63rd Publication- JPBS- 7th Name.pdf

S36 © 2021 Journal of Pharmacy and Bioallied Sciences | Published by Wolters Kluwer - Medknow
This meta‑analysis is intended to evaluate the reliability of evidences published in
current regenerative endodontic publications in a critical way. This meta‑analysis
is used to summarize and analyze the various clinical and radiographic findings
associated with nonvital immature permanent teeth which have been treated
with regenerative endodontic techniques. We also intend to significantly evaluate
the worth of facts provided in the previous published literature. A structured
electronic search by authors was undertaken in August 2020 using MEDLINE
and PubMed search engine. The chosen parameters studied in this systematic
review were presented in flowcharts and were summarized. We observed a good
accomplishment rates in terms of survival of the treated tooth and also in resolution
of any associated pathology in the apical areas; on contrary, our results in relation
to apex closure along with constant root development, our findings from various
studies were quiet variable. Regenerative endodontic procedures are constantly
being restructured and enhanced to benefit present‑day dentistry in all likely ways.
Still, many factors that are important for the success of regenerative endodontic
treatment outcomes still remain unexplained. There are still numerous gaps in our
expertise at the present stage of this study.
Keywords: Meta‑analysis, outcome measures, regenerative endodontic therapy,
scope
Regenerative Endodontic Therapy in the Management of Nonvital
Immature Permanent teeth: A Systematic Review and Meta‑analysis
Izaz Shaik1
, Malti Tulli2
, Priyanka Unnam3
, Sangeetha Karunakaran4
, Durga Susmitha Vaddi5
, Rafiya Jabeen6
,
Rahul Vinay Chandra Tiwari7
Access this article online
Quick Response Code:
Website: www.jpbsonline.org
DOI: 10.4103/jpbs.JPBS_807_20
Address for correspondence: Dr. Izaz Shaik,
Rutgers School of Dental Medicine, Newark, New Jersey, USA.
E‑mail: shaik.ajas@gmail.com
In the present era, various researchers plan to create
improved regenerative treatment procedures that have
the potential beyond existing limits to regenerate new
tissues. This process entails new protocols using stem
cells, scaffolds, and growth factors to be created. To
regenerate the various tissues required to produce a tooth
and its supporting tissues, many approaches relating
stem cells, different scaffolds, and growth factors can be
united. Presently, areas of RE are persistently developing
in managing nonvital immature teeth. With numerous
available prospective studies, together with recently
published randomized controlled studies regenerative
Introduction
Regenerative endodontic (RE) procedures are
described as biologically based techniques intended
to restore damaged tooth structures, comprising dentin
and along with other root structures, and even cells of
the pulp‑dentin complex.[1]
The source for these RE
techniques is to make use of the principles of tissue
engineering. In the process of regeneration, we not only
require the cells to secrete new tissue for regeneration,
but at the same time, we also require sufficient molecular
and cellular signaling to occur so as to stimulate the
cells to secrete new tissue responsible for regeneration.
It is now evident that the dentin matrix comprises a
varied mixture of growth factors and cytokines that
can be released from the matrix during caries which
can contribute considerably to the regenerative process.
1
DMD Student, Rutgers School
of Dental Medicine, Newark,
New Jersey, USA, 2
Dental
Surgeon, Guru Nanak Dev
Dental College and Research
Institutes, Sunam, Punjab,
India, 3
Dental Surgeon,
Narayana Dental College and
Hospital, Nellore, Tamil Nadu,
India, 4
Dental Surgeon, Sri
Ramakrishna Dental College
and Hospital, Coimbatore,
Tamil Nadu, India, 5
Dental
Surgeon, Sibar Institute of
Dental Sciences, Guntur,
Andhra Pradesh, India,
6
Dental Surgeon, AME’S
Dental College, Raichur,
Karnataka, India, 7
Department
of OMFS, Narsinhbhai Patel
Dental College and Hospital,
Sankalchand Patel University,
Visnagar, Gujarat, India
Abstract
This is an open access article distributed under the terms of the Creative Commons
Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows others to remix, tweak,
and build upon the work non‑commercially, as long as the author is credited and the new
creations are licensed under the identical terms.
For reprints contact: WKHLRPMedknow_reprints@wolterskluwer.com
How to cite this article: Shaik I, Tulli M, Unnam P, Karunakaran S, Vaddi DS,
Jabeen R, et al. Regenerative endodontic therapy in the management
of nonvital immature permanent teeth: A systematic review and meta-
analysis. J Pharm Bioall Sci 2021;13:S36-42.
Submitted: 06‑Dec‑2020
Revised: 08-Dec-2020
Accepted: 09-Dec-2020
Published: 05-Jun-2021.
Review Article
[Downloaded free from http://www.jpbsonline.org on Sunday, June 6, 2021, IP: 175.101.146.64]

S37
Journal of Pharmacy and Bioallied Sciences ¦ Volume 13 ¦ Supplement 1 ¦ June 2021
Shaik, et al.: Regenerative endodontic therapy in managing non vital teeth
endodontic treatment (RET) is being reported as one
of the feasible treatment alternatives in the treatment
of nonvital, immature permanent teeth. Hence, its
well‑timed for the current literature to re‑evaluate this
shifting landscape of the feasible treatment alternatives
for nonvital immature permanent teeth in young
individuals.[2]
Hereby in this analysis, we aimed to
evaluate the reliability of data published in the current
literature regarding RE treatment in a critical way. This
meta‑analysis is used to summarize and analyze the
various clinical and radiographic findings for infected
immature permanent teeth which are treated using RE
techniques and importantly also to evaluate the quality
of facts provided in the already published literature.
Materials and Methods
A structured electronic search by authors was
undertaken in August 2020 using MEDLINE and
PubMed search engine. Unpublished literature
was electronically searched on Clinical Trials. gov
(www.clinicaltrials.gov) and the National Research
Register (www.controlled‑trials.com). The search
strategy comprised a combination of different key words
along with some Medical Headings relatable to RET.
The chosen parameters studied in this systematic review
were presented in flowcharts and were summarized as
given in Figure 1.
Outcome measures of data analysis
The challenge begins with every clinical procedure
as we try to describe what a good result is in terms
of outcome of revascularization procedures. Evidence
of root development and root formation is taken into
account. It is essential to restore the pulpal function
to measuring the effectiveness of therapy. The data
reviewed in this analysis was analyzed, and the
primary outcome measures which were analyzed were
as follows: (1) Survival of the tooth, (2) Clinical and
radiographic signs of healing if pathology in periapical
areas, (3) Results of constant root formation as seen
according to the decreased size of apical foramen,
evidence of root lengthening, and formation of root
dentin.
Results
Various clinical studies on RET have been conducted
since 2001. The clinical concerns for regenerative
endodontic procedures of the American Association of
Endodontists (2016) describe performance across three
measures:
1. Primary objective (essential): Symptom removal and
proof of bony healing
2. Secondary (desirable) target: Increased thickness of
the root wall and/or increased root length
3. Tertiary target: Positive response to checking for
vitality.
The main objective of resolving the clinical signs
of infection and bone healing is usually attainable,[3]
while disinfection procedures and limited filing have
been related to failed cases as earlier established. In
two recent systematic reviews by Tong et al. 2017[4]
and Torabinejad et al. 2017[5]
showed that the primary
objective of RET could be reliably accomplished.
Study design
In this analysis, three studies[6‑8]
were seen to estimate the
outcomes of the technique, based on types of intracanal
medicaments used. Four studies evaluated the results of
RET based on different scaffolds used in the studies,[9‑12]
8 studies reported the results based on different treatment
options like that of Ca (OH) 2 for apexification or the
use of MTA apical plug technique[6‑8,10,11]
and included
3 failed cases as well.[13‑15]
Primary outcome
Clinical outcome
The two primary clinical outcomes measures as studied
included firstly survival of the tooth and secondly
clinical signs of healing. Except 2 studies, 100%
positivity in tooth survival was reported in all other
studies evaluated.[7,8]
Radiographic outcomes
The parameters included in the evaluation of
radiographic outcomes included are firstly the resolution
of apical pathology, secondly the amount of apical
closure, thirdly the evaluation of increase in root
length, and finally, the thickening of root due to dentine
deposition. Eight researchers have used computerized
tools and image correction, along with measurement
analysis. Among these, two studies further studied
radiographic results using the measurement of relative
Figure 1: Flowchart summarizing the chosen reporting parameters studied
in systematic reviews and meta‑analysis

S38 Journal of Pharmacy and Bioallied Sciences ¦ Volume 13 ¦ Supplement 1 ¦ June 2021
radiographic field.[8,9]
Periapical healing and Apical
Closure: In the meta‑analysis, almost all 100% studies
evaluated reported periapical pathology resolution
success rates. Apical closure was reported in 11 studies
with variability and apical closure success rates ranging
within 76%–91%.[4,5,9,16‑19]
Root length and root dentin
thickness: four studies evaluated in this meta‑analysis
mentioned on the success rates of root lengthening and
root dentin formation.[12,18‑20]
The results of estimated
success rates for both ranged from 80% to 94%.
Secondary outcomes
Two studies in this meta‑analysis were found to report
that no consistency in achieving root maturation.
[14,21]
Hence, these outcomes seem to be more variable.
In addition, some long‑term potential studies have
also reported outcomes even past 18 months.[4]
Hence,
long‑lasting retention of RET treated teeth is still
questionable. Secondary outcomes included late‑stage
effects and side effects, which were conflicting through
different researches studied. Two most common observed
late‑stage effects included obliteration of the pulp canals
and the presence of tooth discoloration. Discoloration
was observed in almost 50% of studies.[8,9,20,22,23]
Details
of different study characteristics and their outcome
measures are hereby tabulated in Tables 1 and 2.
Discussion
A data analysis of the RET clinical protocol found
that RET protocols differed greatly across all trials.
Different treatment protocols may lead to different
outcomes of treatment. Therefore, in the literature, it
is not viable to assess the exact treatment outcome of
RET. Nevertheless, the largely most favorable outcome
considered for RET clinically is the continuation of root
development and apex closure.
An immature permanent tooth
Young immature permanent teeth with wide‑open apex
permit both cellular and molecular mechanism of the
innate and adaptive immunity to be effectively carried
to the canal space by pulp blood circulation. As a result,
young, immature permanent teeth are supposed to be
more challenging than mature permanent teeth to carious
infections or trauma. As a result, if such teeth are
affected by caries or trauma, it may take probably more
time for the pulp to become fully necrotic and present
with apical periodontitis. This hypothesis was based on
the findings studied during this meta‑analysis with cases
comprising of young permanent teeth with such pulpal
and periapical pathological conditions. These were
clinically diagnosed with when the canals were probed,
bleeding occurred, or patients encountered pain with
hand files.
Microenvironment and tissue repair mechanisms
In developmental biology, the microenvironment is
described as a precise location that maintains the stem
cell. Micro‑environmental signals, such as stromal cells,
extracellular matrix, adhesion molecules, growth factors
and cytokines, decide the fate of stem cells.[24‑26]
If the
microenvironment is altered, the fate of stem cells is
also said to be will also be altered. The pulpal tissue is
enclosed within canal room’s sterile microenvironment.
This microenvironment should be preserved as similar
as practicable to the original sterile microenvironment of
the pulp canal but it is altered when the teeth become
contaminated due to the accumulation of biofilm on
the canal walls, by bacterial toxins and by resorption.
Even after intracanal irrigation and medication, this
microenvironment is also altered. The stem cell fate
in the treated canals and sterile canals may therefore
be distinct. This may be the possible reason as to
why it becomes tough to regenerate pulp tissue with
infected/necrotic pulp after RET, in accordance with the
immature permanent teeth.[27]
In this meta‑analysis, Most
studies have stated that RET has the potential to facilitate
canal wall thickening and/or continued root growth of
immature permanent teeth with necrotic pulps. It was
suggested by various researchers that cells from the
remnants of pulp or the cells obtained from the papilla
may relocate within the disinfected pulpal canal space,
hereby to deposit secondary dentine on the canal walls
and the root apex, and helps in increasing the thickness
of the canal walls and root length. Histologically, results
of various studies suggest from this meta‑analysis,
that evidence of both Hard and soft connective tissue
formation was observed in the root canal space after
RET even after disinfection. The tissues which were
formed in the canal space of these treated immature
teeth were characterized as bone, cement‑and periodontal
ligament‑like tissue in consequent animal study models
as well.[4,5]
The findings of this meta‑analysis showed that
periapical pathology resolution success rates past RET
were equivalent to MTA or apexification therapy. This
indicates that for bacterial removal, together, disinfection
methods have identical efficiency. We observed that the
accomplishment rates for apical closure, enlargement
in root length, and the formation of dentin were higher
in the case of RET in contrast to the normal. It is
been suggested that a 20% increase in the root length
may be associated with a clinically significant change,
according to these studies.[28]
Substantial heterogeneity
was observed in the reporting of results between
studies studied in the analysis. This includes reporting
of pre‑ and postoperative clinical features and also the
quantification of radiographic interpretations. Thus it
was observed that, due to deficient data regarding the

S39
Table 1: Primary and secondary outcome measures
Study Year Number
of teeth
Tooth
under study
Primary outcome Secondary
outcome/
sideeffects
Clinical
evaluation
Radiographic
evaluation
Apical
cosure
Root length Root
thickness
Healing/
resolution
Chen et al. 2012 20 Incisors and
premolars
Tooth
survival/
vitality
Root
development
Increased root
thickness
PA pathology
resolution
15/20
teeth
20/20 teeth 20/20 teeth 20/20
teeth
Hard tissue
barrier
formation (not
at apex)
PCO
Discoloration
Dabbagh
et al.
2012 16 Incisors
premolars
molars
Tooth
survival/
vitality
Increased
root length
PA pathology
resolution
Not
mentioned
12/16 teeth Not
mentioned
9 Teeth Discoloration
Hard tissue
barrier
MTA material
collapsing into
canal
Jeeruphan
et al.
2012 61 Incisors and
premolars
Tooth
survival
Resolution
of clinical
signs and
symptoms
Apical
closure
Increased
root length
Increased
root thickness
PA pathology
resolution
Periapical
closure
Not mentioned
Mctigue
et al.
premolars
Tooth
survival
Sinus
track
resolution
Apical
closure
Increased
root length
Increased
root thickness
PA pathology
resolution
23/32
teeth
21/32 teeth 22/32 teeth 31/32
teeth
Discoloration
Kahler et al. 2014 16 Incisors and
premolars
Tooth
survival
Resolution
of clinical
signs and
symptoms
Apical
closure
Increased
root length
Increased
root thickness
PA pathology
resolution
Periapical
closure
19.4%
complete
closure
2.7%-25.3%
increase
1.9%-72.6%
increase
90.37%
Cases
Discoloration
Alobaid
et al.
others
Tooth
survival
Resolution
of clinical
signs and
symptoms
Apical
closure
Increased
root length
Increased
root thickness
PA pathology
resolution
6/18
cases
4/15 cases 4/15 cases 7/8 cases Hard tissue
barrier
formation (not
at apex)
PCO
Discoloration
Contd...

standardized conclusion of presently accessible data,
it has mostly affected the best possible application and
combination of these outcomes, which are necessary for
accurate interpretation of factors affecting the successful
outcome of RET.
Table 1: Contd...
Study Year Number
of teeth
Tooth
under study
Primary outcome Secondary
outcome/
sideeffects
Clinical
evaluation
Radiographic
evaluation
Apical
cosure
Root length Root
thickness
Healing/
resolution
Nagata et al. 2014 23 Incisors Tooth
survival
Resolution
of clinical
signs and
symptoms
Apical
closure
Increased
root length
Increased root
thickness
PA pathology
resolution
8/12
cases
5/12 cases 5/12 cases 6/6 cases Discoloration
Nagy et al. 2014 36 Incisors Tooth
survival
Resolution
of clinical
signs and
symptoms
Apical
closure
Increased
root length
Increased root
thickness
PA pathology
resolution
17/20
cases
16/20 cases 16/20 cases 17/20
cases
Not mentioned
Bezgin et al 2015 20 Incisors and
premolars
Tooth
survival
Resolution
of clinical
signs and
symptoms
Apical
closure
PA pathology
resolution
13/20
cases
18/20 cases 18/20 cases 15/16
cases
Discoloration
Narang et al. 2015 20 - Tooth
survival
Resolution
of clinical
signs and
symptoms
Apical
closure
Increased
root length
Increased root
thickness
PA pathology
resolution
17/20
cases
15/15 cases 15/15 cases 15/15
cases
Not mentioned
Linsuwanont
P et al.
premolars
Root
maturation
Fully
formed
roots with
various
apical
shapes
Apical
closure
dimensional
changes
of the root
(0%-73%)
- the pattern
of root
maturation
76%
success
14.38±20.92%
mean change
13.82±11.17%
mean change
Not
mentioned
Incomplete
root
development
with wide
Open apices
and fully
Unpredictable
patterning of
radiopaque
deposits
Estefan BS
et al.
2017 40 Permanent
maxillary
incisors
Tooth
survival
Resolution
of clinical
signs and
symptoms
Apical
closure
Dimensional
changes of
the root
Not mentioned
PA: Periapical Pathology, PCO: Pulp canal obliteration, MTA: Mineral Trioxide Aggregate
Side effects
There was comparatively less reporting of multiple
adverse effects such as decoloration, pulp canal
obliteration, anomalies in root morphology during
the growth process, absence of apical seal/closure,

S41
and eventually loss of pulp/tooth vitality after apical
closure. In 50% of studies, tooth decoloration after
RET treatment has been identified. The discoloration is
commonly reported to be associated with minocycline,
even though calcium hydroxide has also been reported
to be associated with tooth discoloration.[20]
MTA can
also cause tooth discoloration, specifically Bismuth
oxide in MTA, which has shown to cause crown
discoloration. Consequently, after contact with blood,
materials exhibit greater color changes, which has
consequences in RET as they are put in close contact
with the BC scaffold. With the use of present‑day
filling materials such as composites and bonding
agents, reduced interaction between antibiotics
and hemosiderin with dentinal walls is observed.
In different studies, though this approach has been
implemented, its usefulness is unpredictable. The use of
Biodentine instead of MTA to minimize the possibility
of discoloration has been reported in several studies.
In general, bleaching of decolored teeth is effective in
improving the esthetic result.[21,29]
We observed a good
accomplishment rates in terms of survival of the treated
tooth and also in the resolution of any associated
pathology in the apical areas; on the contrary, our
results in relation to apex closure along with constant
root development, our findings from various studies
were quiet variable. We observed that at present, there
is a lack of well‑documented, longitudinal studies in
the literature which can focus on long‑term outcomes
of the treated teeth. The interpretation of the processes
underlying angiogenic reactions to dental pulp is still
not yet fully understood. In relation to the production
of new therapies required to regenerate the pulp tissue,
revascularization is important. Hence, regulation
and expression of growth factors such as vascular
endothelial growth factor and fibroblast growth
factor, new therapeutic technique may be applied to
revascularize the pulp tissue of traumatized teeth.
Regenerative endodontic techniques have tremendous
potential to be an effective, healthy, and biological
way of preserving teeth that have damaged structural
integrity if the problems discussed above are addressed.
To advance regenerative therapeutics to the next stage,
significant research and development efforts are needed.
Conclusions
Regenerative endodontic procedures are constantly
being restructured and enhanced to benefit present‑day
dentistry in all likely ways. Still, many factors which
are important for the success of RET outcomes still
remain unexplained. There are still numerous gaps in
our expertise at the present stage of this study.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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