| Abstract|| |
Titanium has gained immense popularity and has successfully established itself as the material of choice for dental implants. In both medical and dental fields, titanium and its alloys have demonstrated success as biomedical devices. Owing to its high resistance to corrosion in a physiological environment and the excellent biocompatibility that gives it a passive, stable oxide film, titanium is considered the material of choice for intraosseous use. There are certain studies which show titanium as an allergen but the resources to diagnose titanium sensivity are very limited. Attention is needed towards the development of new and precise method for early diagnosis of titanium allergy and also to find out the alternative biomaterial which can be used in place of titanium. A review of available articles from the Medline and PubMed database was done to find literature available regarding titanium allergy, its diagnosis and new alternative material for titanium.
Keywords: Allergy, contact dermatitis, lymphocyte transformation test, memory lymphocyte immuno-stimulation assay, polyetheretherketone, titanium
|How to cite this article:|
Goutam M, Giriyapura C, Mishra SK, Gupta S. Titanium allergy: A literature review. Indian J Dermatol 2014;59:630
What was known?
Titanium has been widely accepted as intraosseous implant material due to its
excellent osseointegration and high resistance to corrosion.
| Introduction|| |
Stainless steel was the first metallic biomaterial used successfully as an implant. Later, in 1932, the cobalt-based alloy named Vitallium was developed for medical applications. Titanium and its alloys in past few decades are widely used for dental implants and its prosthesis components. Commercially, pure titanium (CpTi) is used preferentially for endosseous dental implant applications. There are currently four CpTi grades and one titanium alloy specially made for dental implant applications. These metals are specified according to ASTM as grades 1 to 5. Grades 1 to 4 are unalloyed, while grade 5 is alloyed with 6% aluminum and 4% vanadium (Ti6Al4V), is the strongest. 
Titanium has high resistance to corrosion in a physiological environment and has an excellent biocompatibility that gives it a passive, stable oxide film; due to this reason, it is considered as the material of choice for intraosseous use in the medical field. ,,, Apart from its success there are studies which show titanium as an allergen. ,,
An allergic reaction, or hypersensitization, is defined as an excessive immune reaction that occurs when coming into contact with a known antigen.  Titanium to provoke an allergic reaction, must have antigenic properties and must be in contact with the organism. The insertion of titanium implants and their permanence in the human body enhances the amount of internal exposure and it has been proven that titanium ions concentrate in tissues surrounding dental and orthopedic implants, as well as in regional lymph nodes and pulmonary tissue. Concentrations of between 100 and 300 ppm have been discovered in peri-implant tissues, often accompanied by discolorations. ,,,,
Attention is needed towards the development of new and precise method for early diagnosis of titanium allergy and also to find out the alternative biomaterial which can be used in place of titanium. A review of available articles from the Medline and PubMed database was done to find literature available regarding titanium allergy, its diagnosis and new alternative material for titanium.
Allergic reactions to titanium
In their ionic form, metals can be bonded with native proteins to form haptenic antigens, or can trigger the degranulation of mastocytes and basophiles, being capable of developing type I or type IV hypersensitive reactions. , Various allergic reactions to titanium mentioned in literature by many authors is listed in [Table 1]. A synopsis of studies of proving allergy to titanium is given in [Table 2].
The orofacial regions have been associated with types I, III, and IV allergies. One of the most common types of allergy found in the oral cavity is type IV, in which the appearance of characteristic features related to the allergy, can start from a few days to several years from contact with allergens. 
Diagnostic test for allergy
Before implant placement
It has been shown that many patients suffer from multiple allergies,  and that people with a history of allergy to metals or jewelry have a greater risk of developing a hypersensitivity reaction to a metal implant.  Furthermore, although titanium allergy has a low prevalence rate, for patients with a previous history of allergies, it may be advisable to carry out a metal allergy assessment and allergy testing before placing permanent implants, in order to avoid a failure of the implant due to an allergic reaction to titanium.
After implant placement
The failure of implants has been widely studied, and the main causes of dental implant failure are infection and overload. ,, However, some failures are difficult to explain, such as spontaneous rapid exfoliation of the implant, or the successive failure of implants in the same patients, known as "cluster phenomenon", without any infection or overload risk factor identified. Authors agree that in these cases, there must be a systemic determinant of failure that has not been identified or understood. ,
An allergic reaction can be reasonably suspected after dental implant placement, on the basis of signs or symptoms associated with allergy, such as rash, urticaria, pruritus, swelling in the orofacial region, oral or facial erythema, eczematous lesions of the cheeks or hyperplastic lesions of soft tissue (the peri-implant mucosa).  In these cases, allergy testing should be performed.
Diagnostic tests for titanium allergy
Various diagnostic tests are available in the literature. It is difficult to compare the results from different studies related to titanium allergies, because some refer to the use of patch tests, while others use prick tests and/or blood tests. ,
To date no standard patch test for titanium has so far been developed, and positive reactions to titanium have only rarely been demonstrated with skin testing.  The sensitivity of patch tests has been shown to be about 75% for type IV metal allergy. Some authors have suggested that 0.1% and 0.2% titanium sulfate solution and 0.1% and 0.2% titanium chloride are successful reagents for the skin-patch tests and could be a valuable alternative to the titanium oxide normally used for patch testing,  but so far no study related to dental implants allergies has used the method.
Memory lymphocyte immuno-stimulation assay test
The MELISA test has been validated to detect sensitization to titanium and other metals,  but there can be some lack of specificity in lymphocyte proliferation. It would be valuable to have a sensitive and specific test that could help in the diagnosis of titanium sensitization or allergy.
Helps in the diagnosis of a type IV allergy.
Lymphocyte transformation test
vitro testing with the Lymphocyte transformation test (LTT) measure lymphocyte proliferation following contact with an allergen is based on the tritiated thymidine incorporation by lymphocytes. Some authors report that there could be that non-relevant proliferation of lymphocytes happen in non-sensitized patients, leading to some false-positive results.
Future prospects in the diagnosis of sensitization or allergy to titanium
Interleukin-17 (IL-17) and Interleukin-22 (IL-22) are produced by a subset of a recently defined T-cell line, known as Th-17. IL-17 has been associated with many inflammatory diseases in humans, including rheumatoid arthritis, organ rejection and asthma. It has been showed that the number of Th-17 cells and the expression of IL-17 were significantly increased in positive patch test biopsies, regardless of the nature of the antigen. ,, IL-22 is a critical mediator in mucosal host defense, which has complex pro-inflammatory and anti-inflammatory and autoimmune effects. It has been shown that patients with contact dermatitis to nickel had a significantly higher IL-22 blood level, compared with control,  indicating a possible involvement of IL-22 in the pathogenesis of human allergic contact dermatitis.
It would be interesting to develop a blood test, based on the measurement of the production of IL-17 and/or IL-22 by lymphocytes, in order to be able to diagnose with certainty a sensitization to titanium.
| Discussion|| |
Investigations have been carried out about hypersensitivity reactions with titanium orthopedic implants; therefore it is not certain as to what extent the discoveries can be extrapolated to the oral cavity and dental implants. The intraosseus contact surface is smaller in dental implants than in orthopedic ones, , which may be particularly important considering that bone has a very low reactivity potential. On the other hand, oral mucosa and the skin behave very differently from an immunological point of view, partially because of the influence of specific immune systems for each organ, such as skin-associated lymphoid tissue and mucosa-associated lymphoid tissue. A practical application is that, in mucosa, the number of Langerhans' cells, which act as antigen-presenting cells, is much smaller. ,, It is because of this, and perhaps also because of its reduced permeability, that oral mucosa must be exposed to allergen concentrations 5-12 times greater than the skin in order to cause tissue microscopic reactions. Moreover, contact between the metal and the host is hampered, as the implant and prosthetic structures in the oral cavity are coated with a layer of salivary glycoprotein, which act as a protective barrier. 
It is important to recognize the difference between the presence of immunocompetent cells in tissues and clinical features consistent with hypersensitivity. In the future, our understanding of titanium allergy would be advanced by a comparison of histologic features in symptomatic and asymptomatic patients with titanium implants in the maxillofacial region. Sensitivity to titanium is characterized by the local presence of abundant macrophages and T lymphocytes and the absence of B lymphocytes, indicating Type 4 hypersensitivity. Researches are going on to develop a technique using flow cytometry, for the purpose of detecting the activation of lymphocytes stimulated by a metal, and measuring different mediators (cytokines, inflammatory mediators) released in response to the metal.
Evaluation of skin sensitization potential of nickel, chromium, titanium and zirconium salts done by Ikarashi et al.,  proved that a significantly large amount of titanium ion was required to elicit a skin reaction. The amount of titanium ion released from titanium alloys has been considered small because of the surface stabilization and the corrosion resistivity of titanium oxide formed on the surface of titanium alloys. These results may explain the rare case of contact sensitization to titanium.
Incidence of titanium sensitivity is increasing as its use in dentistry is increasing day by day. Research has now focused on designing alternative substitutes to titanium. One of the most promising novel materials is Polytheretherketone (PEEK), which is a partially crystalline polyaromatic linear thermoplastic (typically of 30-35% crystallinity). PEEK offers a set of characteristics superior for biomaterials including excellent mechanical properties. Studies suggest that the implantable grade PEEK has bone forming capacity comparable to rough titanium. 
| Conclusion|| |
Improvements in health care and increased life expectancy of the population demand the design of implant biomaterials demonstrating no or minimal deleterious effects on host tissues. Although traditional materials, such as titanium or its alloys have been widely used and promote osseointegration, there are some concerns such as metal ion and debris release; allergic responses and sensitization. Better understanding and more research are necessary for acquainting the cause of allergy and development of new diagnostic tools for allergic reaction of Titanium. PEEK can be one of such alternatives which could provide a versatile foundation material that could be further suited to a particular purpose through readily tailoring its bulk or surface properties.
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What is new?
Studies show that Titanium acts as a potential allergen, so diagnostic tests
are mandatory before implant placements and more stress should be given
to fi nd new diagnostic tests as well as to design alternatives to Titanium
such as PEEK.
[Table 1], [Table 2]