Titanium intolerance

Titanium is characterised by outstanding corrosion properties, meaning that compared to other metals it is well tolerated immunologically. However, it is known that for some patients implants induce adverse signs of inflammation that may lead to a lack of osseous integration, gingivitis and peri-implantitis.

True cellular type IV allergies to titanium are rare compared to other metals. The reason is that titanium ions have a high affinity for oxygen and so form oxides immediately after their release and, unlike free ions, these oxides cannot form protein bonds and thus allergenic (haptenic) effects cannot develop. The frequently heard statement that ‘there are no allergies to titanium’ is very likely correct from a strictly immunological perspective. However, allergies are not the only cause of immunologically related intolerances. The most common cause of individual hypersensitivity to titanium is excessive pro-inflammatory reactivity of the tissue macrophages.

Titanium particles in the tissue induce an inflammatory response.

Metal wear occurs on the surface of implanted titanium materials. Titanium oxide particles are almost always found in the bone and soft tissue surrounding an implant. The tissue macrophages (‘cleaning cells’) phagocytose these titanium oxide particles (particulate debris). It is a physiological response that macrophages react to contact with titanium oxide particles by releasing pro-inflammatory cytokines, in particular TNF-α and interleukin-1. What is highly individual, however, is the extent of this immune response. The intensity of the cytokine release depends on genetic variants (polymorphisms) for the pro-inflammatory (IL-1 and TNF-α) and anti-inflammatory (IL-1RN) mediators involved. Titanium intolerance is therefore usually a consequence of an increased disposition of the tissue macrophages to inflammation in response to titanium oxide particles. Titanium-specific lymphocytes do not play a role here, which explains the negative LTT and epicutaneous test results. 


The titanium stimulation test detects the cytokine response of tissue macrophages after contact with titanium oxide.

The titanium stimulation test was developed and comprehensively validated for this issue. This whole-blood stimulation test is used to examine whether the monocytes/macrophages of the patient react to contact with titanium particles with an increased inflammatory response. This is apparent in an increased release of the two key pro-inflammatory cytokines TNF-α and/or IL-1ß. For patients with positive results, delayed or impaired healing of titanium dental implants can be explained by the fact that the macrophages around the implant also have a hyperactive response to released titanium particles and primarily induce local, and in some cases systemic, inflammation.

With an increased genetic degree of inflammation, the risk of developing a titanium-associated inflammation also increases.

For functionally relevant polymorphisms in the genes for the cytokines IL-1, IL-1RN and TNF-α, a link with peri-implantitis or loss of implant has now been demonstrated in a number of studies. Approximately 15 to 20% of the population have a genetically determined response with an exceptionally vigorous inflammatory response. The polymorphisms in the genes for TNF-α, IL-1 and IL-1RN which are responsible have been identified in the laboratory.

This molecular genetic approach has the advantage that it is not affected by any existing inflammation or immunosuppressive therapies. Using the combination of polymorphisms, the genetic testing allows a patient to be assigned a degree of inflammation. The genetic degree of inflammation increases depending on the number of polymorphisms present from grade 0 (no polymorphisms present, normal inflammation susceptibility) to grade 4 (all four polymorphisms tested are present, significantly increased inflammation susceptibility). Patients with grade 3 and 4 are considered high responders and thus are at-risk patients for a titanium-associated dental inflammation or loss of implant.

The clinical relevance of these polymorphisms is also assured by the fact that patients with high responder polymorphisms have an increased susceptibility to developing peri-prosthetic bone loss. It is important to emphasise that the genetic polymorphisms are innate predisposition factors which, unlike an allergy, do not require initial contact before they can be detected in a laboratory test. Consequently, both the titanium stimulation test and the genetic analysis can be used preventively, that is, as part of the implantation planning.

The degree of inflammation and a positive titanium stimulation test are significant independent and thus additive risk factors.

One study which was initiated by the German Society for Environmental Dentistry (Deutsche Gesellschaft für Umwelt-ZahnMedizin, DEGUZ) confirmed the prognostic validity of both analyses (Jacobi-Gresser et al. 2012). Compared to the control group (patients whose implants had healed without any complications at least 5 years ago), patients with implant loss with no stress during healing and patients with implant loss after stress had a significantly higher in vitro release of TNF-α and IL-1β induced by titanium oxide in the titanium stimulation test (p < 0.0001). A positive titanium stimulation test is a risk factor independent of age, sex and smoking status and increases the risk of developing a titanium-associated inflammation or loss of implant twelvefold.

The number of risk polymorphisms and the resultant genetic degree of inflammation also had a significant impact on the implant loss (p* = 0.046). With an increasing genetic degree of inflammation, the risk of developing a titanium-associated dental inflammation or loss of implant increases sixfold.

Relative risk for loss of a titanium dental implant:
Negative titanium stimulation test    1.0
Positive titanium stimulation test    12.0
Genetic degree of inflammation  0    1.0
Genetic degree of inflammation  1    1.5
Genetic degree of inflammation  2    2.4
Genetic degree of inflammation  3    3.8
Genetic degree of inflammation  4    6.0

Comment: A patient with a positive titanium stimulation test has a 12-fold higher risk compared to the normal population. If he or she also has a genetic degree of inflammation of 4, the risk increases a further sixfold.

What does a positive result in the titanium stimulation test or an increased genetic degree of inflammation mean?

An abnormal result in one of the two tests indicates the presence of a significant predisposition to developing titanium-associated inflammation, which may be linked to primary or secondary implant loss. It is not the same as an allergy which requires that the allergen has to be avoided as a matter of course. A positive titanium stimulation test or a degree of inflammation of 2 to 4 is therefore not an absolute contraindication for a titanium implant.

However, in these cases alternatives (e.g. ceramic implants, removable bridgework, coated titanium implants) should be critically evaluated and prophylactic measures should be ramped up (prophylaxis, use of reduced rotational speeds, avoiding periodontal probes made of titanium, no immediate implants, removal of the sources of infection, smoking cessation, optimal adjustment of other predisposing diseases (diabetes mellitus), no multiple implants, avoiding any immunostimulation for up to 4 weeks after implantation). The circumstances may require immunosuppressive measures at the time the implant is inserted.

Sample materials required

Titanium stimulation test: 10 mL heparin blood. The heparin Monovettes from the LTT collection set can be used. We are also happy to send you individual collection tubes. The laboratory must receive the samples within 24 hours of collection. The blood should be stored and transported at room temperature. 

Genetic inflammation susceptibility: 2 mL EDTA blood or 2 buccal swabs. For the genetic test we require a declaration of consent of the patient. Transport to the laboratory is not time critical and can be done by post.

Should the LTT also be done prior to an implantation or in cases of suspected titanium intolerance?

Type IV sensitisations to titanium are, as mentioned earlier, extremely rare, which is due to the strong tendency of titanium to oxidise. Thus the LTT is far less important for dental issues compared to the titanium stimulation test.
In terms of type IV sensitisations, contaminating metals are certainly of greater relevance. Traces of nickel, vanadium or aluminium can be released from older models of titanium implant. For this reason, an LTT screening profile was developed to supplement the titanium stimulation test in which these three metals are tested in addition to titanium.

Sample materials required

LTT Titanium/Aluminium/Nickel/Vanadium: 20 mL heparin blood and 5 mL whole blood (use the LTT collection sets!). The laboratory must receive the samples within 24 hours of collection. The blood should be stored and transported at room temperature.