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 Table of Contents  
ORIGINAL HYPOTHESIS
Year : 2021  |  Volume : 12  |  Issue : 4  |  Page : 202-205

Fluoride Plus Calcium Phosphate Varnishes: A Possible Link between Mineral Phase Formations and Observed Clinical Outcomes


Indiana Nanotech, LLC, Indianapolis, IN, USA

Date of Submission18-Aug-2021
Date of Decision11-Nov-2021
Date of Acceptance30-Nov-2021
Date of Web Publication21-Dec-2021

Correspondence Address:
Robert L Karlinsey
Indiana Nanotech, LLC, Indianapolis, IN, Zipcode: 46259
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/denthyp.denthyp_117_21

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  Abstract 


Introduction: Incorporation of calcium phosphate agents into fluoride varnishes might improve anticaries benefits. But when clinical results do not mirror this view, explanations remain unclear. The hypothesis: Our hypothesis is that better clinical outcomes are obtained from fluoride plus calcium phosphate varnishes when there is sustained, controlled release of mineralizing ions. Evaluation of the hypothesis: Calculations of ion activity products and putative mineral phases have been underutilized in assessing clinical outcomes of fluoride varnishes with calcium phosphate agents. In this study, a mineral phase comparison between a low-release varnish comprising functionalized tricalcium phosphate (fTCP) against a high-release varnish comprising casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) was made. These calculations revealed the predominance of hydroxyapatite, fluorapatite, and calcium fluoride formation for the varnish containing fTCP, whereas the varnish containing CPP-ACP produced the same minerals along with β-TCP and octacalcium phosphate. This hypothesis shows the mineral phases expected to form from fluoride plus calcium phosphate varnishes might bear on clinical outcomes.

Keywords: CPP-ACP, fluoride varnish, fTCP, ion-release, mineral phase


How to cite this article:
Karlinsey RL. Fluoride Plus Calcium Phosphate Varnishes: A Possible Link between Mineral Phase Formations and Observed Clinical Outcomes. Dent Hypotheses 2021;12:202-5

How to cite this URL:
Karlinsey RL. Fluoride Plus Calcium Phosphate Varnishes: A Possible Link between Mineral Phase Formations and Observed Clinical Outcomes. Dent Hypotheses [serial online] 2021 [cited 2022 Jan 25];12:202-5. Available from: http://www.dentalhypotheses.com/text.asp?2021/12/4/202/333015




  Introduction Top


Fluoride varnishes are routinely used throughout the world as a minimally invasive anticaries approach, conferring, for example, an estimated 46% reduction in caries risk benefit for children.[1] As caries continues to be an ongoing − and sometimes increasing − problem, boosting varnish efficacy is an appealing strategy and one approach is to incorporate calcium phosphate for possible remineralization benefits. Recent clinical data on two remineralization varnish systems command further scrutiny: one system is MI Varnish (GC America, GC Corporation, Tokyo, Japan), which contains 5% NaF plus casein phosphopeptide-amorphous calcium phosphate (CPP-ACP),[2],[3] and the other is Clinpro White Varnish (3M, St. Paul, MN, USA), a 5% NaF system with a functionalized form of tricalcium phosphate (fTCP).[4],[5]

Recently, a year-long randomized, double-blind clinical study from an independent group was published comparing two 5% NaF varnishes on a high-risk caries group with xerostomia and root caries: one with and one without CPP-ACP, applied 4× throughout the year.[6] Despite the high elution of significant calcium, phosphate, and fluoride mineralizing species,[3],[7] similar to other independent clinical outcomes, these results showed CPP-ACP did not confer additional caries benefits.[8],[9]

Separately, a two-year randomized, double-blind caries clinical study was conducted by an independent group on children with active dentine caries that involved two different 5% NaF varnishes applied twice annually: one with and one without fTCP.[10] Results demonstrated that the 5% NaF varnish with fTCP (Clinpro) produced a significant clinical benefit in arresting carious dentine lesions relative to the fluoride-only varnish.[10] These results are consistent with other independent reports on Clinpro varnish clinical efficacy,[11],[12] but might be surprising, as this varnish is designed to elute relatively low levels of mineralizing ions.[3],[4]

Supported with these recent independent, longer-term clinical studies, it is of high interest to explore limitations of fluoride plus calcium phosphate varnishes. Perhaps inspired by fluoride’s powerful dose–response effect, researchers are often tempted to correlate remineralization capability to high volumes of available mineralizing ions (i.e., “more is better”). But when clinical results do not mirror this view, explanations remain unclear.[6],[8],[9] Therefore, the purpose of this study is to present a hypothesis that specifically points to why fluoride plus calcium phosphate varnishes might yield different clinical outcomes.


  The Hypothesis Top


Our hypothesis is that better clinical outcomes are obtained from fluoride plus calcium phosphate varnishes when there is sustained, controlled release of mineralizing ions. By avoiding a mass “dumping” of calcium, phosphate, and fluoride ions, remineralization pathways are more likely to avoid bulk precipitation of less-desirable mineral phases [such as TCP, octacalcium phosphate (OCP)], while encouraging the formation of highly desirable calcium fluoride (CaF2), hydroxyapatite (HAP), and/or fluorapatite (FAP) minerals.


  Evaluation of the Hypothesis Top


Calculations of ion activity products and putative mineral phases are largely reserved for lab-based and/or theoretical solutions to identify important ionic species believed to play a role in observed remineralization in enamel[13] and dentin.[14] These calculations can provide important mechanistic details about a particular formulation; however, such calculations have not been used to assess clinical outcomes of commercially available fluoride varnish comprising calcium phosphate agents.

The latest reports on two well-designed, independent clinical studies on MI Varnish and Clinpro White Varnish with fTCP,[6],[10] along with published data on ion-release from these two fluoride varnishes,[3] provide an opportunity to determine whether possible mineral phases might help explain the contrasting clinical outcomes. Published concentrations of ions released into water at 1, 4, and 24 hours at 37°C (ppm is used instead of the originally reported μmol/g)[3] were used along with ion-species activity (γ),[13],[14] as this accounts for the nonideal nature of interacting ions. As noted in the footnote of [Table 1], no PO43- was detected from the Clinpro varnish at the 1- or 4-hour timepoint in the original work[3]; while this is not disputed and can be expected based on fTCP design for the varnish format,[4],[5] in the event detection limits of the original methodologies were limited, we used a nonzero value of 1 ppm. One could also use 0.1 ppm (or lower) PO43-, as the same three mineral phases (HAP, FAP, and CaF2) are predicted.
Table 1 Theoretical mineral formation by ions released from Clinpro and MI Varnish Systems

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The Visual MINTEQ software program (KTH, Sweden)[15] was used to calculate the activities, ionic species distribution, and ion activity products listed in [Table 1], with calculations made using the empirically derived Davies equation , where z is the charge of the ionic species and I is the ionic strength. For dilute concentrations (weak ionic strength, which pertains especially to the fTCP system), the Davies equation reduces to the extended Debye–Hückel equation.

The supersaturation index (log IAP − log Ksp) in [Table 1] is a measure of the ion activity product for specific ion concentrations (e.g., Ca2+, PO43-, and F- measured for each varnish at 1-, 4-, or 24-hour timepoints) against the solubility product (Ksp). For positive differences (i.e., oversaturation), the mineral is expected to precipitate, but if negative (i.e., undersaturation) it does not.

[Table 1] summarizes five possible mineral phases expected to precipitate given the concentrations listed: beta-TCP (β-TCP), OCP, HAP, FAP, and CaF2.

At the 1- and 4-hour timepoints, Clinpro varnish produces HAP, FAP, and CaF2. In contrast, MI Varnish produces these three phases, along with two additional calcium phosphate minerals: β-TCP and OCP. Clinically, the 1- and 4-hour timepoints are most realistic, as bulk varnish is likely to be cleared from the oral environment due to natural salivation, dietary, and hygiene events. If bulk elution is allowed to progress undisturbed for 24 hours, then both varnishes produce these five mineral phases. Importantly, the calculations did not predict the formation of dicalcium phosphate anhydrous or dicalcium phosphate dihydrate (DCPD) for either varnish system. For all three timepoints, MI Varnish produces higher degrees of supersaturation relative to Clinpro varnish, suggesting all phases would be readily produced on varnish-coated dentition; in contrast, fTCP is most likely to produce HAP, FAP, and CaF2.

The activity and distribution of ionic species (not shown for brevity) calculated for the fluoride varnish systems are unique, and account for the precipitated mineral phases in the table. Overall, a high fraction of free calcium (i.e., Ca2+) along with low phosphate activity (e.g., HPO42-) favor HAP, FAP, and CaF2 formation with little to no β-TCP and OCP formation. In contrast, a lower fraction of free calcium along with a higher phosphate content increases the likelihood of β-TCP and OCP formation. Examples of activities produced from these varnishes are discussed below.

At the 1-hour timepoint, while the activity of HPO42- is ∼100× larger for MIV Varnish (3.6 × 10−4 ppm for Clinpro varnish compared to 1.2 × 10−2 ppm for MI Varnish), the activity of Ca2+ is ∼2× larger for Clinpro (5.4 × 10−4 ppm and 2.8 × 10−4 ppm, respectively). Likewise, Clinpro and MI Varnish activities for CaHPO4(aq) are 9.9 × 10−7 and 1.8 × 10−3 ppm, respectively (a 10,000× difference). Additionally, from a percent distribution perspective also at the 1-hour timepoint, Clinpro varnish produces 93% Ca2+, 7% CaF+, and 0.1% CaHPO4(aq), whereas MI Varnish produces 36% Ca2+, 55% CaF+, and 8.4% CaHPO4(aq). These activities for MI Varnish are consistent with those previously reported for CPP-ACP, including the precipitation of the additional β-TCP and OCP mineral phases.[2]

The formation of HAP and FAP has obvious clinical benefits, whereas CaF2 (including calcium fluoride-like mineral) is expected to also form from high-fluoride topical treatments.[16],[17] There is broad consensus that CaF2 formation allows the slow dissolution − and thus, incorporation − of fluoride into weakened enamel structure.[17]

When HAP forms in nucleation experiments, it is not unusual for intermediate phases such as β-TCP and OCP to exist.[18] Ideally, these phases would not remain after the conversion to HAP, otherwise they would manifest as calculus-like deposits. As mineral-phase calculations do not provide details regarding kinetics, it is not possible to comment on the duration of possible mineral phases. The mineral-phase calculations are sensitive to the nature of ionic species and the thermodynamic stability of any phases that might form. The possibility that CPP-ACP promotes the concomitant formation of β-TCP and OCP suggests these stable phases might inhibit calcium, phosphate, and fluoride incorporation into weakened enamel. CPP-ACP pastes have been shown to inhibit fluoride’s action in situ.[9] As a carious surface becomes fluoridated, it also becomes restrictive to ion (or, ion pair, such as CaHPO4(aq)[2]) diffusion,[19] and it is known that high calcium concentrations may inhibit ion diffusion.[20] Once sufficient fluoride-based mineralization develops at the tooth surface, it is possible that calcium and phosphate ions freed from β-TCP and OCP during an acidic event might reprecipitate minerals that cannot readily integrate within the tooth. Even if these mineral phases are formed within weakened tooth structure, they are not as mechanically durable or acid-resistant relative to HAP, FAP, and CaF2 mineral. As such, these calculations might help explain the initial short-term but not long-term benefits of CPP-ACP.[6]

One way to form high-quality apatite mineral is to minimize the number of phase transitions traversed. Studies show low supersaturation levels of calcium and phosphate can achieve HAP formation without precipitating bulk amounts of intermediate phases (such as DCPD, β-TCP, or OCP)[21]; in fact, calcium ions may be of lesser importance in lesion remineralization.[22] Clinpro varnish is unique among fluoride varnishes as it delivers low levels of soluble fluoride, calcium, and phosphate.[10] The fact that HAP, FAP, and CaF2 predominate when Clinpro is applied may account for the significant benefits observed in the recent 2-year caries clinical study.[10]

Delivering low fluoride levels has long been recommended[17] and this is based on observations that (1) low-level fluoride prevents caries (e.g., community water-fluoridation programs), and (2) low levels present lower risks of acute fluoride ingestion. The fluoride levels in [Table 1] show MI Varnish releases ∼17,000 ppm fluoride within 4 hours, whereas ∼226 ppm fluoride is released from Clinpro. As clinical data showed MI Varnish did not elicit anticaries benefits, those authors surmised excess fluoride was swallowed or otherwise cleared.[6]

Based on our hypothesis, clinical outcomes of fluoride varnishes with different ion-release profiles might be correlated to expected mineral formation. Well-designed, independent clinical studies with minimal bias risks will further test the strength of the hypothesis presented here.

Financial support and sponsorship

Nil.

Conflicts of interest

RLK is the inventor of the fTCP agent found in the 3M Clinpro™ varnish, and as a result has a relationship with 3M.



 
  References Top

1.
Marinho VCC, Higgins JPT, Logan S, Sheiham A. Fluoride varnishes for preventing dental caries in children and adolescents. Cochrane Database Syst Rev 2002;3:CD002279.  Back to cited text no. 1
    
2.
Reynolds EC. Remineralization of enamel subsurface lesions by casein phosphopeptide-stabilized calcium phosphate solutions. J Dent Res 1997;76:1587-95.  Back to cited text no. 2
    
3.
Cochrane NJ, Shen P, Yuan Y, Reynolds EC. Ion release from calcium and fluoride containing dental varnishes. Aust Dent J 2014;59:100-5.  Back to cited text no. 3
    
4.
Karlinsey RL, Pfarrer AM. Fluoride plus functionalized β-TCP: a promising combination for robust remineralization. Adv Dent Res 2012;24:48-52.  Back to cited text no. 4
    
5.
Karlinsey RL, Mackey AC, Walker ER, Frederick KE. Preparation, characterization and in vitro efficacy of an acid-modified β-TCP material for dental hard-tissue remineralization. Acta Biomater 2010;6:696-78.  Back to cited text no. 5
    
6.
Sleibi A, Tappuni AR, Baysan A. Reversal of root caries with casein phosphopeptide-amorphous calcium phosphate and fluoride varnish in xerostomia. Caries Res 2021;55:475-84.  Back to cited text no. 6
    
7.
Sleibi A, Tappuni AR, Karpukhina NG, Hill RG, Baysan A. A comparative evaluation of ion release characteristics of three different dental varnishes containing fluoride either with CPP-ACP or bioactive glass. Dent Mater 2019;35:1695-705.  Back to cited text no. 7
    
8.
Rechmann P, Bekmezian S, Rechmann BMT, Chaffee BW, Featherstone JDB. MI Varnish and MI Paste Plus in a caries prevention and remineralization study: a randomized controlled trial. Clin Oral Investig 2018;22:2229-39.  Back to cited text no. 8
    
9.
Meyer-Lueckel H, Wierichs RJ, Schellwien T, Paris S. Remineralizing efficacy of a CPP-ACP cream on enamel caries lesions in situ. Caries Res 2015;49:56-62.  Back to cited text no. 9
    
10.
Chen KJ, Gao SS, Duangthip D, Lo ECM, Chu CH. Randomized clinical trial on sodium fluoride with tricalcium phosphate. J Dent Res 2021;100:66-73.  Back to cited text no. 10
    
11.
Salamara O, Papadimitriou A, Mortensen D, Twetman S, Koletski D, Gizani S. Effect of fluoride varnish with functionalized tri-calcium phosphate on post-orthodontic white spot lesions: an investigator-blinded controlled trial. Quintessence Int 2020;51:854-62.  Back to cited text no. 11
    
12.
Juárez-López MLA, Adriano-Anaya MdP, Molina-Frechero NM, Murrieta-Pruneda F. Remineralization effect on incipient carious lesions of a sodium fluoride with tricalcium phosphate varnish. Acta Pediatr Mex 2018;39:263-70.  Back to cited text no. 12
    
13.
Larsen MJ, Pearce EIF. Saturation of human saliva with respect to calcium salts. Archs Oral Biol 2003;48:317-22.  Back to cited text no. 13
    
14.
Hara AT, Karlinsey RL, Zero DT. Dentine remineralisation by simulated saliva formulations with different Ca and Pi contents. Caries Res 2008;42:51-6.  Back to cited text no. 14
    
15.
Gustafsson JP. Visual MINT EQ. Version 3.1 [software]. December 21, 2013. Available at https://vminteq.lwr.kth.se/. [Accessed August 25, 2021].  Back to cited text no. 15
    
16.
Øgaard B. CaF2 formation: cariostatic properties and factors of enhancing the effect. Caries Res 2001;35(Suppl 1):40-4.  Back to cited text no. 16
    
17.
Featherstone JDB. Prevention and reversal of dental caries: role of low level fluoride. Community Dent Oral Epidemiol 1999;27:31-40.  Back to cited text no. 17
    
18.
Habraken WJEM, Tao J, Brylka LJ et al. Ion-association complexes unite classical and non-classical theories for the biomimetic nucleation of calcium phosphate. Nat Commun 2013;4:1-12.  Back to cited text no. 18
    
19.
Ten Cate JM, Arends J. Remineralization of artificial enamel lesion in vitro. Caries Res 1977;11:277-86.  Back to cited text no. 19
    
20.
Silverstone LM. Remineralization phenomena. Caries Res 1977; 11(Suppl 1):59-84.  Back to cited text no. 20
    
21.
Amjad Z, Koutsoukos P, Tomson MB, Nancollas GH. The growth of hydroxyapatite from solution. A new constant composition method. J Dent Res 1978;57:909-10.  Back to cited text no. 21
    
22.
Backer Dirks O. Posteruptive changes in dental enamel. J Dent Res 1966;45:503-11.  Back to cited text no. 22
    



 
 
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