Titanium Allergy: Is Zirconia a Viable Alternative?

Purpose: Highlight and discuss the properties of zirconia compared to titanium, in the case of titanium allergies. Materials and methods: The research was divided into 3 themes: Titanium Allergies: clinical cases reported, with the key-words: Titanium allergy; Dental Implants, in the databases MEDLINE / PubMed, Google Scholar and the archives of the library of the Faculty of Dental Medicine, University of Porto. Results: Dental implants are a good approach for replacement of lost teeth. Titanium and titanium alloys are the material of choice for fabrication of dental implants. However there is a possibility of allergic reactions occur. In that way, zirconia seems to be a potential alternative to titanium implants because of its biocompatibility, mechanical properties, aesthetics and low plaque affi nity. Conclusions: Zirconia dental implants have the potential to become an alternative however further clinical scientifi c information is needed. Review Article Titanium Allergy: Is Zirconia a Viable Alternative? Ana Sofi a de Sousa Moreira1*, Ana Patrícia Silva MAgalhães1, Bruno Miguel Santos Carvalho1, Juliana Cardoso Costa Santos1, Ana Isabel Pereira Portela2 and Mário Ramalho de Vasconcelos2 1Dental Degree, Faculty of Dental Medicine, University of Porto, Portugal 2Dental Materials Department of Faculty of Dental Medicine, University of Porto, Portugal Dates: Received: 06 March, 2017; Accepted: 11 April, 2017; Published: 12 April, 2017 *Corresponding author: Ana Sofi a de Sousa Moreira, Dental Degree, Faculty of Dental Medicine, University of Porto, Rua das Agras, 3104580-796, Lordelo – Paredes, Portugal, Tel: +351 916176122; E-mail:

The pure titanium and the Ti-6Al-4V alloys are mainly used in biomedical applications and in dentistry in particular titanium alloys, aluminum and vanadium are often used instead of pure titanium due to its greater strength [25,26]. However several other elements in the alloys have been detected and these "impurities" may be responsible for initiating the allergic response [26]. The most commonly reported type of hypersensitivity is type IV, which is a delayed-type reaction mediated by T lymphocytes with abundant macrophages and an absence of B-lymphocytes [21,26,27]. There are epidemiological studies of prevalence of specifi c allergy to titanium in the general population, however, since the external exposure to this metal is so important its related pathology is scarce and the cases documented in the literature are few, that is why we suspect that the prevalence is low [22]. It is also reported that cases of hypersensitivity to implants are more common in people with a history of hypersensitivity to other metals or jewelry [24].
This review aims to highlight and discuss the properties of zirconia compared to titanium, in the case of titanium allergies. Titanium allergy is often neglected by dental professionals because of lack of knowledge about its impact. This article draws attention to this topic. Besides that new information on dental implants is regularly published. With this article, we aim to help dental professionals, who want alternatives to titanium implants, by simplifying their research.

Material and Methods
In order to accomplish this work, it was used the databases MEDLINE / PubMed and Google Scholar, as well as the archives of the library of the Faculty of Dental Medicine, University of Porto. The search was limited to articles in English, with full text available, without the year of publication limit.
The research was divided into 3 themes. In the fi rst theme -Titanium Allergies: clinical cases reported, with the search key-words: Titanium allergy; Dental Implants, and taking into account the inclusion factors: studies and clinical cases in humans. In the second theme -Titanium Alternatives, using the search key-words: Titanium alternatives; Dental Implants, taking into account the inclusion factors: alternatives only related to the fi eld of dental implantology.

Results
The research results were 17 articles. After reading them all, were selected [8], according to the exclusion factor: in vitro studies. In the second theme were found 11 in total, of which, after reading them all, were selected [4], according to the following exclusion criteria: articles about substituting titanium abutments instead of titanium implants.
For the third theme -Zirconia implants as an alternative to titanium implants, using the search key-words: Titanium; Zirconia; Implants, having humans species as the only factor of inclusion, 155 articles were found, of which after reading them all, 36 were selected, according to the exclusion criteria: an abstract with no relevance to the comparison of titanium and zirconia implants.

Titanium Allergies: clinical cases reported
Titanium allergies are well demonstrated in orthopedic appliances with symptoms of urticaria, eczema, skin and mucosal itching and redness [22]. However it's not known if those fi ndings can be extrapolated to the oral mucosa surrounding the implants, by two reasons: fi rst the contact surface between bone and implant are smaller and, by other hand, oral mucosa and skin are immunologically distinct.
In oral mucosa the number of Langerhans Cells presenting antigens is much lower than the skin which implies that the oral mucosa needs to be exposed to an allergenic concentration 5 to 12 times higher than the skin to induce an identical hypersensitivity reaction [22]. In this research were found many clinical reports of strange reactions to titanium implants (Table 1) whose authors suspect it may be titanium allergies [21][22][23]31]. Patients that are affected by metal allergens are tested clinically by the epicutaneous "patch" test or alternatively The fi rst patient was a 61 year-old woman with a history of penicillin allergy and was taking calcium supplements and estrogen. Four mandibular implants were placed and within 2 weeks of titanium abutment connection was noted a gingival hyperplasia around all cylinders. The titanium abutments were removed and substituted by custom-fabricated gold abutment cylinders. One of the implants was no longer osseo integrated and was also removed. Histologically a high number of eosinophils around the granulation tissue were observed. The authors suspected that the steroids taken by the patient may had raised the liability to a foreign-body reaction. The second patient was a 44 year-old woman with gingival hyperplasia to titanium abutments 3,5 weeks after its placement. The

Titanium Alternatives
There was not suffi cient evidence, in all the articles found, recommending a viable alternative to completely substitute titanium for another material in clinical practice.
Using titanium alloys like Ti-6Al-4V or Ti-15V rather than Commercially Pure grant better physical properties [34], but in specifi c titanium allergy cases it does not solve the problem as titanium remains present. Ribeiro et al. studied a new TiNbZr alloy with similar characteristics to Ti-6Al-4V [35], but it also does not solve the titanium allergy issue. Zirconia implants are the only remaining titanium-free viable alternative as it is shown in Kohal et al. investigation [36]. Gold-based alloys were classically used but they promoted a fi brous interface between implant and bone [37].
In the next part of the present review, as zirconia remained the only candidate to substitute titanium implants in these patients, we decided to compare its properties against titanium (Table 2).

Zirconia implants as an alternative to titanium implants
Biocompatibility is defi ned as the capacity of a material to be used with an appropriate response by a human host, without any kind of allergic, infl ammatory, toxic, mutagenic nor carcinogenic reactions [38]. Zirconia implants have a high biocompatibility [1,2,5,11,14,28,30,39,40], and a similar to titanium soft tissue response [7]. The infl ammatory response and bone reabsorption induced by ceramic particles are less than those induced by titanium particles which suggests the ceramics biocompatibility [2]. All authors refer that zirconia and titanium have a similar biocompatibility.
Osseointegration is an integration interaction between implant and bone leading to implant-bone anchorage which is vital to the implant success [41]. Osseointegration is similar to zirconia and titanium implants [2,7,11,12,14,17,19,[42][43][44], or even better [10,43]. Long-term osseointegration success is dependent of a rigorous oral hygiene in both types of dental implants and high stress distributions in the bone should be avoided as it can induce severe surrounding bone reabsorption leading to implant loosening and further complete loss of implant [7]. Implant surface is determinant to cellular adhesion41. In implants with roughened surfaces, higher forces are required to break implant-bone anchorage in comparison to smoothsurfaces implants [41]. Yamano et al. [13], investigated the cellular response of human gingival fi broblasts cultured on smooth or rough zirconia or titanium disks. The study demonstrated that smooth zirconia surface promoted more alignment and proliferation of the cells. However after 3 hours of culture smooth zirconia surface showed the weakest spreading compared to the other surfaces. Kohal et al. [41], examined the in vitro and in vivo response of osteoblasts to a novel acidetched and sandblasted zirconia surface. The osteoblasts were cultured on electrochemically anodized titanium, machined titanium, novel zirconia surface and machined zirconia. The in vitro investigation revealed that the osteoblast behavior on the novel zirconia surface was similar to the machined surfaces (cell proliferation) and on the other hand similar to the rough titanium surface (cytoskeleton). However in the in vivo experiment the novel zirconia surface performed worse than standard titanium implant surface modifi cation.
As the implants are exposed to saliva in the oral cavity, an acquired pellicle is formed on its surface. This pellicle acts as an interface between bacteria and the implant surface [42,45]. The presence of bacteria is the major contributor to periimplantitis, which is an infl ammatory reaction in the tissues
Candida albicans is the most common fungus in oral cavity and is related to periodontal and peri-implantar lesions [49]. The attachment of Candida albicans is infl uenced by the surface roughness, which means that rough and textured dental implant surfaces have a higher fungal colonization [49]. Bürgers et al. in his study compared zirconia with three titanium implants (with different roughness) and conclude that zirconia did not show any reduced proneness to adhere to Candida albicans in comparison to titanium [49].
Özkurt and Kazazoglu2 and Wenz et al. [29] in their literature review and Bal et al. and Chang et al. in their in vitro experiences conclude that zirconia and titanium implants have a similar stress distribution in the surrounding bone [1,7]. Mobilio et al. results are the same, but they adds that the stress level caused by zirconia implant on cortical bone is lower than that of the titanium implant [10]. However Fuh et al. found that the stress in the surrounding bone was lower for the zirconia implant [12]. The authors try to explain this with the stress shielding phenomenon (causes a reduction in the bone stress). One of the factors that infl uence the stress shielding is the elastic modulus that in the zirconia implants is almost double that of titanium, which means that stress will be higher adjacent to the zirconia implant and will reduce the high stresses in crestal bone near the interface [12].
Long time success studies on zirconia implants are still lacking [14,17,28]. However Borgonovo et al. in their two year clinical preliminary study reported an overall success rate of 95% [14]. Gahlert et al. in their retrospective clinical study cited two clinical investigations that showed success rate of 98% after one year follow-up and 95% after fi ve years of followup, for zirconia implants with rough surface topographies [28].

Conclusion
Titanium has been used as a biomaterial of choice for dental implants. Since there were cases of allergy to titanium, it was necessary to do further research. Zirconia may have the potential to be a successful implant material because it has been proved to be biocompatible in vitro and in vivo studies; it has very interesting microstructural properties, it is osteoconductive, it has a colour that match natural teeth and a low plaque affi nity.
However, further clinical scientifi c information regarding the clinical use of zirconia dental implants should be investigated.