ENAMEL REMINERALIZATION SYSTEMS�The Next Frontier in Caries Management

Dr Rekha P Thankachan

Modern Caries Management

“ Preserve the tooth structure and restore only when necessary “

( Ismail et al ; 2018 )

Role of saliva

• Supplies Ca2+and PO4 3– ions in a bioavailable form .

​

• At physiological pH, saliva is supersaturated with stabilized Ca2+ and PO4 3– ions, ensures its diffusion to mineral deficient areas.

​

• Surface only remineralization

​

• Longitudinal study : [Mattousch et al., 2007; van der Veen et al., 2007].

​

• This surface-only remineralization neither improves the aesthetics nor the structural properties of the subsurface lesion

[Cochrane et al., 2010].

​

​

​

Natural remineralization alone is not sufficient

Fluoride – Efficacy and Safety

• Widespread use of oral health care products containing flouride drastically decreased the caries incidence from the later half of 20^th century .

[Fejerskov, 2004].

​

​

• Under normal physiological conditions, fluoride and salivary homeostatic mechanisms are often enough to remineralize early lesions.

​

​

​

​

​

​

• But it cannot possible in :

​

- Highly cariogenic oral environments.

• At risk population groups (xerostomia patients, elderly individuals at risk of root caries)

​

• More processed and sugar-laden foods, limiting the repair potential of fluoride

[Duggal et al., 2001].

​

​

​

​

​

• How to improve remineralization potential of fluoride?

: Adding more fluorides to oral care products

​

​

​

​

• Dentifrices with 5,000 ppm fluoride have been found to be more efficacious for remineralization of root caries lesions than 1,000–1,500 ppm fluoride dentifrices.

[Wierichs and Meyer-Lueckel, 2015].

​

Why no fluoride ?

​

• Fluoride as a “neurotoxicant”

​

• Risk for dental fluorosis [Zohoori andMaguire, 2018].

​

• Causative factor for permanent tooth mottling

[McGrady et al., 2012;Pendrys,2000].

​

• Increased incidence of occult caries

(“Fluoride syndrome”)

​

​

​

​

​

​

​

​

• Need for new-age remineralization agents or technologies which enhances the remineralization capacity of fluoride at its optimal concentrations .

​

Non-Fluoride Enamel Remineralizing Systems

1. Biomimetic regenerative systems

(ii) Approaches that synergize fluoride efficacy

( Fluoride Boosters)

Biomimetic regenerative systems

Dentine Phosphoprotein-Derived 8DSS Peptides

​

• Human DPP contains repetitive aspartate-serine-serine (DSS) nucleotide sequences that are believed to promote hydroxyapatite (HA) formation.

​

​

• Among the DPP-derived peptides, the octuplet repeats of aspartate -serine-serine (8DSS) are the most active in promoting biomineralization [Yarbrough et al., 2010].

​

• 8DSS peptides have two mineral-binding surfaces and can strongly bind to free Ca2+ andPO4 3– ions and to to the HA surface .

​

​

• Prevents dissolution of Ca2+ and phosphate ions into the surrounding medium while promote the capturing of these ions from solution.

​

​

• Small apatite crystals with increased surface roughness, and higher hardness and elastic modulus

[Chung et al., 2017; Hsu et al., 2018].

Limitations

​

• Neutralization by hydrolytic enzymes of the oral cavity .

​

• Chance of calculus formation ( due to its increased calcium binding property ,if not controlled)

Self-Assembling P11-4 Peptides�

​

​

​

• P11-4-treated carious lesions showed

- improved visual appearance

- increased radiographic opacity

- stable even 6–12 months after treatment

​

Limitations

• Individual’s quality of saliva ( mineral content, pH, and flow rate )

​

• Reduced efficacy in xerostomia patients.

Amelogenin

• Complex enamel microstructure reproduction using synthetic amelogenin-based systems.

​

​

• Recombinant leucine amelogenin (rL172) was found to stabilize calcium phosphate clusters and promote the growth of hierarchically arranged enamel crystals .

​

• In vitro studties : reduced lesion depth

- linear growth of mature crystals along the c-axis

[Bagheri et al., 2015; Mukherjee et al., 2016; Shafiei et al., 2015].

​

​

​

• Mineralization inhibitors such as inorganic pyrophosphate or matrix metalloproteinase are added to synthetic amelogenin assemblies :

​

- Regulate size, shape, and orientation of new mineral layer,

- Prevents undesirable protein occlusion within newly formed crystals .

Poly(Amido Amine) Dendrimers

​

• Highly branched polymers characterized by the presence of internal cavities, reactive end groups, and a well-defined size and shape .

​

• Referred to as “artificial proteins”

​

• Studies have demonstrated that PAMAM dendrimers exhibited a strong tendency to self-assemble into enamel crystal structures.

​

• The new crystals created by the PAMAM organic templates had the same structure, orientation, and mineral phase of the intact enamel.

[Chen etal., 2013]

Electrically Accelerated and Enhanced Remineralization

“REMINOVA”

​

• Recently developed remineralization technology .

​

• Target on initial and moderate enamel lesions .

• Utilizes iontophoresis to accelerate the flow of remineralizing ions into the deepest part of the subsurface caries lesion.

.

​

​

​

Objectives

​

• Preservation of healthy tissue
• Repairs the full depth of the caries lesion
• Retains (or restores) the mechanical strength of the enamel structure
• Similar or better acid resistance than natural enamel
• Positive aesthetic and health appeal to patients

Nanohydroxyapatite

​

• Biocompatible and bioactive material having similar morphology, structure, and crystallinity to the apatite crystals.

​

• The small size of the particles considerably increase its surface area for binding as well as allowing it to act as a filler to repair small holes and depressions on the enamel surface creating - a new layer of synthetic enamel.

​

​

​

​

​

​

​

• nHA had the potential to remineralize initial enamel lesions with a comparable or even superior efficacy to that of fluoride.

[Huang et al., 2009, 2011; Najibfard et al.,2011; Tschoppe et al., 2011].

​

Fluoride Boosters

Calcium Phosphate Systems

​

​

• The bioavailability of Ca2+ and PO43– ions is often the limiting factor for net remineralization to occur on topical fluoride application.

​

​

• The presence of extrinsic sources of Ca2+ and PO43– ions can increase diffusion gradients and augment the F– ion-mediated remineralization.

• A number of unique calcium phosphate remineralization systems have been commercialized in recent years

​

​

3 types:

​

1. Stabilized amorphous calcium phosphate systems
2. Crystalline calcium phosphate systems
3. Unstabilized amorphous calcium phosphate systems

​

​

Casein Phospho Peptide-Amorphous Calcium Phosphate

​

• Tryptic digestion of milk caseinate produces multiphosphorylated casein phosphopeptides (CPP) (Have the ability to stabilize Ca2+ and PO4 ions.)

​

​

• CPP is a saliva biomimetic with calcium-stabilizing capacity due to the higher content of its phosphoseryl residues.

​

• Readily soluble in saliva, creating a diffusion gradient that allows them to localize in supragingival plaque.

​

​

• Release of calcium and phosphate ions ( releases on acidic pH)

​

​

​

Remineralisation of the incipient lesion by precipitation of the released ions.

​

Functionalized β-Tricalcium Phosphate

​

• Crystalline β-tricalcium phosphate (β-TCP) was modified by coupling it with carboxylic acids and surfactants to yield functionalized β-tricalcium phosphate (fTCP)

​

​

• Designed primarily to boost F– ion activity on the tooth surface, with remineralization driven mostly by salivary Ca2+and PO43– ions.

​

Calcium Sodium Phosphosilicate (NovoMin^TM )

​

• Bioactive glass material.

​

• Releases Na+, Ca2+, and PO4 3– ions, which then interact with saliva and deposit a crystalline hydroxycarbonate apatite layer .

​

​

• Calcium sodium phosphosilicate was initially incorporated into a dentifrice for the treatment of dentin hypersensitivity but there have been suggestions it could be useful for enamel remineralization too.

[Wefel, 2009]

Amorphous Calcium Phosphate ( Enamelon^TM )

​

• ACP is an unstabilized calcium phosphate system

​

• Dual-chamber fluoride toothpaste with the intention of separately delivering Ca2+ and PO4 3– ions into the mouth

​

​

• On brushing, the intraoral mixing of Ca2+ and (PO4) 3– ions results in the immediate precipitation of ACP or amorphous calcium fluoride phosphate.

• Both ACP and amorphous calcium fluoride phosphate are unstable and rapidly transform into more stable HA or fluorhydroxyapatite.

​

​

Limitations

​

• Promotes calculus formation

​

• sequester free F– ions in the oral environment, reducing their availability for lesion remineralization

Polyphosphates�

Sodium Trimetaphosphate

​

• Sodium trimetaphosphate (STMP), calcium glycerophosphate and sodium hexametaphosphate.

​

​

• Among polyphosphates, STMP is seen to be the most effective anticaries agent with an ability to not only inhibit demineralization, but also to enhance remineralization .

• STMP (Na3P3O9) is a condensed inorganic phosphate that is able to strongly bind to phosphate sites on enamel surface and remain adsorbed for a longer time compared to other phosphates .

​

​

• Forms a protective layer on the enamel surface that limits acid diffusion during a cariogenic challenge.

​

​

• The protective barrier against acid diffusion created by the adsorption of STMP on enamel does not seem to hinder the diffusion of Ca2+ and F– ions into the enamel.

Natural Products�

​

• Galla chinensis , a leaf gall produced by parasitic aphids, which has been found to be effective in inhibiting demineralization, enhancing remineralization, and increasing the efficacy of fluoride .

​

• Hesperidin , a citrus flavonoid,
• Gum arabic , an acacia exudate

( supresses demineralization and boost remineralization even under fluoride-free conditions)

​

Hesperidin

Gum arabic

Limitation

​

• Chemical characterization and standardization of the natural products will be required before further application in clinical fields.

​

​

CONCLUSION

• The era of preventive and minimally invasive dentistry clearly dictates the need for developing newer approaches to remineralize enamel caries lesions.

​

​

• Most commercially available non-fluoride remineralizing systems are aimed at enhancing fluoride efficacy and minimizing the potential risks associated with fluoride.

​

​

• The newer remineralizing therapeutic approaches - biomimetic technologies - GROWING ARTIFICIAL ENAMEL which is the future preventive dentistry.

References

• Amaechi BT, van Loveren C: Fluorides and nonfluoride remineralization systems. Monogr Oral Sci 2013; 23: 15–26.

​

• Beerens MW, van der Veen MH, van Beek H, ten Cate JM: Effects of casein phosphopeptide amorphous calcium fluoride phosphate paste on white spot lesions and dental plaque after orthodontic treatment: a 3-month follow-up.Eur J Oral Sci 2010; 118: 610–617

​

• Danelon M, Takeshita EM, Sassaki KT, Delbem AC: In situ evaluation of a low fluoride concentration gel with sodium trimetaphosphate in enamel remineralization. Am J Dent 2013; 26: 15–20.

​

• Dowd FJ: Saliva and dental caries. Dent ClinNorth Am 1999; 43: 579–597.

• Morgan MV, Adams GG, Bailey DL, Tsao CE, Fischman SL, Reynolds EC: The anticariogenic effect of sugar-free gum containing CPP-ACP nanocomplexes on approximal caries determined using digital bitewing radiography. Caries Res 2008; 42: 171–184.

​

• Mukherjee K, Ruan Q, Liberman D, White SN, Moradian-Oldak J: Repairing human tooth enamel with leucine-rich amelogenin peptide- chitosan hydrogel. J Mater Res 2016; 31: 556–563

​

• Feagin F, Patel PR, Koulourides T, Pigman W. 1971. Study of the effect of calcium, phosphate, fluoride and hydrogen ion concentrations on the remineralization of partially demineralized human and bovine enamel surfaces.Arch Oral Biol. 16(5):535–548.