Received: 20 January 2022

| Accepted: 11 May 2022

DOI: 10.1111/iej.13778

REVIEW ARTICLE

Effectiveness of revitalization in treating apical

periodontitis: A systematic review and meta-­analysis

Nastaran Meschi1 | Paulo J. Palma2 | Daniel Cabanillas-­Balsera3

1
Department of Oral Health Sciences, Abstract
Endodontology, KU Leuven &
Background: Revitalization procedures primarily aim to eliminate clinical symp-
Dentistry, University Hospitals Leuven,
Leuven, Belgium toms and heal periapical lesions.
2
Center for Innovation and Research Objectives: The objective of the study was to elucidate the effectiveness of revitali-
in Oral Sciences (CIROS) I Institute zation in treating apical periodontitis in necrotic mature and immature permanent
of Endodontic, Faculty of Medicine,
University of Coimbra, Coimbra, teeth based on the following PICO question: In patients with permanent immature
Portugal or mature teeth and pulp necrosis with or without signs of apical periodontitis (P)
3
Department of Stomatology, Section what is the effectiveness of revitalization (I) in comparison with calcium hydroxide
of Endodontics, School of Dentistry,
apexification, apical plug and root canal treatment (C) in terms of tooth survival,
University of Seville, Seville, Spain
pain, tenderness, swelling, need for medication (analgesics and antibiotics), radio-
Correspondence graphic evidence of reduction of apical lesion size, radiographic evidence of normal
Nastaran Meschi, BIOMAT KU Leuven,
Kapucijnenvoer 7 Blok A –­Bus 7001,
periodontal ligament space, radiographic evidence of increased root thickness and
3000 Leuven, Belgium. length (not for mature teeth), tooth function (fracture and restoration longevity),
Email: [email protected] need for further intervention, adverse effects (including exacerbation, restoration
integrity, allergy and discolouration), oral health-­related quality of life (OHRQoL),
presence of sinus tract and response to sensibility testing (O). (T) = Defined as a min-
imum of 1 year and maximum of as long as possible for all outcome measures, except
‘pain, tenderness, swelling, need for medication (analgesics)’, which is a minimum
of 7 days and maximum of 3 months and OHRQoL which is minimum of 6 months
and a maximum of as long as possible.
Methods: Three databases (PubMed, Embase and Cochrane Library) were searched
for human, experimental and observational studies in English, complemented with
hand search, until 31/10/2021. Studies recruiting teeth with pulp necrosis (with/
without apical periodontitis), with minimum 10 teeth/arm at the end of the study
and with a follow-­up of at least 1 year, were included. Records without an abstract
and a full text were excluded. The qualitative analysis of the included (non-­) rand-
omized controlled clinical trials was performed with the Revised Cochrane risk-­of-­
bias tools (RoB 2 and ROBINS-­I). Meta-­analysis for survival and success (including
a subgroup analysis for mature/immature permanent teeth) was performed using
the Mantel–­Haenszel method. The certainty of evidence was assessed using GRADE
(Grades of Recommendation, Assessment, Development and Evaluation).
Results: From the 365 identified records, five met the inclusion criteria. The
12 months survival rate was 100% for all (im)mature permanent teeth in all groups

© 2022 International Endodontic Journal. Published by John Wiley & Sons Ltd.

Int Endod J. 2022;00:1–23.  wileyonlinelibrary.com/journal/iej | 1

2 |    REVITALIZATION EFFECTIVENESS

(3 studies). The success rate at 12 months was 100% for immature permanent teeth
for I and C (1 study), however, reduced to 92% and 80% for mature teeth in I and C
respectively (1 study, p > .05). The risk of bias for the most critical outcome (survival)
was high for two studies and low for one. For the critical outcome success, all as-
sessed studies were highly biased. Meta-­analyses provided pooled relative risk with
no statistically significant difference between I and C for both survival (RR = 1.00,
95%CI = 0.96–­1.04, p = 1.00) and success (RR = 1.06; 95%CI = 0.83–­1.35, p = .66).
The evidence level for survival was kept ‘low’ and for success was downgraded to
‘very low’ due to inconsistency and imprecision.
Discussion: The survival and success rates were favourable in all included studies
and for all groups; however, these outcomes are not reliable due to the low certainty
level. Clinically, the most reported adverse event was tooth discolouration, hence the
application of bismuth oxide containing calcium silicate cements should be avoided
in revitalization. Radiographically, caution is needed when assessing periapical bone
healing and further root development with periapical radiographs, due to multifac-
torial inaccuracies of this imaging technique. Methodological and assessment con-
cerns need to be addressed in future clinical trials. Long-­term results are necessary
for studies reporting revitalization of mature permanent teeth, as they seem to be
experimental so far.
Conclusions: No robust evidence was discovered to support that revitalization is ef-
fective to treat apical periodontitis in (im)mature permanent teeth. The success and
survival rates of revitalized and fully pulpectomized (im)mature permanent teeth did
not differ significantly.
Registration: Prospero: CRD42021262466.

KEYWORDS
dental pulp, nonvital teeth, permanent dentition, pulp necrosis, regenerative medicine, root canal
therapy

I N T RO DU CT ION tissue regeneration (Langer & Vacanti, 1993; Lin &

Rosenberg, 2011; Murray et al., 2007). Consequently,
Dentine and pulp are histologically different structures since the last 15 years, a novel endodontic treatment mo-
that react to stimuli as one functional unit: the pulp–­ dality named revitalization (also known as regenerative
dentine complex. It regulates dentinogenesis and pulp endodontic procedures or revascularization) attempts to
vitality throughout life. Thus, it is important to under- cure inflamed or necrotic (im)mature permanent teeth
stand the pathobiology of pulp and dentine (Pashley & by respecting the biology of the pulp–­ dentine com-
Tay, 2012). However, when damaged, the regenerative plex (Diogenes et al., 2013; Galler et al., 2016; Wigler
and reparative capacity of pulp and dentine are limited et al., 2013). The main idea behind revitalization is to
(Pashley & Tay, 2012). Regenerated dentine has a greater firstly disinfect the root canal and subsequently attract
ability to protect the pulp against bacterial and phys- (homing) or transplant mesenchymal stem cells from the
icochemical insults than does any restorative or repar- (remaining) dental pulp and apical papilla (in case of im-
ative material (Smith et al., 2000). Hence, regenerative mature teeth) into the root canal (Diogenes et al., 2013;
medicine aims to boost regenerative wound healing, Hilkens et al., 2015; Palma et al., 2019b). More specifi-
based on tissue engineering principles, from which the cally, this therapy is not based on mechanical and (ag-
foundation was provided by Langer and Vacanti in 1993 gressive) chemical debridement as in conventional root
(Langer & Vacanti, 1993; Murray et al., 2007). Increased canal treatment but is supported by the pillars of tissue
knowledge in wound healing of dento-­alveolar struc- engineering: stem cells, growth factors and a scaffold
tures has led to biologically based therapies that favour (Galler et al., 2016; Hilkens et al., 2015).
MESCHI et al.    | 3

Clinically, revitalization has been reported in tri- elucidate the effectiveness of revitalization in treating AP
als mainly applying the cell homing concept (Lin in necrotic mature and immature permanent teeth.
et al., 2021; Torabinejad et al., 2017). Furthermore,
this concept formed the basis for the clinical consider-
ations and a position statement regarding revitalization METHODS
procedures, described by the American Association
of Endodontists (AAE)1 and the European Society of This review was conducted in accordance with the
Endodontology (ESE) respectively (Galler et al., 2016). ‘Preferred Reporting Items for Systematic reviews and
Further root development in immature permanent teeth Meta-­Analyses’ (PRISMA) and is registered on the
and regaining/maintaining pulp sensitivity are import- PROSPERO database2 with number CRD42021262466
ant objectives in revitalization. However, the primary (Moher et al., 2009).
goal is the elimination of symptoms and healing of the
periapical lesion (if one is present) (Galler et al., 2016).
In a previous systematic review, high pooled survival Problem specification
(97.8%; average follow-­up: 16.7 months) and success
(91.3%) rates for periapical bone healing were reported The following review question was formulated: ‘In pa-
(Torabinejad et al., 2017). Nevertheless, reports since tients with permanent immature or mature teeth and pulp
then were not consistent and in accordance with this necrosis with or without signs of AP, what is the effective-
outcome. A prospective clinical trial concerning the ness of revitalization in comparison with calcium hydrox-
impact of apical periodontitis (AP) on revitalization of ide apexification, apical plug and root canal treatment in
immature permanent teeth reported the negative impact terms of tooth survival, pain, tenderness, swelling, need
of preoperative pulp necrosis and AP on further root de- for medication, radiographic evidence of reduction of api-
velopment and complete periapical bone healing post cal lesion size, radiographic evidence of normal periodon-
revitalization (Shetty et al., 2020). In another study, the tal ligament space, radiographic evidence of increased
impact of the microbial load on the revitalization out- root thickness and length, tooth function, need for further
come was assessed (De-­Jesus-­Soares et al., 2020). In that intervention, adverse effects, oral health-­related quality
study, the clinical symptoms and periapical lesions were of life (OHRQoL), presence of sinus tract and response
successfully cured post-­revitalization. Nevertheless, due to sensibility testing’. In Table 1 the importance of the
to residual bacteria, the dentinal wall thickness was outcomes has been subdivided and expressed as a PICO
reduced. Furthermore, as there is a lack of mechani- question. Furthermore, in this context the term ‘apical
cal debridement in revitalization, an in vitro study re- periodontitis (AP)’ was defined prior to literature search:
ported the detrimental role of a residual biofilm on the AP is a common global disease affecting the tissues sur-
release of TGF-­β1 after dentin conditioning (Cameron rounding the roots of teeth with infections within the root
et al., 2019). Moreover, in revitalization cases with a canal system. AP can be subdivided into3:
persistent infection, longer periods of disinfection may
lead to clinical success but histologically to rather repair • asymptomatic AP—­Inflammation and destruction of
than regeneration (Lui et al., 2020). apical periodontium that is of pulpal origin, appears as
Unlike revitalization in immature teeth, where it is known an apical radiolucent area and does not produce clinical
that root development and the elimination of symptoms and symptoms.
signs of the periapical lesion are attainable, to our knowl- • symptomatic AP—­Inflammation usually of the apical
edge, no guidelines nor position statements recommend periodontium, producing clinical symptoms including
revitalization as a treatment option for mature permanent a painful response to biting and/or percussion or palpa-
teeth with pulp necrosis. Nevertheless, a recent systematic tion. It might or might not be associated with an apical
review provided moderate-­quality evidence regarding revi- radiolucent area.
talization instead of conventional root canal treatment of
mature permanent teeth with periapical lesions. Even if this
approach seems experimental, the clinical outcomes seem Literature search plan
promising (Glynis et al., 2021). Nevertheless, an indepen-
dent analysis of survival and treatment success in immature A comprehensive electronic literature search was performed
and mature teeth should be carried out. in three databases (PubMed, Embase and Cochrane Library).
Clearly, infection control and morbidity caused by in- The MeSH/Emtree terms and text words applied during
fection remain hurdles for this novel endodontic treatment the literature search and the search strategy are mentioned
modality. Hence, this systematic review primarily aims to in Table 1. Additionally, a hand search was executed in the
4 |    REVITALIZATION EFFECTIVENESS

TABLE 1 PICO question, search strategy and eligibility criteria

PICO question P = patients with permanent immature or mature teeth and pulp necrosis with or without signs of AP
I = individuals undergoing revitalization (regenerative endodontic procedures) in teeth with pulp necrosis with or
without signs of AP
C = individuals undergoing calcium hydroxide apexification, apical plug or root canal treatment in teeth with pulp
necrosis with or without signs of AP
O = most critical: tooth survival
critical: pain, tenderness, swelling, need for medication (analgesics and antibiotics), radiographic evidence of
reduction of apical lesion size, radiographic evidence of normal periodontal ligament space, radiographic
evidence of increased root thickness and length (not for mature teeth)
additional: tooth function (fracture and restoration longevity), need for further intervention, adverse effects
(including exacerbation, restoration integrity, allergy and discolouration), OHRQoL, presence of sinus tract and
response to sensibility testing
Databases PubMed, Embase and Cochrane Library
Search strategy
I (1) MeSH/Emtree terms: ‘dental pulp’ OR ‘medicine, regenerative’ OR ‘nerve regeneration’ OR ‘regenerative
endodontics' OR ‘regenerative medicine’ OR ‘regenerative medicines’ OR ‘revascularization’ OR ‘root canal
therapy’
OR
Text words: ‘dental pulp’ OR ‘dental pulp regeneration’ OR ‘medicine, regenerative’ OR ‘nerve regeneration’
OR ‘regenerative endodontics’ OR ‘regenerative endodontic procedure’ OR ‘regenerative medicine’ OR
‘regenerative medicines' OR ‘revascularisation’ OR ‘revascularization’ OR ‘revitalisation’ OR ‘revitalization’ OR
‘root canal therapy’ OR ‘root canal therapies’
P (2a) MeSH/Emtree terms: ‘adult dentition’ OR ‘dentition, adult’ OR ‘permanent dentition’ OR ‘permanent tooth’
OR ‘secondary dentition’
OR
Text words: ‘adult dentition’ OR ‘permanent tooth’ OR immature’ OR ‘immature permanent tooth’ OR ‘immature
permanent teeth’ OR ‘mature’ OR ‘mature permanent tooth’ OR ‘mature permanent teeth’ OR ‘permanent
dentition’ OR ‘permanent teeth’
(2b) MeSH/Emtree terms: ‘dental’ OR ‘dental pulp necrosis’ OR ‘dental pulp necroses’ OR ‘necrosis’ OR ‘nonvital
teeth’ OR ‘nonvital tooth’ OR ‘pulp necrosis' OR ‘pulp necroses, dental’ OR ‘pulp necroses' OR ‘teeth, nonvital’
OR ‘tooth, nonvital’
OR
Text words: ‘nonvital’ OR ‘nonvital’ OR ‘nonvital’ OR ‘nonvital tooth’ OR ‘necrosis'OR ‘necrotic’ OR ‘necrotic
pulp’ OR ‘pulp necrosis’
Search combination (1) AND (2a AND 2b)
Inclusion criteria • Language: English
• Study designs: human, experimental ((non-­)randomized controlled clinical trials) and longitudinal
observational studies (retrospective and prospective comparative cohort and case–­control studies)
• Teeth with pulp necrosis (with/without AP) are included
• Number of teeth: at least 20 (10 in each arm) at the end of the study
• Duration of follow-­up: minimum of 1 year and maximum of as long as possible for all outcome measures, except
‘pain, tenderness, swelling, need for medication (analgesics)’, which is a minimum of 7 days and maximum of
3 months and OHRQoL which is minimum of 6 months and a maximum of as long as possible
• Database search and hand search performed on 12/08/2021, updated on 31/10/2021
Exclusion criteria • Animal and In vitro studies
• Tooth type: deciduous teeth
• Studies without abstracts and full texts
Abbreviations: AP, apical periodontitis; C, comparison; I, intervention; O, outcome; OHRQoL, oral health-­related quality of life; P, population.

reference lists of all included papers and in previously pub- Publication retrieval
lished reviews during the last 20 years of the International
Endodontic Journal and the Journal of Endodontics. Two independent reviewers (NM and PJP) identified the
Furthermore, to identify conference papers and other grey records through the databases. The eligibility criteria for
literature, additional searches were performed using Google this review are mentioned in Table 1. Duplicates were re-
Scholar (first 100 returns). moved via the EndNote™ reference manager. The titles,
MESCHI et al.    | 5

abstracts and full texts were screened by both reviewers. as measure of the effect. The pooled RR was calculated
Publications that did not meet the inclusion criteria were using the method of Mantel–­Haenszel, as well as chi-­
excluded upon reviewers' agreement. square and I2 tests were used to assess heterogeneity among
the ORs calculated (Higgins & Thompson, 2002). An I2
test less than 40% was considered as heterogeneity that
Data extraction, quality assessment and might not be important, while I2 test greater than 50% rep-
data synthesis resented substantial heterogeneity (Higgins et al., 2003).
A random effects model was carried out in the presence of
The data extraction was performed by two independent heterogeneity, while a fixed effects model was performed
reviewers (NM and PJP) by means of a pre-­established if heterogeneity was not demonstrated. Finally, 95% con-
and piloted spreadsheet. The following details were fidence intervals for RR were calculated and significance
mentioned in the spreadsheet for each included study: level of p < .05 was considered. A Forest plot was used to
name and country of the first author, year published, show the OR results (Lewis & Clarke, 2001).
name of the journal, type of study design, total number The overall quality of evidence for each of the main
of participants, age distribution, number of participants outcomes per study design was rated by using the Grades
with AP, outcome measures employed, type of radio- of Recommendation, Assessment, Development and
graphic assessment and method of radiographic assess- Evaluation (GRADE) approach (Guyatt et al., 2011). This
ment. In case of incomplete or missing data, the authors certainty assessment was based on four main domains
of the papers were contacted for clarification. If non-­ (risk of bias, inconsistency, indirectness and imprecision),
agreement occurred between the reviewers, the data as well as the (absolute and relative) effect obtained by the
were not used until further clarification was available meta-­analysis. Other considerations, such as publication
(resolved by discussing with a third reviewer). In case of bias and rating the dose–­response gradient, the influence
studies with more than two arms and/or multiple papers of all plausible residual confounding and the magnitude
reporting on the same study, only the relevant data of of the effect, were assessed as well.
interest was extracted.
Critical, qualitative appraisal of the included studies
was performed depending on the study type and for each RESULTS
main outcome. For randomized controlled clinical trials
(RCTs) the second version of the Cochrane risk-­of-­bias Literature identification
tool (RoB 2) was applied.4 This tool assesses five quality
criteria after which the overall risk of bias per study is The database and hand search resulted in 365 articles, of
calculated: (1) the randomization process, (2) deviations which 19 duplicate records were removed. The flow dia-
from intended interventions, (3) missing outcome data, gram of the searches is mentioned in Figure 1, which is
(4) measurement of the outcome and (5) selection of the based on the PRISMA 2020 flow diagram for new system-
reported result. For the non-­randomized comparative clin- atic reviews (Page et al., 2021). Of a total of 346 articles, 302
ical trials (NRCT), the ROBINS-­I tool5 was applied. This were excluded post title screening (almost perfect Kappa
tool assesses seven quality criteria after which the overall agreement of 0.98). Post-­abstract screening of 44 articles
risk of bias per study is calculated: (1) confounding, (2) (almost perfect Kappa agreement of 0.94), 18 ­articles re-
selection of participants into the study, (3) classification mained for full-­text screening. From those, 13 articles were
of interventions, (4) deviations from intended interven- excluded for which the reasons are mentioned in Table 2
tions, (5) missing outcome data, (6) measurement of the (Alobaid et al., 2014; Aly et al., 2019; Botero et al., 2017;
outcome and (7) selection of the reported result. Chen & Chen, 2016; El-­ Kateb et al., 2020; Estefan
Agreement between reviewers was assessed with the et al., 2016; Jeeruphan et al., 2012; Nagy et al., 2014; Peng
intraclass correlation coefficient (ICC). ICC estimates and et al., 2017; Pereira et al., 2020; Rizk et al., 2020; Sallam
their 95% confident intervals were calculated using SPSS et al., 2020; Yılmaz et al., 2019). From the 5 articles that
statistical package version 27 (SPSS Inc) based on a 2-­way met the inclusion criteria post full-­ text screening, the
mixed-­effects model and absolute-­agreement definition. data were extracted and included for further analysis
A meta-­analysis of the main outcomes between the (Tables 3 and 4, Appendix 1) (Arslan et al., 2019; Brizuela
subgroups ‘immature’ and ‘mature’ permanent teeth was et al., 2020; Jha et al., 2019; Lin et al., 2017; Silujjai &
conducted if sufficient data were provided. The statisti- Linsuwanont, 2017). The included studies were classified
cal analyses for the meta-­analysis were performed using into two subgroups, depending on the root development
RevMan software (Review Manager (RevMan) [Computer of the teeth on which revitalization was applied (mature/
program]) version 5.4. The risk ratio (RR) was established immature) (Table 3 and Appendix 1).
6 |    REVITALIZATION EFFECTIVENESS

Identification of studies via databases Identification of studies via other sources

Records identified from:

- Grey literature:
Records identified from: Records removed before
Google Scholar (n=5)
- Pubmed (n = 149) screening:
- Manual search references:
- Embase (n = 132) Duplicate records removed
other systematic reviews
- Cochrane Library (n = 73) (n = 19)
(n = 4)
included articles (n= 2)

Titles screened (n = 335) Records excluded

(n = 302)

Abstracts screened (n = 33) Reports not retrieved Reports sought for retrieval
(n = 26) (n = 11)
Reports excluded: Reasons:
- control group: not root canal
Reports excluded: Reasons: treatment or apexification
- no revitalization in one of the (n = 5)
Full texts assessed for eligibility groups (n = 1) Reports assessed for eligibility - < 10 patients/group at end
(n = 7) - follow-up < 1 year (n = 2) (n = 11) study (n= 1)
- < 10 patients/group at end - erroneous study design and
study (n= 2) pooling of different groups in
1 (n= 2)

Studies included in qualitative

synthesis (n = 5)
Reports excluded: Reasons:
- non-randomized clinical trial
(n = 1)

Studies included in quantitative

analysis (n = 4)

F I G U R E 1 Flow diagram including searches of databases and other sources, screenings (title, abstract and full texts) and the number of
included and excluded articles

TABLE 2 Excluded articles with reasons follow-­up periods varied between 3 months and 5 years.
First author,
Three studies analysed the subject at 12 months (Arslan
publication year Reason for exclusion et al., 2019; Brizuela et al., 2020; Lin et al., 2017), in two
other studies the final analysis was performed at 18 months
Yilmaz, 2019 No revitalization in one of the groups
and later (Jha et al., 2019; Silujjai & Linsuwanont, 2017).
Botero, 2017
The dropout rate ranged between 0% and 43% (Table 3 and
Nagy, 2014 <10 patients/group at the end of the study
Appendix 1).
Pereira, 2020
Peng, 2017 Control group: not root canal treatment
Rizk, 2020 or apexification Subject characteristics
Aly, 2019
Estefan, 2016 Two out of five studies did not report whether male
El-­Kateb, 2020 or female patients were included (Jha et al., 2019; Lin
Silujjai, 2017a Non-­randomized clinical trial et al., 2017). In two studies the age range varied consider-
Alobaid, 2014 Erroneous study design and pooling of
ably (Brizuela et al., 2020; Silujjai & Linsuwanont, 2017)
different groups in 1 even if in one study (age range: 8–­46 years) immature per-
Chen, 2016
manent teeth were treated (Silujjai & Linsuwanont, 2017).
Sallam, 2020 Follow-­up <1 year
In three studies mature permanent teeth with a periapi-
Jeeruphan,2012
cal index (PAI) score of at least 2–­3 were treated (Orstavik
a
Excluded from the meta-­analysis. et al., 1986); however, in Jha et al. (2019) the type of teeth
(incisor/[pre]molar) was not specified (Arslan et al., 2019;
Assessment of heterogeneity Brizuela et al., 2020; Jha et al., 2019). In these studies, re-
vitalization was compared with conventional root canal
Study design and evaluation period treatment (CRCT). In the two other included studies
nonvital, immature permanent teeth were treated and
Four RCTs and one retrospective NRCT were included. in one of those the type of tooth was not specified (Lin
One RCT was a Phase I/II study (Brizuela et al., 2020). The et al., 2017; Silujjai & Linsuwanont, 2017). Only in these
MESCHI et al.    | 7

TABLE 3 Data extraction of the included articles

First author, year Arslan H, 2019 Brizuela C, 2020 Jha P, 2019 Lin J, 2017 Silujjai J, 2017
published
Study design RCT RCT Phase I/II RCT Prospective RCT Retrospective NRCT
Age range 18–­30 y 16–­58 y 9–­15 y 8–­16 y 8–­46 y
Follow-­up 12 m 6, 12 m 6, 12, 18 m 3, 6, 9, 12 m 6 m, 1–­5 y
Groups (n) rev (n = 26) rev + PPP-­UC-­MSCs SealBio rev rev (n = 69) rev (n = 17)
CRCT (n = 20) (n = 18) (n = 15) MTA apex (n = 34) MTA apex (n = 26)
CRCT (n = 18) CRCT (n = 15)
Patient dropout 14%: 56 included, 8 0% 0% 13%: 118 included, 15 42.7%: 75 eligible,
dropout (2 rev, 8 dropout (11 rev, 4 46 contacted, 43
CRCT) MTA apex) attended recall
Results main Success: (p > .05) Survival: all analysed Success: (p = .62) Success and survival: *Success: (p > .05)
outcome(s) at rev: 92.3% teeth SealBio rev: 13 all analysed teeth rev 76.47%
final follow-­up CRCT: 80% healed, 2 100% MTA apex 80.77%
healing *Survival: (p > .05)
CRCT: 12 healed, 3 rev: 88.24%
healing MTA apex: 82.76%
Note: All included teeth had apical periodontitis. Colour indication for subgroups: white: mature teeth, blue: immature teeth.
Abbreviations: CRCT, conventional root canal treatment; DE, dens evaginatus; m, months; MTA apex, mineral trioxide aggregate apexification; n, number of teeth;
(N)RCT, (non-­)randomized controlled clinical trial; PPP-­UC-­MSCs, platelet poor plasma –­umbilical cord mesenchymal stem cells; rev, revitalization; y, year.

two studies, comparing revitalization to mineral trioxide Regarding the number of treatment sessions, in CRCT
aggregate (MTA) apexification, the etiological reason for it was not reported or performed in two sessions with
AP was mentioned (caries, trauma, or dens evaginatus). 1–­3 weeks in between. For MTA apexification this was not
mentioned or performed in three sessions with one-­week
intervals. Revitalization was performed in two to three
Treatment protocols sessions with 1–­3 week intervals. As intermediate root
canal dressing for the comparator, mostly calcium hydrox-
In Brizuela et al. (2020), a combination of the cell hom- ide was used. A tri-­antibiotic paste, combining metroni-
ing and cell-­based concept was applied in revitalization, dazole and ciprofloxacin with minocycline/doxycycline/
more specifically: after triggering a blood clot periapically clindamycin, was applied as an intracanal medication in
(= cell homing), allogenic umbilical cord mesenchymal all revitalization groups.
stem cells encapsulated in plasma-­ derived biomaterial As root canal filling, warm gutta percha was applied
were transplanted into teeth (= cell-­ based) (Diogenes upon the MTA-­plug in the MTA-­apexification groups and
et al., 2013; Lin et al., 2021). This revitalization treatment gutta percha and sealer in the CRCT groups. In the revi-
concept was quite different from that of the four other in- talization groups, a blood clot was triggered in all stud-
cluded studies, as these studies relied on the recruitment ies, and in one study platelet poor plasma with umbilical
of only endogenous mesenchymal stem cells for revitaliza- cord mesenchymal stem cells were added to this blood
tion by triggering a blood clot periapically (= cell homing). clot (Brizuela et al., 2020). In two studies a resorbable
Hence, the pool of mesenchymal stem cells for the revital- collagen sponge was placed upon the blood clot (Brizuela
ized mature teeth in Brizuela et al. (2020) was greater than et al., 2020; Lin et al., 2017). MTA was applied as seal upon
that for Arslan et al. (2019) and Jha et al. (2019). the blood clot in three studies, Biodentine (Septodont) in
Regarding the irrigation protocols, the sodium hypochlo- one study, and in another study no calcium silicate cement
rite (NaOCl) and ethylenediaminetetraacetic acid (EDTA) was applied (Jha et al., 2019). The coronal restoration was
concentrations applied were similar in both groups per study in four studies composite resin and not specified in one
and amounted 1%–­2.5% and 17% respectively (Table 2). In study (Jha et al., 2019).
Arslan et al. (2019) distilled water was additionally applied
in the second revitalization session and in Lin et al. (2017)
in both revitalization sessions 0.9% saline was applied. Assessment methods
To activate the disinfectant, in Brizuela et al. (2020) the
Endoactivator system (Dentsply Tulsa Dental Specialties) Regarding the radiographic assessment, in all studies
was used and in Jha et al. (2019) negative pressure. the radiographic follow-­up was performed by means of
 8
|
  

T A B L E 4 (a) Risk of bias summary: review authors' judgements about each risk of bias item for each included randomized controlled clinical trial per main outcome (success and survival).
(b) Risk of bias summary: review authors' judgements about each risk of bias items for 1 included non-­randomized comparative trial per main outcome (success and survival)

(a)

Deviation from Measurement of Selection of

Aim Ouctome Study Randomization intervention Missing data outcome reported results Overall
Intention-­to-­ Success Arslan et al. (2019) ! - + + - -
treat
Lin et al. (2017) - - - - ! -

Jha et al. (2019) - ! + + ! -

Survival Lin et al. (2017) - - - + ! -

Brizuela et al. (2020) + + + + + +

(b)

Deviation
Intervention from Measurement of Selection of
Study Ouctome Confounding Selection classification intervention Missing data outcome reported results Overall
Silujjai and Linsuwanont (2017) Success - + - + - ! ! -

Survival - ! - + - ! + -

Note: Dots: green = low risk, yellow = some concerns, red = high risk.
REVITALIZATION EFFECTIVENESS
MESCHI et al.    | 9

periapical radiographs (PR). However, in two studies cone In Lin et al. (2017) the 12 months success rate for imma-
beam computed tomography (CBCT) was applied addi- ture teeth amounted 100% in the revitalization as well as in the
tionally (Brizuela et al., 2020; Lin et al., 2017). In two out MTA apexification group. Nevertheless, in Arslan et al. (2019),
of five studies the positioning of the periapical radiographs mature teeth undergoing revitalization were more successful
was standardized (Arslan et al., 2019; Lin et al., 2017). In (92%) than the teeth in the CRCT group (80%) at 12 months,
four studies a qualitative scoring system was used for the but this was statistically insignificant (p > .05).
assessment of the periapical lesion (Arslan et al., 2019; Other critical outcomes such as ‘radiographic evidence
Brizuela et al., 2020; Estrela et al., 2008; Jha et al., 2019; of normal periodontal ligament space’ and ‘need for med-
Lin et al., 2017; Orstavik et al., 1986). Only in one study the ication (analgesics, antibiotics)’ were in 60–­100% of the
periapical lesion was quantitatively measured with CBCT studies respectively not reported (Appendix 1).
(Brizuela et al., 2020). The two studies assessing further Regarding the additional outcomes of the current re-
root development of immature permanent teeth were het- view, as mentioned above ‘OHRQoL’ and ‘response to
erogenous in the device applied (CBCT versus PR) and the sensibility testing’ were rarely assessed. However, the
assessment method (Appendix 1) (Lin et al., 2017; Silujjai other additional outcomes mentioned in Table 1 were re-
& Linsuwanont, 2017). ported in all included studies (but not as main outcome)
Regarding the clinical assessments, clinical signs (Appendix 1).
and adverse events were generally reported in all tri-
als (Appendix 1). However, only one trial adequately
measured the OHRQoL and pain symptoms (Arslan Funding
et al., 2019) and two studies assessed the pulp sensitivity
(Arslan et al., 2019; Brizuela et al., 2020). Only in one trial the funding resources were not men-
tioned (Silujjai & Linsuwanont, 2017). Two studies did not
use any funding and two other trials received institutional
Study outcomes or government grants (Appendix 1).

The most critical outcome ‘survival’ was not reported by

one study (Arslan et al., 2019). However, in 75% of the in- Quality assessment
cluded studies that did report survival, it was considered
as the main outcome (Brizuela et al., 2020; Lin et al., 2017; The results of the qualitative assessment of the four in-
Silujjai & Linsuwanont, 2017) (Table 3). In three studies cluded RCTs are mentioned in Table 4a. For the most
the survival rate at 12 months was 100% for all permanent critical outcome ‘survival’ this assessment resulted in a
teeth in all groups, independent of the tooth type (mature/ high risk of bias for one study (Lin et al., 2017) and in a
immature) or treatment modality (revitalization, CRCT or low risk of bias for another (Brizuela et al., 2020). For the
MTA apexification) (Brizuela et al., 2020; Jha et al., 2019; critical outcome ‘success’ three studies were highly bi-
Lin et al., 2017). ased (Arslan et al., 2019; Jha et al., 2019; Lin et al., 2017).
Regarding the critical outcomes of this review, a combi- Independent of the outcome criteria, mostly the thresholds
nation of clinical symptoms (‘pain, tenderness, swelling’) ‘randomization’, ‘deviations from intended interventions’
and radiographic findings (‘radiographic evidence of re- and ‘selection of reported results’ showed methodological
duction in apical lesion size’ and ‘radiographic evidence of limitations (Figure 2a,b).
increased root thickness and length’ (not for mature teeth)) The only NRCT was assessed with the ROBINS-­I tool
were defined as success, which was the main outcome in (Table 4b). This study was highly biased for both survival
80% of the studies (Arslan et al., 2019; Jha et al., 2019; Lin and success (Silujjai & Linsuwanont, 2017).
et al., 2017; Silujjai & Linsuwanont, 2017) (Table 3 and The qualitative assessments were performed with good
Appendix 1). In immature teeth, Lin et al. (2017) reported inter-­rater reliability for success (ICC = 0.86, 95% CI [0.66;
a significant difference in root lengthening and thickening 0.95) and perfect agreement for survival (ICC = 1).
at 12 months in favour of the revitalized group in compar-
ison with the MTA-­apexification group and independent
of the ethiology (Lin et al., 2017). Nevertheless, in Silujjai Quantitative analysis
and Linsuwanont (2017) this was not the case for root
lengthening and dens evaginatus cases presented the most The subgroups (mature/immature permanent teeth) of
increase in root development in comparison with trauma the RCTs were subjected to quantitative analysis to com-
and dental caries cases (Silujjai & Linsuwanont, 2017) pare the survival and success rates of revitalization with
(Appendix 1). CRCT or MTA apexification.
10 |    REVITALIZATION EFFECTIVENESS

(a) Success

Overall Bias

Selec on of the reported result

Measurement of the outcome

Mising outcome data

Devia ons from intended interven ons

Randomiza on process
0 10 20 30 40 50 60 70 80 90 100
%

Low risk Some concerns High risk

(b) Survival

Overall Bias

Selec on of the reported result

Measurement of the outcome

Mising outcome data

Devia ons from intended interven ons

Randomiza on process

0 10 20 30 40 50 60 70 80 90 100
%

Low risk Some concerns High risk

FIGURE 2 Summary of risk of bias assessments (based on Table 4a) for quality criteria per main outcome (success or survival)

Survival for both subgroups and overall calculated from the meta-­
analysis (Figure 3).
For each included RCT that reported survival rate data
at 12 months (or later), results were extracted, classified
into mature (Brizuela et al., 2020; Jha et al., 2019) or im- Success
mature (Lin et al., 2017) permanent tooth subgroup, and
RRs were calculated. The analysis of pooled heterogene- To analyse the success of the treatment, the results of
ity and variance between the studies was non-­significant each included article that reported success rate data at
(Chi2 = 0.00; df = 2; p = 1.00; I2 = 0), indicating ho- 12 months were extracted, being classified according to
mogeneity between the RRs of the included studies. The the subgroup of mature teeth (Arslan et al., 2019) or im-
Mantel–­Haenszel method with fixed effects provided a mature (Lin et al., 2017), and the RRs were calculated.
pooled RR = 1.00 (95% CI = 0.96–­1.04; p = 1.00), indicat- The analysis of variance between the studies was signifi-
ing non-­statistically significant differences between the cant (Tau2 = 0.03; Chi2 = 4.14; df = 1; p = .04) and the
survival of revitalization group versus the CRCT or MTA I2 test (= 76%) showed substantial heterogeneity between
apexification group. Results without statistically signifi- the RRs of the included studies. Mantel–­Haenszel method
cant differences were also found within the subgroup of with random effects provided a pooled RR = 1.06 (95%
mature (RR = 1.00; 95% CI = 0.92–­1.08; p = 1.00) and im- CI = 0.83–­1.35; p = .66), indicating a slight favour, but
mature teeth (RR = 1.00; 95% CI = 0.96–­1.05; p = 1.00). without statistically significant differences, in the success
Forest plot shows the RRs for each study and the RRs of the revitalization treatment with respect to the CRCT or
MESCHI et al.    | 11

FIGURE 3 Forest plot of subgroup analysis of survival rates

FIGURE 4 Forest plot of subgroup analysis of success rates

MTA apexification treatment. Results without statistically GRADE. However, for NRCT the level of evidence can
significant differences were also found within the treat- be downgraded up to 3 levels in comparison with RCTs
ment of mature (RR = 1.15; 95% CI = 0.90–­1.48; p = .25) (up to 2 levels). Nevertheless, no GRADE assessment was
and immature teeth (RR = 1.00; 95% CI = 0.96–­1.05; performed for Silujjai and Linsuwanont (2017), as it was
p = 1.00). Forest plot shows the RRs for each study and the only NRCT of this review, highly biased and excluded
the RRs for both subgroups and overall calculated from from the meta-­analysis (Table 2). Hence, this study would
the meta-­analysis for the success outcome (Figure 4). have no added value to clinical decision making.
Regarding the critical outcome ‘success’ of the two
RCTs assessed, the level of evidence has been downgraded
Certainty assessment with one level to ‘very low’ due to inconsistency and im-
precision. Regarding the most critical outcome ‘survival’,
The overall quality of the evidence of each main outcome the level of evidence was kept ‘low’. Nevertheless, also
has been rated for the RCTs in the Summary of Findings for this outcome, imprecision due to a small number of
(SoF) Table (Table 5). Non-­randomized studies on inter- events was scored as ‘serious’ (Table 5).
vention effects, such as Silujjai and Linsuwanont (2017),
can be assessed for certainty by means of the ROBINS-­I
tool. The same downgraders (risk of bias, inconsistency, DISCUSSION
indirectness, imprecision and publication bias) and up-
graders (dose–­response gradient, plausible residual con- Revitalization is a biologically based endodontic treatment
founding and effect magnitude) as for RCTs are used in with promising pre-­clinical results, aiming to preserve or
 12
|
  

TABLE 5 Summary of findings table from the GRADEpro Guideline Development Tool (https://grade​pro.org)

Certainty assessment No. of patients Effect

Calcium
hydroxide
apexification,
apical plug
No. of Risk of Other and root canal Relative
studies Study design bias Inconsistency Indirectness Imprecision considerations Revitalization treatment (95% CI) Absolute (95% CI) Certainty Importance

Clinical and radiographic success—­follow-­up at 12 months

2a Randomized Seriousb Seriousc Not serious Seriousd None 93/95 (97.9%) 50/54 (92.6%) RR 1.06 (0.83 56 more per 1000 (from 157 ⨁◯◯◯ Critical
trials to 1.35) fewer to 324 more) Very low
Survival—­follow-­up at 12 months
3e Randomized Seriousf Not seriousg Not serious Seriousd None 102/102 67/67 (100.0%) RR 1.00 (0.96 0 fewer per 1000 (from 40 ⨁⨁◯◯ Most critical
trials (100.0%) to 1.04) fewer to 40 more) Low

Abbreviations: CI, confidence interval; RR, risk ratio.

a
Arslan et al. (2019) and Lin et al. (2017). Jha et al. (2019) was not included in this table as the results for success at 12 months were not mentioned in this study. Results for success at 18 months cannot be extrapolated
to 12 months.
b
See Table 4a.
c
Figure 4: CIs have reasonable overlap. Substantial statistical heterogeneity: p = .04, I2 = 76%. Therefore, inconsistency was downgraded by one level.
d
<400 events = few events and hence not enough power to obtain a reliable level of certainty.
e
Brizuela et al. (2020), Jha et al. (2019) and Lin et al. (2017). Survival was not the main outcome in Jha et al. (2019), nevertheless this outcome was assessed in this study at 18 months (which can be extrapolated to
12 months).
f
See Table 4a: based on Brizuela et al. and Lin et al. (2017).
g
Figure 3: CIs have a perfect overlap. No heterogeneity, but statistically insignificant: p = 1, I2 = 0%.
REVITALIZATION EFFECTIVENESS
MESCHI et al.    | 13

regain as much as possible the entity and functionality of or necrotic pulp to prevent discontinued maturogenesis
the pulp–­dentine complex. The primary goal of revitaliza- (Galler et al., 2016). Nevertheless, ever since, gradually
tion procedures is to eliminate clinical symptoms and heal more trials have implemented this treatment in mature
periapical lesions (Galler et al., 2016). Consequently, it is permanent teeth (Scelza et al., 2021). Furthermore, in
important to verify if this goal has clinically been reached. Silujjai and Linsuwanont (2017) revitalization was per-
formed on permanent teeth with open apices in patients
up to 46 years old. Besides the fact that these studies are
Strengths experimental and the long-­term prognosis of these teeth
is unknown, it is unlikely that further root development
Via a systematic approach, the literature has been re- (in case of immature teeth) will take place at an older
viewed to assess the efficacy of revitalization in treating age as the pool of mesenchymal stem cells depletes with
AP. This approach is of utmost importance to obtain a age (Hilkens et al., 2015). Additionally, none of the mes-
full and impartial view of what has been published so enchymal stem cells could induce further root develop-
far. The carefully selected and consensus-­ based out- ment if the Hertwig's epithelial root sheath has broken
come measures (Duncan et al., 2021), narrow focus down into the epithelial cell rests of Malassez (Tucker
or PICO question (Table 1), comprehensive search for & Sharpe, 2004). Hence, the pool of mesenchymal stem
evidence based on a pre-­established protocol (Figure 1), cells for the cell-­based revitalized mature permanent
criterion-­based selection of evidence (Table 4a,b), thor- teeth in Brizuela et al. (2020) was greater than that for
ough qualitative and quantitative appraisal of validity the cell homing based studies Arslan et al. (2019) and
(Table 5; Figures 3 and 4) and evidence-­based conclu- Jha et al. (2019). Nevertheless, this did not impact the
sions form the strengths of this review. Nevertheless, outcomes (Appendix 1) nor the quantitative analysis of
numerous critical concerns arose during this process the two most comparable studies, Jha et al. (2019) and
that may be considered as limitations. Hence, contradic- Brizuela et al. (2020). Furthermore, in case of mature per-
torily, the ultimate strength of the current review lies manent teeth, the long-­term survival of the coronal res-
in its limitations (described below), which might offer toration in severely restored revitalized teeth should be
new perspectives for further research in revitalization investigated.
procedures.
Remarkably, 80% of the included articles seem not to
have a conflict of interest or partiality based on funding Clinical and radiographic assessment
resources (Appendix 1).
One of the goals in revitalization is to maintain or regain
the pulpal sensibility (Galler et al., 2016). Nevertheless, in
Limitations only 40% of the included trials this is tested (Appendix 1)
and in one study the reliability of this test is doubtable.
Methodological concerns More specifically, in Brizuela et al. (2020), mature perma-
nent teeth post CRCT have been tested for sensibility.
Only a few articles met the eligibility criteria (Figure 1). In Regarding adverse events, MTA discolouration was
all included articles, revitalization seems to be effective to mostly reported in cases where MTA was applied as cal-
treat AP in terms of clinical and radiographic success and cium silicate cement (CSC) in revitalization (Appendix 1).
survival in (im)mature permanent teeth in comparison This is mainly due to leakage of the radio-­opacifier bismuth
with CRCT or MTA apexification (Table 3). Nevertheless, oxide (Palma et al., 2019a; Palma et al., 2020). As in revi-
90% of the articles were highly biased (Table 4a,b and talization the CSCs are applied coronally, in future treat-
Figure 2) and even more downgraded due to mainly incon- ment guidelines it is preferable that CSC without bismuth
sistency and imprecision concerns (Table 5). Furthermore, oxide or other discolouring agents are recommended.
publication bias could not be analysed due to the lack of Regarding the radiographic assessment of revitalized
existing published studies, which may result in a system- teeth, the assessment device and method are of utmost im-
atic overestimation of treatment benefit. portance for reliable outcome determination. Follow-­up
with PR is recommended by the ESE position statement
on revitalization procedures and has been applied the
Mature versus immature teeth most in clinical trials (Galler et al., 2016; Torabinejad
et al., 2017). Nevertheless, interpretation of PRs is influ-
Initially, revitalization procedures were rather recom- enced by the image quality and angulation. Positioning
mended to treat immature permanent teeth with inflamed tools (stents e.g.) to standardize and algorithms to adjust
14 |    REVITALIZATION EFFECTIVENESS

the angulation of PRs might reduce this problem (Bose Daniel Cabanillas-­
Balsera contributed to PICOTS and
et al., 2009). Nevertheless, young patients outgrow indi- meta-­analysis.
vidualized positioning tools during a long follow-­up pe-
riod (Meschi et al., 2021) and adjusting software might ACKNOWLEDGEMENTS
occasionally lead to image distortion and elongation We would like to express our gratitude to Prof. Dr. Kerstin
(Silujjai & Linsuwanont, 2017). Furthermore, it has been Galler (Erlangen University, Erlangen, Germany), Prof.
described that the accuracy of PRs is much less than Dr. Juan Jose Segura-­Egea (University of Sevilla, Sevilla,
that of CBCT (Ezeldeen et al., 2015; Meschi et al., 2018; Spain) and Dr. Trudy Bekkering (Belgian Centre for
Meschi et al., 2021). Hence, especially in multidisciplinary Evidence-­Based Medicine, Leuven, Belgium) for their
decision making in young patients with revitalized teeth guidance throughout this project. A special thanks
with uncertain prognosis, an optimized (low dose) CBCT to Prof. Dr. Ana Messias (Laboratory for Biostatistics
should be recommended to prevent long-­term orthodon- and Medical, Faculty of Medicine of the University of
tic and aesthetic problems (Ezeldeen et al., 2017; Meschi Coimbra, Coimbra, Portugal) for performing the statistics
et al., 2019). of the qualitative analysis. Furthermore, we would like
to thank Dr. Matthias Widbiller (Regensburg University,
Regensburg, Germany) for the discussions during the
Meta-­analysis planning and writing of this review.

Only three studies for survival and two studies for success CONFLICT OF INTEREST
met the criteria to be included in the quantitative analysis. The authors declare that they have no conflict of interest.
Although survival data were reported for 168 treatments
and 143 for success, the statistical power of the meta-­ DATA AVAILABILITY STATEMENT
analysis is limited, and the results should be interpreted Data sharing not applicable -­no new data generated
with caution, with further studies needed to improve the
strength of the combination. ETHICAL STATEMENT
This study did not require ethical approval.

CON C LUS I ON S ORCID

Nastaran Meschi https://orcid.
The success and survival rates of revitalized and fully org/0000-0003-3537-8831
pulpectomized (im)mature permanent teeth did not dif- Paulo J. Palma https://orcid.org/0000-0003-4730-8072
fer significantly. However, the sparse and low-­quality evi- Daniel Cabanillas-­Balsera https://orcid.
dence discovered cannot form a solid basis to support the org/0000-0002-9978-6458
statement that revitalization is effective to treat AP in (im)
mature permanent teeth. Meticulously performed, high-­ ENDNOTES
quality clinical trials are urgently necessary to increase 1
https://f3f14​2zs0k​2w1kg​84k5p​9i1o-­wpeng​ine.netdn​a-­ssl.com/
the clinical credibility in revitalization of the pulp–­dentine speci​alty/wpcon​tent/uploa​ds/sites/​2/2021/08/Clini​calCo​nside​
complex. Hence, clinicians should be cautious with the ratio​nsApp​roved​ByREC​062921.pdf in; https://www.aae.org/speci​
alty/clini​cal-­resou​rces/regen​erati​ve-­endod​ontics [accessed on 12
application of this endodontic treatment modality. Until
November 2021].
reliable evidence is available, revitalization should only be 2
https://www.crd.york.ac.uk/prosp​ero/ [accessed on 12 November
performed in well indicated cases, with the consent of the
2021].
patients (and their guardian) and must be seen as a last 3
AAE Glossary (updated March 2020, Glossary of Endodontic
resort to preserve dentoalveloar tissues.
Terms—­ American Association of Endodontists (aae.org)) [ac-
cessed on 3 June 2021].
AUTHOR CONTRIBUTIONS 4
RoB 2: A revised Cochrane risk-­of-­bias tool for randomized trials |
Nastaran Meschi contributed to PICOTS, PROSPERO
Cochrane Bias [accessed on 30 September 2021].
Protocol, literature search, title/abstract/full-­text screen- 5
https://metho​ds.cochr​ane.org/metho​ds-­cochr​ane/robin​s-­i-­tool
ing, data extraction, qualitative analysis, guidance meta-­
[accessed on 30 September 2021].
analysis, SoF-­table, tables and figures, writing (except for
meta-­analysis and statistics), revisions and correspond-
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Bender's dental pulp, 2nd edition. Chicago: USA Quintessence Cabanillas-­Balsera, D. (2022) Effectiveness of
Publishing Co, Inc. revitalization in treating apical periodontitis: A
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systematic review and meta-­analysis. International
Long-­term treatment outcomes in immature permanent teeth
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terials: a retrospective study. International Journal of Paediatric https://doi.org/10.1111/iej.13778
Dentistry, 27, 454–­462.
Pereira, A.C., Oliveira, M.L., Cerqueira-­ Neto, A., Gomes, B.,
Ferraz, C.C.R., Almeida, J.F.A. et al. (2020) Treatment out-
comes of pulp revascularization in traumatized immature APPENDIX 1
teeth using calcium hydroxide and 2% chlorhexidine gel as DATA EXTRACTION OF THE INCLUDED
intracanal medication. Journal of Applied Oral Science, 28, ARTICLES
e20200217.
Rizk, H.M., Salah Al-­Deen, M.S. & Emam, A.A. (2020) Pulp revas- AB, antibiotic; AP, apical periodontitis; apex, apexifica-
cularization/revitalization of bilateral upper necrotic immature tion; BC, blood clot; CBCT PAI, cone beam computed
MESCHI et al.    | 17

tomography periapical index (Estrela et al., 2008); NSRCT, non-­surgical root canal treatment; OHRQoL,
CBCT, cone beam computed tomography; CEJ, ce- oral health-­ related; PAI, periapical index (Orstavik
mentoenamel junction; CH, calcium hydroxide; CHX, et al., 1986); PPP-­UC-­MSCs, platelet poor plasma -­um-
chlorhexidine; CRCT, conventional root canal treat- bilical cord mesenchymal stem cells; PR, periapical ra-
ment; CSC, calcium silicate cement; d, days; DE, dens diograph; quality of life; RCT, randomized controlled
evaginatus; EDTA, ethylene diamine tetra acetic acid; clinical trial; REP, regenerative endodontic procedure;
GP, gutta percha; m, months; M/F, male/female; MTA, revasc, revascularization; RRA, radiographic root area;
mineral trioxide aggregate; n, number; n.a., not ap- VAS, visual analogue scale; w, weeks; WL, working
plicable; NaCl, saline; NaOCl, sodium hypochlorite; length; y, year.

First author,
country Arslan H, Turkey Brizuela C, Chile Jha P, India Lin J, China Silujjai J, Thailand

Year published 2019 2020 2019 2017 2017

Journal name Journal of Endodontics Journal of Dental International Journal of Journal of Journal of
Research Clinical Paediatric Endodontics Endodontics
Dentistry
Study design RCT RCT Phase I/II RCT Prospective RCT Retrospective,
comparative,
non-­randomized
study
Age range 18–­30 y 16–­58 y 9–­15 y 8–­16 y 8–­46 y
M/F 35 M/11F 11 M/25F not reported not reported 19 M/24F
Teeth type and Nonvital, mature, Maxillary or mandibular Mature, infected Immature teeth Cvek stage 2–­4
maturity single-­rooted incisors/canines permanent teeth with (premolar, central immature,
teeth (anterior, and mandibular AP (PAI score ≥3) incisor) with 1 root nonvital,
premolar), PAI premolars, mature canal, open apices permanent teeth
score ≥3 apex, pulp necrosis larger than 1 mm,
and periapical lesion periapical lesion
(PAI score ≥2 and
CBCTPAI ≥1)
Follow-­up 12 m 6, 12 m 6, 12, 18 m 3, 6, 9, 12 m 6 m, 1–­5 y
n with AP All included All included All included All included All included
Aetiology Not mentioned Not specifically Not reported DE (all premolars), Trauma, caries, DE
mentioned, but not trauma (all
dens invaginatus and incisors)
not avulsion
Groups and n/ Test: REP (28 included, Test: REP + PPP-­UC-­ Test: SealBio (n = 15) Two main groups Test: revasc (n = 17; 5
group 26 analysed) MSCs (n = 18) Control: NSRCT (n = 15) (REP and MTA trauma, 10 DE, 2
Control: CRCT (28 Control: CRCT (n = 18) apex) with 2 caries)
included, 20 subdivisions Control: MTA apex
analysed) (aetiology/type of (n = 26; 15
tooth): trauma, 8 DE, 3
• Test: REP (n = 69; caries)
21 central incisors/
trauma, 48
premolars/DE)
• Control: MTA apex
(n = 34; 13 central
incisors/trauma, 21
premolars/DE)
Patient dropout 14% None None 118 included, 15 75 eligible, 46
(% of recall) (= 13%) dropout contacted, 43
(lost/quit): 11 REP attended recalls
(5 DE, 6 trauma), 4 (patient recall
MTA apex (2 DE, 2 rate = 57.33%)
trauma)
18 |    REVITALIZATION EFFECTIVENESS

First author,
country Arslan H, Turkey Brizuela C, Chile Jha P, India Lin J, China Silujjai J, Thailand

Irrigant CRCT: first visit: 7 ml 20 ml 2.5% NaOCl and SealBio: first session: REP: first session: Revasc: first: 1.5%–­
NaOCl 1%, 5 min. Endoactivator system negative pressure 20 ml 1.5% sodium 2.5% NaOCl, 17%
EDTA 17%; second (Dentsply Tulsa irrigation (Endovac, hypochlorite, 0.9% EDTA; 2nd visit:
visit: 5 min. EDTA Dental Specialties), Discus dental) with saline, and 20 ml not mentioned;
17%, 5 ml saline. 20 ml 17% EDTA 2.5% NaOCl, second 17% EDTA; second Apex: 2.5% NaOCl
REP: first visit: 7 ml session: 17% EDTA; session: 0.9%
NaOCl 1%, 5 min. − NSRCT: negative saline, and 20 ml
EDTA 17%; second pressure irrigation 17% EDTA
visit: distilled with 2.5% NaOCl MTA apex: 20 ml
water, 5 ml NaOCl 1.5% sodium
1% for 1 min., hypochlorite
2 ml 5% EDTA solution 0.9%
for 1 min., 5 ml physiological
distilled water saline, and 20 ml
17% EDTA; second
session: 17%
EDTA
Intracanal CRCT: CH CH SealBio: AB 3mix REP: 0.1 mg/ Revasc: CH or AB
medication REP: AB 3mix (3MixMP: minocyclin, ml AB 3mix 3mix [1:1:1
[doxycycline, metronidazole, [ciprofloxacin, ciprofloxacin
metronidazole, ciprofloxacin) metronidazole, 250 mg,
ciprofloxacin] clindamycin; metronidazole
1:1:1 mixed with 400 mg, and
distilled water] minocycline
MTA apex: CH, after 50 mg]
1 w Vitapex paste Apex: CH
(Neo Dental
International,
Inc) until apical
barrier formation
radiographically
confirmed
Number of visits CRCT: 2, 1w 2, 3 w SealBio: 2, 1–­2 w REP: 2, 3w 2, time between not
and time REP: 3, 3w and 1d NSRCT: not specified MTA apex: 3, 1w mentioned
between respectively between 2 first
sessions
Root canal filling CRCT: gutta-­percha CRCT: gutta-­percha SealBio: blood clot+ REP: blood clot+ Apex: injectable
cones and epoxy cones (Reciproc® calcium sulfate-­based absorbable gutta-­percha
resin sealer (2Seal; VDW, GmbH) and cement (Cavit G) into collagen (Obtura II; Obtura
VDW) Topseal® sealer the cervical 1/3 root barrier (Heal-­ Spartan, Fenton,
REP: blood clot and (Dentsply Sirona) NSRCT: conventional cold all Biological MO) and AH Plus
MTA REP: blood clot, PPP-­ lateral condensation Membrane; sealer (Dentsply
UC-­MSCs and an technique (no further Zhenghai DeTrey)
absorbable gelatin specifications) Biological Revasc: blood clot
sponge hemostats Technology) and MTA
(Gelita-­Spon® GmbH) MTA apex: warm
gutta percha
CSC (type/size) REP: white MTA, REP: Biodentine™ Not applied REP: white ProRoot REP: MTA (brand
3 mm intra-­ (Septodont) MTA (Dentsply not specified;
radicular until CEJ International, Inc) 2–­3 mm);
(Cerkamed MTA; Apex: MTA-­plug
Wojciech) (brand and size
not specified)
Coronal Composite resin Composite resin Not specified Composite resin Composite filling/
restoration crown
MESCHI et al.    | 19

First author,
country Arslan H, Turkey Brizuela C, Chile Jha P, India Lin J, China Silujjai J, Thailand

Type of RX PR PR and CBCT PR PR and limited field of PR

view CBCT (PHT-­
6500; Vatech Co,
Ltd, Gyeonggi-­do,
Korea [90 kV and
7.0 mA])
RX assessment Standardization of pre-­ Not reported Pre-­and postoperative Qualitative: PR: Root length and
method and post-­op PR, RX: bite registration periapical dentin thickness:
Image J (Version as a positioning index, radiolucency measured on
1.41; National same exposure settings Quantitative: preoperative and
Institutes of PAI-­scores = qualitative CBCT: root follow-­up PR
Health, Bethesda, assessment of AP, length: average using the straight-­
MD): to measure measured by 3 blinded of distance CEJ line tool in ImageJ
the change of assessors. -­apical endpoint software;
lesion size pre-­post measured distally Root length: straight
+4 scores: absence and mesially; root line from the
(=1)/reduction thickness: average CEJ to the
(=2)/enlargement of values measured radiographic
(=3) of periapical at 4, 6, and 8 mm apex;
lesion/uncertain from the CEJ at Dentinal wall
(=4) the distal, mesial, thickness: at the
buccal, and lingual apical one third of
positions; apical the preoperative
foramen: averaged root length
from values of measured from
the buccolingual the CEJ.
and mesiodistal
positions, in
apexification
cases, the apical
foramen size was
recorded as 0 if
the apical barrier
formed.
20 |    REVITALIZATION EFFECTIVENESS

First author,
country Arslan H, Turkey Brizuela C, Chile Jha P, India Lin J, China Silujjai J, Thailand

Main outcome(s) Clinical and Safety and efficacy:—­ Primary: change in apical Survival, clinical Clinical and
radiographic safety = root bone density during and radiographic radiographic
success/failure: fracture, severe follow-­up (by means success/failure: success/failure,
RX score 1 or 2 or moderate pain, of PAI)—­secondary: Success = elimination and functional
and clinically and extra/intraoral clinical signs and of symptoms, retention:
asymptomatic = inflammation—­ symptoms during disappearance Success: clinical and
successful efficacy = tooth follow-­up—­final of apical radiographic
RX score 3 or 4 and survival, no outcome = primary + radiolucency presentations
or clinically percussion pain, an secondary at 18 m: with an increase were normal or
symptomatic = apical bone lesion Healed: combined of root length or showed reduced
unsuccessful of equal size in the radiographic and a decrease of the radiolucency
3 dimensions of clinical normalcy apical foramen, or combined with
space, a decrease in Healing: reducing both. normal clinical
some of them, or no radiolucency with Failure = if 1 of presentation;
more than a 0.1-­mm clinical normalcy the following Failure: radiolucency
increase in one of Diseased: if the was present: that emerged or
them (PR and CBCT). radiolucency persisted presence of persisted without
without change with/ clinical symptoms change, even
without clinical (pain, swelling, when the clinical
normalcy or sinus tract), presentation
no change in root was normal,
length or apical or patients'
size, recurrence clinical signs or
of apical symptoms were
periodontitis, present, even if
and external root the radiographic
resorption. presentation was
normal;
Functional retention:
clinical
presentation was
normal, whereas
radiolucency
may have been
absent or present
(newly emerged
or persisting).
Additional REP: positive response Changes in cortical bone Timing treatments: Impact of aetiology Root canal wall
outcome(s) to vitality testing Pulpal response: recorded after on the outcome thickening and
(Digitest ii; Parkell) sensitivity and the teeth were of REP and MTA lenghtening
vitality test anaesthetized and apex
isolated using a Discolouration and
rubber dam till the calcification in
completion of the REP
SealBio procedure
before placing the
coronal restoration
and till the completion
of the obturation
procedure before
placing the coronal
restoration for NSRCT
Pain pre/post VAS: -­CRCT: pre: Pre: not reported Pre: not reported Pre: not reported Not specifically
36.95 ± 35.07, 7d Post: none Post: none Post: none (100% reported
post: 0 asymptomatic)
REP: pre: 44.15 ± 27.25,
7d post: 0
MESCHI et al.    | 21

First author,
country Arslan H, Turkey Brizuela C, Chile Jha P, India Lin J, China Silujjai J, Thailand

Tenderness pre/ CRCT: pre: 30%, 7 d Pre: not reported Pre: not reported Pre: not reported Not specifically
post post: 0; REP: pre: Post: REP: at 6 m, 1 Post: none Post: none (100% reported
50%, 7 d post: 0 individual (5.6%) asymptomatic)
Swelling pre/post CRCT: pre: 40%, post: 0 Pre: not reported Pre: not reported Pre: not reported Not specifically
REP: pre: 46.2%, post: Post: none Post: none Post: none (100% reported, in case
3.8% asymptomatic) of acute apical
abscess: pre: 2
MTA apex, 1
revasc
Need for Not reported Not reported Not reported Pre/post: not Not reported
medication specifically
pre/posta reported
Radiographic Not measured Not measured Not measured Size of apical foramen, Root width: revasc:
evidence of root length and 13.75% ± 19.91%,
increased root thickness: MTA apex:
thickness and REP and MTA −3.30% ± 14.14%
length apex: pre-­op: (p < .05)
no significant Root length: revasc:
difference 9.51% ± 18.14%,
(p > .05); at 12 m: MTA apex:
statistical 8.55% ± 8.97%
difference for all (p > .05).
these parameters Revasc wide range in
(p < .05) in favour root lengthening:
of REP group −4% to 58%
(increase root Based on aetiology:
length: REP DE: mean root length
81.16%, MTA apex 15.1% ± 22.7%,
26.47%; increase mean root width
root thickness: 22.53% ± 25.2%
REP 82.60%, caries: mean root
MTA apex 0%; length 5.3% ± 3%,
apex closure: REP root width −0.42%
65.21%, MTA apex (only 1 case)
82.35%) trauma: mean
DE and trauma root length
at 12 m: DE: 0.49% ± 4.4%,
statistical mean root width
difference for 6.4% ± 8.8%
root length
and thickness
(p < .001) in favour
of REP group;
trauma: increase
in root thickness
significant
difference in
favour of REP
(p < .05)
22 |    REVITALIZATION EFFECTIVENESS

First author,
country Arslan H, Turkey Brizuela C, Chile Jha P, India Lin J, China Silujjai J, Thailand

Radiographic Absence of the Significant difference At 18 m: mean PAI-­score: All included: 100% MTA apex: 80.77%
evidence of periapical lesion: (Mann–­Whitney test SealBio: 1.1 ± 0.35 lesion reduction revasc: 76.47%
reduction of CRCT: 60%, REP: p = .0082) between NSRCT: 1.2 ± 0.41
apical lesion 46.2% the groups only in (p = .62)
size Reduction in the the reduction in
periapical lesion: the anteroposterior
CRCT: 25%, REP: dimension between
46.2% 6 and 12 m, with a
Uncertain: CRCT: 15%, median reduction
REP: 7.7% of 0.35 mm in CRCT
and 0.94 mm in REP
Radiographic Absence of the Not specifically reported Radiographic normalcy Not specifically Not assessed
evidence periapical lesion (= if at 18 m: assessed
of normal the postoperative SealBio: 13/15
periodontal radiographic NSRCT: 12/15
ligament space periodontal space
was smaller than
0.5 mm):
CRCT: 60%
REP: 46.2%
Tooth functionb Sufficient quality of At 12 m: no fracture and Fracture: none Fracture: none MTA apex: 5 root
coronal restoration: no restoration failure No reports concerning All coronal fractures
CRCT: 100% coronal restorations restorations
REP: 88.5% survived
Need for further Not reported None None Not reported Revasc: 3 persistent
intervention infection, 1
reinfection, all
signs of AP
Presence of sinus CRCT: pre: 35%, post: None Pre: not reported None Revasc: in 4 cases that
tract 15%; Post: none needed further
REP: pre: 19.2%, post: intervention
7.7%
Tooth survival Not reported All included All included At 12 m: all assessed Functional retention:
teeth survived MTA apex:
(100%) 82.76%, revasc:
88.24%
Adverse eventsc REP: 38.5% discoloured None None External root See ‘need for further
(p < .05) resorption: 2 in intervention’
trauma subgroup Revasc: 4 cases
REP: 30 calcified root
discolouration, 26 canal
calcification
OHRQoL Pre-­and postoperative Not specifically assessed Not specifically assessed Not specifically Not assessed
pain and assessed
percussion pain:
measured via VAS.
Pain on percussion:
CRCT: pre:
32.10 ± 33.43, 7d
post: 0
REP: pre: 36.15 ± 21.00,
7d post: 0
MESCHI et al.    | 23

First author,
country Arslan H, Turkey Brizuela C, Chile Jha P, India Lin J, China Silujjai J, Thailand

Response to REP: 50% (p < .05) At 12 m: Not assessed Not reported Not assessed
sensibility Cold test: CRCT 6%, REP
testing 56%
Hot test: CRCT 0%, REP:
28%
Electric test: CRCT: 17%,
REP: 50%
Doppler flowmetry:
REP: an increase of
perfusion unit from
baseline, 6 and 12 m:
60.6% to 74.4% to
78.1%
Other results Success: Safety and efficacy: at *Final outcome at 18 m: All analysed cases at *Success rates:
(quantitative CRCT: 80% 12 m 100% success for SealBio: 13 healed, 2 12 m (n = 103): Based on groups:
and REP: 92.3% both groups healing successful MTA apex 80.77%
qualitative) (p > .05) NSRCT: 12 healed, 3 revasc 76.47%
healing (p > .05)
(p = .62) Based on aetiology:
*Mean time treatment trauma: 85%
procedures: DE: 72.22%
SealBio: 16.02 min. caries: 80%
NSRCT: 36.59 min. (p = .292)
(p < .05) *Functional retention:
MTA apex: 82.76%
revasc: 88.24%
(p > .05)
Funding None Grant from ‘Corporación None Supported by Sun Not mentioned
de Yat-­sen University
Fomento de la Clinical Research
Producción’ 5010 Programme
(CORFOd), (no. 2012016)
project number
L214IDL2–­30051,
Santiago, Chile
a
Antibiotics, analgetics.
b
Fracture, restoration longevity.
c
Exacerbation, restoration integrity, allergy, discolouration.
d
Chilean Economic Development Agency.