ISSN: 2320-5407 Int. J. Adv. Res.

10(09), 618-626

Journal Homepage: - www.journalijar.com

Article DOI: 10.21474/IJAR01/15400

DOI URL: http://dx.doi.org/10.21474/IJAR01/15400

RESEARCH ARTICLE
NONFLUORIDATED REMINERALIZING AGENTS

Dr. Serene M.S1, Dr. Shipra Jaidka2, Dr. Rani Somani3, Dr. Deepti Jawa2, Dr. Sarath Kumar R.1, Dr.
Anaswara S.1 , Dr. Anu Susan Joy1 and Dr. Deepa P.1
1. Post Graduate student, Department of Pediatric & Preventive Dentistry, Divya Jyoti College of Dental Sciences
& Research Centre, Ghaziabad, Uttar Pradesh, India.
2. Professor, Department of Pediatric & Preventive Dentistry, Divya Jyoti College of Dental Sciences & Research
Centre, Ghaziabad, Uttar Pradesh, India.
3. Professor & Head of the Department of Pediatric & Preventive Dentistry, Divya Jyoti College of Dental
Sciences & Research Centre, Ghaziabad, Uttar Pradesh, India.
……………………………………………………………………………………………………....
Manuscript Info Abstract
……………………. ………………………………………………………………
Manuscript History Early diagnosis of dental caries is of paramount importance. If we are
Received: 18 July 2022 able to intercept caries lesion at subsurface level with the help of
Final Accepted: 20 August 2022 remineralizing agents, we can actually achieve a caries free
Published: September 2022 mouth.Remineralization was ruled by fluorides from the 1960s. Since
then it has been successfully remineralizing carious lesions & has
Key words:-
Nonfluoridated Remineralizing Agents, certain disadvantages like it is dependant on calcium and phosphate
Amorphous Calcium Phosphate, Casein from saliva to accomplish this. Also overuse of fluorides can cause
Phosphopeptides-Amorphous Calcium dental and skeletal fluorosis. This made researchers to explore
Phosphate, Tri Calcium Phospate
nonfluoridated remineralizing agents.ACP compounds are considered
prime candidates for remineralization therapy due to their high
solubility under oral conditions and ability to rapidly hydrolyze to form
apatite. Casein phospho-peptides are responsible for the high
bioavailability of calcium from milk and other dairy products. CPP
have the ability to bind and stabilize calcium and phosphate in solution,
as well as to bind to dental plaque and tooth enamel. CPP stabilize
ACP, localize ACP in dental plaque, thereby maintaining a state of
supersaturation with respect to tooth enamel, reducing
demineralization. TCP is a new hybrid material & when TCP comes
into contact with the tooth surface and is moistened by saliva, the
protective barrier breaks down making calcium, phosphate and fluoride
ions available to the tooth. Xylitol, sugar substitute especially in
chewing gums which increases salivary flow rate and enhances the
protective properties of saliva. Bioactive glass is made of synthetic
mineral containing sodium, calcium, phosphorous and silica which are
all elements naturally found in the body. Ozone can shift microbial
flora from acidogenic bacteria to normal commensals allowing
remineralization to occur. Nanohydroxyapatite, a bioactive and
biocompatible material, functions by directly filling up the micropores
in early caries lesions.On the basis of the available data authors have
given an insight into different nonfluoridated remineralizing agents in
this article.

Corresponding Author:- Dr. Serene M.S

Address:- Post Graduate Student, Department of Pediatric & Preventive Dentistry, Divya 618
Jyoti College of Dental Sciences & Research Centre, Ghaziabad, Uttar Pradesh, India.
ISSN: 2320-5407 Int. J. Adv. Res. 10(09), 618-626

Copy Right, IJAR, 2022,. All rights reserved.

……………………………………………………………………………………………………....
Introduction:-
The human tooth is the highly mineralized tissues of the body containing hydroxyapatite as the primary constituent.
According to Miller's Chemoparasitic theory caries is brought about by acid dissolution of mineral phase of teeth,
the acid being produced by metabolism of dietary carbohydrates by oral bacteria. This theory emphasizes that there
is an association between mineral content of teeth and dental caries.

Dental caries is a dynamic process which occurs when demineralization exceeds remineralization. But progression
of dental caries is a slow process and during early stages non-invasive intervention can convert the lesion to inactive
state from an active state .A drop in pH of oral cavity results in demineralization .The reversal can occur if pH rises
resulting in deposition of caicium, phosphate and fluoride.

Demineralization starts at the enamel surface as it is the most mineralized tissue of the tooth. This subsurface
demineralization increases porosity and changes the optical properties of the enamel. Thus early diagnosis of dental
caries is of paramount important. If we are able to intercept caries lesion at subsurface level with the help of
remineralizing agents, we can actually achieve a caries free mouth.

Fig 1:- Cycle of demineralization and remineralization in enamel.

Remineralizing agents are of two types, fluoridated and non fluoridated.Fluoridated remineralizing agents are being
used since ages. Fluoride increases caries resistance when applied both topically and systematically. Fluoride level
of 3 parts per million is needed to shift demineralization into remineralization Fluoride is known to promote
remineralization but they have certain disadvantages like it is dependant on calcium and phosphate ions from saliva
to accomplish this .Also improper use of fluoride can lead to adverse effects like fluorosis and fluoride is highly
effective on smooth surface caries but not on pit and fissure caries.

Thus Non fluoridated remineralizing agents are gaining popularity in the field of remineralization because of the
harmful effects of fluoridated agents.Non fluoridated remineralizing systems are not dependent on variable like
quality of saliva and doesn't have a strict regime of topical application like that of fluoridated remineralizing agents..
Non fluoridated remineralizing agents are highly effective on both pit and fissure and smooth surface areas.
Moreover these systems are based on improving efficacy of fluoride and reducing the concern regarding fluoride
toxicity. With newer nonfluoridated techniques, we can re establish the health of oral tissues without adverse effects
of fluorides.

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Ideal Requirements Of Non Fluoridated Remineralizing Agent

• It should deliver calcium and phosphate into the subsurface.
• It should not deliver any excess of calcium.
• It should not favor calculus formation.
• It should work at an acidic pH so as to stop demineralization during a carious attack.
• It should work in xerostomic patients also, as saliva cannot effectively stop the carious process.
• It should be able to boost the remineralizing properties of saliva.
• The novel materials should be able to show some benefits over fluoride. 1

Classification
Non-fluoride-based remineralizing agents can be classified as either calcium-based or non-calcium-based
compounds or compositions. The non-calcium-based technologies focus primarily on pH modification through
micro environmental buffering effects within the saliva, surface biofilm, and/or enamel pellicle. 2
Nonfluoridated remineralizing agents are classified into:
I. Calcium based
a) Amorphous Calcium Phosphate (ACP)
b) Casein Phosphopeptides-Amorphous Calcium Phosphate
c) Tricalcium Phosphate (TCP)
d) Cavistat
e) Bioactive Glass

II. Non calcium based

a) Nano Hydroxy apatite
b) Sugar substitutes (xylitol)
c) Ozone

Indication
1. An adjunct to preventive therapy for reducing caries in high-risk patients
2. Reduce dental erosion in patients with gastric reflux or other disorders
3. To reduce decalcification in orthodontic patients
4. To repair enamel in cases involving whitespot lesions
5. For fluorosis, before and after teeth whitening and to desensitize sensitive teeth1

Contraindication
1. Teeth with cavitated lesions.
2. Teeth with pulpal involvement

AMORPHOUS CALCIUM PHOSPHATE (ACP)

Amorphous calcium phosphate (ACP) is a noncrystalline form of calcium phosphate which remineralizes the tooth
structures and aid in the prevention of tooth decay. Amorphous Calcium Phosphate compounds (ACPs) are
considered prime candidates for remineralization therapy due to their high solubility under oral conditions and
ability to rapidly hydrolyze to form apatite.

Mechanism of action
Amorphous calcium phosphates (ACP) is the reacted complex of calcium and phosphate ions that precipitate and
can grow on the tooth surfaces in the oral environment. These initial Amorphous calcium phosphates complexes are
thermodynamically unstable under the conditions normally prevalent in the oral environment ; pH , temperature etc.

Transformation mechanism of ACP to apatite at physiological pH has been described as followings: firstly ACP
dissolution happens and then a transient Octacalcium phosphate solid phase reprecipitation happens through
nucleation growth, and finally hydrolysis of the transient Octacalcium phosphate phase into the thermodynamically
more stable apatite by a topotactic reaction occurs.

Advantages
1. Application can be done both professionally and at home.
2. Can be used by patients of all age because of its ease of application.

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3. Cosmetic improvements in dimpled, abraded or etched tooth enamel. 3

4. ACP is Biocompatible and no side effects have been reported.

Disadvantages
1. Amorphous calcium phosphate is an unstable compound.
2. ACP has poor mechanical properties due to its unstable nature.

CASEIN PHOSPHOPEPTIDES-AMORPHOUS CALCIUM PHOSPHATE

Casein, a bovine milk phospho-protein is known to interact with calcium and phosphate and is a natural food component.
Its technical name is casein phospho-peptides-amorphous calcium phosphate or CPP-ACP. Other than fluoride, CPP-ACP
is the most extensively researched remineralization technology.

Casein phosphor-peptides (CPP) are naturally present in cows milk and is responsible for the high bioavailability of
calcium from milk and other dairy products.. Calcium phosphate is normally insoluble that is, it forms a crystalline
structure at neutral pH. However, in the presence of CPP calcium and phosphate remain in an amorphous, no crystalline
state. In this amorphous state, calcium and phosphate ions can enter the tooth enamel. Moreover CPP have the ability to
bind and stabilize calcium and phosphate in solution, as well as to bind to dental plaque and tooth enamel . Thus CPP keeps
calcium and phosphate in close proximity to tooth surface and plaque for a longer duration of time. The high-concentration
of calcium and phosphate ions in dental plaque have been extensively researched and proven to reduce the risk of enamel
demineralization and promote remineralization of tooth enamel. CPP stabilize ACP, localize ACP in dental plaque, thereby
maintaining a state of supersaturation with respect to tooth enamel, reducing demineralization and enhancing
remineralization. The CPPs have been shown to keep fluoride ions in solution too, thereby enhancing the efficacy of the
fluoride as a remineralizing agent.4

Advantages
1. CPP-ACP can be used both professionally and personally due to its ease of application.
2. Can be used in patients of all age group.
3. CPP-ACP has a pleasant taste and comes in different flavours.

Disadvantages
1. CPP-ACP is costly to be used regularly.
2. CPP-ACP products are hard to find in all stores because of its restricted availability

TRI CALCIUM PHOSPATE (TCP)

Another calcium phosphate technology is Tri-calcium phosphate (TCP) which provides bioavailable calcium and
phosphate ions to the teeth generating significant remineralization even when used in small amounts.

Mechanism Of Action
Tricalcium phosphate is milled with simple organic materials to create a functionalized tricalcium calcium phosphate
ingredient. This process ensures that prior to use, the active calcium sites are protected from premature interactions
with fluoride, which could otherwise render both calcium and fluoride inactive.Tricalcium phosphate,when comes in
contact with tooth surface and moistened by saliva, the protective barrier breaks making available calcium,
phosphate and fluoride.(fig 2)

Fig 2:- Saliva activates the Ca, braking down the protective layer.

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Since the structure of tricalcium calcium phosphate is similar to hydroxyapatite, once the functionalized calcium
ions are released, they readily interact with the tooth surface and subsurface. While other calcium phosphate
additives may require an acidic pH, which could limit the benefits to the tooth, functionalized Tricalcium calcium
phosphate can offer optimal benefits when delivered in a neutral pH environment. Thus it can be safely
recommended that Tricalcium phosphate in conjuction with fluoride increases the efficacy and decreases the
required concentration of fluoride needed.

Advantage
1. It is biocompatible and bioactive in the oral cavity.
2. Only low levels of functionalized tricalcium phosphate are needed to produce strong, acid-resistant mineral
nucleation.
3. Additionally, tri-calcium phosphate can be custom-tailored for a variety of oral care products like tooth paste ,
varnishes etc.

Disadvantage
Production of TCP and incorporation of it in toothpaste is costly.

XYLITOL
Another caries preventive method is the consumption of food with sweetening content; Xylitol(fig:3) is the most
frequently used sugar variable in this area. As regards oral and dental health, it is essential to use this sugar alcohol
which minimizes dental caries risk in candies, beverages, and gums to replace sucrose. Xylitol which cannot be
fermented by S. mutans shows antiacidogenic and anticariogenic features. Another role of xylitol in oral health is
that it reduces the amount of plaque accumulation in the mouth. 5

Fig 3:- Xylitol gum.

Xylitol works in three major ways.

1. Xylitol acts on the mitochondria of streptococcus mutans and inhibit the process of glycolysis of these
microrganisms, thus interfering their growth and metabolism.
2. Xylitol works by making the pH alkaline. When S. mutans bacteria ferment sugar, they produce acids, which
lower the pH level below 7 and slowly weakens the protective tooth enamel by increasing the dissolution of
calcium and phosphate ions. When xylitol is ingested, the acid attack is reduced because the caries producing
bacteria are unable to ferment xylitol. As a result the growth of these bacteria and simultaneous production of
acid is reduced and oral pH stays higher.
3. At the high pH, the hydrophilic molecule of xylitol is able to form complexes with calcium in solution, thus
stabilizing the calcium and phosphates found in saliva thus promoting remineralization. 6

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Advantages
1. Decrease in caries rates, increment, and/or onset
2. Maternal consumption of xylitol reduce the acquisition of mutans streptococci (MS) and dental caries by their
children."
3. Have pleasant taste and a sweetness which equals that of sucrose.
4. It does not effect blood pressure or blood glucose levels as most sugar substitutes.

Disadvantages
At higher dose, xylitol use is associated with symptoms like gas and osmotic diarrhoea because of slow rate of
absorption of xylitol through the gut wall.

BIOACTIVE GLASS MATERIALS

Bioactive glass is made of synthetic mineral containing sodium, calcium, phosphorous and silica , which are all
elements naturally found in the body. Bioactive glass materials have been used in medicine and dentistry for years.
This unique material has numerous novel features, including the ability to act as a biomimetic mineralizer, matching
the body’s own mineralizing traits, while also affecting cell signals in a way that benefits the restoration of tissue
structure and function. Bioactive glass is considered a break-through advance in remineralization technology.

Mechanism Of Action
When bioactive glass comes in contact with saliva, there is a rapid release of sodium, calcium, and phosphorous ions
into the saliva that are available for remineralization of the tooth surface. The released ions form hydroxycarbonate
apatite directly. They also attach to the tooth surface and continue to release ions and remineralize the tooth surface
after the initial application. These particles have been shown to release ions and transform into HCA for up to 2
weeks.

Bioactive glass formulation commonly used in research studies contains 45 wt% SiO2 4.5 wt% Na2O and CaO and
6 wt% P2O5.7 The network breakdown of silica depends upon the concentration of SiO2 and is time dependent.
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.. It has been
demonstrated that, fine particulate bioactive glasses incorporated into an aqueous dentifrice has the ability to
clinically reduce the tooth hypersensitivity through the occlusion of dentinal tubules by the formation of the CAP
layer.7

Advantages
1. It strengthens and revitalizes your teeth with ionic calcium and phosphates.
2. Biosilicates are Biocompatible
3. They are acceptable in taste and available in different flavours.
4. Easy and safe to use as regular toothpaste.

Disadvantages
1. It is not cost effective on regular basis.
2. Its availability is restricted.

OZONE
Ozone is a naturally occurring compound consisting of three oxygen atoms. It is found in nature, in the form of a gas
in the stratosphere in a concentration of 1–10 ppm. The reliable microbiologic and metabolic properties of ozone, in
either the gaseous or aqueous phases, make it a useful disinfectant with a wide range of activity.

Ozone, in the gaseous or aqueous phase, has been shown to be a powerful and reliable antimicrobial agent against
bacteria, fungi, protozoa, and viruses.

Mechanism of action
Ozone has proven to be effective against bacteria as well as viruses and fungi. It is a strong oxidant, highly
bactericidal. It disrupts the integrity of the bacterial cell envelope by oxidation of phospholipids and lipoproteins and

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thus is used to treat primary root caries or occlusal caries as well as dentinal hypersensitivity.Ozone at low
concentration of 0.1 ppm, is sufficient to inactivate bacterial cells including their spores.

Ozone is also capable of remineralizing lesions within the dentin. It opens dentinal tubules within carious lesion and,
thus enhances remineralization by increasing perfusion of remineralizing agents.

It has been reported that an exposure of about 60 s exhibited 99.9% killing efficiency against cariogenic bacteria
such as Actinomyces naeslundii, Streptococcus mutans and Lactobacillus casei. 8

Advantages
1. It is effective in fighting decay-causing bacteria.
2. It supports gum health and healing. Ozone has been used very successfully to treat periodontal disease.
3. It’s noninvasive.It can be used in plaque control, help decrease sensitive tooth necks, and assist in cavity
preventions without any invasive tools or discomfort.
4. It’s all-natural. Dentists are able to remove harmful bacteria without resorting to the use of other products that
can have toxic and unhealthy side-effects.
5. There is no injection involved in ozone treatment and the ozone delivery system is portable. Therefore, elderly
patients who have limited access to the dental services can highly benefit from this treatment. 9

Disadvantages
People should never inhale ozone. If it enters the mouth, nose, or eyes, it can burn and cause coughing, nausea,
vomiting, or headaches. More severe exposure can lead to respiratory complications.

CAVISTAT
An arginine bicarbonate and calcium carbonate complex has been capable of preventing the development of dental
caries and it prevents caries upto 50%. It is one of the most prevalent and economical method of caries reduction.

Mechanism Of Action
This technology is based on the mechanism that when the toothpaste is used, the amino acids will be deaminated by
the arginine deaminase system in saliva, producing ammonia, which is highly alkaline and causes a rise in pH within
the oral environment, thus presenting an ideal condition for remineralization as well as modifying and reducing the
pathogenicity of the cariogenic plaque .

CaviStat is also comprised of bicarbonate, the main buffer in saliva for neutralizing plaque acid and calcium
carbonate serves as the calcium source for remineralization to occur.

Advantages
1. It Can be used in patients of all age group.
2. It is cost effective.
3. Patients can apply it easily.

Disadvantages
1. Arginine has minor side effects which includes abdominal pain, bloating, diarrhea and gout
2. It can cause worsening of breathing in people.

NANOHYDROXYAPATITE
Hydroxyapatite is the main component of enamel, which gives an appearance of bright white and eliminates the
diffuse reflectivity of light by closing the small pores of the enamel surface. 10

Hydroxyapatite is the main constituent of the mineral part of bone and teeth. Hydroxyapatite is also an important
source of calcium and phosphate, very important for the remineralization of demineralized enamel areas.

The recently developed interest for nanotechnology in many fields, is producing interesting and imminent
applications in dentistry for nano-hydroxyapatite, which presents crystals ranging in size between 50 and 1000 nm.

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Mechanism of action
Nano-hydroxyapatite has a size range between 50 and 1000 nm. The nano-hydroxyapatite has a strong ability to
bond with proteins, as well as with fragments of plaque and bacteria, when contained in toothpastes. This ability is
due to the size of nanoparticles, which considerably increase the surface area to which proteins can bind. Besides,
nano-hydroxyapatite also acts as filler because it repairs small holes and depressions on enamel surface, a function
enhanced by the small size of the particles that compose it.

The biomimetic hydroxyapatite function is to protect the teeth with the creation of a new layer of synthetic enamel
around the tooth, rather than hardening the existing layer with fluorine. A concentration of 10% nano-hydroxyapatite
is considered to be optimal for remineralization of early enamel caries.

Advantages
1. Nano hydroxyapatite is nearly alike in the chemical composition of human teeth and is safe & biocompatible.
2. It can be used by patients of all age because of its ease of application.

Disadvantages
Nanohydroxyapatite containing toothpaste are expensive and cannot be used on daily basis.

Conclusion:-
In the last few decades, advances in technologies, changes in lifestyle, modifications in the diet, and longer life
expectancy are some of the many factors which have affected the health and esthetics of tooth enamel and dentin.
With a clearer understanding of the implementation of these remineralizing agents and new technologies accessible
to dentists, we can create a more favorable relationship in which remineralization occurs more often than
demineralization.

Historically remineralization was ruled by fluorides from the year 1960s. Since then it has been successfully
remineralizing incipient carious lesions. It has certain disadvantages like it is dependant on calcium and phosphate
ions from saliva to accomplish this. Also overuse of fluorides can cause dental and skeletal fluorosis. This made
researchers to explore and study non fluoridated remineralizing agents.

The ACP technology was developed by Dr. Ming S. Tung. In 1999, ACP was incorporated into toothpaste called
Enamelon and later reintroduced in 2004 in Enamel Care toothpaste by Church and Dwight. ACP compounds are
considered prime candidates for remineralization therapy due to their high solubility under oral conditions and
ability to rapidly hydrolyze to form apatite.

CPP–ACP is the acronym for a complex of casein phosphopeptides and amorphous calcium phosphate. Casein
phospho-peptides are responsible for the high bioavailability of calcium from milk and other dairy products. CPP
have the ability to bind and stabilize calcium and phosphate in solution, as well as to bind to dental plaque and tooth
enamel. CPP stabilize ACP, localize ACP in dental plaque, thereby maintaining a state of supersaturation with
respect to tooth enamel, reducing demineralization and enhancing remineralization.

Tricalcium phosphate is a new hybrid material created with a milling technique that fuses beta TCP and sodium
lauryl sulfate or fumaric acid. When TCP comes into contact with the tooth surface and is moistened by saliva, the
protective barrier breaks down making calcium, phosphate and fluoride ions available to the tooth. TCP has also
been considered as one possible means for enhancing the levels of calcium in plaque and saliva.

Xylitol is a commonly used sugar substitute especially in chewing gums. A non-fermentable sugar alcohol act as a
carrier for calcium and phosphates.
The use of chewing gum carrying xylitol increases salivary flow rate and enhances the protective properties of
saliva. This is because the concentration of bicarbonate and phosphate is higher in stimulated saliva, and the
resultant increase in plaque pH and salivary buffering capacity prevents demineralization of tooth structure.
Moreover, the higher concentration of calcium, phosphate, and hydroxyl ions in such saliva also enhances
remineralization

Bioactive glass is made of synthetic mineral containing sodium, calcium, phosphorous and silica, which are all
elements naturally found in the body. When in contact with saliva or water, first releases sodium ions. This elevates

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the pH into the range essential for HAP formation. This increase in ionic concentration, combined with an increase
in pH, causes the ions to precipitate onto the tooth surface and form calcium hydroxycarbonate apatite (HCA) to
remineralize the defect and to occlude open tubules.

Ozone is a chemical compound which is a powerful oxidizing agent. Ozone acts by attacking thiol groups of
cysteine amino acid and destroys the cellular membrane of carious bacteria. Ozone can shift microbial flora from
acidogenic bacteria to normal commensals allowing remineralization to occur.

An arginine bicarbonate and calcium carbonate complex has been capable of preventing the development of dental
caries and it prevents caries upto 50%. It is one of the most prevalent and economical method of caries reduction.

Nanohydroxyapatite, a bioactive and biocompatible material, functions by directly filling up the micropores in early
caries lesions, where it act as a template in the remineralization process by continuously attracting large amount of
calcium and phosphate ions from the oral fluids into the lesion, thus promoting crystal growth. A concentration of
10% nano-HA may be optimal for remineralization of early enamel caries.

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