Hindawi

e Scientific World Journal

Volume 2020, Article ID 7954357, 14 pages
https://doi.org/10.1155/2020/7954357

Review Article
Regenerative Endodontic Therapy in the Management of
Immature Necrotic Permanent Dentition: A Systematic Review

1
Faisal T. Alghamdi and Alaa E. Alqurashi2
1
Department of Oral Biology, Faculty of Dentistry, King AbdulAziz University, Jeddah 80209, Saudi Arabia
2
Ibn Sina National College for Medical Studies, Dental College, Jeddah 22421, Saudi Arabia

Correspondence should be addressed to Faisal T. Alghamdi; dr.faisal2020@hotmail.com

Received 6 May 2020; Revised 22 June 2020; Accepted 27 June 2020; Published 13 July 2020

Academic Editor: Gianandrea Pasquinelli

Copyright © 2020 Faisal T. Alghamdi and Alaa E. Alqurashi. This is an open access article distributed under the Creative
Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the
original work is properly cited.
Background and Objective. Management of immature permanent teeth exhibiting necrotic pulp is clinically challenging. An ap-
propriate diagnosis, case selection, and good management ensure good outcomes. The objective of this review reviews all up-to-date data
in regard to endodontic regeneration therapy in the management of immature permanent teeth with necrotic pulp and which conducts
are most used and appropriate for this procedure in human and animal investigations. Materials and Methods. The electronic databases
PubMed and Google Scholar were used to search the literature for relevant studies after applying specific inclusion and exclusion criteria.
Studies that fulfilled both the inclusion and exclusion criteria were included in this systematic review. The search was conducted by two
independent reviewers following the PRISMA guidelines. Results. Only 46 studies that fulfilled both the inclusion and exclusion criteria,
which were conducted within the last 10 years, were included in this systematic review. These studies investigated different aspects of
regenerative endodontic therapy including different types of scaffolds, intracanal medications, pulpal space/barriers, root maturation
stage, follow-up duration, and updated studies on their use in the management of immature necrotic permanent teeth. Conclusions. This
review concluded the compiled data observed that endodontic regenerative therapy was more efficient in treating immature necrotic
permanent teeth and offered a greater advantage that should lead to wider acceptance among endodontists for effective results compared
to different treatment options. However, more clinical trials with a standardized protocol and defined clinical, radiographic, and
histopathological outcomes with longer follow-up periods are warranted.

1. Introduction or biodentin [5–7]. The apexification was used as a treatment

option for many years, which induces the formation of a
Regenerative endodontic treatment (RET) is a common calcific barrier at the apex by using intracanal calcium hy-
category of biologically based endodontic therapy known as droxide (Ca(OH)2). In spite of the extensive use of the
revascularization or revitalization; RET aims to promote Ca(OH)2-based apexification procedure, the long procedure
normal physiological development in immature permanent time might require several visits and reestablishment of the
teeth with pulpal necrosis [1, 2]. Resolution of apical peri- intracanal dressing [8, 9], arbitrariness of the apical closure
odontitis, retrogression of associated clinical symptoms, and [10], and the predisposition of cervical root fractures after
prolonged survival of teeth are other important outcomes of extended exposure to Ca(OH)2 [11] have raised earnest
RET [2–4], which are favored in children and young indi- disquiet about the eligibility of this procedure technique.
viduals as a viable alternative to traditional (non- Up-to-date, the conventional apexification technique has
regenerative) endodontic procedures [2]. been adjusted by the presentation of artificial apical barrier
In regard to immature necrotic permanent teeth, there methods with mineral trioxide aggregate (MTA) [12–14].
are many treatment options for immature nonvital teeth, The MTA approach enhances patient compliance and good
including periapical surgery and apexification using calcium outcomes to assist in the healing of the periapical tissues,
hydroxide (Ca(OH)2) and mineral trioxide aggregate (MTA) although a shorten treatment period [12, 13, 15, 16]; on the
2 The Scientific World Journal

other hand, unfortunately, the improvement of the apical considered eligible: (1) published studies between the 10
closure and intensification of radicular dentin still cannot be years (2009–2019); (2) original research articles in the En-
achieved by this approach [10, 11]. Based on these con- glish language; and (3) studies performed on human and
siderations, it may be the apexification in future treatment animal subjects. The following were considered as exclusion
protocols for nonvital immature permanent teeth illustrates criteria: (1) published studies that assessed regenerative
to be dubitable [17, 18]. endodontic therapy but excluded immature necrotic per-
The idea of endodontic regeneration as a treatment manent teeth; (2) studies that discuss the management of
option was favored especially after two authors in 2004; they immature necrotic permanent teeth but excluded their effect
illustrated a new technique for the management of immature on root closure or development; and (3) review articles on
permanent teeth with apical periodontitis and termed it the management of immature nonvital permanent teeth.
“revascularization” [19]. The endodontic society found that
“Pulp revascularization” was a significant advance to in-
2.2. Critical Appraisal. All reviewers independently screened
vestigate tracks of pulp and dentin regeneration [20, 21].
the titles and abstracts of retrieved articles according to the
Revascularization depends on the stem cells and growth
eligibility criteria as well as PRISMA guidelines. Disagree-
factors by stimulating them to complete the apex closure. It
ments or inconsistencies were resolved through discussion
is widely used when the opening diameter of the root canal is
and consensus among the two reviewers.
large [22]. Moreover, revascularization treatment enhanced
root elongation and maturation [23].
There are many investigations which confirmed the 2.3. Data Extraction. The data were checked for com-
success rate of the regenerative endodontic procedure con- pleteness, accuracy, and extracted into standardized
ducted on children and young individuals, but the present Microsoft Office Excel worksheets by both reviewers on an
evidence is still disputable in regards to the regenerated tissue independent basis by fully reading the articles and con-
and regenerative protocol. Few systematic review studies are sidering the following variables: title, abstract, material and
available for the management of these teeth by regenerative methods (number of subjects (teeth), type of intracanal
endodontic treatment. Therefore, this current systematic medication, scaffolds, pulpal space/barrier, root maturation
review aims to compile all up-to-date information that in- stage, and follow-up duration), and main results.
vestigated endodontic regeneration therapy in the manage-
ment of immature permanent teeth with necrotic pulp and
2.4. Data Items. Data from the included articles were col-
which conducts are most used and appropriate for this
lected and organized in columns as the following:
procedure in human and animal investigations.

2. Materials and Methods 2.4.1. Human Studies. These studies include the following
information: author and year, age of the patient with mean
This systematic review was designed and executed under the and standard deviation, number of subjects (teeth), type of
PRISMA guidelines [24]. intracanal medication, scaffolds, pulpal space/barrier, root
maturation stage, follow-up duration, and main outcomes.

2.1. Literature Search Strategy. Bibliographical searches were

2.4.2. Animal Studies. These studies include the following
carried out in PubMed and Google Scholar databases in
information: author and year, animal species, number of
December 2019 and then updated in May 2020, using the
subjects (teeth), type of intracanal medication, scaffolds,
Mesh terms, which were combined with Boolean operators
pulpal space/barrier, root maturation stage, follow-up du-
(“AND” and “OR”). The following search strategies were
ration, and main outcomes.
used: “immature teeth” OR “immature tooth” OR “imma-
ture dentition” OR “immature permanent teeth” OR “im-
mature permanent tooth,” AND “young permanent teeth” 2.5. Assessment of Methodological Quality. As part of the
OR “young permanent tooth,” AND “pulp revasculariza- data extraction process, two review authors assessed the risk
tion” OR “pulpal regeneration” OR “pulp revitalization” OR of bias of the included studies. The methodological quality of
“root canal revascularization” OR “root maturation” OR each study was performed by using the risk of a bias as-
“regenerative endodontic” OR “regenerative endodontic sessment tool outlined in the Cochrane Handbook for
therapy” OR “regenerative endodontic treatment” OR “re- Systematic Reviews of Interventions (Version 5.1.0) [25].
generative endodontic procedure,” AND “blood clot” OR
“platelet-rich fibrin” OR “platelet-rich plasma,” AND “cal-
2.6. Synthesis of Results. As mentioned, tables were prepared
cified barrier” OR “apical closure” OR “root end formation”
with the fields included as data items.
OR “root apex closure” OR “apical plug” OR “MTA plug”
OR “apexification” OR “mineral trioxide aggregate” OR
“calcium hydroxide.” The search database was examined by 2.7. Statistical Analysis. Parametric data involving the age of
both examiners, and the final decision for inclusion and the patients of the human studies are presented as mean and
exclusion was made according to the following criteria. standard deviation (M ± SD). Thus, only a descriptive
Studies that meet the following inclusion criteria were evaluation is presented.
The Scientific World Journal 3

3. Results and Discussion 3.2. Discussion. This systematic review was conducted to
summarize and appraise all appreciated studies published
3.1. Results within the last 10 years and fulfilled our study aim. This
current systematic review aimed to compile all up-to-date
3.1.1. Study Selection. Among the 7403 articles selected information that investigated endodontic regeneration
through the keywords using the databases, duplicated or therapy in the management of immature permanent teeth
unrelated records (N � 6165) were excluded; only 181 articles with necrotic pulp and which conducts are most used and
were initially listed according to the inclusion and exclusion appropriate for this procedure in human and animal in-
criteria. Finally, 46 articles were selected to include in this vestigations. Our study presents a comprehensive compi-
systematic review. The summary of the selection process of lation of evidence taken from 46 articles that met our
the articles in this systematic review is delineated in Figure 1. inclusion and exclusion criteria.
Up-to-date, we can only find two old systematic reviews
3.1.2. Study Characteristics. The search culminated in forty- that talked about endodontic regenerative therapy in the
six studies that fulfilled both the inclusion and exclusion management of immature necrotic teeth for human and
criteria. The review included randomized controlled trials, animal studies (Table 4) [66, 67]. Bucchi et al. concluded in
controlled clinical trials, case reports, in vitro with in vivo their systematic review that most of the retrieved studies
studies, in vivo studies, and prospective/retrospective studies about clinical protocols of endodontic regenerative treat-
comparing the effectiveness of pulp revascularization in ment suggest their effectiveness in the management of these
immature necrotic permanent teeth [3, 4, 6, 16, 20, 22, 26–65]. kinds of teeth, however, most of the studies were found to
The studies included in this systematic review were 31 human support specific irrigation and intracanal dressings to better
studies [3, 4, 6, 16, 20, 22, 26–31, 35, 39, 40, 44–47, 50–53, clinical, histological, and radiographic outcomes in end-
55–57, 59, 60, 63–65] and 15 animal studies [32–34, odontic regeneration for clinical human and animal studies
36–38, 41–43, 48, 49, 54, 58, 61, 62]. This systematic review [66]. In contrast, although Antunes et al. focused only on 11
evaluated 46 studies that included a study sample of 1006 articles in regards to pulp revascularization, their results
subjects (teeth). The human studies included patients of confirm the clinical success of this procedure. In addition,
children and young individuals (aged between 7 and 18 years) the ability of this procedure is to activate the apical closure
with a mean age (mean ± SD) 10.1 ± 3.18 years and selected formation and increase the thickening of radicular dentin,
from different dental clinics, hospitals, and dental schools but the key factors of tissue repair, the type of tissue formed,
[3, 4, 6, 16, 20, 22, 26–31, 35, 39, 40, 44–47, 50–53, 55–57, and the long-term prognosis are still not clear in different
59, 60, 63–65]. On the other hand, most of the samples in clinical studies [67]. This clearly shows the discrepancies in
animal studies included different species such as ferrets, the conclusions between the previously published systematic
sheep, dogs, and monkeys [32–34, 36–38, 41–43, 48, 49, reviewers. This may be mainly due to the differences in the
54, 58, 61, 62]. Among the included studies, six studies il- applied inclusion and exclusion criteria in addition to the
lustrated negative outcomes in regard to endodontic regen- authors’ opinions. However, we could find some studies to
eration therapy in the management of immature necrotic support the high success rates for the use of endodontic
permanent teeth [29, 34, 46, 48, 49, 54]. On the other hand, 40 regenerative therapy in the management of immature ne-
studies showed significant positive outcomes for endodontic crotic permanent teeth in human and animal studies
regeneration treatment in these kinds of teeth due to root compared with previously published systematic reviews. In
development, root wall thickening, root lengthening, and addition, the first review [66] covered the period time from
formation of hard tissue barrier or apical closure 2007 to 2016 and the second review [67] covered the period
[3, 4, 6, 16, 20, 22, 26–28, 30–33, 35–45, 47, 50–53, 55–65]. time from 2008 to 2014 (Table 4); thus, our systematic review
The outcomes of these 46 studies include different types of covered all eligible articles published within the last decade
intracanal medications, scaffolds, pulpal space/barrier, root ((Table 1) and (Table 2)).
maturation stage, follow-up duration, and updating studies In our updated systematic review, all 46 studies favored
on their effect in periapical periodontitis and periapical the use of different scaffolds in endodontic regenerative
healing. Table 1 provides a summary of the included human therapy in the management of immature necrotic perma-
studies in this systematic review. An informative description nent teeth ((Table 1) and (Table 2)). The majority of these
of the included animal studies and their main outcomes are studies used blood clot (induced bleeding) as a scaffold in
summarized in Table 2. this procedure ((Table 1) and (Table 2)). Hence, the three
scaffolds such as blood clot (induced bleeding), platelet-rich
plasma (PRP), and platelet rich fibrin (PRF) have a vital role
3.1.3. Quality and Risk Assessment of the Included Studies. to stimulate pulp revascularization and associate to the
The quality and risk assessment of all the included studies treatment of immature necrotic permanent teeth [68]. In
were conducted by two authors and are represented in regards to the different types of intracanal medications and
Table 3. Included studies were assessed following the pulpal space/barriers used in this procedure, most of the
Cochrane collaboration’s tool [25] for assessing the risk of investigations in this review used triple-antibiotics paste
bias. Summarizing, no single study was classified as a high (TAP) as an intracanal medication and mineral trioxide
risk of bias, and most studies demonstrated low or unclear aggregate (MTA) as the pulpal space/barrier due to their
risk of bias (Table 3). effectiveness in pulp revascularization to treat the immature
4 The Scientific World Journal

Total = 7403

Duplicated
or unrelated
studies
Potential removal
relevant articles (n = 6165) Final
identified Records studies
through database screened included in
PubMed (n = 6143) (n = 1238) this review
Google Scholar (n = 46)
(n = 1260)
Study
Records
selection by
after
inclusion and
removing
exclusion
duplicates
Articles criteria
(n = 1238) Full
excluded (n = 181)
articles
based on title
excluded
and abstract
(n = 135)
(n = 1057)

Identification Screening Eligibility Included

Figure 1: Flowchart outlining the protocol adopted in the systematic review based on the preferred reporting items for systematic reviews
and meta-analyses (PRISMA) guidelines.

necrotic permanent teeth in comparison with other intra- development but with some significant morphological dif-
canal medications and pulpal space/barriers ((Table 1) and ferences [69]. Among the 31 human studies in this review, 26
(Table 2)). Most of the studies included in this review do not studies showed partially or completely mature teeth (Cvek
use any classification system to determine the degree of root stages IV and V), 3 studies showed teeth with intermediate
formation and maturation. Each study has measured the root development (Cvek stage III), and 2 studies showed teeth
percentage of root length and width changes to determine with an initial stage of root development (Cvek stages I and II)
root maturation ((Table 1) and (Table 2)). In our review, we (Table 1). In contrast, among the 15 animal studies, 10 studies
used a specific classification system to evaluate the degree of were classified as Cvek stages IV and V, followed by 1 study
root formation and maturation based on these root length and classified as Cvek stage III, 3 studies showed teeth with an
width changes among the included studies ((Table 1) and initial stage of root development (Cvek stages I and II), and
(Table 2)). This classification is called “Cvek’s Classification,” one study was not reported in regard to the root maturation
concerning root formation and maturation [69]. The Cvek’s stage (Table 2). Therefore, regenerative endodontic therapy has
classification system was used in this systematic review due to the potential to induce the root maturation of necrotic im-
didactic radiographic characteristics of this system, which mature permanent teeth and illustrate a significant increase in
allow for a better clinical application than that used in the root length and dentinal wall thickness in most of the included
other classification schemes [69]. This Cvek’s classification studies in this review ((Table 1) and (Table 2)). Although all
system was used to determine the root maturation stage in the these studies were carried out on human and animal models,
following five stages concerning the level of root maturity: we need more studies to be conducted to strengthen the
stage I � less than 1/2 root length, stage II � 1/2 root length, evidence of these studies; thus, we will be very close to finally
stage III � 2/3 root length, stage IV � wide open apical foramen give this procedure the superiority in treating immature ne-
and nearly complete root length, and stage V � closed apical crotic permanent teeth compared with other treatment
foramen and completed root development. Moreover, the options.
teeth in stage V were considered mature and fully apical Studies included in this review illustrated varied follow-
formed teeth, and the other four stages (stages I, II, III, and IV) up times for endodontic regeneration therapy in the man-
described teeth with open apices and lack of apical constriction agement of these kinds of teeth ((Table 1) and (Table 2)).
 Table 1: Summary of the included human studies in this systematic review according to PRISMA guidelines.
No. of Age of
Intracanal Pulpal space/ Follow-up Root maturation stage
Authors (year) subjects patient-years Scaffolds Main outcomes
medications barrier used duration (Cvek’s classification)
(teeth) (mean ± SD)
Stage V (closed apical
Alasqah et al. Significant periapical healing and
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(n � 1) 8 years old Ca(OH)2 + TAP Blood clot MTA plug 2 years foramen and completed root
[26] (2020) complete roots formation
development)
Stage V (closed apical
Rizk et al. [27] Complete maturation of the root
(n � 30) (9.1 ± 1.02) TAP Blood clot + PRP MTA 1 year foramen and completed root
(2019) apex
development)
Micromega- Stage V (closed apical
Ajram et al. Apical closure and complete
(n � 1) 7 years old Ca(OH)2 Blood clot MTA (MM- 2 years foramen and completed root
[28] (2019) periapical healing
MTA) development)
Lack of evidence for increased root
Ulusoy and dimensions and/or apical closure,
Stage I (<1/2 root length
Cehreli [29] (n � 4) (9.2 ± 1.75) TAP Blood clot MTA 1.5 years but the elimination of clinical signs/
with open apex)
(2017) symptoms and resolution of apical
periodontitis have happened.
Stage V (closed apical
Moodley et al. Apical closure and a thickening of
(n � 1) 10 years old Ca(OH)2 + TAP Blood clot MTA 2–5 months foramen and completed root
[30] (2017) the dentinal walls
development)
Timmerman Stage V (closed apical
and Parashos (n � 1) 16 years old Ca(OH)2 Blood clot MTA 3 years foramen and completed root Root development/Apical closure
[31] (2017) development)
Stage V (closed apical
Nosrat et al.
(n � 2) (9.5 ± 0.74) TAP Blood clot MTA 4 months foramen and completed root Root development/Apical closure
[35] (2015)
development)
Stage V (closed apical
Bezgin et al. Complete apical closure, periapical
(n � 20) (9.9 ± 1.9) TAP Blood clot + PRP MTA 1.5 years foramen and completed root
[39] (2015) tissue pathology resolution
development)
Resin-
6 Stage V (closed apical Apical closure, root lengthening,
Narang et al. Blood modified glass
(n � 20) (11.2 ± 3.51) TAP months–1.5 foramen and completed root dentinal wall thickening, and
[40] (2015) clot + PRP + PRF ionomer
years development) periapical healing
cement
Stage V (closed apical
Saoud et al. [4] Apical closure, root lengthening,
(n � 20) (11.3 ± 1.92) TAP Blood clot MTA 1 year foramen and completed root
(2014) and root wall width
development)
5
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Table 1: Continued.
No. of Age of
Intracanal Pulpal space/ Follow-up Root maturation stage
Authors (year) subjects patient-years Scaffolds Main outcomes
medications barrier used duration (Cvek’s classification)
(teeth) (mean ± SD)
Stage V (closed apical
Alobaid et al. 8.5–14.5 Apical closure and hard tissue
(n � 31) (8.8 ± 1.67) TAP + BAP + CH Blood clot MTA foramen and completed root
[44] (2014) months barrier
development)
Stage V (closed apical
Nagata et al. Root thickening/Lengthening/
(n � 23) (11.3 ± 3.12) TAP + Ca(OH)2+ CH Blood clot MTA 9–19 months foramen and completed root
[45] (2014) Apical closure
development)
Kahler et al. Stage II (1/2 root length with Root thickening/lengthening.
(n � 16) (10.1 ± 1.88) TAP Blood clot MTA 1–3 years
[46] (2014) open apex) Negative results for this procedure
Stage V (closed apical
Nagy et al. [47] Blood clot + blood Root thickening/Lengthening/
(n � 36) (10.8 ± 1.54) TAP MTA plug 1 years foramen and completed root
(2014) clot with (FGF) Apical closure
development)
Resin-
Ciprofloxacin + Stage V (closed apical
Jadhav et al. Blood clot + blood modified glass Root thickening/lengthening/
(n � 6) (15.3 ± 6.82) metronidazole + 1 year foramen and completed root
[50] (2013) clot with PRP ionomer Apical closure
minocycline development)
cement
Ciprofloxacin + Stage V (closed apical
Sönmez et al. Apical closure and dentin wall
(n � 3) 9 years old metronidazole + Blood clot MTA 2 years
foramen and completed root
[51] (2013) thickening
minocycline development)
Stage V (closed apical Apical closure and root wall
Mc Tigue et al.
(n � 32) (10.2 ± 1.83) TAP Blood clot MTA 1 year foramen and completed root thickening + periapical tissue
[52] (2013)
development) healing
Martin et al. Stage III (2/3 root length
(n � 1) 9 years old TAP PRP MTA 1 year Root thickening/lengthening
[53] (2013) with open apex)
Stage IV (wide opening Root thickening/lengthening, hard
Dabbagh et al.
(n � 18) (10.5 ± 1.58) TAP Blood clot MTA 2 years apical foramen and nearly tissue barrier, and periapical tissue
[55] (2012)
completed root length) healing
Stage IV (wide opening Root lengthening, dentinal wall
Chen et al. [3]
(n � 20) (10.2 ± 1.49) Ca(OH)2 Blood clot MTA 6–26 months apical foramen and nearly thickening, hard tissue barrier, and
(2012)
completed root length) periapical healing
Jeeruphan et al. 11.7–21.15 Stage III (2/3 root length
(n � 61) (12.9 ± 5.07) Ca(OH)2 Blood clot Gutta-percha Root wall width/lengthening
[6] (2012) months with open apex)
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 Table 1: Continued.
No. of Age of
Intracanal Pulpal space/ Follow-up Root maturation stage
Authors (year) subjects patient-years Scaffolds Main outcomes
medications barrier used duration (Cvek’s classification)
(teeth) (mean ± SD)
Ciprofloxacin +
Kim et al. [56] Stage III (2/3 root length Periapical healing and dentin wall
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(n � 3) (10.6 ± 1.15) metronidazole + Blood clot MTA 2–4 years

(2012) with open apex) thickening
cefaclor
Stage IV (wide opening
Iwaya et al. Continued root development and
(n � 1) 7 years old Ca(OH)2 Empty scaffold Gutta-percha 30 months apical foramen and nearly
[57] (2011) apical closure
completed root length)
Torabinejad Stage V (closed apical
and Turman (n � 1) 11 years old TAP Blood clot MTA 5.5 months foramen and completed root Hard tissue barrier
[20] (2011) development)
Stage V (closed apical
Cehreli et al. Apical closure, periapical tissue
(n � 6) 10 years old CH Blood clot MTA plug 1.5 years foramen and completed root
[16] (2011) healing, and tissue regeneration
development)
Calcium
enriched Stage IV (wide opining
Nosrat et al. 15–18 Root development/Periapical tissue
(n � 2) (8.5 ± 0.70) TAP Blood clot mixture apical foramen and nearly
[59] (2011) months healing
(CEM) completed root length)
cement
Stage V (closed apical
Petrino et al.
(n � 6) (10 ± 3.60) TAP Blood clot MTA 8 months foramen and completed root Hard tissue barrier
[60] (2010)
development)
Thomson and Stage IV (wide opening Continued root development and
Kahler [63] (n � 1) 12 years old TAP Blood clot MTA 1.5 years apical foramen and nearly some of the apical closures are
(2010) completed root length) evident
Stage V (closed apical
Reynolds et al. Significant root development with
(n � 2) 11 years old TAP Blood clot MTA 1.5 years foramen and completed root
[22] (2009) maturation of the dentine
development)
Ciprofloxacin + Stage IV (wide opening
Ding et al. [64]
(n � 12) (9.5 ± 1.16) metronidazole + Blood clot MTA 15 months apical foramen and nearly Continued root development
(2009)
minocycline completed root length)
Stage IV (wide opening
Bose et al. [65] TAP + CH + 6 months-3 Root development/thickening/
(n � 88) Not reported Blood clot MTA apical foramen and nearly
(2009) formocresol years lengthening
completed root length)
SD: standard deviation; Ca(OH)2: calcium hydroxide; TAP: triple-antibiotics paste; BAP: bi-antibiotics paste; CH: chlorhexidine; MTA: mineral trioxide aggregate; blood clot with bFGF: blood clot with basic
fibroblast growth factor; PRP: platelet-rich plasma; PRF: platelet-rich fibrin; blood clot with FGF: blood clot with fibroblast growth factor; and DPCs: dental pulp cells. Gelfoam (Pfizer, New York, NY, USA).
7
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Table 2: Summary of the included animal studies in this systematic review according to PRISMA guidelines.
No. of Root maturation
Animal Intracanal Pulpal space/ Follow-up
Authors (year) subjects Scaffolds stage (Cvek’s Main outcomes
species medications barrier used duration
(teeth) classification)
Stage V (closed apical
Treated dentine matrix
Bakhtiar et al. Ciprofloxacin + foramen and
(n � 32) Dogs (TDM) + tricalcium MTA 1 years Root development/Apical closure
[32] (2017) metronidazole + cefaclor completed root
phosphate (TCP)
development)
Stage V (closed apical
Altaii et al. [33] foramen and
(n � 4) Sheep TAP Blood clot MTA 6 months Root development/Apical closure
(2017) completed root
development)
Not reported in regards to the
root development and apical
Saoud et al. closure, but there are significant
(n � 16) Dogs TAP Blood clot MTA 3 months Not reported
[34] (2015) results of thickening of the
dentinal walls and periapical
healing
Stage IV (wide Significantly more apical
Torabinejad Blood clot/ opening apical narrowing and hard tissue
et al. [36] (n � 24) Ferrets TAP Gelfoam + PRP + empty MTA 3 months foramen and nearly deposition in two scaffold groups
(2015) negative control completed root compared with not using a
length) scaffold
Stage V (closed apical
Londero Cde Blood clot + blood clot with
foramen and
et al. [37] (n � 30) Dogs TAP gelfoam + empty negative MTA 7 months Apical root development
completed root
(2015) control
development)
Stage V (closed apical
Rodrı́guez-
Modified triantibiotic foramen and
Benı́tez et al. (n � 40) Dogs Blood clot + PRP Not report 6 months Root thickening/Apical closure
paste (mTAP) completed root
[38] (2015)
development)
Stage V (closed apical
Apical closure, dentinal wall
Khademi et al. 3–6 foramen and
(n � 36) Dogs TAP Blood clot MTA thickening, and periapical
[41] (2014) months completed root
healing
development)
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 Table 2: Continued.
No. of Root maturation
Animal Intracanal Pulpal space/ Follow-up
Authors (year) subjects Scaffolds stage (Cvek’s Main outcomes
species medications barrier used duration
(teeth) classification)
Stage V (closed apical
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Yoo et al. [42] foramen and Apical closure and dentinal wall
(n � 30) Dogs No report Blood clot MTA 12 weeks
(2014) completed root thickening
development)
Stage V (closed apical
Zhang et al. foramen and Apical closure and root wall
(n � 27) Dogs TAP Blood clot + PRP MTA 3 months
[43] (2014) completed root thickening
development)
Blood clot + blood clot with 1 week, 3 Stage I (<1/2 root Negative results in this study.
Tawfik et al.
(n � 108) Dogs TAP bFGF + empty negative MTA weeks, and length with open Root lengthening/thickness did
[48] (2013)
control 3 months apex) not change.
Blood clot + blood clot with Stage II (1/2 root Root thickening only, and does
Zhu et al. [49]
(n � 56) Dogs TAP DPCs + PRP + PRP with MTA 3 months length with open not report about the apical
(2013)
DPCs apex) closure
Glass
ionomer Stage I (<1/2 root Retardation of root development
Petrović et al. PRP with hydroxyapatite
(n � 24) Monkeys Not report cement 6 months length with open and nonsignificant differences
[54] (2013) (HAP)
(GIC) and apex) among the samples.
amalgam
Stage III (2/3 root
Yamauchi et al. Periapical healing and root wall
(n � 64) Dogs TAP Blood clot MTA 3.5 months length with open
[58] (2011) thickening
apex)
Stage V (closed apical
Zuong et al. foramen and
(n � 6) Dogs TAP Blood clot MTA 8 weeks Apical closure/Root thickening
[61] (2010) completed root
development)
Stage IV (wide
opening apical Hard tissue barrier and increase
Da Silva et al.
(n � 40) Dogs (TAP) Empty scaffold MTA 3 months foramen and nearly of apical periodontal ligament
[62] (2010)
completed root thickness
length)
Ca(OH)2: calcium hydroxide; TAP: triple-antibiotics paste; BAP: bi-antibiotics paste; CH: chlorhexidine; MTA: mineral trioxide aggregate; blood clot with bFGF: blood clot with basic fibroblast growth factor; PRP:
platelet-rich plasma; PRF: platelet-rich fibrin; blood clot with FGF: blood clot with fibroblast growth factor; and DPCs: dental pulp cells. Gelfoam (Pfizer, New York, NY, USA).
9
10 The Scientific World Journal

Table 3: Quality and risk Assessment of all the included studies in this systematic review.
Random Defined Blinding of Other
Allocation Incomplete Selective
Study (year) sequence inclusion/ outcome sources of
concealment outcome data reporting
generation exclusion assessment bias
Alasqah et al. [26]
+ + + + + + +
(2020)
Rizk et al. [27]
+ + + + + ? +
(2019)
Ajram et al. [28]
+ + + + + + +
(2019)
Ulusoy and Cehreli
+ + + ? + + ?
[29] (2017)
Moodley et al. [30]
? + + + + + +
(2017)
Timmerman and
+ + + + + + +
Parashos [31] (2017)
Bakhtiar et al. [32]
+ + + + + + +
(2017)
Altaii et al. [33]
+ + + + + + +
(2017)
Saoud et al. [34]
+ + + + ? + +
(2015)
Nosrat et al. [35]
? ? + + + + +
(2015)
Torabinejad et al.
+ + + + + + +
[36] (2015)
Londero Cde et al.
+ + + + + ? ?
[37] (2015)
Rodrı́guez-Benı́tez
+ + + + + + +
et al. [38] (2015)
Bezgin et al. [39]
+ + + + + + +
(2015)
Narang et al. [40]
+ + + + + + +
(2015)
Saoud et al. [4]
+ + + + + + +
(2014)
Khademi et al. [41]
+ + + + + + +
(2014)
Yoo et al. [42] (2014) + + + + + + +
Zhang et al. [43]
+ + + + + + +
(2014)
Alobaid et al. [44]
+ + + + + + +
(2014)
Nagata et al. [45]
+ + + + + + +
(2014)
Kahler et al. [46]
+ + + + + + +
(2014)
Nagy et al. [47]
+ + + + + + +
(2014)
Tawfik et al. [48]
+ + + + ? + ?
(2013)
Zhu et al. [49] (2013) + + + + + ? +
Jadhav et al. [50]
+ + + + + + +
(2013)
Sönmez et al. [51]
+ + + + + + +
(2013)
Mc Tigue et al. [52]
+ + + + + + +
(2013)
Martin et al. [53]
+ + + + + + +
(2013)
Petrović et al. [54]
+ + + + + + +
(2013)
The Scientific World Journal 11

Table 3: Continued.
Random Defined Blinding of Other
Allocation Incomplete Selective
Study (year) sequence inclusion/ outcome sources of
concealment outcome data reporting
generation exclusion assessment bias
Dabbagh et al.
+ + + + + + +
(2012) [55]
Chen et al. [3] (2012) + + + + + + +
Jeeruphan et al. [6]
+ + + + + + +
(2012)
Kim et al. [56]
+ + + + + + +
(2012)
Iwaya et al. [57]
+ + + + + + +
(2011)
Torabinejad and
+ + + + + + +
Turman [20] (2011)
Cehrelli et al. [16]
+ + + + + + +
(2011)
Yamauchi et al. [58]
+ + + + + + +
(2011)
Nosrat et al. [59]
+ + + + + + +
(2011)
Petrino et al. [60]
+ + + + + + +
(2010)
Zuong et al. [61]
+ + + + + + +
(2010)
Da Silva et al. [62]
+ + + + + + +
(2010)
Thomson and
+ + + + + + +
Kahler [63] (2010)
Reynolds et al. [22]
+ + + + + + +
(2009)
Ding et al. [64]
+ + + + + + +
(2009)
Bose et al. [65]
+ + + + ? ? +
(2009)
+ � low risk; ? � unclear risk; and − � high risk.

Table 4: Summary of all old systematic reviews in the scope of our systematic review.
Number of
Authors Year Method summary Main conclusions
studies used
The systematic review summaries and presents
different clinical and animal studies performed.
Only those articles published up to May 2016 Most of the included studies did not follow a
Bucchi et al.
2017 23 studies were considered for review. Using 7 different standard clinical protocol for regenerative
[66]
databases (MEDLINE, Scopus, Cochrane library, endodontic therapy.
SciELO, Google Scholar, Science Direct, and
EMBASE), an electronic search was performed.
A systematic review summarizes and presents
original articles in the database Web of Science,
PubMed, BVS (Medline, SciELO, Lilacs, and
Significant outcomes have appeared in the pulp
BBO), Scopus, and Cochrane. Only those articles
Antunes revascularization, but several aspects remain
2016 11 studies published up to July 2014 were considered for
et al. [67] unknown, such as the key factors of this repair, the
review, and analysis of the papers published
type of tissue formed, and the long-term prognosis.
during this period took place based on previously
established criteria, through the methodology of
a systematic review.
12 The Scientific World Journal

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