Biocompatibility Protocols for Medical Devices and Materials

Description

Biocompatibility Protocols for Medical Devices and Materials provides comprehensive coverage of the basic science and toxicological testing protocols necessary for the risk assessment and safety analysis of medical devices and materials which are based on the ISO guidelines for body contact and duration of contact. The book begins with device/component selection for toxicological experiments and provides an introduction to topics such as sensitization, irritation tests, material-mediated pyrogenicity, and bacterial-mediated pyrogenicity. Toxicology-related chapters explain the protocols for cytotoxicity, acute systemic toxicity, repeated-exposure systemic toxicity, genotoxicity, carcinogenicity, and reproductive toxicity testing.

Biocompatibility Protocols for Medical Devices and Materials is a practical guide that provides step-by-step toxicological protocols ranging from materials selection to data interpretation for toxicologists, biomedical researchers, healthcare professionals, product developers, and others working in risk assessment and safety analysis of medical devices.

Explains the biocompatibility test protocols for medical devices
Provides an overview about chemical characterization
Describes toxicokinetic, carcinogenicity, and reproductive toxicity studies
Discusses the basic points needed to leverage the data from another device

Front Cover 2
BIOCOMPATIBILITY PROTOCOLS FOR MEDICAL DEVICES AND MATERIALS 3
BIOCOMPATIBILITY PROTOCOLS FOR MEDICAL DEVICES AND MATERIALS 5
Copyright 6
Contents 7
Contributors 13
Author bios 15
Introduction 17
- Risk assessment for biocompatibility testing 17
- Considering existing information to mitigate the risks 19
- ISO 10993-1: a risk-based approach 20
- Biocompatibility endpoints evaluation 21
- Conclusion 22
- References 24
1 - Cytotoxicity 25

Front Cover 2
BIOCOMPATIBILITY PROTOCOLS FOR MEDICAL DEVICES AND MATERIALS 3
BIOCOMPATIBILITY PROTOCOLS FOR MEDICAL DEVICES AND MATERIALS 5
Copyright 6
Contents 7
Contributors 13
Author bios 15
Introduction 17
- Risk assessment for biocompatibility testing 17
- Considering existing information to mitigate the risks 19
- ISO 10993-1: a risk-based approach 20
- Biocompatibility endpoints evaluation 21
- Conclusion 22
- References 24
1 - Cytotoxicity 25
- Introduction 25
- ISO 10993-5 26
- Cytotoxicity 26
- Detection methods 28
  - Extract test 28
- Test by indirect contact 28
  - Molecular filtration 28
  - Agar overlay assay 29
  - Optimizing agar concentration and volume 30
  - Scratching the cell layer and agar preparation 31
  - Preparation of agar gel pellet containing the test substance 32
  - Design of an evaluation grid label 33
  - Culture treatment using agar overlay containing the test substance 33
  - Culture treatment using drug containing pellets 33
  - Direct contact method 34
  - Evaluation of cell migration 34
  - Assessing cell viability by neutral red staining 34
  - Other methods 35
- Quantitative method 35
  - MTT assay 35
  - Cell viability with MTT assay protocol 37
    - Step-by-step cell viability MTT assay 37
    - Materials for MTT assay 37
    - Trypan blue exclusion assay 38
    - Real-time cell analysis system 38
    - Cell titer blue 38
    - Significance of cytotoxicity testing 39
  - Abbreviations 40
  - References 40
- 2 - Sensitization 43
  - Introduction 43
  - Test methods 44
  - ISO 10993-10 44
  - Guinea pig tests 49
    - Preparation of the animals 51
    - Elements common to sensitization tests in Guinea pigs 51
    - Description of the Guinea-pig maximization test method 52
      - Dose levels 52
      - Induction 52
        
        Day 0—control group 53
      - Number of animals 52
      - Induction 53
        
        Day 6–8—control group 53
        
        Day 6–8—treated group 53
      - Challenge 53
      - Clinical observations 54
      - Observations—treated and control groups 54
    - Description of the Buehler test method 54
      - Experimental animals 54
        
        Dose levels 54
      - Challenge 55
        
        Day 27–29—treated and control groups 55
      - Induction 55
        
        Day 0—treated group 55
        
        Day 0—control group 55
        
        Days 6–8 and 13–15—treated and control groups 55
      - Observations—treated and control groups 56
      - Rechallenge 56
      - Clinical observations 56
    - Data and reporting (GPMT and Buehler Test) 56
      - Test report 56
        
        Test substance 56
        
        Reliability check 57
        
        Test animals 57
        
        Results 57
        
        Test conditions 57
        
        Discussion of the results 57
      - Guinea pig tests and sensitization potency assessment 57
      - Guinea pig maximization and Buehler tests 58
      - Advantages and limitations 59
      - Open epicutaneous test 59
      - Local lymph node assay 60
      - The LLNA and sensitization potency assessment 61
      - Advantages and limitations 62
      - Human skin-sensitization testing 63
      - Advantages and limitations 65
      - Application of test methods in risk assessment 65
      - Guinea pig tests 66
      - Local lymph node assay 67
      - Human repeat-insult patch test 67
      - Abbreviation 70
      - References 70
    - 3 - Irritation test 71
      - Introduction 71
      - Selection of animals 72
        
        Animal care and husbandry 72
        
        Animal status 72
      - Test procedure 72
        
        Test sample application 72
        
        Exclusion 72
        
        Animal preparation 73
        
        Evaluation of results 73
        
        Dose administration 73
        
        Controls 73
        
        Observation of animals 73
        
        Test report 74
      - Alternative methods 75
      - In vitro tests methods for irritation 75
        
        Introduction 75
        
        In vitro RhE test models 76
        
        Evaluation of results 76
        
        Test sample and control preparation 76
        
        Viability determination 76
      - References 76
    - 4 - Material-mediated pyrogenicity 79
      - Introduction 79
      - Broad range of pyrogens 80
        
        Nonendotoxin pyrogens 80
      - Tests using fluid extracts 81
      - Animal status 82
      - Animal care and husbandry 82
      - Selection of animal species 82
      - Size of groups 83
      - Number of groups 83
      - Treatment controls 83
      - Route of exposure 84
      - Test sample administration 84
      - Pyrogen tests 84
      - LAL test 85
      - Rabbit test: sham test (in vivo) 86
        
        Principle 86
        
        Preliminary test 86
        
        Temperature measurement 86
        
        Procedure 86
        
        Main test 87
      - Monocyte activation test (in vitro test) 87
      - Interpretation of results 87
      - Procedure of MAT 88
        
        Step 1 88
        
        Step 4 88
        
        Step 2 88
        
        Step 3 88
      - References 89
      - Advantages 89
      - Abbreviations 89
    - 5 - Acute systemic toxicity 91
      - Introduction 91
      - Considerations 92
        
        Selection of animals 92
        
        Acute systemic toxicity 92
        
        Size and number of groups 93
        
        Animal status 93
        
        Animal care and husbandry 93
        
        Routes of exposure 94
        
        Dosing 95
        
        Clinical pathology 96
        
        Body weight and food/water consumption 96
        
        Clinical observations 96
        
        Anatomic pathology 97
        
        Final report 98
        
        Evaluation criteria 98
      - References 100
    - 6 - Repeated-exposure systemic toxicity (subacute, subchronic, and chronic systemic toxicity) 101
      - Introduction 101
      - Size and number of groups 102
      - Animal care and husbandry 102
      - Clinical observations 103
      - Routes of exposure 103
      - Dosing 103
      - Anatomic pathology 104
      - Clinical pathology 104
      - Evaluation criteria 105
      - Final report 105
      - References 106
    - 7 - Implantation 107
      - Introduction 107
      - Selection of animals 108
        
        Animal care and husbandry 108
        
        Animal status 108
      - Test procedure 108
        
        Sample preparation 108
        
        Tissue and implnatation site 109
        
        Test period 110
        
        Animals used 110
        
        Control 110
        
        Surgery 111
        
        Evaluation 112
        
        Test report 113
      - References 114
    - 8 - Hemocompatibility 115
      - Highlights 115
      - Introduction 115
      - Types of devices in contact with blood 117
        
        External communicating devices 117
        
        Noncontact devices 117
        
        Implant devices 118
      - Characterization of blood interactions 118
      - Categories of tests and blood interactions 120
        
        Recommended tests for interactions of devices with blood 120
        
        Indications and limitations 121
        
        External communicating devices 121
        
        Implant devices 121
        
        Noncontact devices 121
        
        Types of test 126
        
        Ex vivo tests 126
        
        In vivo tests 126
        
        In vitro tests 126
        
        Preclinical evaluation of cardiovascular devices and prostheses 127
        
        Classification 127
        
        Advantages and limitations of animal and in vitro testing 128
        
        Test protocols for animal testing 129
        
        Test protocols for in vitro testing 130
        
        Catheters and guidewires 130
        
        Extracorporeal oxygenators, hemodialysers, therapeutic apheresis equipment, and devices for the absorption of specific subs ... 130
        
        Cannulae 130
        
        Heart valve prostheses 131
        
        Ventricular-assist devices and total artificial hearts 131
        
        IVC filters, stents, and stented grafts 132
        
        Vascular grafts 132
        
        Laboratory tests—principles, scientific basis, and interpretation 132
        
        Test conditions 132
        
        Principles for in vitro testing 132
        
        Classification 133
        
        Thrombosis 133
        
        Gravimetric analysis (thrombus mass) 133
        
        Percentage occlusion 133
        
        Light microscopy 133
        
        Flow reduction 133
        
        Antibody binding 134
        
        Imaging techniques—angiography, intravascular ultrasound, Doppler ultrasound, CT, and MRI 134
        
        Retrieval and examination of the device 134
        
        Pressure drop across the device 134
        
        Autopsy of distal organs 134
        
        Coagulation 134
        
        Partial thromboplastin time (PTT) 135
        
        Thrombin generation 135
        
        Prothrombin time (PT) 135
        
        Thrombin time (TT) 135
        
        Specific coagulation factor assays 136
        
        Fibrinogen 136
        
        FPA, D-dimer, F1+2, TAT 136
        
        Fibrinogen and fibrin degradation products (FDP) 136
        
        Platelets and platelet functions 136
        
        Platelet count 136
        
        Blood cell adhesion 137
        
        Platelet aggregation 137
        
        Platelet function analysis 138
        
        Platelet activation 138
        
        Template bleeding time 138
        
        Platelet lifespan (survival) 139
        
        Gamma imaging of radiolabeled platelets 139
        
        Hematology 139
        
        Hemolysis 139
        
        Reticulocyte count 139
        
        Leukocytes 139
        
        Complement system—CH 50 and C3a, C5a, TCC, Bb, iC3b, C4d, SC5b-9 139
        
        Evaluation of hemolytic properties of medical devices and their components 140
        
        Clinical significance of hemolysis 140
        
        Toxic effects 140
        
        Thrombosis 141
        
        Causes of hemolysis 140
        
        Mechanical forces—pressure 140
        
        Mechanical forces—rheology 140
        
        Biochemical factors 140
        
        Determining a pass/fail assessment for hemolysis 141
        
        Hemolysis testing—general considerations 142
        
        Methods 142
        
        Total blood hemoglobin concentration measurements 143
        
        Oxyhaemoglobin method 143
        
        Cyanmethaemoglobin method 143
        
        Iron method 144
        
        Plasma or supernatant hemoglobin concentration measurements 144
        
        Direct optical and added chemical techniques 144
        
        Immunonephelometric method 145
        
        Blood and blood component preservation 145
        
        Protection of employees handling blood 146
        
        Blood collection (phlebotomy) 146
        
        Species selection 147
        
        Evaluation of hemolysis—in vitro, ex vivo, and in vivo exposure to blood or blood components 147
        
        Direct contact versus indirect methods 148
        
        Abbreviations 148
        
        References 148
        
        9 - Tests for genotoxicity 151
        
        Introduction 151
        
        Genotoxicity 152
        
        Test strategy 152
        
        Sample preparation 153
        
        Follow-up evaluation 156
        
        Requirements 152
        
        Example test method: mouse lymphoma mutagenesis assay 157
        
        Dose administration 159
        
        Evaluation criteria 161
        
        Results 162
        
        Conclusion 163
        
        Test report 163
        
        References 163
        
        10 - Carcinogenicity 165
        
        Introduction 165
        
        Carcinogenicity test-specific considerations 167
        
        Principle of the test 169

Author's affiliation

Prakash Srinivasan Timiri Shanmugam: HCL America Inc.Senior toxicologist, Medical device
Thamizharasan Sampath: Professor, Department of Pharmacology & Toxicology, Shri Balaji Institute of Medical Sciences, University of Health Sciences, Raipur, Chhattisgarh, India
Indumathy Jagadeeswaran: Senior Research Associate, Department of Pediatrics, UT Southwestern Medical Center, Dallas, Texas, U.S.A

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