A retrospective study on titanium sensitivity: Patch test materials and manifestations

Background: Titanium is being increasingly used. Although it is considered to be a non-allergenic material, allergic reactions to it have been reported. Titanium dioxide has been found to be an unreliable patch test material. Few studies to date have profiled titanium allergy, and it therefore remains difficult to distinguish its manifestations. Objectives: To evaluate alternatives for titanium dioxide as a patch test preparation, and to profile titanium reactions and manifestations. Methods: A retrospective chart review was conducted with 458 patients who underwent patch testing with at least 1 of 5 different titanium salts. Results: At least 1 positive result was noted in 5.7% of the patients. The frequency of positive results for the tested salts ranged from 0.9% to 7.9%. Titanium(IV) oxalate hydrate had the highest yield and titanium dioxide the lowest. Erythema, dermatitis and local swelling were the most common objective complaints. In 16 (61.5%) patients, the test result had partial or full clinical relevance. Conclusions: No titanium-specific risk factors and clinical picture could be identified. Titanium dioxide is not adequately sensitive for identifying titanium allergy. The titanium salts seem to be possible superior patch test preparations, but appear to be unsuitable if used singly. The patient's medical history and clinical picture remain crucial in the diagnostic work-up

Nickel allergy is associated with a broad spectrum cytokine response

BACKGROUND: Nickel-induced proliferation or cytokine release by peripheral blood mononuclear cells may be used for in vitro diagnosis of nickel allergy. OBJECTIVES: Aim of this study was to explore the nickel-specific cytokine profile to further elucidate the pathogenesis of nickel allergic contact dermatitis (ACD) and to identify potential new biomarkers for nickel ACD. METHODS: Peripheral blood mononuclear cells from patients and controls were cultured with T-cell skewing cytokine cocktails and/or nickel. Cytokine and chemokine concentrations were assessed in culture supernatants using validated multiplex assays. Specific cytokine production was related to history of nickel allergy and patch-test results. RESULTS: Twenty-one of the 33 analytes included in the analysis were associated with nickel allergy and included type1 (TNF-α, IFN-γ, TNF-β), type 2 (IL-3, IL-4, IL-5, IL-13), type 1/2 (IL-2, IL-10), type 9 (IL-9), type 17/1 (IL-17A[F], GM-CSF, IL-21) and type 22 (IL-22) derived cytokines as well as the T-cell/antigen presentation cell derived factors Thymus and activation regulated chemokine (TARC), IL-27 and IP-10. Receiver operator characteristics (ROC) analysis showed that IL-5 was the strongest biomarker for nickel allergy. CONCLUSIONS: A broad spectrum of 33 cytokines and chemokines is involved in the allergen-specific immune response in nickel allergic patients. IL-5 remains, next to the lymphocyte proliferation test, the strongest biomarker for nickel allergy

Nickel allergy is associated with a broad spectrum cytokine response

Background: Nickel-induced proliferation or cytokine release by peripheral blood mononuclear cells may be used for in vitro diagnosis of nickel allergy. Objectives: Aim of this study was to explore the nickel-specific cytokine profile to further elucidate the pathogenesis of nickel allergic contact dermatitis (ACD) and to identify potential new biomarkers for nickel ACD. Methods: Peripheral blood mononuclear cells from patients and controls were cultured with T-cell skewing cytokine cocktails and/or nickel. Cytokine and chemokine concentrations were assessed in culture supernatants using validated multiplex assays. Specific cytokine production was related to history of nickel allergy and patch-test results. Results: Twenty-one of the 33 analytes included in the analysis were associated with nickel allergy and included type1 (TNF-α, IFN-γ, TNF-β), type 2 (IL-3, IL-4, IL-5, IL-13), type 1/2 (IL-2, IL-10), type 9 (IL-9), type 17/1 (IL-17A[F], GM-CSF, IL-21) and type 22 (IL-22) derived cytokines as well as the T-cell/antigen presentation cell derived factors Thymus and activation regulated chemokine (TARC), IL-27 and IP-10. Receiver operator characteristics (ROC) analysis showed that IL-5 was the strongest biomarker for nickel allergy. Conclusions: A broad spectrum of 33 cytokines and chemokines is involved in the allergen-specific immune response in nickel allergic patients. IL-5 remains, next to the lymphocyte proliferation test, the strongest biomarker for nickel allergy

Titanium salts tested in reconstructed human skin with integrated MUTZ-3-derived Langerhans cells show an irritant rather than a sensitizing potential

Background: The nature of clinically related adverse reactions to titanium is still unknown. Objective: To determine whether titanium salts have irritant or sensitizing potential in a reconstructed human skin (RHS) model with integrated Langerhans cells (LCs). Methods: RHS-LCs (ie, reconstructed epidermis) containing primary differentiated keratinocytes and CFSE+CD1a+-LCs generated from the MUTZ-3 cell line on a primary fibroblast-populated collagen hydrogel (dermis) were topically exposed to titanium(IV) bis(ammonium lactato)dihydroxide (TiALH). LC migration and plasticity were determined. Results: TiALH resulted in CFSE+CD1a+-LC migration out of the epidermis. Neutralizing antibodies to CCL5 and CXCL12 showed that LC migration was CCL5 and not CXCL12 mediated. LCs accumulating within the dermis after TiALH exposure were CFSE+Lang+CD68+ which is characteristic of a phenotypic switch of MUTZ-LC to a macrophage-like cell. Furthermore, TiALH did not result in increased interleukin (IL)-1β or CCR7 messenger RNA (mRNA) in the dermis, but did result in increased IL-10 mRNA. In addition, monocultures of MUTZ-LCs failed to increase LC maturation biomarkers CD83, CD86, and CXCL-8 when exposed to noncytotoxic concentrations of four different titanium salts. Conclusion: These results classify titanium salts as irritants rather than sensitizers and indicate that titanium implant-related complaints could be due to localized irritant-mediated inflammation arising from leachable agents rather than a titanium metal allergy

Anti-erosive effects of fluoride and phytosphingosine: an in vitro study

A selection of commercially available products containing stannous fluoride (SnF2)/sodium fluoride (NaF), SnF2/amorphous calcium phosphate (ACP), SnF2/NaF/ACP, tin (Sn)/fluorine (F)/chitosan were compared with phytosphingosine (PHS) with respect to their anti-erosive properties in vitro. One-hundred and twenty bovine enamel specimens were immersed in the respective product slurries for 2 min, twice daily. The formulations were diluted with either remineralization solution or artificial saliva. After each treatment, an erosive challenge was performed for 10 min, twice daily, using citric acid, pH 3.4. The specimens were stored in remineralization solution or artificial saliva until the next treatment-erosion challenge. After 10 d, tissue loss was determined using profilometry. Enamel softening was determined through surface microhardness measurements. Tissue-loss values (measured in μm and expressed as mean ± SD) for PHS, SnF2/NaF, SnF2/ACP, SnF2/ACP/NaF, and Sn/F/chitosan treatment groups and for the negative-control group, were, respectively, 35.6 ± 2.8, 15.8 ± 1.8, 22.1 ± 2.0, 22.9 ± 1.8, 16.2 ± 1.2, and 51.2 ± 4.4 in the presence of remineralization solution and 31.7 ± 3.3, 15.6 ± 2.9, 16.5 ± 2.7, 16.8 ± 2.1, 13.1 ± 3.0, and 50.7 ± 2.8 in the presence of artificial saliva. There were no significant differences in surface microhardness measurements between the treatment groups. In conclusion, PHS resulted in a significant reduction of tissue loss compared with the negative control, but in comparison, the toothpastes containing Sn2+ and F− ions were significantly more effective compared with PHS

Patch test–relevant concentrations of metal salts cause localized cytotoxicity, including apoptosis, in skin ex vivo

Background: Metal alloys containing contact sensitizers (nickel, palladium, titanium) are extensively used in medical devices, in particular dentistry and orthopaedic surgery. The skin patch test is used to test for metal allergy. Objective: To determine whether metal salts, when applied to freshly excised skin at patch test–relevant concentrations and using a method which mimics skin patch testing, cause in changes in the epidermis and dermis. Methods: Tissue histology, apoptosis, metabolic activity, and inflammatory cytokine release were determined for two nickel salts, two palladium salts, and four titanium salts. Results: Patch test–relevant concentrations of all metal salts caused localized cytotoxicity. This was observed as epidermis separation at the basement membrane zone, formation of vacuoles, apoptotic nuclei, decreased metabolic activity, and (pro)inflammatory cytokine release. Nickel(II) sulfate hexahydrate, nickel(II) chloride hexahydrate, titanium(IV) bis(ammonium lactato)dihydroxide, and calcium titanate were highly cytotoxic. Palladium(II) chloride, sodium tetrachloropalladate(II), titanium(IV) isopropoxide, and titanium(IV) dioxide showed mild cytotoxicity. Conclusion: The patch test in itself may be damaging to the skin of the patient being tested. These results need further verification with biopsies obtained during clinical patch testing. The future challenge is to remain above the elicitation threshold at noncytotoxic metal concentrations

Titanium salts tested in reconstructed human skin with integrated MUTZ

Background: The nature of clinically related adverse reactions to titanium is still unknown. Objective: To determine whether titanium salts have irritant or sensitizing potential in a reconstructed human skin (RHS) model with integrated Langerhans cells (LCs). Methods: RHS-LCs (ie, reconstructed epidermis) containing primary differentiated keratinocytes and CFSE+CD1a+-LCs generated from the MUTZ-3 cell line on a primary fibroblast-populated collagen hydrogel (dermis) were topically exposed to titanium(IV) bis(ammonium lactato)dihydroxide (TiALH). LC migration and plasticity were determined. Results: TiALH resulted in CFSE+CD1a+-LC migration out of the epidermis. Neutralizing antibodies to CCL5 and CXCL12 showed that LC migration was CCL5 and not CXCL12 mediated. LCs accumulating within the dermis after TiALH exposure were CFSE+Lang+CD68+ which is characteristic of a phenotypic switch of MUTZ-LC to a macrophage-like cell. Furthermore, TiALH did not result in increased interleukin (IL)-1β or CCR7 messenger RNA (mRNA) in the dermis, but did result in increased IL-10 mRNA. In addition, monocultures of MUTZ-LCs failed to increase LC maturation biomarkers CD83, CD86, and CXCL-8 when exposed to noncytotoxic concentrations of four different titanium salts. Conclusion: These results classify titanium salts as irritants rather than sensitizers and indicate that titanium implant-related complaints could be due to localized irritant-mediated inflammation arising from leachable agents rather than a titanium metal allergy