Review Article
Regenerative Endodontic Treatment or Mineral
Trioxide Aggregate Apical Plug in Teeth with
Necrotic Pulps and Open Apices: A Systematic
Review and Meta-analysis
Mahmoud Torabinejad, DMD, MSD, PhD,* Ali Nosrat, DDS, MS, MDS,†
Prashant Verma, DDS, MS, FAGD,† and Oyoyo Udochukwu, MPH‡
Abstract
Introduction: A mineral trioxide aggregate (MTA) api-
cal plug (MAP) and regenerative endodontic treatment
(RET) have shown acceptable clinical outcomes. Howev-
er, comparative studies are scarce. The aims of this
study were to examine the level of evidence for both
treatments, conduct a systematic review of the literature
on MAP and RET, and run a meta-analysis on the sur-
vival and success rates of teeth treated with these pro-
cedures. Methods: Electronic searches were performed
in MEDLINE, Web of Science, and the Cochrane Library.
Two authors independently screened the titles and ab-
stracts for eligibility. Subgroup analyses were performed
on the clinical outcomes (ie, survival and success) of the
procedures. Results: In all, 750 studies were identified,
and 144 studies were subjected to qualitative synthesis.
Ten randomized clinical trials were included in subgroup
analyses. Most of the studies in both groups were case
reports and case series (72% and 86% in MAP and RET,
respectively). The overall level of evidence in both
groups was low. The pooled survival rates were
97.1% (95% confidence interval [CI], 93.7–100) and
97.8% (95% CI, 94.8–100) for MAP and RET, respec-
tively. The pooled success rates were 94.6% (95% CI,
90.2–99.1) and 91.3% (95% CI, 84.5–98.2) for MAP
and RET, respectively. Very little heterogeneity was
observed among the studies regarding survival and suc-
cess rates (I2 < 50%, P > .10). There was no significant
difference between the 2 groups regarding survival
(P = 1.00) or success rates (P = .58). Conclusions:
The existing literature lacks high-quality studies with a
direct comparison of outcomes of MAP and RET. Ran-
domized multicenter clinical trials with large sample
sizes and long-term follow-ups are needed to address
this gap in knowledge. (J Endod 2017;-:1–15)
From the *Advanced Specialty Education Program in Endodontics, and ‡Department of Dental Education, School of Dentistry, Loma Linda University, Loma Linda,
California; and †Department of Endodontics, Periodontics, and Prosthodontics, School of Dentistry, University of Maryland, Baltimore, Maryland.
Address requests for reprints to Dr Ali Nosrat, Department of Endodontics, Periodontics and Prosthodontics, School of Dentistry, University of Maryland Baltimore,
650 West Baltimore Street, 4th Floor, Baltimore, MD 21201. E-mail address: Nosrat@umaryland.edu
0099-2399/$ - see front matter
Copyright ª 2017 American Association of Endodontists.
http://dx.doi.org/10.1016/j.joen.2017.06.029
JOE — Volume -, Number -, - 2017
Key Words
Immature tooth, meta-analysis, mineral trioxide aggregate apical plug, necrotic pulp,
open apex, outcome, regenerative endodontic treatment, success, survival, systematic
review
T he preservation of nat-
ural dentition has long
been the main objective
Significance
The treatment of immature teeth with pulp necrosis
using an MTA apical plug or regenerative endodon-
in root canal treatment
tic treatment results in high survival and success
(1). Achieving this objec-
rates. The existing literature lacks high-level clinical
tive is more challenging
studies comparing these 2 treatment modalities.
in young patients present-
ing with immature
necrotic teeth. Routine root canal treatment protocols to clean and obturate these teeth
cannot be adequately performed because of immature roots. The current treatment op-
tions are apexification using long-term calcium hydroxide dressing, placing a mineral
trioxide aggregate (MTA) apical plug (MAP), or regenerative endodontic treatment
(RET) (2).
Several studies have shown that the long-term use of calcium hydroxide in imma-
ture teeth weakens the root structure (3, 4). In the MAP technique, placement of an
MTA apical barrier facilitates achieving an apical seal, but it does not promote root
development to prevent root fracture.
The intent of RET is to regenerate the pulp-dentin complex, which would promote
root thickening and normal maturation of the root apex (2). There are 2 challenges yet
to be resolved: a clinically applicable tissue engineering protocol for predictable regen-
eration of the pulp-dentin complex (5, 6) and an efficient disinfection protocol that
eliminates infection completely and renders the microenvironment of the root canal
space conducive to repopulation by stem cells (7–9). As a result, the histologic
outcome of the treatment, type, and amount of newly formed tissue are
unpredictable (10–17).
Clinical decisions about the best treatment option for the patient should be made
based on specific scientific evidence after assessing its validity (18). A systematic review
of the existing literature can provide an objective synopsis of the best available evidence
to help dentists and their patients make these decisions. Systematic reviews are
RET or MTA Apical Plug in Necrotic Teeth 1
Review Article
inherently less biased, more reliable, and more valid than narrative re-
views (19, 20). Comparative studies on the outcomes of different
treatment strategies for teeth with pulp necrosis and open apices are
very limited. Also, a search of the literature shows the absence of
systematic reviews comparing the clinical outcomes of MAP with RET.
The aims of this study were as follows:
1. Examine the level of evidence for MAP and RET
2. Conduct a systematic review of the literature on MAP and RET
3. Run a meta-analysis on the survival and success rates of teeth with
pulp necrosis and open apices treated either with MAP or RET
Materials and Methods
A systematic review protocol was developed following established
guidelines (20). The methodology included formulating review ques-
tions using a patient population, intervention, comparison, and
outcome framework; constructing a search strategy; defining inclu-
sion/exclusion criteria; locating studies; assessing study quality; and ex-
tracting, interpreting, and analyzing data.
Formulating the Review Question
The patient population, intervention, comparison, and outcome
framework was used to formulate the following questions:
1. In teeth with pulp necrosis and open apices, does RET compared
with MAP result in better survival?
2. In teeth with pulp necrosis and open apices, does RET compared
with MAP result in better success?
Inclusion Criteria
In this study, any organized attempt to revitalize a necrotic imma-
ture tooth to induce root development was considered as RET. If the
clinician filled the apical part or the entire root canal space with MTA
without the intention of revitalizing the tooth, the treatment was consid-
ered as MAP. Comparative, noncomparative, prospective, and retro-
spective clinical studies on immature teeth with pulp necrosis treated
with RET (all different methods of disinfection, all types of scaffolds/
growth factors/stem cells, and all types of sealing material) or MAP
(all different methods of disinfection and obturation) published in En-
glish from June 1966 through November 2016 were included.
The exclusion criteria were as follows:
1. Studies that did not meet the previously mentioned inclusion criteria
2. Studies in which calcium silicate–based materials other than MTA
were used for root canal filling in MAP group
3. Studies in which the outcome of interest (ie, survival and/or success
rates) was not presented
Search Methodology
Electronic searches were performed in the MEDLINE database (via
PubMed search engine), Web of Science, and the Cochrane Library to
identify studies meeting the inclusion criteria. The search strategy was as
follows (Appendix 1):
1. Teeth with immature roots and open apices
2. Pulp necrosis
3. MAP
4. RET
5. 1 and 2
6. 3 or 4
7. 5 and 6
2 Torabinejad et al.
In addition, the following alternative key words were used to opti-
mize the search strategy: ‘‘immature teeth/open apex,’’ ‘‘MTA apical
plug/MTA apexification,’’ and ‘‘regenerative endodontic treatment/tooth
revascularization/tooth revitalization.’’
Study Selection
Two authors screened the titles and abstracts of all articles iden-
tified in the electronic search. Articles that did not meet the inclusion
criteria were excluded upon reviewers’ agreement. In case of disagree-
ment between reviewers, a consensus was reached by a third reviewer
who reviewed it independently and helped make the final decision about
inclusion or exclusion. All remaining articles were subjected to a full-
text review. A log of the excluded studies and the reasons for exclusion
was prepared (Table 1). Agreement among reviewers for study inclu-
sion was assessed with the Cohen kappa statistic. A threshold for sub-
stantial agreement was indicated at a level of 0.70.
Study Quality Rating
A 32-question data abstraction form for RET articles and a 28-
question data abstraction form for MAP articles were developed. These
abstraction forms had the same questions except for 4 procedure-
related questions in the RET group about ‘‘type of scaffold,’’ ‘‘source
of stem cells,’’ ‘‘application of growth factors,’’ and ‘‘type of barrier
over scaffold.’’ From the abstracted information, an overall study quality
rating score was developed. Based on criteria used in a systematic re-
view by Torabinejad et al (1), each article was given a quality score with
a maximum possible score of 17 points (61).
The quality of clinical trials was assessed using the Cochrane Col-
laboration’s tool for assessing risk of bias (62). This tool assesses qual-
ity in 6 classifications with respect to risk of bias in sequence generation,
allocation concealment, blinding, incomplete outcome data, selective
outcome reporting, and other potential threats to validity (63).
The quality of observational studies (prospective and retrospective
cohorts) was assessed using a modified version of the Quality Assess-
ment Tool for Observational Cohort and Cross-Sectional Studies pub-
lished by the National Institutes of Health (64, 65). In all, 11 criteria
were assessed for each study: research question, study population,
uniform eligibility criteria, sample size justification, timing of
exposure assessment, sufficient time frame to see an effect, exposure
measures, outcome measures, blinding of outcome assessors, follow-
up rate >80%, and statistical analyses.
Clinical Outcomes
The average follow-up time in each study was calculated and ex-
tracted. Survival was defined as a retained tooth in the oral cavity at
follow-up. Success was defined as a lack of clinical symptoms (ie,
pain on percussion/palpation/function or sinus tract) and complete
radiographic healing of the periapical lesion. Reduction in the size of
the periapical lesion was classified as ‘‘uncertain.’’ The rate of root
development was extracted from RET studies. Root development was
defined as increased root length, increased root thickness, or reduced
apical diameter.
If the study sample was a pool of different clinical scenarios, at-
tempts were made to extract the data and calculate the outcomes
only for teeth with pulp necrosis and open apices. If this was not
possible, the study was excluded from the analysis.
Data Analysis
A subgroup of level 1 studies (ie, clinical trials) was defined for
each group (Table 2). The survival and success rates after MAP or
RET were chosen as the appropriate summary statistics that allow
JOE — Volume -, Number -, - 2017

assessment of treatment outcomes in this context. An observed survival
or success rate greater than 80% indicated a good outcome for the treat-
ment, and differences between treatments were considered statistically
significant if the 95% confidence interval (CI) did not overlap. Compar-
isons of the primary outcome measures between MAP and RET were
conducted as subgroup analyses when sufficient data were provided.
We followed the Preferred Reporting Items for Systematic Reviews
and Meta-Analyses statement for reporting meta-analysis (http://
prisma-statement.org/). All analyses were performed using Statistical
Analysis Software version 9.4 (SAS Institute, Cary, NC) (66).
Results
Descriptive Statistics
In all, 748 studies were initially identified through an electronic
search, and 2 additional studies were identified during a manual
search. Of these, 573 studies were excluded based on our inclusion
and exclusion criteria. The remaining 177 studies were subjected to
full-text review. From these, 33 studies (23 in the MAP group and 10
in the RET group) were excluded because they did not meet the in-
clusion criteria (Table 1), and 144 studies (61 in the MAP group
and 85 in the RET group [2 combined studies]) were included in
the final qualitative synthesis. The outcomes of 10 clinical trials
were subjected to subgroup quantitative synthesis (meta-analysis)
(Fig. 1). One clinical trial (67) was excluded from the subgroup
analysis because no success rate was reported. Interobserver agree-
ment for study selection in the RET group was substantial with
k = .783 (95% CI, .692–.851; P < .001) and near perfect for
MAP with k = .873 (95% CI, .813–.917; P < .001).
Review Article
In the MAP group, the total number of teeth was 543. The sample
size ranged from 1 (in case reports) to 91 in a retrospective cohort
report (68). The patients’ ages ranged from 6–35 years. In the RET
group, the total number of teeth was 455. The sample size ranged
from 1 (in case reports) to 35 (69). The patients’ ages ranged from
6–39 years.
A summary of the level of evidence in both groups is presented in
Table 2. In the MAP group, 17 (28%) studies scored >1. The rest, 44
(72%) studies, were case series and case reports. In the RET group, 12
(14%) studies scored >1. The rest, 73 (86%) studies, were case series
and case reports.
In analytic studies in the MAP group (scored > 1, n = 17), the
sample size was predetermined by the desired significance and power
level in 1 study (33). None of the analytic studies in the RET group
involved predetermination of the sample size.
Operator experience was mentioned in 8 (13%) studies in the
MAP group, and 5 involved treatment by specialists. Operator experi-
ence was mentioned in 10 (12%) studies in the RET group, and 9
involved treatment by specialists. Subject characteristics (ie, sex, age,
and/or race) were adequately presented in 82% of the studies in
both groups.
Trauma was the most common etiology for pulp necrosis in both
groups (all or part of the samples in 37 [60%] and 53 [62%] of the
studies in the MAP and RET groups, respectively). Anterior teeth
were the most common tooth type treated in both groups (48 [78%]
studies in the MAP group and 60 [70%] studies in the RET group)
(Tables 3 and 4). The preoperative diagnostic procedures were
completely described in 27 (44%) studies in the MAP group and 60
(70%) studies in the RET group.

TABLE 1. Studies Excluded after Full-text Review

Study Year Reason for exclusion
MAP Clarke (21) 2015 Outcome measures not related to survival or success
Battepati (22) 2015 Outcome measures not related to survival or success
Alobaid (23) 2014 Apexification group is a combination of Ca(OH)2 apexification and MTA apical plug
Dixit (24) 2014 Previously treated teeth
Cetenovic (25) 2013 Long-term treatment with Ca(OH)2
Gawthaman (26) 2013 Outcome measures not related to survival or success
Gupta (27) 2013 Outcome measures not related to survival or success
Yassen (28) 2013 Sample is a combination of immature teeth and mature teeth with apical root resorption
Vijayran (29) 2013 Outcome measures not related to survival or success
Chakraborty (30) 2012 Used Portland cement for apical plug
Brito-Junior (31) 2012 Previously treated tooth
Beslot-Neveu (32) 2011 Same study as Bonte et al (33)
Kumar (34) 2011 Previously treated tooth
Warner (35) 2011 Outcome measures not related to survival or success
Khatavkar (36) 2010 Outcome measures not related to survival or success
Mente (37) 2009 Mature teeth with apical root resorption or apical opening because of overinstrumentation
Jacobovitz (38) 2009 Long-term treatment with Ca(OH)2
Oliveira (39) 2008 Long-term treatment with Ca(OH)2
Kahler (40) 2008 Root maturation at the time of treatment
Ghaziani (41) 2007 Previously treated teeth
Karp (42) 2006 Long-term treatment with Ca(OH)2
Linsuwanont (43) 2003 Long-term treatment with Ca(OH)2
Maroto (44) 2003 Long-term treatment with Ca(OH)2
RET Martens (45) 2016 Root canals obturated with Biodentine
Meschi (46) 2015 Lack of clinical/radiographic evidence
Cao (47) 2015 Review article; inadequate documentation of presented cases
Kaya-Bu € yu
€ kbayram (48) 2014 Poor documentation; vital tooth with dens canal infection
Law (49) 2013 Review article; lack of detailed documentation on cases presented
Sridhar (50) 2010 Ca(OH)2 apexification
Kvinnsland (51) 2010 No pulp necrosis documented
Wang (52) 2010 No regenerative procedure attempted
Mendoza (53) 2010 Ca(OH)2 apexification
Bose (54) 2009 Retrospective analysis on previously published studies (55–60)
Ca(OH)2, calcium hydroxide; MAP, mineral trioxide aggregate apical plug; MTA, mineral trioxide aggregate; RET, regenerative endodontic treatment.

JOE — Volume -, Number -, - 2017 RET or MTA Apical Plug in Necrotic Teeth 3
Review Article
TABLE 2. Distribution of Studies Based on the Level of Evidence (LoE) common intracanal medicament used in the RET group was different
combinations of antibiotics in 64 (75%) studies followed by calcium
MAP RET
hydroxide in 14 (17%) studies. One study (1%) used formocresol.
LoE (type of study) n (%) n (%) The treatment was performed in 1 visit in 6 (7%) studies (Tables 3
1 (RCT) 7 (11) 4 (5) and 4).
2 (prospective cohort) 5 (8) 5 (6) In the MAP group, the application of intracanal medication
3 (retrospective cohort) 5 (8) 3 (3) ranged from months in 2 (3%) studies to weeks in 25 (41%) studies
4 (case series) 22 (36) 27 (32)
5 (case report) 22 (36) 46 (54)
or days in 19 (31%) studies. The treatment was completed in 1 visit
Total 61 (100) 85 (100) in 9 (14%) studies. Data were missing in 6 (10%) studies. In the
RET group, the application of intracanal medication ranged from
MAP, mineral trioxide aggregate apical plug; RCT, randomized clinical trial; RET, regenerative end-
months in 6 (7%) studies to weeks in 62 (73%) studies or days
odontic treatment.
in 7 (8%) studies. In 6 (7%) studies, the treatment was completed
in 1 session (Tables 3 and 4). In the RET group, the most common
scaffold was a blood clot (65 studies), and the most common barrier
Clinical Procedures and Outcomes over the scaffold was MTA (71 studies). EDTA was used in 17 (20%)
The treatment procedures were described in detail in 44 (72%) studies (Table 4).
studies in the MAP group and 67 (78%) studies in the RET group. In 1 study (93) in the MAP group, no average follow-up time could
Sodium hypochlorite (0.5%–6%) was the only irrigant or the main be calculated. The mean follow-up time ranged from 1.6 (67) to 120
irrigant in 52 (85%) and 81 (95%) studies in the MAP and RET (86) months in the MAP group (Table 3) and 5.5 (187) to 72 (180)
groups, respectively. Calcium hydroxide (alone or combined with months in the RET group (Table 4). In analytic studies, the average
other antibacterial medicaments) was the most common type of in- follow-up time per tooth was 19.9 months in the MAP group and
tracanal medicament in the MAP group (82% of studies). The most 16.7 months in the RET group.

Records identified through database Additional records identified through

Identification

searching other sources

(n = 748) (n = 2)

Records after duplicates removed

(n = 750)
Screening

Records screened Records excluded

(n = 750) (n = 573)
Eligibility

Full-text articles assessed for Full-text articles excluded

eligibility (n = 33)
(n = 177)

Studies included in
qualitative synthesis
(n = 144)
Included

Studies included in
quantitative synthesis (meta-
analysis)
(n = 10)

Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram.

4 Torabinejad et al. JOE — Volume -, Number -, - 2017

 TABLE 3. Included Studies in the Mineral Trioxide Aggregate Apical Plug (MAP) Group
JOE — Volume -, Number -, - 2017

Author Year N Age Male/female ratio Tooth Etiology Irrigant Mdcm/duration EDTA Perm rest Follow-up
Nagmode (70) 2016 3 25.3 34/66 A Trauma NaOCl 5.25% CH/10 d Y Composite 6
Sonali (71) 2016 2 19 0/100 P Caries NaOCl 2.5% CH/2 wk N Composite 12
Purra (72) 2016 2 16.5 50/50 A Trauma NaOCl 0.5% CH/7 d Y Composite 3
Damle (73) 2016 11 10 NS A Trauma Saline 0.9% No Mdcm N GIC 9
Sharma (74) 2016 4 23.7 100/0 A Trauma NaOCl 1.25% CH/2 wk Y IRM 10.5
Bucher (68) 2016 91 NS 33/77 A Trauma/caries NaOCl 3%, CHX 2% CH/7 d Y NS 30
Agrawal (75) 2016 1 13 100/0 P Anomalies NaOCl 2.5% CH/2 wk N Composite 24
Olczak (76) 2015 1 12 0/100 P Caries NaOCl 2.5% CH/2 wk Y Composite 24
Gujjar (77) 2015 1 10 100/0 A Trauma NS CH/2 wk Y NS 24
Park (78) 2015 2 15 0/100 P Anomaly NaOCl 5.25% mTAP/3 wk Y Composite 12
Das (79) 2015 1 20 100/0 A Trauma NaOCl 3% No Mdcm N NS 12
Umashetty (80) 2015 4 15.5 50/50 A Trauma NaOCl 3% CH/2 wk Y NS 15
Badole (81) 2015 2 24 0/100 A Trauma NaOCl 0.5% + CHX 2% CH/7 d Y RMGIC 12
Yadav (82) 2015 1 18 0/100 A Trauma NaOCl 1.25% CH/7 d N Composite 24
Silva (83) 2015 1 15 100/0 A Trauma NaOCl 2.5% CH/3 wk N NS 72
Bonte (33) 2015 17 10.2 47.1/52.9 A Trauma NaOCl 3% CH/2 wk Y NS 12
Lee (67) 2015 20 6.5–10 55/45 A NS NaOCl 2.5% CH/7 d N NS 1.6
Kumar (84) 2014 1 18 0/100 P Anomaly NaOCl 1% + CHX 2% CH/TAP/3.3 wk N Composite 12
Nagy (85) 2014 12 9–13 58/42 A NS NaOCl 2.6% TAP/wk N Composite 18
Pace (86) 2014 15 NS NS NS NS NaOCl 5.25% CH/7 d Y Composite 120
Kumar (87) 2014 2 11 50/50 M Caries NaOCl 2.5% CH + iodoform/2 wk N NS 8
Iqbal (88) 2014 10 13–32 40/60 A NS NaOCl 5% CH/7 d Y Composite 24
Khetarpal (89) 2013 3 16 50/50 A Trauma NaOCl 1.3% CH/7 d Y Composite 3
Floratos (90) 2013 3 11 50/50 A Trauma NaOCl 2.5% CH/7 d N Composite 14.6
Chang (91) 2013 2 15.5 50/50 A Trauma NaOCl 5.25% CH/1–2 wk Y Composite 42
Fayazi (92) 2013 1 16 100/0 A Anomaly NaOCl 1.3% CH/7 d N Composite 6
Mente (93) 2013 13 NS NS NS NS NaOCl 3% + CHX 0.12% CH/NS N NS NS
Giovarruscio (94) 2013 1 26 0/100 A NS NaOCl 1% No Mdcm Y NS 3
Jeeruphan (95) 2012 19 14.6 69/31 A/P Trauma/Caries/Anomaly NaOCl 2.5% No Mdcm N NS 14.21
Nosrat (96) 2012 2 16.5 100/0 A Trauma NaOCl 5.25%, 1% CH/3–4 wk Y Composite 37.5
Paul (97) 2012 1 36 — P/M Trauma/Caries NS CH/wk N Composite 6
Damle (98) 2012 15 8–12 NS A Trauma Saline 0.9% No Mdcm N Composite 12
Albadri (99) 2012 3 11.5 50/50 A Trauma/Anomaly CHX 2% CH/NS N Composite 16
Gu€ neş (100) 2012 3 13.7 33/66 A Trauma NaOCl 2.5% CH/2 wk Y Composite 16
Asgary (101) 2012 1 22 0/100 A Leakage NaOCl 5% CH/wk Y GIC 84
Gharechahi (102) 2012 2 19 0/100 A Anomalies NaOCl 0.5% CH/7 d N Composite 27
Ajwani (103) 2011 1 24 0/100 A Trauma NaOCl 0.5% CH/4 wk N NS 6
Moore (104) 2011 22 10 72.7/27.3 A Trauma/Anomaly CHX 0.2% CH/wk N GIC 23.4
RET or MTA Apical Plug in Necrotic Teeth

Mohammadi (105) 2011 1 35 100/0 M Caries NaOCl 1.3% No Mdcm Y Composite 12

Chung (106) 2011 1 7 0/100 A Trauma NaOCl 1% CH/4 wk N Composite 42
Vanka (107) 2010 2 9 0/100 A Trauma NaOCl 5% CH/2 wk in 1 case Y NS 6
Tezel (108) 2010 1 9 100/0 A Trauma NaOCl 2.5% CH/2 wk N Composite 24
Tahan (109) 2010 1 17 0/100 A Trauma NaOCl 1% + CHX 2% CH/2 wk N Composite 12
Nuvvula (110) 2010 1 13 0/100 A Trauma NaOCl 5.25% CH/3 wk N Composite 4

Review Article
Annamalai (111) 2010 30 8–13 NS A/P NS CHX 0.2% No Mdcm N Composite 12
Nayar (112) 2009 37 8–58 NS A NS NaOCl 5% CH/up to 7 d N Composite 10.67
Raldi (113) 2009 1 28 0/100 A Trauma NaOCl 1% CH/4 wk Y Composite 9
Maturo (114) 2009 1 7 NS A Trauma NaOCl 5.25% CH/7 d N NS 12
Bogen (115) 2009 1 12 0/100 P Anomaly NaOCl 6% CH/7 d N NS 18
Holden (116) 2008 17 7–27 47/53 NS NS NaOCl 5.25–6% CH/7 d Y Composite 24.4
Sarris (117) 2008 17 11.7 80/20 A Trauma NS NS N NS 12.53
(continued )
5
Review Article
The main treatment complication in both groups was crown
Follow-up

A, anterior; CH, calcium hydroxide; CHX, chlorhexidine; GIC, glass ionomer cement; IKI, iodine potassium iodide; IRM, intermediate restorative material; M, molar; Mdcm, medicament; mTAP, modified triple antibiotic paste; N, no; NaOCl, sodium hypochlorite; NS, not stated;
discoloration, which was reported in 13 (21%) studies in the MAP
15
24
24
12
19
60

12
12
12
6
group and 33 studies (40%) in the RET group. Two studies in the
MAP group and 6 studies in the RET group further categorized the com-
plications and reported them with frequencies.
Composite
Composite
Composite
Composite
Composite

Composite

Composite
Perm rest

Risk of bias was assessed in all analytic studies. The results are

IRM
GIC

NS
summarized in Table 5. The details of clinical outcomes (survival, suc-
cess, and root development rates) in analytic studies are shown in
Table 5.
EDTA
N
N

N
N
N
N
N
Y
Y

Y
Subgroup Analyses
The subgroups of randomized clinical trials were subjected to
quantitative analysis to compare the survival and success rates of
Mdcm/duration

CH + IKI/NS

each treatment modality. Overall, very little heterogeneity was

CH/1–6 wk

No Mdcm

No Mdcm
CH/2 mo

CH/2 mo
CH/2 wk
CH/7 d

CH/7 d
CH/7 d

observed among the studies regarding survival and success rates

(I2 < 50%, P > .10) (Fig. 2). However, there was a great deal
of heterogeneity regarding the success rates within the RET group
(Fig. 3). The survival rates for the MAP and RET groups were
97.1% (95% CI, 93.7–100) and 97.8% (95% CI, 94.8–100),
respectively (Fig. 2). The success rates for the MAP and RET
groups were 94.6% (95% CI, 90.2–99.1) and 91.3% (95% CI,
84.5–98.2), respectively (Fig. 3). No statistically significant differ-
NaOCl 5.25%
NaOCl 0.5%

NaOCl 0.5%
NaOCl 5%
NaOCl 5%
NaOCl 5%
NaOCl 5%

NaOCl 5%
NaOCl 5%
Irrigant

ence in survival rates (P = 1.00) or success rates (P = .58)

NaOCl

was observed between the 2 groups (Figs. 2 and 3). The pooled
rate for root development was 79% (95% CI, 67.2–90.8) in the
RET group.

Discussion
Analytic studies are classified into 2 groups: experimental
(eg, randomized clinical trials) and observational (eg, prospective
Trauma/Caries

and retrospective cohorts). Randomized controlled trials provide

Anomaly

Anomaly
Etiology

Trauma
Trauma
Trauma

Trauma
Trauma

Age indicates (if calculable) the average age of patients in each study. Follow-up represents the average follow-up time for all samples.

the strongest evidence of causation (18). Six (10%) studies in

NS

NS

P, premolar; Perm rest, permanent restoration; TAP, triple antibiotic paste; RMGIC, resin-modified glass ionomer cement; Y, yes.

the MAP group and 4 (5%) studies in the RET group were identified
as clinical trials. Only 1 clinical trial directly compared the
outcomes of MAP with RET, and it showed no significant differences
(85).
Among observational studies, retrospective cohorts are relatively
A/P/M
Tooth

weaker than prospective cohorts because they rely on existing records

A
A
A
A

A
A
A
A
A

(18). Prospective cohorts constituted 8% and 6% of the studies in the

MAP and RET groups, respectively. Only 1 study (a retrospective
Male/female ratio

cohort) compared the outcomes of RET with MAP (95). Another retro-
spective cohort (23) compared the outcome of RET with apexification
100/0
66/33
37/63
0/100
40/60
100/0

100/0
100/0

in which the apexification group was a combination of calcium hydrox-

NS
NS

ide apexification and MAP (23).

This review shows that there is a need for comparative studies
on the outcome of MAP and RET. The lack of randomized clinical
trials comparing these 2 treatment modalities makes the comparisons
11–32

less conclusive. Furthermore, the available clinical studies have

6–18
6–12
24.5
Age

9
12
11

18
15

14

diverse clinical protocols and different follow-up times, which

make them less comparable within and between groups. Although
only clinical trials were included in the subgroup analyses, there
11

57

41
15
1
5

2
1
N

was a great deal of heterogeneity regarding success rates within

2008
2008
2007
2007
2007
2006
2006
2006
2002
2002
Year

the RET group (Fig. 3). It is unknown whether the source of hetero-
geneity is primarily from clinical heterogeneity or methodologic het-
erogeneity. Potential sources for clinical heterogeneity include
TABLE 3. (continued )

Kristoffersen (118)

D’Arcangelo (121)

differences associated with study participants, intervention adminis-

Levenstein (127)
El-Meligy (125)
Jaramillo (123)
Ghaziani (124)

tration, or primary outcome classification. Potential sources for

Giuliani (126)
Author

Erdem (119)

Simon (122)

methodologic heterogeneity include study design and each study’s

Pace (120)

risk of bias (200).

This review revealed that the majority of studies in both groups
were case reports and case series (70% and 86% in the MAP and

6 Torabinejad et al. JOE — Volume -, Number -, - 2017

 TABLE 4. Included Studies in the Regenerative Endodontic Treatment (RET) Group
JOE — Volume -, Number -, - 2017

Male/
female Mdcm/
Author Year N Age ratio Tooth Etiology Irrigant period EDTA Scaffold Barrier Perm rest Follow-up
Estefan (69) 2016 35 9–18 58/42 A Trauma NaOCl 2.6% TAP/3 wk Y Blood MTA Composite 12
El Ashiry (128) 2016 16 NS NS A/P NS NaOCl 2.6% TAP/2 wk N Blood MTA Composite 24
Asgary (129) 2016 1 12 0/100 A Trauma NaOCl 5.25% TAP/3 wk N Blood CEM Composite 36
Topçuog lu (130) 2016 3 8.3 33/67 M Caries NaOCl 2.5% No Mdcm Y PRP Biodentine Composite 18
Zhujiang (131) 2016 1 20 100/0 M Caries NaOCl 6% CH/4 wk Y Blood + MTA Composite 15
collatape
Gharechahi (132) 2016 1 9 100/0 A Trauma NaOCl 5.25% TAP/3 wk N Blood MTA Composite 18
Farhad (133) 2016 1 8 100/0 A Trauma NaOCl 5.25% CH/3 wk N Blood MTA Composite 18
Nagaveni (134) 2016 1 11 100/0 A Trauma NaOCl 5.25% TAP/7 d N PRF MTA Composite 12
Wang (135) 2015 2 39 0/100 P Anomaly NaOCl 2.5% TAP/2 wk N PRP MTA Composite 30
Bezgin (136) 2015 20 7–12 55/45 A/P Trauma/caries NaOCl 2.5% mTAP/3 wk Y Blood/PRP MTA Composite 18
McCabe (137) 2015 1 7 0/100 A Trauma NaOCl 5% No Mdcm Y Blood MTA GIC 18
Khoshkhounejad 2015 2 16.5 50/50 A/P Trauma/caries NaOCl 1.5%–5.25% TAP/3 wk Y Blood MTA Composite 12
(138)
Sachdeva (139) 2015 1 16 100/0 A Trauma NaOCl 5.25% TAP/4 wk N PRP MTA Composite 36
EzEldeen (140) 2015 5 10–15 0/100 A/P NS NaOCl 2.5% DAP/2 wk Y Blood MTA Composite 19.4
Al-Ghamdi (141) 2015 1 8 0/100 P Caries NaOCl 5.25% CH/3 wk N Blood MTA Composite 36
Short (142) 2015 3 8 NS A/P Trauma/ NaOCl 3% CH/wk Y Blood MTA/ERRM Composite 16.3
anomaly
Lei (143) 2015 1 10 0/100 P Anomaly NaOCl 1% TAP/4 wk Y Blood MTA Composite 10
Nagaveni (144) 2015 1 10 100/0 A Trauma NaOCl 5.25% TAP/7 d N PRF MTA Composite 12
Nevins (145) 2015 1 14 0/100 P Caries NaOCl 6% DAP/4 wk Y Blood/ ERRM Composite 12
collagen HA
Dudeja (146) 2015 5 23 80/20 A Trauma/ NaOCl 5.25% + CHX 2% TAP/4 wk N Blood MTA Composite 19.2
caries
Faizuddin (147) 2015 1 14 100/0 A Trauma NaOCl 5.25% + CHX 2% TAP/3 wk N PRF MTA Composite 14
Saoud (148) 2014 20 11.3 70/20 A Trauma NaOCl 2.5% TAP/2 wk N Blood MTA Composite 12
Chandran (149) 2014 1 10 100/0 A Trauma NaOCl 5.25% TAP/4 wk N Blood MTA Composite 12
Raju (150) 2014 1 12 NS P Caries NaOCl 2.5% TAP/4 wk N Blood MTA Composite 12
Nagata (151) 2014 23 7–17 NS A Trauma NaOCl 6% + CHX 2% TAP, CH/3 wk Y Blood MTA Composite 15
Saeki (152) 2014 1 9 100/0 P Anomaly NaOCL 5% + HP 3% No Mdcm N No scaffold MTA NS 10
Bezgin (153) 2014 2 12 100/0 P Caries NaOCl 2.5% + CHX 0.12 mTAP/3 wk Y PRP MTA Composite 12
Kahler (154) 2014 16 10.4 31/69 A/P Trauma/ NaOCl 1% mTAP/4 wk N Blood MTA Composite 20.2
anomaly
Kumar (155) 2014 1 10 100/0 A Anomaly NaOCl 1% Clin/months N No scaffold ZOE Composite 28
RET or MTA Apical Plug in Necrotic Teeth

Alobaid (23) 2014 19 8.8 47/53 A Trauma/ NaOCl/CHX T/DAP, CH/wk N Blood MTA NS 14.5
anomaly
Guven Polat (156) 2014 1 10 100/0 P Caries/ NaOCl 2% TAP/2 mo N PRP MTA Composite 24
anomaly
Park (157) 2014 2 10.5 50/50 P Anomaly NaOCl 2.5% CH/1–3 wk N No scaffold MTA Composite 15
Johns (158) 2014 2 9 100/0 A Trauma NaOCl 5.25% No Mdcm N PRF MTA Composite 10
Cantekin (159) 2014 1 6 0/100 A Trauma NaOCl 4% CH/3 wk N Blood MTA Composite 21

Review Article
Becerra (160) 2014 1 11 0/100 P Anomaly NaOCl 5.25% + CHX 2% TAP/4 wk N Blood MTA Composite 24
Lin (161) 2014 1 6 100/0 A Trauma NaOCl 5.25% + CHX 2% TAP, CH/4 wk N Blood MTA Composite 16
Bakhtiar (162) 2014 4 9 0/100 A Trauma NaOCl 0.5% TAP/2 wk N PRGF MTA Composite 22
Nagy (85) 2014 24 9–13 50/50 A NS NaOCl 2.6% TAP/3 wk N Blood/gelatin MTA Composite 18
hydrogel
Nosrat (163) 2013 1 8 100/0 A Trauma NaOCl 2.5% Augmentin/5 wk Y Blood MTA Composite 31
Noy (164) 2013 1 12.5 100/0 A Caries NaOCl 2.5% TAP/3 wk N Blood MTA Composite 48
(continued )
7
 8

Review Article
TABLE 4. (continued )
Male/
Torabinejad et al.

female Mdcm/
Author Year N Age ratio Tooth Etiology Irrigant period EDTA Scaffold Barrier Perm rest Follow-up
Hargreaves (2) 2013 1 9 100/0 A Trauma NaoCl 1.5% DAP/4 wk Y Blood MTA Composite 6
McTigue (165) 2013 32 6–17 NS A/P Trauma/ NaOCl 3% + CHX 1.2% TAP, mTAP/4 wk N Blood MTA Composite 27
anomaly
Mishra (166) 2013 1 10 0/100 A Trauma NaoCl 0.5% TAP/7 d N Blood CH ZOE + GIC 15
Shimizu (15) 2013 1 9 100/0 A Trauma NaoCl 2.6% CH/11 d N Blood MTA Composite 26
Kalaskar (167) 2013 1 10 100/0 A Trauma NaoCl 0.5% TAP/7 d N Blood CH GIC 15
Keswani (168) 2013 1 7 100/0 A Trauma NaOCl 5.25% TAP/3 wk N PRF MTA Composite 15
Soares Ade (169) 2013 1 9 0/100 A Trauma CHX 2% CH + CHX/3 wk Y Blood MTA Composite 24
Martin (14) 2013 1 9 100/0 M Caries NaOCl 5.25% TAP/5 mo N Blood/PRP MTA Composite 24
Forghani (170) 2013 1 9 100/0 A Trauma NaOCl 5.25% TAP/3 wk N Blood MTA Composite 18
Kottoor (171) 2013 1 11 100/0 A Trauma NaOCl 5.25% TAP/3 wk N Blood MTA Composite 60
Jadhav (172) 2013 6 15.3 66/34 A Trauma NaOCl 2.5% TAP/4 wk N Blood/PRP RMGIC RMGIC 12
Yang (173) 2013 1 11 100/0 A Anomaly NaOCl 5.25% TAP/4 wk N Blood GIC Composite 24
Sonmez (174) 2013 3 9 33/66 M Caries NaOCl 5.25% TAP/2 wk N Blood MTA Composite 24
Narayana (175) 2012 1 11 100/0 A Anomaly NaOCl 5.25% TAP/2 wk N Blood MTA Composite 12
Shivashankar (176) 2012 1 9 100/0 A Trauma NaOCl 5.25% + TAP/3 wk N PRF MTA Composite 12
CHX 0.2%
Gelman (177) 2012 1 8 100/0 A Trauma NaOCl 6% TAP/2 wk N Blood MTA Composite 11
Dabbagh (178) 2012 16 9.5 NS A/P/M Trauma/caries/ NaOCl 5% TAP, mTAP/2–6 wk N Blood MTA Composite 24
anomaly
Kim (179) 2012 3 11 100/0 P Anomaly NaOCl 3% mTAP/2 wk N Blood MTA Composite 38
Nosrat (180) 2012 2 14 0/100 A Trauma NaOCl 5.25% TAP/4 wk N Blood MTA Composite 72
Jeeruphan (95) 2012 20 12.9 50/50 A/P/M Trauma/caries/ NaOCl 2.5% TAP/4 wk N Blood MTA NS 21.15
anomaly
Chen (181) 2012 20 10.6 45/55 A/P Trauma/caries/ NaOCl 5.25% CH/up to 4 wk N Blood MTA Composite 11.4
anomaly
Cehreli (182) 2012 2 8.5 100/0 A Trauma NaOCl 2.5% CH/4 wk N Blood MTA Composite 18
Lenzi (183) 2012 2 8 100/0 A Trauma NaOCl 2.5% TAP/5 wk N Blood MTA Composite 21
Aggrawal (184) 2012 1 24 0/100 A Trauma NaOCl 5.25% + TAP/2.5 mo N Blood MTA Composite 24
CHX 2%
Miller (185) 2012 1 9 100/0 A Trauma CHX 2% TAP/6 wk Y Blood MTA Composite 18
Jadhav (186) 2012 20 19.9 70/30 A Trauma NaOCl 2.5% TAP/NS Y Blood/PRP RMGIC RMGIC 12
Torabinejad (187) 2011 1 11 100/0 P Extraction NaOCl 5.25% TAP/3 wk N Blood MTA Amalgam 5.5
Nosrat (188) 2011 2 8.5 50/50 M Caries/leakage NaOCl 5.25% TAP/4 wk N Blood MTA Amalgam/GIC 15
Cehreli (189) 2011 6 9.3 16/84 M Caries/leakage NaOCl 2.5% CH/3 wk N Blood MTA Amalgam/ 9.5
composite
Petrino (60) 2010 6 10 66/34 A Trauma/caries/ NaOCl 5.25% + TAP/2–5 wk N Blood MTA Composite 10
JOE — Volume -, Number -, - 2017

anomaly CHX 0.12%

Kim (190) 2010 1 7 0/100 A Trauma NaOCl 3% TAP/6 wk N Blood MTA Composite 8
Thomson (191) 2010 1 12 0/100 P Anomaly NaOCl 1% mTAP/6 wk N Blood MTA Composite 18
Reynolds (192) 2009 2 11 100/0 P Anomaly NaOCl 6% + CHX 2% TAP/4 wk N Blood MTA Composite 18
Shin (193) 2009 1 12 0/100 P Anomaly + caries NaOCl 6% + CHX 2% No Mdcm N No scaffold MTA Composite 19
Thibodeau (194) 2009 1 9 100/0 A Trauma NaOCl 1.25% mTAP/months N Blood MTA Composite 16
Chueh (56) 2009 23 11 53/47 A/P/M Trauma/ NaOCl 2.5% CH/months N No scaffold MTA Composite/ 27
anomaly/ amalgam
caries
 Review Article
RET groups, respectively). Case reports and case series are descriptive

A, anterior; CEM, calcium-enriched mixture; CH, calcium hydroxide; CHX, chlorhexidine; Clin, clindamycin; DAP, double antibiotic paste; GIC, glass ionomer cement; HA, hydroxyl apatite; ERRM, endosequence root repair material; HP, hydrogen peroxide; IRM, intermediate restorative
material; Mdcm, medicament; M, molar; mTAP, modified triple antibiotic paste; N, no; NaOCl, sodium hypochlorite; NS, not stated; P, premolar; PRF, platelet-rich fibrin; PRGF, plasma rich in growth factors; PRP, platelet-rich plasma; TAP, triple antibiotic paste; RMGIC, resin-modified
observational studies with inherent biases. They represent the 2 lowest
16.2

19.2
28.3

6
16
30

34
24
30
levels of evidence in the evidence pyramid (18). These studies have no
control groups, and the observed results cannot be directly related to

ZOE/amalgam
the given exposure. Also, there is publication bias (ie, the authors focus
Composite
Composite
Composite

Composite
Composite
Composite
Amalgam

on successful cases and do not report the failed cases). Nevertheless,

GIC

this category constitutes the most common type of articles in medical

journals (19). Overall, the level of evidence in both groups in this sys-
tematic review was low.
Both MAP and RET showed highly successful outcomes (94.6%
Cavit + IRM

and 91.3% for the MAP and RET groups, respectively). In this study,
Dycal
MTA
MTA
MTA

MTA

ZOE
GIC

CH

like other studies on endodontic outcomes, success was measured

as the absence of clinical symptoms along with complete radio-
graphic healing of the periapical lesion. However, the criteria for
Collagen calcium
phosphate gel
Blood/no blood

success in the RET group can be stricter by also including root

No scaffold

No scaffold

No scaffold

development as a criterion (201). Root development is considered

Blood
Blood

Blood

Blood

a major advantage of RET over apexification (2). Baseline root

development might be a decision-making factor in the treatment
of extremely immature teeth with a very short root and very thin
root canal walls. MAP is often not viable in these cases, so RET
will be the preferred treatment option. Root development has 3 as-
N
N

N
N
N
N
N

N
N

pects: increased root length, increased root thickness, and reduced

TAP, CH/11 d–4 wk

apical diameter. Among these aspects, apical closure is the most

Formocresol/NS

wk–months
Polyantibiotic

common finding (148). Hypothetically, root development can in-

CH/months

No Mdcm
DAP/4 wk

paste/2
TAP/4 wk
TAP/7 d
CH/7 d

crease the structural strength of the tooth and eventually the survival
rate. However, there is no direct evidence supporting this assump-
tion; therefore, the effect of root development on the long-term
outcome is unclear, specifically when it presents as apical closure
only (148). The pooled rate for root development in randomized
Age indicates (if calculable) the average age of patients in each study. Follow-up represents the average follow-up time for all samples in each study.
NaOCl 5.25% + CHX 0.12%

clinical trials was 79%. The rate of root development varied from
NaOCl 5.25% + HP 3%

NaOCl 5.25% + HP 3%

NaOCl 5% + HP 3%

21% (23) to 100% (95, 140) in analytic studies. This wide

NaOCl 2.5%–5%
NaOCl 5.25%

Sterile water

range shows the unpredictability of root development after RET.

NaOCl 2.5%

Poor root development and a lack of root development have been

Saline

mainly associated with no tissue regeneration after RET. Possible

reasons investigated in studies are residual bacteria (16) and insta-
bility of the scaffold (6, 183). Recent tissue engineering studies are
focused on developing new stable scaffolds that can sustain a
disinfecting feature for an extended period to allow for more
predictable tissue regeneration (202).
Trauma/anomaly

Caries/anomaly

Because the root development occurs in a 3-dimensional (3D)

Anomaly
Anomaly
Anomaly
Trauma

Trauma

Trauma

Trauma

pattern, the most accurate method for the assessment of root develop-
ment is 3D imaging. However, except in 1 study (140), all analytic clin-
ical studies in the RET group assessed root development using 2-
dimensional radiographs. EzEldeen et al (140) showed 100% root
development by comparing pre- and postoperative 3D images of 5
A/P

A/P

consecutive cases (Table 5). Data on 3D assessment of root develop-

A

A
P

P
P
P

ment after RET in immature teeth are very limited.

The absence of clinical symptoms and evidence of radiographic
42/58
0/100
45/55
67/33
50/50
100/0
0/100
100/0

0/100

healing are considered successful from a clinician’s point of view. How-

ever, the patient’s impression of success might be different. From the
glass ionomer cement; Y, yes; ZOE, zinc oxide eugenol.
2009 12 8–11

2008 9 9–14

9.7
2008 14 11.6

patients perspective, success is defined as tooth retention, absence of

9

9
2004 1 11
2001 1 13

symptoms, and esthetic appearance (1, 203). In this study, survival

was defined as a retained tooth in the oral cavity at the follow-up ses-
2008 1

2006 4

1977 1

sion(s). The criteria for survival are unequivocal, whereas the criteria
1966

for success are open to interpretation. Therefore, treatment efficacy

could be evaluated more objectively by measuring survival rather
than success. In addition, from an epidemiologic standpoint, tooth
retention is a more meaningful finding and is often defined as success
Nevins (198)
Iwaya (197)
Banchs (59)
Chueh (55)

(204, 205). Both treatment groups showed very high survival rates
Cotti (196)
Ding (195)

Rule (199)
Shah (57)
Jung (58)

(>97%). Subgroup analyses on the outcome of clinical trials showed

no significant differences between MAP and RET regarding survival
rates.

JOE — Volume -, Number -, - 2017 RET or MTA Apical Plug in Necrotic Teeth 9
Review Article
TABLE 5. Outcomes of Analytic Studies (Randomized Clinical Trials [RCTs] and Observational Studies) and Results of Quality Assessment for Each Study
Author Year Study design N Survival (%) Success (%) Root development (%) Risk of bias
MAP Damle (73) 2016 RCT 11 100 90.9 NA Moderate
Bucher (68) 2016 Retrospective cohort 91 100 90.2 NA Moderate
Bonte (33) 2015 RCT 17 100 80 NA Low
Nagy (85) 2014 RCT 12 100 100 NA Moderate
Pace (86) 2014 Prospective cohort 15 92 92 NA Low
Lee (67) 2014 RCT 20 100 NS NA High
Mente (93) 2013 Retrospective cohort 13 100 92 NA Low
Jeeruphan (95) 2012 Retrospective cohort 19 94.7 68.4 NA Moderate
Damle (98) 2012 RCT 15 100 100 NA Moderate
Moore (104) 2011 RCT 22 100 90.9 NA Moderate
Annamalai (111) 2010 Prospective cohort 30 100 100 NA Moderate
Nayar (112) 2009 Retrospective cohort 37 100 79 NA High
Holden (116) 2008 Retrospective cohort 17 100 85 NA Low
Sarris (117) 2008 Prospective cohort 17 100 76.5 NA Moderate
Simon (122) 2007 Prospective cohort 57 100 79 NA Low
Ghaziani (124) 2006 Prospective cohort 41 100 92.7 NA Moderate
El-Meligy (125) 2006 RCT 15 100 100 NA Moderate
RET Estefan (69) 2016 Prospective cohort 35 100 94.3 NS Low
Bezgin (136) 2015 RCT 20 100 95.4 90.1 Moderate
EzEldeen (140) 2015 Prospective cohort 5 100 100 100 Moderate
Saoud (148) 2014 Prospective cohort 20 100 90 55 Low
Nagata (151) 2014 RCT 23 100 95.6 60.8 Moderate
Kahler (154) 2014 Prospective cohort 16 100 90.3 66.6 Low
Alobaid (23) 2014 Retrospective cohort 19 95 79 21 Moderate
Nagy (85) 2014 RCT 24 100 85 85 Moderate
Jeeruphan (95) 2012 Retrospective cohort 20 100 80 100 Moderate
Jadhav (186) 2012 RCT 20 100 80 75 High
Chueh (56) 2009 Retrospective cohort 23 100 100 92 High
Ding (195) 2009 Prospective cohort 12 100 100 100 High
MAP, mineral trioxide aggregate apical plug; NA, not applicable; NS, not stated; RCT, randomized clinical trial; RET, regenerative endodontic treatment.

Adverse effects and treatment complications were evaluated in
both groups. A substantial portion of the studies (40%) in the RET
group reported tooth discoloration after treatment as a major side ef-
fect. The grayish dark discoloration after the use of triple antibiotic
paste is related to minocycline (190). Discoloration was also reported
in cases in which triple antibiotic paste was replaced by Augmentin
(163) or calcium hydroxide paste (181). This drawback was associated
with the use of MTA at the cervical level in the crown (192). Gray discol-
oration in anterior teeth after RET is a disadvantage from the patient’s
viewpoint (165, 180), which can affect quality of life (206). However,
the discolored crowns can be bleached successfully (207). Crown
discoloration was reported in 21% of studies in the MAP group.
Follow-up time is an important factor in clinical investigations.
Studies have shown that the success rate of a treatment might change
over time and that the short-term outcome might not resemble the
long-term outcome (208). For instance, although surgical treatments
showed a superior success rate over nonsurgical retreatments in the
short-term, the long-term outcome was different (208, 209). Studies
have shown that most endodontic failures happen within 3 years of
treatment (204). The longest follow-up time in the MAP group was

Figure 2. A forest plot of subgroup analysis of survival rates.

10 Torabinejad et al. JOE — Volume -, Number -, - 2017


Figure 3. A forest plot of subgroup analysis of success rates.
10 years in a prospective cohort (86), whereas in the RET group it was
6 years in a case report (180). However, these 2 studies were outliers.
The average follow-up time per tooth in analytic studies was 19.9 months
and 16.7 months in the MAP and RET groups, respectively. Clinical
studies with longer follow-up times are needed.
The length of treatment is a key factor for some patients. Generally,
the disinfection process takes longer in RET compared with MAP. The
intracanal medication took weeks in 41% of the studies in the MAP
group versus 73% of the studies in the RET group. Although a single-
visit treatment is an acceptable approach for the MAP technique
(95), it is not a common approach in RET. Currently, there is no
comparative study on patient satisfaction after RET versus MAP.
Operator experience plays a key role in the outcome of endodon-
tic treatment. Tooth survival is significantly higher when the initial root
canal treatment is performed by a specialist compared with a general
dentist (210). Similar findings have been reported for the survival rate
of nonsurgical retreatments (205, 208). The operator was a specialist
in 5 studies in the MAP group and in 9 studies in the RET group. The
operator experience was not clear in most studies in both groups.
Based on the present evidence and meta-analysis, it appears that
the treatment of immature teeth with pulp necrosis using MAP or RET
enjoys high survival and success rates. The existing literature lacks
high-level clinical studies comparing these 2 treatment modalities. Ran-
domized multicenter clinical trials with large sample sizes and long-
term follow-ups are needed to address this gap in knowledge.
Acknowledgments
The authors deny any conflicts of interest related to this study.
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Appendix 1. Search Strategies for Mineral Trioxide Aggregate Apical Plug/Regenerative Endodontic
Treatment for Immature Teeth with Pulp Necrosis.
(((((((‘‘Child’’[Mesh] OR ‘‘Adolescent’’[Mesh]) AND (‘‘Tooth’’[MeSH] OR ‘‘Tooth Apex’’[MeSH] OR ‘‘Tooth Root’’[Mesh] OR ‘‘Dental
Pulp’’[Mesh])) OR (‘‘Immature teeth’’[tiab] OR ‘‘immature permanent teeth’’[tiab] OR ‘‘immature tooth’’[tiab] OR ‘‘immature permanent tooth’’[-
tiab] OR ‘‘immature apex’’[tiab] OR ‘‘immature permanent anterior teeth’’[tiab] OR ‘‘incompletely developed tooth’’[tiab] OR ‘‘immature apices’’[-
tiab] OR ‘‘immature mandibular incisors’’[tiab] OR ‘‘Immature teeth’’[ot] OR ‘‘immature permanent teeth’’[ot] OR ‘‘immature tooth’’[ot] OR
‘‘immature permanent tooth’’[ot] OR ‘‘immature apex’’[ot] OR ‘‘immature permanent anterior teeth’’[ot] OR ‘‘incompletely developed tooth’’[ot]
OR ‘‘immature apices’’[ot])))) AND (((‘‘Dental Pulp’’[Mesh] AND ‘‘Necrosis’’[Mesh]) OR ‘‘Dental Pulp Cavity’’[Mesh] OR ‘‘Dental Pulp Necrosis’’[-
MeSH] OR ‘‘pulp necrosis’’[tiab] OR ‘‘pulpal necrosis’’[tiab] OR ‘‘tissue necrosis’’[tiab] OR ‘‘traumatized pulp’’[tiab] OR ‘‘pulp necroses’’[tiab] OR
‘‘necrotic pulp’’[tiab] OR ‘‘necrotic pulps’’[tiab] OR ‘‘pulp gangrene’’[tiab] OR ‘‘pulp gangrenes’’[tiab] OR ‘‘pulp mummification’’[tiab] OR ‘‘pulp
mummifications’’[tiab] OR ‘‘pulp autolysis’’[tiab] OR ‘‘pulp autolyses’’[tiab] OR ‘‘diseased pulp’’[tiab] OR ‘‘open apex’’[tiab] OR ‘‘open apices’’[-
tiab] OR ‘‘necrotic tooth’’[tiab] OR ‘‘necrotic teeth’’[tiab] OR ‘‘pulp necrosis’’[ot] OR ‘‘pulpal necrosis’’[ot] OR ‘‘tissue necrosis’’[ot] OR ‘‘trau-
matized pulp’’[ot] OR ‘‘pulp necroses’’[ot] OR ‘‘necrotic pulp’’[ot] OR ‘‘necrotic pulps’’[ot] OR ‘‘pulp gangrene’’[ot] OR ‘‘pulp gangrenes’’[ot]
OR ‘‘pulp mummification’’[ot] OR ‘‘pulp mummifications’’[ot] OR ‘‘pulp autolysis’’[ot] OR ‘‘pulp autolyses’’[ot] OR ‘‘diseased pulp’’[ot] OR
‘‘open apex’’[ot] OR ‘‘open apices’’[ot] OR ‘‘necrotic tooth’’[ot] OR ‘‘necrotic teeth’’[ot])))) AND (((‘‘Dental Restoration, Permanent’’[Mesh]
OR ‘‘Root Canal Therapy’’[Mesh] OR (‘‘Endodontics’’[Mesh] AND ‘‘Regeneration’’[Mesh]) OR (‘‘Endodontics’’[Mesh] AND ‘‘Mesenchymal Stem
Cell Transplantation’’[Mesh]) OR (‘‘Tissue Engineering’’[Mesh] AND ‘‘Endodontics’’[Mesh]) OR ‘‘Pulpectomy’’[Mesh] OR ‘‘Root Canal Filling Ma-
terials’’[Mesh] OR ‘‘Root Canal Filling Materials’’[nm] OR ((‘‘Apexification’’[Mesh] OR ‘‘Tooth Root’’[Mesh] OR ‘‘Tooth Canal Filling Materials’’[-
Mesh] OR ‘‘Root Canal Filling Materials’’[Mesh]) AND (‘‘Calcium Hydroxide’’[nm] OR ‘‘Calcium Hydroxide’’[Mesh])) OR ‘‘dental pulp stem
cells’’[tiab] OR ‘‘dental pulp stem cells’’[ot] OR ‘‘pulp regeneration’’[tiab] OR ‘‘pulp regeneration’’[ot] OR ‘‘regenerative endodontics’’[tiab]
OR ‘‘regenerative endodontics’’[ot] OR ‘‘regenerative endodontic therapies’’[tiab] OR ‘‘regenerative endodontic therapies’’[ot] OR (regenera-
tion[tiab] AND endodontics[tiab]) OR (regenerative[tiab] AND endodontics[tiab]) OR ‘‘endodontic regeneration’’[tiab] OR ((apexification
[tiab] OR apexifications[tiab] OR apexogenesis[tiab] OR apexogeneses[tiab]) AND ‘‘calcium hydroxide’’[tiab]))) OR ((‘‘Apexification’’[Mesh]
AND ‘‘mineral trioxide aggregate’’[nm]) OR (‘‘Apexification’’[Mesh] AND mta[tiab]) OR ((apexification[tiab] OR apexifications[tiab] OR apexo-
genesis[tiab] OR apexogeneses[tiab] OR ‘‘apical plug’’[tiab]) AND (‘‘mineral trioxide aggregate’’[tiab] OR ‘‘mineral trioxide aggregate’’[ot] OR
‘‘MTA cement’’[tiab] OR ‘‘MTA cement’’[ot] OR TheraCal[tiab] OR TheraCal[ot] OR ‘‘MT aggregate’’[tiab] OR ‘‘MT aggregate’’[ot] OR ‘‘MTA-Filla-
pex’’[tiab] OR ‘‘MTA-Fillapex’’[ot] OR ‘‘aggregate ProRoot’’[tiab] OR ‘‘aggregate ProRoot’’[ot] OR ProRoot[tiab] OR ProRoot[ot] OR MTA[tiab] OR
MTA[ot]))))

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