From manufacturers to clinicians, the release of dental implant particles can no longer be ignored

Dental implants offer a widely accepted and viable long-term treatment option for patients with missing teeth.^{1, 2} Since the discovery of its biocompatibility and capability of osseointegration, titanium (Ti) and its alloys have become the gold standard and most widely used in implant dentistry.^{3, 4} There are implants made with other materials, this opinion paper will focus on titanium-based implants. While such implants have proven to be highly reliable and have high success rates, it is not without complications. Some implants fail due to a variety of reasons including peri-implantitis, lack of osseointegration, material wear and corrosion, and hypersensitivity.^5-7

For any implant system on the market, a series of complex and stringent standards need to be met during various stages including in vitro testing, in vivo and clinical trials, and manufacturing. Table 1 summarises the major standards dental implant companies follow.

Authors searched publicly available compliance documentations published by major dental implant companies, including BioHorizons, Dentsply Sirona, Nobel Biocare, Osstem, and Straumann. While all companies demonstrated compliance with ISO 13485 (Medical device quality management system) during the design, development, manufacture, and distribution of dental implants (and related components), information on how tests were conducted in accordance to above-mentioned ISO standards was not readily available to public. In addition, standards for biological evaluation of medical devices such as ISO 10993 permits the use of whole implant, and thus the biological implications of free Ti-based particles and metallic ions can be overlooked.

In patients that had dental implants, Ti particles, as a product of wear and/or degradation, have been detected in both intra- and extra-oral tissues. Ti particles have been found in peri-implant bone and/or soft tissues, submucosal plaque, and in distant lymph nodes in human pilot studies.^13-15 Ti particles have also been shown in both animal and human studies to be present in lungs, kidneys, livers, spleen, and abdominal lymph nodes, with some suggesting that particles were transported in the bloodstream by phagocytic cells and plasma proteins to these distal organs.^16-18 Authors' own ex vivo study has demonstrated that metallic nano- and micro-sized particles were released from dental implants immediately after placement.¹⁹ They can be seen embedded in peri-implant bone tissue as well as internalized by cells such as human gingival fibroblasts and macrophages. Another study involving human biopsies has also reported localization of Ti particles in macrophages and epithelium cells.²⁰ It has been suggested that in cells with phagocytized Ti particles, alterations to basic cell mechanism may occur and subsequently lead to reactive lesions such as pyogenic and/or peripheral giant cell granulomas.^{21, 22} Peri-implantitis is a plaque-associated pathological condition occurring in tissues around dental implants.²³ It is characterized by inflammation in the peri-implant mucosa and subsequent progressive loss of surrounding supporting bone in which the implant is anchored. Peri-implantitis sites had higher concentrations of Ti particles in comparison to healthy implant sites,^24-28 while authors acknowledge that there is no definitive evidence, and there is a strong association between implant particle release and peri-implantitis.

The most common feasible causes of Ti particle release are friction during implant placement procedures, implant surface corrosion, and fretting phenomena at the implant-abutment interphase.²⁹ The use of dental hygiene products and antiseptic agents such as fluoride and chlorhexidine have been linked with alterations to the implant surface topography and increased corrosion.^{30, 31} In addition, implant debridement procedures, for example, surface cleaning with mechanical and/or chemical means, used during implant maintenances and treatment of peri-implantitis, such as implantoplasty, were also reported to be the causes of particle release.^{25, 32} Authors' own ex vivo study has found that the amount of metallic particle and ion release during placement was dependent on both implant material and design, where grade 5 titanium alloy (Ti-6AL-4V) implants resulted in more release compared to commercial pure (grade 4) or Roxolid® (Ti-15Zr, a Ti alloy composed of ~15% zirconium) implants.¹⁹ In an in vitro study that investigated particle release due to frictional wear, it was also reported that wear signs were evident in all implant-abutment couplings (grade 4 or Roxolid® implants paired with Ti or Zr abutments).³³ More interestingly, it was found that larger particles were generated in Roxolid® with Ti or Zr abutment pairings in comparison to grade 4 implants. These findings emphasize the need of careful pre-manufacturing evaluations of the implant materials and designs as there is increasing evidence of potential risks of these wear particles.

As the use of Ti and its alloy increases, concerns over their safety are also increasing as the number of research and reports focusing on Ti toxicity showed a rapid upward trend in recent years.³⁴ Both micro- and nano-sized particles can be generated during an implant's life span.^{19, 32, 34} There is evidence that TiO₂ nanoparticles are associated with cellular DNA damage and pro-inflammatory effects.^{35, 36} It has been reported that the TiO₂ nanoparticles could adsorb CXCL8 (and IFN-γ), clinically relevant pro-inflammatory chemokines, thus resulting in the disruption of neutrophil chemotaxis and local inflammatory mediator concentration and subsequently reduced inflammatory response.³⁶ Particle release as an inflammation catalyst mechanism is an emerging concept in dental medicine that may help explain the pathogenesis of peri-implantitis.^{27, 28, 37, 38}

Implant losses can be associated with inflammatory complications due to Ti particles.^{15, 39} Peri-implant diseases can be peri-implantitis or peri-implant mucositis, which are characterized by the presence or the lack of peri-implant bone loss, respectively. The general consensus is that peri-implant mucositis is inflammatory disease involving mucosa only, whereas peri-implantitis sites extend to supporting bone.²³ Souza and colleagues demonstrated that Ti particles affected biofilm composition, increasing population of four bacterial species (Streptococcus anginosus, Prevotella nigrescens, Capnocytophaga sputigena, and Actinomyces israelli), while Ti ions resulted in a higher level of pathogens from disease-associated complex as well as a reduction of health-associated complex.⁴⁰ This suggests Ti particles and ions may encourage the growth of peri-implant pathogenic species, resulting in subsequent microbial dysbiosis and eventually peri-implantitis.

While many tests can be performed to determine parameters such as implant surface topography, composition, and their effects on adhesion, proliferation, and differentiation of various clinically relevant cell populations, suffice it to say that the current setups in accordance to ISO and regulatory bodies do not reflect the extremely complex physiological microenvironment surrounding an implant. More importantly, the effects of Ti particle and metallic ion released from implants are often overlooked by implant companies and clinicians placing the implants. This clearly indicates a need of awareness in the field of implant dentistry as well as a reliable testing protocol that yields highly reproducible and translatable results with regards to the biological response of patients after implantation.

Some manufacturers and independent organizations have already taken steps to carry out additional standardized tests in addition to those required by regulatory bodies such as the U.S. Food and Drug Administration (FDA) and European health, safety, and environmental protection standards (CE marking). CleanImplant Foundation, for example, utilizes scanning electron microscope (SEM) and energy-dispersive x-ray spectroscopy (EDS) in a clean room environment (according to Class 100 US Federal Standard 209E, Class 5 DIN EN ISO 14644-1) to assess surface homogeneity and contaminations of implants during manufacturing and packaging process.⁴¹ While this is an important development in the field of Implant Dentistry to acknowledge the risk of adverse effects caused by “impurities” such as Ti particles as well as organic particles originated from manufacturing and/or packaging, further biological tests and a more stringent threshold should be applied. CleanImplant argued that single organic particles smaller than 50 μm in diameter were considered less damaging than numerous particles, with a maximum of 30 particles along the circumference of the implant.⁴¹ In addition, major plaque-like organic contaminants exceeding the size of 50 μm and PTFE particles, presumably originating from Teflon molds used during implant production, were considered unacceptable.⁴¹ There are studies reporting the density of Ti particles to be as high as 40 million per mm³ of tissue.²⁷ It should be noted however, that there may be differences in the adverse effects of impurities from defective manufacturing and particle release from appropriately manufactured implants. Further studies are required.

While some clinical/human studies, for example, by Rakic and colleagues,⁴² argued that there is no clear evidence of direct pathological effects of implant particles, particles were identified in all peri-implantitis samples in this study, while another reported presence of particles in 90% peri-implant soft tissue biopsies from patients diagnosed with peri-implantitis.⁴³ Authors believe the prevalence of the particles depicts a strong association between Ti particles and peri-implant disease. As mentioned above that both nanometer- and micrometer-sized Ti particles can be detected in peri-implant tissues.^{19, 26, 44} The size of particles can vary depending on the implant size, design, and material.^{19, 33} Authors acknowledge that it is currently unclear which particle configuration (e.g. size and surface chemistry) and location of distribution results in unfavorable biological response. It is therefore important to apply a standardized set of testing methods to each variation of the same implant system. The biological effects of wear particles, especially nanometer-sized particles, remain unclear and debatable. Some have observed positive antibiofilm properties with either Ti nanoparticles alone, or in combination with other metal nanoparticles, leading to suggestions that these nanoparticles can protect against peri-implantitis pathogens.^{45, 46} Ti nanoparticles have been proposed as a commercially viable anti-plaque and anti-biofilm strategy in products such as tooth pastes and mouthwashes.⁴⁷ Others on the other hand, have reported adverse effects such as induction of apoptosis, genotoxicity, collagen, and lipid deformation as well as alveolar epithelial metaplasia.^{39, 48, 49} It has been reported that nano- and micro-sized Ti particles are associated with the activation of inflammatory response and the release of pro-inflammatory cytokines such as TNF-α and IL-1β.^{50, 51} In addition, Ti particles have been shown to induce M1 macrophage phenotype polarization and associated bone resorption.⁵² Ti nanoparticles have been reported to initiate the TLR4 (toll-like receptor 4)-dependent pathway and the subsequent overproduction of MUC5B (mucin 5B), which is involved in the inflammatory response in human airways.⁵³ Although the body of evidence suggests that the biological effects of implant (nano)particles is inflammatory, more specific toxological research is needed and biomarker assays should be incorporated during the evaluation process of an implant.

Another possible cause of implant failure can be attributed to allergic reactions to titanium, albeit there is limited evidence. Hypersensitivity reactions such as erythema, eczema, necrosis, and bone loss due to Ti dental implants have been reported in some studies.^{7, 54, 55} Concerns of adverse effects of Ti and its alloys have led to the research and development of alternative implant materials. One example is zirconia and polyaryletherketone (PEEK), which have gained increasing interest as a material in dental applications mainly due to its good biocompatibility and biomechanical characteristics.^56-58 However, further investigations are required before such material can become a viable commercial and clinical alternative to Ti. This commentary focused exclusively on titanium-based metal implants, and authors do acknowledge there is also propensity for particle release and accumulation from implants made with alternative materials.²⁷

Ti-based dental implants currently have an undisputed high survival rate clinically and will continue to be successful commercially. However, attention now must be placed on the potential adverse effects associated with Ti implants, in particular, their wear particles. A new set of standards for the evaluation of biological response to implant wear particles and metallic ions needs to be developed with the aim to increase the predictive power of preclinical assessment of materials and dental implants. These testing data should be readily available such that clinicians as well as patients are aware of the biological and mechanical implications of materials used in dental implants. Dental implant providers, be it the manufacturers or the clinicians placing the implants, need to be aware of these potential risks and the need for additional testing standards as they inevitably bear the responsibility of the products used and treatments provided to the general public.

FB contributed to the conception, drafting, critical revision, and approval of article. SL contributed to the drafting and critical revision of article.

The authors declare no conflicts of interest.