Regenerative endodontic procedures for the treatment of necrotic

VISION
ORAL HEALTH CARE FOR ALL
MISSION
 PROVIDE ACCESS TO ORAL HEALTH CARE.
 IMPART PATIENT CENTERED CARE AND VALUE BASED
TRAINING.
 CONDUCT NEED BASED RESEARCH.

Regenerative endodontic procedures for the
treatment of necrotic mature teeth
-A preliminary randomized clinical trial
International Endodontic Journal, January 2022
AUTHORS : Ahmed Youssef, Magdy Ali, Amr ElBolok, Reham Hassan
KEYWORDS : blood clot, mature necrotic teeth, periapical healing, platelet-rich fibrin, pulp
sensibility, regenerative endodontic procedures
Guided by
Dr. K. MADHU VARMA
PROFESSOR
Presentation by
Dr. M. JAGAPATHI BABU
I MDS

 fails to restore pulp tissue vitality
 loss of protective mechanisms
 increases the brittleness of the tooth (Gupta et al., 2015)
 Discoloration and loss of natural translucency of teeth (Ahmed &
Abbott, 2012)
Mature permanent teeth with necrotic pulps have long been treated
with conventional root canal therapy,
INTRODUCTION

REGENERATIVE ENDODONTIC PROCEDURES (REPs) :
 ‘Biologically based procedures designed to replace damaged structures,
including dentin and root structures, and cells of the pulp–dentin
complex’ (Murray et al., 2007).

TISSUE
ENGINEERING
TRIAD
STEM CELLS
GROWTH FACTORS SCAFFOLD
 Biological events of REP are the interplay of tissue engineering
traid :(Bohl et al., 1998; Hargreaves et al., 2008; Sedgley & Botero,
2012)

In REPs, blood clots (BCs), which are formed in an adequately
disinfected root canal space by intentionally provoking periapical tissue
bleeding, create a 3D-scaffold that entraps undifferentiated stem cells and
supports the growth of new tissue (Murray et al., 2007).

Drawbacks of BC induction :
 Procedure is traumatic and may cause discomfort for the patients.
 Induction of periapical bleeding into the canal space is not always
attainable. (Nosrat et al., 2012)

 Difficult to control the bleeding volume to the desired level.
 Precise placement of mineral trioxide aggregate (MTA) over the BC to
the desired level is a technique-sensitive procedure (Petrino et al., 2010)

To overcome the disadvantages;
 Platelet-rich fibrin (PRF), a second-generation platelet concentrate.
 Autologous high-density fibrin clot packed with an increased
concentration of growth factors acts as a biological scaffold (Dohan et
al., 2006; Huang et al., 2010).

REPs are highly successful in immature permanent teeth with necrotic
pulps (Diogenes et al., 2016).
Advantages :
 Resolution of clinical signs and symptoms and periapical healing
 An increase in the root length, which encourages the thickening of the
canal walls and subsequent apical closure (Diogenes et al., 2016).

 REPs have recently been suggested for treating mature permanent teeth with
closed and fully formed apices (Digka et al., 2020; Glynis et al., 2021).
 Case reports of mature teeth treated with REPs have revealed favourable
outcomes in the resolution of signs, symptoms and in the healing of apical
periodontitis
Abou Samra et al., 2018; Paryani & Kim, 2013; Saoud, Martin, et al., 2016; Saoud et al., 2014; Shah & Logani, 2012

 In a histologic study, Arslan, Şahin, et al. (2019) revealed that the
ingrowth of vital tissue (fibrous connective and bone-like substance
combined with vascular-like structures) within the root canal system is
achievable after REPs in mature teeth.
 This tissue contribute to the re-establishment of the innate immune
system, which could control root canal system reinfection (He et al.,
2017).

AIM;
To assess the radiographic healing and the possibility of regaining pulp
sensibility in mature permanent teeth with necrotic pulps that were treated
using two REPs: revitalization and a PRF-based technique.
NULL HYPOTHESIS;
No statistically significant difference would be found between the tested
groups in terms of periapical healing and regaining sensibility.

APPROVAL; Ethical Committee of the Faculty of Dentistry at Minia
University (Minia, Egypt; approval no. 58/306).
 A single-blinded randomized controlled pilot trial
 two-arm parallel groups with an allocation ratio of 1:1
 Conducted over a period of 1 year

 The study followed the Consolidated Standards of Reporting Trials
(CONSORT) guidelines
 Preferred Reporting Items for Randomized Trials in Endodontics
guidelines (Nagendrababu et al., 2020)

INCLUSION CRITERIA ;
 Patients aged 18–40 years without any known allergic reactions or
systemic disease who required RCT of a nonvital single-rooted maxillary
anterior tooth with a mature root.
 Periapical lesion with a periapical index (PAI) score ≥3, according to the
classification of Ørstavik et al. (1986).
A diagnosis was based on history, clinical and radiographic examination findings. Sensibility
testing was conducted by using an electric pulp tester

EXCLUSION CRITERIA :
 Pregnant women
 Patients with generalized chronic periodontitis
 Patients with non-restorable teeth
 Previous root canal treated teeth
 Developmental anomalies
 Teeth with external or internal resorption (Nageh et al., 2018; Rizk et
al., 2019)

 Informed consent form in Arabic or in English.
 A detailed explanation of treatment procedures, possible outcomes,
complications, and follow-up period.

AAE Clinical Considerations for a Regenerative Procedure Revised ,6-8-16

RANDOMIZATION AND BLINDING;
 Computer sequence generation (www.random.org), which provided a
table for groups I and II with randomized participant numbers (n = 10)
in each group.
 Diagnosis and implementation of the random allocation sequence were
performed by Magdy Ali

 The operator (Ahmed Youssef) and the patient could not be
blinded. The assigned treatment protocol was revealed to the
patient by drawing blood from the patient's forearm.
 Data collectors (Reham Hassan and Amr ElBolok) were blinded.

PRE-OPERATIVE ASSESSMENT;
 To evaluate the size of the periapical lesion, a preoperative radiograph was
taken using the standardized paralleling technique with #2 periapical film,
which was mounted on a custom-made anterior bite block connected to the
X-ray tube via an adapter ring.
 Numerical readings of pulp sensibility were recorded using an electric pulp
tester.

a) Construction of the stent on prefabricated cast
b) Radiographic stent
c) Periapical film mounted on an anterior bite block with radiographic stent

 After drying and isolating the examined tooth, a small piece of
toothpaste was applied to the tooth.
 A lip clip was placed and the test was conducted.
 The average of three readings was recorded for each tooth at an interval
of 5 min.

TREATMENT PROCEDURES (INTERVENTIONS);
First visit:
Chlorhexidine mouthwash
1 Carpule of mepivacaine 3%[ infiltration technique]
Rubber dam isolation , a straight-line access cavity
Working length [ Electronic apex locator ]

Intraoral periapical radiograph [confirmation]
Canal preparation up to a size #60 K-file
During instrumentation, 1.5% NaOCl using side-
vented irrigation needles 2mm from the W.L

Final irrigation ; 20 ml 1.5% NaOCl, followed by the
same amount of 17% EDTA for 1 min each
Dentine bonding agent applied to the access
cavity wall, coronal third of the canal
Root canal received calcium hydroxide intracanal medication,
access cavity was sealed with dry sterile cotton pellets and GIC

SECOND VISIT;
Local infiltration anesthesia without a vasoconstrictor
Ca(OH)2 was removed by irrigation with 5ml sterile saline followed by
20 ml of 17% EDTA activated by using an E1 Irrisonic ultrasonic tip [1 Min.]
Final irrigation was administered using 5ml saline, and the canals were dried
with suitably sized paper points.

GROUP I [Blood clot (n = 10)] :
Bleeding was evoked in the canal by over-instrumentation using a
sterile #25–#35 K-file 2–3 mm beyond the apex
Bleeding was controlled at a level just below the CEJ by using a dry
cotton pellet canals were left for 7 min to allow for BC formation

White MTA was placed 3 mm below the CEJ, followed by a moist
cotton pellet and a temporary filling to allow for the complete setting
of the MTA
temporary filling was replaced by a glass–ionomer cement base, resin
composite restoration after 2 days to seal the access cavity

GROUP II Platelet-rich fibrin (n = 10) ;
Preparation of PRF Platelet-rich fibrin was prepared, based on Choukroun's
technique (Dohan & Choukroun, 2007), by drawing blood from the patient's
forearm (right median cubital vein) into a test tube without an anticoagulant
It was centrifuged immediately using a tabletop centrifuge at 400 g for 10 min.
The product contained three layers: a top layer of acellular platelet-poor plasma, a middle layer
of PRF and a bottom layer of red blood corpuscles

The PRF was segregated and squeezed to form a membrane. After the
bleeding was evoked in the canal as in group I
The freshly prepared PRF membrane was fragmented and placed
incrementally in the canal using a hand plugger and a finger spreader
size 40 up to the level of the CEJ
A 3-mm-thick layer of white MTA was placed directly over the PRF
matrix.
To reduce inter-operator variability all procedures were performed by the same operator (A.A.Y.), who was
trained to perform REPs using both techniques

POSTOPERATIVE EVALUATION
Radiographic assessment; [6th and 12thmonth visits]
 Standardized radiographs
 Periapical status was assessed using the PAI score (Ørstavik et al.,
1986).
 All radiographs were scanned using a flat-bed scanner (Scanmaker II,
Microtek International Inc.) and stored on a computer for evaluation.

 Before the evaluation, 20 reference radiographs were used to calibrate
the investigator.
 All PAI scores were remeasured by the same examiner 1 week after the
first measurement. Intra-observer reproducibility was verified, based on
intraclass correlation coefficients (ICCs)

Assessment of pulp sensibility; [6 months and 12 months ]
 Numerical readings of pulp sensibility were recorded after by using an
electric pulp tester in the same manner that was used preoperatively.

STATISTICAL ANALYSIS
 The PAI score showed a nonparametric distribution.
 The Wilcoxon signed-rank test was used to compare follow-up periods
within each group, followed by multiple comparisons with Dunn–
Bonferroni correction.
 The Mann–Whitney test was used to compare the tested groups for the
PAI data.

 Pulp sensibility data after EPs showed a parametric distribution.
 Repeated measure analysis of variance (ANOVA) was used to
investigate the effect of different tested groups and follow-up periods
on pulp sensibility after REPs, using SPSS (version 23; IBM).

 The results showed no statistically significant differences between the
groups in terms of preoperative radiographic lesion score (p = .579).
 There was a significant increase in peri-radicular healing in both groups
at 6 and 12 months compared to baseline [p<0.01]. After 12 months,
there was no significant difference in the PAI scores between the two
groups

Based on the electric pulp test manufacturer's
instructions,
• 1 – 39 ; a tooth with vital pulp
• 40 -- 79 ; part of the tooth nerve is nonvital
• 80 -- a tooth with necrotic nonvital pulp
PULP SENSIBILITY EVALUATION;

 The results showed a decrease in the mean readings of the electrical pulp
tester during the follow-up period.
 Readings of tooth sensibility showed that, after 6 and 12 months, there was
no statistically significant difference between the BC and PRF groups.
 Within each group, a statistically significant difference was found between
the preoperative reading and each of the 6 and 12 months follow-up
periods.

DISCUSSION ;
 Findings in this study indicated that REPs using the BC technique or PRF
technique can be a treatment option for mature teeth with a necrotic pulp.
 Regeneration of a diseased pulp was once thought to be impossible.
 first successful revitalization case - Iwaya et al. (2001) , followed by the
report of Banchs and Trope (2004)

REPs in mature teeth have been recently suggested as an attempt to
overcome the drawbacks of RCT
 lack of sensation and immune mechanisms,
 increased susceptibility to root fracture of treated teeth (Nageh et al.,
2018)
 reinfection due to coronal leakage or microleakage (Dammaschke et al.,
2003).

Use of regenerative endodontics in the treatment of mature permanent
teeth holds promise for more complicated cases such as
 root fracture
 perforating root resorption
 avulsion (Saoud, Mistry, et al., 2016).

 REPs may contribute to the re-establishment of the innate immune
system, which could control root canal system reinfection (He et al.,
2017), and may lead to regaining tooth sensibility
 Possible proprioceptive defense mechanisms of the pulp, which provide
an alarm system against any tissue injury and protect the pulp from
further damage (Lin et al., 2021).

 Differences in the REPs between immature and mature teeth is the
mechanical preparation phase, which is avoided in immature teeth to
prevent further weakening of the thin dentine walls (American
Association of Endodontics [AAE], 2016).
 Regaining pulp sensibility in necrotic permanent fully mature teeth
using REPs has been a controversial subject among scientists (El-Kateb
et al., 2020)

 The presence of stem cells using the evoked bleeding technique in
mature permanent teeth was confirmed by Chrepa et al. (2015)
 Intracanal blood samples ---- quantitative reverse transcription-
polymerase chain reaction.

 NaOCl (1.5%) was used with the aid of side-vented needles to avoid apical
extrusion of NaOCl into the periapical tissue (AAE, 2016; Ng et al., 2011).
 Higher concentrations of NaOCl were cytotoxic to stem cells in the apical
tissue and decreased odontoblastic differentiation.

 EDTA conditioning was linked to the release of growth factors embedded
in dentine (Galler et al., 2011).
 In addition, it was found to promote cell proliferation, migration, and
odontoblastic differentiation (Kawamura et al., 2016).
 EDTA (17%) was used for 1 min after NaOCl to moderate the adverse
effects of NaOCl.

 Increasing growth factors improves cellular viability and migration, and
it acts as chemoattractant and differentiation factor for MSCs from the
apical papilla or periapical tissues (Chrepa et al., 2015)
 EDTA activation with ultrasonics was used because it appears to
increase the transforming growth factor-beta 1 (TGF-β) release from
dentine (Aksel et al., 2020; Widbiller et al., 2017).

 In the second visit, 3% mepivacaine without a vasoconstrictor was used to
facilitate bleeding from the periapical tissues into the canal system.
 The apex was violated by over instrumentation using K-file #20–#35 to
allow the migration of MSCs into the root canal space from the periapical
area (Hargreaves et al., 2013).

 The placement of MTA after REPs upregulates various cytokines and
biological markers such as interleukin (IL)-1α, IL-1β, IL-4, IL-6, IL-8,
alkaline phosphatase, bone sialoprotein, osteopontin, and bone
morphogenetic protein 2 (BMP-2) (Rudagi & Rudagi, 2012; Torabinejad &
Parirokh, 2010).
 To avoid discolouration caused by MTA, a dentine bonding agent was
applied to the access cavity walls and coronal third of the canal
(Shokouhinejad et al., 2017)

 Radiographic outcomes in the current study showed a marked decrease in
PAI scores of the periapical lesions in both groups 6 months and
12 months after a REP.
 This finding might be due to process of natural wound healing which
started with the induction of bleeding from periapical tissues as the first
phase of the wound healing process (Holland et al., 2017).

The other possible explanation seems to be antimicrobial clearance, which
was enhanced by the induction of periapical bleeding during REPs as it
brings components of the innate and adaptive immune system such as
 cytokines,
 complement components,
 Immunoglobulins,
 phagocytes and antimicrobial peptides, which allow the localization and
opsonization of bacteria, to facilitate phagocytosis(Saoud, Martin, et al.,
2016).

 REPs promotes bone repair, as reported in studies of immature
permanent teeth (Ezeldeen et al., 2015). Our results confirm previous
findings by Arslan, Ahmed, et al. (2019) and El-Kateb et al. (2020), which
revealed a reduction in the size of the periapical lesions in mature
permeant teeth 12 months after REPs.

 In this study, mean PAI score decreased at the end of 12 months in
both groups, when compared to the 6-month scores. Furthermore, the
periapical lesion healing response in the PRF group was better than
that in the BC group at the end of 6 months and 12 months.

 In a meta-analysis, clinical efficacy of the revascularization of immature
teeth using BC, platelet-rich plasma (PRP) and PRF techniques show
that the periapical lesion healing response is 88.9% for BC, 100% for
PRP and 100% for PRF (p > .05), and that apical closure occurred more
frequently after PRP and PRF than with BC (p < .0011) (Murray, 2018).

 The PRF, a second-generation platelet concentrate prepared without adding
anticoagulants (Dohan et al., 2010), when used as a scaffold in REPs, allows
the release of various growth factors such as platelet-derived growth factor
(PDGF), TGF-β, basic fibroblast growth factor (bFGF) and vascular
endothelial growth factor (VEGF) for up to 28 days(He et al., 2009; Naik et
al., 2013).

 These growth factors direct stem cell migration, proliferation and
differentiation; supplement angiogenesis; and have an important role in
the self-regulation of inflammatory and infectious phenomena (Toffler et
al., 2009).

 Kim et al,(2010) showed that multiple cytokines, bFGF, VEGF or PDGF,
alone or in combination with basal set of nerve growth factor and bone
morphogenetic protein-7, could induce cell homing, angiogenesis and
mineralized tissue formation with regeneration of dental pulp-like tissue in
the root canals of mature human teeth after in vivo ectopic implantation in
mice.

 PRF forms a fibrin network which protects the growth factors from
proteolysis and traps essential circulating immune cells and cytokines that
act against infection (Jadhav et al., 2015).
 The results of the current study showed that after 1 year of follow-up, two
(20%) patients in the BC group and five (50%) patients in the PRF group
regained tooth sensibility.

This finding is in agreement with the finding of Nageh et al. (2018) in which
60% of their patients treated with the PRF-based technique regained tooth
sensibility at the end of 12 months.
Similar findings were observed in the study by Arslan, Ahmed, et al. (2019)
and El-Kateb et al. (2020) in which 50% and 77% respectively, of mature
teeth responded positively to electric pulp testing (EPT) after 1 year of REP.

However, the results of the present study were inconsistent with the
results of the case series by Saoud, Martin, et al. (2016), who reported a
negative response to sensibility testing after 26 months in mature teeth.
case series by Bakhtiar et al. (2017), who reported that four immature
teeth with necrotic pulp responded negatively to EPT after 12 months of
PRF revascularization treatment.

Percentage of patients who regained tooth sensibility PRF Group >> BC
Group Growth factors in PRF --- Neurogenesis
GROWTH FACTORS FUNCTION
TGF-β Stimulates neurite outgrowth and
regulates differentiation of Schwann cells
(SCs)
PDGF Induces SC proliferation, differentiation
and formation of myelin
Insulin growth factor 1 Supports the extension of nerve fibres and
suppresses apoptosis in motor, sensory
and sympathetic neurons
bFGF, Facilitates neuroprotection and SC
regeneration

 The use of PRF can add to the time and complexity of the procedure as it
requires a venous blood draw from the arm of the patient.
 Unlike PRP, PRF can be easily prepared without an anticoagulant added to
the blood and requires only one centrifugation cycle.

 A statistically significant difference was found in our study between EPT
readings at baseline and 6 months in both groups.
 The EPT readings significantly decreased after a 1-year follow-up, which
suggested that a longer follow-up period may be required to detect the gain
of nerve function and regain sensitivity after REPs in mature teeth (El-
Kateb et al., 2020).

 It must be emphasized that a positive response to pulp testing is not a
definitive indicator of the regeneration of pulp tissue in the canal space,
and the absence of a pulp response does not imply a lack of vitality.
 The regenerated vital pulp-like tissue may have an immature innervation
system that requires a longer time for the development of a more organized
nerve-like tissue (Nakashima et al., 2017).

 By using MRI, a recent study by El-Kateb et al. (2020) confirmed the
presence of vital pulp tissue after REPs in vivo and revealed no statistically
significant difference when comparing the baseline MRI signal intensity of
the normal contralateral teeth and that of teeth 12 months after treatment
with REPs (p > .05).
 In immature teeth, the continuation of root development indicates the
existence of vital tissues in the canal space, which is not the case in mature
teeth.

 Song et al. (2017) reported that the prevalence of intracanal calcification
associated with revascularization of immature teeth was 62.1% (18/29
patients)
 27.8% (5/18 patients) ------ calcific barriers
 72.2% (13/18 patients) ------ canal obliteration
 Lei et al. (2015) confirmed nervous tissue regeneration by using
immunohistochemistry in an extracted immature permanent premolar
tooth treated with REPs via BC.

LIMITATIONS :
 low number of participants
 short follow-up period
however, future clinical directions will include extended monitoring and
follow-up

 The accumulation of evidence regarding the successful outcome of REPs
in treating mature teeth with necrotic pulp using different protocols could
contribute to the development of a specific position statement and
recommendations similar to the available ESE position statement (Galler
et al., 2016) for immature teeth revascularization procedures

CONCLUSION;
 The findings of this preliminary trial indicate the potential for using
REPs, such as revitalization or PRF-based techniques, as treatment
options for mature teeth with necrotic pulp.
 A higher level of evidence is required however, with appropriately sized
prospective clinical trials and longer follow-ups to conclusively validate
the different outcomes of REPs.

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