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Authors : Dr. Ranjith Kumar P, Dr. Rohit Raghavan, Dr. Nadeem Abdul Rahman .
 

ABSTRACT

In dentistry, allergic reactions to Titanium implants have not been studied, nor considered by professionals. Placing permanent metal dental implants in allergic patients can provoke Type IV or I hypersensitivity reactions. Several symptoms have been described, from skin rashes, lichenoid reactions, burning mouth syndromes, cheilitis and lip swelling, oral granulomatous reactions, gingival hyperplasia, gingivitis or even periodontitis and implant failure, to non-specific immune suppression.

Degradation products of metallic biomaterials including titanium may result in metal hypersensitivity reaction. Although titanium hypersensitivity is a growing concern, epidemiological data on incidence of titanium-related allergic reactions are still lacking. The incidence appears to be quite low, but increases with increased quantity and duration of exposure to a causative antigen. In this paper, hypersensitivity reactions to titanium implants are reviewed with citing various metal allergy tests.
 

KEY WORDS – Allergy, Dental implants, Hypersensitivity, Titanium, Titanium alloys,

 

Introduction

Titanium is the ninth most abundant element and the fourth most abundant structural metal in the earth’s crust. The use of titanium (Ti) in medicine and dentistry increased during the last three decades. Ti alloys have been widely used for dental implants, endo-prostheses, pacemakers, stents, orthodontic brackets, and eyeglass frames. An oxide film is immediately formed on the surface of this highly reactive transition metal, and this has been claimed to result in good corrosion behaviour and high biocompatibility 1. Therefore, Ti has been considered to be particularly suitable for use in both dental and prosthetic implantation. Nevertheless, sporadic cases of intolerance have been reported1,3,5,7

At the same time, no standard patch test for Ti has so far been developed, and positive reactions to Ti have therefore only rarely been demonstrated with skin testing 1, 13. Patch testing in general has been validated only for epidermal antigen contact, may itself induce sensitization of naive T lymphocytes, and is relevant primarily for detecting dermal effects of hypersensitivity (contact dermatitis) 12. In vitrotesting with the lymphocyte transformation test (LTT), on the other hand, can detect both dermally and non-dermally sensitizing allergens (e.g. beryllium [Be]). As an in vitrotest, LTT cannot sensitize the patient. It has been used successfully to detect hypersensitivity leading to both local and systemic effects, for example those resulting from drug allergies 7.
 

PATHOPHYSIOLOGY OF TITANIUM ALLERGIC REACTIONS

An allergic reaction, or hypersensitization, is defined as an excessive immune reaction that occurs when coming into contact with a known antigen. According to this, in order for titanium to provoke an allergic reaction it must have antigenic properties and must be in contact with the organism.

First of all, we know that in their ionic form, metals can be bonded with native proteinsto form haptenic antigens, or can trigger the degranulation of mastocytes and basophiles, being capable of developing type I or type IV hypersensitive reactions. Secondly, our external exposure, in this case to titanium, is massive. However, 95% of the global use of titanium is not in its metal form, but as titanium dioxide, for its whitening effect (in all kinds of paints and whitening agents), sunscreen properties and use as a safe content in the cosmetic, pharmaceutical and food industries. This exposure means our body usually has a titanium content of around 50 ppm (Parr et al. 1985).

Additionally, the insertion of titanium implants and their permanence in the human body can also cause internal exposure. It has been proven that titanium ions concentrate in tissues surrounding dental and orthopaedic 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, which can be well tolerated or by type IV hypersensitivity reactions, with titanium particles inside the macrophages, lysosomes.

In blood, given its poor solubility (Lalor et al. 1991; Bianco et al. 1996), no significant rise of titanium levels was detected after placing three dental implants in humans (Smith et al. 1997); however, a significant rise has been show in patients with a failed, loose titanium hip prosthesis compared with controls (Jacobs et al. 1991). In this area, patients with a metal-on-metal total joint replacement – both joint surfaces made from titanium – have shown an increase in friction-induced corrosion, with a consequent rise in the internal release of particles, which can lead to cell sensitization, granulomatous infiltration and osteolysis .

Hypersensitivity reaction to a metal comes from the presence of ions following ingestion, skin or mucosal contact, or from implant corrosion processes (Ahnlide et al. 2000; Hallab et al. 2001). These ions, although not sensitizers, form complexes with native proteins and act as allergens causing hypersensitivity reactions. Their clinical effects are difficult to assess due to their infrequent appearance and subtle. In the case of titanium allergy, medical literature has described cases where it has mainly appeared as the fundamental cause of urticaria, eczema, oedema, redness and pruritis of the skin or mucosa, either localized, at distant sites, or generalized. In special cases, allergic reactions have been associated with more serious problems such as atopic dermatitis (Tamai et al. 2001), impaired healing of fractures (Thomas et al. 2006), pain, necrosis and weakening of orthopaedic implants (Haug 1996) and tolerance phenomena (Thomas 2000).

In the field of dental implants, the appearance of facial erythaema (Matthew &Frame 1998; Bircher & Stern 2001) and non-keratinized, oedematous, proliferative hyperplastic tissue (Mitchell et al. 1990) have been described.

In dentistry application, galvanic corrosion occurs when two or more dental prosthetic devices with dissimilar alloys come into contact while subjected to oral liquids like salvia; the difference between the corrosion potentials results in a flow of electric current between them. Therefore, the galvanic cell is formed and causes the increasing corrosion rate of the anode and enhancing the amount of ion metal released. The galvanic current passes not only through the metal/metal connections, but also through the tissues, which may cause pain. Galvanic currents in the oral environment may cause sharp pain when they exceed 20 mA 13.

Geis-Gerstorfer et al. [14] believes that the galvanic corrosion of dental devices is important in two respects:
 
  1. the biological effects which may result from the dissolution of alloys and
  2. the current flow resulting from galvanic cell that could cause bone destruction.

The galvanic corrosion may be started due to the interaction of prosthetic devices. For example, a restoration or prosthesis in physical contact with amalgam in an adjacent tooth or between dental implants, fillings or crowns 9.

Many of these investigations have been carried out with titanium orthopaedic implants; therefore it is not certain as to what extent the discoveries can be extrapolated to the oral cavity and dental implants. On the one hand, the intraosseus contact surface is smaller in dental implants than in orthopaedic ones (Brunski et al. 2000; Akagawa & Abe2003), which may be particularly important considering that bone has a very low reactivity potential (Schramm & Pitto 2000).

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 related 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 glycoproteins, which act as a protective barrier (Bass et al. 1993).
 

BACKGROUNG STUDIES

Scientific evidence on the clinical features of a metal allergy is based on cohort studies, case series and isolated clinical cases. It is estimated that cutaneous hypersensitivity to metals fluctuates between 10% and 15% (Hallab et al. 2001). There are no epidemiological studies on the prevalence rate of titanium allergy in the general population, although the fact that external exposure to titanium is so important, and that related pathology is scarce, makes one suspect it to be low (Lalor et al. 1991).

Studies performed with epicutaneous tests show a percentage of Ti-sensitive individuals between 1% and 3% (Lhotka et al. 1998; Okamura et al. 1999); one study with the LMI test reached 4% (Merritt & Rodrigo 1996b), while those performed with the MELISA test fluctuated between 1.5% and 28%, with authors indicating that the most recent studies have shown an increase in sensitizations (Valentine-Thon & Schiwara 2003).

Titanium allergy has been described in deodorant and cosmetics users, after local reactions to pacemakers, in patients with bronchopulmonary pathology through exposure to titanium powder, in monitored hip prosthesis patients, in failed hip and knee prostheses and in patients with titanium plate osteosynthesis.5,7 In the maxillofacial area, titanium allergy has been described in patients with miniplates to treat mandibular fractures (Katou et al. 1996), with few and inaccurate references to titanium-allergenic processes in patients with dental implants (Mitchell et al. 1990; Matthew & Frame 1998; Bircher & Stern 2001).
 
FIGURE 1 - Atypical gingivitis in individual hypersensitive to titanium


The fact that hypersensitization can take months or even years to develop (Haug 1996), along with its infrequency and the uncertainty of its symptomatic expression (Hallab et al. 2001), makes it difficult to perform deeper studies in this field.

In the area of dental implantology, the failure of implants has been widely studied (Esposito et al. 1999), as has their use in compromised patients, with the main causes for failure being infection, impaired healing and overload (Esposito et al. 1999). However, not all failures can be explained by these three factors; some are more difficult to explain, such as implant spontaneous rapid exfoliation (Deas et al. 2002) and other situations in which the effect of a possible hypersensitivity reaction to titanium may be taken into consideration. Taking all these points into account, it seems there is a problem – somewhat infrequent – but nevertheless one that has been systematically overlooked by the profession. Titanium is considered by some to be non-allergenic 11, 14 but reactions have been reported and titanium ions are found in large quantity in contacting tissues and often throughout the body
 
FIGURE 2: IMPLANT FAILURE


A hypersensitivity reaction to titanium may have devastating results since the material is used in implanted devices such as pacemakers, automatic implanted cardioversion devices (AICDs), joint replacements and dental implants 15, 16.
 

Testing for metal hypersensitivity

The diagnosis of metal allergy is typically based on the patient’s medical record, clinical findings and the results from epicutaneous tests. It has been described that people have a susceptibility to suffer from metal allergy – possibly genetically based (Thomas 2000) – as it has been observed that many patients can suffer from multiple allergies and that individuals with previous reactions to metals or jewellery have a greater risk of developing a hypersensitivity reaction to a metal implant (Hallab et al. 2001). In light of this, although the titanium allergy has a low prevalence rate, for patients with a history of previous significant allergies, it may be particularly advisable to carry out a metal allergy assessment and specific allergy tests before placing permanent implants of such material. Interpretation of results is subjective and consequently should probably only be undertaken by an allergist, dermatologist or other individuals well trained in the diagnostic process.

Currently there is no generally accepted test for the clinical determination of metal hypersensitivity to implant devices. Historically Type IV hypersensitivity reactions are tested invivo by patch testing and in vitro by lymphocyte transformation testing and leucocyte migration inhibition testing
 

Patch testing (2)

Patch testing is considered by many to be the “gold standard” for contact allergy testing although its use continues to be controversial because it may yield false negative or false positive results. For example a weak (macular erythematic) response to a particular metallic salt may represent an irritant effect rather than a true hypersensitivity reaction. At present it is not possible to predictably differentiate between these two outcomes. Several agencies have offered standardized guidelines for performing the test and the tester should be familiar with the guidelines and compliant with them.

Patch testing involves incorporating an antigen in a carrier and exposing this to dermal tissue by means of an affixed bandage for 48-96 hours. There are concerns about the applicability of skin testing to the study of immune responses to implants. One concern is the short length of the test because typical reactions to implants occur after weeks to months of constant exposure. There are also concerns that patch testing could possibly be affected by immunological intolerance or by impaired host immune response and testing could induce hypersensitivity in the patient.

Results from epicutaneous tests are acceptable as proof of sensitivity to a specific allergen (Bass et al. 1993). This is considered a standard procedure (Thomas 2000) and is widely used to assess type IV hypersensitivity reactions to titanium.
 

Lymphocyte transformation test(2)

LTT is a measure of the proliferative response of lymphocytes following activation. A radioactive marker is added to isolated lymphocytes along with the desired challenge agent. On the sixth day, radioisotope uptake is measured with use of liquid scintillation. The proliferation factor, or stimulation index, is calculated with use of measured radiation counts per minute (cpm):

Proliferation factor = mean cpm with treatment
                                    -----------------------------------------------
                                    Mean com without treatment

LTT is less popular than patch testing, but has been well established as a method for testing metal sensitivity in a variety of clinical settings.
 

Leucocyte migration inhibition2

LMI testing involves the measurement of mixed-population leucocyte migration activity. Leucocytes in cultural actively migrate in a random pattern, but they can be attracted preferentially to chemo-attractants. In the presence of a sensitizing antigen, leucocytes migrate more slowly, losing the ability to recognize chemo-attractants and are said to be migration inhibited. Migration testing may lack the sensitivity for detecting a DTH response at certain times over the course of a hypersensitivity reaction.
 

MELISA allergy blood test

MELISA is a blood test which measures cellular hypersensitivity (typeIV allergy) to metals and other low molecular allergens. MELISA has been validated by an independant laboratory and the results are published.

MELISA measures the patient’s lymphocyte reaction to allergens by two separate technologies. First by the uptake of radioisotope by dividing lymphocytes and second by classical evaluation by microscopy. The level of reactivity is measured as a stimulation index. A value over 3 indicates a positive reaction to a given allergen. Results are available within ten days.
 

DISCUSSIONS

Titanium and its alloys are used in dentistry for implants because of its unique combination of chemical, physical, and biological properties. They are used in dentistry in cast and wrought form. The titanium /titanium alloys are widely used as dental implants. In general, although they have exceptional properties which make them ideal for corrosion and wear resistance dental applications, failures of some implants are noted mainly due to unknown cause or due to hypersensitivity or due to the galvanic-type corrosion.

The long term presence of corrosion reaction products and ongoing corrosion lead to fractures of the alloy-abutment interface, abutment, or implant body. The combination of stress, corrosion, and bacteria contribute to implant failure. A spectrum of responses, varying from benign reactions to excessive inflammation and systemic hypersensitivity reactions are reported.

Focal areas of gingival hyperplasia surrounding the transmucosal portions of titanium implants have been attributed to poor hygiene, lack of attached gingival tissues, and titanium allergy. These reactions should be considered relative to the context of their application.

There can be of two chances for these atypical phenomenon to occur. First, while Ti generally appears to be biocompatible for most individuals, a certain subgroup of people seems to be capable of developing a clinically-relevant hypersensitivity to this metal. Sporadic reports supporting this concept have been published since the 1980s, most of which, however, have lacked laboratory evidence both pre- and post-implant removal 1, 3, 13, 17.

Recently, Thomas et al. demonstrated LTT reactivity to Ti in a patient suffering from impaired fracture healing and eczema following implantation of a Ti miniplate and screws; both clinical symptoms and LTT reactivity decreased after removal of the implant.

To explain this apparent sensitivity to Ti, several hypotheses have been proposed. Under unfavorable conditions (acidic pH, mechanical friction, close contact to amalgam or gold restorations, etc.), Ti implants may corrode and release ions or micro-particles which can induce inflammation in affected tissues 4, 8, 9, 11, 14.

This mechanism has been suggested to play a role in the loosening of implants 17. Furthermore, Ti, like other transition metals, has a high affinity to proteins; Ti bound cell membrane proteins (neo-antigens) may induce autoimmune reactions, whereas Ti-bound intra-cellular proteins may disrupt normal cell physiology 16. Finally, Ti has been reported to activate macrophages, either directly or subsequent to phagocytosis 14, 17. Such activated macrophages may secrete both pro- and anti-inflammatory cytokines, an imbalance of which has been implicated in various disease processes 2,5,10.

Alternatively, in those symptomatic Ti-exposed patients who did not show hypersensitivity (MELISA®reactivity) to Ti, the possibility of an immune reaction to contaminating metals must be considered.

As reported by Schuh et al. 21, Ti alloys may contain low levels of Ni which can induce or exacerbate allergic reactions.

As patch testing has been validated only for dermally-sensitizing antigens, its relevance for systemically-sensitizing antigens, such as Ti (mucosal) or Be (aerosol), will be limited. In analogy, the standardized and validated MELISA®Test, accredited in Germany since 2001, should be considered for patients with suspicion of Ti allergy.
 

CONCLUSIONS

Nonetheless,it appears reasonable to conclude that titanium allergy can be detected, albeit with a low prevalence (0.6%), in dental implant patients. Bearing this in mind, perhaps it should be considered as a clinical diagnostic process for suspected titanium allergy in patients intending to receive implants made from such material, with allergy tests performed on those patients at risk. There is scarce information on the frequency of substantiable clinical complications in patients with metallic implants and cutaneous reactivity to the same material.

Nevertheless, once the allergy has been diagnosed, the professional must then determine whether it is suitable to place a titanium implant in patients with a positive reaction to it, given the potential medical and legal complications that could derive from such a procedure.

Nowadays, the great biocompatibility of titanium has caused the emergence of techniques, which, in various fields of medicine, imply the permanent retention (Haug 1996) of implants in the body. This requires the assessment not only of the general biological suitability of the implant material (biocompatibility) but also of the individual, seeking out methods to identify any patients sensitized to its components, as well as alternative materials in allergic patients, such as tantalum, hydroxyapatite or zirconium.

In conclusion, the data presented here demonstrate that Ti can induce clinically-relevant hypersensitivity and other immune dysfunctions in certain patients chronically exposed to this reactive metal. Ti should no longer, therefore, be considered biologically inert and has to be further studied to come to conclusion whether it is a real worry or not.
 

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More References Are Available On Request

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