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TITANIUM & PERI-IMPLANTITIS

Scientific evidence for the role
of titanium in peri-implantitis

A Literature Review Study on Atomic Ions Dissolution of Titanium and Its Alloys in Implant Dentistry

Noumbissi S, Scarano A, Gupta S. Materials (Basel). 2019 Jan 24;12(3). pii: E368. doi: 10.3390/ma12030368.
https://www.mdpi.com/1996-1944/12/3/368

The literature surveyed showed that corrosion related to titanium and its alloys has an effect on the health of peri-implant soft and hard tissue and the long term survival of metal dental implants. It can be concluded that presence of the long-term corrosion reaction along with continuous corrosion leads to the release of ions into the peri-implant tissue but also to a disintegration of the implant that contribute to material fatigue and even fracture of the abutments and implant body or both. This combined impact of the corrosion, bacterial activity, chemical reactions, and functional stresses are to be looked at as important factors of implant failure.

The effect of metal ions released from different dental implant-abutment couples on osteoblast function and secretion of bone resorbing mediators

Alrabeah GO, Brett P, Knowles JC, Petridis H.J Dent. 2017 Nov;66:91-101. doi: 10.1016/j.jdent.2017.08.002. Epub 2017 Aug 4. 

RESULTS:
 Metal ions in concentrations representing the platform-matched groups led to a reduction in cell viability (P<0.01) up to 7days of exposure. Stimulated cells showed higher rates of early apoptosis (P<0.01) compared to non-treated cells. Metal ions up-regulated the expression of interleukin-6, interleukin-8, cyclooxygenase-2 and RANKL in a dose dependent manner after 1day of exposure (P<0.05). The up-regulation was more pronounced in the groups containing the corrosion products of platform-matched implant-abutment couples.
CONCLUSION:
Osteoblastic cell viability, apoptosis, and regulation of bone resorbing mediators were significantly altered in the presence of metal ions. The change in cytokine levels expressed was directly proportional to the metal ion concentration.

Increased Levels of Dissolved Titanium Are Associated With Peri-Implantitis - A Cross-Sectional Study.

Safioti LM, Kotsakis GA, Pozhitkov AE, Chung WO, Daubert DM.
J Periodontol. 2017 May;88(5):436-442. doi: 10.1902/jop.2016.160524. Epub 2016 Nov 18.

RESULTS:
Implants with peri-implantitis harbored significantly higher mean levels of titanium (0.85 ± 2.47) versus healthy implants (0.07 ± 0.19) after adjusting for amount of plaque collected per site (P = 0.033).

CONCLUSIONS:
Greater levels of dissolved titanium were detected in submucosal plaque around implants with peri-implantitis compared with healthy implants, indicating an association between titanium dissolution and peri-implantitis. Factors triggering titanium dissolution, as well as the role of titanium corrosion in the peri-implant inflammatory process, warrant further investigation.

Titanium release in peri-implantitis.

Pettersson M, Pettersson J, Johansson A, Molin Thorén M.A. J

RESULTS:
All patients lost one or more implants despite undergoing peri-implant or treatment. Peri-implantitis tissue contained significantly higher concentrations of Ti than control samples with a mean ± SD of 98.7 ± 85.6 and 1.2 ± 0.9 μg/g, respectively. Particulate metal was identified in peri-implantitis and control biopsies, but element analyses could confirm only the presence of Ti in peri-implantitis tissue.


CONCLUSION:
We showed that high contents of particulate and submicron Ti were present in peri-implantitis tissue. These high Ti contents in peri-implant mucosa can potentially aggravate inflammation, which might reduce the prognosis of treatment interventions.

Can degradation products released from dental implants affect peri-implant tissues?

Noronha Oliveira M, Schunemann WVH, Mathew MT, Henriques B4, Magini RS, Teughels W, Souza JCM.

RESULTS:
The results showed that pro-inflammatory cytokines, infiltration of inflammatory response cells and activation of the osteoclasts activity are stimulated in peri-implant tissues in the presence of metal particles and ions. Moreover, degenerative changes were reported in macrophages and neutrophils that phagocytosed titanium microparticles, and mutations occurred in human cells cultured in medium containing titanium-based nanoparticles. Debris released from the degradation of dental implants has cytotoxic and genotoxic potential for peri-implant tissues. Thus, the amount and physicochemical properties of the degradation products determine the magnitude of the detrimental effect on peri-implant tissues.

Potential Causes of Titanium Particle and Ion Release in Implant Dentistry: A Systematic Review.

Delgado-Ruiz R, Romanos G.

Implant surface characteristics, as well as physical and mechanical properties, are responsible for the positive interaction between the dental implant, the bone and the surrounding soft tissues. Unfortunately, the dental implant surface does not remain unaltered and changes over time during the life of the implant. If changes occur at the implant surface, mucositis and peri-implantitis processes could be initiated; implant osseointegration might be disrupted and bone resorption phenomena (osteolysis) may lead to implant loss.
Titanium particle and ions are released during the implant bed preparation, during the implant insertion and during the implant decontamination. In addition, the implant surfaces and restorations are exposed to the saliva, bacteria and chemicals that can potentially dissolve the titanium oxide layer and, therefore, corrosion cycles can be initiated. Mechanical factors, the micro-gap and fluorides can also influence the proportion of metal particles and ions released from implants and restorations.

Association of Global DNA Methylation to Titanium and Peri-Implantitis: A Case-Control Study.

Daubert DM, Pozhitkov AE, Safioti LM, Kotsakis GA.  JDR Clin Trans Res. 2019 Jul;4(3):284-291. doi: 10.1177/2380084418822831. Epub 2019 Jan 31.

Introduction:
Epigenetic changes are associated with various inflammatory diseases and are influenced by environmental factors. Recent data support an association between titanium dissolution products and peri-implantitis. We hypothesize that site-specific changes in gene methylation, a form of epigenetic regulation, around dental implants may be influenced by local environmental factors, such as titanium dissolution particles.

Conclusions:
Peri-implantitis cases exhibited increased levels of methylated DNA cytosine (5mC) as compared to controls, suggesting that peri-implantitis is associated with epigenetic alterations in the peri-implant tissues. In addition, the finding that titanium concentrations were associated with global methylation levels independent of peri-implantitis status suggests that methylation may be affected by titanium dissolution products. Collectively, these results support further investigations to determine if these associations are causal or ecological in nature.


Metal Nanoparticles Released from Dental Implant
Surfaces: Potential Contribution to Chronic
Inflammation and Peri-Implant Bone Loss

Eriberto Bressan , Letizia Ferroni , Chiara Gardin , Gloria Bellin , Luca Sbricoli ,

ABSTRACT
Peri-implantitis is an inflammatory disease affecting tissues surrounding dental implants. Although it represents a common complication of dental implant treatments, the underlying mechanisms have not yet been fully described. The aim of this study is to identify the role of titanium nanoparticles released form the implants on the chronic inflammation and bone lysis in the surrounding tissue. We analyzed the in vitro effect of titanium (Ti) particle exposure on mesenchymal stem cells (MSCs) and fibroblasts (FU), evaluating cell proliferation by MTT test and the generation of reactive oxygen species (ROS). Subsequently, in vivo analysis of peri-implant Ti particle distribution, histological, and molecular analyses were performed. Ti particles led to a time-dependent decrease in cell viability and increase in ROS production in both MSCs and FU. Tissue analyses revealed presence of oxidative stress, high extracellular and intracellular Ti levels and imbalanced bone turnover. High expression of ZFP467 and the presence of adipose-like tissue suggested dysregulation of the MSC population; alterations in vessel morphology were identified. The results suggest that Ti particles may induce the production of high ROS levels, recruiting abnormal quantity of neutrophils able to produce high level of metalloproteinase. This induces the degradation of collagen fibers. These events may influence MSC commitment, with an imbalance of bone regeneration.

Macrophage polarization in aseptic bone resorption around dental implants induced by Ti particles in a murine model.

Wang X, Li Y, Feng Y, Cheng H, Li D. J Periodontal Res. 2019 Aug;54(4):329-338. doi: 10.1111/jre.12633. Epub 2019 Jan 11.

ABSTRACT
Background & Objectives:
Titanium particles/ions detected in peri-implant tissues have been considered as a potential etiologic factor for crestal bone loss around oral implants. However, the definite impact of titanium wear particles on the health of surrounding structures remains undetermined. The purpose of this study was to investigate the effects of titanium particles-induced foreign body reaction on peri-implant bone level and the related mechanism by using clodronate liposomes to deplete macrophages.
Conclusions:
Titanium particles had a negative effect on peri-implant tissue by activating macrophages which induced an M1 macrophage phenotype promoting local secretion of inflammatory cytokines. It was found that clodronate liposome treatment attenuated the severity of inflammation and bone loss by depletion of macrophages. Therefore, the present study revealed the marked impact of macrophage polarization with respect to peri-implant bone loss caused by titanium particles.

Titanium particles in tissues from peri-implant mucositis: An exfoliative cytology-based pilot study

Shree Lakshmi Deepika Penmetsa, Rucha Shah, Raison Thomas, Amanna Baron Tarun Kumar, Pamidimarri Sai Divya Gayatri, and Dhoom Singh Mehta. J Indian Soc Periodontol. 2017 May-Jun; 21(3): 192–194. doi: 10.4103/jisp.jisp_184_16

ABSTRACT
Background:
To evaluate the presence of titanium particles in the peri-implant mucosa of unloaded single implants.

Materials and Methods:
Forty participants with single unloaded implants were selected. They were divided equally into two groups: Group 1 with mild and Group 2 with moderate-to-severe peri-implant mucositis. Cytologic smears of peri-implant mucosa were obtained using cytobrush during second-stage surgery.

Results:
Study states that 60% of participants of Group 2 were positive for titanium particles in peri-implant cytology.

Conclusion:
This study concludes that the titanium particles might be the initiators of the inflammation around implant.

Titanium as a modifier of the peri-implant microbiome structure.

Daubert D, Pozhitkov A, McLean J, Kotsakis G. Clin Implant Dent Relat Res. 2018 Dec;20(6):945-953. doi: 10.1111/cid.12676. Epub 2018 Sep 25.

ABSTRACT
Background:
Recent data support the implication of accelerated titanium dissolution products in peri-implantitis. It is unknown whether these dissolution products have an effect on the peri-implant microbiome, the target of existing peri-implantitis therapies.

Purpose:
This study assessed the relationship between the peri-implant microbiome, dissolved titanium levels, and peri-implantitis.

Results:
Fifteen implants were assessed. According to established case definitions, six had a diagnosis of peri-implantitis; nine were healthy. The genera Streptococcus, Prevotella and Haemophilus characterized peri-implant health. Peri-implantitis was associated with a marked increase in Veillonella. Quantities of dissolved titanium were identified in 40% of sites. Titanium presence was associated with peri-implant disease status (P = .02) and correlated to the first principal component of the microbiome (rho = 0.552) and its alpha-diversity (rho = -0.496). Canonical correlation analyses found that titanium levels, but not health or disease status of the implant, were significantly associated with the microbiota composition (P = .045).

Conclusion:
These findings suggest an association between titanium dissolution products and peri-implantitis and support a role for these products in modifying the peri-implant microbiome structure and diversity.

The Biological Effect of Particulate Titanium Contaminants of Dental Implants on Human Osteoblasts and Gingival Fibroblasts.

Happe A, Sielker S, Hanisch M, Jung S. Int J Oral Maxillofac Implants. 2019 Feb 26. doi: 10.11607/jomi.6929. [Epub ahead of print]

CONCLUSION:
Cell viability is negatively correlated with titanium concentration. Further, titanium debris might lead to an inflammatory biologic response of dental peri-implant tissue. Also, cells interact with the debris, eg, with incorporation of particles.

Intracellular uptake and toxicity of three different Titanium particles.

He X, Hartlieb E, Rothmund L, Waschke J, Wu X, Van Landuyt KL, Milz S, Michalke B, Hickel R, Reichl FX, Högg C. Dent Mater. 2015 Jun;31(6):734-44. doi: 10.1016/j.dental.2015.03.017. Epub 2015 Apr 21.

CONCLUSION:
Compared to titanium microparticles and Nickel-Titanium (NiTi) microparticles, titanium nanoparticles induced higher cellular uptake efficiency and higher toxic potential in periodontal ligament hTERT cells. Nickel in the alloy NiTi induced an increase in the toxic potential compared to Titanium microparticles.

Biological reaction to alumina, zirconia, titanium and polyethylene particles implanted onto murine calvaria.

Warashina H, Sakano S, Kitamura S, Yamauchi KI, Yamaguchi J, Ishiguro N, Hasegawa Y. Biomaterials. 2003 Sep;24(21):3655-61.

The inflammatory response and bone resorption induced by ceramic particles were much smaller than those induced by polyethylene and Ti6Al4V. These biological features suggest the biocompatibility of ceramics as a joint surface material for artificial joints.

Note from the webmaster:  it should be noted that the release of zirconia particles from a ceramic implant will be significantly less than a titanium implant since zirconia is much more stable and resistant to corrosion than titanium in the oral environment.

Mechanism and Prevention of Titanium Particle-Induced Inflammation and Osteolysis.

Eger M, Hiram-Bab S, Liron T, Sterer N, Carmi Y, Kohavi D, Gabet Y. Front Immunol. 2018 Dec 18;9:2963. doi: 10.3389/fimmu.2018.02963. eCollection 2018.

"Here we show that a strong inflammatory response occurs; however, very few of the titanium particles are phagocytosed by the macrophages. We then measured a dramatic Ti particle-induced stimulation of IL1β, IL6, and TNFα secretion by these macrophages using multiplex immunoassay. The particle-induced expression profile, examined by FACS, also indicated an M1 macrophage polarization."

Can genetic polymorphisms (SNPs) increase the risk?

Genetic and immunological markers predict titanium implant failure: a retrospective study.

Jacobi-Gresser E, Huesker K, Schütt S.
Int J Oral Maxillofac Surg. 2013 Apr;42(4):537-43. doi: 10.1016/j.ijom.2012.07.018. Epub 2012 Aug 24.

Abstract
This study evaluates diagnostic markers to predict titanium implant failure. Retrospectively, implant outcome was scored in 109 subjects who had undergone titanium implant surgery, IL1A -889 C/T (rs1800587), IL1B +3954 C/T (rs1143634), IL1RN +2018 T/C (rs419598) and TNFA -308 G/A (rs1800629) genotyping, in vitro IL-1β/TNF-α release assays and lymphocyte transformation tests during treatment. TNF-α and IL-1β release on titanium stimulation were significantly higher among patients with implant loss (TNF-α: 256.89 pg/ml vs. 81.4 pg/ml; p<0.0001; IL-1β: 159.96 pg/ml vs. 54.01 pg/ml; p<0.0001). The minor alleles of the studied polymorphisms showed increased prevalence in the implant failure group (IL1A: 61% vs. 42.6% in controls, IL1B: 53.7% vs. 39.7% in controls, TNFA: 46.3% vs. 30.9% in controls, IL1RN: 58.5% vs. 52.9% in controls). Increasing numbers of risk genotypes of the studied polymorphisms were associated with an increasing risk of implant loss, suggesting an additive effect. Multiple logistic regression analysis showed positive IL-1β/TNF-α release assay scores (p<0.0001, OR=12.01) and number of risk genotypes (p<0.046, OR=1.57-6.01) being significantly and independently associated with titanium implant failure. IL-1/IL1RN/TNFA genotyping and cytokine release assay scores provide prognostic markers for titanium implant outcome and may present new tools for individual risk assessment.

Titanium Sensitivity Testing

IMD Labor Berlin
1IMD Berlin MVZ,  Nicolaistrasse 22, 12247 Berlin (Steglitz)
info@IMD-Berlin.de, www.IMD-Berlin.de

A variety of studies have shown the relationship between peri-implantitis and functionally relevant polymorphisms in the genes of cytokines IL-1A, IL-1B, IL-RN and TNFA. 
Using genetic testing allows for the allocation of a certain degree of inflammation to the detected combination of alleles.
Patients with degree 3-4 are considered high responders and are thus risk patients for titanium associated inflammatory processes/ loss of implant. Tab 1.

RELATIVE RISK OF LOSS OF IMPLANTS

Degree of inflammation 0   |  Risk 1.0

Degree of inflammation 1  |   Risk 1.5

Degree of inflammation 2  |   Risk 2.4

Degree of inflammation 3  |   Risk 3.8

Degree of inflammation 4  |   Risk 6.0

In Germany a Titanium Stimulation test is also available. A positive result to titanium stimulation increases the risk by a further 12 fold.

Polymorphisms, Bone Health & Peri-implantitis

Multiple Studies Available

Other relevant polymorphisms adversely impacting on bone health can increase the risk of peri-implantitis by affecting the rate of bone turnover, the bone mineral density and the formation of the collagen based bone matrix.

Polymorphisms also impact other physiological functions that can indirectly have an influence on the health of the bone tissue around an implant. Methylation, lipid metabolism, oxydative stress damage, detoxification can all be impacted by polymorphisms.

Genetic factors thus play an important role in the selection of materials for implantology as well as patient assessment for such procedures.  SNPs should be taken into account and suitable epigenetic mitigation should be implemented.

More importantly the presence of metals other than titanium in the mouth of an individual should also be taken into account since other metals also have a physiological impact.
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IT SHOULD THEN BE ADDED THAT COMPARABLE REACTIONS TO ZIRCONIA IMPLANTS HAVE NOT BEEN DEMONSTRATED DUE TO A MORE STABLE, MORE CORROSION-RESISTANT SURFACE AND A SIGNIFICANTLY LOWER IMMUNOGENIC EFFECT OF ZIRCONIA PARTICLES.

Pathogenesis of peri-implantitis

Dr. Elisabeth Jacobi-Gresser | dr.jacobi-gresser@web.de | https://www.dimagazin-aktuell.de/implantologie/periimplantitis/story/pathogenese-der-periimplantitis__6705.html 

Conclusion:
Peri-implantitis is a pathogenetically complex clinical picture and, in addition to local effects, has systemic effects depending on individual genetic susceptibility. It has some similarities to periodontitis but differs in the taxonomic biofilm composition and is also involved in foreign body reactions to the implant material. Patients with a periodontitis history have a genetically higher risk of developing peri-implantitis. Pre-implantological risk diagnostics for appropriately scheduled patients allows for a differentiated implant-prosthetic procedure with the aim of avoiding peri-implantitis development. For early diagnosis and therapy monitoring, laboratory biomarkers such as calprotectin or the aMMP-8 determination from the sulcus fluid are now available to initiate anti-inflammatory measures at an early stage and to control their efficiency. An adapted to the patient monitoring in defined time intervals is indispensable due to individual risk burdening. 

What about systemic effects ?

Titanium implants and silent inflammation in jawbone—a critical interplay of dissolved titanium particles and cytokines TNF-α
and RANTES/CCL5 on overall health?

Johann Lechner & Sammy Noumbissi  & Volker von Baehr
EPMA Journal (2018) 9:331–343

Results:  All DTI (Dental Titanium Implant)-FDOJ (Fatty Degeneration with Osteonecrosis of the Jaw) samples showed RANTES/CCL5 (R/C) as the only extremely overexpressed cytokine. DTI-FDOJ cohort
showed a 30-fold mean overexpression of R/C as compared with a control cohort of 19 healthy JB samples. Concentration of  dissolved Ti particles in DTI-FDOJ was 30-fold higher than an estimated maximum of 1.000 μg/kg.
Conclusion: From a systemic perspective, we recommend that more attention be paid to the cytokine cross-talk that is provoked by dissolved Ti particles from DTI in medicine and dentistry. This may contribute to further development of personalized strategies in preventive medicine.

Cytokine pathways in the
implant area during
osseointegration from TNF-α to
RANTES/CCL5 overexpression with longterm,
negative immune response,
and effects

Ischaemic hypoxic medullary bone occurs when there is a disruption in the vascular supply of that bone tissue. Such disruption can occur when a thrombus (clot) is formed and does not subsequently break down (fibrinolysis).

Individuals who are more susceptible to increased clot formation (thrombophilia) and/or a reduced ability to break down such clot (hypofibrinolysis) are at risk of such bone ischaemic events. 

Bone ischaemic events lead to gradual damage ranging in severity from mild (bone marrow oedema), to bone marrow degeneration (fibrosis, adipocytes apoptosis ect...) such as fatty degeneration and eventually to osteonecrosis (bone cell dealth).

Titanium is a highly thrombogenic biomaterial: possible implications for osteogenesis.

Hong J, Andersson J, Ekdahl KN, Elgue G, Axén N, Larsson R, Nilsson B. Thromb Haemost. 1999 Jul;82(1):58-64.

 This study indicates that titanium is unsuitable as a biomaterial in devices which are in direct contact with blood for a prolonged period.
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OTHER METALS CAN INDUCE HYPOFIBRINOLYSIS
(Cadmium, Lead, Nickel, Mercury... can accumulate in the jawbones especially mercury)

Effects of chronic mercury poisoning on blood coagulation and fibrinolysis systems.
Song YG. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 2005 Dec;23(6):405-7.
Toxicity of cadmium and lead on vascular cells that regulate fibrinolysis.
 Yamamoto C. Yakugaku Zasshi. 2000 May;120(5):463-73. ) 

OTHER POSSIBLE EFFECTS:
Hypersensitivity/Allergies/Toxicity

Mobirise gives you the freedom to develop

Allergic contact dermatitis caused by titanium screws and dental implants. MakiHosoki, KeisukeNishigawa, YoujiMiyamoto, GoOhe, YoshizoMatsuka, Journal of Prosthodontic Research Volume 60, Issue 3, July 2016, Pages 213-219 

General review of titanium toxicity.
Kim KT1, Eo MY2, Nguyen TTH2, Kim SM3,4,5.
Int J Implant Dent. 2019 Mar 11;5(1):10. doi: 10.1186/s40729-019-0162-x.

Titanium allergy: could it affect dental implant integration?
Siddiqi A, Payne AG, De Silva RK, Duncan WJ. Clin Oral Implants Res. 2011 Jul;22(7):673-80. doi: 10.1111/j.1600-0501.2010.02081.x. Epub 2011 Jan 20. 
This review of the literature indicates that titanium can induce hypersensitivity in susceptible patients and could play a critical role in implant failure. 

Titanium Exposure and Human Health

Anita V. Tibau Blanche D. Grube Braulio J. Velez Victor M. Vega Joachim Mutter. https://onlinelibrary.wiley.com/doi/full/10.1002/osi2.1001

 Conclusion:
This review is based on current titanium research demonstrating the many factors that can pose a negative impact on human health when exposed to the various forms of titanium, including its relationship and interactions with other metals.

We looked at environmental, medical, and dental devices to show how these exposures can impact human health.

Most of the literature available indicates an increased risk to allergies due to titanium exposure. These allergies are also associated with particular genetic individual factors, which validate the need for the use of precision medicine in these particular patients. We need to continue to expand our knowledge on the genetic factors associated with titanium and metal exposure in order to provide better management and care to this group of susceptible populations, which are at a higher risk. There are many available tests that can be administered prior to any medical or dental procedure that can determine allergic reactions and biocompatibility for individual patients.

Most of the medical and dental practitioners commonly overlook these allergy tests increasing a health risk to the patients.

These types of tests should always be utilized to allow for the most suitable materials to be used on an individual patient.

Based on this review, it would be prudent to reduce the risk to all patients when considering exposure to titanium, and to avoid its improper use as much as possible. Moreover, when a patient has titanium implants it is critically important to take the utmost care to protect the patient from any and all risks of potential harm.

Titanium release in serum of patients with different bone fixation implants and its interaction with serum biomolecules at physiological levels

Yoana Nuevo-Ordóñez. M. Montes-Bayón. E. Blanco-GonzálezJ. Paz-AparicioJ. Diánez RaimundezJ. M. TejerinaM. A. PeñaA. Sanz-Medel. Analytical and Bioanalytical Chemistry , November 2011, 401:2747

Summary:

Titanium implants are routinely used for bone fractures as well as dental work. It has recently been shown that titanium-based implants both corrode and degrade, generating metallic debris. There is some concern over the increased concentrations of circulating metal-degradation products derived from these implants, and their potential harmful biological effects over a period of time, including hepatic injury and renal lesions.

Nuevo-Ordóñez and team collected blood from 40 healthy individuals and 37 patients with titanium implants -- 15 had tibia implants, eight had femur implants, and 14 had humerus implants (eight internal and six external fixation implants). They used their new method, based on isotope dilution analysis and mass spectrometry, or IDA-ICP-MS, to analyze the blood samples.

They found that control individuals had very low levels of titanium in the blood whereas titanium concentrations were significantly higher for all the patients with implants. The sensitivity of the method was such that the researchers were also able to show significant differences in titanium levels for different types of bone fixation devices. The more invasive implants shed more metallic debris into the blood than the external, superficial designs. The work also identified how the titanium from the implants is transported in the bloodstream and potentially distributed and accumulated.

Evaluation of the biological effect of Ti generated debris from metal implants: ions and nanoparticles.

Soto-Alvaredo J, Blanco E, Bettmer J, Hevia D, Sainz RM, López Cháves C, Sánchez C, Llopis J, Sanz-Medel A, Montes-Bayón M. Metallomics. 2014 Sep;6(9):1702-8. doi: 10.1039/c4mt00133h.

Abstract :
Metallic implants placed in humans exhibit wear and corrosion that result in the liberation of metal-containing by-products. In the case of titanium (Ti) containing implants, the metal containing debris may exist in a number of states, including metallic particles produced by mechanical wear and the products of metal corrosion in biological environments, such as the joints and surrounding fluids and tissues. In addition, these constituents may dissolve in both intracellular and extracellular solutions generating Ti ions. Both species, ions and nanoparticles, show different cellular toxicities. In this work we have evaluated the possible evolution of TiO2 nanoparticles (NPs) into soluble Ti metal ions by contact with biological fluids. For this aim, an in vitro study to address quantitative Ti solubilisation from TiO2 nanoparticles (with a diameter of 21 nm) after incubation with human serum at different concentrations has been conducted. Total Ti determination revealed low solubilisation rates ranging from 0.53 to 0.82% after just one week of incubation in the serum. The incubated serum was then subjected to speciation analysis by anion exchange liquid chromatography using an inductively coupled plasma mass spectrometer (ICP-MS) as an elemental detector for Ti monitoring. The obtained results revealed a significant increase in the Ti signal associated with the fraction of the protein transferrin and preferentially with one of the metal binding sites of the protein, the N-lobe. Thus, the effect of Ti at the cellular level has been evaluated by considering that it can be present either as ions or as nanoparticles using two different cells lines: human enterocytes HT29 and murine osteoblasts MC3T3. Significant toxicity was found at the highest concentration assayed (50 μg mL(-1)) for both Ti species (ions and NPs) and slightly higher for the ionic species at lower concentrations (1 and 10 μg mL(-1)).

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