Review Article

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An update on remineralizing agents

Shashi Prabha Tyagi, Paridhi Garg, Dakshita Joy Sinha, Udai Pratap Singh
Department of Conservative Dentistry and Endodontics, Kothiwal Dental College and Research Centre, Moradabad,
Uttar Pradesh, India

Address for correspondence: Dr. Paridhi Garg, Email: paridhigarg03@gmail.com

ABSTRACT
Modern dentistry aims to manage noncavitated carious lesions noninvasively through remineralization in an attempt to prevent
disease progression, and to improve form, function, strength and esthetics of teeth. The emphasis currently is being laid upon
new technologies for enamel remineralization. Further studies are required on biomimetic molecules involved in calcium fluoride
phosphate stabilization and nucleation that may provide further improvements in the development of novel remineralization
treatments. The aim of this paper is to review the contemporary remineralizing systems available for remineralization therapy
and their implementation into clinical practice. A search of articles from Pubmed and Medline with the keywords
Remineralization- demineralization, Casein derivatives, fluoridated remineralizing agents and nonfluoridated remineralizing
agents was conducted. A total of 810 abstracts were collected, of which 351 articles that discussed the current technologies
of remineralizing agents were read and 71 most relevant articles were included in this paper.

CLINICAL RELEVANCE TO INTERDISCIPLINARY DENTISTRY

All work in the health field is aimed at conservation of the human body and its function; similarly, dentistrys goal
should be to preserve healthy, natural tooth structure. Modern dentistry aims to manage noncavitated carious lesions
noninvasively through remineralization. Remineralizing agents can also find its application in other fields of dentistry
like pedodontics, periodontics and orthodontics. It can help in mineralization and management of hypocalcified lesions. It
can be used for desensitization of exposed dentine affected by dental erosion. It can be used after debonding of brackets
in lieu of completion of orthodontic treatment.
Key words: Caries, demineralization, enamel, remineralization, remineralizing agents

INTRODUCTION

emineralization is defined as the process

whereby calcium and phosphate ions
are supplied from a source external to the tooth
to promote ion deposition into crystal voids in
demineralized enamel to produce net mineral gain.[1]
Extension for Prevention has given way to the new
paradigm of minimally invasive dentistry. The minimally
invasive approach to treat dental caries incorporates
the dental signs of detecting, diagnosing, intercepting
and treating dental caries on the microscopic level.[2]
Access this article online

The principles of minimal intervention in the

management of dental caries (adopted by the FDI
General Assembly, 1st October, 2002, Vienna) are:
Modification of oral flora
Patient education
Remineralization of cavitated lesions of enamel
and dentin
Minimal intervention of cavitated lesions
Repair of defective restorations.
The purpose of this review is to have an indepth
knowledge of the natural phenomenon of enamel
demineralization and remineralization while discussing
the clinical relevance of remineralizing products
aiming to treat early carious lesions Table 1.[3,4]

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Website:
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DOI:
10.4103/2229-5194.131200

Journal of Interdisciplinary Dentistry / Sep-Dec 2013 / Vol-3 / Issue-3

DEMINERALIZATION AND
REMINERALIZATION
Demineralization occurs by disassociation of lactic
acid, produced by bacterial carbohydrate metabolism,
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Tyagi, etal.: Remineralizing agents

Table 1: Saliva and the functions of its various

components
Function
Remineralization
Acid buffering
Digestion
Lubrication
Aggregation
and clearance of
microorganisms
Antibacterial
agents
Antifungal and
antiviral agents
Bolus formation
Taste

Salivaderived components
Prolinerich glycoproteins, statherins, calcium, phosphate,
fluoride, mucins
Bicarbonate, phosphate, carbonic anhydrate, sialin, basic
alkaline proteins, urease
Amylase, lipase, protease, DNase, RNase
Mucins, prolinerich glycoproteins
Mucins, lactoferrin, immunoglobulin A, prolinerich
glycoproteins, statherin, lysozyme
Mucins, lysozyme, lactoferrin, lactoperoxidase, histatine,
cystatins, agglutinin, defensins, cathelicidin, prolinerich
glycoproteins
Immunoglobulins A, mucins, histatins
Mucins
Mucins, zinc

with tooth mineral. The reaction leads to release of mineral

ions into the solution:
Ca10(PO4)6(OH)2 + 14 H+ 10 Ca+ + 6 H2PO4+ H2O
The extent to which tooth mineral dissolves in a given
solution is governed by the thermodynamic ion activity
product (IAP):
IAP = (Ca 2+)10(PO43)6(OH)2
When the IAP equals a constant called the solubility
product constant of Ksp, the solution is in equilibrium
with the solid and is said to be saturated with respect
to the solid.[5] The only requirement for dimeralization
to occur is that the IAP in the demineralizing solution
should be less than the Ksp.
(Ca ) (PO4 ) (OH ) < Ksp (tooth mineral)
2+ 10

3 6

The subsurface lesion is reversible via a remineralization

process. The increase in oral fluid calcium and phosphate
drives the remineralization process.

REQUIREMENTS OFA REMINERALIZING

AGENT




152

Should deliver calcium and phosphate into the

subsurface
Should not deliver any excess of calcium
Should not favor calculus formation
Should work at an acidic pH so as to stop
demineralization during a carious attack

Should be able to work in xerostomic patients as saliva

cannot effectively stop the carious process
Should be able to boost the remineralizing properties
of saliva
The novel materials should be able to show some
benefits over fluoride.[6]

INDICATIONS

An adjunct preventive therapy to reduce caries in

highrisk patients
Reduce dental erosion in patients with gastric reflux
or other disorders
To reduce decalcification in orthodontic patients
To repair enamel in cases involving whitespot lesions
Orthodontic decalcification or fluorosis or before and
after teeth whitening and to desensitize sensitive
teeth.[7]

FLUORIDES
The first theories concerning the mechanism of action of
fluoride were based exclusively on its preeruptive effect.
Arnold, in 1957, was the first author to mention the
posteruptive effect of fluoride in the drinking water and the
ability of topical fluoride to reduce the incidence of caries.[8]
The mechanism by which fluoride increases caries
resistance may arise from both systemic and topical
applications of fluoride and can be broadly grouped as
follows increased enamel resistance, increased rate of
maturation, remineralization of incipient caries, interference
with microorganisms and improved tooth morphology.[8]
Enamel is dissolved by lowering of pH in dental plaque due
to acid production every time sugar is ingested. However,
if F is present in the biofilm fluid, and the pH is not lower
than the critical pH, hydroxyapatite (HA) is dissolved and
at the same time fluorapatite is formed. Furthermore, FA
is deposited on the surface layer of enamel while HA is
dissolved from the subsurface. This indirect effect of F in
reducing enamel demineralization when the pH drops is
complemented by its natural effect on remineralization
when the pH rises enhancing the redeposition of Ca2+
and PO43 present in the biofilm fluid on demineralized
enamel.[9] Its ability to promote net remineralization is
limited by the availability of calcium and phosphate ions.
Hence, this can be the limiting factor.[10] Also, fluoride
might be highly effective on smooth surface caries but its
effect is limited on pit and fissure caries. Overexposure
of fluoride can also cause fluorosis. All these limitations
have prompted researchers to look for nonfluoridated
alternatives for remineralization.
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CASEIN PHOSPHOPEPTIDE
AMORPHOUS CALCIUM PHOSPHATE
The casein phosphopeptides (CPPs) are produced from the
tryptic digest of casein, aggregated with calcium phosphate
and purified through ultrafiltration.[6] Casein has the ability
to stabilize calcium and phosphate ions by releasing small
sequences of peptides (CPPs) through partial enzymic
digestion that led to the development of a remineralization
technology based on casein phosphopeptidestabilized
amorphous calcium phosphate complexes (CPPACP) and
casein phosphopeptidestabilized amorphous calcium
fluoride phosphate complexes (CPPACFP).[1012]
This technology was developed by Eric Reynolds,
Australia. CPPs contain the cluster sequence of -Ser
(P)Ser (P)Ser (P)GluGlu from casein.[13,14] This protein
nanotechnology combines the precise ratio of 144 calcium
ions plus 96 phosphate ions and six peptides of CPP. The
nanocomplexes form over a pH range of 5.0-9.0. Under
neutral and alkaline conditions, the CPPs stabilize calcium
and phosphate ions, forming metastable solutions that
are supersaturated, which increase as the pH increases.
A 1% CPP solution at pH 7.0 can stabilize 60 mM calcium
and 36 mM phosphate.[15,16] Calcium interacts with CPP
through the negatively charged residues of the peptides.[17]
However, CPPs bind more calcium and phosphate ions
than can be attributed to just the calciumbinding motif
-Ser (P)-Ser (P)-Ser (P)-Glu-Glu-, indicating that other
acidic residues of the phosphopeptide sequence also
contribute to the stabilization of calcium phosphate,
preventing the growth of the calcium and phosphate ion
clusters to a critical size required for nucleation and phase
transformations.[17]
The size and electroneutrality of the CPP nanocomplexes
allows them to diffuse down the concentration gradient
into the body of the subsurface lesion.[10,12] Once present
in the enamel subsurface lesion, the CPPACP releases the
weakly bound calcium and phosphate ions,[1719] depositing
them into crystal voids. The CPPs have a high binding
affinity for apatite;[20] thus, on entering the lesion, the CPPs
binds to the more thermodynamically favored surface of
an apatite crystal face.
It is pH responsive, i.e. with increasing pH, the level
of bound ACP increases, stabilizing free calcium
and phosphate and thus providing an anticalculus
action.[14] The anticaries action influences the properties
and behavior of dental plaque through (1) binding with
adhesion molecules on mutans Streptococci, impairing
their incorporation into plaque, (2) elevating plaque
calcium ion levels to inhibit plaque fermentation and
(3) providing protein and phosphate buffering of plaque
fluid pH to suppress overgrowth of aciduric species when
fermentable carbohydrate is in excess.
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Tooth crmes using CPPACP (Recaldent technology) such

as MIPaste and ToothMousse[21] recognize the importance
of the neutral ion species, gaining access to the subsurface
lesion through a porous enamel surface. This is the reason
why arrested white spot lesions should have a surface
etching treatment before remineralization with Recaldent
products, unlike fluoride treatments with conventional
dentifrices (1000 ppm) that deposit surface mineral but
do not eliminate a whitespot lesion.[22]
CPPACP is a useful cariostatic agent for the control of dental
caries.[7] A dentifrice containing CPPACP with fluoride will
provide remineralization, which is superior to both CPPACP
alone and to conventional and high fluoride dentifrices.[23]
Reynolds and colleagues found a reduction of 15% and 46%,
respectively, in 0.1% and 1.0% w/v CPPACP.[24]
Thus, it is evident that other than for fluoride, the strongest
level of clinical evidence for remineralization is for the
CPPbased Recaldent technology, with both longterm
largescale clinical trials and randomized controlled clinical
trials to support its efficacy.

BIOACTIVE GLASS
Bioactive glass (Bioglass) was invented by Dr. Larry Hench
in1960s. It acts as a biomimetic mineralizer matching the
bodys own mineralizing traits while also affecting cell
signals in a way that benefits the restoration of tissue
structure and function.[25]
Bioglass in an aqueous environment immediately begins
surface reaction in three phases, leaching and exchange
of cations, network dissolution of SiO2 and precipitation
of calcium and phosphate to form an apatite layer. The
critical stages for glass surface reactions are the initial
Na+ and H+/H3O+ ion exchange and dealkalinization
of the glass surface layer is quite rapid, within minutes
of implantation and exposure to body fluids. [26] The
net negative charge on the surface and loss of sodium
causes localized breakdown of the silica network with
the resultant formation of (silanol) Si (OH) groups, which
then repolymerize into a silicarich surface layer. [27]
Within 3-6 h in vitro, the calcium phosphate layer will
crystallize into the carbonated hydroxyapatite (CAP)
layer, which is essentially the bonding layer. Chemically
and structurally, this apatite is nearly identical to bone
and tooth mineral. These Bioglass surface reactions
from implantation to formation of 100-150 m CAP
layer takes 12-24 h.[26,28]
Bioactive glass formulation commonly used in research
studies contains 45 wt% SiO2 4.5 wt% Na2O and CaO and
6 wt% P2O5. The network breakdown of silica depends
upon the concentration of SiO2 and is time dependent.
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Tyagi, etal.: Remineralizing agents

Thus, keeping the silica below 60 wt% and maintaining a

high CaO/P2O5 ratio guarantees a highly reactive surface.
Novamin, a trade name for bioactive glass, is manufactured
by Novamin Technologies Inc. (Alachua, FL, USA). It has
been demonstrated that fine particulate bioactive glasses
(<90 m) incorporated into an aqueous dentifrice have the
ability to clinically reduce the tooth hypersensitivity through
the occlusion of dentinal tubules by the formation of the CAP
layer.[29] Investigators using bioactive glass compositions
have demonstrated a significant antimicrobial effect
toward caries pathogens (S. mutans, S. sanguis) upon
exposure to bioactive glass powders as well as solutions
and extracts.[30]

Products available with TCP include a 5000 ppm sodium

fluoride dentifrice and a 5% sodium fluoride varnish.
Studies have concluded that TCP provided superior
surface and subsurface remineralization compared with
a 5000 ppm fluoride and CPPACP.[35] There has been no
significant research about TCP added to fluoride varnish.
All published studies supporting this material have been in
vitro studies. The potential of TCP is promising, but more
studies are needed, including clinical trials supporting its
efficacy in boosting remineralization.

ACP TECHNOLOGY
[ENAMELON, ENAMEL CARE]

Caries can also result from inadequate saliva, without

which fluoride is of limited value.[31] Thus, individuals
who experience reduced calcium, phosphate and fluoride
ions caused by hyposalivation can benefit from the use of
bioactive glass. In addition, women are at increased caries
risk due to inadequate salivary calcium levels at different
points in their lives, including ovulation, pregnancy and
postmenopause, resulting in the same net effect as
reduced saliva fluoride efficacy.

The ACP technology requires a twophase delivery system

to keep the calcium and phosphorous components from
reacting with each other before use. The current sources
of calcium and phosphorous are two salts, calcium sulfate
and dipotassium phosphate. When the two salts are
mixed, they rapidly form ACP that can precipitate on to
the tooth surface. This precipitated ACP can then readily
dissolve into the saliva and can be available for tooth
remineralization.[36]

Thus, the use of bioactive glass (Novamin Technology) in

remineralization of enamel is quite promising, especially
in patients with systemic problems, but further research
needs to be undertaken to prove its efficacy.

The ACP technology was developed by Dr. Ming S. Tung.

In 1999, ACP was incorporated into toothpaste called
Enamelon and later reintroduced in 2004 as EnamelCare
toothpaste.[37] There is a modest evidence for Enamelon
for its caries inhibitory action.[38]

TRICALCIUM PHOSPHATE
[CLINPRO TOOTH CRME]

An inherent technical issue with Enamelon is that

calcium and phosphate are not stabilized, allowing the
two ions to combine into insoluble precipitates before
they come into contact with saliva or enamel. This is unlike
Recaldent, which has the casein phosphoproteins to
stabilize calcium and phosphate.

TCP is a new hybrid material created with a milling

technique that fuses beta tricalcium phosphate (TCP)
and sodium lauryl sulfate or fumaric acid. This blending
results in a functionalized calcium and a free
phosphate, designed to increase the efficacy of fluoride
remineralization.[32,33] TCP is similar to apatite structure
and possesses unique calcium environments capable of
reacting with fluoride and enamel. While the phosphate
floats free, these exposed calcium environments are
protected, preventing the calcium from prematurely
interacting with fluoride. [34] TCP provides catalytic
amounts of calcium to boost fluoride efficacy and may
be well designed to coexist with fluoride in a mouthrinse
or dentifrice because it will not react before reaching the
tooth surface.[34] When TCP finally comes into contact
with the tooth surface and is moistened by saliva, the
protective barrier breaks down, making the calcium,
phosphate and fluoride ions available to the teeth. The
fluoride and calcium then react with weakened enamel
to provide a seed for enhanced mineral growth relative
to fluoride alone.
154

XYLITOL [SPRY]
Xylitol is a noncariogenic fivecarbon sugar alcohol that
occurs naturally in plants and is used as a substitute for
sugar. Sources are fruits, berries, mushrooms, lettuce,
hardwoods and corn on the cob. The dental significance
of xylitol was discovered in Finland in the early 1970s.
Xylitol has the ability to:
Reduce dental plaque formation
Make plaque less adhesive
Neutralize plaque acids by decreasing the production
of lactic acid
Reduce the levels of S. mutans
Reduce cavities by up to 80%
Demonstrate significant longterm reduction in caries
(88-93%)
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Assist in the remineralization of tooth enamel

Reduce gum tissue inflammation
Help with dry mouth and bad breath.

Xylitol has been employed for many years as a

nonacidogenic sweetener in numerous applications as
it cannot be fermented by plaque bacteria.
It works by interfering with the metabolism of S. mutans.
When S. mutans is transported into a cell, xylitol makes
it to bind to proteins. This bond is unbreakable and the
transport protein is unable to go out of the cell and bring
more glucose into the cell. Because the bacteria are
bound, they are unable to produce the sticky extracellular
polysaccharides that bind bacteria together. As a result,
there is less plaque buildup and the decaycausing bacteria
cannot stick to the enamel.[39]
Xylitol also stimulates salivary flow. Increased salivary
flow offers protection to both the oral soft tissues and
the teeth.[40]
It has also been shown that a combination of fluoride and
xylitol is more effective than fluoride alone.[4144]
The recommended dose varies upon its intended action.
For the maximum prevention of dental caries, 7-20 g/day
is given, divided into several doses in candies or chewing
gum. The best time to use xylitol is immediately after
eating and clearing the mouth by swishing with water. One
of its advantages is that it does not raise blood pressure or
blood glucose levels as most sugar substitutes do. Thus, it
has been proven to be an effective remineralizing agent
in conjunction with fluoride, or even otherwise.

REMINERALIZATION OF DENTIN
The collagen fibrils in dentin serve as a scaffold for mineral
crystallites that reinforce the matrix, supporting the
surrounding enamel. From a biomechanical perspective,
the mineralized dentin matrix preserves tooth function
by helping to prevent propagation of cracks from the
brittle enamel through the dentin-enamel junction into
the dentin[45] thus preventing fracturing of the enamel
crown. Although previous investigations have suggested
the importance of the mechanical recovery of dentin after
remineralization,[46] there is a lack of information in the
current literature with regard to this phenomenon.

(calcium, phosphate and fluoride) from the oral fluid on

to the remnant crystallites in the demineralized tissue[48]
or by treatments that incorporate the same ions from
external sources.
Remineralization of dentin can occur either by precipitation
of mineral between collagen fibrils or functionally, bound
to its structure. Therefore, simple precipitation of mineral
into the loose demineralized dentin matrix, the socalled
net remineralization, provides an increased mineral
content, but may not necessarily provide an optimal
interaction with the organic components of the dentin
matrix. Hydration is significant in the evaluation of the
mechanical response of the tissue after remineralizing
treatments. In the absence of the intrafibrillar mineral and
an optimal interaction of the granular precipitate within
the collagen fibrils, the dentin matrix can incorporate more
water and tends to swell more than the sound tissue. As
a result, the compressive stresses that consolidated the
mineral lying between the collagen fibrils no longer exist,
and the elastic constants become largely determined by
the highly deformable organic network and are therefore
quite low. The net effect may be one of relatively high
mineral content, but very low mechanical properties.
Hence, in agreement with our previous hypothesis,[49] we
suggest that changes in the mineral content alone do not
necessarily result in recovery of the mechanical properties
of remineralized dentin.
Ideally, the regrowth of intrafibrillar and extrafibrillar
mineral between the fibrils would lead to the full
mechanical recovery of the demineralized dentin. This
would yield properties comparable to normal dentin
and indicate successful functional remineralization. In
this situation, the collagen fibrils become reinforced by
the reincorporated mineral, which facilitates the transfer
of load on to the extrafibrillar mineral. A remineralized
tissue that has restored its mechanical properties under
hydration is an indication that mineral crystallites are in
tight association or perhaps chemically bound to the
collagenous matrix.
More detailed determinations of biological, microstructural
and other biomechanical changes of remineralized dentin
will perhaps provide us with a broader understanding
of the overall functionality of treated tissues. These
developments should be encouraged so that better future
strategies for remineralization of dentin can be designed.

GRAPE SEED EXTRACT

When the carious lesion reaches the dentin matrix,

it progresses much more rapidly as compared with
the enamel thus creating different zones that reflect
differences of mineral content, mechanical properties and
optical appearance.[47] Remineralization of carious dentin
can occur either by a spontaneous incorporation of ions

Root caries is especially prevalent among the elderly

population due to gingival recession and the exposure
of susceptible root surface.[50] Dentin mineral is dissolved
by acid produced from the oral bacterial biolm and

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the demineralized dentin matrix is further degraded,

allowing bacteria to infiltrate the intertubular area.[51]
The preservation and stability of dentin collagen may be
essential during the remineralization process, because it
acts as a scaffold for mineral deposition. It has also been
suggested that the presence of an organic matrix may
reduce the progression of erosion in dentin.[52,53] One of
the important strategies regarding preventive therapies for
root caries is to promote remineralization of demineralized
dentin.[5457]

Another approach is to improve the biomimetic peptides

used to stabilize, deliver and control remineralization. With
modern peptide synthetic approaches,[69] it is possible to
incorporate additional phosphoseryl residues.

Polyphenols are plantderived substances that have

antioxidant and antiinflammatory properties.[5860] They
interact with microbial membrane proteins, enzymes and
lipids, thereby altering cell permeability and permitting
the loss of proteins, ions and macromolecules. One
such polyphenol is proanthocyanidin (PA), which is a
bioflavanoidcontaining benzenepyranphenolic acid
molecular nucleus.[60] The PA accelerates the conversion of
soluble collagen to insoluble collagen during development
and increases collagen synthesis.[58]

CONCLUSION

Grape seed extract (GSE) has a high PA content.

PAtreated collagen matrices are nontoxic and inhibit
the enzymatic activity of glucosyl transferase, FATPase
and amylase. glucosyl transferases, which are produced
by S. mutans that polymerize the glucosyl moiety
from sucrose and starch carbohydrates into glucans.
This constitutes the sucrosedependent pathway for
S. mutans to establish on the tooth surface and is of
central importance in plaque formation and development
of caries. The adherent glucan also contributes to the
formation of dental plaque, in which accumulation of
acids leads to localized decalcification of the enamel
surface by facilitating bacterial adherence to the tooth
surfaces, interbacterial adhesion and accumulation of
biofilms. Hence, inhibition of glucosyl transferases by PA
in turn inhibits caries.[59,61,62]

Another problem is that preclinical models may not

necessarily be predictive of clinical performance for all
the nonfluoride agents and the new agents still require
direct clinical validation to ensure efficacy.

A goal of modern dentistry is the noninvasive management

of noncavitated caries lesions involving remineralization
systems to repair the enamel with fluorapatite or
fluorhydroxyapatite.
With a clearer understanding of the implementation
of these remineralizing agents, we can create a more
favorable relationship in which remineralization can occur.
It is important for dental professionals to be aware that it
takes significant time to establish the bonafides of a new
technology.[70,71]

REFERENCES

Active whitespot lesions have been shown to have

a greater likelihood of regression (remineralization)
compared with inactive lesions [63] as they have a
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Possible appr oaches that have been suggested
include: Microabrasion,[64] acid etching,[65] bleaching/
deproteination[66,67] or a combination approach such as
bleaching and etching.[68]

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How to cite this article: Tyagi SP, Garg P, Sinha DJ, Singh UP. An update
on remineralizing agents. J Interdiscip Dentistry 2013;3:151-8.
Source of Support: Nil, Conflict of Interest: None declared.

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