Pulp Regeneration—Translational Opportunities

Depth and Activity of Carious Lesions as Indicators for the

Regenerative Potential of Dental Pulp after Intervention
Lars Bjørndal, DDS, PhD, Dr Odont,* Sune Demant, DDS,*† and Sally Dabelsteen, DDS, PhD†

Abstract
Studies on dental regeneration involving interventions
for pulp therapy such as regeneration and revasculariza-
tion procedures are promising for the injured tooth;
A lthough oral health care in many parts of the Western world has been improving,
with a marked decline in caries activity among children and adolescents (1), data
indicate that caries is still the most frequent reason for performing endodontic treat-
however, a complete replication of the original pulp tis- ment. In a questionnaire survey, 55% of previously performed root canal treatments
sue does not seem to take place. In cases in which we were performed because of caries in a vital tooth by general dental practitioners
wish to preserve or maintain parts of the pulp during (GDPs) (2). It is apparent that the effectiveness of healing or biological regeneration
treatment, it is apparent that the effectiveness of heal- is dependent on the degree of inflammation in the pulp tissue (3) when preserving
ing or biological regeneration is dependent on the de- or maintaining parts of the pulp during caries treatment. This produces a dilemma
gree of inflammation of the pulp tissue. Thus, the not only in the clinic but also between the clinic and the laboratory because GDPs still
control or prevention of a pulp infection is still a major lack a device for noninvasive measurements of pulp inflammation. How can pulp ther-
issue for the clinicians. Data indicate that the typical apies be improved if the actual clinical condition of the pulp remains a diagnostic prob-
reason for performing endodontic treatment is deep lem? A recent review dealing with the diagnosis of dental pulp has shown that the
caries. The biological concept of vital pulp therapy asso- available diagnostic tools were insufficient to assess the proper status of the pulp
ciated with deep caries takes the treatment and evalua- (4). Is it possible to obtain information regarding the condition of the pulp if the diag-
tion of the unexposed as well as the exposed pulp into nostic process was more focused on the characteristics of a specific carious lesion? Can
account. Interestingly, the clinical diagnosis is typically patient age be related to the depth of the lesion? Similarly, when GDPs assess lesion ac-
the same. Deep caries with reversible pulpitis may tivity by including established clinical variables on caries activity, is it possible to use this
receive differing treatments such as excavation proce- information as indicators for the regenerative potential of dental pulp after intervention?
dures aiming to avoid pulp exposure or more pulp inva-
sive treatments such as pulp capping or pulpotomy. This Treatment Variation
should not be the case. Consequently, huge treatment The biological concept of vital pulp therapy associated with deep caries involves
variation is noted among clinicians based on the same the treatment and evaluation of unexposed and exposed pulp, but, interestingly, the clin-
caries diagnosis. Which treatment should be selected? ical diagnosis is typically the same (5, 6). In a dental practitioner environment, deep
High-quality trials are needed, and it is important to caries with reversible pulpitis may receive differing treatment modalities such as
obtain information on the actual lesion depth and an es- avoidance of pulp exposure, pulp capping, or pulpotomy. These treatment options
timate of the lesion activity before treatment. These may have led to both pulp-invasive (7, 8) and non–pulp-invasive treatment strategies (9–
be basic indicators for the regenerative potential of 13). From network-based studies, it has been documented that GDPs are prone to
dental pulp. Recent clinical trials dealing with the treat- perform different treatment modalities for the same ‘‘deep caries lesion scenario’’
ment of deep caries lesion are discussed, including pulp (14). The vast majority of GDPs suggest 1 complete excavation or a root canal treatment,
invasive and noninvasive concepts, to attempt to solve and less than 20% prefer a less invasive excavation procedure aiming to avoid exposure
the task of getting the best clinical outcome for adult pa- of the pulp. In a large questionnaire survey, this trend was recently confirmed because 2
tients. (J Endod 2014;40:S76–S81) groups of GDPs were identified with opposite approaches to caries excavation (15).
Apparently, it matters which GDP is treating the deep carious lesion. The patient may
Key Words receive a root canal treatment, a pulp capping procedure, complete caries excavation,
Caries, direct pulp capping, endodontics, indirect pulp or a less invasive excavation procedure. From the viewpoint of the patient, this treatment
therapy, pulpotomy, stepwise excavation variation is not an optimal scenario. Efforts have been made to solve this clinical
dilemma, and the contemporary perspectives on vital pulp therapy have been discussed
by both endodontists and pediatric dentists (16), but, of course, more profound educa-
tional initiatives are needed to reduce treatment variation. Consensus within the clinical

From the Departments of *Cariology and Endodontics and †Oral Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
This paper is based on a presentation from the International Association for Dental Research (IADR) Pulp Biology and Regeneration Group Satellite Meeting, which
was held March 24–26, 2013 in San Francisco, California.
Address requests for reprints to Dr Lars Bjørndal, Department of Cariology and Endodontics, Faculty of Health Sciences, University of Copenhagen, Nørre All
e 20,
DK-2200 Copenhagen N, Denmark. E-mail address: [email protected]
0099-2399/$ - see front matter
Copyright ª 2014 American Association of Endodontists.
http://dx.doi.org/10.1016/j.joen.2014.01.016

S76 Bjørndal et al. JOE — Volume 40, Number 4S, April 2014
 Pulp Regeneration—Translational Opportunities

Figure 1. At the macroscopical level, it is possible to observe pulp reactions in relation to progressive stages of caries development.

community is an important prerequisite for developing improved treat- ogenic plaque, and a typical light yellow or yellow demineralized dentin is
ment strategies for future collaboration within the scientific community. noted, reflecting an actively progressing lesion (Fig. 2A, inset). In a fully
erupted maxillary third molar without the presence of cariogenic surface
plaque, the occlusal surface displays a chronic/inactive discolored sur-
Caries Progression and the Pulp-Dentin Organ face lesion and the appearance of a dark brown/black discolored demin-
The belief that there is no correlation between pulp inflammation eralized dentin (Fig. 2B, inset). Alterations in the odontoblast cell layer
and the presence or absence of a toothache including an abnormal can be noted both in arrested and active lesion sites, whereas a different
response to thermal testing has led to the opinion among clinicians appearance of the subodontoblastic region is apparent in subjacent active
that it is justified to excavate deep caries to pulp exposure (7) because sites (Fig. 2C) as compared with the unaffected control (Fig. 2D). This
the pulp may be severely inflamed even though it remains ‘‘silent’’ in may indicate that the pulp is able to react dynamically to caries without
terms of subjective symptoms. If caries remains untreated, a frank expo- necessarily reaching stages of irreversible pulpitis, necrosis, or infection.
sure may occur, and classic articles have shown that the pulp reacts with In short, using classic qualitative histologic parameters, a different pulp
an infiltration of acute inflammatory cells and perhaps also the develop- response can be noted toward rapidly and slowly progressing caries
ment of a small abscess (17, 18). Therefore, it seems logical that the (20–22). It is also well-known that dentin is a bioactive extracellular ma-
removal of infected pulp tissue in such cases is the treatment of trix (23–26), and during demineralization there is a release of bioactive
choice. The pulp becomes increasingly inflamed as caries progresses molecules (27–29). Our knowledge of the odontoblast is steadily
(Fig. 1). But, when is the point of no return? What happens if the speed increasing (30) as well as our knowledge regarding the role of inflamma-
of caries progression is reduced? tion (31). Taken together, it might be possible to further investigate the
Since the article by Br€annstr€om and Lind (19), a missing link has relative influence of carious activity with respect to the use of both indirect
been made between the early signs of caries and the inflammatory re- pulp therapy (IPT) and pulp therapy. In particular, more information is
actions of the pulp. Because of histologic difficulties, this link could needed during the dynamic nature of human caries progression and the
not be shown directly but rather by comparing tooth halves in the lab- clinical importance of the reservoir of bioactive molecules in the dentin
oratory. Changes along the odontoblastic and subodontoblastic layers during various concepts of caries excavation.
were noted subjacent to enamel lesions. Later, the use of thin undemin- Several studies on the proteomics of human dentin have been per-
eralized tooth sections made it possible to simultaneously examine the formed that have shed light on the protein composition of the dentinal
enamel lesion and the pulp-dentin organ, confirming not only early matrix (32, 33). Interestingly, the dentinal matrix appears, among a
odontoblast cell reactions (20) but also a difference in tertiary dentin myriad of other proteins, to contain sequestered growth factors, and
formation as a response to slow and active lesion activity (21). it has been shown that the dentinal matrix plays an active role
Extracted third molars show findings regarding the influence of because the sequestered bioactive substances can be released
caries lesion activity on dentin and pulp (Fig. 2). A partially erupted because of acidic and enzymatic dissolution of the dentinal matrix
mandibular third molar (Fig. 2A) shows evidence of an undisturbed cari- within the caries lesion (27–29). To our knowledge, no studies have

Figure 2. (A) A mandibular third molar (partly erupted) presents a cariogenic local environment in which the surface plaque can remain undisturbed. (A, inset)
A macroscopical cutting profile of the tooth shows a light yellow/yellow appearance of the discolored demineralized dentin. (B) A maxillary third molar is observed
with an arrested occlusal enamel lesion. (B, inset) A macroscopical cutting profile of the tooth shows a dark brown/black appearance of the discolored demin-
eralized dentin. Along an active site, (C) a specific qualitative subodontoblastic reaction is apparent compared with (D) an unaffected control.

JOE — Volume 40, Number 4S, April 2014 Carious Lesion Definition Needs Improvement S77
Pulp Regeneration—Translational Opportunities
performed a comprehensive proteomic analysis of the caries lesion per
se. In order to elucidate the proteomic profile of the caries lesion, a
proteomic analysis of the carious dentin is currently being performed
in our laboratory using the stepwise excavation procedure as the
experimental setup. During the first visit, excavation of clinical active
caries dentin is excavated and assessed on parameters developed by
Bjørndal et al (34). After the initial excavation, a temporary glass ion-
omer filling is placed. During the second visit (4–6 months after the
initial excavation), the temporary filling is removed, and the remaining
caries dentin are excavated and evaluated as inactive based on the pre-
viously referenced criteria. Active and inactive carious dentin samples
are analyzed regarding their proteome, and results are compared
with the proteome of sound human dentin. To sum up, the aim of
this study was to evaluate whether caries activity can be linked with a
certain biochemical profile, which may stimulate the pulp. Our hypoth-
esis is that this profile may be used to characterize the resulting inflam-
matory state of the pulp. Might there be a difference in the inflammatory
changes noted during active and arrested caries progression? Can these
changes be linked to the differences seen in tertiary dentinogenesis? In
short, can the biochemical profile of the carious lesion help in predict-
ing the inflammatory changes seen histologically and maybe lead to a
more evidence-based diagnosis of the dental pulp in cases of deep
caries lesions and associated vital but inflamed dental pulps? In this
light, various lesion activities (Fig. 2A and B) may have the potential
of releasing different profiles of bioactive molecules.

The Conversion of Lesion Activity in Caries

It has previously been described in detail how the cariogenic
ecosystem may change during the natural development of a deep caries
lesion (35). When the demineralized enamel breaks down and the mi-
crobial ecosystem is converted from a closed environment toward a
more open environment, the activity of the lesion is declining. Of course,
in a clinical setting, it is not possible to follow a deep lesion during total
breakdown, but when IPT is performed, the same principle changes
within the cariogenic ecosystem are happening. The aim of IPT is to
change the cariogenic environment and to reduce the transmission of
cariogenic stimuli into the pulp. Clinically, a conversion is taking place
as the carious dentin changes color from light to dark brown and the sur-
face moisture from wet to dry (34, 36). IPT can be performed in either 1
or 2 steps; the latter is also described as the stepwise excavation
approach. The IPT approach has become an acceptable treatment
modality for asymptomatic carious permanent teeth in young patients
(12–14). Notably, this technique has also shown success in case
reports of symptomatic permanent teeth in children (37), but mainly
the success of this approach has been documented in adults (9, 38, 39).

How Can Lesion Activity and Depth Be Monitored

in a Clinical Setup?
A principle classification can categorize estimates on lesion activity
in clinical terms (Fig. 3A–C). An example of an active progressing caries
lesion is displayed showing a premolar during caries removal. The dem-
ineralized discolored dentin has a light yellow/yellow appearance, the
surface texture has a wet/moist appearance, and it is easy to disintegrate
the soft organic matrix (Fig. 3A). The signs of slowly progressing caries
are a browner and dry surface texture (Fig. 3B). In cases of arrested Figure 3. A principle classification plate is shown that in clinical terms cat-
caries, this pattern can be more marked (Fig. 3C). The darkest area egorizes the estimation on lesion activity. (A) Actively progressing carious
of the demineralized dentin reflects the oldest part of the caries lesion. dentin is light yellow/yellow and wet. (B) Slowly progressing carious dentin
Such classification plates have been used to classify changes in lesion appears light brown and dry. (C) Arrested carious dentin is dark brown/black.
activity previously (34, 40, 41). Color classification used in Bjørndal et al (34).

S78 Bjørndal et al. JOE — Volume 40, Number 4S, April 2014
 Pulp Regeneration—Translational Opportunities
The specific depth of the carious lesions is seldom mentioned in
clinical studies. This may also be a problem in getting a more precise
estimation of the degree of pulp inflammation. It is well-known that
GDPs have different thresholds for expecting an exposure of the pulp
during caries excavation, and it may vary from caries penetrating half
way into the dentin to caries involving the entire dentinal thickness
(9). It is obvious that the inflammation of the pulp would not be the
same within these 2 borderline cases. It can be hypothesized that the
enrollment of various carious lesion sizes in a clinical trial may affect
the final evaluation of the outcomes.
In a recent randomized clinical trial (38), this aspect was ap-
proached using an inclusion plate based on radiographs showing exam-
ples of caries lesions that could be either included or excluded. In the
actual study, the inclusion of the lesion was defined as caries penetrating
three quarters or more into the dentin and with a well-defined radio-
dense line separating the pulp from the demineralized dentin
(Fig. 4). Data on lesion depth and activity might be the missing link
that could be used in both the clinic and the laboratory as indicators
for the regenerative potential of the dental pulp after intervention.

Direct and Indirect Pulp Therapy and

Level of Evidence
Caries is mentioned several times in the review of the diagnostic
condition of the pulp (4), but, as discussed earlier, it is not defined
more accurately in terms of activity and depth. Nadin et al (42) per-
formed a systematic Cochrane Review about pulp therapy in so-called
extensive caries in primary molars. All included participants had
symptom-free, cariously exposed vital pulp as a baseline description.
However, it was not possible from the review to gain information about
the carious depth before pulp exposure. The authors indicate that they
primarily focused on the exposed pulp, but they did not exclude that IPT
could have been an alternative treatment modality. Although based on
primary molars, this clearly reflects the controversial aspect of the
deep caries topic.
Randomized controlled clinical trials and meta-analyses are
needed in order to obtain the best platform for selecting the correct
treatment (43). This may explain 1 of the major reasons why treat-
ment variation exists. The lack of the highest level of evidence does
not mean that GDPs should select what they believe to be the best
treatment modality; instead, they should rely on the best available
data, which are typically reflected in country or specialty guidelines.
Systematic reviews have addressed the need of high evidence trials
concerning vital pulp therapy in cariously exposed and unexposed
pulps (42,44–46), and the reviews all emphasize the limitation of
comparing studies that are different in study design and the need
for further studies of high quality.
Based on weighted pooled success rates (over time), evidence ta-
bles have recently been aligned for direct pulp capping, partial pulpot-
omy, and full pulpotomy (47). A range of patient age was included, with
the youngest patients undergoing direct pulp capping and the oldest full
pulpotomy. The success rate was 72.9% for direct pulp capping with
a recall period more than 3 years (6–10 years of age, n = 231),
99.4% for partial pulpotomy (6–27 years of age, n = 23), and
99.3% (6–70 years of age, n = 37) for full pulpotomy. Note the remark-
ably low number of recalls after more than 3 years for all the pulpotomy
treatments. Again, the only information that can be extracted from these
studies regarding the inclusion criteria was that all the teeth had cari-
Figure 4. An example of an inclusion and exclusion plate is shown for the well-
ously exposed pulps. No specific characteristics about the caries lesions
defined enrollment of deep caries lesions in a clinical trial. (Reprinted ª 2010
Eur J Oral Sc. Bjørndal L, Reit C, Bruun G, et al. Treatment of deep caries lesions were presented. This may be a problem when using pooled data.
in adults: randomized clinical trials comparing stepwise vs. direct complete exca- A more recent retrospective observational study (48) observed a
vation, and direct pulp capping vs. partial pulpotomy. 2010;118:290–7.) 2-year survival rate of 56.2% (mean age = 41 years, N = 51) of teeth

JOE — Volume 40, Number 4S, April 2014 Carious Lesion Definition Needs Improvement S79
Pulp Regeneration—Translational Opportunities
after pulp capping. The relatively low survival rate confirms previous 5. Reporting the actual caries lesion depth (eg, determined by radio-
observational data suggesting that the prognosis of pulp capping may graphs) (Fig. 4) should be included.
be related to age (49). Concomitantly, a randomized clinical multi- 6. Carious lesion characteristics should be reported irrespective of the
center trial examined pulp capping versus partial pulpotomy in cari- clinical suggested pulp diagnosis.
ously exposed pulps in adults after the excavation of well-defined
The knowledge of lesion activity and lesion depth before treatment
deep caries lesions (38). The results showed an even worse outcome
may create an important baseline and detailed platform for explaining
after both pulp therapies, with a pooled pulp survival rate of only
and predicting treatment outcome in cases of pulp exposure after treat-
33.2% after 1.5 years. As opposed to other studies, this trial docu-
ment. There may be a difference in the regenerative potential of dental
mented a more specific description of deep lesions being enrolled
pulp related to active and slowly progressing caries because dentin
(Fig. 4). The results showed that a caries lesion, located in the inner
color, consistency, and surface environment (ie, wet or dry) may in re-
quarter of the dentin in adults, may represent the threshold for success
ality reflect various gradients of bioactive molecules within carious
for pulp capping, which may be expected with our present treatment
modalities. In addition, the low level of success in this study may also dentin and, therefore, be more indicative of pulp inflammation and
regeneration.
be related to the use of a concealed allocation sequence in relation
to the randomization procedure. This is often underestimated in ran-
domized clinical trials because without concealment the results may Acknowledgments
lead to overestimation of the treatment effect (42–44). The authors deny any conflicts of interest related to this study.
It has been suggested that a full pulpotomy might be a better alter-
native treatment for adults after pulp exposure (50). Based on prelim- References
inary data in a small serial case report, an outcome rate of 82% was 1. Marthaler TM. Changes in dental caries 1953-2003. Caries Res 2004;38:173–81.
obtained (children and adults, mean age = 37 years, N = 17). When 2. Bjørndal L, Laustsen MH, Reit C. Root canal treatment in Denmark is most often
addressing the inclusion criteria, cases of exposure after the excavation carried out in carious vital molar teeth and retreatments are rare. Int Endod J
of caries were included as well as cases of exposure after preparation 2006;39:785–90.
3. Goldberg M, Farges JC, Lacerda-Pinheiro S, et al. Inflammatory and immunological
for prosthodontics restorations. This might be an important prognostic aspects of dental pulp repair. Pharmacol Res 2008;58:137–47.
difference that should be evaluated before the initiation of a larger-scale 4. Mej
are IA, Axelsson S, Davidson T, et al. Diagnosis of the condition of the dental
study. pulpa: a systematic review. Int Endod J 2012;45:597–613.
When patients with pain and clinical signs of irreversible pulpitis 5. Dumsha T, Hovland E. Considerations and treatment of direct and indirect pulp-
are included in clinical trials, it would be interesting to know the actual capping. Dent Clin North Am 1985;29:251–9.
6. Seale NS. Indirect pulp therapy: an alternative to pulpotomy in primary teeth. Tex
depth of carious lesions (described as extensive) in order to specify Dent J 2010;127:1175–83.
cases in which less invasive pulp therapies have to be excluded. 7. Witherspoon DE, Small JC, Haris GZ. Mineral trioxide aggregate pulpotomies: a case
Recently, a large randomized clinical multicenter study showed that series outcome assessment. J Am Dent Assoc 2006;137:610–8.
full pulpotomy in extensive carious lesions with ‘‘partial’’ irreversible 8. Bogen G, Kim JS, Bakland LK. Direct pulp capping with mineral trioxide aggregate:
an observational study. J Am Dent Assoc 2008;139:305–15.
signs of pulpitis disclosed remarkably successful outcomes among pa- 9. Bjørndal L, Thylstrup A. A practice-based study on stepwise excavation of deep
tients (mean age = 27 years) using biomaterials (51). Because the ma- carious lesions in permanent teeth. A 1-year follow-up study. Community Dent
jority of the actual scored pain levels appeared to be mild to moderate Oral Epidemiol 1998;26:122–8.
(and not severe), it would again have been relevant to know whether the 10. Maltz M, de Oliveira EF, Fontanella V, et al. A clinical microbiological, and radio-
actual lesions size varied as well. graphic study of deep caries lesions after incomplete caries removal. Quintessence
Int 2002;33:151–9.
Of course, the present theme is complex. It is important to note 11. Fagundes TC, Barata TJE, Prakki A, et al. Indirect pulp treatment in a permanent
that the topic of dressing materials and final restorations has not molar: case report of 4-year follow-up. J Appl Oral Sci 2009;17:70–4.
been covered. The tools used for caries excavation should not be 12. Gruythuysen R, van Strijp G, Wu M-K. Long-term Survival of indirect pulp treatment
forgotten. At a case report level and with the use of the operating micro- performed in primary and permanent teeth with clinically diagnosed deep carious
lesions. J Endod 2010;36:1490–3.
scope, the technical aspect of excavation might push the borders of what 13. Orhan AI, Oz FT, Orhan K. Pulp exposure occurrence and outcomes after 1- or 2-
we would expect. Notably, in asymptomatic cases in young teeth, a direct visit indirect pulp therapy vs complete caries removal in primary and permanent
cap can be successfully performed even when caries radiographically molars. Pediatr Dent 2010;32:347–55.
reaches the pulp (8). 14. Oen KT, Thompson VP, Vena D, et al. Attitudes and expectations of treating deep
caries: a PEARL network survey. Geriatric Dent 2007;55:197–203.
15. Schwendicke F, Meyer-Lueckel H, D€orfer C, et al. Attitudes and behaviour regarding
Conclusions deep dentin caries removal: a survey among german dentists. Caries Res 2013;47:
It might be beneficial to incorporate more details in clinical 566–73.
16. Seal NS, Glickman GN. Contemporary perspective on vital pulp therapy: views from
studies regarding the characteristics of caries lesions as indicators the endodontists and pediatric dentists. J Endod 2008;34:S57–61.
for the regenerative potential of the dental pulp after intervention. Liter- 17. Seltzer S, Bender IB, Ziontz M. The dynamics of pulp inflammation: correlations be-
ature is sparse within this topic. The following are suggested: tween diagnostic data and actual histologic findings in the pulp. Oral Surg Oral Med
Oral Pathol 1963;16:846–71.
1. Future protocols for the regenerative potential of dental pulp (in the 18. Seltzer S, Bender IB, Ziontz M. The dynamics of pulp inflammation: correlations be-
clinic as well in the laboratory) should include more details about tween diagnostic data and actual histologic findings in the pulp. Oral Surg Oral Med
the caries lesion before intervention (if present and possible). Oral Pathol 1963;16:969–77.
19. Br€annstr€om M, Lind PO. Pulpal response to early caries. J Dent Res 1965;44:
2. It is hypothesized that the inclusion of unspecific caries lesions 1045–50.
makes it difficult to interpret the actual degree of pulp inflammation, 20. Bjørndal L, Darvann T, Thylstrup A. A quantitative light microscopic study of the
hence the actual clinical outcome. odontoblastic and subodontoblastic reactions to active and arrested enamel caries
3. The protocol should not only state teeth with cariously exposed without cavitation. Caries Res 1998;32:59–69.
21. Bjørndal L, Darvann T. A light microscopic study of odontoblastic and non-
pulps but also the caries lesion depth behind. odonotoblastic cells involved in the tertiary dentinogenesis in well-defined cavitated
4. Classifying lesion activity by established clinical variables should be carious lesions. Caries Res 1999;33:50–60.
attempted (Fig. 3). 22. Massler M. Pulpal reactions to dental caries. Int Dent J 1967;17:441–60.

S80 Bjørndal et al. JOE — Volume 40, Number 4S, April 2014
 Pulp Regeneration—Translational Opportunities
23. Begue-Kirn C, Smith AJ, Ruch JV, et al. Effects of dentin proteins, transforming 38. Bjørndal L, Reit C, Bruun G, et al. Treatment of deep caries lesions in adults:
growth factor b1 (TGFb1) and bone morphogenetic protein 2 (BMP2) on the dif- randomized clinical trials comparing stepwise vs. direct complete excavation,
ferentiation of odontoblasts in vitro. Int J Dev Biol 1992;36:491–503. and direct pulp capping vs. partial pulpotomy. Eur J Oral Sci 2010;118:
24. Begue-Kirn C, Smith AJ, Loriot M, et al. Comparative analysis of TGF beta s, BMPs, 290–7.
IGF1, msxs, fibronectin, osteonectin and bonesialoprotein gene expression during 39. Maltz M, Garcia R, Jardim JJ, et al. Randomized trial of partial vs. stepwise caries
normal and in vitro-induced odontoblast differentiation. Int J Dev Biol 1994;38: removal: 3-year follow-up. J Dent Res 2012;91:1026–31.
405–20. 40. Orhan AI, Oz FT, Ozcelik B, et al. A clinical and microbial comparative study of deep
25. Smith AJ, Tobias RS, Plant CG, et al. In vivo morphogenetic activity of dentine matrix carious lesion treatment in deciduous and young permanent molars. Clin Oral Invest
proteins. J Biol Buccale 1990;18:123–9. 2008;12:369–78.
26. Sloan AJ, Smith AJ. Stimulation of the dentine–pulp complex of rat incisor teeth by 41. Petrou MA, Alhamoui FA, Welk A, et al. A randomized clinical trial on the use of
transforming growth factor-b isoforms 1–3 in vitro. Arch Oral Biol 1999;44: medical Portland cement, MTA and calcium hydroxide in indirect pulp treatment.
149–56. Clin Oral Investig 2013 Sep 17; http://dx.doi.org/10.1007/s00784-013-1107.
27. Graham L, Cooper PR, Cassidy N, et al. The effect of calcium hydroxide on solubi- [Epub ahead of print].
lisation of bio-active dentine matrix. Biomaterials 2006;27:2865–73. 42. Nadin G, Goel BR, Yeung CA, et al. Pulp treatment for extensive decay in primary
28. Tomson PL, Grover LM, Lumley PJ, et al. Dissolution of bio-active dentine matrix teeth. Cochrane Database Syst Rev 2003;(1):CD003220.
components by mineral trioxide aggregate. J Dent 2007;35:636–42. 43. Sackett DL, Strauss S, Richardson S, et al. Evidence-based Medicine: How to Prac-
29. Smith AJ, Scheven BA, Takahashi Y, et al. Dentine as a bioactive extracellular matrix. tice and Teach EBM, 2nd ed. London: Churchill Livingstone; 2000.
Arch Oral Biol 2012;57:109–21. 44. Miyashita H, Worthington HV, Qualtrough A, et al. A pulp management for caries in
30. Couve E, Osorio R, Schmachtenberg O. The amazing odontoblast: activity, auto- adults: maintaining pulp vitality. Cochrane Database Syst Rev 2007;(2):CD004484.
phagy, and aging. J Dent Res 2013;92:765–72. 45. Ricketts D, Lamont T, Innes NP, et al. Operative caries management in adults and
31. Cooper PR, Takahashi Y, Graham LW, et al. Inflammation-regeneration interplay in children. Cochrane Database Syst Rev 2013;(3):CD003808.
the dentine-pulp complex. J Dent 2010;38:687–97. 46. Schwendicke F, Meyer-Lueckel H, D€orfer C, et al. Failure of incompletely excavated
32. Park ES, Cho HS, Kwon TG, et al. Proteomics analysis of human dentin reveals teeth - a systematic review. J Dent 2013;41:569–80.
distinct protein expression profiles. J Proteome Res 2009;8:1338–46. 47. Aguilar P, Linsuwanont P. Vital pulp therapy in vital permanent teeth with cariously
33. J
agr M, Eckhart A, Pataridis S, et al. Comprehensive proteomic analysis of human exposed pulp: a systematic review. J Endod 2011;37:581–7.
dentin. Eur J Oral Sci 2012;120:259–68. 48. Miles JP, Gluskin AH, Chambers D, et al. Pulp capping with mineral trioxide aggre-
34. Bjørndal L, Thylstrup A, Larsen T. A clinical and microbiological study of deep gate (MTA): a retrospective analysis of carious pulp exposures treated by under-
carious lesions during stepwise excavation using long treatment intervals. Caries graduate dental students. Oper Dent 2010;35:20–8.
Res 1997;31:411–7. 49. Hørsted P, Søndergaard B, Thylstrup A, et al. A retrospective study of direct pulp
35. Bjørndal L. Dentin and pulp reactions to caries and operative treatment: biological capping with calcium hydroxide compounds. Endod Dent Traumatol 1985;1:29–34.
variables affecting treatment outcome. Endod Top 2002;2:10–23. 50. Simon S, Perard M, Zanini M, et al. Should pulp champer pulpotomy be seen as a
36. Bjørndal L. Buonocore memorial lecture. Dentin caries: progression and clinical permanent treatment? Some preliminary thoughts. Int Endod J 2013;46:79–87.
management. Oper Dent 2002;27:211–7. 51. Asgary S, Eghbal MJ. Treatment outcomes of pulpotomy in permanent molars with
37. Torabzadeh H, Asgary S. Indirect pulp therapy in a symptomatic mature molar using irreversible pulpitis using biomaterials: a multi-center randomized controlled trial.
calcium enriched mixed cement. J Conserv Dent 2013;16:83–6. Acta Odontol Scand 2013;71:130–6.

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