BMC Oral Health

BioMed Central

Open Access

Proceedings

Biotech and Biomaterials Research to Reduce the Caries Epidemic

Rebecca L Slayton*1, James D Bryers2 and Peter Milgrom3
Address: 1Department of Pediatric Dentistry, University of Washington, Seattle, WA 98195, USA, 2Department of Bioengineering and University
of Washington Engineered Biomaterials (UWEB) Center, University of Washington, Seattle, WA 98195, USA and 3Department of Dental Public
Health Sciences, University of Washington, Seattle, WA 98195, USA
Email: Rebecca L Slayton* - rslayton@u.washington.edu; James D Bryers - jbryers@u.washington.edu; Peter Milgrom - dfrc@u.washington.edu
* Corresponding author

from Biotechnology and Biomaterials to Reduce the Caries Epidemic

Seattle, USA. 1315 June 2005
Published: 10 July 2006
<supplement> <title> <p>Biotechnology and Biomaterials to Reduce the Caries Epidemic</p> </title> <editor>Rebecca L Slayton, James D Bryers, Peter Milgrom</editor> <note>Proceedings</note> <url>http://www.biomedcentral.com/content/pdf/1472-6831-6-S1-info.pdf</url> </supplement>

BMC Oral Health 2006, 6(Suppl 1):S1

doi:10.1186/1472-6831-6-S1-S1

2006 Slayton et al; licensee BioMed Central Ltd.

This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract
The goal of this workshop is to develop a consensus within the biomaterials/bioengineering
community for a research agenda focused on creating technologies that will address the current
dental caries pandemic. The workshop will bring together expertise from academia, industry, and
the NIH institutes in the areas of oral biofilm microbiology and innovative biomaterials. The
rationale for the workshop is that science and technology have not produced sufficient practical
tools for public health practitioners and the private delivery system to address the pandemic in
dental caries that exists for children and adults from families with low incomes and for numerous
ethnic minority and racial groups. Moreover, it is unclear whether the barriers are remediable
bioengineering and technical problems or fundamental science questions. Nevertheless, the
obligation to address the gap between scientific research and practical application is especially
relevant today. The U.S. and state governments bear the majority of the cost of trying to control
this pandemic through Medicaid, the Public Health Service, Indian Health Service and other similar
programs. These costs continue to escalate as continued applications of existing technology are
unlikely to markedly reduce disparities. The mainstays of caries prevention, topical and systemic
fluorides and pit and fissure sealants, are technologies developed in the 1950s and 1960s.

Introduction
The caries process has been well understood since 1960
when Fitzgerald and Keyes demonstrated in animals that
acidogenic bacteria are transmitted from mother to offspring and between animals sharing the same cage [1].
These bacteria metabolize carbohydrates and produce
acid, which in turn leads to demineralization of dental
enamel. Dental caries is thought to be an almost completely preventable disease. Prevention requires minimizing the frequency of ingesting simple carbohydrate foods
and beverages, regular oral hygiene measures to remove

plaque and to introduce topical fluoride in the form of

toothpaste, and flossing to remove plaque and debris
from between the teeth. It is recognized that even when
the appropriate preventive measures are taken, there are
some individuals who have increased susceptibility to
dental caries.
At a group level, people living in poverty, ethnic and racial
minorities, and recent immigrants to the U.S. are at
increased risk for dental caries. There is also evidence that
people with poor access to dental care are at increased
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BMC Oral Health 2006, 6:S1

risk. In children, dental caries is the most common

chronic illness and is five times more common than
asthma [2].
The discovery of the role of fluoride in dental caries prevention led to significant decreases in caries prevalence in
the U.S. and many other countries as a result of community water fluoridation and the widespread use of fluoridated toothpaste [3]. At the turn of the current century,
the U.S. Centers for Disease Control and Prevention determined that water fluoridation was one of the top 10 public health achievements of the century [4].
In the last decade, there has been an increased interest in
research related to microbial biofilms as well as in bioengineering and biotechnology. It has become increasingly
evident that dental researchers need to look beyond their
traditional mind set and investigate the opportunities for
collaborating with researchers outside of dentistry in
order to bring new insights to the prevention and management of a disease that continues to affect a large percentage of the population in all countries of the world.
This need for a new, innovative approach to the management and prevention of dental caries resulted in the
National Institute for Dental and Craniofacial Research
(NIDCR) and others providing funding for an interdisciplinary conference on biotechnology, biomaterials, and
dental caries (Dr. Peter Milgrom, P.I.). The purpose of this
conference was to develop a research agenda that will leverage new discoveries and lead to innovative approaches
to reduce caries in high risk populations. An esteemed
group of internationally recognized scientists representing
cariology, behavioral sciences, bioengineering, and
microbiology were invited to present research on topics
aimed at developing a better understanding of this multifactorial disease. Emphasis was placed on the development of interdisciplinary collaboration between dentistry
and bioengineering.
There were 57 participants including 34 nationally and
internationally known scientists, four dental practitioners, four representatives from the dental industry and 15
graduate and undergraduate students. The meeting was
spread out over two and a half days with four plenary sessions and three breakout sessions.
Two keynote lectures were given during lunch on the second day and breakfast on the third day, respectively. The
first lecture was given by Pierre Mourad, PhD, Principal
Physicist, Applied Physics Laboratory, Research Associate
Professor, Department of Neurological Surgery, University of Washington School of Medicine and was entitled
"Translational Medical Research: Examples and Lessons."
Dr. Mourad discussed important considerations when

moving a research method or device from the laboratory

into market. Since he has gone through this process with
a number of his own inventions, he was able to provide
valuable tips to the participants.
The second lecture was given by Christopher J. Elias, MD,
MPH President, Program for Appropriate Technology in
Health (PATH). His talk was entitled "Public-Private Partnerships to Advance Technologies for Neglected Diseases." In his talk, Dr. Elias emphasized that partnerships
with private companies must be in keeping with the mission of PATH and must "lead to positive impact on availability, accessibility, and affordability of important health
products for public health programs in developing countries." He also pointed out the importance of recognizing
the need for profitability for the private company and that
"PATH must recognize the company's need for commercial benefit in order to ensure a sustainable commitment
to the collaboration." He used the example of the meningitis vaccine project in which PATH, with a grant from the
Bill and Melinda Gates Foundation, partnered with the
World Health Organization and an emerging vaccine
manufacturer in India to produce an affordable vaccine
for use in Sub-Saharan Africa. In this initiative and in
many others, PATH has demonstrated that public-private
partnerships are an effective means to advance technologies to treat neglected diseases. This is particularly relevant
for dental caries since it is prevalent in both developed
and underdeveloped nations and frequently affects individuals with the least ability to access limited resources.
It was clear from the presentations at this conference that
there have been major advances in both biotechnology
and bioengineering in the last decade. The themes that
presenters were asked to address were divided into three
general categories: 1) ways to modify or enhance existing
technologies (fluoride- or xylitol-related) to make them
more effective; 2) development of new targets or novel
strategies (related to adhesion, oral ecology, or probiotics); 3) development of new technologies or delivery systems (related to anti-adhesives or fluoride replacement
methodologies).
Presenters discussed emerging research in the prevention
of dental caries including: specific species bacterial adhesion prevention, biofilm ecology manipulation, targeting
of microbial species using lytic enzymes, probiotics using
natural anti-microbial peptides, circumvention of
sucrose-driven acid production, and fluoride- and other
antimicrobial-release coatings. These topics were the
focus of discussion during the conference and informed
the breakout sessions each day.

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Challenges to Participants
The conference opened with remarks from Dr. Peter Milgrom, followed by a series of talks that described the challenges faced by clinicians and researchers in their efforts to
minimize the impact of dental caries. Dr. Burton Edelstein
discussed the term "pandemic" and the appropriateness
of using this term to describe dental caries. He made the
point that use of the term "caries pandemic" suggests a
disease that is highly prevalent globally and has severe
consequences to society. He also initiated the discussion
of caries being a disease that is amenable to prevention
and that is experienced disproportionately within the
population, with poor and disadvantaged people being
more frequently affected. This theme was continued and
refined by Dr. Clemencia Vargas who defined health disparities as the occurrence of a disproportionate share of
the burden of health being received by one particular
group of people. She went on to describe Early Childhood
Caries (ECC) as a disease with disparities in both the prevalence and treatment. Dr. Vargas presented compelling
data to show that when white children are compared to
non-white children in the U.S., non-white children have a
greater caries experience and a higher level of untreated
caries.

Dr. Donald Patrick presented a theoretical framework for

understanding and investigating disparities in oral health.
This model, which discusses the various factors that contribute to oral health and disease and identifies interventions that target each of these factors, will bring new
direction for research and policy that is focused on reducing oral health disparities.
Evidence shows that education alone is not sufficient to
change behavior. Since a significant component of dental
disease is related to behaviors such as diet, oral hygiene,
and fluoride exposure, it makes sense that any strategy to
improve oral health must improve health-related behaviors. Dr. Philip Weinstein's presentation on motivational
interviewing as a technique to assess a person's readiness
to change and to subsequently effect that change, was an
important reminder to all participants that any solution to
dental caries must consider adherence or lack of adherence by individuals. He also discussed this same theory
relative to the practitioner's readiness to change, as frequently there are effective methods to prevent dental caries that dentists choose not to incorporate into their
practices.
The final presentation in this section was by Dr. Joel Berg
and was focused on the opportunities for developing and
marketing new technologies for caries prevention. Dr.
Berg emphasized the importance of knowing the market
and identifying unmet needs on the part of both the buyer
and seller. Once this is accomplished, then the market

should be divided into segments, and the particular segment of interest can be targeted. The dental market in the
U.S. is approximately $80 Billion, and 20 percent of this
market is for consumer or professional products. In terms
of categories of expenditures, 60 percent of the total
expenditures are for either the results or effects of dental
caries. As caries detection technologies become more sensitive, there will be greater opportunities to manage the
caries process (to remineralize the enamel surface) rather
than to intervene surgically. In general, the market for new
products (such as early detection devices) is very difficult.
The marketplace will ultimately not be receptive to these
newer highly sensitive tools, even with increased specificity, unless the appropriate compensation systems are in
place.
Delivery Challenges for Caries Preventive Agents
Caries preventive agents, such as fluorides and chlorhexidine, have been shown to be very effective at remineralizing surface enamel or controlling cariogenic bacteria,
respectively. However, both of these agents rely on patient
compliance at home or regular visits to the dentist. Recent
studies also show promise for other agents such as xylitol
(a sugar alcohol) and amorphous calcium phosphate in
toothpaste and chewing gums. All of these agents require
action on the part of the patient in order to have the
desired effect. Some are not particularly palatable. That is,
the characteristics of both the agent and the delivery system have an impact on its effectiveness, and current
approaches might be redesigned to advantage.

The first plenary session of the conference focused on

delivery challenges associated with proven preventive
agents. In his talk, Dr. John Featherstone discussed the
shortcomings of current delivery methods, including the
short duration of therapeutic levels of fluoride and chlorhexidine when administered as a varnish or rinse and the
need for ways to deliver these agents over an extended
period of time. Xylitol has been shown to be effective
when consumed as a gum or lozenge, but neither of these
delivery methods is appropriate for an infant. In his presentation, Dr. Featherstone argued for research focusing on
strategies that combine agents that would be desirable
because the effectiveness of fluorides in remineralization
would be enhanced if the bacterial load were reduced first.
The traditional delivery mechanisms for fluorides and
other remineralizing agents have been in dentifrices and
mouth rinses. Dr. Domenick Zero discussed the regulatory issues related to getting approval for adding new cariostatic agents to toothpaste or mouth rinses as they are
tested and found to be effective. Dr. Zero identified a
number of factors that interfere with the development of
the most effective caries preventive agents for the U.S.
including: 1) U.S. Food and Drug Administration guidelines that focus on safety and efficacy (not level of effi-

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cacy); 2) rising costs of clinical trials; 3) Laboratory testing

requirements that use antiquated methods which no
longer reflect our current understanding of the action of
fluoride. In his paper, he recommends that oral health disparities can be addressed by making certain that at-risk
individuals are obtaining the maximum benefit from fluoride dentrifice by making available the most effective
products and educating individuals on how to obtain the
greatest benefit.
Dr. Per Axelsson reported the results of a 20-year study
that implemented a caries-preventive program for children in different age groups or developmental stages.
Risks were associated with initial acquisition of mutans
streptococci in infants, eruption of first permanent molars
in 57-year-olds, and eruption of second permanent
molars in 1113-year-olds. Individual risk for caries was
determined annually, and those children considered at
high risk were given additional preventive interventions
including fluoride varnish application and more frequent
professional mechanical tooth cleaning. This program has
been very successful in reducing the caries experience in
children in Varmland, Sweden. Among 19-year-olds cross
sectionally, the average caries prevalence was reduced
from more than 24 DFS in 1979 to only 2 DFS in 1999.
This study is an example of how our current technologies,
applied intensively on a risk basis in schools and public
dental health centers and timed to coincide with the eruption of new, susceptible tooth surfaces, can be very effective at reducing the burden of disease.
Dental Caries Microbiology
Very early in the study of dental caries (in the late 19th century), W.D. Miller recognized that enamel demineralization was mediated by a mixed bacterial infection in whole
saliva [5]. What he didn't know was which bacterial species were responsible for metabolizing carbohydrates,
converting sugar to acid and leading to demineralization
of dental enamel. The identification of Streptococcus
mutans as a possible caries-causing agent occurred much
later [1] and has since been expanded to include other
Streptococci species, referred to collectively as mutans streptococci [6]. Caries research since that time has focused primarily on mutans streptococci as a target for prevention of
disease through the use of anti-microbial agents, vaccines,
and probiotics.

The second plenary session focused on new technologies

and approaches used to understand the microbiology of
dental caries and ways to interfere with the caries process.
Dr. David Stahl discussed the composition of the oral biofilm and the evidence that this biofilm is inhabited by
more than 600 microbial species. Less than half of these
bacteria are cultivatable by traditional means. Dr. Stahl's
laboratory uses microchip technology to identify bacteria

within the biofilm and to determine their relative frequency within plaque samples.
Dr. Howard Kuramitsu discussed the importance of interactions between S. mutans and other biofilm constituents
in determining the cariogenicity of plaque samples. In
particular, his laboratory investigated the ability of S. gordonii to weaken some of the properties of S. mutans that
contribute to its virulence, including its ability to produce
bacteriocin, its ability to form a biofilm, and its ability to
transform its genetic makeup. Research regarding these
strategies, he argued, may be valuable in findings methods to control or manage dental caries in some individuals. Additional strategies were suggested by Dr. Phil
Marsh, who focused on the importance of understanding
oral ecology and the factors that disrupt microbial homeostasis as an essential part of caries control mechanisms.
He asserted, in his lecture, that it is necessary to identify
critical control points on an individual basis in order to
interfere with the disease process rather than just treating
the consequence of disease.
Research on oral biofilms is essential to the understanding
of dental caries. Biofilms are composed of multiple bacterial species that adhere to a solid surface (the tooth) and
are held together by a matrix of extracellular polymeric
substances (EPS). Characteristics of biofilms that make
their control challenging include the increased resistance
to antimicrobial agents of the bacteria within the biofilm
and the rapidity of re-colonization after mechanical
removal. Dr. John Cisar presented research from his lab
regarding the bacteria that initiate colonization of tooth
surfaces. His lab identified streptococcal receptor polysaccharides (RPS) that interact with viridans group streptococci and Actinomyces naeslundii in early biofilm
formation. Understanding this important component of
the biofilm and how it differs from one individual to
another may provide new insights and through research
lead to new approaches to the management and prevention of dental caries.
The recognition that antimicrobial peptides are present in
saliva provides some interesting possibilities for the management of oral diseases such as dental caries and periodontal disease. Dr. Beverly Dale-Crunk measured levels of
antimicrobial peptides in school-aged children with or
without dental caries. In her study, she found that mean
levels of alpha-defensins were significantly higher in some
children without caries than in other children with caries.
These results, she argues, suggest possibilities both for
early detection of caries risk and for early preventive strategies through research.

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Emerging Technologies
Technologies with the potential to prevent or manage
dental caries could take a number of forms, including
ways to detect caries risk prior to disease occurrence, species-specific targeting of acidogenic bacteria, reduction of
bacterial adherence to tooth surfaces, and prolonged
release of therapeutic agents. Interdisciplinary research
that combines the expertise of dentistry, molecular biology, and bioengineering holds great promise for new,
innovative approaches to the prevention of dental caries.

Dr. Vincent Fischetti presented a study on the use of bacteriophage lytic enzymes to control pathogenic bacteria.
These enzymes are species specific and are capable of
destroying large numbers of bacteria in blood or on
mucosal surfaces in seconds. They target the bacterial cell
wall of the specific bacteria they were developed from and
do not attack human cells. Lytic enzymes have many
potential uses in the food industry, in hospitals and nursing homes, and in the treatment of diseases such as dental
caries that are mediated by bacteria. He suggested that an
enzyme specific to S. mutans is being developed.
One of the key ingredients in the caries process is diet. A
diet rich in sugars and simple carbohydrates provides the
oral bacterial with a substrate from which they produce
acid. Recent evidence suggests that a person's preference
for sweet-tasting foods is more complex than simply what
foods or sweets the child is exposed to early in life. Dr.
Danielle Reed demonstrated in her work that sweet perceptions and preferences have an important genetic component, suggesting that some people may actually have a
"sweet tooth." Having the genetic makeup that leads to a
preference for sweet-tasting foods does not necessarily
predict the choices an individual will make. It does, however, suggest another potential avenue for the investigation of risk factors leading to dental caries.
Technologies to control biofilm formation have been
developed in many disciplines other than in dentistry.
Management or elimination of microbial biofilms is
important in fields as diverse as medicine and the boating
industry. In the boating industry the management of biofilms has led to the development of anti-fouling polymers
such as poly(ethylene glycol) (PEG), or a poly(N-substituted glycine) (polypeptoid). Dr. Phil Messersmith discussed his research with these polymers and how these
technologies may have interesting possibilities for the
management of oral biofilms and dental disease.
Dr. Buddy Ratner expanded on the topic of anti-adhesive
polymers and discussed a number of other strategies that
have potential with future research for disrupting the oral
biofilm or delivering therapeutic agents in a controlledrelease manner. The controlled delivery systems he dis-

cussed include passive delivery systems and responsive

drug delivery systems. Examples of the passive systems
include diffusion-controlled systems wherein the drug is
either in a reservoir device surrounded by an inert barrier
or membrane or the drug is dissolved in an inert polymer.
Another type of passive system is chemically controlled. A
bioerodible system is used to hold and subsequently
release the drug. Responsive drug delivery systems are
either open- or closed-loop systems. Open-loop systems
are regulated externally using magnetism or ultrasound.
In closed-loop systems, the release is in response to local
conditions such as temperature, pH, or other factors.
Advances in understanding of the caries process and of the
many new engineered biomaterials has provided many
future opportunities for collaborative efforts aimed at
eliminating dental caries in the most susceptible individuals.
Future Goals
One of the stated goals of this conference was to develop
a research agenda that, if adopted by investigators and
funders, will leverage recent discoveries and lead to innovative new approaches to reduce caries in high-risk populations. To allow discussion leading to a research agenda,
there were three breakout sessions with three sub-topics in
each session. Participants were charged with identifying
1) ways to enhance existing technologies; 2) new targets
or novel strategies and 3) new technologies or delivery
systems to decrease the incidence of dental caries. Strategies identified in the breakout sessions were then organized into specific topics that could inform a future request
for applications from government, foundations, or industry in the area of biotechnology and bioengineering
approaches to reduce disparities in dental caries.

Studies that would be responsive to the goals of this RFA

would include but not be limited to the following:
Enhancing Existing Technologies
Methods to improve the substantivity of topical fluorides; techniques to enhance the diffusion of fluoride into
plaque; innovative, controlled release delivery devices;
combinations of fluoride and antimicrobial therapies;
and high-concentration fluoride varnishes.

Education programs to inform the public and the health

care community about disease management and prevention using psychological approaches, including motivational interviewing and other approaches used effectively
outside the field of oral health.
Clarification and enhancement of mechanisms of action
v/v inhibition of acid production and glucan production.

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BMC Oral Health 2006, 6:S1

Development of toothpaste with fluoride encapsulated

in controlled-release "microcapsules" substantive to
plaque, or pellicle/tooth surface.

Development of New Technologies or Delivery Systems

Modification of xylitol delivery systems to reduce the
number of doses while maintaining its effect.

Formulation of toothpastes with complimentary agents

such as lytic enzymes or anti-microbial peptides.

Research to understand how xylitol is affecting the bacterial ecology in plaque and saliva.

Incorporation of novel technology such as quorum sensors, adherence inhibitors, bacterial toxins, and polymerreleasing salicylic acid derivatives.

Development and testing of the efficacy of sustained

release of xylitol.

Development of New Targets or Novel Strategies

Methods to effectively balance the oral ecology through
the delivery and retention of agents such as antimicrobial
peptides, arginine, urea, and fluoride.

Methods to identify the full range of oral bacteria and

understand the metabolic activity of acidogenic species.
Methods to recognize and inhibit virulence factors.
Methods to inhibit metabolic pathways and to deliver
and retain buffers in plaque.
Development of delivery systems that can be done at
home rinse, brush or wipes.
Enhanced production of antimicrobial peptides.
Development of probiotic approaches such as introducing S. gordonii prior to establishment by Mutans streptococci.
Development of novel methods to target Mutans streptococci such as lytic enzymes, competence-stimulating peptide (CSP), and mutacin.
Identification and development of lytic enzymes to target other acid producing oral bacteria.
Identification of biomarkers for inhibitors of quorum
sensing and for inhibitors of bacterial metabolism.
Development of new delivery systems to provide for distribution throughout the mouth and release over
extended periods of time.
Development and testing of antiadhesive coatings for
controlling oral biofilms, including research to define the
chemical and structural characteristics desired in antifouling polymers.

Testing the ability of small molecular-weight antimicrobial compounds (peptides, etc.) tethered to antifouling
polymers to be active in controlling bacterial colonization
and biofilm formation.
Evaluation of the behavior of microorganisms in contact
with antifouling polymer coatings.
Evaluation of the ability of antifouling polymer coatings
to be combined with release of active compounds (fluoride, chlorhexidine, etc.) to more effectively treat/prevent
caries. Possibilities include entrapping nanoparticles
within coatings for long-term release of antibacterials.
Testing the ability to design antifouling polymers that
encourage colonization of tooth/device surfaces by
"good" microorganisms over "bad" (acid secreting)
microorganisms.
Development of methods to improve the residual capacity of fluoride delivery including sustained-release materials, "responsive" release materials (e.g. pH-triggered),
combination therapy (antibiotic/fluoride) release, and
biomaterials that buffer pH.

Conclusion
Successful outcomes of this conference include the promotion of a dialogue between end-users, oral microbiologists, and materials and bioengineering experts in order
to develop novel prevention technologies and implement
the transfer of such technologies to industry and practice.
Efforts to address the question of what can be done to
more effectively use the large body of basic and applied
caries science already available to speed solutions to the
public health community should be the focus of future
research initiatives.

Competing interests
The author(s) declare that they have no competing interests.

Authors' contributions
Development and testing of the chemical and structural
characteristics of glycoproteins and polysaccharides
present in oral biofilms.

All authors read and approved the final manuscript.

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Acknowledgements
The authors would like to thank Virginia Lynn, Jackie Stein, Justin Coyne
and Mary Beth Cunningham for their assistance in the planning of this conference. This conference was supported by NIH/NIDCR grant
R13DE015798-01 and by the Whitaker Foundation. Additional financial
support was provided by generous donations from Danisco Sweeteners,
Colgate-Palmolive Co., and Kerr Corporation.

References
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Fitzgerald RJ, Keyes PH: Demonstration of the etiologic role of

streptococci in experimental caries in the hamster. Journal of
the American Dental Association 1960, 61:9-19.
Edelstein BL: Disparities in oral health and access to care: findings of national surveys. Ambul Pediatr 2002, 2:141-147.
Bratthall D: Dental caries: intervened interrupted interpreted. Concluding remarks and cariography. European Journal
of Oral Sciences 1996, 104:486-491.
Ten Great Public Health Achievements United States,
19001999. MMWR Weekly 1999, 48:1141.
Miller WD: The microorganisms of the human mouth Philadelphia, PA: SS
White and Co; 1890.
Loesche WJ: Role of Streptococcus mutans in human dental
decay. Microbiol Rev 1986, 50:353-380.

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