Review Caries Res 2015;49(suppl 1):11–17 DOI: 10.1159/000380887
Published online: April 13, 2015
Noninvasive Dentistry: A Dream or Reality? B.H. Clarkson a R.A.M. Exterkate b a
Key Words Cavitated lesions · Precavitated lesions · Remineralization
Abstract Various caries prevention and repair strategies are reviewed in this article ranging from the use of fluoride to nanohydroxyapatite particles. Several of the strategies which combine fluoride and calcium and phosphate treatments have both in vitro and in vivo data showing them to be efficacious if the surface integrity of the lesion is not breached. Once this has occurred, the rationale for cutting off the nutrient supplies to the pathogenic bacteria without the removal of the infected dentine, a noninvasive restorative technique, is discussed using existing clinical studies as examples. Finally two novel noninvasive restorative techniques using fluorohydroxyapatite crystals are described. The need for clinical data in support of emerging caries-preventive and restorative strategies is emphasized. © 2015 S. Karger AG, Basel
Despite all the efforts and advances that are made in the prevention and reversal of tooth decay, caries still affects large numbers of patients. Ideally, prevention of tooth decay would be the goal to achieve. Complete inhibition of caries has been a utopia until now. © 2015 S. Karger AG, Basel 0008–6568/15/0497–0011$39.50/0 E-Mail [email protected] www.karger.com/cre
Caries is caused by acid-producing bacteria in oral biofilms that metabolize carbohydrates in our food and produce organic acids [Geddes, 1975]. These acids dissolve the dental hard tissues (carbonated hydroxyapatite) and gradually penetrate more deeply into the teeth causing white spot lesions and eventually cavitation. Fortunately, this process can be reversed by the natural presence of calcium and phosphate, originating mainly from saliva that can recrystallize inside the lesion under favorable conditions [Silverstone, 1973]. In order for teeth to remain sound, a balance is required between the dissolution (demineralization) and repair (remineralization) of the dental hard tissues. Fluoride has been shown to play an important role in these processes. Demineralization of dental hard tissues is inhibited by the presence of fluoride, and fluoride is also capable of increasing the rate and magnitude of remineralization of lesions [ten Cate and Duijsters, 1982; ten Cate and Featherstone, 1991; Zero, 2006]. However, in order for remineralization to be effective there is also a need for the building blocks of hydroxyapatite, calcium and phosphate, to be present during the periods that allow for lesion repair. The mere presence of fluoride is not always enough to allow remineralization to be effective. Fluoride is still the most used caries-preventive agent, with fluoridated toothpastes being the most used vehicle for delivery. Several factors have challenged the effectiveness of fluoride. Eating habits are changing Prof. B.H. Clarkson Department of Cariology, Restorative Sciences and Endodontics University of Michigan School of Dentistry Ann Arbor, MI 48109 (USA) E-Mail bricla @ umich.edu
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Department of Cariology, Restorative Sciences and Endodontics, University of Michigan School of Dentistry, Ann Arbor, Mich., USA; b Department of Preventive Dentistry, Academic Centre for Dentistry Amsterdam, Amsterdam, The Netherlands
Remineralization Strategies
In recent years several approaches have been developed to increase the availability of calcium and phosphate at the sites of risk. They have all been proven to be efficacious in in vitro studies, but it is generally acknowledged that clinical data are needed to prove their in vivo efficacy. Combining a Calcium Rinse and Fluoride Rinse One of the earliest approaches in increasing the concentrations of the building blocks of hydroxyapatite in dental plaque was combining a calcium prerinse with a fluoride rinse. This approach was mainly aimed at increasing fluoride levels in plaque and not so much at increasing the calcium concentration of plaque. Several authors [Grande et al., 1997; Vogel et al., 1997; Pessan et al., 2006; Vogel et al., 2006; Chen et al., 2014] demonstrated that the use of a calcium rinse prior to a fluoride rinse or fluoride toothpaste increased the substantivity of fluoride in plaque and/or saliva, but only limited data are available on the cariostatic effects of these elevated levels of fluoride. Shern et al. [1984] and Schreiber et al. [1988] showed in rat studies that combining an acidic calcium phosphate rinse with a fluoride rinse resulted in a higher fluoride content of the enamel, but failed to show a significant additional reduction in caries scores compared with a fluoride rinse alone. 12
Caries Res 2015;49(suppl 1):11–17 DOI: 10.1159/000380887
Pearce and Moore [1985] showed that a mineral-enriching rinse resulted in more remineralization in an in situ experiment. Singh and Papas [2009] showed in a group of xerostomia patients that combining a supersaturated Ca3(PO4)2 rinse with a 1.1% NaF rinse resulted in lower caries increments compared to the use of a 1.1% NaF rinse alone. In an in situ model, a calcium-lactate prerinse before a NaF rinse showed a reduction of erosion of enamel compared to a NaF rinse alone [Turssi et al., 2014]. Calcium Glycerophosphate Another nonfluoride agent that has been studied extensively is calcium glycerophosphate (Ca-GP). In a review by Lynch [2004], the possible modes of action have been described. The use of Ca-GP can buffer the plaque pH, increase the calcium and phosphate levels in plaque and can interact directly with the tooth surface. Ca-GP, added to the diet, has been shown to reduce caries scores in rat studies [Grenby, 1973; Grenby and Bull, 1978]. Grenby [1973] showed that also a topical application of a saturated (approx. 4%) solution of Ca-GP 3 times per week reduced caries scores in rats. Cariostatic effects of the addition of Ca-GP to dentifrices have been studied in 2 large clinical trials. In a 3-year clinical trial by Naylor and Glass [1979], a combined Ca-GP/sodium monofluorophosphate (SMFP) dentifrice did not show an additional effect compared to the SMFP dentifrice. However, in a 4-year trial by Mainwaring and Naylor [1983] adding Ca-GP to an SMFP dentifrice did show an additional effect. In recent years only limited additional data has been generated. Lynch and ten Cate [2006] studied the effect of Ca-GP on enamel and dentine demineralization in an in vitro biofilm model. Ca-GP showed the largest effect on demineralization when it was pulsed prior to a sucrose pulse. Pulsing together with or after a sucrose pulse was less effective in reducing demineralization. Zaze et al. [2014] showed in an in situ study that adding 0.25% Ca-GP to a 500-ppm F dentifrice resulted in enhanced remineralization compared to a 500-ppm F dentifrice. The F-Ca-GP combination resulted in a similar mineral gain than a 1,100-ppm F dentifrice. Overall data suggest a cariostatic effect of Ca-GP; however, studies supporting the role of Ca-GP in caries reversal are limited. Trimetaphosphate Trimetaphosphate (TMP) has been studied in several clinical trials. Stadtler et al. [1996] showed that a 3% TMP dentifrice had a caries-reducing effect when compared to a nonfluoride control. O’Mullane et al. [1997] showed in Clarkson/Exterkate
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rapidly [Adair and Popkin, 2005; Johansson et al., 2010], resulting in more frequent intake of food and drinks, the so-called grazing. This behavior results in more frequent periods of low pH in the oral cavity, resulting in a shift towards demineralization in the de-/remineralization balance. Also, as orthodontic treatment has become more popular, caries is seen at sites which normally are not caries prone, i.e. the buccal surfaces of the teeth [Heymann and Grauer, 2013]. A real challenge either in caries prevention or reversal of lesions is to change the local conditions at the sites at risk. This can be achieved by changing the habits of the individual through lower carbohydrate intake and better oral hygiene. It can also be achieved by introducing agents that help to shift the composition of the oral microflora or the de-/remineralization balance towards remineralization. However, once the surface integrity of the carious lesion is breached either by the disease or restorative intervention, what are the treatment options? Are there promising agents, besides fluoride, that allow for the enhancement of remineralization and/or provide a noninvasive approach to the restoration of cavitated lesions?
a 3-year clinical trial no additional caries-reducing effect of 3% TMP when added to a 1,000- or 1,500-ppm NaF dentifrice. In recent years interest in TMP has been renewed as a possible way of reducing the fluoride content of dentifrices. Several in vitro studies [Takeshita et al., 2009; Delbem et al., 2012; Favretto et al., 2013] demonstrated that adding TMP to a fluoride regime resulted in enhanced efficacy of low F groups, indicating that a combination of TMP and F would allow for lowering F concentrations without losing efficacy, but currently no clinical data supporting these in vitro findings is available.
cream to be superior to a placebo cream with respect to lesion regression of white spot lesions, with an ICDAS II score of 2 or 3 at baseline, 12 weeks after orthodontic debracketing. Beerens et al. [2010] could not show a beneficial effect of an ACP-CPP cream on lesion regression 12 weeks after debracketing compared to normal oral hygiene procedures without additional cream treatment. A finding that was confirmed in a study by Brochner et al. [2011], an ACP-CPP cream combined with regular fluoridated toothpaste use was not superior to the sole use of fluoridated toothpaste in a 4-week study.
Casein Phosphopeptide-Stabilized Amorphous Calcium Phosphate Maybe one of the most studied compounds that is aimed at shifting the de-/remineralization balance is the nanocomplex casein phosphopeptide-stabilized amorphous calcium phosphate (ACP-CPP) [Cochrane and Reynolds, 2012]. The product is aimed at reducing demineralization and enhancing remineralization by increasing the bioavailability of calcium and phosphate at the sites at risk. Numerous in vitro studies have shown the efficacy of ACP-CPP, but until recent years the number of clinical studies was limited. In two review papers [Cochrane and Reynolds, 2012; Nongonierma and Fitzgerald, 2012], an extensive overview of clinical studies on the use of ACP-CPP for the prevention or reversal of caries has been reported. Hay and Thomson [2002] showed that a casein derivative calcium-phosphate rinse was as efficient as a 0.05% NaF rinse in a group of patients with salivary gland dysfunction. Morgan et al. [2008] compared the effect of an ACP-CPP-containing sugar free chewing gum with a regular sugar free gum in a large population of secondary schoolchildren. Despite the low caries prevalence the authors showed that the ACP-CPP gum slowed down lesion progression and enhanced lesion regression. However, it should be noted that approximately 95% of the measured surfaces was sound and remained sound in the 24-month experimental period. Rao et al. [2009] showed in a clinical trial that a 2% ACP-CPP toothpaste performed comparable to 1,190 ppm F (as SMFP) in a 24-month clinical trial. In recent years ACP-CPP has also been used to treat patients with white spot lesions on their buccal surfaces as a result of orthodontic treatment. Andersson et al. [2007] showed that the regression of white spot lesions, using a clinical score (Andersson), was superior for ACPCPP compared to a 0.05% NaF rinse. Using fluorescence E (Diagnodent®), both regimes did not differ statistically in their efficacy. Bailey et al. [2009] showed an ACP-CPP
Nanohydroxyapatite A relatively new approach to increase the bioavailability of calcium and phosphate is the use of nano-sized hydroxyapatite particles. Hannig and Hannig [2012] have presented an overview of the status of nanoparticles in caries therapy. Although promising in vitro findings have been reported [Huang et al., 2009, 2010, 2011; Tschoppe et al., 2011; Chen et al., 2013; Besinis et al., 2014], clinical data are still scarce. Najibfard et al. [2011] measured remineralization of presoftened enamel blocks in an in situ study. They showed that a 5% nanohydroxyapatite and 10% nanohydroxyapatite toothpaste performed as well as a 1,100-ppm F toothpaste in remineralizing the enamel blocks during a 28-day in situ period. Moreover, it was demonstrated that the 10% nanohydroxyapatite toothpaste prevented demineralization of a sound enamel block that was also placed in situ during 28 days. It can be seen from this discussion that prevention of caries and repair of carious lesions cannot be guaranteed. So, which strategies can be employed once caries prevention and repair fail?
Remineralization Therapies for Precavitated and Cavitated Lesions
Caries Res 2015;49(suppl 1):11–17 DOI: 10.1159/000380887
The classical treatment and teaching for restoring caries is, by and large, the complete removal of the diseased tissue from the carious lesion. A movement in the late 1990s and early 2000s called minimal invasive dentistry has not been generally accepted worldwide. The removal of all carious tissue, except in the case of indirect pulp capping, an enigma that will be discussed later, from a prepared cavity remains the standard of care. However, knowing that caries is a bacterial disease and bacteria cannot metabolize without a nutrient supply, is there a place in our clinical armamentarium for a procedure entitled ‘noninvasive dentistry’, a combination of restorative and caries-preventive therapy? 13
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Noninvasive Restorative Strategies
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Caries Res 2015;49(suppl 1):11–17 DOI: 10.1159/000380887
preventive materials and therapies. A smart restorative/ caries-preventive dental material would react to changes in the oral environment, for example pH, while a bioactive one would affect bacterial and cellular activity. A smart, bioactive noninvasive restorative material must have these capabilities, and most importantly it needs to seal the margins of the cavity. Further it should be easy to apply, nontoxic, biocompatible, inexpensive and aesthetic. Can such a material be designed, manufactured, tested and achieve clinical acceptability? It appears that the ‘new’ materials and therapies are still focused on repairing carious lesions without either incorporating the other smart, bioactive attributes mentioned earlier and/or being noninvasive. The use of self-assembling molecules to penetrate into carious lesions and, when assembled, attract calcium [Kirkham et al., 2007; Brunton et al., 2013], and the ICON technique, which uses resin penetration to repair lesions [Meyer-Lueckel and Paris, 2008; Rocha Gomes Torres et al., 2011] are microinvasive procedures. Both of these techniques require the removal, by etching, of the surface zone of enamel lesions to allow penetration into the lesion and do not wholly embrace the concept of noninvasive dentistry. Closer to this noninvasive ‘dream’ is the use of phosphorylated peptides to penetrate into lesions and attract calcium, and phosphorus is in the in vitro stage of testing [Yang et al., 2014]. In caries prevention the use of time release devices or particles containing calcium/phosphorus/fluoride and using the oral mucous membrane as the delivery platform still remains unexploited. Even in the nanotechnology arena the use of functionalized dendrimers to deliver caries-preventive agents and/or change the surface activity of dental hard tissues to encourage surface penetration of lesions and discourage biofilm formation remains untested. This may be either because of the cost or an unspoken thought that it is ‘like taking a hammer to crack a nut’. Fluorohydroxyapatite Composites Over the past several years a synthesis process has been developed to produce enamel-like crystals and surfaces [Chen et al., 2006]. The fluorohydroxyapatite (FOHA) crystals and surfaces produced by this process have led to a number of product prototypes to be formulated which may allow noninvasive dentistry to become a reality rather than a dream. These crystals have the capacity to release calcium, phosphorus and fluoride as the pH in the oral environment drops and the ion release slows as the pH rises. This ebb and flow of ions from the crystals is indicative of a ‘smart-like’ material which reacts to the pH change in the tooth biofilm. These FOHA crystals and Clarkson/Exterkate
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This is not a totally new concept, highlighted by the enigma mentioned above of the indirect pulp cap! As clinicians we are taught to leave ‘active’ caries in a cavity if the pulp will be exposed by its removal and place a restoration to seal the cavity. The rationale is that by cutting off the bacteria’s nutrient supply it renders the bacteria nonviable and the pulp may survive. Why is this strategy not applied to the diseased tissue in all carious cavities, unless the structural integrity of the tooth is compromised and needs support? Even under this scenario does all the diseased tissue need to be removed? There is clinical evidence to support that caries can be controlled and its progression prevented by inhibiting bacterial metabolism: the early studies of Handleman which showed the reduction of viable bacteria in carious dentine after repeated 6-month sampling of the sealed tissue [Handleman et al., 1973]; the seminal 10-year-long study of Mertz-Fairhurst et al. [1998] in preventing the caries progression by sealing carious lesions, and the use of the ‘Hall’ technique, which uses stainless steel crowns to restore primary teeth without removing caries [Innes et al., 2007]. Furthermore, the process of restoration and re-restoration of teeth has its own risks as reported by Anusavice [1995]. He cited an increase in cavity size during re-restoration of teeth, iatrogenic damage to virgin tooth surfaces and a 72% chance of leaving carious tissue in a prepared cavity! Thus a noninvasive approach for the treatment and prevention of caries would seem to be clinically appropriate but it would mean a paradigm shift in our teaching and restorative care. Obviously the choice is not wholly black and white, and in cases where the structural integrity is compromised, some but not all of the carious tissue may have to be removed to provide a sufficient bulk of material to support the remaining tooth tissue. The success of a noninvasive treatment will depend on the seal at the cavity margins [Mertz-Fairhurst et al., 1998]. The advent of the acid, self-etch and total etch techniques prior to or during composite restoration placement should guarantee the seal, if clinicians pay sufficient attention to this detail. However, no dental procedure is 100% successful and restorative/caries preventive materials must be designed to minimize the failures of a noninvasive technique. The most likely nominees for such materials are smart, bioactive materials. Restorative materials have and continue, on the whole, to be designed to ‘fill a hole’ with a material that has optimal mechanical properties and aesthetics. Less attention has been paid to rendering them bioactive except for the introduction of fluoride-releasing compounds and, perhaps, calcium and phosphate. The same applies to caries-
FOHA Crystal/Euradgit Combination An extension of the use of the FOHA crystals is their incorporation into a polymer carrier called Euradgit. This material is used to coat tablets to prevent gastric irritation. It is, therefore, Federal Drug Administration approved for human use. The resulting FOHA/Euradgit combination produces a flexible laminate which can be molded to any tooth surface and cut with scissors to any shape. It can then be bonded to the tooth surface or treated with alcohol, which renders the laminate sticky, and it can then be applied to the tooth surface. The alcohol then evaporates and the laminate will adhere tenaciously to the tooth surface, another noninvasive type of treatment for carious smooth surfaces [Czajka-Jakubowska and ClarkRemineralization Therapies for Precavitated and Cavitated Lesions
son, 2014]. Where the structural integrity of the tooth is compromised and some, but not all, of the diseased tissue has to be removed, a combination of a FOHA composite and FOHA/Euradgit can be used.
Concluding Remarks
A number of approaches to shift the de-/remineralization balance towards remineralization has been described in this paper. The question remains whether the introduction of new caries-preventive agents next to or on top of fluoride regimes merely reduces caries progression or actually enhances lesion reversal. The latter would greatly improve the possibilities of clinicians to abstain from restorative treatments. However, if restorative care is needed, this article has introduced 2 novel prototype materials which might be used in the noninvasive restoration of teeth. It should not be forgotten either that these crystals release ions which may have a caries-preventive effect on adjacent tooth surfaces and at the material/tooth interface. These prototype materials may be a model for a noninvasive, bioactive restorative and caries-preventive dental material. Unfortunately there is no data on the clinical efficacy of these novel agents on lesion reversal. More studies aimed at measuring clinical efficacy are needed. Merely demonstrating positive effects in in vitro studies is no guarantee for actual beneficial effects in the oral cavity. The oral cavity is a challenging environment. Therefore, caries-preventive agents need to show substantivity, they need to be at the site of risk and they have to compete with other naturally available molecules. In vitro models generally lack the complexity that preventive/restorative agents will encounter in the oral cavity.
Disclosure Statement The authors declare to have no conflict of interest.
References
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Remineralization Therapies for Precavitated and Cavitated Lesions
Singh ML, Papas AS: Long-term clinical observation of dental caries in salivary hypofunction patients using a supersaturated calciumphosphate remineralizing rinse. J Clin Dent 2009;20:87–92. Stadtler P, Muller-Bruckschwaiger K, Schafer F, Huntington E: The effect of sodium trimetaphosphate on caries: a 3-year clinical toothpaste trial. Caries Res 1996;30:418–422. Takeshita EM, Castro LP, Sassaki KT, Delbem AC: In vitro evaluation of dentifrice with low fluoride content supplemented with trimetaphosphate. Caries Res 2009;43:50–56. Ten Cate JM, Duijsters PP: Alternating demineralization and remineralization of artificial enamel lesions. Caries Res 1982;16:201–210. Ten Cate JM, Featherstone JD: Mechanistic aspects of the interactions between fluoride and dental enamel. Crit Rev Oral Biol Med 1991; 2:283–296. Tschoppe P, Zandim DL, Martus P, Kielbassa AM: Enamel and dentine remineralization by nano-hydroxyapatite toothpastes. J Dent 2011;39:430–437.
Turssi CP, Hara AT, Amaral FL, Franca FM, Basting RT: Calcium lactate pre-rinse increased fluoride protection against enamel erosion in a randomized controlled in situ trial. J Dent 2014;42:534–539. Vogel GL, Chow LC, Carey CM, Schumacher GE, Takagi S: Effect of a calcium prerinse on salivary fluoride after a 228-ppm fluoride rinse. Caries Res 2006;40:178–180. Vogel GL, Mao Y, Carey CM, Chow LC: Increased overnight fluoride concentrations in saliva, plaque, and plaque fluid after a novel two-solution rinse. J Dent Res 1997;76:761–767. Yang Y, Lv XP, Shi W, Li JY, Li DX, Zhou XD, Zhang LL: 8DSS-promoted remineralization of initial enamel caries in vitro. J Dent Res 2014;93:520–524. Zaze AC, Dias AP, Amaral JG, Miyasaki ML, Sassaki KT, Delbem AC: In situ evaluation of low-fluoride toothpastes associated to calcium glycerophosphate on enamel remineralization. J Dent 2014;42:1621–1625. Zero DT: Dentifrices, mouthwashes, and remineralization/caries arrestment strategies. BMC Oral Health 2006;6(suppl 1):S9.
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Rao SK, Bhat GS, Aradhya S, Devi A, Bhat M: Study of the efficacy of toothpaste containing casein phosphopeptide in the prevention of dental caries: a randomized controlled trial in 12- to 15-year-old high caries risk children in Bangalore, India. Caries Res 2009; 43: 430– 435. Rocha Gomes Torres C, Borges AB, Torres LM, Gomes IS, de Oliveira RS: Effect of caries infiltration technique and fluoride therapy on the colour masking of white spot lesions. J Dent 2011;39:202–207. Schreiber CT, Shern RJ, Chow LC, Kingman A: Effects of rinses with an acidic calcium phosphate solution on fluoride uptake, caries, and in situ plaque pH in rats. J Dent Res 1988;67: 959–963. Shern RJ, Chow LC, Couet KM, Kingman A, Brown WE: Effects of sequential calcium phosphate-fluoride rinses on dental plaque, staining, fluoride uptake, and caries in rats. J Dent Res 1984;63:1355–1359. Silverstone LM: Structure of carious enamel, including the early lesion. Oral Sci Rev 1973; 3: 100–160.
Published online: April 13, 2015
Noninvasive Dentistry: A Dream or Reality? B.H. Clarkson a R.A.M. Exterkate b a
Key Words Cavitated lesions · Precavitated lesions · Remineralization
Abstract Various caries prevention and repair strategies are reviewed in this article ranging from the use of fluoride to nanohydroxyapatite particles. Several of the strategies which combine fluoride and calcium and phosphate treatments have both in vitro and in vivo data showing them to be efficacious if the surface integrity of the lesion is not breached. Once this has occurred, the rationale for cutting off the nutrient supplies to the pathogenic bacteria without the removal of the infected dentine, a noninvasive restorative technique, is discussed using existing clinical studies as examples. Finally two novel noninvasive restorative techniques using fluorohydroxyapatite crystals are described. The need for clinical data in support of emerging caries-preventive and restorative strategies is emphasized. © 2015 S. Karger AG, Basel
Despite all the efforts and advances that are made in the prevention and reversal of tooth decay, caries still affects large numbers of patients. Ideally, prevention of tooth decay would be the goal to achieve. Complete inhibition of caries has been a utopia until now. © 2015 S. Karger AG, Basel 0008–6568/15/0497–0011$39.50/0 E-Mail [email protected] www.karger.com/cre
Caries is caused by acid-producing bacteria in oral biofilms that metabolize carbohydrates in our food and produce organic acids [Geddes, 1975]. These acids dissolve the dental hard tissues (carbonated hydroxyapatite) and gradually penetrate more deeply into the teeth causing white spot lesions and eventually cavitation. Fortunately, this process can be reversed by the natural presence of calcium and phosphate, originating mainly from saliva that can recrystallize inside the lesion under favorable conditions [Silverstone, 1973]. In order for teeth to remain sound, a balance is required between the dissolution (demineralization) and repair (remineralization) of the dental hard tissues. Fluoride has been shown to play an important role in these processes. Demineralization of dental hard tissues is inhibited by the presence of fluoride, and fluoride is also capable of increasing the rate and magnitude of remineralization of lesions [ten Cate and Duijsters, 1982; ten Cate and Featherstone, 1991; Zero, 2006]. However, in order for remineralization to be effective there is also a need for the building blocks of hydroxyapatite, calcium and phosphate, to be present during the periods that allow for lesion repair. The mere presence of fluoride is not always enough to allow remineralization to be effective. Fluoride is still the most used caries-preventive agent, with fluoridated toothpastes being the most used vehicle for delivery. Several factors have challenged the effectiveness of fluoride. Eating habits are changing Prof. B.H. Clarkson Department of Cariology, Restorative Sciences and Endodontics University of Michigan School of Dentistry Ann Arbor, MI 48109 (USA) E-Mail bricla @ umich.edu
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Department of Cariology, Restorative Sciences and Endodontics, University of Michigan School of Dentistry, Ann Arbor, Mich., USA; b Department of Preventive Dentistry, Academic Centre for Dentistry Amsterdam, Amsterdam, The Netherlands
Remineralization Strategies
In recent years several approaches have been developed to increase the availability of calcium and phosphate at the sites of risk. They have all been proven to be efficacious in in vitro studies, but it is generally acknowledged that clinical data are needed to prove their in vivo efficacy. Combining a Calcium Rinse and Fluoride Rinse One of the earliest approaches in increasing the concentrations of the building blocks of hydroxyapatite in dental plaque was combining a calcium prerinse with a fluoride rinse. This approach was mainly aimed at increasing fluoride levels in plaque and not so much at increasing the calcium concentration of plaque. Several authors [Grande et al., 1997; Vogel et al., 1997; Pessan et al., 2006; Vogel et al., 2006; Chen et al., 2014] demonstrated that the use of a calcium rinse prior to a fluoride rinse or fluoride toothpaste increased the substantivity of fluoride in plaque and/or saliva, but only limited data are available on the cariostatic effects of these elevated levels of fluoride. Shern et al. [1984] and Schreiber et al. [1988] showed in rat studies that combining an acidic calcium phosphate rinse with a fluoride rinse resulted in a higher fluoride content of the enamel, but failed to show a significant additional reduction in caries scores compared with a fluoride rinse alone. 12
Caries Res 2015;49(suppl 1):11–17 DOI: 10.1159/000380887
Pearce and Moore [1985] showed that a mineral-enriching rinse resulted in more remineralization in an in situ experiment. Singh and Papas [2009] showed in a group of xerostomia patients that combining a supersaturated Ca3(PO4)2 rinse with a 1.1% NaF rinse resulted in lower caries increments compared to the use of a 1.1% NaF rinse alone. In an in situ model, a calcium-lactate prerinse before a NaF rinse showed a reduction of erosion of enamel compared to a NaF rinse alone [Turssi et al., 2014]. Calcium Glycerophosphate Another nonfluoride agent that has been studied extensively is calcium glycerophosphate (Ca-GP). In a review by Lynch [2004], the possible modes of action have been described. The use of Ca-GP can buffer the plaque pH, increase the calcium and phosphate levels in plaque and can interact directly with the tooth surface. Ca-GP, added to the diet, has been shown to reduce caries scores in rat studies [Grenby, 1973; Grenby and Bull, 1978]. Grenby [1973] showed that also a topical application of a saturated (approx. 4%) solution of Ca-GP 3 times per week reduced caries scores in rats. Cariostatic effects of the addition of Ca-GP to dentifrices have been studied in 2 large clinical trials. In a 3-year clinical trial by Naylor and Glass [1979], a combined Ca-GP/sodium monofluorophosphate (SMFP) dentifrice did not show an additional effect compared to the SMFP dentifrice. However, in a 4-year trial by Mainwaring and Naylor [1983] adding Ca-GP to an SMFP dentifrice did show an additional effect. In recent years only limited additional data has been generated. Lynch and ten Cate [2006] studied the effect of Ca-GP on enamel and dentine demineralization in an in vitro biofilm model. Ca-GP showed the largest effect on demineralization when it was pulsed prior to a sucrose pulse. Pulsing together with or after a sucrose pulse was less effective in reducing demineralization. Zaze et al. [2014] showed in an in situ study that adding 0.25% Ca-GP to a 500-ppm F dentifrice resulted in enhanced remineralization compared to a 500-ppm F dentifrice. The F-Ca-GP combination resulted in a similar mineral gain than a 1,100-ppm F dentifrice. Overall data suggest a cariostatic effect of Ca-GP; however, studies supporting the role of Ca-GP in caries reversal are limited. Trimetaphosphate Trimetaphosphate (TMP) has been studied in several clinical trials. Stadtler et al. [1996] showed that a 3% TMP dentifrice had a caries-reducing effect when compared to a nonfluoride control. O’Mullane et al. [1997] showed in Clarkson/Exterkate
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rapidly [Adair and Popkin, 2005; Johansson et al., 2010], resulting in more frequent intake of food and drinks, the so-called grazing. This behavior results in more frequent periods of low pH in the oral cavity, resulting in a shift towards demineralization in the de-/remineralization balance. Also, as orthodontic treatment has become more popular, caries is seen at sites which normally are not caries prone, i.e. the buccal surfaces of the teeth [Heymann and Grauer, 2013]. A real challenge either in caries prevention or reversal of lesions is to change the local conditions at the sites at risk. This can be achieved by changing the habits of the individual through lower carbohydrate intake and better oral hygiene. It can also be achieved by introducing agents that help to shift the composition of the oral microflora or the de-/remineralization balance towards remineralization. However, once the surface integrity of the carious lesion is breached either by the disease or restorative intervention, what are the treatment options? Are there promising agents, besides fluoride, that allow for the enhancement of remineralization and/or provide a noninvasive approach to the restoration of cavitated lesions?
a 3-year clinical trial no additional caries-reducing effect of 3% TMP when added to a 1,000- or 1,500-ppm NaF dentifrice. In recent years interest in TMP has been renewed as a possible way of reducing the fluoride content of dentifrices. Several in vitro studies [Takeshita et al., 2009; Delbem et al., 2012; Favretto et al., 2013] demonstrated that adding TMP to a fluoride regime resulted in enhanced efficacy of low F groups, indicating that a combination of TMP and F would allow for lowering F concentrations without losing efficacy, but currently no clinical data supporting these in vitro findings is available.
cream to be superior to a placebo cream with respect to lesion regression of white spot lesions, with an ICDAS II score of 2 or 3 at baseline, 12 weeks after orthodontic debracketing. Beerens et al. [2010] could not show a beneficial effect of an ACP-CPP cream on lesion regression 12 weeks after debracketing compared to normal oral hygiene procedures without additional cream treatment. A finding that was confirmed in a study by Brochner et al. [2011], an ACP-CPP cream combined with regular fluoridated toothpaste use was not superior to the sole use of fluoridated toothpaste in a 4-week study.
Casein Phosphopeptide-Stabilized Amorphous Calcium Phosphate Maybe one of the most studied compounds that is aimed at shifting the de-/remineralization balance is the nanocomplex casein phosphopeptide-stabilized amorphous calcium phosphate (ACP-CPP) [Cochrane and Reynolds, 2012]. The product is aimed at reducing demineralization and enhancing remineralization by increasing the bioavailability of calcium and phosphate at the sites at risk. Numerous in vitro studies have shown the efficacy of ACP-CPP, but until recent years the number of clinical studies was limited. In two review papers [Cochrane and Reynolds, 2012; Nongonierma and Fitzgerald, 2012], an extensive overview of clinical studies on the use of ACP-CPP for the prevention or reversal of caries has been reported. Hay and Thomson [2002] showed that a casein derivative calcium-phosphate rinse was as efficient as a 0.05% NaF rinse in a group of patients with salivary gland dysfunction. Morgan et al. [2008] compared the effect of an ACP-CPP-containing sugar free chewing gum with a regular sugar free gum in a large population of secondary schoolchildren. Despite the low caries prevalence the authors showed that the ACP-CPP gum slowed down lesion progression and enhanced lesion regression. However, it should be noted that approximately 95% of the measured surfaces was sound and remained sound in the 24-month experimental period. Rao et al. [2009] showed in a clinical trial that a 2% ACP-CPP toothpaste performed comparable to 1,190 ppm F (as SMFP) in a 24-month clinical trial. In recent years ACP-CPP has also been used to treat patients with white spot lesions on their buccal surfaces as a result of orthodontic treatment. Andersson et al. [2007] showed that the regression of white spot lesions, using a clinical score (Andersson), was superior for ACPCPP compared to a 0.05% NaF rinse. Using fluorescence E (Diagnodent®), both regimes did not differ statistically in their efficacy. Bailey et al. [2009] showed an ACP-CPP
Nanohydroxyapatite A relatively new approach to increase the bioavailability of calcium and phosphate is the use of nano-sized hydroxyapatite particles. Hannig and Hannig [2012] have presented an overview of the status of nanoparticles in caries therapy. Although promising in vitro findings have been reported [Huang et al., 2009, 2010, 2011; Tschoppe et al., 2011; Chen et al., 2013; Besinis et al., 2014], clinical data are still scarce. Najibfard et al. [2011] measured remineralization of presoftened enamel blocks in an in situ study. They showed that a 5% nanohydroxyapatite and 10% nanohydroxyapatite toothpaste performed as well as a 1,100-ppm F toothpaste in remineralizing the enamel blocks during a 28-day in situ period. Moreover, it was demonstrated that the 10% nanohydroxyapatite toothpaste prevented demineralization of a sound enamel block that was also placed in situ during 28 days. It can be seen from this discussion that prevention of caries and repair of carious lesions cannot be guaranteed. So, which strategies can be employed once caries prevention and repair fail?
Remineralization Therapies for Precavitated and Cavitated Lesions
Caries Res 2015;49(suppl 1):11–17 DOI: 10.1159/000380887
The classical treatment and teaching for restoring caries is, by and large, the complete removal of the diseased tissue from the carious lesion. A movement in the late 1990s and early 2000s called minimal invasive dentistry has not been generally accepted worldwide. The removal of all carious tissue, except in the case of indirect pulp capping, an enigma that will be discussed later, from a prepared cavity remains the standard of care. However, knowing that caries is a bacterial disease and bacteria cannot metabolize without a nutrient supply, is there a place in our clinical armamentarium for a procedure entitled ‘noninvasive dentistry’, a combination of restorative and caries-preventive therapy? 13
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Noninvasive Restorative Strategies
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preventive materials and therapies. A smart restorative/ caries-preventive dental material would react to changes in the oral environment, for example pH, while a bioactive one would affect bacterial and cellular activity. A smart, bioactive noninvasive restorative material must have these capabilities, and most importantly it needs to seal the margins of the cavity. Further it should be easy to apply, nontoxic, biocompatible, inexpensive and aesthetic. Can such a material be designed, manufactured, tested and achieve clinical acceptability? It appears that the ‘new’ materials and therapies are still focused on repairing carious lesions without either incorporating the other smart, bioactive attributes mentioned earlier and/or being noninvasive. The use of self-assembling molecules to penetrate into carious lesions and, when assembled, attract calcium [Kirkham et al., 2007; Brunton et al., 2013], and the ICON technique, which uses resin penetration to repair lesions [Meyer-Lueckel and Paris, 2008; Rocha Gomes Torres et al., 2011] are microinvasive procedures. Both of these techniques require the removal, by etching, of the surface zone of enamel lesions to allow penetration into the lesion and do not wholly embrace the concept of noninvasive dentistry. Closer to this noninvasive ‘dream’ is the use of phosphorylated peptides to penetrate into lesions and attract calcium, and phosphorus is in the in vitro stage of testing [Yang et al., 2014]. In caries prevention the use of time release devices or particles containing calcium/phosphorus/fluoride and using the oral mucous membrane as the delivery platform still remains unexploited. Even in the nanotechnology arena the use of functionalized dendrimers to deliver caries-preventive agents and/or change the surface activity of dental hard tissues to encourage surface penetration of lesions and discourage biofilm formation remains untested. This may be either because of the cost or an unspoken thought that it is ‘like taking a hammer to crack a nut’. Fluorohydroxyapatite Composites Over the past several years a synthesis process has been developed to produce enamel-like crystals and surfaces [Chen et al., 2006]. The fluorohydroxyapatite (FOHA) crystals and surfaces produced by this process have led to a number of product prototypes to be formulated which may allow noninvasive dentistry to become a reality rather than a dream. These crystals have the capacity to release calcium, phosphorus and fluoride as the pH in the oral environment drops and the ion release slows as the pH rises. This ebb and flow of ions from the crystals is indicative of a ‘smart-like’ material which reacts to the pH change in the tooth biofilm. These FOHA crystals and Clarkson/Exterkate
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This is not a totally new concept, highlighted by the enigma mentioned above of the indirect pulp cap! As clinicians we are taught to leave ‘active’ caries in a cavity if the pulp will be exposed by its removal and place a restoration to seal the cavity. The rationale is that by cutting off the bacteria’s nutrient supply it renders the bacteria nonviable and the pulp may survive. Why is this strategy not applied to the diseased tissue in all carious cavities, unless the structural integrity of the tooth is compromised and needs support? Even under this scenario does all the diseased tissue need to be removed? There is clinical evidence to support that caries can be controlled and its progression prevented by inhibiting bacterial metabolism: the early studies of Handleman which showed the reduction of viable bacteria in carious dentine after repeated 6-month sampling of the sealed tissue [Handleman et al., 1973]; the seminal 10-year-long study of Mertz-Fairhurst et al. [1998] in preventing the caries progression by sealing carious lesions, and the use of the ‘Hall’ technique, which uses stainless steel crowns to restore primary teeth without removing caries [Innes et al., 2007]. Furthermore, the process of restoration and re-restoration of teeth has its own risks as reported by Anusavice [1995]. He cited an increase in cavity size during re-restoration of teeth, iatrogenic damage to virgin tooth surfaces and a 72% chance of leaving carious tissue in a prepared cavity! Thus a noninvasive approach for the treatment and prevention of caries would seem to be clinically appropriate but it would mean a paradigm shift in our teaching and restorative care. Obviously the choice is not wholly black and white, and in cases where the structural integrity is compromised, some but not all of the carious tissue may have to be removed to provide a sufficient bulk of material to support the remaining tooth tissue. The success of a noninvasive treatment will depend on the seal at the cavity margins [Mertz-Fairhurst et al., 1998]. The advent of the acid, self-etch and total etch techniques prior to or during composite restoration placement should guarantee the seal, if clinicians pay sufficient attention to this detail. However, no dental procedure is 100% successful and restorative/caries preventive materials must be designed to minimize the failures of a noninvasive technique. The most likely nominees for such materials are smart, bioactive materials. Restorative materials have and continue, on the whole, to be designed to ‘fill a hole’ with a material that has optimal mechanical properties and aesthetics. Less attention has been paid to rendering them bioactive except for the introduction of fluoride-releasing compounds and, perhaps, calcium and phosphate. The same applies to caries-
FOHA Crystal/Euradgit Combination An extension of the use of the FOHA crystals is their incorporation into a polymer carrier called Euradgit. This material is used to coat tablets to prevent gastric irritation. It is, therefore, Federal Drug Administration approved for human use. The resulting FOHA/Euradgit combination produces a flexible laminate which can be molded to any tooth surface and cut with scissors to any shape. It can then be bonded to the tooth surface or treated with alcohol, which renders the laminate sticky, and it can then be applied to the tooth surface. The alcohol then evaporates and the laminate will adhere tenaciously to the tooth surface, another noninvasive type of treatment for carious smooth surfaces [Czajka-Jakubowska and ClarkRemineralization Therapies for Precavitated and Cavitated Lesions
son, 2014]. Where the structural integrity of the tooth is compromised and some, but not all, of the diseased tissue has to be removed, a combination of a FOHA composite and FOHA/Euradgit can be used.
Concluding Remarks
A number of approaches to shift the de-/remineralization balance towards remineralization has been described in this paper. The question remains whether the introduction of new caries-preventive agents next to or on top of fluoride regimes merely reduces caries progression or actually enhances lesion reversal. The latter would greatly improve the possibilities of clinicians to abstain from restorative treatments. However, if restorative care is needed, this article has introduced 2 novel prototype materials which might be used in the noninvasive restoration of teeth. It should not be forgotten either that these crystals release ions which may have a caries-preventive effect on adjacent tooth surfaces and at the material/tooth interface. These prototype materials may be a model for a noninvasive, bioactive restorative and caries-preventive dental material. Unfortunately there is no data on the clinical efficacy of these novel agents on lesion reversal. More studies aimed at measuring clinical efficacy are needed. Merely demonstrating positive effects in in vitro studies is no guarantee for actual beneficial effects in the oral cavity. The oral cavity is a challenging environment. Therefore, caries-preventive agents need to show substantivity, they need to be at the site of risk and they have to compete with other naturally available molecules. In vitro models generally lack the complexity that preventive/restorative agents will encounter in the oral cavity.
Disclosure Statement The authors declare to have no conflict of interest.
References
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surfaces have other properties: they are antibacterial [AlHilou et al., in press]; they stimulate cellular activity of various stem cell lines including dental pulp stem cells [Liu et al., 2010, 2011, 2012]; they are nontoxic; they prevent the progression of caries in an in vitro setting [Clark et al., 2013], and they are gingival fibroblast biocompatible. These are some of the ideal properties for use as filler for a dental material. However, these crystals and surfaces need a carrier. To reiterate what was mentioned earlier, the success of noninvasive dentistry products and therapies is dependent on effectively sealing the material/cavity interface. Thus, incorporating the FOHA crystals into a self-etch or conventional resin would allow a ‘paint-on smart’ enamel-like material to be produced which can be tinted to match any tooth color and will effectively seal the cavity/material margin [Czajka-Jakubowska and Clarkson, 2014] without the need, in small lesions, to remove any of the diseased tissue. The ‘paint-on enamel’ containing 20– 30% by weight fill of a mixture of nano/microcrystals allows the material to be of a viscosity which is easy to apply. Where the structural integrity of the tooth has been compromised and the remaining tissue needs support, a conventional resin, compatible with ‘paint-on enamel’, filled at 60–70% by weight, could be used [CzajkaJakubowska and Clarkson, 2014] and then the ‘paint-on enamel’ material applied to seal the cavity margins. However, for this crystal/resin combination to be bioactive rather than inert there needs to be release of ions from the cured FOHA/resin which we have shown even if the crystals are silanated [Czajka-Jakubowska and Clarkson, 2014]. This is a step towards a noninvasive type therapy for fissures, buccal and lingual surfaces, but it may be more difficult to apply the ‘paint-on’ enamel-like material in the interproximal regions.
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