Enamel Remineralization systems

State of the Art Enamel Remineralization
Systems: The Next Frontier in Caries
Management
Caries research 2019
Presented by
Dr. Mettina
II MDS
Conservative dentistry & Endodontics

Tooth development is a fascinating process that begins at about the 6th
week in utero……
2

Introduction
 The principles of minimally invasive dentistry clearly dictate the need for clinically
effective measures to re-mineralize early enamel caries lesions.
 While fluoride-mediated remineralization is the cornerstone of current caries management
philosophies, a number of new remineralization strategies have been commercialized or
are under development that claim to promote deeper remineralization of lesions, reduce
the potential risks associated with high-fluoride oral care products, and facilitate caries
control over a lifetime.
 These non-fluoride re-mineralizing systems can be broadly categorized into biomimetic
enamel regenerative technologies and the approaches that repair caries lesions by
enhancing fluoride efficacy.
 This article discusses the rationale for non-fluoride remineralization and the mechanism of
action, challenges, and evidence behind some of the most promising advances in enamel
remineralization therapies.
 Dental caries pathophysiology is not simply a continual cumulative loss of tooth minerals,
but rather a dynamic process characterized by alternating periods of demineralization and
remineralization.
3

 Remineralization can occur as a natural repair process where plaque/salivary calcium (Ca2+)
and phosphate (PO4 3–) ions are deposited into crystal voids of the demineralized tooth
structure, resulting in net mineral gain.
 The presence of free fluoride (F–) ions in the oral environment can drive the incorporation of
Ca2+ and PO4 3– ions into the crystal lattice, with the ensuing fluorapatite mineral
significantly more resistant to a subsequent acid challenge [Ten Cate, 1999].
 A better understanding of regenerative and physiochemical mechanisms has influenced the
development of a number of innovative remineralization technologies that go beyond
fluoride-mediated remineralization.
 While traditional fluoride-based remineralization remains the cornerstone for caries
management with the highest level of supporting evidence, additional remineralizing agents
to enhance fluoride effects are often needed in high caries risk individuals and population
groups [Amaechi and van Loveren, 2013; Fontana, 2016]
 . The first International Conference on Novel Anticaries and Remineralizing Agents had
suggested that the broad aim of new remineralization therapies should be to “facilitate caries
control over a lifetime using evidence-based, clinically effective, multifactorial prevention to
keep the caries process in balance” [Pitts and Wefel, 2009].
 This article discusses the rationale for using non-fluoride remineralization systems and the
mechanisms, challenges, and evidence underpinning some of the technological advances in
enamel remineralization therapies.
4

Hydroxyapatite- (Ca)10 (PO4)6 (OH)2 6

7
Re-mineralization
Demineralization

8
When the mouth has a healthy balance, saliva crushes
starches, and keeps calcium and phosphates flowing around
so teeth can re-mineralize.

Remineralization Strategy
Precondition
Activate
Remineralize
Maturate
9

Why Non- Fluoride Enamel remineralizing systems?
Natural remineralization alone is not sufficient.
 The remineralization potential of saliva is well documented [Stookey, 2008], it delivers Ca2+
and PO43– ions in a bioavailable form for hard tissue development and maintenance throughout
life [Cochrane and Reynolds, 2012].
 At physiological pH, saliva is supersaturated with phosphoprotein-stabilized Ca2+ and PO43–
ions, ensuring that the ions remain bioavailable to diffuse into mineral deficient lesions.
10

Fluoride – Improving Its Efficacy and Safety
 The discovery of fluorides as an agent for caries remineralization- landmark
 The dramatic decline in caries prevalence rates of developed countries from the latter half of the
20th century has been largely attributed to the widespread use of oral care products containing
fluoride [Fejerskov, 2004].
 Fluoride remains the gold standard for arresting caries lesions
11
5000 ppm
fluoride
1000-
1500 ppm
fluoride

Modern day caries management
 The principal approach to modern-day caries
management should be to “preserve the tooth
structure and restore only when necessary”
[Ismail et al., 2013].
12

Non-Fluoride Enamel Remineralizing Systems: Types
and Mechanisms
13
Biomimetic
regenerative
systems
Approaches that
synergise fluoride
efficacy

Biomimetic remineralization
 Oral care products containing fluoride are effective in remineralizing enamel but do not
have the potential to promote formation of organized apatite crystals [Ruan and Moradian-
Oldak, 2015].
 Shift from Reparative to regenerative biomineralization strategies.
 Enamel regeneration is however particularly challenging as mature enamel is acellular and
does not resorb or remodel itself unlike bone or dentine [Moradian-Oldak, 2012].
 Advances in tissue engineering- Biomimetic methods.
14

Dentine Phosphoprotein-Derived 8DSS Peptides
 Dentine phosphoprotein (DPP) is the most abundant
non-collagenous extracellular matrix component in
dentine and is known to play a critical role in tooth
mineralization [Hsu et al., 2011].
 DPP contains repetitive aspartate- serine –serine
nucleotide sequences that promote Hydroxyapatite
formation.
 Dual mechanism- [Hsu et al., 2011; Yang et al., 2014].
15

Dual mechanism of action of 8DSS Peptides. 16
Limit the
dissolution of
Calcium &
phosphate ions.
Promote the
capture of these
ions to form new
mineral deposits.

Self-Assembling P11-4 Peptides
 An ideal enamel regenerative approach would involve substituting the degraded enamel matrix
with a biomimetic matrix that favours in-depth remineralization of enamel lesions [Alkilzy et al.,
2018a].
 Monomeric peptide consisting of 11 amino acids called P11-4.
 This rationally designed peptide self-assembles into hierarchical 3-dimensional fibrillar scaffolds
in response to local conditions such as high ionic strength and acidic pH found in the lesion body
[Kirkham et al., 2007].
 The P11-4 fibrillar matrix has a high affinity for Ca2+ ions and acts as a nucleator for de novo HA
formation resulting in remineralization of the lesion body [Kind et al., 2017; Kirkham et al.,
2007].
 Analysis of in vitro data showed that the presence of P11- 4 fibres in the lesion body resulted in
faster HA formation, yielding tangentially arranged needle-shaped crystals, with increased
microhardness of the remineralized subsurface lesion [Schmidlin et al., 2016; Sousa et al., 2017;
Takahashi et al., 2016].
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 [Schlee et al., 2018] P 11 4 relies on natural remineralization driven by saliva.
19
Quality of
saliva
pH
Flow rate
Mineral
content

Amelogenin
 The amelogenin rich enamel organic matrix plays a critical role in regulating the growth,
shape, and arrangement of HA crystals during enamel mineralization.
 However, mature enamel lacks matrix proteins and cannot regenerate the mineral loss caused
by dental caries or erosion [Ruan and Moradian-Oldak, 2015].
 Several promising strategies have been proposed to replicate the complex enamel
microstructure using synthetic amelogenin-based systems.
 Recombinant porcine amelogenin (rP172) was found to stabilize calcium phosphate clusters
and promote the growth of hierarchically arranged enamel crystals on acid-etched lesions,
improving its hardness and elastic modulus [Fan et al., 2009; Ruan et al., 2013, 2016].
 This biomimetic re-growth of HA crystals also generated a robust interface between the
newly formed layer and native enamel ensur-ing efficacy and durability of restorations
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 An excellent low-cost and safer alternative to the
full length amelogenin is a leucine-rich amelogenin
peptide that is comprised of only 56 amino acids.
 The addition of mineralization inhibitors such as
inorganic pyrophosphate or matrix
metalloproteinase to synthetic amelogenin
assemblies was able to better regulate size, shape,
and orientation of a strongly adherent new mineral
layer, while preventing undesirable protein
occlusion within newly formed crystals
21

Poly (Amido Amine) dendrimers ( PMAM)
 Poly amido amine dendrimers are highly branched polymers characterized by a
number of reactive end groups, and a well-defined size and shape [Chen et al., 2013].
 These amelogenin inspired dendrimers have been referred to as “artificial proteins” as
they can mimic the functions of organic matrices in modulating the biomineralization
of tooth enamel.
 Several in vitro studies have demonstrated that amphiphilic, carboxyl-terminated, and
phosphate-terminated PAMAM dendrimers exhibited a strong ten-dency to self-
assemble into hierarchical enamel structure.
22

Electrically accelerated & enhanced
remineralization
 Electrically accelerated and enhanced remineralization (EAER) is a recently developed
remineralization technology targeted at initial and moderate enamel lesions with the
treatment objectives of preserving all healthy tissue, restoring the full depth of the
caries lesion, and improving mechanical properties of the treated enamel [Pitts and
Wright, 2018].
 It utilizes iontophoresis to accelerate the flow of remineralizing ions into the deepest
part of the subsurface caries lesion. This creates an environment that favours
remineralization of the lesion that then matures to give the repaired lesion optimal
hardness and mineral density.
 Unlike the biomimetic peptides, EAER does not “regenerate” lost enamel via matrix
proteins or the organic capture of Ca2+ and PO43– ions.
 However, the EAER-treated lesions have a very similar appearance to healthy enamel,
with no broken rods or degraded prisms visible under scanning electron microscopic
examination [Pitts and Wright, 2018].
24

26
• Researchers at King’s College in London are
presently testing a device that may one day
make the dental drill as obsolete, this
promises to be quick, effective, and painless.
• Pitts and his team used a minute electric
current to help the tooth take up necessary
minerals. If the technology they are
pioneering is successful, a “healing hand
piece” (instead of a drill) might one day be
placed on the prepared tooth for an easy and
painless cavity-reversing procedure.

Nanohydroxyapatite
 Synthetic nanohydroxyapatite (nHA) is considered one of the most biocompatible and
bioactive materials having similar morphology, structure, and crystallinity to the
apatite crystal within enamel [Hanning and Hanning, 2010].
 The nano-sized particles can strongly bind to enamel surfaces and with fragments of
plaque and bacteria.
 The small size of the particles that compose nHA considerably increase its surface
area for binding & allow it to act as a filler to repair small holes and depressions on the
enamel surface [Pepla et al., 2014].
 In vitro dynamic pH-cycling experiments have shown that 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].
 Another in vitro study found that nHA gel had significant potential for enamel
remineralization around restoration margins.
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Mechanism of action
 Promotes remineralization through the creation of a new layer of synthetic enamel around
the tooth or by depositing apatite nanoparticles in the enamel defects [Li et al., 2008; Pepla
et al., 2014].
 Nano HA acts as calcium phosphate reservoir maintaining a state of supersaturation with
respect to enamel minerals, thereby inhibiting demineralization and enhancing
remineralization [Huang et al., 2011]
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Calcium phosphate systems
 The need to enhance the remineralizing efficacy of fluoride in high caries risk patients is
largely met by calcium phosphate systems.
 The bioavailability of Ca2+ and PO43– ions is often the limiting factor for net
remineralization to occur on topical fluoride application, and this is especially exacerbated
under hyposalivation conditions [Reynolds et al., 2008; Vogel et al., 2008].
 A number of unique calcium phosphate remineralization systems have been
commercialized in recent years.
 Cochrane et al. [2010] catego-rized them into 3 types:
(i) Stabilized amorphous calcium phosphate systems;
(ii) Crystalline calcium phosphate systems;
(iii) Unstabilized amorphous calcium phosphate systems.
30

Casein phosphopeptide – Amorphous calcium
phosphate systems
 This remineralization system was developed based on the idea that the tryptic digestion of
milk caseinate produced multiphosphorylated casein phosphopeptides (CPP), substantially
increasing the milk protein’s solubility and ability to stabilize Ca2+ and PO43– ions
[Reynolds, 1987].
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CPP- ACP
 Low pH conditions that arise during a cariogenic attack
facilitate the release of Ca2+ and PO43– ions.
 This inhibits demineralization and favors the
remineralization of the incipient lesion by precipitation of the
released ions [Reynolds, 2009].
 The subsurface remineralization pattern produced by CPP-
ACP has been shown to significantly improve the aesthetics,
strength, and acid resistance of the remineralized WSL
[Cochrane et al., 2010; Mayne et al., 2011].
 CPP-ACP enhanced remineralization of enamel subsurface
lesions compared to predominantly surface-only
remineralization produced by fluoride alone products [Shen
et al., 2011].
32

Functionalized Beta- 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) [Karlinsey et
al., 2010].
 The purpose of functionalizing β-TCP was to create barriers preventing premature fluoride-
calcium interactions, thereby allowing it to act as a targeted low-dose delivery system when
applied to teeth via dentifrices or mouthwashes [Karlinsey and Pfarrer, 2012].
 While the pH responsive CPP-ACP nanocomplexes can deliver stabilized Ca2+ and PO43–
ions over an extended time.
 fTCP appears to supply only a small amount of unbound ions during the short period of
brushing before being expectorated from the mouth [Walsh, 2009].
33

Calcium sodium phosphosilicate
 Calcium sodium phosphosilicate is a bioactive glass material originally developed as a
biocompatible bone regenerative agent.
 When introduced into the aqueous oral environment, it releases Na+, Ca2+, and PO43–
ions, which then interact with saliva and deposit a crystalline hydroxycarbonate apatite
layer that is structurally and chemically similar to tooth mineral [Burwell et al., 2009]
34

Amorphous calcium phosphate
35
ACP is an unstabilized calcium phosphate system that has been
incorporated into a dual-chamber fluoride toothpaste with the intention of
separately delivering Ca2+ and PO43– ions into the mouth [Tung and
Eichmiller, 2004]..

Sodium Trimetaphosphate
 One way to reduce the potential risk of fluorosis while maintaining the anticaries efficacy of
conventional dentifrices is to partly replace fluoride with polyphosphate salts like sodium
trimetaphosphate (STMP), calcium glycerophosphate, or hexametaphosphate [da Camara et
al., 2016; Takeshita et al., 2016].
 Among the 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.
 a recent 18-month double-blinded RCT showed that a 500-ppm low-fluoride dentifrice
supplemented with STMP was significantly su-perior to a 1,100-ppm fluoride dentifrice in
lowering the caries increment of children [Freire et al., 2016].
37

Natural products
 Among the most promising is 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 [Cheng et al., 2008, 2010]
 Polyphenols present in G. chinensis interact with and stabilize the organic matrix remnants,
thereby blocking the ion diffusion pathways, and slowing demineralization [Huang et al., 2017;
Zhang et al., 2015].
 G. chinensis remineralization is believed to be mediated through different polyphenol
compounds that act as Ca2+ ion carriers into the lesion body [Cheng et al., 2015].
38

 Hesperidin, a citrus flavonoid, and gum arabic, an Acacia exudate, are other natural products that
have been found to suppress acid-dependent demineralization and boost remineralization even
under fluoride-free conditions [Islam et al., 2012; Onishi et al., 2008
39

40
Non-fluoride Enamel remineralizing technologies
Technology Commercial product
1 Dentin phosphoprotein 8DSS peptides Not available
2 P11-4 peptides Curodont Repair/Curodont Protect
3 Leucine-rich amelogenin peptides Not available
4 Poly(amido amine) dendrimers Not available
5 Electrically accelerated and enhanced
Remineralization Not available
6 Nanohydroxyapatite Apagard toothpaste/Desensin oral rinse

Fluoride boosters
Calcium-phosphate systems
 Stabilized calcium phosphates – Casein phosphopeptide-amorphous calcium phosphate Tooth Mousse/MI
Paste crèmes Recaldent/Trident White sugar-free gum MI Paste One toothpaste
 Crystalline calcium phosphates – Functionalized β-tricalcium phosphate, ClinPro toothpaste
 Calcium sodium phosphosilicate -Oravive toothpaste (NovoMinTM technology)
 Unstabilized calcium phosphates – Amorphous calcium phosphate ,Enamelon toothpaste (EnamelonTM
technology)
 Polyphosphate systems -Oral-B Pro Expert toothpaste
 Sodium trimetaphosphate – Calcium glycerophosphate, Sodium hexametaphosphate- 3
 Natural products – Galla chinensis – Hesperidin – Gum Arabic , Not available
41

Repair of tooth enamel by a biomimetic mineralization frontier ensuring
epitaxial growth
Changyu Shao1, Biao Jin1, Zhao Mu1, Hao Lu2, Yueqi Zhao1, Zhifang Wu3, Lumiao Yan1, Zhisen
Zhang2, Yanchun Zhou4, Science Advances 2019
 The regeneration of tooth enamel, the hardest biological tissue, remains a considerable
challenge because its complicated and well-aligned apatite structure has not been
duplicated artificially. We herein reveal that a rationally designed material composed of
calcium phosphate ion clusters can be used to produce a precursor layer to induce the
epitaxial crystal growth of enamel apatite, which mimics the biomineralization crystalline-
amorphous frontier of hard tissue development in nature. After repair, the damaged enamel
can be recovered completely because its hierarchical structure and mechanical properties
are identical to those of natural enamel. The suggested phase transformation–based
epitaxial growth follows a promising strategy for enamel regeneration and, more generally,
for biomimetic reproduction of materials with complicated structure.
43

Conclusion
 Effective non-fluoride remineralizing strategies can prevent a non-cavitated lesion from
being subjected to a “death spiral of restorations” due to secondary caries at the enamel-
restoration interface .
 Currently, most commercially available non-fluoride remineralizing systems are aimed at
enhancing fluoride efficacy and minimizing the potential risks associated with fluoride.
 However, a biomimetic strategy for enamel regeneration may well be the future, where
organized enamel apatite crystals with robust attachment to the tooth surface are grown to
replace demineralized tissue.
44

Enamel Remineralization systems

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