Biologic Responses to Metal Implants Sept. 2019 FDA Review
In this blog post we will aim to present information to consider when placing titanium dental implants the review was a full 143 pages.
4.2.3 Inflammatory Response
As part of the body’s normal host response, an implant may elicit a low-level acute inflammatory response which is generally of short duration, lasting minutes to days, depending on the extent of the implantation-related tissue injury. Myeloid cells such as neutrophils and macrophages are the primary cells involved in the expected acute inflammation with subsequent peri-implant wound healing. An implant may continue to elicit a chronic inflammatory response, lasting for months or longer and characterized by a broader immune cell infiltration including both myeloid and lymphoid cells. Chronic inflammation by implanted metal devices or metal wear debris may lead to adverse clinical effects. For example, sustained chronic inflammation at the implant-bone interface has been implicated for aseptic (free of infection) loosening of total joint replacements (Abu-Amer, Darwech, and Clohisy 2007; Gallo et al. 2013). As noted in Section 4.2.2, the local tissue response to a metal implant is currently evaluated in an implantation study by placing the implant at a clinically relevant site in accordance with the ISO 10993-6 standard or in a functional animal study conducted to evaluate the performance and safety of the implant. Histopathological evaluation includes characterization of inflammatory response by assessing the intensity of response as well as identifying the inflammatory cell types (e.g., polymorphonuclear cells, lymphocytes, plasma cells, eosinophils, macrophages, multinucleated cells) involved in the tissue response.
4.2.5 Systemic Toxicity
Systemic toxicity testing can be designed to evaluate both local and systemic responses to devices, but this section will focus only on systemic evaluations. See also Section 4.2.2 on implantation for local toxicity evaluations.
Systemic toxicity refers to adverse effects (other than systemic sensitization, genotoxicity, and carcinogenicity) that occur in tissues other than those at the site of local contact between the body and the device. The development of systemic toxic effects typically requires the release of chemical compounds from the device and distribution of these compounds to distant target tissue sites where deleterious effects are produced.
Systemic toxicity is included as a recommended endpoint in the biological evaluation of devices depending on the nature and duration of device contact with the patient (see Table A.1 of the CDRH’s 2016 Biocompatibility Guidance (FDA 2016). The evaluation of acute systemic toxicity is recommended for essentially all devices except for devices that contact intact skin, regardless of the duration of contact, and those that contact mucosal membranes for less than 24 hours. FDA recommends that subacute/subchronic toxicity be evaluated for all devices with prolonged (> 24 hour-30 days) and permanent/long-term (> 30 day) contact with the patient, again except for devices that contact intact
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skin. In addition, an evaluation of the potential for chronic toxicity to occur may be requested for devices with permanent/long-term tissue contact. A pyrogenic response (fever) to devices may be caused by material-mediated pyrogens including metal particulates and metal salts, as described in ISO 10993-11 “Biological response to medical devices – Part 11: Tests for systemic toxicity,” Annex F (ISO 2006). Material-mediated pyrogenicity is generally evaluated using the rabbit pyrogen test (USP 2017).
There are three approaches that are typically used to assess the potential for adverse systemic effects to occur following the release of chemical compounds from a device:
Biological testing of extracts of the device in experimental animals;
Identification of the compounds extracted from the device using analytical chemistry methods
and evaluation of the potential for systemic effects to occur using toxicological risk assessment
principles; and
Leveraging of data from large animal studies or implantation studies where systemic
information is included.
Each of these approaches for evaluating the potential for toxic systemic effects to occur has merits and limitations.
Biological testing of extracts of the device in experimental animals
Devices have traditionally been assessed for their potential to produce systemic toxicity using the biological testing approach that involves extracting the device in both polar and nonpolar solvents, then administering the extract of the device to experimental animals. Methods for conducting systemic toxicity testing are outlined in the ISO 10993-11 standard, “Biological evaluation of medical devices – Part 11: Tests for systemic toxicity” (ISO 2006). To minimize animal use, other data as described below can be leveraged to assess systemic toxicity.
Chemical characterization/risk assessment
As an alternative to the biological testing of device extracts, the chemical characterization/risk assessment approach, which does not require the use of animals, has gained increased acceptance to evaluate the potential for systemic toxicity to occur in response to compounds released from a device. In this approach, compounds are identified and quantified and the amount is compared to a health- protective threshold value, using the method described in ISO 10993-17 “Biological evaluation of medical devices - Part 17: Establishment of allowable limits for leachable substances” (ISO 2002). Since threshold values are readily available for many of the metal ions and elements released from metallic devices, the implementation of the chemical characterization/risk assessment approach is typically feasible for most metals released from metallic devices.
A limitation of the chemical characterization/risk assessment approach is that it cannot typically be used to assess the potential for metal particles to produce adverse systemic effects unless toxicity data are available for particles with the same physical-chemical properties (e.g., size, charge) as the particles released from the device and administered in the toxicity study by the clinically relevant route of exposure.
Leveraging data from safety/efficacy studies in large animal or implantation studies
Systemic toxicity endpoints can also be evaluated in safety/efficacy studies in large animal or in implantation studies of a device, if sufficient animals and appropriate controls are used. For evaluation
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of systemic toxicity in these studies, the potential for adverse effects at distant target tissues is evaluated using clinical chemistry, hematology, and histopathology.
General considerations for systemic toxicity assessments
Humans and experimental animals respond similarly to the toxic effects of chemical compounds. Any systemic effects seen in routine systemic toxicity tests or in a large animal safety/efficacy study or in an implantation study are typically relevant for patients, unless there are mechanistic reasons to suggest that the results in experimental animals are not relevant for humans (e.g., alpha-2μ globulin associated nephrotoxicity in male rats). This also applies when literature data is used to support the chemical characterization/risk assessment approach.
5 CORROSION AND METAL ION RELEASE
5.1 INTRODUCTION
Understanding how metallic products change or degrade in different environments is an important concept when speaking about potential host responses. This section provides a summary of scientific information related to metal/metallic implant corrosion and test methods to assess those changes.
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Corrosion is defined as metal degradation due to electrochemical reactions between the metal and its environment. For metallic implants placed in the body, these reactions (known as oxidation and reduction reactions) can cause release of metal ions at the implant surface resulting in degradation of the implant. The ramifications of corrosion are dependent on many factors (corrosion severity, type, etc.), and may lead to issues with device integrity or adverse biological responses. There are five common types of corrosion that may occur when a device is implanted: general, pitting, crevice, fretting, and galvanic corrosion (Gilbert 2017). Each of these is described in more detail below.
General corrosion/metal ion release is the uniform release of metal ions over an exposed surface. For metals with surface oxides, it has been shown that the amount of metal ions released from the implant is dependent on the composition and structure of its oxide layer (Sullivan et al. 2015). Typically, the release of metal ions is greatest immediately after implantation and the release rate reduces over time. However, in cases where the implant’s oxide layer is not protective, release of metal ions may continue for longer durations and exhibit dramatic increases in release rate after implantation.
Pitting corrosion occurs when the surface of metallic devices develops localized pits or cavities that penetrate the surface of the device over time. Pits are initiated in specific regions such as inclusions, cracks, or other surface defects, which are sometimes unavoidable during manufacturing. This damage results in a release of metal ions (metal dissolution) into surrounding tissue. These “holes” in the device are typically round or cup-shaped, and if severe, may compromise the integrity or performance of the implant.
Crevice corrosion occurs in localized areas where the metallic device is in contact with small volumes of stagnant (non-flowing) liquid. The chemistry of the local environment within these crevices can change, resulting in depletion (loss) of oxygen and a drop-in pH, making the metal surface more prone to corrosion. For example, modular orthopedic devices may facilitate local fluid stagnation increasing the potential for corrosion; even in metals that normally have good corrosion resistance.
Fretting corrosion occurs due to oscillatory (moving back and forth) micro-motion between contacting metallic surfaces. This motion can cause wear and disrupt the passive oxide film of the opposing metal surfaces. Even slight relative micro-motion between contacting surfaces may lead to continuous disruption of their passive films leading to corrosion of the exposed metal. The severity of fretting is
6 This work was performed by US Government employees and is in the public domain in the US
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Figure 1: Example of pitting corrosion on the surface of stainless steel (Di Prima, Guiterrez, and Weaver 2017).6
6.1.1 Foreign Body Response (FBR)
Wound healing and other host responses to metal implants involve innate immune mechanisms that are collectively described as the foreign body response (FBR). The FBR can be characterized as a coordinated cascade of inflammatory and cellular mechanisms that are critical to acceptance of the implanted device (Christo et al. 2015). Abnormal immune responses may lead to adverse local tissue reactions (ALTR) including osteolysis, necrosis, pseudotumor formation, tissue granulation, and fibrous capsule contractions (Major et al. 2015).
Most immediately following implantation, host protein adsorption to the implant surface initiates the FBR. Injury to host tissues is rapidly followed by activation of coagulation and complement pathways and adsorption of proteins including fibrinogen, fibronectin, vitronectin, and globulins to the implant surface; this heterogenous mixture of stress response proteins and extracellular matrix components forms a matrix on and around the implant (Anderson, Rodriguez, and Chang 2008). With time, recruitment of immune cells, most notably macrophages, leads to the formation of foreign body giant cells (FBGCs) and fibrous encapsulation of the implant (Moore and Kyriakides 2015).
Early events in the response to an implant and, by extension, minor perturbations from stereotyped programs can therefore have significant consequences further downstream in the concerted response.
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As with other kinds of biological cascade reactions, perturbations from the stereotypical, canonical program may arise from crosstalk between multiple pathways, as well as bystander inflammation and immunity at distant sites, unrelated to the implant. This rapid innate response equilibrates to steady state within one to two weeks following implantation. Failure to resolve acute inflammation proceeds to chronic inflammation which may precipitate ALTR and potential implant failure (Gibon et al. 2017;Klopfleisch and Jung 2017).
6.2. INNATE IMMUNE RESPONSES TO METAL IMPLANTS
Innate immune mechanisms are critical first responders to both microbial and toxicological insults. This characteristic holds true for immune responses to metal implants. Multiple factors influence the nature and magnitude of the innate response to metal implants, downstream inflammatory and immune responses, and the ultimate success or failure of the implanted device. The elemental composition; physical, chemical form (i.e., ion versus particulate), structural form; and amount of metal exposure may influence the nature of the innate immune response elicited following implantation. Location- or tissue- specific physiology and immunology may also provide numerous complicating factors, as well as the timing and course of implantation and implant-directed responses. The typical response to metal implants is characterized by rapid inflammation and innate immune response that equilibrates to steady state within one to two weeks following implantation. This resolution is critical to limiting tissue pathology and precluding subsequent implant failure.
6.2.1. Innate Immune Recognition of Metals
Recognition and uptake of metal debris initiates multiple inflammatory pathways including the inflammasome and pattern recognition receptor (PRR) pathways (Goodman, Konttinen, and Takagi 2014). While hematopoietic-origin leukocytes are enriched and specialized for these pathways, signals derived from injury of non-hematopoietic host tissues are also important, bridging immediate injury to tissues with early inflammatory and innate immune responses. The importance of signals derived from host tissues in providing impetus to initial inflammatory and innate immune responses undergirds the identity of these signals as “alarmins” or “danger”-associated molecular patterns (DAMPs) (Schaefer 2014; Rider et al. 2017).
The NALP3 (also known as NLRP3, CIAS1) inflammasome pathway comprises a multiprotein complex containing NALP3 and ASC, responsible for the activation of intracellular enzymes that lead to the production of inflammatory cytokines from immune cells, including IL1β and IL18 through activation of caspase 1 (Dostert et al. 2008). The NALP3 inflammasome is a primary sensing mechanism by which metal debris, both ions and particulates, induce the secretion of pro-inflammatory cytokines and recruit myeloid-lineage cells. Along with other types of implant related debris, metal debris was shown to activate the NALP3 inflammasome which is implicated in inflammatory processes such as osteolysis (St Pierre et al. 2010; Burton et al. 2013). Triggering of the NALP3 inflammasome by varying sizes and forms of metal debris may underlie divergent features of local inflammatory features at different device-tissue interfaces (Caicedo et al. 2009; Cobelli et al. 2011; Konttinen et al. 2014; Reddy et al. 2014; Scharf et al. 2014).
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Subclinical Response to Metal Implants
Pattern recognition receptors, exemplified by Toll-like receptor 4 (TLR4), also serve as critical triggers of inflammation following recognition of endogenous “alarmin” molecules released by injured tissues including heat-shock proteins, biglycan fragments, and heparan sulfates among others (Cobelli et al. 2011). Metal ions and particulates have been shown to directly activate TLR4, promoting local inflammation and tissue remodeling through driving NFκB-mediated cytokine production (Schmidt et al. 2010; Raghavan et al. 2012; Burton et al. 2013; Potnis, Dutta, and Wood 2013; Tyson-Capper et al. 2013; Konttinen et al. 2014; Lawrence et al. 2014; Lawrence et al. 2016; Samelko et al. 2017). In addition to TLR4, enriched expression of type A scavenger receptor (SR-A), interleukin-33 (IL-33), and integrin adhesion molecules on myeloid lineage cell types further couples sensing of metals and metal-induced tissue injury to endogenous wound healing responses (Kzhyshkowska et al. 2015).
Release of alarm signals from injured host tissues couple initial implantation to immediate inflammatory and innate immune responses; however, ongoing, persistent responses to implant-derived metal debris may also continue to modulate these inflammatory and immunogenic signals. Metal particles or ions can induce the apoptosis or necrosis of cells, including responding leukocytes (Peters et al. 2001; Catelas et al. 2003; Huk et al. 2004; Caicedo et al. 2008; Gill et al. 2012; Posada et al. 2014; VanOs et al. 2014; Posada, Tate, and Grant 2015). Sensing of physical and chemical characteristics of metal debris may determine apoptotic or necrotic programming in the context of other inflammatory microenvironmental signals, tuning further inflammatory signaling (Rosario et al. 2016). Tissue injury, presenting as necrosis in association with failed or compromised implants may perpetuate these maladaptive pathways (Grammatopoulos et al. 2016).
Altogether, these findings underscore that early, innate sensing of metallic implants and debris can be performed by multiple pathways – both direct (e.g. receptor recognition of metal ions, particulates, or surfaces) and indirect (e.g. recognition of alarmins released by tissue injury) (Samelko et al. 2016). These multiple mechanisms may comprise critically decisive determinants for the success or failure of the implant, and other downstream adverse events.
6.2.2. Innate Cellular Responses to Metals
Central to the FBR is the predominant infiltration of peri-implant tissues by macrophages ‒ phagocytic cells specialized for defense against microbial pathogens, scavenging damaged tissue, and wound healing. As sentinels of innate immunity, macrophages express a wide range of PRRs. Triggering of PRRs expressed on macrophages elicits pro-inflammatory responses that are important for antimicrobial activity, profibrotic remodeling, induction of adaptive immunity, scavenging, and subsequent tissue repair (Mantovani et al. 2013; Wynn and Vannella 2016).
Macrophages are consistently present in significant numbers in tissues surrounding implants, particularly in cases of failure (Mahendra et al. 2009; Paukkeri, Korhonen, Hamalainen, et al. 2016). Macrophages and monocyte precursors are recruited to the implantation site by chemoattractants and growth factors including transforming growth factor (TGFβ), platelet-derived growth factor (PDGF), CXCL4/PF4, Leukotriene B4 (LTB4), and complement fragments (Anderson, Rodriguez, and Chang 2008). Macrophages at the implant site can be activated by metal debris and DAMPs released upon tissue injury and cell death, which signal through the NALP3 inflammasome and TLR pathways, leading to the production of pro-inflammatory cytokines, including IL1β, IL6, IL18, and TNFα; as well as the chemokines CXCL8/IL8, CCL2/MCP-1, and CCL3/MIP-1α; ;and other small molecule inflammatory mediators such as
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nitric oxide, cyclooxygenase-2-derived lipids, 4-hydroxynonenal, nitrotyrosine, and high-mobility group protein B1 (HMGB1) (Cobelli et al. 2011; Steinbeck et al. 2014; Kzhyshkowska et al. 2015; Hallab and Jacobs 2017). In coordination, these numerous pathways further augment cellular infiltration and inflammation.
Uptake of particulate metal debris by macrophages through phagocytosis is a key mechanism by which implants may trigger inflammatory responses (Nich et al. 2013; Nich and Goodman 2014; Athanasou 2016). The specific mechanisms of uptake of metal debris by phagocytic cells is dependent on the size, shape, and chemical composition; by extension, these parameters impact downstream inflammatory and immunologic responses. Activation of the NALP3 complex is dependent upon the size, shape, and chemistry of metal debris (Caicedo et al. 2009; Cobelli et al. 2011; Scharf et al. 2014). Phagocytosed metal particles less than 10 μm in diameter are endocytosed and transported to lysosomes where the acidic microenvironment of these vesicles promotes particle corrosion, stimulating the further release of metal ion species (Hallab and Jacobs 2009; Gill et al. 2012). Because metal particles are resistant to complete degradation by lysosomes, cell death is a common endpoint for macrophages responding to metal debris, further perpetuating inflammatory signaling.
Particulates too large to be engulfed by an individual cell may trigger the fusion of macrophages, resulting in the formation of multinucleated, syncytiated foreign body giant cells (FBGCs) to sequester indigestible particles. This process, dubbed “frustrated phagocytosis”, has a central role in the formation of foreign body granulomas and perpetuation of implant-associated inflammatory responses (Klopfleisch and Jung 2017). Metal debris released from implants promotes the formation of FBGCs (Shahgaldi et al. 1995). Histological tissue sections from patients with failed implants, often evidence FBGC surrounding large metal debris, even in distal tissues. (Anderson, Rodriguez, and Chang 2008; Cobelli et al. 2011).
Neutrophils are also a canonical feature of the acute response to implanted devices and are implicated in adverse responses to metal implants and metal debris. Neutrophils rapidly mobilize to the site for 2-3 days following the implant; however, their lifespan in situ is short-lived. Production of IL-1α, IL-1β, and TGFβ by macrophages in response to metallic debris augments neutrophil recruitment (St Pierre et al. 2010; Akbar et al. 2012). This rapid response by neutrophils may be characterized as an acute highly localized stress program, through the release of proteases, lysozymes, and reactive radicals in the form of extracellular traps (NETs), contributing to opsonization, clearance, and scavenging at the implant site (Liu et al. 2014; Jhunjhunwala et al. 2015; Jorch and Kubes 2017). Several of these mechanisms implicate neutrophils in the initial production of metallic debris, via production of oxidizing agents and pro- inflammatory chemokines and cytokines (Sutherland et al. 1993; Labow, Meek, and Santerre 2001; Goncalves, Chiasson, and Girard 2010; Ye et al. 2010). Persistent accumulation of neutrophils following the foreign body reaction may be an indicator of maladaptive responses to a metal implant, potentially predicting adverse events, particularly septic modes of implant failure (Grammatopoulos et al. 2016).
Mast cells also participate in acute inflammatory responses to metal implants and possibly the immunopathology associated with device failure. Release of histamine by tissue-resident mast cells is a key instigator of the recruitment of phagocytic cells to the implant site, by driving expression of adhesion molecules on endothelial cells (Tang, Jennings, and Eaton 1998; Zdolsek, Eaton, and Tang 2007). Histologic signatures associated with dendritic cells and eosinophils can also be found in association with metal orthopedic devices (Thewes et al. 2001). While the roles of these cell types in biological responses to metals are less understood, the importance of dendritic cells in eliciting and
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Subclinical Response to Metal Implants
programming T cell responses implies a role for these cells in amnestic T cell-driven responses (Keselowsky and Lewis 2017).
6.4. TISSUE AND ORGAN LOCALIZATION OF INFLAMMATORY RESPONSES TO METAL IMPLANTS
While many molecular, cellular, and signaling pathways associated with inflammatory and immune responses to metal implants are shared across device types, intended uses, anatomy, and physiology, there is a growing appreciation for device-tissue interface as an independent dimension of functional specialization in inflammatory and immune processes. At the intersection of anatomy and physiology, specific cellular subpopulations and specialized pathways are known to exist within many tissue types and solid organs. In this section, some of these specialized response pathways will be addressed. Similarly, other location- and tissue-specific context can inform and modulate common pathways through which metal devices and host response interact.
6.4.4. Oral and Dental Implants
In the oral cavity, interactions between host response and metallic dental implants are highly influenced by the oral microbiota. The highly diverse communities of bacterial and fungal microbes within the oral habitat (Pokrowiecki et al. 2017); the composition of the microbiome in the oral habitat is among the most diverse in the human body (Human Microbiome Project 2012). There are many device characteristics that influence microbial colonization and composition. Roughness of metallic surfaces correlates with initial microbial colonization (Chin et al. 2007). Metallic composition of dental alloys is a significant modulator and determinant of bacterial colonization and outgrowth in a manner that can be selective for microbial species, influencing the composition of oral microbial communities (Nakajo et al. 2014; Svensson et al. 2014; Urushibara et al. 2014).
Oral microbiota largely survive within biofilms ‒ polyglycan matrices, composed of both microbial and host proteins (Perrin et al. 2009), providing a dynamically regulated habitat for bacterial and fungal microbiota. Bacteria embedded in biofilms have been shown to communicate via small molecules, resulting in coordination of their outgrowth and adaptation via quorum sensing across species (Jayaraman and Wood 2008; Hojo et al. 2009; Huang, Li, and Gregory 2011; Willems, Xu, and Peters 2016). This community organization and response is thought to underlie the acquisition of pathogenicity and virulence factors, including antibiotic resistance (Shao and Demuth 2010).
The development of microbial biofilms associated with metallic dental and orthodontic devices can promote carious lesions and gingival disease (Eliades and Athanasiou 2002). Nickel surfaces have been shown to elicit biofilm formation by driving microbial expression of Curli, an extracellular amyloid fibrous protein (Perrin et al. 2009). Microbial biofilms elicit an acidic, oxidizing microenvironment in collaboration with host inflammatory processes, possibly leading to eventual peri-implantitis (Rodrigues et al. 2013). Bacterial lipopolysaccharide (LPS) was shown to further facilitate corrosion of titanium alloys, particularly in the weakly acidic oral environment (Yu et al. 2015). These electrochemical modes of corrosion may enhance or synergize with mechanical wear or tribocorrosion in facilitating failure of dental implants (Mathew et al. 2012).
Oral microbial composition and biofilms exert immunomodulatory pressures on host response. As with many other mucosal habitats, microbiota communities elicit low-grade, tonic inflammatory and immune signaling in normal healthy conditions (Belkaid and Hand 2014). Oral microbial communities effectively induce numerous pro-inflammatory cytokines and chemokines including IL1β, IL6, CXCL1, CXCL3, CXCL8/IL8, GM-CSF, and TNFα (Ramage et al. 2017). Pathogenic and opportunistic overgrowth and dysbiosis selectively retune these signals; periodontic microorganisms elicit host responses involving NALP3 inflammasome activation and subsequent expression of pro-inflammatory IL1β and IL18 as well as osteoclastogenic RANK-L (Bostanci et al. 2007; Bostanci et al. 2009; Hamedi et al. 2009). Recruitment of neutrophils to oral tissues is particularly key in amplifying homeostatic basal inflammatory signaling into persistent, pathogenic responses (Pokrowiecki et al. 2017). Biofilm microbial ecology and host responses to implant-associated microbes at other anatomic sites have been implicated in infectious and septic modes of implant failure (Costerton, Montanaro, and Arciola 2005; Arciola et al. 2015; Arciola, Campoccia, and Montanaro 2018).
7.4.4 Cancer
Cancer concerns regarding metal implants are raised mostly due to in vitro carcinogenic effects exerted by metals such as Co and Ni as well as possible neoplastic changes in peri-implant tissues (Bitar and Parvizi 2015; Cheung et al. 2016; Zywiel et al. 2016).
A review of early epidemiologic studies on implant-related hematopoietic cancers found conflicting evidence, with only two studies suggesting an increased risk of lymphoma and leukemia after THA (Gillespie et al. 1996). The reintroduction of MoM hip implants heightened concerns about possible carcinogenicity of metal wear debris (Jacobs et al. 2003; Wagner et al. 2012), resulting in further epidemiologic studies.
A 30-year follow-up based on the Swedish Knee Arthroplasty registry showed a significantly higher overall risk of cancer among the osteoarthritis (OA) and rheumatoid arthritis (RA) patients with arthroplasty; however, only the risks of myelodysplastic syndromes and, to a lesser degree, prostate cancer and melanoma were associated with orthopedic implant-related metal exposure (Wagner et al. 2011). A population-based US study, which involved 1,435,356 person-years of follow-up and 20,045 cases of cancer, did not reveal an increase of overall risk of cancer following THA; however, the risks of prostate cancer and especially melanoma appeared slightly higher (incidence ratios: 1.12; 95% CI, 1.08- 1.16 and 1.43; 95% CI, 1.13-1.79, respectively) (Onega, Baron, and MacKenzie 2006). The elevated melanoma risk was postulated to be from a long-term exposure to metal ions, particularly to hexavalent Cr which has been shown to have effects on melanocytes (Meyskens and Yang 2011).
In a linkage study based on the National Joint Registry of England and Wales (NJR), overall cancer risk was similar in patients with MoM hip replacements and other implants (Lalmohamed et al. 2013). A population based prospective longitudinal cohort study using the same registry also noted no increase in cancer risk with MoM bearing arthroplasty (Hunt et al. 2018). Similarly, no increased risk for any cancer
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Clinical Response to Metal Implants
was found in the NJR-based linkage study on patients with hip replacements using MoM vs. alternative bearings (Smith et al. 2012). A Finnish study on patients with MoM (McKee-Farrar) vs. MoP hip replacements (Visuri et al. 2010) showed that after 20 years post-implantation, both cohorts had increased mortality compared to the general population; the MoM cohort had higher cancer mortality compared to MoP during the first 20 years post-implantation, but not thereafter. Another study using the Finnish registry also showed no increase in overall risk of cancer in their MoM cohort (Ekman et al. 2018).
In a large-scale Finnish cohort study on patients with MoM vs. conventional hip replacement, overall risk of cancer was not increased and overall risk of death was even lower, but the risks of soft-tissue sarcoma and basalioma were higher in the MoM cohort (Mäkelä et al. 2014). In a large-scale Scottish study on total hip replacement or resurfacing (Note: the study was not able to distinguish between MoM and non-MoM replacements), the risks for all cancers, prostate cancer, and especially multiple myeloma were slightly increased (Brewster et al. 2013).
Possible links between implant reactivity and certain cancers were also discussed in some case reports. Demehri et al. (2014) presented a rare case of aggressive cancer that, in the authors’ opinion, was prompted by the metal implant-related chronic allergic contact dermatitis (ACD) located in the sun- exposed area (Demehri et al. 2014). A 46-year-old female with no prior history of skin cancer had an ankle fracture that was repaired using a Ni-containing metal rod for stabilization. After developing a non-healing skin lesion and testing positive for Ni allergy, she had the rod removed, but the skin lesions including significant erythema, oozing, and pain persisted. Three years later, she was diagnosed with Marjolin’s ulcer, an invasive squamous cell carcinoma that developed in the ACD area over the implant site. In addition to this case of squamous cell carcinoma associated with orthopedic implant (Demehri et al. 2014), there were case reports linking squamous cell carcinoma to metal allergy due to dental restorations (Hougeir et al. 2006; Weber et al. 2012) as well as implant-related inflammatory responses in general (Jané-Salas et al. 2011).
Considering the recent evidence on breast implant-associated anaplastic large cell lymphoma (ALCL), some reports suggested possible development of ALCL in relation to other, including metal, implants. Palraj et al. (2010) reported the case of ALCL that was associated with a stainless-steel fixation plate implanted several years earlier for repair of a tibial fracture (Palraj et al. 2010). (Yoon, Choe, and Jeon 2015) described the case of mucosal CD30+ T-cell lymphoproliferative disorder that developed several years after placement of dental implants. Antigenic stimulation and chronic inflammation brought about by the presence of implants made of silicone, metal, or other (e.g., polyethylene terephthalate) materials have been suggested as possible neoplastic triggers (Palraj et al. 2010; Menter et al. 2019). Resembling lymphomas associated with other inflammatory conditions, implant-associated lymphomas are believed to share the following features: (1) development in the setting of prolonged inflammation, (2) localization to a confined body space (e.g., between an implant and the surrounding tissue), (3) a long latency period between the onset of the inflammatory process and the development of the lymphoid malignancy, and (4) the large-cell phenotype (Palraj et al. 2010).
In summary, while isolated reports exist of cancers associated with metal implants, data from multiple large registries has failed to support any increased risk of malignancy with metal implants.
7.5.3 Dental and Oral/Maxillofacial Devices
A variety of metals are used in dentistry. This includes precious metal alloys such as gold, platinum, silver, palladium, iridium, rhodium, osmium, and ruthenium and base metal alloys such as cobalt- chromium and nickel-chromium used to fabricate crowns, bridges, and partial dentures. Other metals used include nickel titanium and cobalt chromium nickel alloys for orthodontic arch wires, stainless steel alloys for preformed crowns and orthodontic brackets; titanium alloys for endosseous implants and bone fixation plates and screws; dental amalgam (mercury, silver, copper and tin) for tooth restoration; and cobalt chromium for temporomandibular joint (TMJ) implants. Except for TMJ implants, endosseous implants, and bone fixation plates and screws, most of these devices are not metal implants but are surface or external communicating devices. Dental amalgam is included in the discussion of metal implants because its use has been associated with increased mercury body burden ((SCENIHR) 2015) However, FDA has completed and posted a separate review of health effects of dental amalgams.
Temporomandibular Joint (TMJ) Implants
The bilateral TMJs, formed by the articulation of the condylar head of the mandible and the mandibular fossa and articular tubercle of the temporal bone of the cranium, are unique in that the two joints must function together as one unit. The fibrocartilage covered articulating surfaces are separated by an articular disk which splits the joint into two synovial joint cavities, and three extracapsular ligaments act to stabilize the joint during the initial rotation of the condylar heads, followed by translation where the condyle and meniscus slide forward and downward beneath the articular eminence (Kreutziger KL 1975).
Clinical conditions that may result in deformity/destruction of the TMJ include irreparable condylar fractures (trauma), joint ankyloses, dentofacial deformities, neoplasms, severe inflammatory and degenerative joint disease with condylar bone loss, as well as failure of autogenous grafts, may be addressed through partial or total TMJ replacement of the mandibular fossa /condylar head of the mandible implant(s) (Driemel et al. 2009). The history of TMJ surgical interventions also includes implantation of an intraarticular disc composed of polytetrafluoroethylene (PTFE) as a meniscus
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replacement post discectomy, as a means to maintain vertical dimension of the jaw (Lypka and Yamashita 2007) . However, as the TMJ is a loaded joint under continuous movement, PTFE discs commonly fragmented resulting in an intense foreign body (giant cell mediated) reaction and significant loss of bone (Lypka and Yamashita 2007) and possible additional surgical procedures including partial or total joint replacement (Henry and Wolford 1993).
In response to detection of significant history of failure with total or partial TMJ replacements, the FDA ordered all TMJ implant manufacturers to conduct 522 Postmarket Surveillance Studies11 to help determine causes of TMJ implant failure. As of Spring 2019, these studies are showing that the most common reasons for subsequent surgical intervention include fibrous ankylosis, heterotopic bone formation, infection, and pain/swelling.
Endosseous Dental Implants, Dental Restorations, and Dental Appliances
Endosseous dental implants are used to replace teeth and restore chewing function by supporting dental restorations such as crowns or bridges. Endosseous dental implants are placed in the maxilla or mandible to replace the root and prepared crown portions of the tooth. Dental appliances have a variety of intended uses; for example, orthodontic wires are intended to assist in tooth movement as part of orthodontic treatment of malocclusion. Ni and Ti are commonly found in dental restorations and appliances such as crowns and orthodontic wires. Although Ti in endosseous dental implants, dental restorations, and dental appliances have been generally considered inert in terms of the interactions with the oral cavity, recent reviews of the literature suggest possible adverse reactions to various constituent metals including Ti (Siddiqi et al. 2011; Levi, Barak, and Katz 2012).
Bone Fixation Plates and Screws
Bone fixation plates and screws for use in the oralmaxillofacial areas are devices composed of titanium or titanium alloy that are intended to stabilize injured or congenitally deficient oral and maxillofacial bones. These devices share many of the same sensitivity concerns as titanium orthopedic fixation devices (Goutam et al. 2014).
Dental Amalgam
Dental amalgam, a filling material used to fill cavities caused by tooth decay, consists of a mixture of metals including liquid mercury (Hg) and a powdered alloy composed of silver, tin, and copper. Approximately 50% of dental amalgam (by weight) is elemental mercury. High levels of mercury vapor exposure may cause potential toxic effects endangering patients and dental professionals as well. However, the exposure to mercury from dental amalgam occurs mainly during placement or removal of amalgam restorations. After the placement, long-term exposure to the hardened dental amalgam usually results in a much lesser mercury release that is considered far below the current health standard (About Dental Amalgam Fillings, FDA12).
Exposure to dental amalgam may result in increased Hg levels, often in correlation with the number of personal or placed/removed dental amalgam fillings {Nicolae, 2013 #798}; (Yin et al. 2016); (Goodrich et
11 For information on 522s see: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pss.cfm?s=t12https://www.fda.gov/medicaldevices/productsandmedicalprocedures/dentalproducts/dentalamalgam/ucm1710
94.htm#risks
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al. 2016). Among dental professionals, elevated Hg levels were associated with occupational hygiene behavior and certain hazardous habits (Goodrich et al. 2016); (Duncan et al. 2011).
Dental amalgam has been associated with hypersensitivity reactions, mostly attributed to mercury and manifested as allergic dermatitis (Kirshen and Pratt 2012), orofacial granulomatosis (Tomka et al. 2011), and oral lichenoid lesions (Gönen et al. 2016). Dental amalgam is also capable of causing “amalgam tattoos”, i.e., asymptomatic dark macules on the oral mucosa which occur when amalgam particles are inadvertently implanted into oral soft tissues during dental procedures and which may be accompanied by histopathologically detectable foreign body reaction (Amano et al. 2011). Some isolated studies suggested possible systemic effects, linking dental amalgam exposure to possible neurological diseases such as Parkinson’s (Hsu et al. 2016) and autoimmune conditions such as ASIA (Stejskal, Ockert, and Bjorklund 2013); (Alijotas-Reig et al. 2018). Pediatric studies on putative associations with neurodevelopmental outcomes due to personal or maternal exposure to dental amalgam mostly reported negative (Maserejian et al. 2012); (Watson et al. 2013); (Wright et al. 2012) or inconclusive (Geier 2009) evidence.
FDA has conducted periodic reviews of the amalgam literature to assess for new information concerning its safety. The latest review was conducted in 2019, for which a separate report has been prepared13. This report found no clinical evidence from controlled studies that would unequivocally support the causal associations between occupational or non-occupational exposure to dental amalgam and systemic adverse outcomes. However, the reliability of evidence from many currently available clinical studies was questioned by the emerging evidence on in vivo transformation of inorganic mercury into methylmercury (Uchikawa et al. 2016); (Martín-Doimeadios, Mateo, and Jiménez-Moreno 2017); (Li et al. 2019) and subsequent limitations of conventional approaches for distinguishing between inorganic Hg from dental amalgam and dietary methylmercury, which postulate urine and hair measurements as their respective indicators (Sherman et al. 2013); (Manceau et al. 2016). As a result, dental amalgam is included as a separate topic for the upcoming panel meeting(s) aimed to solicit input and advice for addressing potential safety issues of metal-containing medical devices.
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