Introduction: Titanium dental implants are the most common type of dental implants. Although titanium and its alloys are considered biocompatible, there are concerns about the induction of metal allergy with dental implants.

Aim: To evaluate the presence of titanium sensitization by patch testing in patients who intend to have titanium dental implants.

Materials and methods: A retrospective study was performed in which data on sensitization to titanium collected from the Allergy Office at the Faculty of Dentistry in Plovdiv from January 2022 to April 2024 were analyzed. We analyzed data from 95 patients who had patch testing done before their dental implant surgery.

Results: Thirty-eight (40.0%) patients exhibited positive patch test reactions to at least one metal. The most common allergen was nickel (32.6%). Titanium (IV) oxalate was the only one with a positive rate (7.4%) among titanium reagents. Almost one-half (42.9%) of the patients were monosensitized to titanium (IV) oxalate. No association between positive reaction to titanium (IV) oxalate and history of suspected metal allergy was identified (p=0.064).

Conclusions: The absence of positive reactions to other titanium reagents, as well as a correlation with a history of metal allergy and other allergies in patients who tested positive for titanium oxalate, makes determining the clinical relevance of the positive reactions difficult. Standardization in titanium allergy research is required to ensure the accuracy of the findings.

dental implants, diagnostic difficulties, titanium sensitization

Titanium dental implants are widely accepted as the gold standard for tooth replacement due to their superior mechanical properties, biocompatibility, and high corrosion resistance. As the most commonly used type of dental implant, titanium has been extensively studied for its biological performance and long-term success rate. According to the American Society for Testing and Materials (ASTM), titanium is available in two primary forms: commercially pure titanium (Grades 1-4), which varies in oxygen content and mechanical strength (with Grade 1 being the weakest), and titanium alloys, such as Ti-6Al-4V (ASTM Grade 5), which contains 6% aluminum (Al) and 4% vanadium (V) by weight. Additionally, a binary alloy consisting of approximately 85 mass% titanium (Ti) and 15 mass% zirconium (Zr) is used, though it is not yet standardized.^[1] While titanium and its alloys exhibit high corrosion resistance and biocompatibility, increasing evidence suggests that titanium ions and particles released from dental implants may contribute to local and systemic immunological reactions. ^{[2, 3]} Furthermore, trace amounts of other metals present as impurities in titanium implants—such as nickel, cobalt, chromium, and copper—are known contact sensitizers and may also trigger hypersensitivity reactions.^[4] Consequently, the role of metal allergies in implant failure has been increasingly scrutinized.^[5] Comino-Garayoa et al.^[6] conducted a comprehensive review of 52 studies on hypersensitivity reactions related to titanium dental implants, analyzing mechanisms, clinical manifestations, diagnostic approaches, and management strategies. Although titanium allergies are uncommon, they can cause localized reactions such as erythema, edema, pruritus in peri-implant tissues, and proliferative hyperplasia. Systemic reactions, though uncommon, may present as dermatitis, urticaria, or other hypersensitivity responses distant from the implant site. Poli et al.^[7] provided evidence suggesting that implant failure in some patients is associated with allergic reactions rather than mechanical or infectious causes. They reported a clinical case of an epulis-like lesion in the peri-implant mucosa, histologically confirmed as an allergic response to titanium. Since dental implant treatment is both time-consuming and expensive, many patients seek assurance that they will not experience implant intolerance. As a result, implantologists frequently refer patients for epicutaneous testing to metals before implant surgery. Individuals with multiple allergies, particularly those with a history of metal allergy, have a higher risk of developing allergic reactions to titanium implants.^[8] Moreover, titanium, not in its metallic form but as titanium dioxide, is widely used in cosmetics, pharmaceuticals, and food products, raising concerns that prior exposure may contribute to titanium sensitiza- tion.^[9] The risk of titanium sensitization should be evaluated preoperatively to prevent implant failure. If a positive reaction to titanium is detected, alternative implant materials are considered. Metal allergy is traditionally considered a type IV hypersensitivity reaction. Patch testing remains the gold standard method for assessing delayed-type (type IV) hypersensitivity reactions, including those potentially triggered by titanium compounds.^[10] In the literature, various titanium salts have been used as testing agents. Titanium dioxide 10.0% is the most common patch test formulation; however, it has certain limitations, such as poor penetration through the epidermis and the inability of oxides, in general, to bind to proteins and function as haptens.^[11]

The objective of this study was to evaluate the presence of titanium sensitization using patch testing in patients who intend to receive titanium dental implants.

A total of 95 patients underwent patch testing, including 71 (74.7%) women and 24 (25.3%) men, with a mean (±SD) age of 48.1±13.8 years. Of these, 24 patients (25.3%) reported a history of suspected metal allergy, with wo- men reporting this condition more often than men (31.0% vs. 8.3%, p=0.031). The remaining 71 patients reported no symptoms of metal allergy, though 23 of these patients (32.4%) had other allergic conditions, which were also more common in women than men (40.8% vs. 13.6%, p=0.029). Among them, 16 reported atopic disease, 5 had drug allergies, and 2 had food allergies.

Titanium is widely used as a material for dental implants due to its high corrosion resistance resulting from the oxide layer that protects the implant from the surrounding tissues. For this reason, it is accepted as an inert and completely biocompatible material.^[13] However, metal particles have been detected in the tissues surrounding titanium dental implants, both in the presence and absence of periimplantitis.^[14–16] These particles can be deposited into tissue at any stage of dental implant treatment—from insertion to maintenance—with rough implant surfaces releasing more particles than smoother ones.^{[17, 18]} The tribocorrosion process facilitates the release of titanium ions into the surrounding tissues, where they can form complexes with native proteins and potentially act as allergens, leading to hypersensitivity reactions.^[19] Patients with a history of metal allergy are reasonably referred for patch testing, as multisensitization to metals is common, and traces of the most common metal sensitizers may be present in dental implants.^[4] Despite the lack of legislative recommendations for routine allergy testing prior to dental implant surgery, some patients scheduled for dental implant surgery, even without any allergies, insist on doing the test as a guarantee against an intolerant reaction.

Our retrospective study evaluated patients scheduled for dental implant surgery who were tested for titanium contact hypersensitivity in the Allergy office of the Faculty of Dental Medicine. The overall prevalence of titanium sensitization was 7.4%, with positive reactions observed only to titanium (IV) oxalate. This rate was significantly higher than the 0.6% titanium sensitization prevalence reported by Sicilia et al.^[20] However, their study did not include testing of titanium (IV) oxalate, which might account for the difference in sensitization rate from that in our study. In contrast, Niels et al. found that titanium oxalate had the highest reactivity among tested titanium compounds, with 17 patients (7.9%) exhibiting positive reactions^[21], a prevalence similar to ours.

While patients with a history of metal allergy are typically referred for patch testing before implantation^{[5, 6]}, our study found no significant association between a history of metal allergy or other allergies and titanium sensitization. Unexpectedly, patients without a history of allergies were more likely to exhibit positive reactions to titanium (IV) oxalate, although this trend did not reach statistical significance. Titanium sensitivity in patients suspected of metal allergy was estimated to be 4.2%, which is lower than the prevalence of 6.3% reported by Hosoki et al.^[22] in the study conducted among patients suspected of dental metal allergy. While Hosoki et al. hypothesized that the prevalence of titanium sensitization in the general population would be significantly lower, our study found three times higher prevalence of titanium sensitization in individuals without a history of allergy. This might be attributed to the difference of tested titanium agents, as titanium chloride was used in their study, and all the titanium-positive patients also exhibited a positive reaction to other types of metal allergens. In contrast to their study, a positive test to titanium (IV) oxalate was identified as monosensitization in 42.7% of the positive patients in the current study.

A high incidence of positive reactions to titanium oxalate (86%) was identified by Wang et al., and they were attributed to irritant reactions, as no hypersensitivity skin reaction was detected to other titanium salt formula- tions.^[23] In accordance with their study, we also identified a high rate of irritant reactions (21.1%), and those that were registered as positive met the criteria for a positive result in at least two readings. In our study, titanium (IV) oxalate did not induce any crescendo-pattern positive reactions. Most reactions were weak (57.1%), and a decrescendo pattern was observed in 42.9% of cases. Among these, two out of three decrescendo reactions fully declined by the late reading, suggesting not only an allergic response but also resolution following the removal of an irritant.^[24] We speculate that the positive reactions developed over time, possibly influenced by early-stage irritation. Ultimately, differentiating between a true allergic reaction and an irritant reaction remains particularly challenging, making the assessment of reactions to the current titanium (IV) oxalate preparation notably difficult, especially given the lack of established clinical relevance for the positive test results. In contrast, the other four positive reactions exhibited a plateau time course, which is a more reliable indicator of true contact hypersensitivity compared to the decrescendo pattern.^[25] Determining the clinical relevance of these positive reactions to titanium oxalate in pretreatment testing remains challenging, as patients often lack a relevant medical history or clinical symptoms, making diagnostic interpretation difficult. The 2-year follow-up of the titanium oxalate-positive patient who proceeded with titanium dental implant surgery revealed no signs of hypersensitivity or implant failure, questioning the predictive value of positive reactions to titanium (IV) oxalate in assessing implant intolerance. While the observation of this clinical case was not the aim of the study, it highlights the potential for successful titanium implant integration despite positive patch test results. Nevertheless, this observation is limited by the single clinical case and the relatively short follow-up period. However, it raises additional questions regarding the risk of implant failure. The oral mucosa exhibits a weaker immune response compared to the skin, likely due to a lower density of Langerhans cells^[26], and bone demonstrates a low reactivity potential.^[27] Whether these factors may contribute to a tolerant response to a single dental implant or indicate the need to reevaluate the diagnostic value of titanium (IV) oxalate preparation remains unclear. Currently, no standardized protocol exists for evaluating patients scheduled for dental implant surgery. Our patch test results indicate that positive reactions to titanium were registered in patients without a history of allergy, a group generally considered low risk and not routinely referred for allergy testing. On the other hand, there is a need for reliable results from the patch test, as the false positive reactions might lead to inappropriate recommendations of alternative materials such as zirconium implants that are much more expensive.

The frequency of Ti sensitivity in our patch test group was 7.4% recorded only to titanium (IV) oxalate. The lack of both positive reactions to other titanium reagents and a correlation with a history of metal allergy and other allergies in these patients makes it difficult to determine the clinical relevance of the positive reactions and raises the question of whether the recommendation for alternative materials for dental implants is justified in the cases of pre-implant surgery epicutaneous testing. Standardization in research into titanium allergy is needed to ensure the reliability of results.

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The authors have declared that no competing interests exist.

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