REVI EW

Revascularization of immature permanent teeth

with apical periodontitis
M. C. Moreno-Hidalgo, C. Caleza-Jimenez, A. Mendoza-Mendoza & A. Iglesias-Linares
School of Dentistry, University of Seville, Seville, Spain
Abstract
Moreno-Hidalgo MC, Caleza-Jimenez C, Mendoza-
Mendoza A, Iglesias-Linares A. Revascularization of
immature permanent teeth with apical periodontitis.
International Endodontic Journal, 47, 321331, 2014.
The aim of this minireview was to identify and review
the scientic evidence regarding regenerative end-
odontic protocols claiming to revascularize permanent
immature teeth with apical periodontitis. The litera-
ture was identied using the PubMed/MEDLINE, Sco-
pus, Scirus, EMBASE and Cochrane databases up to
February 2013. Studies were selected independently
by two different researchers (kappa index: 0.88), based
on established inclusion/exclusion criteria. The meth-
odological quality of the reviewed papers was classi-
ed as high, medium or low (HQ, MQ, LQ). The
search strategy identied 285 titles. Nine studies, both
human and animal based, were selected after applica-
tion of the criteria (LQ:5; MQ:4). In most of these
studies (seven of nine), the revascularization protocol
included a triple antibiotic combination as canal dis-
infectant for a period of 14 weeks after blood clot
formation (LQ:5; MQ:4), although there is no clear
consensus about the treatment protocol. Two studies
reported tooth discoloration after the revascularization
process (LQ:2), and only three (LQ:1; MQ:2) reported
a success rate of 54.9% in dogs and 73.6% and 80%
in humans, respectively.
Revascularization of immature permanent teeth
with apical periodontitis is possible and preferable to
apexication. Nevertheless, there is a widespread lack
of randomized clinical trials and blinded measures. In
addition, the small sample sizes that are common in
these studies as well as the generally low quality of
the analysed publications require the results to be
viewed with caution. There is a high risk of bias, with
a low quality of available information, for developing
clinical guidelines for regenerative endodontic proto-
cols; rigorous randomized clinical trials are therefore
needed.
Keywords: apexication, immature tooth, tooth
revascularization.
Received 4 February 2013; accepted 29 June 2013
Introduction
The treatment of immature permanent teeth with
pulp necrosis and apical disease remains a challenge
for endodontists (Banchs & Trope 2004, Thibodeau &
Trope 2007). Traditionally, clinicians have resorted to
classical apexication techniques or have used apical
barriers to treat immature teeth with pulp necrosis
(Rafter 2005). Traditional apexication uses calcium
hydroxide dressings for prolonged periods of time to
promote the formation of a calcied barrier over
which lling material can be placed. The procedure is
moderately predictable (successful in 74100% of
cases) (Sheehy & Roberts 1997), but requires many
visits over a period of months and moreover causes
increased vulnerability to cervical tooth fracture
(Andreasen et al. 2002, Doyon et al. 2005). The arti-
cial apical barrier technique uses a barrier material
placed at the apex to facilitate the lling procedure by
containing the lling material within the canal. The
material of choice for this procedure is mineral
Correspondence: Alejandro Iglesias-Linares, School of Den-
tistry. University of Seville, C/Avicena sn, 41009 Seville,
Spain (e-mail: aiglesiaslinares@us.es).
2013 International Endodontic Journal. Published by John Wiley & Sons Ltd International Endodontic Journal, 47, 321331, 2014
doi:10.1111/iej.12154
321
trioxide aggregate (Felippe et al. 2006). The disadvan-
tage of both traditional apexication and the use of
an articial apical barrier is that thickening of the
root wall or continuous development of the root is
not possible (Felippe et al. 2006).
At present, these classical concepts are being
questioned as a result of the introduction of regener-
ative endodontic protocols, also referred to as revas-
cularization processes in infected, immature teeth
with necrotic pulps. These protocols contemplate the
continuation of full root development and thickening
of the root walls in immature permanent teeth with
pulp necrosis (Banchs & Trope 2004, Thibodeau &
Trope 2007). Iwaya et al. (2001) and Banchs &
Trope (2004) have demonstrated the advantages of
this type of treatment, which gives rise to radio-
graphically evident normal maturation of the entire
root, compared with the formation of a calcied bar-
rier only in the apex when conventional apexica-
tion is used.
According to Windley et al. (2005), the successful
revascularization of immature teeth with apical peri-
odontitis is mainly dependent upon:
1. Canal disinfection: This is regarded as a key factor
for successful treatment. The disinfectant material
used varies amongst authors and includes metro-
nidazole, ciprooxacin and minocycline. Success-
ful clinical results have been obtained with this
combination of three antibiotics (Sato et al. 1993,
1996, Hoshino et al. 1996, Banchs & Trope 2004,
Jung et al. 2008). However, some studies have
reported revascularization success on disinfecting
with calcium hydroxide (Chueh & Huang 2006,
Cotti et al. 2008, Chueh et al. 2009, Cehreli et al.
2011) or formocresol (Shah et al. 2008);
2. Scaffold placement in the canal for the growing tis-
sues: Once canal disinfection has been completed,
the apex is mechanically irritated to induce clot
formation, which will serve as a scaffold for tissue
generation (Banchs & Trope 2004, Thibodeau &
Trope 2007, Thibodeau et al. 2007). On the other
hand, some authors have performed revasculari-
zation without inducing clot formation in the
pulp space (Das et al. 1997, Chueh & Huang
2006, Chueh et al. 2009);
3. Bacteria-tight sealing of the access aperture: The
access cavity is restored using a material that seals
it against bacteria. In most studies, the material of
choice is ProRoot mineral trioxide aggregate
(MTA) (Thibodeau et al. 2007, Bose et al. 2009,
da Silva et al. 2010), although some authors have
sealed the aperture with glassionomer resin, in
animal models (Das et al. 1997, Shah et al. 2008)
and in humans (Windley et al. 2005).
The effective therapeutic application of this kind of
protocol, the diagnostic prole of cases of this type
and the success rates obtained using these conserva-
tive clinical procedures are all issues that currently
give cause for discussion (Chueh et al. 2009, da Silva
et al. 2010, Cehreli et al. 2011, Garcia-Godoy & Mur-
ray 2012). The present minireview offers a critical
analysis, evaluating the common diagnostic criteria
used in applying protocols of this kind and assessing
the scientic quality of the studies published to date
in the eld of tooth revascularization.
Review
Search strategy
The basis for this research were the PRISMA guide-
lines (www.prisma-statement.org) (Turpin 2010),
using the MEDLINE database (Entrez PubMed, www.
ncbi.nim.nih.gov) covering the period from January
1995 to February 2013, and the Medical Subject
Headings (MeSH): Apexication or Apexications or
Tooth revascularization or Immature tooth. Follow-
ing the electronic literature search, screening and
selection were made on the basis of the abstracts.
Articles were initially selected on the basis of the title
and abstract, with the complete article being reviewed
whenever there was doubt as to whether it should be
included or not. Examiner conicts in turn were
resolved by discussing each article to reach a consen-
sus. Afterwards, a manual search of the main JCR-
indexed orthodontic journals was undertaken to iden-
tify potential studies not included under the above-
mentioned criteria. In addition, the SCOPUS, EMBASE,
EBSCOhost, Scirus and Cochrane databases were
explored to nd possible papers matching our estab-
lished selection criteria. Two reviewers (C.C. and
M.M.) independently applied the inclusion and exclu-
sion criteria to each article.
Selection criteria
The papers selected for this review met the following
inclusion criteria.
Population
Any experimental animal/human study or clinical
investigation that included at least one experimental
Revascularization Moreno-Hidalgo et al.
2013 International Endodontic Journal. Published by John Wiley & Sons Ltd International Endodontic Journal, 47, 321331, 2014 322
group with a minimum of 10 specimens or samples
per experimental group.
Intervention
Revascularization of nonvital immature permanent
teeth. The term revascularization describes a regen-
erative endodontic procedure, following a previously
described protocol, performed on immature teeth with
nonvital pulps, to obtain clinical healing of periapical
abscesses and continued root formation (Iwaya et al.
2001, Huang & Lin 2008). Briey, it should include
the following: disinfection of the canal, blood clot
formation and bacteria-tight sealing of the access
aperture.
Comparison
A control group without revascularization or that
employed a different method of continuing root for-
mation.
Outcome
Healing of periapical radiolucency and continued root
development and/or formation of the root end in
immature teeth with nonvital pulps or histological
evidence of healing in the periapical area. Case
reports, case series, descriptive studies, review articles,
opinion articles and letters, articles not corresponding
to the objectives of this review and those studies
failing to provide an adequate description of the
technique, administration dose and regimen were
excluded from the selection.
Data collection and quality analysis
Data were collected for the following items: author
and year, study design, sample (size, animal or
human sample, gender and age), results obtained
(clinical, radiographical and histological), success rate
(percentage of immature teeth with nonvital pulps
that showed all the parameters of clinical success
after following the described endodontic regeneration
protocol, namely healing of periapical radiolucency
and continued root and root end formation), conclu-
sions drawn by the authors and citations received.
The methodological quality of the selected papers
was assessed using a modied version (Iglesias-Linares
et al. 2010) of the method described by Antczak et al.
(1986) and Jadad et al. (1996). Independent quality
assessment of the included studies was performed
according to a modied NewcastleOttawa scale by
two investigators. Adapted from Chen et al. (2010),
the variables analysed were as follows: study design,
representativeness of a sample of more than 20 sub-
jects/specimens per group, analysis of method error
(statistical analysis to determine the reliability of
intra- or interobserver measurements or classica-
tions) (Pretty & Maupome 2004), adequacy of statisti-
cal provision (Lucena et al. 2013), a statement of
blinded assessment, previous power calculation and
report of dropouts from the study. Based on this
checkpoint analysis, the risk of bias and the quality of
each paper were scored as low, medium or high, as
detailed in Table 1. Briey, and as previously
Table 1 Quality assessment of the included studies
Study
Representative
sample of
20/group
Method
error
analysis
Adequate
statistics
provided
Blinded
assessment
stated
Previous
power
calculation
Reported
dropouts Total
Risk
of bias Quality
a
Jeeruphan
et al. 2012,
1 1 1 0 0 1 4 Moderate Medium
a
Chen et al. 2012, 1 0 0 0 0 1 2 High Low
a
Bose et al. 2009, 1 0 1 0 0 1 3 Moderate Medium
a
Ding et al. 2009, 0 0 0 0 0 1 1 High Low
a
Shah et al. 2008, 0 0 0 0 0 0 0 High Low
b
Yamauchi
et al. 2011,
1 0 1 1 0 0 3 Moderate Medium
b
Da da Silva
et al. 2010,
0 0 0 1 0 0 1 High Low
b
Wang et al. 2010, 1 0 0 0 0 0 1 High Low
b
Thibodeau
et al. 2007
1 1 1 0 0 1 4 Moderate Medium
a
Study performed with humans.
b
study performed with animals.
Moreno-Hidalgo et al. Revascularization
2013 International Endodontic Journal. Published by John Wiley & Sons Ltd International Endodontic Journal, 47, 321331, 2014 323
described (Chen et al. 2010), one point was given to
each criterion if fullled. Half a point was granted if
part of the criterion was met. Studies with less than
two points were considered to be at high risk of bias;
from two to less than four points, the risk of bias was
considered moderate; and for four points and above,
the risk of bias was considered low.
Results
The electronic search identied 285 titles and
abstracts. An overview of the selection process is pro-
vided in the PRISMA ow diagram (Fig. 1). Nine arti-
cles were included after applying the inclusion and
exclusion criteria, yielding a total of ve studies per-
formed on human subjects (Shah et al. 2008, Bose
et al. 2009, Ding et al. 2009, Chen et al. 2012, Jeeru-
phan et al. 2012) and four using animals (Thibodeau
et al. 2007, da Silva et al. 2010, Wang et al. 2010,
Yamauchi et al. 2011). Good interobserver concor-
dance (kappa index: 0.88) was observed between both
experienced operators.
Study quality
Most of the studies involved small samples sizes, and
in no case were prior sample size calculations made.
Only two studies (Thibodeau et al. 2007, Jeeruphan
et al. 2012) conducted an analysis of method error.
Few studies used adequate statistical methodology
(Thibodeau et al. 2007, Bose et al. 2009, Yamauchi
et al. 2011, Jeeruphan et al. 2012), specied the
excluded cases (Thibodeau et al. 2007, Bose et al.
2009, Ding et al. 2009, Chen et al. 2012, Jeeruphan
et al. 2012) or used masking techniques (da Silva
et al. 2010, Yamauchi et al. 2011). Accordingly, ve
285 articles identified in data
base searching
4 articles studies identified
through manual search
152 articles excluded
Articles in a language other than English (n = 12)
Articles a case report , "cases series",
"reviews" and "letters, comments" (n = 140)
136 of full-text articles
assessed for eligibility
128 full-text
articles excluded
Articles that didnt follow the
objective of this review (n = 122)
Articles that not induce blood clot
to induce revascularization (n = 4)
9 articles included in
this revision
5 human studies included in this revision
4 animals studies included in this revision
Articles with less than 10 teeth in
the sample (n = 1)
Articles that only test the efficacy
of the triantibiotic paste (n = 1)
Figure 1 PRISMA ow diagram of the literature search.
Revascularization Moreno-Hidalgo et al.
2013 International Endodontic Journal. Published by John Wiley & Sons Ltd International Endodontic Journal, 47, 321331, 2014 324
(Shah et al. 2008, Ding et al. 2009, da Silva et al.
2010, Wang et al. 2010, Chen et al. 2012) of the 9
studies were classied as being at high risk of bias
and were thus of low clinical quality (Table 1).
Treatment protocol
Most studies included in the review used a triple anti-
biotic paste, composed of metronidazole, ciprooxacin
and minocycline, for disinfection during the revascu-
larization process, whether in humans (Bose et al.
2009, Ding et al. 2009, Wang et al. 2010, Jeeruphan
et al. 2012) or animals (Thibodeau et al. 2007, da
Silva et al. 2010, Yamauchi et al. 2011) (Tables 2
and 3). In the study by da Silva et al. (2010) using a
rat model, an alternative disinfection protocol involv-
ing apical negative pressure irrigation was followed
and compared with the conventional technique. Other
articles mentioned calcium hydroxide and formocresol
for disinfecting the canal in humans (Shah et al.
2008, Bose et al. 2009, Chen et al. 2012).
The length of time the antiseptic remained in the
canal also varied amongst the studies, lasting from 1
to 4 weeks in two of the ve studies performed with
humans (Table 3) and 2 weeks in experimental
research using an animal model (Table 2). Most of
Table 2 Summary data of eight animal-based studies included in this review
Author, year Study design Size Species Age Sex Type of t Irrigation Disinfectant Duration MTA
Yamauchi et al. 2011, CEs 64 t a(dogs) 6 ms NT pm NaOCl 2.5% TD 2w yes
Da da Silva et al. 2010, CEs 40 t a (dog) 4 ms NT pm NaOCl 2.5% ANPI, TD 2w yes
Wang et al. 2010 CEs 60 t a (dog) 6 ms NT pm NaOCl 1.25% TD NT yes
Thibodeau et al. 2007, CEs 60 t a (dog) 6 ms NT pm NaOCl 1.25% TD NT yes
Author,
year
Adequate
root
length
Adequate
root
thickness
Resolution
of
radiotransparency
Apical
closure
(RX)
Apical
closure
(H)
Success
rate Authors conclusions Citations*
Yamauchi
et al. 2011,
NT Yes
(> with
scaffold)
Yes
(> with
scaffold)
NT Yes
(> with
scaffold)
NT The use of a cross-linked
collagen scaffold
combined with bleeding
induction signicantly
enhanced mineralized
tissue formation in the
canal space.
13
Da da Silva
et al. 2010,
NT NT NT NT Yes
(> with
TD)
NT ANPI may represent an
important technical
option for the treatment
of teeth with apical
periodontitis.
11
Wang
et al. 2010,
NT NT NT NT NT NT R allows ingrowth of
vital tissue consisting
of cement-like tissue,
bone-like tissue and
PDL. These do not
function as pulp tissue
35
Thibodeau
et al. 2007
NT Yes
(48.8%)
Yes
(64.6%)
Yes
(54.9%)
Yes
(54.9%)
54.9% Inclusion of a blood clot
in the canal space
tended to improve
the outcome. R of
previously infected
r is possible, provided
effective disinfection
is achieved.
54
Ds, Descriptive study; CEs, comparative experimental study; CCS, casecontrol study; Is, intervention study; t, teeth; a, animal; y,
years; ms, months; NT, not tested; m, male; f, female; i, incisors; pm, premolars; c, canines; ml, molars; d, days; w, weeks; NaOCl,
sodium hypochlorite; sr, saline rinse, H
2
O
2,
hydrogen peroxide; sdw, sterile distilled water; Ca (OH)
2,
calcium hydroxide; ANPI, api-
cal negative pressure irrigation; TD, triple antibiotic dressing; F, formocresol; T, tetracycline; MTA, mineral trioxide aggre-
gate. r, root; RX, radiography; H, histology; br, bacterial reduction; R, revascularization; ANPI, apical negative pressure irrigation;
TD, triple antibiotic dressing; t, teeth; T, tetracycline; *SCOPUS database [3 February 2013].
Moreno-Hidalgo et al. Revascularization
2013 International Endodontic Journal. Published by John Wiley & Sons Ltd International Endodontic Journal, 47, 321331, 2014 325
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Revascularization Moreno-Hidalgo et al.
2013 International Endodontic Journal. Published by John Wiley & Sons Ltd International Endodontic Journal, 47, 321331, 2014 326
the studies documented carried out irrigation with
NaOCl (Thibodeau et al. 2007, Da da Silva et al.
2010, Wang et al. 2010, Yamauchi et al. 2011) in
the animal research and in all human studies
included from recent years (Shah et al. 2008, Ding
et al. 2009, Yamauchi et al. 2011, Chen et al. 2012,
Jeeruphan et al. 2012), although the concentration
and volume varied (Tables 2 and 3). In the study
published by Shah et al. (2008), such irrigation was
combined with hydrogen peroxide (Table 3).
Clinical, radiographical, histological and
microbiological analyses
The studies in this review reported good clinical
results, with no symptoms in the clinical studies per-
formed on humans or in the experiments using ani-
mals (Tables 2 and 3). Only the clinical studies by
Chen et al. (2012) and Ding et al. (2009) described
colour changes after disinfection (Table 3).
In both the animal and human research models,
those studies that analysed radiographical results
(Thibodeau et al. 2007, Shah et al. 2008, Bose et al.
2009, Ding et al. 2009, Yamauchi et al. 2011, Chen
et al. 2012, Jeeruphan et al. 2012) reported adequate
root length and dentinal wall thickness, with resolu-
tion of the radiolucency and apical sealing in the vast
majority of cases following the revascularization pro-
cedure (Tables 2 and 3).
All 4 studies that used animals examined the histo-
logical results, reporting correct apical sealing (Thibo-
deau et al. 2007, da Silva et al. 2010, Wang et al.
2010, Yamauchi et al. 2011) (Table 2).
None of the studies conducted microbiological eval-
uations after disinfection of those teeth with apical
periodontitis (Tables 2 and 3).
Success rate
Success rates (as dened in the data collection and
quality analysis) for this type of treatment can only
be found in one animal study (Thibodeau et al. 2007)
and two human studies (Shah et al. 2008, Jeeruphan
et al. 2012) with reported rates of 54.9%, 73.6% and
80%, respectively (Tables 2 and 3).
Discussion
Following application of the dened inclusion and
exclusion criteria, only nine studies were nally con-
sidered. Most of the excluded studies involved very
small samples or were case reports. When the meth-
odological designs of the studies were examined, most
studies were found to be of low quality (Shah et al.
2008, Ding et al. 2009, da Silva et al. 2010, Wang
et al. 2010, Chen et al. 2012). This points to the need
for new and better-quality randomized clinical trials
(RCTs) involving larger samples. In addition, a modi-
ed NewcastleOttawa scale was used to assess the
quality of the papers included. Some authors (Stang
2010) have expressed concern that this scale may
provide a quality score of unknown validity or even
including invalid quality items, so giving arbitrary
results. On the other hand, Sanderson et al. (2007),
after identifying and analysing the existing tools in
the literature for quality assessment, concluded in
their 2007 review that it was necessary to agree on
the critical elements for assessing susceptibility to bias
introduced by authors in observational epidemiology
and to develop appropriate evaluation tools. Until
such consensus is reached, the type of scale used in
the present study has been proposed as a valid option
for reducing the interpretation bias of the authors
themselves.
Consistent with the stated conclusions of the lack
of randomized control trials and the need for larger
study samples in this eld of clinical research, one of
the ndings during this review was that there was
substantial heterogeneity in terms of study types,
treatments, evaluation periods, and species (human
and animals), not to mention the many different vari-
ables evaluated, and that no statistical comparison
could be made; at least, it would have been mislead-
ing to present statistical conclusions that were neither
accurate nor well chosen from the readers point of
view. Given such ndings, it was impossible therefore
to conduct a meta-analysis, which reinforces the need
for high-quality randomized clinical trials, which
allow the expert clinical reader to draw worthwhile
clinically useful conclusions in this new topic of
debate in apical treatment.
Some authors (Huang & Lin 2008) have pointed
out that the term revascularization when referring
to the new kind of regenerative endodontic procedure
is found in the American Association of Endodontics
Glossary alongside the terminology for apexication
and apexogenesis (American Association of Endodon-
tists 2003). These authors emphasize that the use of
this term implies that: (i) the type of case reported is
not concerned with traumatic injuries, but conven-
tional root canal infections, (ii) when pulp sensitivity
testing to check the vitality of the pulp after a
Moreno-Hidalgo et al. Revascularization
2013 International Endodontic Journal. Published by John Wiley & Sons Ltd International Endodontic Journal, 47, 321331, 2014 327
successful revascularization procedure is positive,
what is basically established is the reinnervation of
that tooth, not true revascularization, (iii) re-estab-
lishing the blood supply in the pulp space after a
revascularization procedure is a natural physiological
process of healing and repair. There is no creation of
an articial blood supply, and blood vessels are not
grafted into the root canal. In the main, a cellular
microenvironment is generated, including one for
endothelial cells from the vital tissue in the periapical
region, which enables them to migrate through the
created blood clot into the pulp space, and (iv) what
occurs following successful revascularization is basi-
cally a process of healing and repair. In this scenario,
periodontal ligament, cementum, bone, dentine or
pulp tissues may also be generated, rather than just
vasculature in the canal space. To support their argu-
ments, the authors suggested other pathological terms
to describe such ndings, such as healing or repair of
necrotic pulps. The term induced or guided tissue
generation and regeneration was used to describe the
technical aspect of the clinical treatment protocols.
Irrespective of the term used to refer to regenerative
endodontic protocols, an immature tooth with nonvi-
tal pulp and infected root canal presents with thin
divergent or parallel dentinal walls. This creates clini-
cal problems related to disinfection and consequently
affects the long-term treatment outcome (Wang et al.
2010). Calcium hydroxide has traditionally been used
as intracanal medication in apexication procedures
(Rafter 2005). However, because of its high pH, cal-
cium hydroxide causes necrosis of the tissues which
theoretically can differentiate into new pulp tissue. On
the other hand, apexication procedures leave a short
root with thin dentinal walls and a high risk of root
fracture (Andreasen et al. 2002). The contemporary
research articles seek alternatives to apexication for
the formation of natural roots, even in the presence
of extensive periapical disease. Revascularization has
emerged as a favourable alternative, being able to
yield a longer and thicker root, with a lesser vulnera-
bility to fracture (Shin et al. 2009). Despite the low
quality of almost all the reviewed articles, good clini-
cal and radiographical results were reported, and the
conclusions drawn by most of the authors underscore
the advantages of this treatment over apexication.
On the other hand, regarding the effectiveness of
the triple antibiotic paste as established from the
polymicrobial composition of the root canal infection,
different authors have proposed the use of a combina-
tion of ciprooxacin, metronidazole and minocycline
for treating the diverse microora, based fundamen-
tally on the results of in vitro studies and clinical
cases (Hoshino et al. 1996, Sato et al. 1996, Windley
et al. 2005, Thibodeau et al. 2007, Akgun et al.
2009, Bose et al. 2009, Ding et al. 2009, Reynolds
et al. 2009, da Silva et al. 2010, Wang et al. 2010,
Scarparo et al. 2011, Yamauchi et al. 2011).
The efcacy of the triple antibiotic paste in disin-
fecting the root canal was rst evaluated and con-
rmed by Sato et al. (1996), who found this drug
combination to be effective in eliminating bacteria
from the deep dentinal layers of the canal. Hoshino
et al. (1996) in turn conducted a laboratory study of
the antibacterial efcacy of these drugs and found
that although none of them were individually able to
fully eliminate the bacteria, their combined use affor-
ded effective sterilization of all the infected dentinal
and pulp samples.
Despite the bactericidal efcacy of this combination,
its use may have clinical and biological side effects,
such as the development of bacterial resistance and
allergic reactions, as found in the animal studies
(Cohenca et al. 2010), or crown discoloration (Rey-
nolds et al. 2009) in humans. Such discoloration has
been associated with the use of minocycline (Kim
et al. 2010). However, in this review, only the studies
of Chen et al. (2012) and Ding et al. (2009) both
involving humans reported changes in crown
colour.
The bactericidal efcacy of the combination of cip-
rooxacin, metronidazole and minocycline when used
as disinfectant method was conrmed by most of the
studies (Thibodeau et al. 2007, Bose et al. 2009, da
Silva et al. 2010, Wang et al. 2010, Yamauchi et al.
2011, Jeeruphan et al. 2012). Nevertheless, full con-
sensus has not been reached regarding the material
of choice for disinfection in revascularization pro-
cesses, whilst good results have also been described
with other materials, in humans (Shah et al. 2008,
Chen et al. 2012) and animals (da Silva et al. 2010).
Regarding the need for blood clot formation, a
number of authors consider that it affords a scaffold
and a source of growth factors facilitating regenera-
tion and repair of the tissues within the canal (Ban-
chs & Trope 2004, Thibodeau & Trope 2007). This
concept was rst proposed by Ostby (1961), who con-
sidered bleeding and blood clot formation in the
canals of mature teeth to be essential for guiding
canal tissue repair. All the studies in this review were
included, as they induced blood clot formation to per-
form the regenerative protocol, in the presence of
Revascularization Moreno-Hidalgo et al.
2013 International Endodontic Journal. Published by John Wiley & Sons Ltd International Endodontic Journal, 47, 321331, 2014 328
growth and differentiation factors. However, some
studies excluded from this review one concerning
humans (Chueh et al. 2009) and two (Das et al.
1997, Cohenca et al. 2010) referring to dogs and
monkeys, respectively did not induce blood clot for-
mation as a scaffold to allow a similar regenerative
process to develop. The study conducted on dogs by
Yamauchi et al. (2011) reported improved results in
terms of root wall thickness, periradicular healing
and the formation of mineralized tissue by adding a
reticulate collagen and ethylenediaminetetraacetic
acid (EDTA) matrix to the blood clot. Recently, Tora-
binejad & Turman (2011) presented a clinical case of
successful tooth revascularization in which plasma
rich in platelets (PRP) was injected into the root canal
space after disinfection with the triple antibiotic paste.
PRP has been mentioned as a potential scaffold in
regenerative endodontic treatment (Hargreaves et al.
2008, Ding et al. 2009).
Regarding apical sealing, most of the recent studies
that were appraised in this review used animals
(Thibodeau et al. 2007, da Silva et al. 2010, Wang
et al. 2010, Yamauchi et al. 2011) or humans (Bose
et al. 2009, Ding et al. 2009) and placed MTA in con-
tact with the blood clot, so affording sealing against
bacteria. MTA has been shown to prevent coronal
bacterial ltration, is biocompatible with the adjacent
pulp tissue, induces the proliferation of pulp cells,
raises the pH during prolonged periods of time and
allows exceptional marginal adaptation (Parirokh &
Torabinejad 2010). However, a number of authors
have used other materials for access sealing, such as
glassionomer (Das et al. 1997, Windley et al. 2005,
Shah et al. 2008) or silver amalgam (Cohenca et al.
2010, Scarparo et al. 2011), and recently, Nosrat
et al. (2011) have evaluated a new endodontic bio-
material, calcium-enriched mixture (CEM) cement,
placed over the blood clot instead of MTA. However,
the effectiveness of these should be addressed in the
future by means of the randomized clinical trials to
raise the level of clinical scientic evidence of this
procedure.
Finally, the reader should bear in mind that the
inclusion of both animal and human clinical studies
in a review is not advisable and should be interpreted
with caution as host responses to intervention are
very different between animals and humans. How-
ever, this minireview has tried to present the limited
knowledge available from experiments with animals
and the clinical setting as a summary of current
knowledge about the new endoregenerative protocols.
Conclusions
1. Many studies have shown the local application of
a triple antibiotic paste (metronidazole, ciprooxa-
cin and minocycline) to be effective for disinfect-
ing immature teeth with apical periodontitis, in
both animal (Wang et al. 2010, Yamauchi et al.
2011) and human (Bose et al. 2009, Ding et al.
2009, Chen et al. 2012, Jeeruphan et al. 2012)
studies.
2. There is no rm consensus concerning any clear
treatment protocol for completing the revasculari-
zation process (Thibodeau et al. 2007, Shah et al.
2008, Bose et al. 2009, Ding et al. 2009, da Silva
et al. 2010, Wang et al. 2010, Yamauchi et al.
2011, Chen et al. 2012, Jeeruphan et al. 2012).
3. The studies evaluated in the present review were
found to have high risk of bias and low methodo-
logical quality. Well-designed randomized clinical
trials are needed to generate sound scientic evi-
dence for this treatment procedure.
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