Role of titanium tetrafluoride (TiF₄) in conservative dentistry: A systematic review

Abstract

The role of fluoride to reduce demineralization and enhance remineralization of dental hard tissue has been well documented. Different forms of fluoride solutions have been topically used in dentistry as prophylactic agents against tooth decay. In the recent past, metal fluorides, especially titanium tetrafluoride, have become popular in the fraternity of dental research due to their unique interaction with dental hard tissue. Many studies on titanium tetrafluoride, with positive and negative conclusions, have been published in many research journals. This gives the reader a plethora of inconclusive results with one study neutralizing the outcome of other, which confuses us regarding the present status of titanium tetrafluoride in the field of dentistry. This is an endeavor to organize and present the various studies of this unique compound, to provide us with a lucid overall review of its versatile potential application in dentistry, along with its fallacy/drawbacks. We have discussed its role as a cariostatic agent, pit and fissure sealant, tooth desensitizer, against dental erosion, as a root canal irrigant and others.

INTRODUCTION

The preventive value of topically applied fluorides has been well accepted. However, unlike the commonly used fluorides (e.g., NaF, SnF₂, APF), titanium tetrafluoride TiF₄) has shown to offer greater protection against caries and tooth erosion. The unique interaction of TiF₄ with tooth structure leads to the formation of a resistant tenacious coating (referred as glaze-like layer) on the tooth surface,[1,2] and it has a higher and a rapid uptake of fluoride in enamel, dentin and root surface.[3,4] The advantage has been credited to the titanium group present in the compound, which synergizes the effect of fluoride.[2,5]

This paper critically analyzes this compound after gleaning the information and a thorough evaluation of the various studies done in the past and the present, under different protocols.

MECHANISTICS OF FLUORIDE

It was thought for many years that fluoride acted basically by its incorporation in the hydroxyapatite lattice and the reduced solubility of the so-formed fluoridated hydroxyapatite.[6,7] On the contrary, it was shown that shark enamel, which consists of solid fluorapatite, also developed carious lesion in an in situ experiment in high caries challenge regimen.[8] Thus, even the complete substitution of fluoride for hydroxyl ions of apatite crystals did not prevent demineralization. Later studies revealed that it was not the intrinsic fluoride content of tissues but rather the loosely bound or labile fluoride present at the tooth–oral fluid interface, which was responsible for effective inhibition of lesion formation.[9,10] It was observed that a continuous low level of fluoride influences the rate at which the lesions develop (demineralization) and are repaired (re-mineralization). This has initiated the research aimed at developing “slow releasing devices for fluoride”. Fluoride topical applications, particularly when acidified, result in the formation of globular deposits of CaF₂ and CaF₂-like materials. These CaF₂-like globules do not dissolve as quickly as expected presumably because of the interaction of the outer surface of the CaF₂ globules with phosphate and/or protein, i.e., there seems to be a phosphate-induced inhibition of calcium fluoride dissolution. The dissolution of the fluoride from the globules is pH dependant, presumably because the phosphate ions on the surface are released when protonated at a low pH. Therefore, phosphate-induced inhibition of calcium fluoride dissolution was found to be decreased at a pH below 5.[11] By this mechanism, fluoride is dissolved from the globules at the time fluoride is most needed (i.e., at low pH). This mobile fluoride gets firmly bound, forming fluoridated hydroxyapatite crystals. The acid cycle thus contributes to the conversion of loosely bound to firmly bound fluoride, and consequently, to the reduction of the source of fluoride that can be mobilized, emphasizing on the requirement of the frequent application of topical fluoride.

It has also been suggested that fluoride topical application with high concentration of fluoride may be effective due to the antimicrobial effects of fluoride ; however, this is still debatable.[12]

TiF₄ AND DENTAL CARIES

McCann[13] suggested an additional mechanism for fluoride fixation in enamel in which the fluoride is bound to a polyvalent metal ion in the form of a strong complex. He studied the effect of various metals (Al, Ti, Zr, La, Fe, Be, Sn, Mg, Zn) on the uptake and retention of fluoride. He discovered that both fluoride uptake and retention could be enhanced when the tooth is pretreated with any polyvalent metal capable of forming strong fluoride complexes while simultaneously binding to the apatite crystals. This suggested the use of fluoride complexes in topical treatment as a means of increasing fluoride in enamel. Titanium ion pre-treatment showed the maximum uptake and retention, followed by aluminum. Andrew J Reed's[14] preliminary test in animals showed that topical application of TiF₄ (1%) was more effective in reducing enamel solubility and in preventing caries than the application of stannous fluoride, sodium fluoride and aluminum phosphate fluoride. These results along with the lack of irritating properties, stability of the TiF₄ solution and nontoxicity of titanium suggested its use for prevention of caries in man; however, its high acidity was questionable.

Skartviet et al.[15] evaluated the demineralizing effect of highly acidic TiF₄. In his study, root surface reactions of TiF₄ were compared with native and acidified SnF₂. After an application period of 1 minute, acidified SnF₂ (pH 1) showed marked complete demineralization (4–7 μm deep). TiF₄ solution (pH 1) produced only partial demineralization of 8–10 μm zone in spite of the low pH, whereas SnF₂ at a native pH produced a 0.5–1.0 μm partially demineralized zone. Although a high fluoride uptake has been reported after topical application of acidified SnF₂ to roots,[16] this agent may be less appropriate for clinical use due to the marked complete demineralization. Partial demineralization by TiF₄ at the same pH was explained by Tveit[16] based on the fact that titanium ion has a very strong affinity to oxygen atom as compared to stannous ion. Titanium ion can readily hydrolyze H₂O (as compared to Sn) to expel proton (H+) and render the solution a low pH value. This attributes to the fact that TiF₄ solution is very acidic, whereas SnF₂ has a higher pH value. Also, this great affinity of titanium ion to oxygen imparts a strong tendency to form titanium phosphate complex (i.e., titanium ion reacting with the oxygen atom of the phosphates of the tooth structure). The bond of the complex thus formed is so strong that it is not easily substituted by protons (H+) even at low pH (pH 1), thereby rendering the altered tooth surface more resistant to demineralization despite the fact that TiF₄ solution is highly acidic. Similarly, it is established and can be concluded from the fact that since stannous ion has a limited affinity to oxygen, neither will it efficiently hydrolyze water to provide a high H+ concentration nor the tin-phosphate complex so formed is that strong. Therefore, in the case of highly acidified SnF₂, the H+ will easily displace the Sn from the tin–phosphate complex and the protonated phosphate from the tooth structure will go into the solution, leaving a deep demineralized surface. But in native SnF₂ solution, the H+ concentration is not adequate enough (due to weak hydrolysis) to displace Sn from the tin–phosphate complex, so limited surface demineralization is evident when such a solution is used. Penetration of fluorides into dental hard tissues is enhanced if the surface is slightly demineralized. Therefore, the low pH of TiF₄ appears to be a boon in disguise due to the unique property of titanium ion. The slight demineralization that occurs is expected to remineralize within a few weeks in the oral cavity.[17,18]

When compared with other topically used fluorides, the use of TiF₄ seems to have great advantages. Higher uptake and greater penetration of fluoride and lower acid solubility of the tissues has been seen with TiF₄ when compared to NaF.[3] In the case of acidulated phosphate fluoride, a considerable uptake and penetration of fluoride has been seen but is accompanied with marked surface demineralization.[3] A 1% solution of TiF₄ produces a high and long lasting fluoride concentration in root surfaces after an application period of as less as 10 seconds.[19] The rapid reaction with hard tissue as well its high potential for caries inhibition both in humans[14] and animals[20] prompted further investigation.

It was observed that in addition to increasing the fluoride content, topical application of TiF₄ may also change the surface morphology of enamel. The aqueous solution of TiF₄ when applied topically on dental hard tissue, results in the formation of a surface coating. The surface coating was first detected with the naked eye and was identified as glaze like.[21] Subsequent scanning electron microscopy (SEM) examination clearly demonstrated a massive coating containing numerous spherical particles,[1,2,4] which was not removed by 24 hour inorganic wash, KOH wash[4] or after acid etching.[22] Thus, interaction between TiF₄ and tooth appears to differ from that of other fluoride preparations. The marked protective effect of TiF₄ is attributed to the following: 1) chemically decreasing enamel solubility by increasing the fluoride content and 2) physically providing a protective glaze resistant to any acid penetration.

TiF₄ AS A PIT AND FISSURE SEALANT

Buyukyilmaz and Sen[23] observed that the glaze formed after application of 4% TiF₄ on the occlusal surface of deciduous enamel was retained in the area of pits and fissures even after a period of 12 months despite the masticatory and abrasive forces working in the mouth. Due to the formation of the resistant glaze and its long-term retention, topical TiF₄ application may be an effective way of sealing pits and fissures. Also, when compared with other commonly used sealants (modified glass ionomer and resin-based sealant) which require completely dry field, TiF₄ application appears to be less technique sensitive and less time consuming. Thus, the ease of application and reduced operating time seems to be an added benefit, along with the absence of any tooth discoloration and gingival irritation.

TiF₄ AND DENTAL EROSION

Dental erosion is a pathologic, chronic, localized loss of dental hard tissue that is chemically etched away from the tooth surface by acid and\or chelation without bacterial involvement.[24] Frequent consumption of acid containing food is a well-known etiologic factor.[25] Endogenous cause of dental erosion is vomiting in patients suffering from anorexia bulimia and long-term gastroesophageal reflux diseases.[26] Dental erosion is so prevalent worldwide that it has raised concern of our profession for its prevention and arrest. Many topical fluoride preparations have been used, but with certain limitations.[27,28] Enamel erosion leaves a partly demineralized softened surface which can remineralize by the mineral deposition after topical fluoride application. The protective action of topical fluoride is the precipitation of CaF₂-like material on the eroded tooth surface. However, one of the major disadvantages of these protective coatings is that they possibly readily dissolve in acidic solution,[29] so the effectiveness of these fluorides in preventing enamel erosion is limited.[30] Hughes et al.[31] found that in-vitro neutral fluoride pretreatment and treatment with acidulated fluoride gel led to a reduction of enamel erosion by acidic beverages by about 10% and 24%, respectively . Vanrijkom et al.[32] found that enamel erosion was reduced by about 20% by a NaF gel compared to untreated controls. In dentinal erosion, fluoride application is much more effective, the reason being that unlike enamel erosion, dentinal erosion results in a fully demineralized outermost layer, leaving exposed organic dentine matrix followed by a partly demineralized zone and then inner sound dentine.[33,34] The demineralized matrix layer firstly serves as a barrier for further loss of minerals from the deeper dentinal layers. Secondly, the buffering potential of the organic matrix layer (due to the ampholytic nature of proteins present) is sufficient to retard or stop (in the presence of high amount of fluoride) any further demineralization. Therefore, after an initial demineralization, an intensive fluoridation is capable of inhibiting erosive mineral loss in dentine, which is related to exposed dentinal matrix.[35] An intensive fluoridation measure requires frequent rinsing and applications, which is cumbersome. Hence, a better modification of tooth surface is desired, and this became the need of the hour. The unique ability of TiF₄ to form precipitates other than CaF₂, which are particularly resistant to any kind of dissolution or disintegration, attracted many researchers. Buyukyilmaz et al.[2] found that enamel treated with 1% and 4% TiF₄ and subsequently with hydrochloric acid (HCl) for 5 minutes showed a massive surface layer covering the enamel, which appeared to be resistant to HCl, even after continuous exposure for 5 minutes. Hove et al.[36] also found that the superior effect of TiF₄ over NaF in inhibiting the erosive effect of hydrochloric acid on enamel could possibly be due to this coating. Schlueter et al.,[37] in his in-vitro study, also found that the overall effect of TiF₄ in reducing mineral loss exceeds that of NaF, when both solutions had a pH of 1.2 . Hove et al.[38] compared the protective effects of TiF_4, SnF₂ and NaF on the development of erosion like lesion in human enamel. NaF (2.1%) had no significant protective effect. TiF₄ (1.5%) and SnF₂ (3.9%) reduced the etching depth by 100% and 91%, respectively, as compared to the controls, and both the treatments resulted in an amorphous surface layer. A coating has also been described following SnF₂ treatment of enamel by Hove et al.,[36] but was found to be less resistant than the TiF₄ glaze.

TiF₄ IN ENDODONTICS

Since it was first reported in 1975 that there was smear layer on the walls of instrumented root canal,[39] there has been an enormous amount of research and debate on the advantages and disadvantages of removing the smear layer before obturation. But none could win the consensus agreements of the endodontic community. Hence, a mid pathway of modifying the smear layer in such a way that it completely becomes resistant to dissolution or disintegration has been conceptualized. Furthermore, the modified layer blocks all the dentinal tubules of the root canal wall completely and permanently to minimize the chances of re-infection. Such a promising bio-mechanical and bio-chemical alteration of root canal wall has been observed when treated with TiF₄ due to its unique interaction with the hard tissue. Sen[40] did a preliminary investigation on the effect of TiF₄ on the root canal walls using scanning electron microscope. He observed the presence of a massive and definite surface coating of the canal walls, blocking the dentinal tubules, regardless of the presence or absence of a smear layer. The smeared surfaces showed a thicker coating (1–5 μm) than the unsmeared surfaces hence it was assumed that TiF₄ might have interacted with the smear layer. His further studies also showed that the commonly used irrigants (17% EDTA and/or 5.25% NaOCl) were not able to remove or reduce the thickness of this surface coating. Also, study of Kazemi et al.[41] has shown the modification of the smeared dentine surface to an acid stable and resistant state due to application of TiF₄. This exclusive finding of the TiF₄ smear layer interaction, giving a resistant structure, indicated the potential use of TiF₄ in reducing the microleakage in Endodontics.

Furthermore, as the surface coating has shown to block the dentinal tubules completely and permanently, TiF₄ application on dentinal surface may reduce dentinal hypersensitivity.[42]

PHYSICAL AND CHEMICAL LITERATURE OF TiF₄

Counting on the added advantages of TiF₄ compared to other topical fluorides, like the formation of acid-resistant coating, increased and rapid uptake of fluoride along with greater permeation[3] and longer retention of fluoride[43] along with no undesired demineralization, one becomes quite inquisitive to know the chemistry behind its action. There have been several hypotheses, suggestions and theoretical derivatives postulated as to how the glaze layer is formed, but the precise proven chemistry of its genesis is yet to be known. Some suggestive findings of the mechanism of action have been reviewed here.

Mundorff et al.[21] reported the physical appearance of dry glazed enamel as hard and glassy, reflecting spectrum colors, and as being strongly hydrophobic in nature. When an attempt was made to know the underlying chemistry, it was found that both sub-surface as well as surface organic material were possibly involved in glaze formation. The finding was based on the fact that less glaze was formed on enamel that had the organic material of the tooth removed with hot ethylenediamine. A study by Gu et al.[44] also proved that the organic components in enamel play an important role in the fluoride uptake after topical application of TiF₄. The chemical literature suggests that many types of reactions between the organic material and titanium are possible, forming organic titanates. These organic titanates are used as cross-linking agents for a wide variety of resin monomers. The physical appearance and the resistant nature of the glaze also reflected a similar polymeric texture. The glaze formed could be the result of cross linking taking place in the organic substances, making the layer resistant to any physical destruction. Also, the observed hydrophobicity of the glaze could be due to this polymeric layer. Bibby et al.[14] also suggested that both fluoride and titanium combine in some way with organic material of dental enamel. The earlier gleaned information was further strengthened by a recent study of Wiegend.[45] He found that TiF₄ reduced dental erosion but was more effective on dentine than on enamel. Also, the efficacy was found to be greater on pellical covered specimens compared to pellical free specimens. The increased protective effect was attributed to the higher organic component in dentine and pellicle (pellicle is an acellular organic film deposited on teeth).[46]

Despite the diverse studies proving the effects and beneficial properties of TiF₄, its performance is still questionable and the chemistry is not completely understood.

Alves et al.[47] have tested and proven the invalidity of two clinical studies dealing with the preventive and cariostatic potential of TiF₄. With regard to sample size and method of selection, the studies conducted by Buyukyilmaz et al.[48] and Reed and Bibby[14] were not considered ideal. Randomized controlled clinical trials are still necessary in some proven studies to confirm the effectiveness of TiF₄ clinically. Wiegand[45] analyzed the protective effect of different tetrafluoride compounds and found that enamel protection against short time erosion was more enhanced by zirconium tetrafluoride (ZrF₄) and hafnium tetrafluoride (HfF₄) compared to TiF₄ application overtime. In addition, SEM images of enamel/dentine treated with TiF₄ varnish/solution show microcraks in the surface coatings.[33,34] The explained reason was the dehydration procedure done for specimen preparation to be observed under SEM. Conversely, no cracks were observed with the control group which had undergone similar dehydration technique. A more thorough understanding of the etiology of the cracks should be provided as these cracks may grow in size and depth and possibly may lead to the failure of the modified (TiF₄-treated) smear layer in permanently and completely occluding the dentinal tubules. Also, the risk associated with the irrigation of root canal with the highly acidic TiF₄ is obvious and has to be evaluated. The high fluoride concentration present in TiF₄ solutions may cause possible damages of overdosing.

Recently, a study reported that the application of TiF₄ solution increased the softening of deciduous enamel caused by an erosive challenge in-situ , the effect being unexplained.[49] Similarly, studies conducted by Magalhaes in 2007[50] and 2008[51] regarding the potential of TiF₄ as varnish have given contradictory findings, and hence, inconclusive results regarding its efficacy. It can be concluded that TiF₄ is very hygroscopic, making its handling difficult.

FUTURE

Future research should focus on the following.

1. Further evaluation of TiF₄ as a root canal irrigant. Interaction of TiF₄ treated smear layer with bonded and non-bonded restoration, routinely used obturating materials, sealers and endodontic irrigants.

2. Effect of this modified smear layer on microleakage as well as its resistance to bacteria and bacterial by-products perpetrating the dentinal tubules.

3. In vivo evaluation of the cytotoxic effect of TiF₄, in case of extrusion into the periradicular tissue.

4. Detangling the real chemistry behind the acid resistance property of TiF₄.