head JofIMAB
Journal of IMAB - Annual Proceeding (Scientific Papers)
Publisher: Peytchinski Publishing
ISSN: 1312-773X (Online)
Issue: 2017, vol. 23, issue 2
Subject Area: Medicine
DOI: 10.5272/jimab.2017232.1550
Published online: 23 May 2017

Review Article

J of IMAB 2017 Apr-Jun;23(2):1550-1559
Maya Lyapina1ORCID logoCorresponding Autoremail, Mariana Cekova2, Mariela Deliverska3, Jordan Galabov2, Angelina Kisselova2ORCID logo,
1) Department Hygiene, Medical Ecology and Nutrition, Medical Faculty, Medical University - Sofia,
2) Department Oral and Image Diagnostic, Faculty of Dental Medicine, Medical University - Sofia,
3) Department Medical Ethics and Law, Faculty of Public Health, Medical University - Sofia, Bulgaria.

Titanium (Ti) is a non-essential metal element. TiO2 is used predominantly in the form of micro and nanoparticles in consumer products, including cosmetics and food. Because of its excellent biocompatibility, the trade-pure titan and its alloys are widely used as an alternative of certain metals in invasive medicine, surgery, dental medicine. Contemporary data concerning the sources of exposure to titanium, immune reactions to Ti alloys, current knowledge and perspectives of diagnosis of sensitization or allergic reactions to titanium are discussed.
Conclusion: TiO2 is much more stable than pure Ti and alloys used in the implants, that should be taken into account when conducting research and analyzing the results. The evidences of possible toxic effects are insufficient. It is difficult to assess the frequency of Ti allergy due to the uncertainty of diagnostic methods, but it is believed that it is very low. This is supported by the evidence that Ti and TiO2 (often as NP) doesn’t penetrate through healthy skin. Skin patch testing with currently available formulations of Ti and TiO2 has no significant value in clinical practice, and currently it is assumed that there is no reliable method for diagnosis Ti allergy. The functional analysis of cytokine release and investigation of genetic characteristics could be useful for individual risk assessment in dental implantology. Such studies may also help to investigate separately early and late implant loss, as well as to develop new diagnostic tools.

Keywords: titanium, dental implants, biocompatibility, allergic response, cytokines,

pdf - Download FULL TEXT /PDF 528 KB/
Please cite this article in PubMed Style or AMA (American Medical Association) Style:
Lyapina M, Cekova M, Deliverska M, Galabov J, Kisselova A. Immunotoxicological aspects of biocompatibility of titanium. J of IMAB. 2017 Jan-Mar;23(2):1550-1559.
DOI: 10.5272/jimab.2017232.1550

Corresponding AutorCorrespondence to: Maya Lyapina, MD; Department of Hygiene, Medical Ecology and Nutrition, Medical Faculty, Medical University, Sofia; 15, Acad. Ivan Evstr. Geshov Blvd., 1431 Sofia, Bulgaria; E-mail: saly_grigory@abv.bg

1. Brown D. All you wanted to know about titanium, but were afraid to ask. Br Dent J. 1997 May 24;182(10):393-94. [PubMed]
2. van Noort R. 3.3. Casting alloys for metallic restorations. In: Introduction to dental materials. (2nd ed). Mosby, Edinburgh, 2002. pp.221-230. [Internet]
3. Maia A. Titânio. Balanço Mineral Brasileiro. 2001;1:1–23.
4. Williams F. Titanium for Medical Applications. In: Titanium in Medicine. Material Science, Surface Science, Engineering, Biological Responses and Medical Applications. Brunette DM, Tengvall P, Textor M, Thomsen P. (Eds.). Springer-Verlag Berlin Heidelberg. 2001. Chapter 2:p.13-24. [CrossRef
5. Niinomi M. Mechanical biocompatibilities of titanium alloys for biomedical applications. J Mech Behav Biomed Mater. 2008 Jan;1(1):30-42. [PubMed] [CrossRef]
6. Parr GR, Gardner LK, Toth RW. Titanium: the mystery metal of implant dentistry. Dental materials aspects. J Prosthet Dent. 1985 Sep;54(3):410-4. [PubMed] [CrossRef]
7. Williams DF. Implants in dental and maxillofacial surgery. Biomaterials. 1981 Jul;2(3):133-46. [PubMed]
8. Andreiotelli M, Koutayas SO, Madianos PN, Strub JR. Relationship between interleukin-1 genotype and peri-implantitis: a literature review. Quintessence Int. 2008 Apr;39(4):289-98. [PubMed]
9. Steinemann S. Titanium--the material of choice. Periodontol 2000. 1998 Jun;17:7-21. [PubMed] [CrossRef]
10. Kasemo B. Biocompatibility of titanium implants: surface science aspects. J Prosthet Dent. 1983 Jun;49(6):832-37. [PubMed]
11. Kaus T, Probster L, Weber H. Clinical follow-up study of ceramic veneered titanium restorations -- three-year results. Int J Prosthodont. 1996; 9:9-15.
12. Strietzel R, Hosch A, Kalbfleisch H, Buch D. In vitro corrosion of titanium. Biomaterials 1998 Aug;19(16):1495-1499. [PubMed] [CrossRef]
13. ADA Council on Scientific Affairs. Titanium applications in dentistry. J Am Dent Assoc. 2003 Mar;134(3):347-49. [PubMed] [CrossRef]
14. Keegan GM, Learmonth ID, Case CP. Orthopaedic metals and their potential toxicity in the arthroplasty patient: a review of current knowledge and future strategies. J Bone Joint Surg Br. 2007 May;89(5):567-73. [PubMed] [CrossRef]
15. Elias C, Lima J, Valiev R, Meyers M. Biomedical applications of titanium and its alloys. J Miner Met Mater Soc. 2008; 60:46-9.
16. Harloff T, Hönle W, Holzwarth U, Rainer Bader R, Thomas P, Schuh A. Titanium allergy or not?‘Impurity of titanium implant materials. Health. 2010; 2(4):306-10. [CrossRef]
17. Hamann D, Thyssen JP, Hamann CR, Hamann C, Menné T, Johansen JD, et al. Jewellery: alloy composition and release of nickel, cobalt and lead assessed with the EU synthetic sweat method. Contact Dermatitis. 2015 Oct;73(4):231-38. [PubMed] [CrossRef]
18. Park YH, Jeong SH, Yi SM, Choi BH, Kim YR, Kim IK, et al. Analysis for the potential of polystyrene and TiO2 nanoparticles to induce skin irritation, phototoxicity, and sensitization. Toxicol In Vitro. 2011 Dec;25(8):1863-69. [PubMed]
19. Robichaud CO, Uyar AE, Darby MR, Zucker LG, Wiesner MR. Estimates of upper bounds and trends in nano-TiO2 production as a basis for exposure assessment. Environ Sci Technol. 2009 Jun 15:43(12):4227-33. [PubMed]
20. Yang Y, Westerhoff P. Presence in, and release of, nanomaterials from consumer products. Adv Exp Med Biol. 2014; 811:1-17. [PubMed] [CrossRef]
21. Weir A,Westerhoff P, Fabricius L, Hristovski K, von Goetz N. Titanium dioxide nanoparticles in food and personal care products. Environ Sci Technol. 2012 Feb 21;46(4):2242-50. [PubMed] [CrossRef]
22. Newman MD, Stotland M, Ellis JI. The safety of nanosized particles in titanium dioxide- and zinc oxide-based sunscreens. J Am Acad Dermatol. 2009 Oct;61(4):685-92. [PubMed] [CrossRef]
23. Lomer MC, Thompson RP, Commisso J, Keen CL, Powell JJ. Determination of titanium dioxide in foods using inductively coupled plasma optical emission spectrometry. Analyst. 2000 Dec;125(12):2339-43. [PubMed]
24. Squier CA. The permeability of oral mucosa. Crit Rev Oral BiolMed. 1991; 2(1):13-32. [PubMed]
25. Wertz PW, Cox PS, Squier CA, Downing DT. Lipids of epidermis and keratinized and non-keratinized oral epithelia. Comp Biochem Physiol B. 1986; 83:529-31.
26. Galey WR, Lonsdale HK, Nacht S. The in vitro permeability of skin and buccal mucosa to selected drugs and tritiated water. J Invest Dermatol. 1976 Dec;67(6):713-17. [PubMed]
27. Teubl BJ, Leitinger G, Schneider M, Lehr CM, Fröhlich E, Zimmer A, et al. The buccal mucosa as a route for TiO2 nanoparticle uptake. Nanotoxicology. 2015 Mar;9(2):253-61. [PubMed] [CrossRef]
28. Bosshardt DD, Lang NP. The junctional epithelium: from health to disease. J Dent Res. 2005 Jan;84(1):9-20. [PubMed] [CrossRef]
29. Fine DH, Pechersky JL, McKibben DH. The penetration of human gingival sulcular tissue by carbon particles. Arch Oral Biol. 1969; 14:1117-19.
30. Tolo KJ. A study of permeability of gingival pocket epithelium to albumin in guinea pigs and Norwegian pigs. Arch Oral Biol. 1971 Aug;16(8):881-88. [PubMed]
31. Roblegg E, Frohlich E, Meindl C, Teubl B, Zaversky M, Zimmer A. Evaluation of a physiological in vitro system to study the transport of nanoparticles through the buccal mucosa. Nanotoxicology. 2012 Jun;6(4):399-413. [PubMed] [CrossRef]
32. Teubl BJ, Schimpel C, Leitinger G, Bauer B, Fröhlich E, Zimmer A, et al. Interactions between nano-TiO2 and the oral cavity: impact of nanomaterial surface hydrophilicity/hydrophobicity. J Hazard Mater. 2015 Apr 9;286:298-305. [PubMed] [CrossRef]
33. Akagawa Y, Abe Y. Titanium: The ultimate solution or an evolutionary step? Int J Prosthodont. 2003; 16 Suppl:28-9; discussion 47-51. [PubMed]
34. Brunski JB, Puleo DA, Nanci A. Biomaterials and biomechanics of oral and maxillofacial implants: Current status and future developments. Int J Oral Maxillofac Implants. 2000 Jan-Feb;15(1):15-46. [PubMed]
35. Bass JK, Fine H, Cisneros GJ. Nickel hypersensitivity in the orthodontic patient. Am J Orthod Dentofacial Orthop. 1993; 103(3):280-85.
36. Barao VA, Mathew MT, Assuncao WG, Yuan JC, Wimmer MA, Sukotjo C. The role of lipopolysaccharide on the electrochemical behavior of titanium. J Dent Res. 2011 May;90(5):613-18. [PubMed] [CrossRef]
37. Barao VA, Mathew MT, Yuan JC, Knoernschild KL, Assunção WG, ;Wimmer MA, et al. Influence of corrosion on lipopolysaccharide affinity for two different titanium materials. J Prosthet Dent. 2013 Dec;110(6): 462-70. [PubMed]
38. Koike M, Fujii H. The corrosion resistance of pure titanium in organic acids. Biomaterials. 2001 Nov;22(21):2931-36. [PubMed] [CrossRef]
39. Nakagawa M, Matsuya S, Udoh K. Effects of fluoride and dissolved oxygen concentrations on the corrosion behavior of pure titanium and titanium alloys. Dent Mater J. 2002 Jun;21(2):83–92. [PubMed] [CrossRef]
40. Noguti J, de Oliveira F, Peres RC, Renno AC, Ribeiro DA.. The role of fluoride on the process of titanium corrosion in oral cavity. Biometals. 2012 Oct;25(5):859-62. [PubMed] [CrossRef]
41. Molina C, Nogues L, Martinez-Gomis J, Peraire M, Salsench J, Sevilla P, et al. Dental casting alloys behaviour during power toothbrushing with toothpastes of various abrasivities. Part II: corrosion and ion release. J Mater Sci MaterMed. 2008 Sep;19(9):3015-19. [PubMed] [CrossRef]
42. Faverani LP, Barao VA, Ramalho-Ferreira G, Ferreira MB, Garcia-Junior IR, Assunção  WG. Effect of bleaching agents and soft drink on titanium surface topography. J Biomed Mater Res B Appl Biomater. 2014 Jan;102(1):22-30. [PubMed] [CrossRef]
43. Lindholm-Sethson B, Ardlin BI. Effects of pH and fluoride concentration on the corrosion of titanium. J Biomed Mater Res. 2008 Jul;86(1):149-59. [PubMed] [CrossRef]
44. Nakagawa M, Matsuya S, Udoh K. Corrosion behavior of pure titanium and titanium alloys in fluoride-containing solutions. Dent Mater J. 2001 Dec;20(4):305-14. [PubMed] [CrossRef]
45. Bilhan H, Bural C, Geckili O. Titanium hypersensitivity. A hidden threat for dental implant patients? N Y State Dent J. 2013 Jun-Jul;79(4):38-43. [PubMed]
46. Novak N, Gros E, Bieber T, Allam JP. Human skin and oral mucosal dendritic cells as ‘good guys’ and ‘bad guys’ in allergic immune responses. Clin Exp Immunol. 2010 Jul;161(1):28-33. [CrossRef]
47. Fors R, Stenberg B, Stenlund H, Persson M. Nickel allergy in relation to piercing and orthodontic appliances – a population study. Contact Dermatitis. 2012 Dec;67(6):342-50. [CrossRef]
48. van Hoogstraten IM, Andersen KE, von Blomberg BM. Reduced frequency of nickel allergy upon oral nickel contact at an early age. Clin Exp Immunol. 1991; 85:441-45.
49. Haug RH. Retention of asymptomatic bone plates used for orthognathic surgery and facial fractures. J Oral Maxillofac Surg. 1996 May;54(5):611-7. [PubMed] [CrossRef]
50. Matthew I, Frame JW. Allergic responses to titanium. J Oral Maxillofac Surg. 1998 Dec;56(12):1466-67. [PubMed] [CrossRef]
51. Torgersen S, Gjerdet N, Erichsen E, Bang G. Metal particles and tissue changes adjacent to miniplates: A retrieval study. Acta Odontol Scand. 1995 Apr;53(2):65-71. [PubMed]
52. Ikarashi Y, Momma J, Tsuchiya T, Nakamura A. Evaluation of skin sensitization potential of nickel, chromium, titanium and zirconium salts using guinea-pigs and mice. Biomaterials. 1996 Nov;17(21):2103-8. [PubMed] [CrossRef]
53. Thierse HJ, Gamerdinger K, Junkes C. T cell receptor (TCR) interaction with haptens: metal ions as non-classical haptens. Toxicology. 2005; 209:101–107.
54. Nakashima Y, Sun DH, Trindade MC. Induction of macrophage C-C chemokine expression by titanium alloy and bone cement particles. J Bone Joint Surg Br. 1999; 81:155–162.
55. Nakashima Y, Sun DH, Trindade MC, Maloney WJ, Goodman SB, Schurman DJ, et al. Signaling pathways for tumor necrosis factor-alpha and interleukin-6 expression in human macrophages exposed to titaniumalloy particulate debris in vitro. J Bone Joint Surg Am. 1999; 81(5):603-15.
56. Lalor PA, Revell PA, Gray AB. Sensitivity to titanium. A cause of implant failure? J Bone Joint Surg Br. 1991;73:25-28.
57. Flatebш RS, Johannessen AC, Grшnningsaeter AG. Host response to titanium dental implant placement evaluated in a human oral model. J Perio­dontol. 2006;77:1201-1210.
58. Wang JY,Wicklund BH, Gustilo RB, Tsukayama DT. Prosthetic metals impair murine immune response and cytokine release in vivo and in vitro. J Orthop Res. 1997;15:688-699.
59. Kaufman AM, Alabre CI, Rubash HE, Shanbhag AS. Human macrophage response to UHMWPE, TiAlV, CoCr, and alumina particles: analysis of multiple cytokines using protein arrays. J Biomed Mater Res A. 2008;84(2):464-74.
60. SternerT, Schutze N, Saxler G, Jakob F, Rader CP. Effects of clinically relevant alumina ceramic, zirconia ceramic and titanium particles of different sizes and concentrations on TNF-alpha release in a human macrophage cell line. Biomed Tech. 2004; 49(12): 340-4.
61. Perala DG, Chapman RJ, Gelfand JA, Callahan MV, Adams DF, Lie T. Relative production of IL1B and TNF-a by mononuclear cells after exposure to dental implants. J Periodontol. 1992; 63(5):426-30.
62. Montes CC, Pereira FA, Thomeґ G, Alves ED, Acedo RV, de Souza JR, et al. Failing factors associatedwith osseointegrated dental implant loss. Implant Dent. 2007;16(4):404-12.
63. Laine ML, Leonhardt A, Roos-Jansaker AM, Pena AS, Winkelhoff VAJ, Winkel EG, et al. IL1RN gene polymorphism is associated with peri-im­plan­titis. Clin Oral Implants Res. 2006; 17(4):380-5.
64. Jansson H, Hamberg K, De Bruyn H, Bratthall G. Clinical consequences of IL-1 genotype on early implant failures in patients under periodontal maintenance. Clin Implant Dent Relat Res. 2005;7(1):51-9.
65. Montes CC, Alvim-Pereira F, de Castilhos BB, Sakurai ML, Olandoski M, Trevilatto PC. Analysis of the association of IL1B (C + 3954 T) and IL1RN (intron 2) polymorphisms with dental implant loss in a Brazilian population. Clin Oral Implants Res. 2009; 20(2):208-17.
66. Shimpuku H, Nosaka Y, Kawamura T, Tachi Y, Shinohara M, Ohura K. Genetic polymorphisms of the interleukin-1 gene and early marginal bone loss around endosseous dental implants. Clin Oral Implants Res. 2003;14(4):423–9.
67. Assuma R, Oates T, Cochran D, Amar S, Graves DT. IL-1 and TNF antagonists inhibit the inflammatory response and bone loss in experimental periodontitis. J Immunol. 1998; 160(1): 403-9.
68. Campos MI, Santos MC, Trevilatto PC, Scarel-Caminaga RM, Bezerra FJ, Line SR. Evaluation of the relationship between interleukin-I gene cluster polymorphisms and early implant failure in non-smoking patients. Clin Oral Implants Res. 2005; 16(2): 194-201.
69. el Askary AS, Meffert RM, Griffin T. Why do dental implants fail? Part I. Implant Dent. 1999;8(2):173-85.
70. Alvim-Pereira F, Montes CC, Mira MT, Trevilatto PC. Genetic susceptibility to dental implant failure. A critical review. Int J Oral Maxillofac Implants. 2008; 23(3):409-16.
71. Dцrner T, Haas J, Loddenkemper C, von Baehr V, Salama A. Implant-related inflammatory arthritis. Nat Clin Pract Rheumatol. 2006; 2(1):53-6.
72. Baumann B, Rolf O, Jakob F, Goebel S, Sterner T, Eulert J, et al. Synergistic effects of mixed TiAlV and polyethylene wear particles on TNF alpha response in THP-1 macro­phages. Biomed Tech. 2006; 51(5-6):360-6.
73. Boyce BF, Xing L. Biology of RANK, RANKL, and osteoprotegerin. Arthritis Res Ther. 2007; 9(Suppl. 1):S1.
74. Birkedal-Hansen H. Role of cytokines and inflammatory mediators in tissue destruction. J Periodontal Res. 1993; 28:500-10.
75. Danesh-Meyer MJ. Dental Implants. Part I. Biological basis, implant types, and the periimplant sulcus. J N Z Soc Periodontol. 1994; 77:15-22.
76. Kronstrom M, Svenson B, Hellman M, Persson GR. Early implant failures in patients treated with Brane­mark System titanium dental implants: a retrospective study. Int J Oral Maxi­llofac Implants. 2001; 16(2):201-7.
77. Esposito M, Hirsch JM, Lekholm U, Thomsen P. Biological factors contributing to failures of osseointegrated oral implants. (I). Success criteria and epidemiology. Eur J Oral Sci. 1998;106(1):527–51.
78. Jacobi-Gresser E., Huesker K., Schutt S. Genetic and immunological markers predict titanium implant failure: a retrospective study. Int. J. Oral Maxillofac. Surg. 2013;42:537–543.
79. Hallab N, Jacobs JJ, Black J. Hypersensitivity to metallic biomaterials: a review of leukocytemigration inhibition assays. Biomaterials. 2000; 21:1301-14.
80. Hallab N, Merritt K, Jacobs JJ. Metal sensitivity in patients with orthopaedic implants. J Bone Joint Surg Am. 2001; 83-A:428-36.
81. Bernard S, Baeck M, Tennstedt D. Chromate or titanium allergy – the role of impurities? Contact Dermatitis. 2013; 68:191-92.
82. Forte G, Petrucci F, Bocca B. Metal allergens of growing significance: Epidemiology, immunotoxico­logy, strategies for testing and prevention. Inflamm Allergy. 2008; 7:1-18.
83. Okamura T, Morimoto M, Fukushima D, Yamane G. A skin patch test for the diagnosis of titanium allergy. J Dent Res. 1999; 78:1135.
84. Evenness KM, Gawkrodger DJ, Botham PA, Hunter JA. The discrimination between nickel-sensitive and non-nickel-sensitive subjects by an in vitro lymphocyte transformation test. Br J Dermatol. 1990; 122:293-98.
85. Summer B, Sander CA, Przybilla B, Thomas P. Molecular analysis of T-cell clonality with concomitant specific T-cell proliferation in vitro in nickel-allergic individuals. Allergy. 2001; 56:767-70.
86. Thomas P, Bandl WD, Maier S. Hypersensitivity to titanium osteosynthesis with impaired fracture healing, eczema, and T-cell hyperresponsiveness in vitro: case report and review of the literature. Contact Dermatitis. 2006; 55:199-202.
87. Hallab NJ, Mikecz K, Jacobs JJ. A triple assay technique for the evaluation of metal-induced, delayed-type hypersensitivity responses in patients with or receiving total joint arthroplasty. J Biomed Mater Res. 2000; 53:480-89.
88. Merritt K, Rodrigo JJ. Immune response to synthetic materials. Sensiti­zation of patients receiving orthopaedic implants. Clin Orthop Relat Res. 1996; 326:71–79.
89.    Valentine-Thon E, Schiwara HW. Validity of MELISA for metal sensitivity testing. Neuro Endocrinol Lett. 2003; 24:57-64.
90. Granchi D, Ciapetti G, Savarino L. Expression of the CD69 activation antigen on lymphocytes of patients with hip prosthesis. Biomaterials. 2000; 21:2059-65.
91. Granchi D, Cenni E, Trisolino G. Sensitivity to implant materials in patients undergoing total hip replacement. J Biomed Mater Res B Appl Biomater. 2006;77:257-64.
92. Muller K, Valentine-Thon E. Hypersensitivity to titanium: clinical and laboratory evidence. Neuro Endocrinol Lett. 2006; 27(Suppl. 1):31-35.
93. Larsen J, Bonefeld C, Poulsen S, Geisler C. IL-23 and IL-17-mediated inflammation in human allergic contact dermatitis. J Allergy Clin Immunol. 2009; 123:486-42.
94. Oboki K, Ohno T, Saito H, Nakae S. Th17 and allergy. Allergol Int. 2008; 57:121-34.
95. Zhao Y, Balato A, Fishelevich R, Chapoval A, Mann D, Gaspari A. Th17/Tc17 infiltration and associated cyto­kine gene expression in elicitation phase of allergic contact dermatitis. Br J Dermatol. 2009; 161:1301-6.
96. Ricciardi L, Minciullo P, Saitta P, Trombetta D, Saija A, Gangemi S. Increased serum levels of IL-22 in patients with nickel contact dermatitis. Contact Dermatitis. 2009; 60:57-8.
97. Thyssen J P, Menne T, Schalock P C. Pragmatic approach to the clinical work-up of patients with putative allergic disease to metallic orthopaedic implants before and after surgery. Br J Dermatol. 2011; 164:473-78.
98. Matthew IR, Frame JW. Ultrastructural analysis of metal particles released from stainless steel and titanium miniplate components in an animal model. J Oral Maxillofac Surg. 1998; 56:45-50.
99. Thomas P, Thomas M, Summer B. Impaired wound-healing, local eczema, and chronic inflammation following titanium osteosynthesis in a nickel and cobalt-allergic patient: a case report and review of the literature. J Bone Joint Surg Am. 2011; 93:e61.
100. Coulter I, Lee M, Zakaria R, Barrett C. Pin site allergic contact dermatitis: an unusual complication of halo fixation. Br J Neurosurg. 2012; 26:566-67.
101. Chaturvedi T. Allergy related to dental implant and its clinical significance. Clin Cosmet Investig Dent. 2013; 5:57-61.
102. Danesh M, Murase JE. Titanium dioxide induces eyelid dermatitis in patients allergic to gold. J Am Acad Dermatol. 2015; 73:e21.

Received: 20 March 2017
Published online: 23 May 2017

back to Online Journal