatory Basis
		2.1.1 Regulations: General Considerations for the United States
	2.2 Regulations Versus Law
	2.3 Organizations Regulating Device Safety in the United States
	2.4 Classification of Devices
	2.5 Toxicity Testing: Medical Devices
	2.6 Device Categories: Definitions and Examples
	2.7 Biological Tests
	2.8 United States Pharmacopoeial Testing
	2.9 ISO Testing Requirements
	2.10 MHW Requirements
	2.11 CE Marking of Devices
	2.12 Risk Assessment
	2.13 Standards and Guidances
	2.14 Method
	2.15 Case Studies
	2.16 Sources of Data
	2.17 Uncertainty Factors (UCFs)
	2.18 Safety Margins
	2.19 End Note
	References
Chapter 3: Biocompatibility Testing: The Biologic Tests
	3.1 Sample Preparation (ISO 10993-12)
		3.1.1 Apparatus
			3.1.1.1 Autoclave
			3.1.1.2 Oven
			3.1.1.3 Extraction Containers
		3.1.2 Preparation of Apparatus
	3.2 Procedure
		3.2.1 Preparation of Sample
		3.2.2 Preparation of Extracts
		3.2.3 Reference Materials
	3.3 Cytotoxicity Testing (ISO 10993-5)
		3.3.1 Background
		3.3.2 Neutral Red Uptake (NRU) Assay
		3.3.3 MTT
		3.3.4 Agar Diffusion Test
		3.3.5 Direct Contact Test
			3.3.5.1 Sample Preparation
			3.3.5.2 Procedure
			3.3.5.3 Interpretation of Results
		3.3.6 Elution Test
			3.3.6.1 Sample Preparation
			3.3.6.2 Procedure
			3.3.6.3 Interpretation of Results
		3.3.7 Correlation with In Vivo Results
		3.3.8 Conclusion
	3.4 Sensitization (ISO 10993-10)
		3.4.1 Hypersensitivity
			3.4.1.1 Type I Hypersensitivity
			3.4.1.2 Type IV Delayed-Type Hypersensitivity (DTH)
		3.4.2 Objectives and General Features
			3.4.2.1 Induction Phase
			3.4.2.2 Challenge Phase
			3.4.2.3 Rechallenge Phase
		3.4.3 Modified Buehler Procedure
			3.4.3.1 Animals
			3.4.3.2 Pretest Screen
			3.4.3.3 Induction Phase
			3.4.3.4 Challenge Phase
			3.4.3.5 Rechallenge Phase
			3.4.3.6 Interpretation of Results
			3.4.3.7 Strengths and Weaknesses
		3.4.4 Guinea Pig Maximization Test
			3.4.4.1 Animals
			3.4.4.2 Pretest
			3.4.4.3 Induction Stage 2 (Day 7)
			3.4.4.4 Challenge Stage (Day 21)
			3.4.4.5 Rechallenge (Day 28)
			3.4.4.6 Observations: Challenge and/or Rechallenge Readings
			3.4.4.7 Interpretation of Results
		3.4.5 Local Lymph Node Assay (LLNA)
			3.4.5.1 Test System Manipulation (For All In Vivo Test Systems)
	3.5 Irritation (Local Tissue Tolerance) (ISO 10993-10)
		3.5.1 Dermal Irritation
			3.5.1.1 Primary Dermal Irritation Test
				Rabbit Testing Procedure
				Study Procedure
				Observations
				Evaluation of Results
	3.6 Intracutaneous Reactivity
		3.6.1 Intracutaneous Test
			3.6.1.1 Test Animal
			3.6.1.2 Procedure
	3.7 Ocular Irritation Testing
		3.7.1 Primary Eye Irritation Test
			3.7.1.1 Test Article Screening Procedure
			3.7.1.2 Rabbit Screening Procedure
			3.7.1.3 Study Procedure
			3.7.1.4 Observations
		3.7.2 Alternatives
	3.8 Other Nonparenteral Route Irritation Tests
		3.8.1 Pyrogenicity
		3.8.2 Reference Standard and Control Standard Endotoxins
		3.8.3 Preparatory Testing
		3.8.4 Inhibitions or Enhancement Test
			3.8.4.1 Test Procedure
			3.8.4.2 Preparation
			3.8.4.3 Maximum Valid Dilution
			3.8.4.4 Procedure
			3.8.4.5 Calculation and Interpretation
			3.8.4.6 Interpretation
		3.8.5 Material-Mediated Pyrogenicity (USP Rabbit Pyrogen Test)
			3.8.5.1 Apparatus and Diluents
			3.8.5.2 Temperature Recording
			3.8.5.3 Test Animals
			3.8.5.4 Procedure
			3.8.5.5 Test Interpretation and Continuation
	3.9 Acute Systemic Toxicity Testing (ISO 10993-11)
		3.9.1 Introduction
		3.9.2 Acute Systemic Toxicity Characterization
			3.9.2.1 Body Weight Considerations
			3.9.2.2 Factors that Can Affect Acute Tests
	3.10 Implantation Studies and Implantation Biology (ISO 10993-6)
		3.10.1 ISO 10993 Implantation Test
			3.10.1.1 Preparation of Specimens for Implantation
				Solid Specimens (Excluding Powders)
				Nonsolid Specimens (Including Powders)
				Control Specimens
				Animals and Tissues
			3.10.1.2 Test Periods
			3.10.1.3 Surgery
			3.10.1.4 Postoperative Assessment
			3.10.1.5 Euthanasia
			3.10.1.6 Evaluation of Biological Response
			3.10.1.7 Macroscopic Assessment
			3.10.1.8 Preparation for Histology: Implant Retrieval and Specimen Preparation
			3.10.1.9 Histological Assessment
			3.10.1.10 Implant Specimens
			3.10.1.11 Animals and Implantation
			3.10.1.12 Retrieval and Histological Procedure
			3.10.1.13 Evaluation
			3.10.1.14 Test Method for Implantation in Subcutaneous Tissue
				Field of Application
				Principle
				Test Specimens
				Test Animals and Implant Sites
			3.10.1.15 Implantation Procedure
				Implantation Along Dorsal Midline
				Implantation in Neck
				Implantation Period
			3.10.1.16 Evaluation of Biological Response
			3.10.1.17 Test Method for Implantation in Muscle
				Field of Application
				Principle
				Test Specimens
				Test Animals and Implant Sites
				Implantation Procedure
				Implantation Period
			3.10.1.18 Test Method for Implantation in Bone
				Field of Application
				Principal
				Shape of Implant Specimens
				Size of Test Specimens
				Test Animals
				Implant Sites
				Implantation Procedure
				Implantation Period
			3.10.1.19 Control Materials
				Response
				Metallic Control Materials
				Polymeric and Ceramic Control Materials
				Implantation as a Method for Other End Points
	3.11 Long-Term Implant Studies
		3.11.1 Number of Test and Control Implants
		3.11.2 Conditioning
		3.11.3 Implantation Period
			3.11.3.1 Implantation (Muscle)
			3.11.3.2 Implantation (Femur)
		3.11.4 Sacrifice and Implant Retrieval
			3.11.4.1 Postmortem Observations
			3.11.4.2 Histological Procedure
				Tissue Sample Preparation
				Histopathological Observations
		3.11.5 Considerations
	3.12 Genotoxicity (ISO 10993-3)
		3.12.1 Test Systems
		3.12.2 ISO Test Profile
		3.12.3 ICH Test Profile
		3.12.4 In Vitro Test Systems
			3.12.4.1 In Vitro Metabolic Activation
		3.12.5 Bacterial Mutation Tests
			3.12.5.1 Reversion Test Background
			3.12.5.2 Genetic Makeup of Tester Strains
			3.12.5.3 Protocol for Dose Ranging and Selection
			3.12.5.4 Ames Salmonella/Plate Incorporation Method
			3.12.5.5 Controls
				Positive Controls
				Untreated/Vehicle Controls
				Evaluation of Results
			3.12.5.6 Preincubation Tests
		3.12.6 Forward Mutation Tests
			3.12.6.1 The Forward Mutation Test
	3.13 In Vitro Cytogenetic Assays
		3.13.1 Cell Types
		3.13.2 Chinese Hamster Cell Lines
		3.13.3 Human Peripheral Blood Lymphocytes
		3.13.4 Positive and Negative Controls
		3.13.5 Treatment of Cells
		3.13.6 Scoring Procedures
		3.13.7 Presentation of Results
	3.14 In Vivo Cytogenetics Assays
		3.14.1 Somatic Cell Assays
			3.14.1.1 Metaphase Analysis
			3.14.1.2 Micronuclei
	3.15 Subacute, Subchronic and Chronic Toxicity (ISO 10993-11)
		3.15.1 Objectives
		3.15.2 Regulatory Considerations
		3.15.3 Regulatory Requirements for Study Design
		3.15.4 Study Design and Conduct
			3.15.4.1 Animals
			3.15.4.2 Parameters to Measure
			3.15.4.3 Study Designs
		3.15.5 Study Interpretation and Reporting
		3.15.6 Objectives
		3.15.7 Regulatory Requirements for Study Design
		3.15.8 Study Design and Conduct
			3.15.8.1 Animals
		3.15.9 Parameters to Measure
			3.15.9.1 Body Weight
			3.15.9.2 Food Consumption
			3.15.9.3 Clinical Signs
			3.15.9.4 Clinical Pathology
		3.15.10 Histopathology
		3.15.11 Study Interpretation and Reporting
	3.16 Hemocompatibility (ISO-10993-4)
		3.16.1 Non-contact Devices
		3.16.2 External Communicating Devices
		3.16.3 Implant Devices
		3.16.4 Standard Tests
		3.16.5 Hemolysis Tests
		3.16.6 The Osmotic Fragility Test
			3.16.6.1 Method
			3.16.6.2 Calculation and Results
			3.16.6.3 Factors Influencing the Results
			3.16.6.4 Normal Range
		3.16.7 Erythrocyte Stability
		3.16.8 Whole Blood Clotting Time
		3.16.9 Thrombogenicity
			3.16.9.1 Percent Occlusion, Flow Reduction and Gravimetric Analysis
			3.16.9.2 Scanning Electron Microscopy
			3.16.9.3 Angiography
		3.16.10 Complement Activation
		3.16.11 Protein Adsorption
		3.16.12 Coagulation
			3.16.12.1 Clotting Time
			3.16.12.2 Thromboplastin
			3.16.12.3 Prothrombin
			3.16.12.4 Thrombin
			3.16.12.5 Plasma Fibrinogen
			3.16.12.6 Fibrin/Fibrinogen Degradation Products
			3.16.12.7 Specific Coagulation Factor Assays
		3.16.13 Platelets
			3.16.13.1 Platelet Count
			3.16.13.2 Platelet Aggregation
		3.16.14 Conclusion
	3.17 Carcinogenicity (ISO 10993-3)
		3.17.1 Animal Model
		3.17.2 Dose Selection
			3.17.2.1 Number of Dose Levels
		3.17.3 Group Size
		3.17.4 Route of Administration
		3.17.5 Study Duration
		3.17.6 Survival
		3.17.7 Parameters Evaluated
		3.17.8 Statistical Analysis
		3.17.9 Interpretation of Results
			3.17.9.1 Criteria for a Positive Result
			3.17.9.2 Use of Historical Controls
	3.18 Immunotoxicology (ISO 10993-20)
		3.18.1 Immunotoxic Effects
		3.18.2 Immunosuppression
		3.18.3 Immunostimulation
		3.18.4 Autoimmunity
	3.19 Evaluation of the Immune System
		3.19.1 Regulatory Positions
		3.19.2 Immunopathologic Assessments
			3.19.2.1 Organ and Body Weights
			3.19.2.2 Hematology
			3.19.2.3 Clinical Chemistry
			3.19.2.4 Histopathology
		3.19.3 Humoral Immunity
			3.19.3.1 Antibody Plaque-Forming Cell (PFC) Assay
			3.19.3.2 B-Cell Lymphoproliferation Response
		3.19.4 Cell-Mediated Immunity
			3.19.4.1 T-Cell Lymphoproliferation Response
			3.19.4.2 Mixed Lymphocyte Response (MLR) Assay
			3.19.4.3 Cytotoxic T Lymphocyte (CTL)-Mediated Assay
			3.19.4.4 Delayed-Type Hypersensitivity (DTH) Response
		3.19.5 Nonspecific Immunity
			3.19.5.1 Natural Killer Cell Assays
			3.19.5.2 Macrophage Function
			3.19.5.3 Mast Cell/Basophil Function
		3.19.6 Host-Resistance Assays
		3.19.7 Hypersensitivity
			3.19.7.1 Type I Hypersensitivity
			3.19.7.2 Types II and III Hypersensitivity
		3.19.8 Approaches
			3.19.8.1 Suggested Approaches to Testing
		3.19.9 Suggested Approaches to Evaluation of Results
		3.19.10 Problems and Future Directions
			3.19.10.1 Data Interpretation
			3.19.10.2 Appropriate Animal Models
			3.19.10.3 Indirect Immunotoxic Effects
			3.19.10.4 Hypersensitivity Tests
			3.19.10.5 Autoimmunity
			3.19.10.6 Functional Reserve Capacity
			3.19.10.7 Significance of Minor Perturbations
		3.19.11 Challenges and Special Cases
	References
Chapter 4: Considerations for Leachables and Extractables Testing
	4.1 Introduction
	4.2 US Regulatory Basis for E&L Testing in Medical Devices
		4.2.1 Definitions of an Extractable and Leachable
		4.2.2 Current, Common Regulatory Guidance and Standards Exercised in the USA
			4.2.2.1 ISO 10993-1: Biological Evaluation of Medical Devices: Evaluation and Testing in the Risk Management Process
			4.2.2.2 ISO 10993-12: Biological Evaluation of Medical Devices – Sample Preparation and Reference Materials
			4.2.2.3 ISO 10993-18: Biological Evaluation of Medical Devices – Chemical Characterization of Medical Device Materials Within a Risk Management Process
			4.2.2.4 ISO 14971: Medical Devices – Application of Risk Management to Medical Devices
	4.3 Fit for Purpose Experimental Design in E&L Testing
		4.3.1 Identification of Study Needs Based Upon Device Type
		4.3.2 Test Article Considerations and Solvent Selection in E&L Testing
		4.3.3 Common Extraction Techniques
			4.3.3.1 Soxhlet Extraction
			4.3.3.2 Reflux Extraction
			4.3.3.3 Maceration
			4.3.3.4 Shaking Extraction
			4.3.3.5 Sonication
			4.3.3.6 Sealed Container Extraction
			4.3.3.7 Pressurized Solvent Extraction
			4.3.3.8 Headspace, Thermal Desorption, and Dynamic Headspace
			4.3.3.9 Microwave-Assisted Extraction
			4.3.3.10 Supercritical Fluid Extraction
		4.3.4 Common Analytical Methods Used to Assess Extracts
	4.4 Common Analytical Methods Used in E&L Testing
		4.4.1 Definition Mass Spectrometry and/or Chromatography
			4.4.1.1 Chromatography
			4.4.1.2 Mass Spectrometry
			4.4.1.3 Ionization Techniques
		4.4.2 Analytical Techniques that Involve Mass Spectrometry and/or Chromatography
			4.4.2.1 Liquid Chromatography-Mass Spectrometry (LCMS)
			4.4.2.2 Gas Chromatography-Mass Spectrometry (GCMS)
			4.4.2.3 Inductively Coupled Plasma-Mass Spectrometry (ICP-MS)
		4.4.3 Other Analytical Methods
			4.4.3.1 Fourier-Transform Infrared (FTIR) Spectroscopy on Nonvolatile Residue (NVR)
			4.4.3.2 Liquid Chromatography-Ultraviolet (LCUV)
	References
Chapter 5: Where the Data Is and What Is It?
	References
Chapter 6: Bridging Issues of Route
	6.1 Route-to-Route Extrapolation and Relevance to Assessment of Medical Devices
	6.2 Considerations Regarding Applicability of Route-to-Route Extrapolation
		6.2.1 Critical Target Tissue of Toxicity Following Exposure
		6.2.2 Metabolism of the Compound
		6.2.3 Toxicokinetic Characteristics
		6.2.4 First-Pass Effects
		6.2.5 Physicochemical Properties of the Compound in Regard to Toxicokinetics
		6.2.6 Intended Route/Duration of Patient Exposure
		6.2.7 Data Quality and Availability
	6.3 Regulatory Approaches to Route-to-Route Extrapolation
		6.3.1 US Environmental Protection Agency (US EPA)
		6.3.2 Interdepartmental Group on Health Risks and Chemicals (IGHRC)
		6.3.3 ECHA
		6.3.4 European Medicines Agency
		6.3.5 ICH Harmonized Guideline Q3D
	6.4 Route-Specific Considerations
	6.5 Derivation of Safe Exposure Limits
		6.5.1 Derivation of a Permissible Daily Exposure (PDE) Value
		6.5.2 Derivation of Tolerable Intake (TI) and Tolerable Exposure (TE) Values
		6.5.3 Adjustment of Cramer Classification Values
		6.5.4 Consideration of ISO 18562-3
		6.5.5 Consideration of ISO/TS 21726
	6.6 Conclusions
	References
Chapter 7: Risk Assessments for Medical Devices
	7.1 Overview of Device Regulation
	7.2 Classification of Medical Devices
	7.3 Medical Devices and Risk Assessment
		7.3.1 Standards and Guidances
		7.3.2 Elements of Human Health Risk Assessment
	7.4 Sources of Data
		7.4.1 Toxicity Databases
		7.4.2 Biomedical Search Engines
		7.4.3 Published Toxicological Guidance
		7.4.4 Industrial and Environmental Regulations Guides and Other Regulatory Sources
	7.5 Establishment of the Tolerable Intake (TI) for Chemicals in Medical Devices
		7.5.1 Calculating the TI
	7.6 Establishment of the Tolerable Exposure (TE) for Chemicals in Medical Devices
		7.6.1 Determining the Bodyweight of the Intended Patient Population
		7.6.2 Calculation of the Utilization Factor (UTF) from Intended Use Pattern
	7.7 Extrapolation Factors
		7.7.1 Uncertainty Factor
		7.7.2 Safety Factor (SF)
	7.8 Margin of Safety (MOS)
	7.9 Case Studies
		7.9.1 Metered-Dose Inhaler
		7.9.2 Implant Blood Vessel Support Device
	References
Chapter 8: An Introduction to (Q)SAR with Respect to Regulatory Submissions
	8.1 Introduction
	8.2 Key Principle of (Q)SAR
	8.3 Molecular Descriptors Used in (Q)SAR
		8.3.1 Physicochemical Properties
		8.3.2 Structural Alerts
	8.4 Endpoints Encoded in (Q)SARs
	8.5 Regulatory Submission Requirements for Compounds Evaluated in Silico
	8.6 Widely Accepted Expert-Based and Statistical-Based (Q)SAR Models
		8.6.1 Statistical Models
		8.6.2 Expert Models
		8.6.3 Cramer’s Classification
		8.6.4 (Q)SAR Domains of Applicability
	8.7 How to Interpret (Q)SAR Prediction Results
		8.7.1 DEREK
		8.7.2 Leadscope Model Applier (LSMA)
		8.7.3 Toxtree
		8.7.4 Disscussion
	8.8 Conclusion
	References
Chapter 9: Pathology and Histopathology Evaluations of Biomaterials and Medical Devices
	9.1 Introduction
		9.1.1 Regulatory Standards and General References
		9.1.2 Risk Assessment Plan
		9.1.3 Biocompatibility and In Vivo Biologic Response Determinations
	9.2 General Pathology Considerations for Study Designs
		9.2.1 ISO and GLP Compliance
		9.2.2 Standardized Nomenclature and Controlled Terminology
			9.2.2.1 Anatomy and Histology
			9.2.2.2 Best Practices and Position Papers
			9.2.2.3 International Harmonization of Nomenclature and Diagnostic (INHAND) Criteria
		9.2.3 FDA Considerations for ISO Testing and Animal Studies for Medical Devices
			9.2.3.1 FDA-Specific Guidance Documents
			9.2.3.2 Standard for Exchange of Nonclinical Data (SEND)
	9.3 Workflow Involving the Pathologist
		9.3.1 Limitations of Test Animals and Animal Models of Disease
		9.3.2 Pilot and Proof-of-Concept Studies
		9.3.3 Pathology Observers at Implantation or Surgery
		9.3.4 Submission of Study Materials to the Pathologists
	9.4 Pathology Evaluations
		9.4.1 Necropsy
			9.4.1.1 Responsibility
			9.4.1.2 Scheduled Necropsy
			9.4.1.3 Unscheduled Deaths
			9.4.1.4 Organ Weights
			9.4.1.5 Recording Necropsy Findings
			9.4.1.6 Digital Gross Photography (Macrophotography)
		9.4.2 Tissue Collection
			9.4.2.1 Study Endpoints
			9.4.2.2 Tissue Handling
			9.4.2.3 Marking Implant Sites and Tissues
			9.4.2.4 Tissue Lists
			9.4.2.5 Sample Selection from Test Sites
			9.4.2.6 Sampling Large and Complex Implants
			9.4.2.7 Identification and Collection of Regional Lymph Nodes
			9.4.2.8 Special Sampling Procedures
				Biopsy Samples
				Fresh Frozen Tissues
				Hemocompatibility
				Immunotoxicity
				Carcinogenicity Studies
		9.4.3 Tissue Fixation
		9.4.4 Tissue Trimming
		9.4.5 Histology
			9.4.5.1 Pre-study Preparations
			9.4.5.2 Tissue Embedding and Sectioning
				Formalin-Fixed and Paraffin-Embedded Tissues
				Resin Embedment
				Troubleshooting Histology Preparation of Implants in Tissues
			9.4.5.3 Tissue Stains
			9.4.5.4 Immunohistochemistry
	9.5 Histopathology Evaluations
		9.5.1 ISO 10993-6:2016 Limitations in Qualitative and Quantitative Histopathology
		9.5.2 Primary Histopathology Evaluations
			9.5.2.1 Histopathology Qualitative (Subjective) Evaluations
				Local Implantation Sites
				Lymphoid Tissues
				Regional and Systemic Sites
				Efficacy Evaluations in Animal Models
			9.5.2.2 Histopathology Semiquantitative (Subjective) Scoring
			9.5.2.3 Quantitative (Objective) Morphometry and Stereology
		9.5.3 Masked (Blinded) Histopathology
		9.5.4 Peer and Expert Review of Histopathology
		9.5.5 Histopathology Determination of Causality of Morbidity and Mortality
		9.5.6 Histopathology Reporting for Biocompatibility and Biologic Responses
		9.5.7 Digital Photomicrography
	9.6 Special Imaging Techniques and Technologies
		9.6.1 Improving Histopathology Visualization of Biomaterials
		9.6.2 Specialized Light Microscopy Techniques
		9.6.3 Electron Microscopy
		9.6.4 High-Resolution Imaging
		9.6.5 Microscopic Molecular and Chemical Analysis of Tissues
	9.7 Biologic Responses to Medical Materials and Finished Medical Devices
		9.7.1 Modifiers of Tissue Responses
			9.7.1.1 Physiochemical Factors
			9.7.1.2 Species-, Strain-, and Sex-Related Effects and Tissue Factors
		9.7.2 Local Tissue Responses
			9.7.2.1 Foreign Body and Tissue Responses
			9.7.2.2 Unintended Tissue Sequelae Identified by Histopathology
			9.7.2.3 Carcinogenicity of Medical Materials
		9.7.3 Systemic Responses and Immunotoxicity
			9.7.3.1 Local and Systemic Immune Reactions
	9.8 Biologic Fates and Adverse Tissue Responses
		9.8.1 Stable Tissue/Device Interface (Integration) of Permanent Biomaterials and Medical Devices
		9.8.2 Biodegradation of Biomaterials and Medical Devices
			9.8.2.1 Determination of Complete Biodegradation and Return to Normal Form and Function
		9.8.3 Device Failures
			9.8.3.1 Infections and Biofilms
			9.8.3.2 Biotribology
	9.9 Conclusions
	References
Chapter 10: Nanodevices
	10.1 Introduction
	10.2 Nanomaterial Nomenclature
	10.3 Characterization of Nanomaterials
	10.4 Engineered Nanomaterial Biological Interactions and Fate
	10.5 Use of Nanomaterials in Medical Devices
	10.6 Regulation of Nanodevices (US FDA, EU, Asia Regulations and International Standards)
		10.6.1 United States of America
		10.6.2 European Union
		10.6.3 Asia (China, Japan, and India)
	10.7 Risk from Exposure to Medical Device Nanomaterials
	10.8 Engineering Safe Nanoparticles for Medical Device Applications and Therapeutics
	10.9 Safety Evaluation of Nano-Enabled Medical Devices
	10.10 Summary and Conclusions
	References
Chapter 11: Integrated Safety Assessment of Medical Devices
	11.1 Introduction
	11.2 Underpinning Assumptions in Risk Assessment
	11.3 Integration Across Routes
	11.4 Integration Across Species
	11.5 Integration Across What We Know (Table 11.2)
	11.6 Failure Modes
	11.7 Endnote
	References
Chapter 12: Toxicity of Common Extractables and Leachables of Medical Devices
	12.1 Background
	12.2 L&E Profile by Material
		12.2.1 Polymers
		12.2.2 Glass
		12.2.3 Ceramics
		12.2.4 Metals
	12.3 Summary
	References
Appendix A: Biocompatibility CROs for Medical Devices
Appendix B
Appendix C: Selected Regulatory and Toxicological Acronyms
Index