Patophysiology of Dental Caries - Conrads2018 PDF

The Philosophical Evolution
Schwendicke F, Frencken J, Innes N (eds): Caries Excavation: Evolution of Treating Cavitated Carious Lesions.
Monogr Oral Sci. Basel, Karger, 2018, vol 27, pp 1–10 (DOI: 10.1159/000487826)
Pathophysiology of Dental Caries

Georg Conrads a · Imad About b
a Divisionof Oral Microbiology and Immunology, Department for Operative Dentistry, Periodontology and Preventive Dentistry,
RWTH Aachen University Hospital, Aachen, Germany; b Aix Marseille University, CNRS, ISM, Institute of Movement Sciences,
Marseille, France
Abstract cells. After carious stimulation, odontoblasts initiate an in-

Carious lesion dynamics are dependent predominantly on flammatory reaction by producing chemokines and syn-
the availability of fermentable sugars, other environmental thesise a protective tertiary dentine. After the destruction
conditions, bacteria, and host factors. Our current under- of these cells, the pulp still has a high capacity to synthesise
standing of the microorganisms involved in the initiation this tertiary dentine thanks to the presence of adult stem
and progression of caries is still rather incomplete. The cells within the pulp. Also, in addition to the systemic regu-
most relevant acidogenic-aciduric bacterial species known lation, the pulp which is located within inextensible the
to date are Streptococcus mutans, bifidobacteria, and lacto- confines of the dentine walls has a well-developed local
bacilli. Whereas mutans streptococci are initiators, bifido- regulation of its inflammation, regeneration, and vascular-
bacteria and lactobacilli are more enhancers for progres- isation. This local regulation is due to the activity of differ-
sion. Boosters for microbial activity are specific ent pulp cell types, mainly the fibroblasts, which secrete
environmental conditions, such as the presence of fer- soluble molecules that regulate all these processes.
mentable dietary sugars and the absence of oxygen. Based © 2018 S. Karger AG, Basel
on these conditions, the necrotic and/or contaminated
zone fulfils all criteria for disease progression and has to be
removed. For those deep lesions where the pulp vitality is Microbiology of Tooth Decay
not affected, a selective removal of the contaminated
leathery dentine should take place as this approach lowers Dentistry dates as far back as 5,000 BC when peo-
the risk of regrowth of the few embedded microbial cells ple in India, Egypt, Japan, and China thought
here. In repelling the microbial attack and repairing dam- dental caries were a result of a “tooth worm.” The
age, the host has developed several ingenious strategies. term “dental caries” ﬁrst appeared in the litera-
A major resistance to carious lesion progression is mount- ture around 1634 and is derived from the Latin
ed by the dentine-pulp tissues. The signalling molecules word cariēs for decay and from ancient Irish ara-
and growth factors released upon dentine demineralisa- chrinn, it decays. The term was originally used
tion upregulate the odontoblast activity and act as sensor simply to describe holes in the teeth with little
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knowledge of the aetiology and pathogenesis of ulation of microorganisms of low cariogenicity to
the disease [1]. a consortium of high cariogenicity and to an in-
Concepts and beliefs about the cause of dental creased production – and correlated tolerance –
caries have evolved over many centuries, with the of organic acids promoting dental hard tissue net
involvement of microorganisms recognised since mineral loss. That is why we call this consortium
the late 1800s. Readers interested in the concepts acidogenic and acidophil (synonym aciduric).
in caries microbiology and their development Besides the presence of fermentable dietary car-
over time can find comprehensive literature on bohydrates and selection of acidogenic-aciduric
the topic [2, 3]. Despite thousands of publica- bacterial species, the host susceptibility, which is
tions, however, the central question of the relative a rather simplified term for a multifactorial com-
importance of different bacteria in the disease re- plexity, is the third major player.
mains unanswered. The acidogenic-aciduric bacterial species
With technical advances in our ability to iden- Streptococcus mutans is recognised as being emi-
tify, cultivate, and count different microorgan- nently involved in cariogenic processes, includ-
isms, our views have evolved regarding the con- ing early childhood caries, enamel carious lesions,
tribution of particular species of plaque bacteria cavitated lesions, or carious dentine. However,
to the caries process [4]. But it might take another over time its attributed role changed from that of
20–50 years, as a rough estimate, before deep-se- a true pathogen (specific plaque hypothesis [5])
quencing technologies and the gene databases to enhancer (active role) and/or indicator (pas-
have reached such a quality that the entire gene sive role) of a sugar-triggered cariogenic vicious
repertoire and interactions within a carious tissue circle (extended caries ecological hypothesis [6,
can be determined. The limits so far are the length 7]), and the discussion still goes on [8]. As a mat-
of an ambiguity-free sequence read (which is cur- ter of fact, S. mutans is detected in a few caries-
rently as short as 500 bp applying the leading Il- free and found absent in several caries-active in-
lumina sequencing technology) and, as a conse- dividuals, impairing its outstanding caries indica-
quence, the need to select a short but taxon-rep- tory potential. Furthermore, most relevant
resentative region, usually a variable region, e.g., acidogenic-aciduric bacterial species are: (i) S.
V1-V3, V3-V4, or V3-V5 of the 16S rDNA (total mutans relatives (called mutans streptococci or
length 1,545 bp) or – even better – of the 23S MS) with a similar virulence potential, namely S.
rDNA (total length 2,905 bp). For instance, V3- sobrinus; (ii) bifidobacteria, including Bifidobac-
V4 sequence results will leave many saccharolytic terium dentium and other closely related oral Bi-
Streptococcus and Actinomyces species as “unclas- fidobacterium spp., but also the more distantly re-
sified.” That means our current picture about the lated species Scardovia wiggsiae, and (iii) lactoba-
microorganisms involved in the initiation and cilli, especially those with pellicle-adhesive
progression of caries or other especially polymi- potential [9].
crobial diseases is still rather incomplete. How- A number of epidemiological and in vitro
ever, the species known to be involved so far and studies suggested that S. sobrinus – under circum-
the correlated pathomechanisms of dental caries stances yet to be determined – may be even more
can be taken as a draft model and are thus dis- cariogenic than S. mutans [8–11]. In addition,
cussed below. targeted clinical studies have suggested that pre-
In dental caries, we see an ecologic shift within school and 15-year-old school children harbour-
the dental biofilm environment, driven by fre- ing both S. mutans and S. sobrinus had a higher
quent access to fermentable dietary carbohy- incidence of dental caries than those with S. mu-
drates. This leads to a move from a balanced pop- tans alone (for a review see Conrads et al. [10]).
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Unlike MS, the highly aciduric bifidobacteria, such as MS) or indirectly (beneficiaries such as
especially B. dentium, do not colonise hard sur- bifidobacteria and lactobacilli; for a review see
faces per se, since denture plaque associated with Conrads et al. [10]).
denture stomatitis harboured high levels of MS, 2 Environmental conditions favouring the
lactobacilli, and yeasts, but not B. dentium. This multiplication and metabolism of such species:
indicates that B. dentium does not simply colo- access to low-molecular sugars, especially su-
nise intact dental hard surfaces but instead sug- crose, and low redox potential at the same time.
gests that it is the lesion initiated by other species High sugar and low oxygen leads to rapid fermen-
that facilitate the attachment and proliferation of tation and acid production.
B. dentium. In contrast to MS, the presence of this With these simple principles, it is possible to
species might therefore be more a result than the identify (constitute) what a carious tissue actually
cause of initial lesions. Clearly, B. dentium and is and how much tissue must or should be re-
MS are significant independent indicators [9]. moved or excavated to stop further decay.
A similar role (more profiteer than initiator)
was recently proposed for lactobacilli, with Lacto-
bacillus fermentum, L. rhamnosus, L. gasseri, L. Histology of a Carious Tissue –
salivarius, L. plantarum, and the L. casei-paraca- The Microbiological Perspective
sei group as the most abundant species. Accord-
ing to this concept, precaries lesions become a re- The degree of success in eliminating bacteria dur-
tentive, low pH niche for lactobacilli accumula- ing cavity preparation and prior to the insertion
tion, which take advantage of their proclivity for of a restoration may increase the longevity of the
making and surviving in an increasingly reduced restoration and therefore the success of the re-
pH environment. In some cases, the lactobacilli storative procedure. The complete eradication of
can even outcompete and exclude the MS that bacteria in a caries-affected tooth during cavity
created the retentive niche, which might explain preparation is considered a difficult clinical task
why caries lesions are sometimes free of MS but and – from the perspective of a microbiologist –
not or very rarely free of lactobacilli [9]. almost impossible, and also not required any-
Other less investigated but interesting caries- more, as is discussed in the chapter by Bjørndal
indicator candidates are Atopobium spp., Slackia [this vol., pp. 68–81]. Attempts to excavate com-
exigua and a few others [11, 12]. The entire net- pletely extensive carious tissue may affect the vi-
work of microbial organisms involved, which are tality of the pulp and weaken the tooth structure.
not only bacteria but also saccharolytic yeasts In principal, disinfection of the cavity prepara-
(e.g., Candida albicans), Archaea (enhancer of tion after caries excavation can aid in the elimina-
fermentation processes by consuming end prod- tion of bacterial remnants, reducing the risk for
ucts such as CO2 and H2), or bacteriophages (en- recurrent caries and failure of the restoration.
hancer of lateral gene transfer and thus of evolu- However, the side effects of chemical disinfec-
tion), is extremely complex and diverse. tants (e.g., chlorhexidine or benzalkonium chlo-
Taken together, every cavity might have its ride) on the restorative treatment, including re-
own demineralising consortium of active organ- duced dentine bond strength, have been a major
isms and genes, but the following simple princi- concern for both dental clinicians and researchers
ples are universal: [13], and therefore alternatives still have to be
1 Presence of acidogenic-aciduric microor- found and their efficacy proven.
ganisms and their ability to attach to the pellicle- As shown in Figure 1, the carious tissue consists
coated tooth surface, either directly (pioneers of 4 different zones, but only 3 clinically noticeable
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Pathophysiology of Caries 3
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Cross-section of Enlarged cross-section of Dentine Histological Dentine:
tooth with occlusal carious lesion tubule terms clinical (tactile)
carious lesion manifestations
Necrotic zone
Soft dentine
Contaminated zone
Demineralised
Leathery dentine
zone
Translucent zone Firm dentine
Sound dentine Hard dentine

Tertiary dentine
Fig. 1. Histology of carious tissue. Note the correlations between cross-section, ultrastructure zones, and clinical (tac-
tile) manifestations. modified from Innes et al. [14] and Ogawa et al. [15].
layers. The outer layer, clinically the soft dentine, removal (incomplete excavation to protect the
consists of the necrotic zone with the microbial pulp) should be limited to soft dentine, excluding
biofilm attached, and the contaminated zone. The the removal of contaminated leathery dentine
soft dentine is characterised by a gradient of mi- [14]. From the microbiological point of view, this
croorganisms with cell-numbers between 101 and approach is tolerable as electron transport within,
108 per mg (measured from the inside to outside, and acid production by, the few cells is also very
pulpal to coronal), including aciduric, facultative low in this zone. However, bacteria have several
anaerobic bacteria. Comparing the conditions strategies to overcome harsh conditions and –
here with the principles mentioned above, this ne- after preparation, disinfection if applicable, infil-
crotic and/or contaminated zone fulfils all criteria tration if applicable, and restoring – might still be
for disease (demineralisation) progression as it is alive although in a dormant state [16, 17]. This
anaerobic (low redox potential demanding a fast means the lesion and the bacteria are arrested, but
substrate turnover for sufficient energy resourc- only temporarily. If there is gap formation at the
ing) and, at least temporarily, fed by high concen- tooth-restoration interface, possibly further sup-
trations of fermentable dietary carbohydrates. This ported by the microleakage of fluids and salivary
layer has to be removed. proteins to the gap, this leads to inevitable micro-
The next layer is the demineralised zone, bial colonisation from saliva, but also to the pos-
which correlates clinically with leathery dentine. sible regrowth of dormant cells and, ultimately,
This zone is characterised by few microorganisms secondary caries formation. Therefore, for less
per milligram, very little nutrients (since already deep lesions, selective removal should take place
consumed by the bacteria and yeasts in the outer down to firm dentine, which not only has clinical
layer), and a strictly anaerobic atmosphere. While advantages (more depth for a solid restoration),
the latter condition favours demineralisation by but also lowers the risk of regrowth of surviving
acid production, the sheer low number of fer- microbial cells.
menting bacteria and the very low nutritional Finally, pulpally the translucent zone of firm
source prohibits substantial multiplication and softer dentine is characterised by demineralisa-
metabolism. It is the consensus that for deep le- tion since acids, but not the bacterial cells, pene-
sions, extending beyond the inner (pulpal) third trate to this depth. Here, the plate-form apatite
or quarter of dentine radiographically, selective crystals apparently dissolve and recrystallise into
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500 μm 500 μm
a b
500 μm 500 μm
c d
Fig. 2. a Histology of sound dentine in a premolar. b Dentine tubules are numerous and wide
open on the pulp side. c They are less numerous and appear more narrow at mid-distance be-
tween the pulp and the dentine-enamel junction. d Dentine tubules are very narrow and many of
them appear completely obliterated upon approaching the dentine-enamel junction.
a rhomboid form, defined as whitlockite bacteria invasion is hindered by the dentine itself
[Ca9(MgFe)(PO4)6PO3OH]. This crystalline form and how this dentine provides signalling mole-
seems to be softer and less resistant to cutting and cules to induce dentine regeneration during the
acids [15]. This layer might not be absolutely ster- carious process. In the case of a deep carious le-
ile, but metabolism of aciduric microorganisms is sion reaching the odontoblasts, the pulp tissue it-
almost impossible and thus negligible. For repel- self has also elaborated efficient strategies to hin-
ling and combatting the microbial attack and re- der or even arrest the carious lesion progression
pairing damages, the host has developed several and the bacterial infiltration into the pulp.
ingenious strategies.
Dentine Histology at the Dentine Enamel

Pulp Response to Dental Caries Junction Is Different from that of Deep
Dentine
Host pulp response to dental caries is a key ele-
ment in understanding the carious process and its Dentine has a unique histological tubular appear-
consequences. In this regard, enamel acts as a ance. The tubules close to the dental pulp are nu-
physical mineralised barrier preventing bacterial merous and wide open. Their diameter decreases
infiltration into the dentine and pulp. Also, the gradually as they get away from the pulp and be-
underlying dentine histology, composition, and come very narrow or completely obliterated upon
function provide significant information on how approaching the dentine-enamel junction (Fig. 2).
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This suggests that the superficial dentine hin- within the dentine tubules to decrease their per-
ders bacterial infiltration when they reach the meability to cariogenic bacteria and their toxins,
dentine surface. On the other hand, when bacte- leading to the protection of the underlying pulp.
ria reach the open dentine tubules they can in- Thus, odontoblasts represent the first defence
vade the dental pulp more rapidly through the tu- mechanism in case of carious lesion develop-
bules. This may suggest significant consequences ment. Indeed, these cells also express receptors
to the underlying pulp only if we consider the called Toll-like receptors (TLRs) 2 and 4 [23, 24],
bacterial invasion consequences. However, the which recognise specific structures on Gram-pos-
dental pulp established efficient protective mech- itive and Gram-negative bacteria, respectively.
anisms against this invasion. These TLRs belong to a big family of pattern rec-
ognition receptors that are activated after contact
with common molecules on the pathogen surface.
Dentine Matrix Contains Sequestered In moderate carious injuries, TLRs 2 are highly
Signalling Molecules expressed in the underlying odontoblasts [25].
Upon activation, these TLRs induce the secretion
While the major dentine inorganic component is of antimicrobial molecules such as β-defensins
hydroxyapatite, its organic matrix is mainly com- and nitric oxide by the odontoblasts which have
posed of collagen I and non-collagenous proteins an antibacterial effect against S. mutans, thus lim-
such as dentine sialoprotein [18] and dentine ma- iting cariogenic bacteria progression towards the
trix protein-1 [19]. These are involved in the ini- pulp [26]. Also, upon activation of their recep-
tiation and the regulation of dentine mineralisa- tors, odontoblasts secrete proinflammatory che-
tion. In addition, different signalling molecules mokines which lead to dendritic cell recruitment
have been reported to be secreted by the odonto- in order to eliminate the pathogenic agents [27].
blasts and sequestered in the dentine matrix, Overall, in the case of moderate dentine cari-
mainly in an inactive form. Among others, these ous lesions, the odontoblasts act as a barrier ex-
include transforming growth factor-β1 (TGF-β1), erting antimicrobial effects and initiating the se-
basic fibroblast growth factor (FGF-2), vascular cretion of a tertiary dentine to protect the under-
endothelial growth factor (VEGF), and platelet lying pulp (Fig. 3).
derived growth factor (PDGF) [20, 21]. During However, in the case of severe and rapidly pro-
the carious dissolution of the dentine matrix, gressive carious lesions, tertiary dentine focal
these molecules can be released and reach the un- synthesis may not be enough and bacteria may
derlying odontoblasts leading to the upregulation destroy the newly synthesised tertiary dentine,
of their synthetic activity. reach the underlying pulp, and induce an inflam-
In addition to the responsiveness to these matory reaction (Fig. 4).
growth factors, recent data demonstrated that
odontoblasts act as sensor cells as they express
transient potential channel receptors. These re- The Dental Pulp Defence Strategies
ceptors allow the odontoblast to be responsive to
the external stimulations, such as noxious heat, When the odontoblastic barrier is destroyed by
noxious cold, as well as chemical and mechanical the carious lesion and either bacteria or their
stimulations [22]. Thus, upon stimulation, odon- toxins reach the underlying pulp, a tertiary den-
toblasts synthesise a new tertiary dentine at the tine secretion can still be observed. This dentine,
pulp periphery facing the stimulation site. This which is secreted after the odontoblast destruc-
focally secreted dentine can also be deposited tion, is synthesised by another cell type originat-
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Carious dentine Tertiary dentine
od
500 μm 500 μm
a b
Fig. 3. a Histology of a moderate carious lesion in a molar. It is characterised by a disorganised

dentine with a loss of the typical tubular structure at the carious site. b Tertiary dentine is secret-
ed locally by the underlying odontoblasts (od). At this stage, bacterial infiltration is arrested at a
distance from the pulp, which has a normal aspect.
ing for the differentiation of adult pulp stem tion into odontoblast-like cells secreting the ter-
cells. This reparative dentine usually contains tiary dentine [32].
fewer tubules than the physiological one. This Additionally, recent investigations on dental
might decrease the bacterial infiltration or their pulp, which has a terminal circulation, revealed
toxins to the underlying pulp. While little was that, in addition to the systemic regulation, it has
known about the cells secreting this dentine, the a local regulation of its vascularisation, inflam-
discovery of adult stem cells within the dental mation, and regeneration. This allows the dental
pulp provided a significant step forward. Indeed, pulp to resist bacterial invasion by different
all dental pulps in permanent and primary teeth mechanisms, as explained below.
and at all ages comprise, at least, a population of
adult stem cells [28]. This was first demonstrated
in a culture system of cells isolated from the Dental Pulp Local Regulation
pulps of third molars, where pulp cells were able
to produce a mineral matrix with molecular and It is well established that carious injury leads to
mineral characteristics of dentine [29]. Addi- pulp hypoxia. Different pulp cell types, such as
tionally, when isolated with specific mesenchy- fibroblasts, endothelial, and stem cells, have been
mal stem cell markers such as STRO-1 and trans- reported to upregulate the synthesis of hypoxia-
planted after mixing with hydroxyapatite/trical- inducible factor, which increases the synthesis of
cium phosphate ceramic powder subcutaneously angiogenic growth factors such as VEGF, FGF-2,
in mice, they generated a dentine/pulp-like tis- and PDGF. This leads to vasodilation and the in-
sue [30]. There is converging evidence that one creased formation of blood vessels at the carious
of the niches of these stem cells is located in the injury site. Overall, this increases nutrient, blood,
perivascular area. After pulp injury, these cells and oxygen supply to the injured tissue. This also
are activated and migrate to the injury site to allows inflammatory cell recruitment to carry out
synthesise the tertiary dentine [31]. It has been phagocytosis of pathogens. After complete pulp
reported that TGF-β1, which can be released af- healing, there is a downregulation of angiogenic
ter the dissolution of dentine, is involved in the factor secretion and a return to normoxia with
recruitment of these cells and their differentia- normal pulp vascularisation [33].
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Carious dentine
Tertiary dentine
500 μm b 100 μm
a
Bacteria
c 500 μm d 50 μm
Fig. 4. a Histology of a severe carious lesion in a molar. It is characterised by a disorganised den-

tine at the carious site. b Tertiary dentine is produced in the form of a bridge by the underlying
odontoblasts. At this stage, bacteria infiltrated the dentine tubules (c) and the pulp, which ap-
pears inflamed and infiltrated by numerous inflammatory cells (d).
Carious injury also leads to a pulp inflamma- tive bacteria, such as S. mutans and S. sanguinis.
tory reaction initiated by complement activation. Upon activation, several biologically active mol-
Complement is the name given to about 40 pro- ecules are released. Among these, C5a has been
teins synthesised mainly by the liver and released shown to be involved in the recruitment of pulp
in the plasma. During the inflammatory process, stem cells [35] and in the guidance of nerve
the complement is activated, leading to the syn- growth to the stimulation site [36]. Another frag-
thesis of biologically active complement frag- ment, C3a, is involved in the proliferation of both
ments. These play a major role in eliminating pulp fibroblasts and stem cells and in guiding fi-
pathogenic agents. Pulp fibroblasts have been re- broblast migration to the stimulation site [37].
cently reported as the only non-immune cell ca- This clearly illustrates the involvement of com-
pable of synthesising all complement proteins plement in the pulp regeneration process facing
[34]. After complement activation, biologically bacterial infiltration during carious disease. In-
active fragments are released. Recent investiga- deed, reparative dentine is efficient in arresting
tion of these fragments revealed their involve- the carious injury progression (Fig. 3). This may
ment in the pulp anti-inflammatory and regen- be partially explained by the fact that pulp com-
eration processes. Indeed, pulp complement can plement activation also leads to the synthesis of a
be activated by lipoteichoic acids of Gram-posi- complex molecular structure called membrane
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attack complex. This complex structure can be pulp and provide the adequate signals not only to
produced by the fibroblasts and has been shown kill cariogenic bacteria, but also to initiate the re-
not only to be fixed on S. mutans and S. sanguinis, generation process by recruiting the stem cells
but also to kill these cariogenic bacteria [33]. and nerve regeneration.
When this complex polymerises on bacteria walls, Overall, a carious lesion should be regarded
it creates numerous holes leading to the entry of as a dynamic process. Its progression does not
electrolytes and water, which results in bacteria only depend on the bacterial infiltration and the
destruction. Thus, the fibroblasts dampen down, local environment, but also on the host pulp re-
and may even arrest the bacterial invasion to the sponse.
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For microbiology: Georg Conrads

Division of Oral Microbiology and Immunology, Department for Operative Dentistry
Periodontology and Preventive Dentistry, RWTH Aachen University Hospital
Pauwelsstrasse 30
DE–52074 Aachen (Germany)
E-Mail gconrads@ukaachen.de
For histology: Imad About

Aix Marseille University, CNRS, ISM, Institute of Movement Sciences
FR–13385 Marseille (France)
E-Mail imad.about@univ-amu.fr
150.216.68.200 - 6/4/2018 7:16:18 PM
10 Conrads · About
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The Philosophical Evolution

Pathophysiology of Dental Caries

Abstract cells. After carious stimulation, odontoblasts initiate an in-

Sound dentine Hard dentine

Dentine Histology at the Dentine Enamel

Fig. 3. a Histology of a moderate carious lesion in a molar. It is characterised by a disorganised

Fig. 4. a Histology of a severe carious lesion in a molar. It is characterised by a disorganised den-

For microbiology: Georg Conrads

For histology: Imad About

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