## 4 Discussion
### Evidence of Titanium Allergy  
Most allergy tests (41.6%) were positive for other metals, while 15.9% of cases tested positive for Titanium and 7.2% for Titanium dioxide. Coherently, commercially pure Titanium, when exposed to an aqueous medium or air, forms a passive oxide surface film that creates a high resistance to corrosion induced by acids, chlorides, and wet environments, with low elution of the Titanium ions [22]. However, disruption of the oxide layer can lead to metal corrosion and subsequent biocompatibility reduction [22]. This mechanism could explain the higher incidence found in the present study of allergy to pure Titanium compared to Titanium dioxide or others, which have been rarely detected--3.1% for titanium(IV) oxalate; 1.4% for titanium(IV) isopropoxide; 0.4% for titanium lactate; 0.2% to titanium citrate. Evidence of Titanium (IV) oxide or Titanium chloride sensitivity was never recorded, and in almost 30% of cases, the type of metal involved in the hypersensitivity reactions was not specified. Several tests are currently available to identify metal allergies. The Epicutaneous Patch Test is one of the most diffuse tests for metal allergy [22], although capable of only detecting about 75% of type IV metal allergies [81] and lacking standardization. Accordingly, 3145 epicutaneous Patch Tests [35; 36; 37] were recorded. The other diagnostic procedure most commonly conducted to identify the allergen responsible for the hypersensitivity reactions was Memory Lymphocyte Immuno-Stimulation Assay (MELISA) tests [36; 37] in 37 cases. The MELISA test is a modified form of the lymphocyte transformation test (LTT) used to analyze the local and systemic effects of mucosal-sensitizing allergens in vitro [22]. [PERSON] et al. [82] compared the Patch Test, MELISA test, and conventional LTT and pointed out that the MELISA test is accompanied by a high number of false positives, whereas the Patch Test should be considered the gold standard for investigating the presence of metal allergy. Oral mucosa patch tests may be introduced to assess Titanium allergy, as previously proposed for dietary Nickel [83]. Titanium allergy was detected through MELISA testing in 1 case [36] and N/D tests in 16 cases [36], diagnosed with lesions likely resembling peri-implant mucositis and peri-implantitis (77.27%), respectively, and through both MELISA and Patch tests in five cases with orofacial, periodontal and peri-implant hypersensitivity reactions (22.72%). In contrast, no evidence of Titanium allergy was retrieved for reactive lesions (Figure 4). The main limitation of the present umbrella review may rely on the few systematic reviews retrieved, despite the very inclusive eligibility criteria. Consequently, the presently computed prevalence of cases diagnosed with inflammatory, reactive, and hypersensitivity lesions potentially due to Titanium (alloy) and other metal nanoparticles released from dental implants and implant-supported restorations may have been biased by underreporting, underdiagnosis and misdiagnosis. The incomplete data recorded on lesions' macroscopic, imaging, and microscopic features may have led to an inaccurate categorization of lesions resembling or ascribable to peri-implant mucositis and peri-implantitis, of peri-implant reactive lesions, and of orofacial, periodontal, and peri-implant hypersensitivity reactions. However, lacking data may be presumably due to the fact that Titanium has long been regarded as highly biocompatible, that the phenomenon of dental implant degradation has been only recently disclosed, and that, contrary to other orofacial conditions and disorders [84; 85], investigated lesions may be asymptomatic. For the same reasons, no definitive conclusions could be drawn on the potential role of cases' and implant characteristics, as well as of Titanium allergy, on lesions onset, development, and treatment responsiveness, thus highlighting the need for further investigations on the topic.