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in Dental Research

Calcium Sodium Phosphosilicate (NovaMin): Remineralization Potential

A.K. Burwell, L.J. Litkowski and D.C. Greenspan
ADR 2009 21: 35 originally published online 31 July 2009
DOI: 10.1177/0895937409335621

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 Calcium Sodium Phosphosilicate (NovaMin):
Remineralization Potential
A.K. Burwell1*, L.J. Litkowski2, D.C. Greenspan1
1
NovaMin Technology, Inc., 13859 Progress Blvd, #600, Alachua, FL
32615, USA; and 2University of Maryland, College of Dentistry,
Baltimore, MD, USA. *corresponding author, present address, Department
of Preventive and Restorative Dental Sciences, University of California
San Francisco, anora.burwell@ucsf.edu
Adv Dent Res 21:35-39, August, 2009
N ovaMin is the trade name for a calcium sodium phospho-
silicate bioactive glass that has been developed for use
in oral health care. Originally developed for the treatment of
hypersensitivity by the physical occlusion of dentinal tubules,
recent studies have demonstrated a potential for this material
to prevent demineralization and/or aid in remineralization of
tooth surfaces. The mode of action of this material results from
interactions with aqueous solutions. When introduced into the
oral environment, the material releases sodium, calcium, and
phosphate ions, which then interact with oral fluids and result in
the formation of a crystalline hydroxycarbonate apatite (HCA)
layer that is structurally and chemically similar to natural tooth
mineral. This article will focus on the mechanisms of action of
NovaMin and present results from a series of in vitro and in situ
studies demonstrating the potential of this material in the areas
of remineralization and caries prevention.
Introduction
The rate of coronal caries has declined substantially since the
broad use of fluoride began. Over the last 10-20 years, however,
overall caries rates are on the rise again, due to a significant
increase in root and secondary caries among adults and an
increasingly aging population (Shay, 2004). It is estimated that
the prevalence rate of root caries is equal to age minus about 20,
so the prevalence rate of root caries at age 50 is 30% and at age
70 is 50% (Leake, 2001). These types of data led the United
States Surgeon Generals Report on Oral Health to identify root
caries as a key emerging issue in oral health and a major con-
tributor to the silent epidemic of dental caries (US Department
of Health and Human Services, 2000).
Current treatment regimes for root caries include the use of
fluoride and antimicrobial products in dental offices and at
home. Although the use of fluoride products remains the pri-
mary treatment modality for root caries, there is some question
DOI: 10.1177/0895937409335621
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Copyright 2009 by the International Association for Dental Research
regarding the efficacy of these products for the reversal or
prevention of the disease. A study on the effects of a complex,
multi-faceted treatment regimen on the development of root
caries found that, over a 12-month period, 54% of active buc-
cal root-surface lesions were converted to inactive lesions,
whereas only 8-27% of active proximal lesions were consid-
ered inactive after 12 mos (Fejerskov et al., 1993). In a review
of data from a two-year study in a diverse population (723
participants), it was concluded that root caries is a substantive
dental problem (Gilbert et al., 2001). These findings suggest
that fluoride is not as effective on root surfaces as has gener-
ally been perceived.
White-spot lesions are the earliest macroscopic evidence of
enamel caries (Silverstone, 1977). The majority of demineral-
ization in white-spot lesions occurs in the subsurface region of
enamel. This subsurface demineralization increases porosity and
changes the optical properties of the enamel. Typically, the
enamel surface layer stays intact during subsurface demineral-
ization, but without treatment will eventually collapse into a full
cavity (Mann and Dickinson, 2006).
Calcium sodium phosphosilicate (NovaMin) is a bioactive
glass in the class of highly biocompatible materials that were
originally developed as bone-regenerative materials (Hench and
Andersson, 1993). These materials are reactive when exposed to
body fluids and deposit hydroxycarbonate apatite (HCA), a
mineral that is chemically similar to natural tooth mineral
(Andersson and Kangasniemi, 1991; Hench and Andersson,
1993). When incorporated into a dentifrice, NovaMin particles
are deposited onto dentin surfaces and mechanically occlude
dentinal tubules (Litkowski et al., 1997).
In aqueous environments, such as saliva, sodium ions (Na+)
in calcium sodium phosphosilicate particles immediately (within
one minute) begin to exchange with hydrogen cations (H+ or
H3O+) (Andersson and Kangasniemi, 1991; Hench and
Andersson, 1993; Cerruti et al., 2005). This rapid exchange of
ions allows calcium (Ca2+) and phosphate (PO43) species to be
released from the particle structure. A modest localized, tran-
sient increase in pH occurs that facilitates the precipitation of
calcium and phosphate from the particles and from saliva to
form a calcium phosphate (Ca-P) layer on tooth surfaces. As
the reactions and the deposition of Ca-P complexes continue,
Key Words
Bioactive glass, remineralization, demineralization, dentin, enamel.
Presented at the International Conference on Novel Anti-caries and
Remineralizing Agents, held in Vina del Mar, Chile, January 10-12,
2008
The authors declare no conflict of interest.
35
36 Burwell et al. Adv Dent Res 21: 2009
Figure 1A. Microhardness data from Study IIn vitro protection against
dentin demineralization (mean SEM, n = 15). Treatment with a den-
tifrice containing calcium sodium phosphosilicate prevented softening
of dentin surfaces during a 10-day pH-cycling study.
this layer crystallizes into hydroxycarbonate apatite, which is
chemically and structurally similar to biological apatite
(Andersson and Kangasniemi, 1991). The combination of the
residual calcium sodium phosphosilicate particles and the HCA
layer results in the physical occlusion of dentinal tubules, which
will relieve hypersensitivity.
The chemical reactions initiated by calcium sodium phos-
phosilicate to promote the formation of an HCA layer for the
treatment of dentinal hypersensitivity may also be useful in
treating demineralized tooth structure and/or preventing further
demineralization. This article will present a series of research
studies that focus on the ability of this material to enhance
remineralization and prevent demineralization (on its own and
combined with fluoride) under a variety of conditions.
Materials & Methods
A series of in vitro studies was designed according to estab-
lished pH-cycling protocols (Featherstone et al., 1988, 1990;
ten Cate, 1990). Study I was designed to investigate the ability
of dentifrices to prevent demineralization of dentin surfaces.
Study II explored the potential of dentifrices to remineralize
existing lesions on root tissue. Study III investigated the abil-
ity of dentifrices to heal existing white-spot lesions on enamel.
Finally, an in situ study (IV) was designed to characterize the
morphological changes on tooth surfaces that were subjected
to different types of damage and then treated with a dentifrice.
Studies I-III were conducted according to similar in vitro
pH-cycling protocols; parameters that were identical in all
three studies are listed separately from the individual study
descriptions.
Demineralization solution composition
The demineralization solution used in Studies I-III had the fol-
lowing composition: 2.2 mM CaCl22H2O, 2.2 mM
NaH2PO47H2O, 0.05 M lactic acid, and 0.5 ppm fluoride ion.
The final pH was adjusted to 4.52 at 37C with 50% NaOH.
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Figure 1B. Microhardness data from Study IIIn vitro remineralization
of root caries (mean SEM, n = 18). Treatment with fluoride dentifrices
(1000 ppm or 5000 ppm) did not effectively re-harden the surfaces
of artificial root caries. Treatment with dentifrices containing calcium
sodium phosphosilicate (with and without fluoride) resulted in statisti-
cally significant re-hardening of the lesions.
Artificial saliva composition
The artificial saliva used in Studies I-III had the following com-
position: 2.200 g/L gastric mucin, 0.381g/L NaCl, 0.213 g/L
CaCl22H2O, 0.738 g/L K2HPO43H2O, and 1.114 g/L KCl. The
final pH was adjusted to 7.00 at 37C with 85% lactic acid.
Surface microhardness measurements
The microhardness of all samples in Studies I-III was measured
with a Knoop indenter on a MicroMet 5101 Hardness Tester
(Buehler Ltd., Lake Bluff, IL, USA). Microhardness was mea-
sured with a load of 50-100 grams with a dwell time of 20 sec.
The dimensions of all indentations were measured immediately
following indentation, with OmniMet imaging software
(Buehler Ltd.), to avoid possible shrinkage caused by mechani-
cal recovery of tooth surfaces.
Statistical analysis
All data were statistically analyzed and plotted with SigmaPlot
Software (Systat Software, Inc., San Jose, CA, USA).
Study IIn vitro protection against
dentin demineralization
Bovine tooth roots were acrylic-mounted, ground, polished, and
lightly acid-etched to expose the dentin layer. Samples were sub-
jected to a 10-day pH-cycling protocol that included twice-daily
soaks in demineralization solution (30 min each, 37C), immedi-
ately followed by dentifrice treatments (two-minute manual
brushing). Between demineralization/brushing periods, the sam-
ples were soaked in artificial saliva (37C). Sample groups were:
prepared dentin (no pH cycling), water (treated with de-ionized
water during pH cycling), SootheRx (7.5% calcium sodium
phosphosilicate, NovaMin), and MI Paste (10% casein phos-
phopeptide-amorphous calcium phosphate, CPP-ACP). Results
Adv Dent Res 21: 2009 NovaMin: Remineralization Potential 37

were statistically analyzed by

ANOVA and Holm-Sidak meth-
ods (p < 0.01).

Study IIIn vitro

remineralization of root
caries
The surface preparation and
treatment used were similar to
those of Study I, except that
caries-like lesions were pre-
formed on the dentin by immer-
sion in demineralization
solution (96 hrs, 37C) before
the pH-cycling protocol began.
The length of the study was
shortened to 7 days, and the
protocol remained the same,
except that instead of being
brushed, the samples were
soaked in 1:3 dentifrice slurries
with de-ionized water. Sample
groups were: artificial lesion
(no pH cycling), 1000 ppm F
(NaF) dentifrice, 5000 ppm F
(NaF) dentifrice, 5% NovaMin
dentifrice, and 5000 ppm F
(NaF) dentifrice with 5%
NovaMin. Data were analyzed
by ANOVA on Ranks and
Student-Newman-Keuls statis-
tical methods (p < 0.01).

Study IIIIn vitro healing

of enamel white-spot
lesions
Figures 2A-2E. SEM images (2000X) from Study IIIIn vitro healing of enamel white-spot lesions. (A)
Bovine tooth crowns were prepared enamel, (B) artificial lesion, (C) treated with 5000-ppm-F dentifrice, (D) treated with fluoride
acrylic-mounted, ground, and dentifrice with CPP-ACP, and (E) treated with fluoride dentifrice with NovaMin. The formation of white-spot
polished to expose the enamel lesions significantly altered the prismatic structure of sound enamel. Treatment with a prescription-level fluo-
ride dentifrice partially restored the surface structure of enamel, and this restoration was enhanced by the
layer. Surfaces were taped to addition of calcium sodium phosphosilicate to the dentifrice.
leave 5 5 mm windows
exposed. Artificial white-spot
lesions were pre-formed on the enamel via immersion in demin- morphology were qualitatively evaluated by scanning electron
eralization solution (48 hrs, 37C). The samples were then sub- microscopy (SEM).
jected to the same 10-day pH-cycling protocol as previously
described, except that the treatment periods were 5 min in
Study IVIn situ treatment of surface defects
length. During the treatment periods, dentifrice was placed
directly on the wet lesions, 0.50 mL de-ionized water was Two-millimeter disks of enamel and dentin were prepared from
placed on the dentifrice, the system sat undisturbed for 5 min, unerupted human third molars. Surface defects were created via
and was then rinsed with de-ionized water to remove all visible abrasion (600-grit paper) or acid-etching (37% phosphoric acid).
dentifrice. Sample groups were: prepared enamel (no pH All disks were fractured though the center into two halves, and the
cycling), artificial lesion (no pH cycling), Prevident 5000 irregular fracture interface was later used to re-approximate the
(5000 ppm F, NaF), MI Paste Plus (10% CPP-ACP, 900 ppm halves. One half of each type of disk (abraded enamel, etched
F, NaF), and ReNew (5% NovaMin, 5000 ppm F, NaF). Data enamel, and etched dentin) was bonded into the palatal area of a
were analyzed by ANOVA on Ranks and Student-Newman- passive orthodontic appliance with the treated surface exposed
Keuls statistical methods (p < 0.01). Changes in surface to the oral fluids. Study participants were instructed to wear the

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38 Burwell et al. Adv Dent Res 21: 2009
Figure 3. Surface roughness data from Study IVIn situ treatment of
surface defects (mean SEM, n = 11). Twenty-eight days of in situ
treatment with a calcium sodium phosphosilicate dentifrice significantly
reduced the surface roughness of all 3 defect types.
appliance 24 hrs per day for 28 days and to brush twice per day
with SootheRx (7.5% NovaMin) dentifrice. After 28 days,
the appliances were collected, and the experimental tooth disks
were re-approximated with the control halves (stored in
de-ionized water during the study). Surfaces were analyzed for
surface roughness (Ra) by non-contact optical profilometry
(NewView 100 Profilometer; ZYGO; Middlefield, CT, USA)
and were imaged by SEM. Ra data from treated samples were
averaged and compared with the appropriate control samples by
a paired t test (p < 0.01).
Results
Study IIn vitro protection against
dentin demineralization
Analysis of surface microhardness data suggests that treatment
with a NovaMin-containing dentifrice creates a tenacious sur-
face layer that protects dentin from demineralization caused by
repeated acidic and mechanical challenges (Fig. 1A). In this
model, CPP-ACP did not provide the same protection.
Study IIIn vitro remineralization of root caries
Fluoride alone (1000-5000 ppm) did not effectively repair
demineralized dentin (Fig. 1B). However, NovaMin-containing
dentifrices (with and without fluoride) re-hardened and, theo-
retically, repaired the lesions.
Study IIIIn vitro healing of enamel white-spot lesions
Knoop microhardness results (mean SEM, n = 18) were: (A)
prepared enamel, 119.39 6.78; (B) artificial lesion, 5.17
0.35; (C) 5000 ppm F, 14.40 1.30; (D) CPP-ACP, 900 ppm F,
6.53 0.70; and (E) NovaMin, 5000 ppm F, 33.52 4.96, with
A > E > C > B = D (p < 0.01). This in vitro model was validated
by the ability of a prescription-level fluoride dentifrice to harden
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Figure 4. SEM image of re-approximated enamel disks (54X) from Study
IVIn situ treatment of surface defects. (left half) Abraded enamel
(control); (right half) abraded enamel after 28 days of treatment
with SootheRx. SEM examination of the re-approximated disk halves
showed that the defect height remained the same and, therefore, that
the surface smoothing was accomplished by filling in the defects.
enamel white-spot lesions. Inclusion of NovaMin in a prescription-
level fluoride dentifrice improved hardening of white-spot
lesions. In this model, treatment with a fluoride dentifrice con-
taining CPP-ACP had no hardening effect.
SEM micrographs were examined at 2000X magnification
for all treatment groups (Fig. 2). Loss of prismatic enamel struc-
ture with demineralization was seen (Figs. 2A, 2B). Comparison
of Figs. 2C and 2E shows restoration of the surface structure to
a greater degree than in Fig. 2D.
Study IVIn situ treatment of surface defects
A significant reduction of surface roughness in all 3 defect types
was seen following treatment with SootheRx (Fig. 3). Fig. 4 is
an SEM image of re-approximated disc halves of abraded
enamel (control) and abraded enamel after treatment with
SootheRx at 54X magnification. This Fig. illustrates the abil-
ity of a NovaMin-containing dentifrice to treat enamel surface
abrasions during 28 days of in situ application. SEM analysis at
higher magnifications of the re-approximated discs clearly
shows equal thicknesses of the control and treated halves, indi-
cating that the repair was accomplished by a deposition of mate-
rial onto the defects rather than by wear.
Discussion
Calcium sodium phosphosilicate is an inorganic compound that
reacts in aqueous environments to release calcium, sodium,
and phosphate ions over time. Originally developed as a bone-
regenerative material, this compound has been shown to be
effective at physically occluding dentinal tubules through the
development of a hydroxyapatite-like mineral layer (Andersson
and Kangasniemi, 1991; Hench and Andersson, 1993). Clinical
evaluations of NovaMin for the treatment of dentin hypersensi-
tivity have shown statistically significant and clinically positive
results (unpublished data from IRB-approved clinical trial at the
University of Maryland, 1998; Du et al., 2008). The significant
Adv Dent Res 21: 2009 NovaMin: Remineralization Potential 39
clinical treatment of hypersensitivity through the formation of
crystalline apatite led researchers to hypothesize that NovaMin
could be useful in remineralization and the prevention of demin-
eralization of tooth structures, especially dentin.
While it is clear that commercially available fluoride denti-
frices (1000-1500 ppm) have been very successful in reducing the
incidence of juvenile coronal caries, it is also clear that root caries
and erosion lesions are increasing at a significant rate (Fejerskov
et al., 1993; Lussi and Schaffner, 2000). The use of 5000-ppm-
fluoride compositions appears to be better at controlling root car-
ies than standard fluoride compositions, although the use of these
products is not without some controversy (Lynch and Baysan,
2001). Since fluoride requires a source of calcium to be effective
in remineralization, and salivary insufficiency is a common issue
in persons with root caries, an additional source of calcium, in
combination with fluoride, could be beneficial in the treatment of
root caries. The studies presented here show that the combination
of therapeutic levels of fluoride with NovaMin increases the
remineralization of caries lesions.
Standard in vitro models have been established to predict the
clinical efficacy of active ingredients in oral health care products.
The results of the in vitro studies presented here demonstrate that
NovaMin, alone and in combination with fluoride, can enhance
the remineralization of enamel and dentin lesions, as well as pre-
vent demineralization from acid challenges. The strong potential
of clinical benefits of this active ingredient is supported by the
fact that results from three in vitro studies all exhibited the same
trends. The in situ results of the repair of surface lesions and abra-
sions with NovaMin further demonstrate the mechanisms of
action of the material and suggest the potential of this material to
repair tooth structures (both dentin and enamel).
If this technology is to be fully accepted, it is necessary to
demonstrate the efficacy of calcium sodium phosphosilicate
(NovaMin), both alone and in combination with fluoride, in
prospective, randomized clinical trials, several of which are cur-
rently in progress.
Acknowledgments
The assistance of the Major Analytical Instrumentation Center
at the University of Florida in conducting SEM analysis is
greatly appreciated. The authors also acknowledge Angela
Stone for her contributions to the in vitro studies conducted at
NovaMin Technology, Inc.
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