Biological Responses to Metal Implants U.S. Food and Drug Administration Center for Devices and Radiological Health Office of Product Evaluation and Quality Office of Science Engineering and Laboratories September 2019 i | Page www.fda.gov TABLE OF CONTENTS 1 Introduction ...................................................................................................................................... 1 2 Background: Definitions, History, and Landscape ............................................................................ 3 3 Metals in Human Physiology and Pathology ..................................................................................... 5 3.1 Introduction .................................................................................................................................. 5 3.2 Essential Trace Metal Elements .................................................................................................... 6 3.3 Non-Essential Metals .................................................................................................................... 7 4 Current Nonclinical Pre-market Evaluation of Metal Implants ......................................................... 9 4.1 Introduction .................................................................................................................................. 9 4.2 Biocompatibility .......................................................................................................................... 10 4.2.1 Sensitization ........................................................................................................................ 10 4.2.2 Implantation ........................................................................................................................ 12 4.2.3 Inflammatory Response ...................................................................................................... 12 4.2.4 Genotoxicity and Carcinogenicity ....................................................................................... 13 4.2.5 Systemic Toxicity ................................................................................................................. 14 4.3 CDRH’s Immunotoxicity Guidance .............................................................................................. 16 5 Corrosion and Metal Ion Release .................................................................................................... 17 5.1 Introduction ................................................................................................................................ 17 5.2 Corrosion Susceptibility .............................................................................................................. 19 5.2.1 Physiological Environment .................................................................................................. 19 5.2.2 Mechanical Interactions ...................................................................................................... 20 5.2.3 Active Devices ..................................................................................................................... 20 5.2.4 Processing ........................................................................................................................... 22 5.3 In Vitro Corrosion Testing ........................................................................................................... 22 5.3.1 General Corrosion ............................................................................................................... 22 5.3.2 General Corrosion - Active Implants ................................................................................... 23 5.3.3 Pitting Corrosion ................................................................................................................. 24 5.3.4 Crevice Corrosion ................................................................................................................ 25 5.3.5 Fretting ................................................................................................................................ 25 5.3.6 Galvanic Corrosion .............................................................................................................. 25 5.4 In Vivo Corrosion ......................................................................................................................... 26 i | Page www.fda.gov 5.4.1 Corrosion in Cardiovascular Devices ................................................................................... 27 5.4.2 Corrosion in Orthopedic Devices ........................................................................................ 27 5.4.3 Corrosion in Active Devices ................................................................................................. 28 5.4.4 Correlation to In Vitro Testing ............................................................................................. 28 6 Subclinical Response to Metal Implants ......................................................................................... 31 6.1. Introduction ................................................................................................................................ 31 6.1 Wound Healing ........................................................................................................................... 32 6.1.1 Foreign Body Response (FBR) ............................................................................................. 33 6.2. Innate Immune Responses To Metal Implants ........................................................................... 34 6.2.1. Innate Immune Recognition of Metals ............................................................................... 34 6.2.2. Innate Cellular Responses to Metals ................................................................................... 35 6.3. Adaptive Immune Responses to Metal Implants ........................................................................ 37 6.4. Tissue and Organ Localization of Inflammatory Responses to Metal Implants .......................... 39 6.4.1. Orthopedic Devices ............................................................................................................. 39 6.4.2. Neurologic Devices .............................................................................................................. 40 6.4.3. Cardiovascular Devices ....................................................................................................... 41 6.4.4. Oral and Dental Implants .................................................................................................... 42 6.4.5. Urogenital Devices .............................................................................................................. 43 6.5. Conclusions, Summary, Inflammatory Regulation Underlying Clinical Outcomes ..................... 43 7 Clinical Response to Metal Implants ............................................................................................... 45 7.1 Introduction ................................................................................................................................ 46 7.2 Terminology Pertaining to Potential Clinical, Imaging, and Morphological Manifestations of Metal Implant-Related Adverse Outcomes ............................................................................................ 46 7.2.1 Systemic ARMDs ................................................................................................................. 48 7.2.2 Elevated Metal Ion Levels ................................................................................................... 48 7.2.3 Different Manifestations of Systemic Hypersensitivity and Inflammation ......................... 49 7.3 Sex-Related Issues in Clinical Responses to Metal Implants ....................................................... 51 7.4 Clinical Observations and Investigations of Systemic Responses to Metal Implants ................. 51 7.4.1 Cardiotoxicity ...................................................................................................................... 51 7.4.2 Neurotoxicity ....................................................................................................................... 52 7.4.3 Thyroid toxicity ................................................................................................................... 52 7.4.4 Cancer ................................................................................................................................. 52 7.5 Specific Device Areas .................................................................................................................. 54 ii | Page www.fda.gov 7.5.1 Orthopedic devices ............................................................................................................. 54 7.5.2 Cardiac and Endovascular Implants .................................................................................... 57 7.5.3 Dental and Oral/Maxillofacial Devices ................................................................................ 60 7.5.4 Neurological Devices ........................................................................................................... 62 7.5.5 Gastroenterological Devices ............................................................................................... 63 7.5.6 Gynecological devices ........................................................................................................