Una review del Dott. Titanix

Il Titanio è da decenni il materiale più utilizzato per protesi ortopediche e per impianti dentali, infatti non c’è una nonnina che non abbia l’anca o il ginocchio in titanio.
Tuttavia negli ultimi anni sono nati come funghi articoli che ne dimostrano:
• l’instabilità dal punto di vista chimico ed elettrolitico
• la dannosità clinica sia su animali da laboratorio sia su esseri umani.

Non vi sono però lavori clinici che dicano esplicitamente che impianti e protesi in titanio facciano venire questa o quella patologia.
La scienza – si sa – lavora su statistiche, su lavori complicati e costosi, per cui le semplici osservazioni cliniche di uno o più casi – i cosiddetti “case report” – valgono poco o niente; ci vuole l’Università superblasonata che fa un lavorone complicatissimo, che dopo interpretazioni statistiche certificate, sentenzia una certa cosa che da quel momento in poi diventa certa.
Ma quale Università ha i fondi e l’interesse di dimostrare una cosa che non ha impatto economico immediato? I fondi – si sa – vengono dalle ditte produttrici di farmaci e presidi medicali, che non pagano una seconda volta se non ci sono risultati utili ad avere … utili.
Cito tuttavia alcuni lavori che ho raccolto negli anni sulla tossicità del titanio e sulla sua instabilità nel corpo umano, lasciando al lettore la deduzione sulla sicurezza di questo materiale.
Partiamo dall’inizio! Dove è nata la mania del titanio come materiale per implantoprotesi?

La fake news della biocompatibilità del titanio

La ditta Synthes, leader nella produzione di protesi in titanio, pubblica una guida che allego che a pag. 1 rigo 1 dice: “questa guida vuole essere un riepilogo delle caratteristiche uniche del titanio e delle sue leghe, nei mezzi di osteosintesi” e cita il lavoro di Steinmann del 1988 (30 anni fa !!), su cui si è basata finora la fiducia degli Odontoiatri e degli Ortopedici, che dichiara al punto 3:
“ Resistenza alla corrosione e biocompatibilità” e al rigo 4: “il corpo è saturo di titanio, quindi nessuna quantità di titanio solubile in contatto con il corpo può diventare attiva. Per questo motivo il titanio e le sue leghe possone essere considerate uno dei materiali più biocompatibili presenti sul mercato”.
Ma dov’è l’evidenza scientifica sufficientemente consolidata?! L’articolo è consolidato dal punto di vista scientifico? da chi? Non sono riuscito a trovare né su PubMed né da altre parti l’articolo originale (!!!) per cui devo far fede alla “guida” dove l’autore, in palese conflitto di interessi poichè creatore dei “chiodi di Steinmann” in titanio (parametro oggi sufficiente ad annullare l’articolo), ci spiega che il titanio solubile (quindi ammette che si scioglie !?!) già satura il corpo, per cui non può sciogliersi più, ma, anche sciogliendosi nel corpo, non evidenzia attività biochimica o elettrica, poichè il titanio già presente la satura, ovvero svolge in modo soddisfacente la sua azione. Ma quale azione? Entrambe le affermazioni sono smentite nelle centinaia di lavori pubblicati negli anni successivi, e, se l’assioma “titanio = biocompatibilità” si basa su questo pessimo lavoro dell’altro millennio, sarebbe ora di rivederlo. Inoltre, che l’autore ci dica in quali reazioni chimiche entra il titanio, e per quale misterioso principio, aumentandone la quantitá, la reazione chimica non viene modificata !!!
Interessante anche che, secondo Steinmann, tutte le leghe al titanio diventano biocompatibili grazie alla presenza magica del titanio!! Che produrre la lega Ni-Ti sia un modo per neutralizzare il Nichel per le persone sensibili al Nichel? Pura follia!
Non esiste una reazione chimica che non si modifichi cambiando la concentrazione dei reagenti né un materiale che renda biocompatibile materiali non biocompatibili!!!

Una bella tesi dell’Università di Monaco sul titanio
Il Prof. Dr. Reinhard Hickel, Direttore della Klinik und Poliklinik für Zahnerhaltung und Parodontologie der Ludwig- Maximilians-Universität München;  il Prof. Dr. Thomas Gudermann, Direttore del Walther-Strauβ-Institut für Pharmakologie und Toxikologie der Universität München
:  il Prof. Dr. Franz-Xaver Reichl:  il Prof. Dr. Dennis Nowak; – il Prof. Dr. med. dent. Reinhard Hickel_
hanno messo la firma per la pubblicazione della Tesi di Dottorato: “Dissertation
zum Erwerb des Doktorgrades der Naturwissenschaften an der Medizinischen Fakultät der Ludwig-Maximilians-Universität zu München” dal titolo: : “Ti release from dental implants in human jawbone and the toxicity and cellular uptake of Ti particles in human cells”.
Questo lavoro, pubblicato nel 2016 “Mit Genehmigung der Medizinischen Fakultät der Universität München“, ovvero con l’espressa validazione dell’Università di Monaco, rappresenta una pietra miliare per l’implantologia, in quanto scuote le certezze sulla biocompatibilità del titanio, e nella sinopsi scrive: “In recent years, Ti is commonly used for dental implants [6] due to its high corrosion resistance, high biocompatibility, high strength and light weight. However, the animal studies indicated that Ti implant can release debris including particles and ions into the surrounding bone or bone marrow tissues [7, 15-17]. The released Ti species can even be circulated in blood and lymph [12, 18, 19]. Possible side effects (including bone marrow fibrosis, necrosis and allergic reactions) relating to Ti implants were also reported [20-23]. Therefore, it would be of great significance to find out whether the Ti-implants can induce health problems to human beings and how the Ti-implant causes the health problems” (tra parentesi quadre, i lavori citati nella prima lista seguente).

Per quanto riguarda la citotossicità, il lavoro rileva alta tossicità di particolari particelle di titanio: “XTT test and trypan blue exclusion test were used to measure the cytotoxicity of Ti-NPs, Ti-MPs and NiTi-MPs in PDL-hTERT cells. The results of XTT test indicated that the EC50 value of Ti-NPs (2.84mg/ml) was more than 350-fold lower than the EC50 of Ti-MPs (>999 mg/ml). Therefore, Ti-NPs induced higher cytotoxicity than Ti-MPs, which is also confirmed by the trypan blue exclusion test: a significant increase in nonviable cells was observed after exposure to 0.28 mg/ml of Ti-NPs; 120-fold of this concentration (33.3mg/ml) was required for Ti-MPs to get the same effect as after Ti-NPs exposure. “ Per quanto riguarda i danni al DNA, la tesi rivela: “ 14 µg/ml of Ti-NPs induced a 1.5 fold increase in OTM value compared to negative control….”
Per chiarimenti sulla tossicità delle diverse dimensioni delle particelle di titanio rilasciate nell’organismo, vi è un bellissimo articolo : “Intracellular uptake and toxicity of three different Titanium particles” di He X, Hartlieb E, Rothmund L, Waschke J, Wu X, Van Landuyt KL, Milz S, Michalke B, Hickel R, Reichl FX, Högg C, scaricabile su “https://www.ncbi.nlm.nih.gov/pubmed/25910990 “, che dice “Cytotoxicity for Ti microparticles (Ti-MPs, <44 μm), NiTi microparticles (NiTi-MPs, <44 μm), and Ti nanoparticles (Ti-NPs, <100 nm) in periodontal ligament (PDL)-hTERT cells was measured with XTT test. DNA damage was determined with comet assay. Particle size was measured with scanning electron microscope, intracellular uptake was determined with laser scanning confocal microscopy and transmission electron microscopy”, con il risultato che “Compared to Ti-MPs and NiTi-MPs, Ti-NPs induced higher cellular uptake efficiency and higher toxic potential in PDL-hTERT cells. Ni in the alloy NiTi induced an increase in the toxic potential compared to Ti-MPs.”, quindi addirittura il titanio risulta più citotossico della lega NiTi.”

La bibliografia di questa tesi è molto ricca e sconvolge le certezze che tutti avevamo fino a qualche anno fa sulla biocompatibilità del titanio:
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Questo per la bibliografia riguardante la tesi citata.

Su PubMed troviamo inoltre una miriade di lavori interessanti:
– Dei Professori Skocaj M, Filipic M, Petkovic J, Novak S. per la pubblicazione su Radiol Oncology 2011 Epub 2011 Nov 16 del lavoro “Titanium dioxide in our everyday life; is it safe?” in cui conlude:“ Until relevant toxicological and human exposure data that would enable reliable risk assessment are obtained, TiO(2) nanoparticles should be used with great care”.
– Dei Professori Márquez-Ramírez SG1, Delgado-Buenrostro NL, Chirino YI, Iglesias GG, López-Marure R. per la pubblicazione dell’articolo: “Titanium dioxide nanoparticles inhibit proliferation and induce morphological changes and apoptosis in glial cells”, in cui viene dimostrato come le particelle di biossido di titanio creano alterazioni morfologiche nelle cellule e ne inibiscono l’apoptosi. E cos’è il tumore se non cellule alterate con inibizione dell’apoptosi?
– Pubblicazione sull’allergia agli impianti in TITANIO: “Allergies to dental metals. Titanium: a new allergen di Evrard L1, Waroquier D, Parent D.”, in cui si dice: “Recently, titanium, used in orthopedic devices and oral implants, considered as an inert material, can induce toxicity or allergic type I or IV reactions”.

ed altri lavori minori…

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43. Schedle A, Ortengren U, Eidler N, Gabauer M, Hensten A. Do adverse effects of dental materials exist? What are the consequences, and how can they be diagnosed and treated? Clin Oral Implants Res. 2007;18( Suppl 3):232–256. [PubMed]
44. Okamura T, Morimoto M, Fukushima D, Yamane G. A skin patch test for the diagnosis of titanium allergy. Journal of Dental Research. 1999;78:1135.
45. Olmedo DG, Paparella ML, Brandizzi D, Cabrini RL. Reactive lesions of peri-implant mucosa associated with titanium dental implants: a report of 2 cases. Int J Oral Maxillofac Surg. 2010;39(5):503–507. [PubMed]
46. Harloff T, Hönle W, Holzwarth U, Bader R, Yhomas P, Schuh A. Titanium allergy or not? “Impurity” of titanium implant materials. Health. 2010;2(4):306–310.
47. Schuh A, Thomas P, Kachler W, et al. Allergic potential of titanium implants. Orthopade. 2005;34(4):327–328. 330–333. German. [PubMed]
48. Kulak Y, Arikan A. Effect of dental base metal alloys on IgE levels and some blood parameters. J Oral Rehabil. 1997;24(10):749–754. [PubMed]
– Lavoro freschissimo pubblicato nel settembre 2018 sull’EPMA Journal (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107454/) dal titolo : “Titanium implants and silent inflammation in jawbone – a critical interplay of dissolved titanium particles and cytokines TNF-α and RANTES/CCL5 on overall health?” Autori: Johan Lechner, Sammy Noumbissi, Volker von Baehr.
Material and methods: The signaling pathways involved in the induction of cytokine release were analyzed by multiplex analysis. We examined samples of jawbone (JB) for seven cytokines in two groups: specimens from 14 patients were analyzed in areas of DTI for particle-mediated release of cytokines. Each of the adjacent to DTI tissue samples showed clinically fatty degenerated and osteonecrotic medullary changes in the JB (FDOJ). Specimens from 19 patients were of healthy JB. In five cases, we measured the concentration of dissolved Ti particles by spectrometry.
Conclusions: “… we recommend that more attention be paid to the cytokine cross-talk that is provoked by dissolved Ti particles from Dental Titanium Implants in medicine and dentistry.”

Carcinogenicità del titanio

Per quanto riguarda la carcinogenicità del titanio, su Internet ci sono 1.120.000 risultati riferentesi soprattutto ad articoli scientifici. Uno in particolare, pubblicato su “Critical reviews in oral Biology & Medicine” dal titolo: “Electrical implications of corrosion for Osseointegration of titanium implants “ dice: “While implant loosening is less prominent in the dental literature, metal traces originating from dental implants have been found in blood, liver, lungs, and lymph nodes (Lugowski et al., 1991; Smith et al., 1997; Finet et al., 2000). These metal ions and wear debris may also contribute to aseptic loosening by promoting inflammatory complications that may result in macrophage activation, bone resorption, and, rarely, in the potential development of neoplasia (Poggio, 2007; McGuff et al., 2008). Recently, titanium dioxide (TiO2) was classified as possibly carcinogenic to human beings (i.e., group 2B) at the International Agency for Research on Cancer (IARC) (Baan et al., 2006). Animal studies in rodents provided sufficient evidence of the carcinogenic effects of TiO

Altri lavori scientifici:
Maxillary osteosarcoma associated with a dental implant: report of a case and review of the literature regarding implant-related sarcomas. McGuff HS1, Heim-Hall J, Holsinger FC, Jones AA, O’Dell DS, Hafemeister AC.
Plasmacytoma of the mandible associated with a dental implant failure: a clinical report. Poggio CE1.
– Carcinogenicity of metal alloys in orthopedic prostheses: clinical and experimental studies. Sunderman FW Jr1.

In particolare, sul carcinoma squamoso in bocche in cui si trovavano impianti in titanio, troviamo l’articolo “Squamous Cell Carcinoma in Association With Dental Implants: An Assessment of Previously Hypothesized Carcinogenic Mechanisms and a Case Report” Neel B. Bhatavadekar, MS, MPH, con 29 referenze che rilevano la concomitanza impianto Titanio – carcinoma squamoso.

REFERENCES
ABBREVIATIONS:  SCC: squamous cell carcinoma  SIR: standardized incidence ratio  Ti: titanium

1. Schache A, Thavaraj S, Kalavrezos N. Osseointegrated implants: a potential route for squamous cell carcinoma of the mandible. Br J Oral Maxillofac Surg. 2008;46:397–399.
2. Block MS, Scheufler E. Squamous cell carcinoma appearing as peri-implant bone loss: a case report. J Oral Maxillofac Surg. 2001;59:1349–1352.
3. Kwok J, Eyeson J, Thompson I, McGurk M. Dental implants and squamous cell carcinoma in the at risk patient—report of 3 cases. Br Dent J. 2008;205:543–545.
4. Czerninski R, Kaplan I, Almoznino G, Maly A, Regev E. Oral squamous cell carcinoma around dental implants. Quintessence Int. 2006;37:707–711.
5. Gallego L, Junquera L, Baladro ́n J, Villarreal P. Oral squamous cell carcinoma associated with symphyseal dental implants: an unusual case report. J Am Dent Assoc. 2008;139: 1061–1065.
6. Eguia del Valle A, Mart ́ınez-Conde Llamosas R, Lo ́pez Vicente J, Uribarri Etxebarria A, Aguirre Urizar JM. Primary oral squamous cell carcinoma arising around dental osseointegrated implants mimicking peri-implantitis. Med Oral Patol Oral Cir Bucal. 2008;13:E489–E491.
7. WinterGreen Research. Worldwide nanotechnology dental implant market shares, strategies, and forecasts, 2009 to 2015. http://www.researchandmarkets.com/reportinfo.asp?report_id1⁄4 941893&t1⁄4d&cat_id1⁄4. Accessed March 10, 2011.
8. Abu El-Naaj I, Trost O, Tagger-Green N, et al. Peri- implantitis or squamous cell carcinoma. Rev Stomatol Chir Maxillofac. 2007;108:458–460.
9. Clapp C, Wheeler JC, Martof AB, Levine PA. Oral squamous cell carcinoma in association with dental osseointegrated implants. An unusual occurrence. Arch Otolaryngol Head Neck Surg. 1996;122: 1402–1403.
10. Gallego L, Junquera L, Llorente S. Oral carcinoma association with dental implant overdenture trauma. Dent Trau- matol. 2009;25:e3–e5.
11. Gulati A, Puthussery FJ, Downie IP, Flood TR. Squamous cell carcinoma presenting as peri-implantitis: a case report. Ann Rev Coll Surg Engl. 2009;91:8–10.
12. Moxley JE, Stoelinga PJ, Blijdorp PA. Squamous cell carcinoma associated with a mandibular stable implant. J Oral Maxillofac Surg. 1997;55:1020–1022.
13. Shaw R, Sutton D, Brown J, Cawood J. Further malignancy in field change adjacent to osseointegrated implants. Int J Oral Maxillofac Surg. 2004;33:353–355.
14. Verhoeven JW, Cune MS, van Es RJ. An unusual case of implant failure. Int J Prosthodont. 2007;20:51–54.
15. Vahey JW, Simonian PT, Conrad EU III. Carcinogenicity and metallic implants. Am J Orthop. 1995;24:319–324.
16. Olmedo DG, Tasat DR, Duffo ́ G, Guglielmotti MB, Cabrini RL. The issue of corrosion in dental implants: a review. Acta Odontol Latinoam. 2009;22:3–9.
17. Chaturvedi TP. An overview of the corrosion aspect of dental implants. Indian J Dent Res. 2009;20:91–98.
18. Chang JC, Oshida Y, Gregory RI, Andres CJ, Thomas M, Barco DT. Electrochemical study on microbiology related corrosion of metallic dental materials. Biomed Mater Eng. 2003;13:281–295.
19. Hallab NJ, Jacob JJ. Biologic effects of implant debris. Bull NYU Hosp Joint Dis. 2009;67:182–188.
20. Spector M, Shortkoff S, Hsu HP, Lane N, Sledge CB, Thornhill TS. Tissue changes around loose prosthesis: a canine model to investigate the effects of an anti-inflammatory agent. Clin Orthop 1990;261:139–145.
21. Thornbill TS, Ozuma RM, Shortkoff S, Keller K, Sledge CB, Spector M. Biochamical and histological evaluation of the synovial-like tissue around failed total joint replacement prosthe- ses in human subjects and a canine model. Biomaterials. 1990;11: 69–72.
22. Cochran DL, Hermann JS, Schenk RK, Higginbottom FL, Buser D. Biologic width around titanium implants. A histometric analysis of the implanto-gingival junction around unloaded and loaded nonsubmerged implants in the canine mandible. J Periodontol. 1997;68:186–198.
23. Galante J, Lemons J, Spector M, Wilson PD, Wright TM. The biologic effects of implant materials. J Orthop Res. 1991;9:760–775.
24. Gillespie WJ, Frampton CMA, Henderson RJ, Ryan PM. The incidence of cancer following total hip replacement. J Bone Joint
Surg. 1998;70B:539–542.
25. Black J. Metallic ion release and its relationship to oncogenesis. In: Fitzgerald, RH, ed. The Hip. St Louis, MO: CV Mosby; 1985:199–213.
26. Martin A, Bauer TW, Manley MT, Marks KE. Osteosarcoma at the site of total hip replacement. J Bone Joint Surg. 1988;70A:1561– 1567.
27. Tierney J. Not to worry. Hippocrates. 1988; Jan/Feb:29.
28. De Ceulaer J, Magremanne M, van Veen A, Scheerlinck J. Squamous cell carcinoma recurrence around dental implants. J Oral Maxillofac Surg. 2010;68:2507–2512.
29. Meijer GJ, Dieleman FJ, Berge ́ SJ, Merkx MA. Removal of an oral squamous cell carcinoma including parts of osseointegrated implants in the marginal mandibulectomy. A case report. Oral Maxillofac Surg. 2010;14:253–256.

Ovviamente anche sugli impianti ortopedici in titanio ci sono centinia di lavori interessanti, di cui cito qui un Case study: “Diagn Pathol. 2014 Jan 20;9:6. doi: 10.1186/1746-1596-9-6. Low-grade myxofibrosarcoma following a metal implantation in femur: a case report.” Li W, Li D1, Zhu X, Lu S, He C, Yang Q.”, ma rimaniamo pure nell’Odontoiatria.

Allergia al titanio

Alcuni dei lavori pubblicati:
– Metal Allergens of Growing Significance: Epidemiology, Immunotoxicology, Strategies for Testing and Prevention. Forte G. et al. Inflamm Allergy Drug Targets. 2008 Sep;7(3):145-62.
– Full-mouth oral rehabilitation in a titanium allergy patient using zirconium oxide dental implants and zirconium oxide restorations. A case report from an ongoing clinical study.
– Oliva X. et al. Eur J Esthet Dent. 2010 Summer;5(2):190-203.
Study on patch test reagent for titanium. Nakajima K. Kokubyo Gakkai Zasshi. 2007 Jun;74(2):92-8.
– Allergies to dental metals. Titanium: a new allergen. Evrard L, Waroquier D, Parent D. Rev Med Brux. 2010 Jan-Feb;31(1):44-9.
– Implant failure due to Titanium hypersensitivity/allergy? – Report of a case SADJ February 2007
– Ultrafine titanium dioxide particles in the absence of photoactivation can induce oxidative damage to human bronchial epithelial cells Toxicology 2005
– Titanium particles stimulate bone resorption by inducing differentiation of murine osteoclast J Bone Joint Surg Am. 2001
– Immunohistochemical study of the soft tissue around long-term skin-penetrating titanium implants Biomaterials 1995
– Titanium dermatitis after failure of metal-backed patellas, Am J Knee Surg 1993
– In vitro corrosion of titanium Biomaterials. 1998 Strietzel R1, Hösch A, Kalbfleisch H, Buch D.
– Sensitivity to titanium. A cause of implant failure? Bone Joint Surg Br. 1991
– A case of allergic reaction to surgical metal clips inserted for postoperative boost irradiation in a patient undergoing breast-conserving therapy Breast Cancer. 2001
– Biocompatibility of dental casting alloys Crit Rev Oral Biol Med. 2002
– Validity of MELISA® for metal sensitivity testing Neuro Endocrinol Lett. 2003
– Das Allergiepotenzial von Implantatwerkstoffen auf Titanbasis A. Schuh, et al. Der Orthopäde
Volume 34, Number 4, 327-33
– Tissue reaction to bone plates made of pure titanium: a prospective, quantitative clinical study.
A. Ungersboeck, et al. Journal of Materials Science: Materials in Medicine
Volume 6, Number 4, 223-229
– Maternal exposure to nanoparticulate titanium dioxide during the prenatal period alters gene expression related to brain development in the mouse. M Shimizu et al.Particle and Fibre Toxicology 2009, 6:20.

Concludendo:
La Scienza odierna è molto complicata, basta vedere la gerarchia dei lavori scientifici qui sotto per capire che un povero medico isolato non può far niente: occorre lavorare in équipe, e le équipes di solito seguono specifiche direttive.
Forse ci vorranno decenni prima che il titanio venga bandito, ma spero che questa mia ricerca serva a insinuare nella mente della gente e dei medici che lo usano un dubbio, ovvero:

” Il titanio non è così sicuro come si credeva finora” .

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Vera Paola Termali

Giornalista scientifica, direttore responsabile di Medicina di Frontiera

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