doi:10.1111/iej.

13064

EDITORIAL

Dissecting dentine–pulp injury and wound

healing responses: consequences for regenerative
endodontics
H. F. Duncan1, P. R. Cooper2 & A. J. Smith2
1
Division of Restorative Dentistry & Periodontology, Dublin Dental University Hospital, Trinity College Dublin, Dublin, Ireland;
and 2Institute of Clinical Sciences, School of Dentistry Birmingham, UK

Summary dentine produced in response to milder injury is gen-

erated from surviving primary odontoblasts, repara-
tive dentine, in response to more intense injury,
A thorough understanding of the biology of the den-
requires the differentiation of new odontoblast-like
tine–pulp complex is essential to underpin new treat-
cells derived from progenitor/stem cells recruited to
ment approaches and maximize clinical impact for
the injury site. These two diverse processes result in
regenerative endodontics and minimally invasive vital
very different outcomes in terms of the tertiary den-
pulp treatment (VPT) strategies. Following traumatic
tine produced and reflect the intensity rather than
and carious injury to dentine–pulp, a complex inter-
specific nature (nonexposure versus exposure) of the
play between infection, inflammation and the host
injury. The subsequent identification of the odonto-
defence responses will occur, which is critical to tissue
blast-like cell phenotype remains challenging due to
outcomes. Diagnostic procedures aim to inform treat-
lack of unique molecular or morphological markers.
ment planning; however, these remain clinically
Furthermore, the cells ultimately lining the newly
subjective and have considerable limitations. As a
deposited dentine provide only a snapshot of events.
consequence, significant effort has focussed on identi-
The specific source and plasticity of the progenitor
fication of diagnostic biomarkers, although these are
cells giving rise to the odontoblast-like cell phenotype
also problematic due to difficulties in identifying
are also of significant debate. It is likely that improved
appropriate diagnostic fluid sources and selecting
characterization of tertiary dentine may better clarify
reproducible biomarkers. This is further compounded
the influence of cell derivation for odontoblast-like
by the link between inflammation and repair as many
cells and their diversity. The field of regenerative
of the molecules involved exhibit significant multi-
endodontics offers exciting new treatment opportuni-
functionality. The tertiary dentine formed in response
ties, and to maximize outcomes, we propose that the
to dental injury has been purposefully termed reac-
term regenerative endodontics should embrace the
tionary and reparative dentine to enable focus on
repair, replacement and regeneration of dentine–pulp.
associated biological processes. Whilst reactionary

treatment (VPT) strategies is a topical and exciting

Introduction
The concept of regenerative endodontics and the
development of minimally invasive vital pulp
Correspondence: Hal F. Duncan, Division of Restorative Den-
tistry and Periodontology, Dublin Dental University Hospital,
Trinity College Dublin, Lincoln Place, Dublin, Ireland (e-mail:
Hal.Duncan@dental.tcd.ie).
clinical focus for the dental profession. In these proce-
dures, the biology of the pulp and surrounding tissues
is exploited to optimize the healing response following
injurious events. Such translational strategies require
careful consideration, and understanding and descrip-
tion of the biological processes taking place if they are
to achieve maximal clinical impact. In this editorial,
some of the key biological processes upon which
attention should be directed are highlighted in

© 2019 International Endodontic Journal. Published by John Wiley & Sons Ltd International Endodontic Journal, 52, 261–266, 2019 261
 Editorial
addition to a clarification of the scientific background
to the reparative events in the dentine–pulp complex.
Injury
The effects of injury to the dentine–pulp reflect the
complex and exquisite architecture of this organ,
as well as the dynamics of the pathogenic events
taking place during the injurious challenge. In
the context of the oral environment, where both
traumatic and carious injuries will be accompa-
nied by infectious and inflammatory events, it is
important to consider the interplay between direct
tissue injury, infection, inflammation and the host
defence responses, where the balance between any
of these processes will be critical to final out-
comes.
The concepts of reversible and irreversible pulpitis
have long been recognized in clinical endodontics
where they represent valuable diagnostic labels
adopted for treatment planning purposes with the
aim of informing anticipated treatment outcomes.
Their use is based on clinical experience and a sub-
jective assessment of tissue conditions rather than
upon definitive diagnostic criteria, and whilst they
remain useful diagnostic terms, with the recent focus
on pulpotomy techniques in teeth exhibiting the
signs and symptoms associated with irreversible pul-
pitis, their applicability has been questioned (Wolters
et al. 2017). The limitations of current diagnostic
methods are well recognized (Dummer et al. 1980,
Swedish Council on Health Technology Assessment
2010, Mej are et al. 2012) and provide significant
opportunity for identification and assessment of
novel biomarkers of disease with the potential to
robustly support treatment outcomes, as well as to
guide the most appropriate treatment strategies. The
complexity of the challenge being faced in identifying
these novel diagnostic markers, however, should not
be underestimated. Many of the potential molecular
markers that might reflect the nature and extent of
cell death and matrix degradation, such as matrix-
metalloproteinases [MMP] 9 or 13, can be regarded
as pulp inflammatory markers (Zehnder et al. 2011,
Rhim et al. 2013); however, they may also be asso-
ciated with reparative events (Duncan et al. 2016a,
Yuan et al. 2017). In addition, clinical obstacles
such as determining the appropriate fluid to analyse,
establishing an accurate inflammatory threshold and
the efficiency of delivering the result at chairside,
still need to be overcome.
262 International Endodontic Journal, 52, 261–266, 2019
Notably, the breakdown and release of components
of the dentine matrix (Smith et al. 2016) can also
contribute to reparative events (Okamoto et al. 2018).
In addition, it is apparent that early inflammatory
defence responses that resolve can lead to a promo-
tion of regenerative events, whilst more concerted,
prolonged and intense inflammation can lead to a
shift in the balance of events away from regeneration
(Cooper et al. 2014, 2017). The terms ‘good’ and
‘bad’ inflammation are frequently used colloquially;
however, for them to be useful clinically it is essential
that the meaning of these terms is defined clearly.
Indeed, it is likely that they refer to resolving and
nonresolving inflammation, respectively, and whilst
clinical intervention may enable the former, it
remains unclear as to whether nonresolving or ‘bad’
inflammation is purely bacterially driven or whether
there are any other underlying pathological factors. It
is thus very clear that each individual clinical case
must be carefully assessed not only on its presenta-
tion but also on the course and dynamics of the
development of the presenting lesion(s). Therapeuti-
cally, even partial elimination of the injurious chal-
lenge can have a marked effect on clinical outcomes
– with recent data highlighting that partial (Taha &
Khazali 2017) and full pulpotomies (Simon et al.
2013), which reduce the microbial challenge at the
lesion front, can be successful management strategies
for the inflamed pulp. Such bespoke management
strategies are based on careful consideration and
assessment of the biological and pathological events
responsible for inflammatory and reparative processes.
Indeed, the pulpal response to injury is related to
specific environmental factors, such as the presence of
infection (Al-Hiyasat et al. 2006), as well as to
genetic and epigenetic influences (Duncan et al.
2016b).
Research that has helped to underpin the concept
of regenerative endodontics, and other broader biolog-
ical approaches to VPT, has sought to understand the
molecular and cellular events taking place during
traumatic and carious injury to the tooth together
with the associated biological responses. Importantly,
some of these studies have investigated how the bio-
logical repair-associated events mimic those taking
place during tissue development (Smith & Lesot
2001) since this can affect how closely newly regen-
erated tissues resemble their physiological counter-
parts. Tertiary dentine is a tissue formed in response
to dental injury, which helps both to provide a physi-
cal barrier to the injurious challenge stimulating its
© 2019 International Endodontic Journal. Published by John Wiley & Sons Ltd

formation and to contribute to restoration of tissue
integrity through repair and regeneration. A variety
of subtypes of tertiary dentine have been described in
the literature, including irritation, reactive, replace-
ment, adventitious or defence dentine, which do not
readily provide clues to understanding the biological
processes responsible for their formation. The terms
reactionary and reparative dentinogenesis were pro-
posed to focus attention on their associated biological
processes (Lesot et al. 1993, Smith et al. 1995).
Reactionary dentine was defined as being formed
following milder injury where the primary odonto-
blasts survive, whilst reparative dentine was a
response to more intense injury with local death of
the primary odontoblasts at the injury site and differ-
entiation of a new generation of odontoblast-like cells
from progenitor/stem cells recruited to that site.
Whilst reactionary dentine is often associated with
nonexposed pulpal injury and reparative dentine with
pulpal exposure, it is important to recognize that the
simple absence or presence of pulpal exposure is
insufficient to categorize these two tertiary dentino-
genic processes. Local odontoblast death can occur in
the absence of pulpal exposure due to traumatic and
carious injury. Some of the principal factors in deter-
mining odontoblast death are the intensity and rate
of the injurious challenge, the remaining dentine
thickness, which provides a physical barrier and any
protection to cellular and molecular damage from
clinical interventions. It is therefore important for
robust definition of the nature of the tertiary dentino-
genic response to assess cellular damage in each indi-
vidual case rather than the recent trend in biological
studies, which simply assumes that a particular inju-
rious challenge, for example preparation of a nonex-
posed cavity in a tooth, will be sufficiently indicative
of cell damage or death. In experimental studies, such
assessment of injury might be determined by direct
histological and morphological assessment of cellular
structure on a time-course basis following injury and
through morphological assessment of dentine matrix
tubular structure. Both primary dentine and sec-
ondary dentine secreted by the primary odontoblast
population show complete tubular continuity, whilst
tertiary dentine can show a spectrum of regularity of
tubular structure from completely regular (like pri-
mary and secondary dentine) to atubular morphology
depending on whether the primary odontoblasts or
replacement odontoblast-like cells are responsible for
its structure. If the primary odontoblasts are responsi-
ble, then a completely regular tubular structure
© 2019 International Endodontic Journal. Published by John Wiley & Sons Ltd
Editorial
should be present with no areas of tubular dysplasia
or any lack of tubular continuity between primary,
secondary and tertiary dentine for identification of a
reactionary dentinogenic response.
Focus on whether a response is reactionary or repar-
ative in nature is important and not simply a question
of semantics. During reparative dentinogenesis, the cel-
lular responses are much more challenging in that
stem/progenitor cells have to be recruited to the site of
injury, their numbers expanded and then appropriate
molecular signalling directed to induction of differentia-
tion of a new generation of odontoblasts-like cells
before any new dentine matrix formation can take
place. Histological assessment of dentinogenic responses
is not feasible in a clinical situation, and it remains
unclear as to how well animal models replicate the
human cellular processes involved in dentine–pulp
complex repair. However, considerable data have been
compiled on the tertiary dentinogenic responses seen in
human teeth beneath deep carious lesions (Bjørndal
et al. 1998) and these studies can provide an invalu-
able guide by which to direct treatment planning
clinically.
Wound healing
The importance of distinguishing between reactionary
and reparative dentinogenesis has been highlighted
in the preceding section, especially for interpretation
of the injury to the tissues and the complexity of the
resulting biological responses. These responses reflect
the extent of injury to the dentine–pulp complex and,
in a clinical situation, are frequently seen alongside
one another with reparative often superimposed on
reactionary dentine especially in cases of exposure.
This simply reflects the chronology of lesion develop-
ment in the tooth with an initial milder injury stimu-
lating reactionary dentinogenesis, and if defence
reactions are insufficient to arrest lesion formation,
then increasing injurious challenge will generally
lead to reparative dentinogenesis. Wound healing in
dentine–pulp is a pathological event though, and
consequently, each individual case must be consid-
ered independently in the context of its presenting
history.
Following tooth injury, the odontoblasts are likely
the first cells to die due to their location at the periph-
ery of the pulp; however, cell death can subsequently
be more extensive. Consideration of the identity and
phenotype of replacement cells in the pulp during
wound healing, initially may seem academic, but in
International Endodontic Journal, 52, 261–266, 2019 263
 Editorial
reality, is fundamental to clinical treatment strategies
to:
• ensure the successful recruitment/introduction of
the appropriate stem/progenitor cells at the injury
site;
• analyse the specificity of the dentinogenic wound
healing responses and as a result determine how
closely the new tissues resemble physiological den-
tine–pulp structure and function.
In reparative dentinogenesis, death of primary odon-
toblasts is followed by differentiation of a new genera-
tion of odontoblast-like cells, which are considered to
function in a similar manner to physiological primary
odontoblasts. A lack of unique molecular or morpho-
logical markers for physiological odontoblasts, and
the changing nature of these cells through their life
cycle (Couve 1986), severely constrains absolute iden-
tification of an odontoblast-like cell. Expression of den-
tin-sialophosphoprotein (DSPP), nestin or several
other markers, whilst a part of the odontoblast’s
molecular profile, are certainly not definitive markers
of this cell’s phenotype. Morphological evidence of the
secretion of an at least partially tubular dentine-like
matrix by these cells contributes to odontoblast-like
cell identification; however, morphological evidence
alone must be interpreted with great care. The forma-
tive cells observed lining the pulp interface with den-
tine represent those cells functioning at that location
at the time of the morphological assessment. The den-
tine matrix morphology at more peripheral parts of
the dentine away from these cells may or may not be
a direct consequence of the secretory activity of those
cells and could be the result of a different population
of cells, which were subsequently replaced by those
cells at the pulpal interface. This makes it challenging
to robustly identify cellular events from the past, and
thus, considerable caution in data interpretation is
required. Whilst less conclusive reports do not provide
such exciting headlines, it is critical that we do not
misdirect future progress in the field through over
interpretation of data. In reality, there has been no
substantive characterization of the odontoblast-like
cell phenotype reported in the literature and it may
well represent a broader phenotype than generally
acknowledged. This would perhaps not be surprising
since the emergence of these cells reflects pathological
events, and no clear blueprint exists for their differen-
tiation. Despite the variability in this cell phenotype,
odontoblast-like cell continues to be a useful descrip-
tive term for those cells replacing primary
264 International Endodontic Journal, 52, 261–266, 2019
odontoblasts during tertiary dentinogenesis, which
secrete a matrix showing strong similarities to pri-
mary dentine morphologically and in terms of its
molecular structure. Further studies on the composi-
tion of tertiary dentine, however, are warranted to
clarify the influence of cell derivation for odontoblast-
like cells (Volponi et al. 2015).
A consensus is still lacking on the precise derivation
of odontoblast-like cells, although several mesenchymal
cell (MSC) populations have been implicated (Harg-
reaves et al. 2013, Dimitrova-Nakov et al. 2014).
There have been recent reports that fibroblasts may
give rise to odontoblast-like cells and that fibrocytes
may be involved in repair, although the evidence for
this is limited (Ricucci et al. 2014, Yoshiba et al.
2018). Perhaps, the lack of a precise odontoblast-like
cell characterization is masking the fact that this phe-
notype may be more ‘fluid’ than generally acknowl-
edged. If the odontoblast-like cell phenotype is broader,
this may be a reflection of different derivations of the
stem/progenitor cells. Although the concept of a
broader odontoblast-like cell phenotype adds greater
complexity to interpretation of research studies in this
area, it does help to explain the lack of consensus on
the derivation of these cells. Recognition of a broader
odontoblast-like cell phenotype imposes greater respon-
sibilities on researchers to provide clear details of tran-
scriptional and morphological data to allow robust
scrutiny by others and also, not to over-interpret such
data. Secretion of an atubular, osteodentine- or fibro-
dentine-like matrix can sometimes be seen following
injury to dentine–pulp and is suggestive of a less speci-
fic dentinogenic response. The derivation/origin and
identification of the cells responsible for secretion of
such matrices are unclear, but multiple derivations/
identities are likely and may not be the same as during
reparative dentinogenesis.
The important role of inflammation in determining
the fate of endodontic lesions is well recognized; how-
ever, the concept of pulpal inflammation being only
destructive is shifting as it is now recognized that low
levels of resolving inflammation can actually stimulate
and enable regenerative events (Farges et al. 2015).
This is particularly relevant when considering the
chronology and intensity of dentine–pulp injury. Dur-
ing injury, pro-inflammatory cytokines are released
from dentine with dissolution of the matrix and a vari-
ety of inflammatory/immune cell signalling events
occur (Smith et al. 2016). Both these and other events
can significantly influence the environment in which
repair and regeneration take place as well as impacting
© 2019 International Endodontic Journal. Published by John Wiley & Sons Ltd

on how closely reparative responses recapitulate pri-
mary dentinogenesis. Most experimental studies of
repair and regeneration in dentine–pulp have adopted
models, essentially reflecting health, and the influences
of infection, inflammation and disease are generally
lacking (Fransson et al. 2016). Consideration and mod-
elling of the interplay of infection and inflammation
with injury and reparative events (Renard et al. 2016)
offer significant opportunities for identification of novel
diagnostic tools to underpin treatment planning and
importantly to determine how disease modifies pulpal
healing responses. Development of novel reparative
and regenerative endodontic therapies must take
account of how inflammatory disease modifies these
responses to achieve optimal outcomes.
Regenerative endodontics
No consensus exists in the field as to what reflects true
‘pulp regeneration’; however, progress with clinical
translation of regenerative endodontics is at risk if there
is too much emphasis on semantics. There is merit in
considering regenerative endodontic outcomes in a
hierarchical manner with respect to the goals of
patients, clinicians and scientists (Diogenes et al. 2016).
This would help to identify a translational pathway
where regeneration of a true physiological pulp-like tis-
sue is the ultimate goal, but in the interim, the stimula-
tion of wound healing responses that satisfy some of
the clinical issues in dentine–pulp post-injury would
provide acceptable solutions. The concept of VPT is
long-established and encourages natural wound healing
responses in the pulp. Other ‘regenerative’ approaches,
including revitalization and cell homing treatments,
also promote pulp wound healing. Encompassing all of
these and other approaches under the banner of the
regenerative endodontics translational pathway can
only be of benefit and reinforces the approach taken in
the wider field of regenerative medicine. Regenerative
medicine has sought to be a broadly inclusive disci-
pline as evidenced by statements from major bodies
such as National Institutes of Health (NIH) in the Uni-
ted States (https://report.nih.gov/nihfactsheets/ViewFac
tSheet.aspx?csid=62 – accessed 29/11/18) and the
Medical Research Council (MRC) in the UK (https://
mrc.ukri.org/research/initiatives/regenerative-medicine/
– accessed 29/11/18). Both of these bodies demon-
strate considerable concurrence in their definitions of
regenerative medicine – NIH: Regenerative medicine is
the process of creating living, functional tissues to
repair or replace tissue or organ function lost due to
© 2019 International Endodontic Journal. Published by John Wiley & Sons Ltd
Editorial
age, disease, damage or congenital defects. MRC:
Regenerative medicine is an interdisciplinary field that
seeks to develop the science and tools that can help
repair or replace damaged or diseased human cells or
tissues to restore normal function, and holds the pro-
mise of revolutionizing treatment in the 21st century.
We propose that the term regenerative endodontics
should embrace the repair, replacement and regenera-
tion of dentine–pulp lost due to age disease, trauma or
congenital defects to restore normal function.
Conclusions
Exciting future opportunities exist for development of
novel biologically based wound healing strategies aimed
at pulp regeneration processes. The points raised above
highlight some of the issues within this field, which
may be potential barriers to effective progress. A focus
on these areas to encourage clarity in data presentation
and interpretation will benefit future progress. Improved
use of terminology and better understanding of the
reparative and regenerative response in the dentine–
pulp complex is required in order to provide robust ther-
apeutic targets for next-generation restorative materials
and diagnostic approaches.
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