Regenerative Endodontics
Regenerative Endodontics: Burning Questions
Anthony J. Smith, PhD, and Paul R. Cooper, PhD
Abstract
Pulp regeneration and its clinical translation into regen-
erative endodontic procedures are receiving increasing
research attention, leading to significant growth of the
published scientific and clinical literature within these
areas. Development of research strategies, which
consider patient-, clinician-, and scientist-based out-
comes, will allow greater focus on key research ques-
tions driving more rapid clinical translation. Three key
areas of focus for these research questions should
include cells, signaling, and infection/inflammation.
A translational pathway is envisaged in which clinical
approaches are increasingly refined to provide regener-
ative endodontic protocols that are based on a robust
understanding of the physiological processes and events
responsible for the normal secretion, structure, and bio-
logical behavior of pulpal tissue. (J Endod 2017;-:1–6)
Key Words
Cell signaling, clinical translation, dentin, inflammation,
pulp, regeneration, regenerative endodontics, stem cells
From the School of Dentistry, University of Birmingham, Birmingham, United Kingdom.
Address requests for reprints to Dr Anthony J. Smith, School of Dentistry, University of Birmingham, 5 Mill Pool, Edgbaston, Birmingham B5 7EG, United Kingdom.
E-mail address: a.j.smith@bham.ac.uk
0099-2399/$ - see front matter
Copyright ª 2017 American Association of Endodontists.
http://dx.doi.org/10.1016/j.joen.2017.06.002
JOE — Volume -, Number -, - 2017
D entistry has long been
a pioneer of regenera-
tive medicine by using
Significance
This article explores key priorities and strategic
areas of focus for clinical translation of regenera-
many biologically inspired
tive endodontics. It provides a translational
therapeutic approaches (1).
pathway robustly underpinned by sound scientific
Although the term regen-
principles with a strong focus on development of
erative endodontics has
effective clinical protocols.
become specifically asso-
ciated with revasculariza-
tion procedures originally proposed more than 50 years ago (2), the wealth of
research activity in the area of dental pulp regeneration emphasizes the range of oppor-
tunities to clinically translate the many exciting advances in pulp biology for a wide va-
riety of new therapies. Rapid progress toward such clinical translation demands focus
and prioritization of key questions within the research agenda, and this article seeks to
elucidate a number of these.
A Web of Science search for the period 1973–2016 by using the term ‘‘dental pulp
regeneration’’ identifies 1064 publications, only approximately 4% of which were pub-
lished before 2000 (Fig. 1). Clearly, absolute numbers will vary with the specific words
used in the search term (eg, repair versus regeneration, etc), and some publications
will be missed through inappropriate choice of key words by authors, but nevertheless,
there has been a considerable increase in apparent activity in this area during the last
decade. This significant proliferation of the newer published literature can obscure
some of the existing literature in the field, and many key publications are often not
readily visible or being cited. Basing future research questions and agenda on robust
appraisal and interpretation of the existing published literature will help to avoid ‘‘re-
inventing the wheel,’’ refine our research focus, and more rapidly advance the field.
Nevertheless, that focus may be deflected by the desired outcomes for regenerative end-
odontics, and consideration of the context of these outcomes (Fig. 2) may be valuable
(3). Initial prioritization of those patient-centered outcomes at the base of the pyramid
that is followed by the clinician-related outcomes and rising to the scientist-centered
outcomes at the peak of the pyramid offers a valuable approach to identification of
an effective path leading to clinical translation. This in no way detracts from the need
to still understand and address scientist- and clinician-centered factors to provide
optimal therapeutic solutions for patient-centered outcomes, but it helps to focus atten-
tion on the extent to which each factor needs to be fully resolved at each step along the
clinical translation pathway.
For clarity of presentation, this article will consider 3 key areas of focus: cells,
signaling of regenerative events, and infection/inflammation.
Cells
Must Newly Regenerated Cells Behave like Odontoblasts?
The concept of tissue regeneration implies generation and secretion of new tissue
by cellular activity. Although the formative cells of soft connective tissues like pulp share
the fibroblast phenotype, dentin is secreted by the highly specialized odontoblasts,
Burning Questions 1
Regenerative Endodontics

Figure 1. Chart of numbers of publications in each year derived from search of the Web of Science by using the search term ‘‘pulp regeneration’’.

which are responsible for the tubular and mineralized structure of this
tissue. The mineralized nature of dentin is important for its structural
role as a component of the tooth, but the necessity for its tubular
morphology in a regenerated tissue could be questioned. In an end-
odontic therapeutic situation, any mineralized tissue seal (tubular or
atubular) for the pulp may suffice, and an atubular dentin matrix offers
reduced permeability and possibly a more effective seal to protect the
pulp. However, it has become apparent that the roles of true odonto-
blasts are not simply matrigenic (secretory) alone, and a number of
other complex functions for these cells are starting to be characterized
including local communication, environmental sensing, and innate im-
munity and mediation of pain transmission (4, 5). These diverse but
linked functions, and others that may yet be identified, highlight the
specialized nature of the odontoblast, and a long-term goal should be
to develop regenerative endodontic approaches that fully exploit the
functional and behavioral ranges of these cells. In the shorter term,
however, regenerative procedures that are based on cells secreting
any type (tubular or atubular) of mineralized matrix may suffice and
illustrate how consideration of patient-centered versus clinician-
centered versus scientist-centered outcomes (Fig. 2) can be helpful.
How Can We Effectively Deliver Stem/Progenitor Cells
for Regenerative Endodontics?
There is considerable merit in learning from advances in other
areas of regenerative medicine where various cell transplantation ther-
apies have been introduced. Isolation of pulp stem cells to good
manufacturing practices standards for medical uses (6) represents
an important step toward development of tissue engineering–based
regenerative endodontic therapies, but without specialist hospital

Figure 2. Schematic representation of hierarchy of patient-, clinician-, and scientist-centered outcome visions. Reproduced from Diogenes AR, Smith AJ.
Regenerative endodontics. In: Rotstein I, Ingle JI, eds. Ingles Endodontics. 7th ed. Shelton, CT: People’s Medical Publishing House–USA; 2016.

2 Smith and Cooper JOE — Volume -, Number -, - 2017

 Regenerative Endodontics
clinically based surgical facilities, current routine use of such cells in the engineering a conducive environment in which tissue regeneration oc-
dental office setting will be problematic. The need for new therapies to curs. Adoption of combinatorial engineering strategies for creating a
be applicable to the routine dental office setting is especially true as the conducive environment for regeneration would be exciting and might
global burden of oral disease among all age groups continues to be sig- target the niche for promotion of paracrine effects by MSCs, the scaffold
nificant (7). In the short term at least, new treatment modalities will for cellular regenerative events to occur on as well as providing a cock-
achieve maximum impact if widely available and not limited by global tail of bioactive signaling molecules to direct regenerative events.
health inequalities. Treatment modalities that are based on advanced
technology using stem cell implantation and only available to a relative How Do We Robustly Identify Differentiated Cells as
few might be more of a longer-term focus until resources improve. Odontoblast-like Cells?
However, mesenchymal stem cell (MSC) delivery could be available
Although there is a need to stimulate differentiation and organiza-
widely without special equipment and facilities simply by the use of clin-
tion of a variety of cell types in pulp, including fibroblasts, endothelial
ical evoked bleeding by instrumentation (8, 9). Such a procedure
cells, and dendritic cells among others during regeneration, the need to
allows use of autologous cells, thereby avoiding any issues associated
stimulate odontoblast-like cell differentiation is especially challenging
with immune rejection, and provides a clinically viable short-term so-
in view of the unique nature of these cells. Thus, a fundamental question
lution for regenerative endodontics.
when designing strategies for pulp regeneration and tissue engineering,
as well as for assessment of the success of such strategies, is how we
Are There Better Stem/Progenitor Cell Populations Than robustly identify cells as odontoblast-like cells. Primary odontoblasts
Others for Regenerative Endodontics or Does It Matter? are post-mitotic cells, many of which will survive for the life of a tooth.
These characteristics highlight the unique nature of the odontoblast,
A number of different mesenchymal-derived stem cell populations
which outlives most other cell types in the body unless exposed to inju-
have now been described in the dental and oral tissues (10). During
rious challenge. Despite this unique character, robust identification of
embryonic tooth development, the concept of competency for progen-
odontoblasts continues to remain a challenge because neither the cell’s
itor cells able to differentiate into odontoblasts has arisen (11), which
transcriptome nor its proteome appears sufficiently unique to allow
may reflect a combination of cell cycling and environmental cues and
discrimination from a number of other cell types (4, 20). During the
signals. In developing novel regenerative therapies, it is important to
last 4–5 decades, various novel transcripts and proteins have been
consider whether any one stem/progenitor cell population provides a
reported to be uniquely associated with odontoblasts only for
better candidate or whether the different populations simply reflect
subsequent studies to identify these markers in other, often
the various niches they have been isolated from. If environmental
mineralized cell types. The post-mitotic nature of primary odontoblasts
cues within a cell’s niche can direct its phenotypic characteristics,
means that these cells do not turn over and divide like many other cell
then exciting opportunities exist for mimicry of those cues as a part
types, and any replacement odontoblasts (odontoblast-like cells) differ-
of niche engineering (12). Interestingly, growing pulp cells on surfaces
entiate under pathologic conditions. Although many parallels can be
coated with isolated preparations of pulp matrix components leads to
identified between physiological and pathologic odontoblast differenti-
increased expression of transcripts characteristic of a stem cell rather
ation, tissue dysplasia often results during the latter because of the
than dentinogenic phenotype (13). Thus, niche engineering may be a
absence of the close temporospatial control of events seen during em-
feasible approach within the pulp and could provide a second level
bryonic tooth development (21). Where such tissue dysplasia is seen,
strategy for promoting regeneration after clinical evoked bleeding pro-
inevitably there will be issues with identification of the formative cells
cedures, which provide less control over cells targeted.
as odontoblast-like cells. Currently, a combination of transcriptomal
Much emphasis in the published literature has been placed on the
and proteomic profiles together with cellular and matrix morphologies
use of pulp-derived stem cells for pulp regeneration. In contrast, there
provide us with our best criteria for identification of odontoblast-like
is increasing interest in the use of easily isolated adipose-derived stem
cells (4, 20, 22). However, the rigor of these criteria remains in
cells, induced pluripotent stem cells, and other stem cell sources for a
question, and having more robust criteria would be valuable. One of
variety of applications in regenerative medicine. There is now consider-
the problems is that the odontoblast phenotype varies with activity of
able evidence that non-odontogenic–derived MSCs may be capable of
the cell and its age (23). These phenotypic variations have been
giving rise to odontoblast-like cells (14–18). Although these
elegantly demonstrated at the morphologic level (23) as well as at
observations are perhaps not surprising in view of our understanding
the transcriptomal and proteomic levels (20). When nestin was first re-
of the role of reciprocal epithelial-mesenchymal interactions in direct-
ported in odontoblasts, it was hoped that it would provide a valuable
ing tooth development (11), they help to guide strategies for develop-
marker for odontoblast identification until its expression was shown
ment of regenerative procedures and define the variety of cell types that
to vary with the stage of maturation of these cells (24). A number of tran-
might be used.
scripts have now been shown to differ significantly in their expression
The ability to act as an odontoblast-like cell progenitor may not be
between young and old odontoblasts (20), highlighting the phenotypic
the only consideration when targeting cell sources for pulp regenera-
variations in this cell type and the issues posed for their identification.
tion. Pulp-derived stem cell populations show many immunomodula-
tory properties, which are likely to be important during wound
healing and tissue regeneration. The paracrine action of MSCs, via Signaling of Regenerative Events
secretion of cytokines and other signaling molecules (ie, their secre- The biological events taking place during pulp regeneration
tome/exosome), may be as important, if not more important, in require signaling of a number of cellular processes including stem/pro-
reducing local inflammation and immune responses and enhancing tis- genitor cell recruitment, expansion of these cell populations, and their
sue function as direct differentiation into new matrigenic cells. Recently, subsequent differentiation to odontoblast-like cells (22, 25). These
this has been emphasized by the ability of stem cells from human exfo- cellular signaling processes, which are initially extracellular in nature
liated deciduous teeth cell exosomes to restrain inflammation (19). but in turn initiate intracellular events, have been the subject of
Tissue engineering encompasses a wide variety of approaches, and intensive research in recent decades, allowing the parallels with
niche engineering is one aspect of a broader approach to creating or physiological odontoblast differentiation to be identified (21).

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Regenerative Endodontics
Many of the molecules responsible for signaling these processes have
been assessed by using a variety of in vitro and in vivo dentin-pulp
regeneration experimental models with application of individual either
isolated tissue-derived or recombinant molecules (4, 22). However,
early studies on the autoinductive effects of displaced dentin chips on
reparative dentinogenesis (26) have inspired much research on the
bioactive properties of dentin and pulp matrix components and their
possible exploitation for novel regenerative endodontic therapies. We
now recognize that there is a rich cocktail of bioactive molecules in
dentin and pulp matrices capable of directing all of the signaling events
involved in dentin-pulp regeneration (4, 25). It is likely that synergistic
interactions between individual molecules within this rich cocktail may
be important to the overall orchestration of signaling events during
regeneration rather than them being the result of just one or a very
few molecules. Such interplay between molecules can inform
regenerative strategies emphasizing the advantages of exploiting
endogenous bioactive molecules within dentin pulp rather than
application of relatively simplistic mixtures of recombinant or
synthetic growth factors and cytokines.
Rapid progress toward achieving at least patient-related and
clinician-related successful outcomes for regenerative endodontics
could potentially result from exploitation of these tissue-associated
bioactive molecules, especially if their local release can be realized
by using existing tissue irrigation and conditioning procedures
(27–32). Dissolution of the non-collagenous matrices of dentin and
bone by using demineralizing agents, including mineral acids and
EDTA, has been recognized for more than 5 decades and has provided
the basis for isolation and characterization of the proteins in these
matrices (33, 34). Identification of a range of growth factors in
dentin (4) has enabled examination of the ability of various chemicals
used in cavity preparation, irrigation, and conditioning to release some
of these growth factors from dentin. Transforming growth factor beta 1
(TGF-b1) has often been used as a surrogate marker for bioactive mole-
cule release, and both EDTA (27, 28) and a number of acids used in
operative dentistry (29) were shown to release TGF-b1 from powdered
human dentin. These studies provided important proof-of-principle that
EDTA and various mineral and organic acids release soluble TGF-b1
from dentin. Subsequent studies have shown that EDTA treatment of
dentin surfaces can also expose immobilized TGF-b1 molecules, which
can be imaged at the ultrastructural level by using immunoprobing tech-
niques (29, 30). Phosphoric and other acids used in restorative
dentistry can also release and expose these growth factors (29, 31).
Furthermore, an ex vivo model has provided histologic evidence of
stimulation of tertiary dentinogenesis after EDTA treatment after cavity
preparation (32). The release and exposure of TGF-b1 and other bioac-
tive molecules in dentin will likely contribute to signaling many of the
cellular processes involved in dentin-pulp regeneration (Fig. 3).
Although the various studies to date have demonstrated the potential
for exploitation of these bioactive molecules (25), we now need to
examine their release and exposure under conditions simulating those
typically used in clinical endodontic procedures. Key questions relating
to signaling events and exploitation of bioactive molecules in dentin
pulp include the following.
What Is the Optimal Clinical Protocol for Exploiting
Bioactive Molecules in Dentin While Achieving
Disinfection?
This question will need to address the issues of the chemical na-
ture of irrigant or releasing agent, concentration, and times of treat-
ment, all within the context of achieving realistic disinfection and the
potentially conflicting actions of disinfectants like hypochlorite in
4 Smith and Cooper
achieving effective microbial control while minimizing oxidative and
degradative/cytotoxic effects on bioactive molecules, thereby reducing
their biological integrity or potency.
How Do We Balance Release of Soluble versus Exposure
of Immobilized Bioactive Signaling Molecules or Does
Solubility Matter?
The relative importance of solubility in terms of the signaling ac-
tivities of bioactive components from dentin pulp is still unclear. The
signaling of terminal differentiation of odontoblasts during physiolog-
ical tooth development is dependent on the presentation of growth fac-
tors, in particular from the TGF-b superfamily, immobilized on the
dental basement membrane to the peripheral cells of the dental papilla
(11), and the exposure of immobilized growth factors on the dentin
surface by irrigants and other agents during endodontic procedures
may well parallel these physiological events. Recruitment of stem/pro-
genitor cells to injury sites by chemotactic actions of bioactive dentin-
pulp components may be enhanced if a gradient of soluble components
can be established; however, there may not be an absolute requirement
for release of soluble chemotactic molecules because time-lapse video
imaging demonstrates dentin chips can attract pulp-derived cells, and
the migratory cells were characterized by expression of a range of
typical MSC transcript markers (35).
How Can We Protect Bioactivity Once Molecules Are
Released from Protection by the Mineral and Other
Tissue Components and What is the Half-life of These
Molecules?
An important characteristic of the bioactive molecules in dentin is
that their bioactivity is protected until they are released from the dentin
matrix and mineral. Once released, however, these bioactive molecules
are exposed to the general extracellular environment, which may be
relatively harsh and impact on their integrity and biological half-life.
For example, it has been reported that plasma TGF-b1 has a half-life
of the order of only a few minutes (36). We have few data on the bio-
logical life span of bioactive molecules once released from dentin pulp,
although this may be of less importance if the immobilization of bioac-
tive molecules is critical to their actions in regeneration (see preceding
question). Nevertheless, it might be expected that the extracellular envi-
ronment (eg, matrix metalloproteinases of tissue and bacterial origin,
bacterial acids) after dental injury and the subsequent inflammatory re-
sponses will impact on the potencies and lifetimes of any bioactive mol-
ecules within that environment.
Infection and Inflammation
Pulp regeneration must be considered and modeled in the context
of the infection and inflammation seen clinically. Although there have
been many exciting reports contributing to our understanding of the
biological events associated with pulp regeneration, the absence of
infection and inflammation within many of the experimental models
now requires that these models be developed to include these elements.
Clinically, a primary barrier for successful regenerative endodontics is
case selection, and progress with this is hampered by the need for better
clinical prognostic markers of infection and inflammation, especially in
determining what tips the balance between reversible and irreversible
pulpitis (10). There is considerable scope for further research in the
area of infection and inflammation, which could contribute significantly
to regenerative endodontic outcomes at all levels (37). Open questions
include the following.
JOE — Volume -, Number -, - 2017
 Regenerative Endodontics

Figure 3. Schematic representation of actions of irrigants and medicaments in releasing soluble bioactive molecules from their sequestration within dentin and
also exposing bioactive molecules immobilized on surface of dentin (1). Released and/or immobilized bioactive molecules can then participate in signaling of many
of the events associated with pulp regeneration including stem/progenitor cell recruitment, differentiation of mineralizing odontoblast-like cells, angiogenesis, and
neurogenesis (1). Both free and exposed bioactive molecules interact with recruited stem/progenitor cells leading to odontoblast-like cell differentiation (2).
Reproduced from Smith AJ, Duncan HF, Diogenes A, et al. Exploiting the bioactive properties of the dentin-pulp complex in regenerative endodontics. J Endod
2016;42:47–56.

Is Reduction in Microbial Load (for Example, Partial
Pulpotomy), Rather Than Complete Eradication of
Bacteria, Sufficient to Overcome Many of the Infection
Issues Associated with Clinical Endodontic Treatment?
The beneficial effects of a more superficial partial pulpotomy have
been reported (38), and adoption of such an approach as part of a clin-
ical regenerative endodontic protocol has shown encouraging results
(39). Further clinical studies using this approach would now be valu-
able because it would be readily translatable within most clinical envi-
ronments and could make significant progress toward achievement of
good patient-based and clinician-based outcomes.
Low Levels of Inflammation/Infection May Contribute to
Regenerative Events: How Can We ''Tip'' the Balance?
Understanding the basis of inflammation-regeneration interplay
offers opportunities to improve regenerative endodontic outcomes at
all levels (37). Several articles within this issue of the journal address
this point.
Clinical management of common inflammatory diseases such as
rheumatoid arthritis suggests that the significant promise offered by
cytokine inhibitors for disease control might be constrained a little by
the loss of efficacy of these drugs with treatment time in some cases
(40). The canonical and non-canonical pathways of nuclear factor
kappa B activation and the actions of therapeutic inhibitors (41) high-
light the complexity of inflammatory responses and the need to better
understand the variety of inflammatory signaling events that need to
be controlled.
The importance of understanding how inflammation takes place in
the pulp and its influencing factors emphasizes the way in which under-
standing the disease process at the biological level can impact strongly
on patient-based and clinician-based regenerative outcomes.
Tight transcriptional control (eg, long non-coding RNAs restrain
responses) of genes can restrain inflammation at the chromatin level
(42). Would this be a possible target for epigenetic-based therapies
(43)? Recent evidence has indicated a significant role for MSC secre-
tomes/exosomes in modulating inflammation (19), and this may also
offer an interesting target in the development of novel therapies.
Conclusion
Many exciting areas of endodontic research are emerging and
contributing to an increasing momentum of activity in this discipline.
Careful attention to the key research questions will help to rapidly

JOE — Volume -, Number -, - 2017 Burning Questions 5

Regenerative Endodontics
advance clinical translation in this area supported by the relative prior-
itization of patient-, clinician-, and scientist-based outcomes.
Acknowledgments
The authors deny any conflicts of interest related to this study.
References
1. Dammaschke T. The history of direct pulp capping. J Hist Dent 2008;56:9–23.
2. Ostby BN. The role of the blood clot in endodontic therapy. An experimental histo-
logic study. Acta Odontol Scand 1961;19:324–53.
3. Diogenes AR, Smith AJ. Regenerative endodontics. In: Rotstein I, Ingle JI, eds. Ingles
Endodontics, 7th ed. Shelton, CT: People’s Medical Publishing House–USA; 2016.
4. Smith AJ, Scheven BA, Takahashi Y, et al. Dentine as a bioactive extracellular matrix.
Arch Oral Biol 2012;57:109–21.
5. Goldberg M. Pulp anatomy and characterization of pulp cells. In: Goldberg M, ed.
The Dental Pulp: Biology, Pathology & Regenerative Therapies. New York, NY:
Springer Publishing; 2014.
6. Nakashima M, Iohara K. Mobilized dental pulp stem cells for pulp regeneration:
initiation of clinical trial. J Endod 2014;40(Suppl):S26–32.
7. FDI. The Challenge of Oral Diseases: A Call for Global Action. Available at: http://www.
fdiworldental.org/media/77552/complete_oh_atlas.pdf. Accessed June 21, 2016.
8. Trope M. Regenerative potential of dental pulp. J Endod 2008;34:S13–7.
9. Chrepa V, Henry MA, Daniel BJ, Diogenes A. Delivery of apical mesenchymal stem
cells into root canals of mature teeth. J Dent Res 2015;94:1653–9.
10. Hargreaves KM, Diogenes A, Teixeira FB. Treatment options: biological basis of
regenerative endodontic procedures. J Endod 2013;39(Suppl):S30–43.
11. Ruch JV, Lesot H, Begue-Kirn C. Odontoblast differentiation. Int J Dev Biol 1995;39:
51–68.
12. Pumberger M, Qazi TH, Ehrentraut MC, et al. Synthetic niche to modulate regener-
ative potential of MSCs and enhance skeletal muscle regeneration. Biomaterials
2016;99:95–108.
13. Smith JG, Smith AJ, Shelton RM, Cooper PR. Dental pulp cell behavior in biomimetic
environments. J Dent Res 2015;94:1552–9.
14. Ohazama A, Modino SA, Miletich I, Sharpe PT. Stem cell-based tissue engineering of
murine teeth. J Dent Res 2004;83:518–22.
15. Modino SA, Sharpe PT. Tissue engineering of teeth using adult stem cells. Arch Oral
Biol 2005;50:255–8.
16. Wu G, Deng ZH, Fan XJ, et al. Odontogenic potential of mesenchymal cells from hair
follicle dermal papilla. Stem Cells Dev 2009;18:583–9.
17. Lei G, Yu Y, Jiang Y, et al. Differentiation of BMMSCs into odontoblast-like cells
induced by natural dentine matrix. Arch Oral Biol 2013;58:862–70.
18. Yu Y, Wang L, Yu J, et al. Dentin matrix proteins (DMPs) enhance differentiation of
BMMSCs via ERK and P38 MAPK pathways. Cell Tissue Res 2014;356:171–82.
19. Pivorait_e U, Jarmalaviciut_e A, Tunaitis V, et al. Exosomes from human dental pulp
stem cells suppress carrageenan-induced acute inflammation in mice. Inflammation
2015;38:1933–41.
20. Simon S, Smith AJ, Lumley PJ, et al. Molecular characterization of young and mature
odontoblasts. Bone 2009;45:693–703.
21. Smith AJ, Lesot H. Induction and regulation of crown dentinogenesis: embryonic
events as a template for dental tissue repair? Crit Rev Oral Biol Med 2001;12:425–37.
6 Smith and Cooper
22. Smith AJ. Formation and repair of dentin in the adult. In: Hargreaves KM, Goodis HE,
Tay FR, eds. Seltzer & Bender’s Dental Pulp, 2nd ed. Hanover Park, IL: Quintes-
sence; 2012.
23. Couve E, Osorio R, Schmachtenberg O. The amazing odontoblast: activity, auto-
phagy, and aging. J Dent Res 2013;92:765–72.
24. About I, Laurent-Maquin D, Lendahl U, Mitsiadis TA. Nestin expression in embryonic
and adult human teeth under normal and pathological conditions. Am J Pathol
2000;157:287–95.
25. Smith AJ, Duncan HF, Diogenes A, et al. Exploiting the bioactive properties of the
dentin-pulp complex in regenerative endodontics. J Endod 2016;42:47–56.
26. Anneroth G, Bang G. The effect of allogeneic demineralized dentin as a pulp capping
agent in Java monkeys. Odontol Revy 1972;23:315–28.
27. Cassidy N, Fahey M, Prime SS, Smith AJ. Comparative analysis of transforming growth
factor-beta isoforms 1-3 in human and rabbit dentine matrices. Arch Oral Biol
1997;42:219–23.
28. Smith AJ, Smith G. Solubilisation of TGF-B1 by dentine conditioning agents. J Dent
Res 1998;77(Suppl):1034.
29. Zhao S, Sloan AJ, Murray PE, et al. Ultrastructural localisation of TGF-b exposure in
dentine by chemical treatment. Histochem J 2000;32:489–94.
30. Galler KM, Buchalla W, Hiller KA, et al. Influence of root canal disinfectants on
growth factor release from dentin. J Endod 2015;41:363–8.
31. Ferracane JL, Cooper PR, Smith AJ. Dentin matrix component solubilization by so-
lutions of pH relevant to self-etching adhesives. J Adhes Dent 2013;15:407–12.
32. Murray PE, Smith AJ, Garcia-Godoy F, Lumley PJ. Comparison of operative proced-
ure variables on pulpal viability in an ex vivo model. Int Endod J 2008;41:389–400.
33. Herring GM, Kent PW. Some studies on mucosubstances of bovine cortical bone.
Biochem J 1963;89:405–14.
34. Leaver AG, Triffit JT, Holbrook IB. Newer knowledge of non-collagenous proteins in
dentin and cortical bone matrix. Clin Orthop Relat Res 1975;110:269–92.
35. Smith JG, Smith AJ, Shelton RM, Cooper PR. Recruitment of dental pulp cells by
dentine and pulp extracellular matrix components. Exp Cell Res 2012;318:
2397–406.
36. Wakefield LM, Winokur TS, Hollands RS, et al. Recombinant latent transforming
growth factor beta 1 has a longer plasma half-life in rats than active transforming
growth factor beta 1, and a different tissue distribution. J Clin Invest 1990;86:
1976–84.
37. Cooper PR, Holder MJ, Smith AJ. Inflammation and regeneration in the dentin-pulp
complex: a double-edged sword? J Endod 2014;40(Suppl):S46–51.
38. Mejare I, Cvek M. Partial pulpotomy in young permanent teeth with deep carious
lesions. Endod Dent Traumatol 1993;9:238–42.
39. Simon S, Perard M, Charpentier E, Lumley PJ. Should pulp chamber pulpotomy be
seen as a permanent treatment? preliminary findings of a pilot study. Int Endod J
2013;46:79–87.
40. Neovius M, Arkema EV, Olsson H. ARTIS Study Group. Drug survival on TNF inhib-
itors in patients with rheumatoid arthritis: comparison of adalimumab, etanercept
and infliximab. Ann Rheum Dis 2015;74:354–60.
41. Brown KD, Claudio E, Siebenlist U. The roles of the classical and alternative nuclear
factor-kappaB pathways: potential implications for autoimmunity and rheumatoid
arthritis. Arthritis Res Ther 2008;10:212.
42. Atianand MK, Hu W, Satpathy AT, et al. A long noncoding RNA lincRNA-EPS acts as a
transcriptomal brake to restrain inflammation. Cell 2016;165:1672–85.
43. Duncan HF, Smith AJ, Fleming GJ, Cooper PR. Epigenetic modulation of dental pulp
stem cells: implications for regenerative endodontics. Int Endod J 2016;49:431–46.
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