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 Table of Contents  
Year : 2017  |  Volume : 9  |  Issue : 3  |  Page : 201-207  

Effect of the inclusion nanocomplex formed of titanium tetrafluoride and β-Cyclodextrin on enamel remineralization

1 Department of Pediatric Dentistry and Orthodontics, School of Dentistry, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
2 Department of Drugs and Medicines, School of Pharmacy, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
3 Department of Clinic and Social Dentistry, School of Dentistry, Universidade Federal da Paraíba, Paraíba, Brazil

Date of Web Publication14-Sep-2017

Correspondence Address:
Lucianne Cople Maia
Department of Pediatric Dentistry and Orthodontics, School of Dentistry, Federal University of Rio de Janeiro, Rua Rodolpho Paulo Rocco, Cidade Universitária, Ilha do Fundão, Rio de Janeiro
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jpbs.JPBS_161_16

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Objective: Titanium tetrafluoride (TiF4) is a topical agent used in the control of dental caries; however, it is highly acidic. To minimize this effect, cyclodextrins (CDs) are used. This study evaluated the in vitro potential of TiF4and β-CD on remineralization. Methods: Forty bovine enamel blocks were selected by microhardness and randomly assigned to four groups (n = 10 per group): control (distilled and deionized water), 1% β-CD solution, 1% TiF4solution, and TiF4: β-CD solution. The blocks were subjected to a pH cycling regimen for 8 days. After that, samples were evaluated by cross-sectional microhardness (CSMH), scanning electron microscopy (SEM), and energy dispersive spectrometry (EDS). Data were assessed for normality and analyzed using ANOVA and Tukey's tests (α = 0.05). Results: Regarding CSMH, TiF4: β-CD was statistically superior to the control (P = 0.033), β-CD (P = 0.022), and TiF4(P = 0.006). SEM photomicrography revealed the titanium dioxide coating on slabs treated with TiF4and TiF4: β-CD. EDS assessment demonstrated the presence of titanium on the surface of slabs treated with TiF4and TiF4: β-CD. Conclusion: The solution containing the inclusion nanocomplex formed of TiF4and β-CD was able to reharden the enamel subsurface.

Keywords: Beta-cyclodextrins, dental caries, fluoride, microhardness, tooth remineralization

How to cite this article:
Vieira TI, Nassur C, Alexandria AK, Pomarico L, Sousa VP, Cabral LM, Valença AG, Maia LC. Effect of the inclusion nanocomplex formed of titanium tetrafluoride and β-Cyclodextrin on enamel remineralization. J Pharm Bioall Sci 2017;9:201-7

How to cite this URL:
Vieira TI, Nassur C, Alexandria AK, Pomarico L, Sousa VP, Cabral LM, Valença AG, Maia LC. Effect of the inclusion nanocomplex formed of titanium tetrafluoride and β-Cyclodextrin on enamel remineralization. J Pharm Bioall Sci [serial online] 2017 [cited 2022 Aug 13];9:201-7. Available from:

   Introduction Top

The use of fluoride (F -) is known as a major factor in reducing the occurrence of caries.[1] Among the main products, titanium tetrafluoride (TiF4) has been widely used as a minimally invasive treatment for the disease [2],[3] and in vitro[4],[5],[6],[7],[8] or in situ studies.[9],[10] While fluoride topical applications (especially sodium fluoride) result in the formation of globular deposits of calcium fluoride (CaF2) and CaF­like materials that serves as fluoride reservoir that release fluoride and reduce enamel dissolution,[11] the mechanism of action of TiF4 consists of a physicochemical barrier based on an acid-resistant coating formed of titanium dioxide referred as glaze-like layer over tooth surface associated to fluoride materials formation that protects enamel from mineral loss.[12] Despite the positive effects of TiF4 on the rehardening of the previous artificial carious lesions,[5] it has never found broad application in the clinical dental field. On the other hand, literature indicates that remineralization is also inhibited by TiF4.[9] The very low pH (1.0) of the pure solution is one of the major disadvantages of TiF4.[13],[14] Although promising, its instability represents a limitation to clinical use; therefore, to obtain a therapeutic improvement using TiF4, inclusion complexes should be adopted.[6]

Molecular complexation is an area of great interest in biotechnology because it enables the selection, separation, solubilization, and stabilization of various biomolecules.[15] For the purpose of achieving improvements in stability and treatment efficacy of certain chemical compounds, cyclodextrins (CDs) have been the subject of many studies in different areas. β-CD is the most accessible, the lowest-priced and generally, the most useful. It is structurally organized in a truncated cone form with the ends exposing hydrophilic sites due to the presence of hydroxyl groups, and the cavity presents hydrogen atoms and glycosidic oxygen bridges, assigning a highly hydrophobic character.[16] In the inclusion complex formation with drug molecules, no covalent bonds are created between the carrier and its guest. The drug molecules included within the CDs cavity may therefore be dissociated on dilution or displaced by a more suitable guest.[17] They are used to increase the solubility of liposoluble drugs in water, stabilizers, and as host-guest delivery carriers for a variety of drugs.[18]

Owing to the paucity of in vitro studies that analyze the effect of this compound incorporated into solution on remineralization, the present study was performed as a laboratory rehearsal. The null hypothesis was that TiF4 associated with β-CD would not remineralize the enamel surface and subsurface. Taking into account these considerations, the aim of this study was to evaluate the in vitro effect of TiF4 with a β-CD inclusion complex on remineralizing predemineralized artificial enamel blocks.

   Methods Top

Experimental design

This randomized, blind study evaluated the enamel remineralization capacity of a TiF4: β-CD solution in vitro adopting a previously validated protocol.[19] This study assessed the remineralizing ability of a new inclusion complex (TiF4: β-CD) on previously demineralized bovine enamel blocks. Four groups with ten predemineralized bovine enamel blocks in each were randomly chosen to evaluate the following four treatment groups: Control (distilled deionized water), a solution containing 1% β-CD, a solution carrying 1% TiF4 and the experimental formulation containing TiF4: β-CD.

The response variables investigated were cross-sectional microhardness (CSMH) and energy dispersive X-ray spectrometry (EDS) analysis. A qualitative analysis of the blocks was also applied by scanning electron microscopy (SEM) after the pH-cycling regimens and treatments with the formulations.

Preparation of cyclodextrin complexes

The inclusion complexes of TiF4: β-CD were made by kneading, solubilization, and freeze drying at molar ratios of 1:4. Physical mixtures were prepared by mixing β-CD and TiF4 in a mortar at the same molar ratios and blending them in a mortar for 5 min. An ethanol: water (70:30; v/v) solution was added and mixed for 30 min to obtain a homogeneous paste, which was dried under reduced pressure and the granulometry adjusted using a 40-mesh sieve.[6]

Regarding the solution preparation method, the appropriate proportions of TiF4 and β-CD were blended in 20 mL of distilled water with a magnetic stirrer for 72 h. The samples remained frozen in liquid nitrogen and were lyophilized. The particle size was calibrated with a 40-mesh sieve. The inclusion yield was calculated by ultraviolet spectroscopy.

Preparation of bovine enamel blocks

Forty bovine sound enamel blocks (4 mm × 4 mm × 3 mm), which had been stored in 2% formaldehyde solution, were selected from 100 bovine teeth, incorporated into acrylic devices, and polished with 600- and 1200-grit silicon carbide paper, followed by 3- and 1-μm diamond abrasive slurry (Buehler Ltd., Lake Bluff, Illinois, USA).[6] Each enamel slab was prepared from a separate bovine tooth, and blocks were selected on the basis of baseline surface microhardness (SMH) (mean 321.35 ± 32.13 kg/mm 2). SMH was measured using a microhardness tester (Buehler, Micromet 5104, 679-MIT4-00335, Japan) with a Knoop diamond under a 50 g load for 5 s, by making five indentations spaced 100 μm from each other at the center of the enamel surface.[20]

Enamel demineralization

Forty enamel blocks were immersed a demineralizing solution (0.05 M acetate buffer, pH 5.0, 1.28 mM Ca, 0.74 mM P, 0.03 μg/mL F; 2 mL/mm 2 of enamel area) for 16 h, and mineral loss was evaluated. The time of 16 h was chosen to induce caries-like lesions on the enamel because the enamel blocks presented measurable caries-like subsurface lesions without surface erosion, allowing the evaluation of mineral loss or gain by determining SMH.[19] The slabs with known SMH (sound enamel) were exposed to the demineralizing solution for 16 h, the SMH was again determined (demineralized enamel), and the blocks with caries-like lesions were used for the further evaluation.

Enamel surface treatment and pH-cycling regimen

The solutions were applied only once on the surface of the blocks with a Microbrush ® and left for 1 min.[6] After this, the blocks were rinsed with deionized and distilled water and dried with soft paper. Subsequently, the pH cycling started. The investigators were blinded to the solutions used.

The pH-cycling regimen occurred over 8 days, and the blocks were kept at 37°C for 2 h in the demineralizing solution and 22 h in the remineralizing solution. The demineralizing solution contained 0.05 M acetate buffer, pH 5.0, 1.28 mM Ca, 0.74 mM P, and 0.03 μg/mL F. The remineralizing solution contained 1.5 mM Ca, 0.9 mM P, 150 mM KCl, and 0.05 μg/mL F in 0.1 M Tris buffer, pH 7.0. The proportion of de- and remineralizing solutions per area of the block was 6.25 mL/mm 2 and 3.12 mL/mm 2, respectively. The solutions were replaced by fresh ones on the 4th day. Then, on the 8th day of the cycle, the block remained in the remineralizing solution for an additional 24 h until analysis.[19]

Cross-sectional microhardness analysis

The slabs were longitudinally sectioned in the middle of the fragment with a cutting machine (Isomet, Buehler, Lake Bluff, IL, USA), resulting in two halves. One-half was included in the stub, and the cut surfaces were exposed and polished with 600- and 1200-grit silicon carbide paper. The CSMH evaluation was performed using a microhardness tester (Buehler, MICROMET 5104, 679-MIT4-00335, Japan) with a Knoop diamond and a 25-gauge static load, which was applied for 10 s.

Two lines of 15 indentations were made, 100 μm apart, from depths of 10 μm to 100 μm from the outer enamel surface, at 10-μm intervals, and from depths of 100 μm to 200 μm from the outer enamel surface, at 20-μm intervals.[6] Specific Excel spreadsheet was used with ΔZ values for the depth of 40 μm.

Scanning electron microscopy analysis

The blocks were mounted on aluminum stubs and analyzed using SEM (JEOL-JSM, 6460 LV, Tokyo, Japan). The topography of the sectioned surfaces and the enamel surfaces was analyzed in backscattered electrons at 20 kV voltage, low vacuum mode (45 Pa) to achieve images at ×1000 magnification. The area to be examined was the central part of the sample on the surface and on the cross-sectional half.

Energy dispersive X-ray spectrometry analysis

The mineral amount assessment from the enamel surface and from the cross-sectional side was performed using EDS with the Kontron link and automatic image analyzer system. This part of the study was carried out to identify the chemical elements in the inner enamel after the experimental protocol was completed. Potassium, silicon, chlorine, phosphorus, aluminum, magnesium, sodium, carbon, calcium, oxygen, and titanium were analyzed.[6]

Data analysis

SPSS 17.0 (SPSS 17.0, SPSS Inc., Chicago, IL, USA) was used for the statistical analysis. P < 0.05 was considered to indicate a significant result. The Shapiro–Wilk test was employed to verify the normal distribution. For analyses of CSMH, the area under the curve (ΔZ) was calculated and the differences among treatments were analyzed by one-way ANOVA and Tukey's post hoc test.

   Results Top

Cross-sectional microhardness

As seen in [Table 1] and [Figure 1], as the depth increased, the mean CSMH values in the TiF4: β-CD group increased relative to the other treatment groups. TiF4: β-CD was able to increase internal enamel microhardness when compared with the control (P = 0.033), β-CD (P = 0.033) and TiF4 group (P = 0.006).
Table 1: Values (means and standard deviation) of surface microhardness analysis of enamel blocks before and after pH-cycling according to the groups and ΔZ (cross-sectional microhardness)

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Figure 1: Values (means) of cross-sectional microhardness (y-axis) versus depth for enamel blocks (x-axis) previously demineralized. ΔZ values were obtained from the 40-μm depth

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Scanning electron microscopy and energy dispersive spectrometry evaluation

The surface images demonstrated the formation of an acid-resistant titanium dioxide coating on the slabs treated with TiF4 and TiF4: β-CD, as can be seen in [Figure 2]. Chemical analysis (EDS) revealed the presence of titanium element in all slabs treated with TiF4 and TiF4: β-CD on the surface, in accordance with [Figure 2]. The presence of titanium element was not evident at the subsurface of the blocks treated with TiF4 and TiF4: β-CD at the surface, as shown in [Figure 3].
Figure 2: Scanning electron microscope photomicrography (left) of surface enamel and energy dispersive spectrometry evaluation (right). (a) control group (distilled and deionized water), (b) β-cyclodextrin group, (c) titanium tetrafluoride group, (d) titanium tetrafluoride: β-cyclodextrin group

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Figure 3: Scanning electron microscope photomicrography (left) of subsurface enamel and energy dispersive spectrometry evaluation (right). (a) control group (distilled and deionized water), (b) β-cyclodextrin group, (c) titanium tetrafluoride group, (d) titanium tetrafluoride: β-cyclodextrin group

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   Discussion Top

There are significant differences in the inner layer, with increased CSMH in the blocks treated with a TiF4: β-CD solution. TiF4 is a topical fluoride agent that forms a titanium-rich glaze/coating following its application. Attributed to this coating is the anticaries effect observed in enamel treated with this agent in de- and re-mineralization studies. This layer offers a diffusion barrier and retains fluoride, leading to slow release onto the tooth and into its environment.[21] The hydrolysis of TiF4 has been known since 1967,[13] and in light of these data, a huge effort has been made to create new compounds to establish and realize its clinical use.[6]

The ability of β-CD to improve the pH of TiF4 has already been examined in the literature.[6] The remineralizing pH-cycling study was chosen because its potential to penetrate the demineralized enamel had not yet been studied. This is the first study to analyze the effect of TiF4 associated with β-CD incorporated into solution in a remineralization study design.

As described in [Table 1], the inclusion complex tested here was capable of rehardening the enamel subsurface after pH cycling. According to [Figure 1] and [Table 1], the TiF4: β-CD inclusion complex solution was capable of remineralizing the predemineralized enamel subsurface up to a depth of 40 μm as mentioned previously. An in situ study evaluating the effect of sodium fluoride and TiF4 varnish and solution on carious demineralization of enamel demonstrated that TiF4 was not able to reharden the enamel subsurface.[10] We can hypothesize that the in situ conditions utilized in that study (presence of biofilm) did not allow the penetration of the titanium to the subsurface.

Some researchers agree with our results with respect to the enhancement of subsurface hardness. When conducting an in vitro study on demineralization and remineralization of bovine enamel by 4% TiF4 varnish, it was observed that 4% TiF4 varnish significantly enhanced the mineral content compared with the other treatments (Duraphat ® and Duofluorid ®) up to a depth of 30 μm.[5] The inclusion complex tested here was able to improve the mineral content up to a depth of 40 μm, according to [Figure 1]. A difference concerning these two studies refers to the adopted concentration, which was 1% and the solution of a nanoinclusion complex of TiF4: β-CD instead of a TiF4 varnish. It is important to point out that that study [5] and the present paper adopted a single application of TiF4 over the enamel blocks.

The SEM study of the predemineralized enamel blocks showed the formation of an acid-resistant TiO2 coating changing the resistance of this surface to acid attack [8],[12],[22] as can be observed in [Figure 2]. From this coating, we can speculate that titanium could penetrate the enamel layers, resulting in increased mineral hardness. However, in spite of the presence of elements such as oxygen, chlorine, potassium, carbon, phosphorus and sodium, which were available in surface and subsurface enamel, according to [Figure 2] and [Figure 3], the presence of titanium was only observed on the enamel surface in the TiF4 and TiF4: β-CD groups. Although the depth of titanium penetration could not be observed at subsurface cross-sectional slabs using an EDS analysis method, one can conclude that the titanium released from TiF4: β-CD induced the rehardening of the enamel subsurface. We can suppose that a small amount of this compound was able to be incorporated into the enamel, favoring its mineral content. Another possibility that can explain the absence of titanium in the inner enamel is that its penetration seems to be greater in sound enamel than in predemineralized enamel.[7],[14] This difference could be related to a larger quantity of water, carbonate, and oxygen, improving the reactivity between titanium and the oxygen available in the dental structure.[6]

It is well known that fluoride uptake is higher in decalcified enamel when compared with sound enamel [23] due to the porosity of the decayed enamel.[24] However, titanium penetration occurred more deeply into sound enamel compared with artificially demineralized enamel.[7] This can be explained by the decrease in water and carbonate in the carious enamel, which decreased the titanium connection with oxygen in the dental structure. It is reasonable to suggest that the titanium applied to the predemineralized enamel blocked the surface used in this study, contributing to the enhancement of inner enamel microhardness by modifying the underlying enamel; however, this amount of titanium was not sufficient to be detected in the EDS analysis.

The cavity of the CD molecule is lipophilic (lined with skeletal carbons and ethereal oxygens of the glucose residues), resulting in a microenviroment into which suitably sized drug molecules may enter and be included, bestowing a useful property of these excipients, such as retarding or accelerating degradation. The CD molecule shields the drug molecule from attack by various reactive molecules. In others words, the CD can insulate a labile compound from a potentially corrosive environment, thereby reducing drug hydrolysis, oxidation, steric rearrangement, racemization, polymerization, and enzymatic decomposition.[25]

Among all natural CDs, β-CD is the most accessible, the lowest-priced and generally the most useful.[16] The advantages to using β-CD as employed here have already been illuminated.[6] The use of β-CD can improve on the methods by increasing the pH of the TiF4 nanosystems in solution, allowing professional use and increasing thermal stability. Further studies are necessary to assess the rehardening of other inclusion complexes to investigate if this phenomenon is similar to the findings presented in this paper.

Several studies were limited in scope to the potential of TiF4 to reduce the demineralization of dental hard tissue.[2],[3],[4],[6] The fact that remineralization is inhibited by TiF was explained by assessing the effect of a new TiF on enamel remineralization. It was observed that treatment with a TiF derivative resulted in strongly reduced calcium loss, but calcium uptake was also inhibited.[14] This finding highlights that this compound may not be capable of improving lesion repair.

A previous in vivo study showed that a single application of 4% TiF4 solution for 1 min produced an unexpected pigmented layer over the enamel surface.[26] This phenomenon may have occurred probably because the interaction between TiF4 and the proteins of the tooth that provoked changes in the glaze-like layer. The solutions reported in the current study are not 4% but 1%, and over the bovine enamel slabs, this undesirable pigmented layer was not observed in vitro.

In this in vitro study, the TiF4: β-CD inclusion complex was effective in rehardening artificially predemineralized bovine enamel blocks. TiF4 is also advantageous in protecting enamel from demineralization.[6],[14] Lesion arrest seemed to be the maximum achievable result because TiF4 provides long-lasting fluoride delivery and leaves large amounts of titanium on the surface glaze layer.[22]

   Conclusion Top

A single application of the solution containing the inclusion nanocomplex formed of TiF4 and β-CD over the enamel blocks was able to reharden the enamel subsurface. This paper highlights a new inclusion nanocomplex used for the treatment of demineralized enamel. Future studies should be carried out before the clinical application of this compound.


We are grateful to FAPERJ (Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro) and CNPq (National Counsel of Technological and Scientific Development).

Financial support and sponsorship

This study was supported by FAPERJ (No. E-26/201.316/2014) and National Council for Scientific and Technological Development-CNPq. The updated grant number is 303535/2016-4.

Conflicts of interest

There are no conflicts of interest.

   References Top

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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1]

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