doi:10.1111/iej.
12480
REVIEW
Formation of a hard tissue barrier after
experimental pulp capping or partial pulpotomy in
humans: an updated systematic review
H. Fransson, E. Wolf & K. Petersson
Department of Endodontics, Faculty of Odontology, Malm€
o University, Malm€
Abstract
Fransson H, Wolf E, Petersson K. Formation of a hard
tissue barrier after experimental pulp capping or partial
pulpotomy in humans: an updated systematic
International Endodontic Journal, 49, 533–542, 2016.
The aim was to update a systematic review of pulp cap-
ping and partial pulpotomy by Olsson et al. (2006), by
evaluating new evidence on formation of a hard tissue
barrier after pulp capping and partial pulpotomy of
experimental exposures in humans. PubMed (01-01-
2005 to 01-03-2014) and CENTRAL were searched
using specific keywords. Hand searches were made and
the level of evidence for each included article was evalu-
ated by the authors. The evidence of the conclusions was
graded as strong, moderately strong, limited or insuffi-
cient. The initial search in PubMed yielded 215 abstracts.
Hand searches of reference lists yielded no additional
Introduction
Pulp capping and partial pulpotomy are treatment
procedures, whereby a material is applied to an
exposed pulp with the aim of restoring and preserving
pulpal vitality and function. In clinical studies, the
outcome of such vital pulp treatments is typically
considered successful when the patient is symptom
free, and there are no signs of apical periodontitis and
the tooth reacts to sensitivity testing, thus showing
Correspondence: Helena Fransson, Department of Endodon-
tics, Faculty of Odontology, Malm€
o University, SE-205 06
Malm€o, Sweden (Tel.: +46-40-665 83 15; fax: +46-40-665
83 15; e-mail: Helena.Fransson@mah.se).
© 2015 International Endodontic Journal. Published by John Wiley & Sons Ltd
o, Sweden
original scientific articles. After a selection process and
interpretation, 22 articles were included and rated for
level of evidence: no article was rated as high and seven
as moderate. Overall the methodological quality of stud-
review.
ies has improved since the previous systematic review
was published in 2006. The conclusions are that there is
limited scientific evidence that application of calcium
hydroxide or mineral trioxide aggregate to an exposed
pulp frequently results in formation of a hard tissue bar-
rier, whereas adhesives or enamel matrix derivatives do
not. There is insufficient scientific evidence that mineral
trioxide aggregate promotes hard tissue formation more
frequently than calcium hydroxide.
Keywords: calcium hydroxide, dental hard tissue
formation, dental pulp capping, mineral trioxide
aggregate, pulp capping and pulpectomy agents.
Received 3 July 2014; accepted 5 June 2015
signs that pulpal health has been preserved. However,
the success rates vary considerably and seem to
decline over time (Hørsted et al. 1985, Mejare & Cvek
1993, Barthel et al. 2000, Bjørndal et al. 2010).
The preoperative status of the pulp is a factor that
seems to influence the success rate. Teeth with trau-
matic or mechanical pulp exposures have higher suc-
cess rates than teeth with cariously exposed pulps,
which are often severely inflamed (Hørsted et al.
1985, Bjørndal et al. 2010). A possible explanation for
late-onset failures may be that an adequate hard tissue
barrier has not formed over the exposure: hence, there
is no functional barrier to protect the pulp from bacte-
rial microleakage along the restoration margins.
All surfaces in the body including the skin, the gastro-
intestinal tract and the mucosa have barrier functions
International Endodontic Journal, 49, 533–542, 2016 533
 13652591, 2016, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/iej.12480, Wiley Online Library on [24/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Formation of a barrier Fransson et al.

protecting the body from external harmful agents Systematic literature search
(Elias 2008, Turner 2009). In the tooth, the physio-
Publications were retrieved from PubMed using
logical barrier function is mainly within the pulp–den-
MeSH-terms as presented in Table 1. The search was
tine complex that has the capability to respond to
limited to human material and publications with
microbial leakage with functions such as dentinal
abstracts in English. Case reports were excluded. The
fluid, formation of peri-tubular dentine and tertiary
PubMed search was combined with a search of The
dentine. Moreover, upon activation of Toll-like recep-
Cochrane Controlled Trials Register (CENTRAL) using
tors, the odontoblasts may discharge substances that
the phrase pulp capping.
will affect angiogenesis and the regulation of blood
After reading the abstracts, relevant publications
flow that are key elements of the inflammatory process
were identified:
(Botero et al. 2006, Soden et al. 2009): thus, an opti-
1. Original scientific studies:
mal goal for the treatment of the exposed pulp would
Human teeth with exposed pulps, with or without
be healing of the lesion by formation of a new dentine
caries, treated by a pulp capping procedure
barrier.
(including partial pulpotomy),
Systematic reviews have a relatively short lifespan
The hard tissue and the pulp were subjected to
and require frequent updating, in order to remain rel-
microscopic examination; the proportion of teeth
evant not only to the scientist, but also to the clini-
with a complete hard tissue barrier after the proce-
cian (Moher et al. 2008). In 2006, a systematic
dure was presented or could be calculated from
review was published, evaluating evidence supporting
the raw data.
the formation of a hard tissue barrier after pulp cap-
2. Reviews:
ping or partial pulpotomy. The systematic review
The phrase pulp capping should appear in the title
included experimental studies in which the hard tis-
or the abstract and
sue and the pulp had been examined histologically.
The type of publication should be indexed as a
No conclusions could be drawn at the time of publica-
Review.
tion (Olsson et al. 2006). The quality of the included
Selected studies were retrieved in full text. Reviews
studies provided insufficient scientific evidence with
were used only to identify studies not indexed in Pub-
respect to the impact of different pulp capping agents
Med or CENTRAL; that is, the reference lists were
on the formation of a hard tissue barrier and the sta-
accessed for hand searching. The reference lists of
tus of the pulp tissue as seen in histological sections.
included original scientific studies were also hand
In subsequent years, new pulp capping agents have
searched, to identify titles containing any of the fol-
been proposed and there is greater awareness of the
lowing phrases: pulp capping, pulp exposure, partial
importance of an appropriate study protocol to
pulpotomy or vital pulp therapy.
achieve scientific evidence.
The aim of this study was to identify new evidence
of hard tissue formation after dental pulp capping in Interpretation, assessment and data synthesis
humans and to incorporate this into the previously
In the previous study, data extraction and data
published systematic review (Olsson et al. 2006). The
assessment protocols had been modified after Guyatt
intended readers are oral biologists and dentists.
et al. (1993, 1994) with minor adjustments and can
be retrieved from the published systematic review
Materials and methods (Olsson et al. 2006). The data were extracted
These questions defined the problem: Table 1 Data base search (PubMed) and number of publica-
1. Can a pulp exposure heal, that is form a hard tis- tions retrieved
sue barrier over pulp tissue that is free from signs Indexing terms No. of publications
of inflammation after pulp capping?
#1 ‘Dental Pulp Capping’ [MeSH] 215
2. What are the prerequisites for formation of a hard
#2 ‘Case report’ [Publication Type] 259 077
tissue barrier? #3 ‘Dental Pulp Capping’ [MeSH] 192
3. What happens to the pulp and the newly formed NOT ‘Case report’ [MeSH]
hard tissue over time?
Limits: Publication dates from 01/01/2005 to 01/03/2014 and
The systematic review includes also partial pulpoto- indexed as ‘only items with abstracts’, ‘English’ and ‘Human’.
my but does not address indirect pulp capping. The search was performed on the 3rd of June 2014.

534 International Endodontic Journal, 49, 533–542, 2016 © 2015 International Endodontic Journal. Published by John Wiley & Sons Ltd

independently by the three reviewers. The extracted
data could be stratified into subsets according to study
design, description of the subjects and materials used
and outcome measures. Disagreements were resolved
by discussion. The individual studies were assigned a
level of evidence, and the concluding evidence was
graded as strong, moderately strong, limited or insuffi-
cient, in accordance with the criteria applied in the
previously published review (Table 2).
Results
Literature search and interpretation
The search in PubMed yielded 215 abstracts (Fig. 1).
After scrutiny, 31 articles were selected and read in
Table 2 Levels of evidence and criteria for evidence
synthesis
High level of evidence:
The study was judged to have a high level of evidence if it
fulfilled all of the criteria below:
There was a sufficiently large sample of patients and teeth
to detect a treatment effect, preferably calculated by a
power analysis.
The study was a true prospective experiment in which
investigators randomly assigned the sample of patients
and teeth to one or more intervention groups and a
control group.
The sample was described so that the pulp status was
clear.
The study personnel were blinded regarding the
intervention.
The procedure for performing the pulp capping was
described in sufficient detail regarding size, type and site
of exposure as well as materials used, to permit
replication.
There was a proper account of the patients and teeth that
entered the trial and attributed to its conclusion.
The analysis of the hard tissue formation and status of the
pulp were adequate; that is, the criteria were specified in
the text or with a reference.
The results were well documented and presented in terms
of relevant data.
Moderate level of evidence:
A study was judged to have a moderate level of evidence if
any of the above criteria was not met. On the other hand, the
study was judged not to have deficits that are described for
studies with a low level of evidence.
Low level of evidence:
A study was judged to have a low level of evidence if it met
any of the following criteria:
There was not a sufficiently large sample of patients and
teeth.
There was not a randomization process.
The sample and procedure were not described in sufficient
detail to permit replication.
© 2015 International Endodontic Journal. Published by John Wiley & Sons Ltd
13652591, 2016, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/iej.12480, Wiley Online Library on [24/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Fransson et al. Formation of a barrier
full text. Nine studies were excluded because the
reported results were outside the scope of this system-
atic review. The reasons for exclusion are presented
in Fig. 1. Neither the search in CENTRAL nor manual
searching of the reference lists yielded any additional
publications. Thus, the systematic review was based
on 22 articles.
Assessment of studies
Seven of the 22 studies were rated as presenting mod-
erate levels of evidence; no study was assigned a high
level of evidence. The data from the seven studies as
well as the one study identified in the former system-
atic review as providing a moderate level of evidence,
in total eight studies, are presented in Table 3. The
quality of evidence provided by the remaining 15
studies was assessed as low with reference to the
research question addressed by this systematic review,
and those studies were therefore excluded from fur-
ther analysis (Table 4).
In seven of the eight studies with moderate level of
evidence, a calcium hydroxide-based material served
as a control. All studies were undertaken in healthy
teeth; that is, there were no studies of teeth with cari-
ous exposures. Five of eight studies had several fol-
low-up periods. The follow-up periods of the included
studies, regardless of level of evidence, varied between
1 day and 609 days. There were no reports of hard
tissue barriers for observation periods under 30 days.
Bonding materials
The update of the literature search identified two
studies with moderate levels of evidence (Silva et al.
2006b, Lu et al. 2008), using two different bonding
materials as the pulp capping materials. These were
added to the study previously identified (Horsted-
Bindslev et al. 2003) in the systematic review
published in 2006, giving in total three studies with
moderate level of evidence. All had several follow-up
periods: in some studies, the initial follow-up was
undertaken very soon after the pulp capping proce-
dure. None of the studies reported hard tissue cover-
ing the exposed pulp after capping with a bonding
material, whereas high frequencies of hard tissue for-
mation were recorded for capping with the calcium
hydroxide-based materials used as controls.
Lu et al. (2008) compared the pulpal status of teeth
treated with a bonding material and those treated
with calcium hydroxide and reported similarly high
International Endodontic Journal, 49, 533–542, 2016 535

Formation of a barrier Fransson et al.
Records identified
through PubMed and
CENTRAL
(n = 215)
Full-text articles
assessed for eligibility
(n = 31)
Studies included in
qualitative synthesis
(n = 22)
Figure 1 Flow diagram of identification, screening, assessment of eligibility and included studies modified to PRISMA statement
(Moher et al. 2009).
frequencies of slight or no inflammation in test and
control groups. Horsted-Bindslev et al. (2003) and
Silva et al. (2006b) reported a lower frequency of slight
or no inflammation in pulpal exposures treated with a
bonding material compared to calcium hydroxide.
Mineral trioxide aggregate (MTA)
A moderate level of evidence was assigned to three
studies evaluating MTA (Min et al. 2008, Accorinte
et al. 2009, Nair et al. 2009). Accorinte et al. (2009)
compared two different brands of MTA and thus did
not have a separate control material such as calcium
hydroxide. There was no difference between the two
brands with respect to either formation of hard tissue
or the frequency of slight or no pulp inflammation.
However, the sample size may have been too small to
ensure disclosure of a possible difference (Table 3).
The study by Min et al. (2008) used grey MTA and
the study by Nair et al. (2009) used white MTA, with
different follow-up periods. With respect to the forma-
tion of a hard tissue barrier using MTA, the results
were quite similar between the two studies, with high
frequencies of hard tissue barriers at later follow-up
periods. In both studies, the control material was
Dycal (Dentsply-Caulk, Milford, DE, USA). However,
the results for the control groups differed consider-
ably: Min et al. (2008) reported complete hard tissue
bridge formation in 6 of 10 control teeth at
2 months, whereas Nair et al. (2009) reported com-
plete hard tissue bridge formation in 0 of 4 control
teeth at 3 months. The heterogeneity was substantial
and it was not possible to perform a meta-analysis.
536 International Endodontic Journal, 49, 533–542, 2016
13652591, 2016, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/iej.12480, Wiley Online Library on [24/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Additional records
identified through
hand searches
(n = 0)
Records excluded (n = 9) due to:
•no examination of hard tissue(Piva
et al. 2006, D´Arcangelo et al. 2007,
Fernandes et al. 2008, Pereira et al.
2009, Yoshiba et al. 2012, Silva et al.
2013)
•full pulpotomy (Chacko & Kurikose
2006)
•no pulp exposure (Mousavinasab et
al. 2008)
•data impossible to assess (Silva et
al. 2006a)
The reported inflammatory status associated with the
test material (MTA) differed somewhat between the
two studies, but was mainly characterized as slight or
no inflammation.
Enamel matrix derivative-based material
Two studies evaluating a commercially available
product containing enamel matrix derivative [Emdo-
gainâGel (Biora AB, Malm€ o, Sweden)] as a pulp cap-
ping material were assessed as having moderate level
of evidence (Olsson et al. 2005, Kiatwateeratana et al.
2009). The methodologies of these two studies were
very similar, as well as their results. Hard tissue was
formed, although not as a bridge covering the pulp
exposure. In the two studies, a total of 14 teeth were
treated with the enamel matrix derivative: none
showed formation of a hard tissue barrier. Calcium
hydroxide in saline was used as the control material,
and hard tissue was formed as a bridge covering the
pulp exposure in 19 of 22 teeth. The frequency of
teeth with little or no inflammation was lower in the
teeth treated with enamel matrix derivative than in
those treated with calcium hydroxide. Severe inflam-
mation was observed in some teeth treated with
enamel matrix derivative.
Calcium hydroxide-based materials
Seven of eight of the included studies used a calcium
hydroxide-based material as a control: four used Dy-
cal (Dentsply-Caulk) (Horsted-Bindslev et al. 2003, Lu
et al. 2008, Min et al. 2008, Nair et al. 2009), one
© 2015 International Endodontic Journal. Published by John Wiley & Sons Ltd
 Table 3 Data from articles on pulp capping assigned moderate level of evidence. No study with high level of evidence was identified

Material
Method Test (T), no of teeth Reported results
Study design Control (C), no of teeth Test (T)
First author (year) Observation time No of subjects Control (C)

Bonding materials
Horsted- RCT T: Single Bond Adhesive System (3M At 56–71 days:
Bindslev et al. 3 observation Dental Products, St Paul, MN, USA) T: no complete hard tissue formation, 2 of 10
(2003) periods: 7, 10–15 n = 17 incomplete hard tissue formation.
and 56–71 days C: Dycal n = 17 C: 5 of 11 complete and 3 of 11 incomplete
Subjects n = 16 hard tissue formation.
No or slight inflammation in:
T: 8 of 10
C: 11 of 11
Lu et al. (2008) RCT T: Clearfil SE Bond (Kuraray Medical, At 90 days:
3 observation Osaka, Japan) n = 21 T: 0 of 7 full bridge
periods: 7, 30 and C: Dycal (Dentsply, Weybridge, UK) C: 5 of 6 full bridge
90 days n = 20 No or slight inflammation in:
Subjects n = 27 T: 7 of 7
C: 6 of 7

© 2015 International Endodontic Journal. Published by John Wiley & Sons Ltd
Silva et al. RCT T1: 37% phosphoric acid n = 26 At 30 days dentin bridge deposition in:
(2006b) 4 observation T2: 10% phosphoric acid n = 26 T1: 0 of 5
periods: 1, 3, 7 and followed by pulp capping with Single T2: 0 of 5
30 days Bond Adhesive System (3M Dental C: 5 of 5
Products) No or slight inflammation in:
C: Calcium hydroxide powder covered T1: 2 of 5
with Dycal (Dentsply Ind e Com Ltda, T2: 2 of 5
RJ, Brazil) n = 26 C: 4 of 5
Subjects n = not known
Mineral trioxide aggregate
Accorinte et al. RCT T1: ProRoot MTA (Dentsply Tulsa Complete hard tissue bridge at 30 days:
(2009) 2 observation Dental, Tulsa, OK, USA) n = 20 T1: 5 of 8
periods: 30 and T2: MTA (Angelus, Londrina, PR, Brazil) T2: 5 of 8
60 days n = 20 Complete hard tissue bridge at 60 days:
Subjects n = not known T1: 5 of 8
T2: 6 of 10
No inflammation in:
T1: 5 of 22
T2: 10 of 18
Teeth in which microorganisms were found
were excluded.

International Endodontic Journal, 49, 533–542, 2016

Fransson et al. Formation of a barrier

537
13652591, 2016, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/iej.12480, Wiley Online Library on [24/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
 538
Table 3 Continued

Material
Method Test (T), no of teeth Reported results
Study design Control (C), no of teeth Test (T)
First author (year) Observation time No of subjects Control (C)

Min et al. (2008) RCT T: MTA ProRoot (Dentsply, Tulsa, OK, T: 9 of 9 complete bridge
Formation of a barrier Fransson et al.

2 months USA) n = 10 C: 6 of 10 complete bridge

C: Dycal (Dentsply-Caulk, Milford, DE, No or slight inflammation in:
USA) n = 10 T: 9 of 9

International Endodontic Journal, 49, 533–542, 2016

Subjects n = 16 C: 9 of 10
Nair et al. (2009) RCT T: White MTA (ProRrootâ, Dentsply, At 1 month:
3 observation Tulsa Dental, OK, USA) n = 20 T: 3 of 6 complete bridge
periods: 1 week, 1 C: Dycalâ Ivory (Dentsply Caulk) n = 13 C: 1 of 5 complete bridge
and 3 months Subjects n = 23 At 3 months:
T: 4 of 5 complete bridge
C: 0 of 4 complete bridge
No or slight inflammation in:
T: 10 of 11
C: 6 of 9
Enamel matrix derivative material
Kiatwateeratana RCT T: EmdogainâGel (Biora AB) n = 15 T: No complete hard tissue bridge
et al. (2009) 6 months C: Calcium hydroxide mixed with C: 10 of 13 complete hard tissue bridge
water n = 15 No or slight inflammation in:
Subjects n = 15 T: 0 of 15
C: 10 of 13
Olsson et al. RCT T: EmdogainâGel (Biora AB) n = 9 Complete hard tissue bridge
(2005) 12 weeks C: Calcium hydroxide mixed with T: 0 of 9
saline n = 9 C: 9 of 9
Subjects n = 8 No or slight inflammation in:
T: 0 of 9
C: 8 of 9
One tooth in C was necrotic.

© 2015 International Endodontic Journal. Published by John Wiley & Sons Ltd
13652591, 2016, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/iej.12480, Wiley Online Library on [24/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

Table 4 Reasons for assigning included studies to low level of evidence
Reason
Not sufficiently large sample Shahravan et al. (2011)
No randomization Accorinte Mde et al. (2005b), Subay & Demirci (2005), Caicedo et al. (2006),
Elias et al. (2007), Accorinte et al. (2008a,b), Accorinte Mde et al. (2008), Parolia et al. (2010),
Zarrabi et al. (2010)
Sample and procedure Accorinte Mde et al. (2005a), Ersin & Eronat (2005), De Lourdes Rodrigues Accorinte et al. (2006),
not sufficiently described Iwamoto et al. (2006), Sawicki et al. (2008)
calcium hydroxide powder covered by Dycal (Silva
et al. 2006b) and two a slurry of calcium hydroxide
and saline (Olsson et al. 2005, Kiatwateeratana et al.
2009). In all but the study by Nair et al. (2009), a
high frequency of hard tissue formation, covering the
exposed pulp, was reported after application of a cal-
cium hydroxide-based material to the exposure. The
reported inflammatory status was mainly slight or no
inflammation, although there were isolated reports of
teeth with pulpal necrosis.
Concluding evidence grade
Combining the results from the published systematic
review with this new literature search leads to the fol-
lowing conclusions with respect to the pulp capping
materials:
1. The use of calcium hydroxide-based materials as
a pulp capping agent frequently results in the for-
mation of hard tissue covering the pulp exposure
(limited scientific evidence).
2. The use of MTA as a pulp capping agent frequently
results in the formation of hard tissue covering the
pulp exposure (limited scientific evidence).
3. The use of enamel matrix derivative as a pulp
capping agent does not result in the formation of
hard tissue covering the pulp exposure (limited
scientific evidence).
4. The use of bonding materials as pulp capping
agents does not result in the formation of hard
tissue covering the pulp exposure (limited scien-
tific evidence).
5. There is a lack of scientific evidence that pulp
capping with MTA material is associated with a
higher frequency of hard tissue formation than
calcium hydroxide-based materials.
Discussion
There is no consensus about when and how a
systematic review should be updated. A Cochrane
review on the topic concluded that there has been lit-
© 2015 International Endodontic Journal. Published by John Wiley & Sons Ltd
13652591, 2016, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/iej.12480, Wiley Online Library on [24/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Fransson et al. Formation of a barrier
References
tle research into the question (Moher et al. 2008).
There is some indication that grading of the level of
evidence in systematic reviews leads to improved
awareness of how to conduct and present studies and
a tendency for the proportion of studies with higher
levels of evidence to increase with time (Cunningham
et al. 2013). This seems to be the case with the cur-
rent updated systematic review that disclosed a num-
ber of articles with a moderate level of evidence,
compared to only one in the earlier review. The hand
search of reference lists yielded no additional publica-
tions, which indicated that the literature searches in
the earlier review had been adequately broad-ranging
and thorough. As there was no attempt to identify
nonpublished data, there is, however, a possibility
that publication bias could change the conclusions.
The value of systematic reviews is highly dependent
on the availability and quality of the results of pri-
mary research (Juni et al. 2001). Flaws in any
included article may lead to errors in the conclusions
of the review. In studies of hard tissue formation after
pulp capping, the internal validity may be adversely
affected by bias with respect to selection, performance,
detection and attrition. In selecting articles for inclu-
sion in the present review, the policy adopted was to
exclude trials which failed to meet a certain standard
of quality: only studies with at least a moderate level
of evidence were reported in detail.
The overall methodology of the included articles
had improved since the earlier systematic review was
published. However, some common validity problems
persist. With respect to the control group, it is crucial
that it is identical to the test group in all respects
apart from the pulp capping material: this requires
randomization. It may be difficult to double-blind the
procedure, but we suggest that in order to minimize
bias, the randomization procedure should not be
undertaken until the pulp exposure is prepared up to
the point of applying the pulp capping material. We
also recommend calcium hydroxide as the pulp
capping material in the control group: when the pulp
capping procedure is adequately carried out, calcium
International Endodontic Journal, 49, 533–542, 2016 539

Formation of a barrier Fransson et al.
hydroxide will predictably give rise to the formation
of hard tissue bridging and no or slight inflammation.
In pulp capping studies, sample sizes tend to be
small: this is understandable as recruitment of sub-
jects is difficult. Therefore, it is essential to use the
subjects effectively. The use of several follow-up peri-
ods makes the size of the subgroups so small that it is
uncertain whether conclusions can be drawn about
the treatment effect. We strongly suggest that in the
study design phase, the use of several follow-up peri-
ods should be critically assessed. The potential advan-
tage of very short follow-up periods must be weighed
against the disadvantage of the resultant reduction in
sample size.
If the aim of a study is to investigate the formation
of hard tissue after pulp capping as an important indi-
cator that the physiological barrier has been reformed
and the vitality of the pulp has been preserved, it is
important that the results clearly present the number
of teeth with complete bridging over the pulp expo-
sure. Outcomes such as ‘attempted bridging’, ‘modest
hard tissue formation’, or ‘irregular hard tissue’ can-
not be interpreted as indicating formation of a func-
tioning barrier. To present such data, the specimens
should be serially sectioned, as defects of the hard tis-
sue may be seen in one part of the tooth, whilst else-
where the bridge appears to be complete. This, as well
as the lack of consistency of terminology, may explain
the reported differences in outcomes when the same
materials have been studied, as exemplified by the
included studies by Min et al. (2008) and Nair et al.
(2009), in which the results differ widely. The
reported outcomes also direct attention to one of the
research questions for this systematic review: ‘Can a
pulp exposure heal, i.e. form a hard tissue barrier
over pulp tissue that is free from signs of inflamma-
tion after pulp capping’, as healing denotes restora-
tion of integrity to injured tissue. Complete bridging
would at its best mean dentine regeneration with a
physiological barrier function, as it has been shown
that odontoblasts play an active role in host defence
(Dommisch et al. 2007, 2008, Goldberg et al. 2008).
It is questionable whether the mere formation of a
hard tissue bridge actually restores the physiological
barrier function, but it has been used as an indicator
for such healing. If the dentine barrier is inadequate,
then pulp tissue which is free from signs of inflamma-
tion after pulp capping may be at risk for later micro-
bial exposure and subsequent development of pulp
inflammation. Therefore, in this and the previous
systematic reviews, the histological outcome measure
540 International Endodontic Journal, 49, 533–542, 2016
13652591, 2016, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/iej.12480, Wiley Online Library on [24/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
after experimental pulp capping or partial pulpotomy
was the formation of a hard tissue barrier combined
with pulp tissue which is free from signs of inflamma-
tion.
Studies to date show that application to the exposed
pulp, not only of calcium hydroxide-based materials
but also of MTA, achieves a very high frequency of
hard tissue barriers. The time has probably come to
study other outcomes, such as the functions of the
barrier, rather than the mere presence of hard tissue
covering the pulp exposure. Moreover, none of the
included studies with moderate level of evidence was
undertaken on teeth with carious exposures: this is
also a highly relevant topic for future studies of barrier
formations after pulp capping procedures.
Conclusions
Based on studies of experimental pulp exposures in
healthy teeth with no caries, there is limited evidence
that the use of calcium hydroxide or MTA as pulp cap-
ping agents frequently gives rise to the formation of
hard tissue barriers. In contrast, adhesives or enamel
matrix derivative do not achieve hard tissue barriers.
To date, there is insufficient scientific evidence that
MTA promotes hard tissue formation more frequently
than calcium hydroxide. To improve our knowledge in
this area, there is need for pulp biologists and end-
odontists to establish uniform terminology and stan-
dard histological assessment techniques in this area.
References
Accorinte Mde L, Loguercio AD, Reis A, Muench A, de Ara-
ujo VC (2005a) Adverse effects of human pulps after direct
pulp capping with the different components from a total-
etch, three-step adhesive system. Dental Materials 21,
599–607.
Accorinte Mde L, Loguercio AD, Reis A, Muench A, de Ara-
ujo VC (2005b) Response of human pulp capped with a
bonding agent after bleeding control with hemostatic
agents. Operative Dentistry 30, 147–55.
Accorinte Mde L, Holland R, Reis A et al. (2008) Evaluation
of mineral trioxide aggregate and calcium hydroxide
cement as pulp-capping agents in human teeth. Journal of
Endodontics 34, 1–6.
Accorinte ML, Loguercio AD, Reis A et al. (2008a) Response
of human dental pulp capped with MTA and calcium
hydroxide powder. Operative Dentistry 33, 488–95.
Accorinte ML, Loguercio AD, Reis A, Costa CA (2008b)
Response of human pulps capped with different self-etch
adhesive systems. Clinical Oral Investigations 12, 119–27.
© 2015 International Endodontic Journal. Published by John Wiley & Sons Ltd

Accorinte ML, Loguercio AD, Reis A et al. (2009) Evaluation
of two mineral trioxide aggregate compounds as pulp-cap-
ping agents in human teeth. International Endodontic Jour-
nal 42, 122–8.
Barthel CR, Rosenkranz B, Leuenberg A, Roulet JF (2000)
Pulp capping of carious exposures: treatment outcome
after 5 and 10 years: a retrospective study. Journal of End-
odontics 26, 525–8.
Bjørndal L, Reit C, Bruun G et al. (2010) Treatment of deep
caries lesions in adults: randomized clinical trials compar-
ing stepwise vs. direct complete excavation, and direct
pulp capping vs. partial pulpotomy. European Journal of
Oral Sciences 118, 290–7.
Botero TM, Shelburne CE, Holland GR, Hanks CT, N€ or JE
(2006) TLR4 mediates LPS-induced VEGF expression in
odontoblasts. Journal of Endodontics 32, 951–5.
Caicedo R, Abbott PV, Alongi DJ, Alarcon MY (2006) Clini-
cal, radiographic and histological analysis of the effects of
mineral trioxide aggregate used in direct pulp capping and
pulpotomies of primary teeth. Australian Dental Journal 51,
297–305.
Chacko V, Kurikose S (2006) Human pulpal response to
mineral trioxide aggregate (MTA): a histologic study. The
Journal of Clinical Pediatric Dentistry 30, 203–9.
Cunningham BP, Harmsen S, Kweon C et al. (2013) Have
levels of evidence improved the quality of orthopaedic
research? Clinical Orthopaedics and Related Research 471,
3679–86.
D’Arcangelo C, Di Nardo-Di Maio F, Patrono C, Caputi S
(2007) NOS evaluations in human dental pulp-capping
with MTA and calcium-hydroxide. International Journal of
Immunopathology and Pharmacology 20, 27–32.
De Lourdes Rodrigues Accorinte M, Reis A, Dourado
Loguercio A, Cavalcanti de Araujo V, Muench A (2006)
Influence of rubber dam isolation on human pulp
responses after capping with calcium hydroxide and
an adhesive system. Quintessence International 37, 205–
12.
Dommisch H, Winter J, Willebrand C, Eberhard J, Jepsen S
(2007) Immune regulatory functions of human beta-
defensin-2 in odontoblast-like cells. International Endodontic
Journal 40, 300–7.
Dommisch H, Steglich M, Eberhard J, Winter J, Jepsen S
(2008) Phosphatidylinositol-3-kinase inhibitor LY 294002
blocks Streptococcus mutans-induced interleukin (IL)-6
and IL-8 gene expression in odontoblast-like cells. Interna-
tional Endodontic Journal 41, 763–7.
Elias PM (2008) Skin barrier function. Current Allergy and
Asthma Reports 8, 299–305.
Elias RV, Demarco FF, Tarquinio SB, Piva E (2007) Pulp
responses to the application of a self-etching adhesive in
human pulps after controlling bleeding with sodium hypo-
chlorite. Quintessence International 38, e67–77.
Ersin NK, Eronat N (2005) The comparison of a dentin
adhesive with calcium hydroxide as a pulp-capping agent
© 2015 International Endodontic Journal. Published by John Wiley & Sons Ltd
13652591, 2016, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/iej.12480, Wiley Online Library on [24/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Fransson et al. Formation of a barrier
on the exposed pulps of human and sheep teeth. Quintes-
sence International 36, 271–80.
Fernandes AM, Silva GA, Lopes N Jr, Napimoga MH, Benatti
BB, Alves JB (2008) Direct capping of human pulps with
a dentin bonding system and calcium hydroxide: an
immunohistochemical analysis. Oral Surgery, Oral Medi-
cine, Oral Pathology, Oral Radiology, and Endodontics 105,
385–90.
Goldberg M, Farges JC, Lacerda-Pinheiro S et al. (2008)
Inflammatory and immunological aspects of dental pulp
repair. Pharmacological Research 58, 137–47.
Guyatt GH, Sackett DL, Cook DJ (1993) Users’ guides to the
medical literature. II. how to use an article about therapy
or prevention. A. Are the results of the study valid? Evi-
dence-Based Medicine Working Group. JAMA: The Journal
of the American Medical Association 270, 2598–601.
Guyatt GH, Sackett DL, Cook DJ (1994) Users’ guides to the
medical literature. II. How to use an article about therapy
or prevention. B. What were the results and will they help
me in caring for my patients? Evidence-Based Medicine
Working Group. JAMA: The Journal of the American Medical
Association 271, 59–63.
Hørsted P, Søndergaard B, Thylstrup A, El Attar K, Fejerskov
O (1985) A retrospective study of direct pulp capping with
calcium hydroxide compounds. Endodontics & Dental Trau-
matology 1, 29–34.
Horsted-Bindslev P, Vilkinis V, Sidlauskas A (2003) Direct cap-
ping of human pulps with a dentin bonding system or with
calcium hydroxide cement. Oral Surgery, Oral Medicine, Oral
Pathology, Oral Radiology, and Endodontics 96, 591–600.
Iwamoto CE, Adachi E, Pameijer CH, Barnes D, Romberg EE,
Jefferies S (2006) Clinical and histological evaluation of
white ProRoot MTA in direct pulp capping. American Jour-
nal of Dentistry 19, 85–90.
Juni P, Altman DG, Egger M (2001) Systematic reviews in
health care: assessing the quality of controlled clinical
trials. British Medical Journal 323, 42–6.
Kiatwateeratana T, Kintarak S, Piwat S, Chankanka O, Kam-
aolmatyakul S, Thearmontree A (2009) Partial pulpotomy
on caries-free teeth using enamel matrix derivative or cal-
cium hydroxide: a randomized controlled trial. International
Endodontic Journal 42, 584–92.
Lu Y, Liu T, Li H, Pi G (2008) Histological evaluation of
direct pulp capping with a self-etching adhesive and cal-
cium hydroxide on human pulp tissue. International End-
odontic Journal 41, 643–50.
Mejare I, Cvek M (1993) Partial pulpotomy in young perma-
nent teeth with deep carious lesions. Endodontics & Dental
Traumatology 9, 238–42.
Min KS, Park HJ, Lee SK et al. (2008) Effect of mineral triox-
ide aggregate on dentin bridge formation and expression
of dentin sialoprotein and heme oxygenase-1 in human
dental pulp. Journal of Endodontics 34, 666–70.
Moher D, Tsertsvadze A, Tricco AC et al. (2008) When and
how to update systematic reviews. The Cochrane Database
International Endodontic Journal, 49, 533–542, 2016 541

Formation of a barrier Fransson et al.
of Systematic Reviews 1, MR000023. doi: 10.1002/
14651858.MR000023.pub3.
Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred
reporting items for systematic reviews and meta-analyses:
the PRISMA statement. British Medical Journal 339,
b2535.
Mousavinasab M, Namazikhah MS, Sarabi N, Jajarm HH, Bi-
dar M, Ghavamnasiri M (2008) Histopathology study on
pulp response to glass ionomers in human teeth. Journal of
the California Dental Association 36, 51–5.
Nair PN, Duncan HF, Pitt Ford TR, Luder HU (2009) Histologi-
cal, ultrastructural and quantitative investigations on the
response of healthy human pulps to experimental capping
with Mineral Trioxide Aggregate: a randomized controlled
trial. 2008. International Endodontic Journal 42, 422–44.
Olsson H, Davies JR, Holst KE, Schroder U, Petersson K
(2005) Dental pulp capping: effect of Emdogain Gel on
experimentally exposed human pulps. International End-
odontic Journal 38, 186–94.
Olsson H, Petersson K, Rohlin M (2006) Formation of a hard
tissue barrier after pulp cappings in humans. A systematic
review. International Endodontic Journal 39, 429–42.
Parolia A, Kundabala M, Rao NN et al. (2010) A compara-
tive histological analysis of human pulp following direct
pulp capping with Propolis, mineral trioxide aggregate and
Dycal. Australian Dental Journal 55, 59–64.
Pereira SA, de Menezes FC, Rocha-Rodrigues DB, Alves JB
(2009) Pulp reactions in human teeth capped with self-
etching or total-etching adhesive systems. Quintessence
International 40, 491–6.
Piva E, Tarquinio SB, Demarco FF, Silva AF, de Araujo VC
(2006) Immunohistochemical expression of fibronectin
and tenascin after direct pulp capping with calcium
hydroxide. Oral Surgery, Oral Medicine, Oral Pathology, Oral
Radiology, and Endodontics 102, e66–71.
Sawicki L, Pameijer CH, Emerich K, Adamowicz-Klepalska B
(2008) Histological evaluation of mineral trioxide aggre-
542 International Endodontic Journal, 49, 533–542, 2016
13652591, 2016, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/iej.12480, Wiley Online Library on [24/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
gate and calcium hydroxide in direct pulp capping of
human immature permanent teeth. American Journal of
Dentistry 21, 262–6.
Shahravan A, Jalali SP, Torabi M, Haghdoost AA, Gorjestani
H (2011) A histological study of pulp reaction to various
water/powder ratios of white mineral trioxide aggregate as
pulp-capping material in human teeth: a double-blinded,
randomized controlled trial. International Endodontic Journal
44, 1029–33.
Silva AF, Tarquinio SB, Demarco FF, Piva E, Rivero ER
(2006a) The influence of haemostatic agents on healing of
healthy human dental pulp tissue capped with calcium
hydroxide. International Endodontic Journal 39, 309–16.
Silva GA, Lanza LD, Lopes-Junior N, Moreira A, Alves JB
(2006b) Direct pulp capping with a dentin bonding system
in human teeth: a clinical and histological evaluation.
Operative Dentistry 31, 297–307.
Silva GA, Gava E, Lanza LD, Estrela C, Alves JB (2013) Sub-
clinical failures of direct pulp capping of human teeth by
using a dentin bonding system. Journal of Endodontics 39,
182–9.
Soden RI, Botero TM, Hanks CT, N€ or JE (2009) Angiogenic
signaling triggered by cariogenic bacteria in pulp cells.
Journal of Dental Research 88, 835–40.
Subay RK, Demirci M (2005) Pulp tissue reactions to a den-
tin bonding agent as a direct capping agent. Journal of
Endodontics 31, 201–4.
Turner JR (2009) Intestinal mucosal barrier function in
health and disease. Nature Reviews Immunology 9, 799–
809.
Yoshiba N, Yoshiba K, Ohkura N et al. (2012) Expressional
alterations of fibrillin-1 during wound healing of human
dental pulp. Journal of Endodontics 38, 177–84.
Zarrabi MH, Javidi M, Jafarian AH, Joushan B (2010) Histo-
logic assessment of human pulp response to capping with
mineral trioxide aggregate and a novel endodontic cement.
Journal of Endodontics 36, 1778–81.
© 2015 International Endodontic Journal. Published by John Wiley & Sons Ltd