DR.

GÖZDE KANDEMİR DEMİRCİ (Orcid ID : 0000-0001-7327-1010)

DR. MEHMET EMIN KAVAL (Orcid ID : 0000-0003-2388-2846)

Accepted Article
PROF. MEHMET KEMAL CALISKAN (Orcid ID : 0000-0002-6714-4282)

Article type : Original Scientific Article

Treatment of immature teeth with nonvital pulps in adults : A prospective comparative clinical

study comparing MTA with Ca(OH)2

G Kandemir Demirci1, ME Kaval1, P Güneri2, MK Çalışkan1

1
Department of Endodontology and 2Department of Oral and Maxillofacial Radiology, School of

Dentistry, Ege University, Izmir, Turkey

Running title: Apexification treatment

Keywords: adult tooth, apexification, calcium hydroxide, immature tooth, MTA, open apex,

periapical healing.

Correspondence Author:

Dr. Gözde Kandemir Demirci

Department of Endodontology, School of Dentistry, Ege University,

Izmir, 35100, Turkey

Telephone number: +90 232 3114608

Fax number: +90 232 3880325

E-mail address: dt.gozdekandemir@hotmail.com

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1111/iej.13201
This article is protected by copyright. All rights reserved.
 Abstract

Aim To evaluate and compare the influence of various predictors on outcomes of apexification
Accepted Article
treatment using either mineral trioxide aggregate (MTA) or calcium hydroxide (CH) in permanent

immature anterior teeth with necrotic pulps and periapical lesions of adults.

Methodology Ninety immature teeth with necrotic pulps and periapical lesions on adult patients (aged

18-40y) were treated with MTA(45 teeth) or CH(45 teeth) between 2015 and 2018. Patients of both

groups were recalled for the follow-up examinations after the first intervention at 1,3,6 and 12 months

for the first year, every 6 months for the second year, and every year thereafter until the end of the

study (median 32.3 months). The treatment outcome based on clinical and radiographic criteria was

assessed by calibrated examiners and dichotomized as “healed+healing” or “not healed”. The age,

gender, stage of root development, preoperative signs and symptoms of apical periodontitis and size

of periapical lesion were recorded. The cumulative success proportion and mean time were analysed

with the Kaplan-Meier test. The Generalized Logrank Statistic was used to describe prognostic

clinical variables. Fisher’s exact test was applied for the evaluation of the healing rates.

Results Thirty-nine of the 45 teeth treated with MTA were available for recall. Of these, 29 teeth

(74%) revealed calcific apical barrier formation with complete resolution of periapical lesions, 7 teeth

(18%) were healing, and 3 teeth (8%) had persistent disease. Thirty-four of the 45 teeth in the CH

group were available for recall. Of these, 27 teeth (79%) had complete healing of periapical lesions

and had calcific barrier formation, 4 teeth (12%) were healing, and the remaining 3 teeth (9%) were

considered as not healed. The survival rate of teeth treated with MTA was similar to the survival rates

observed in teeth treated with CH (90% and 91% respectively, P>0.05). The generalized logrank

statistic revealed that the cumulative success rate of both materials was not significantly different

(P>0.05). None of the tested predictors had an influence on the treatment outcomes of teeth in both

groups (P>0.05).

Conclusions Apexification treatment with both MTA and CH demonstrated similar treatment

outcomes. MTA may be proposed as a material for apexification treatment in immature teeth of adult

patients due to the decreased treatment time associated with its use.

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 Introduction

The majority of traumatic incidents in children involve the immature permanent maxillary
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incisors, often resulting in pulpal inflammation, necrosis and periapical lesions (Andreasen et al.

2015).

Apexification treatment is defined as a method that involves the biomechanical debridement

of the root canal that is followed by the placement of an intracanal medicament to stimulate apical

healing and formation of an apical barrier in a root with an open apex. Historically, a number of

materials have been advocated as biologic activators to induce apexification, and calcium hydroxide

(CH) has been reported as the material of choice due to its favourable biological performance,

antibacterial action, and low cost (Rafter 2005). On the other hand, CH apexification treatment has

several inherent disadvantages, including variability of the treatment time because of frequent CH

dressings required to complete apical closure (Ghose et al. 1987, Yates 1988, Mackie et al. 1988,

Kinirons et al. 2001), which also leads to difficulty of the patient’s recall management and delayed

treatment (Metzger et al. 2001). This increases the vulnerability of the temporary coronal restoration

to re–infection (Sheehy & Roberts 1997) and susceptibility of the teeth to cervical fracture

(Andreasen et al. 2002, Sahebi et al. 2010). Moreover, tissue altering and dissolving effects

(Andersen et al. 1992) and histologically poor apical closure when using CH have been reported

(Felippe et al. 2005). Despite the above-mentioned disadvantages, many interesting case reports

(Caliskan et al.1998, Caliskan 1999, Soares et al. 2008) and short- and long-term studies have

reported a success rate of 74-100% with CH in pulpless immature teeth with or without periapical

lesions of young children aged between 6 and 16 years (Webber 1984, Ghose et al. 1987, Yates 1988,

Cvek 1992, Mackie et al. 1988, 1993, Thater & Marechaux 1988, Morfis & Siskos 1991, Kleier &

Barr 1991, Finucane & Kinirons 1999, Kinirons et al. 2001, Dominguez Reyes et al. 2005).

Mineral trioxide aggregate (MTA) has been advocated as an effective alternative to CH for

apexification since it has demonstrated good success rates, ranging from 77%-100% (Simon et al.

2007, Witherspoon et al. 2008, Holden et al. 2008, Sarris et al. 2008, Pace et al. 2014) with the

advantage of reduced treatment time (Simon et al. 2007, Witherspoon et al. 2008), good sealing

ability (Torabinejad et al. 1995, Al-Kahtani et al. 2005), biocompatibility and bioactivity (Mitchell et

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 al. 1999, Tomson et al. 2007), antibacterial ability (Eldeniz et al. 2006) and immediate canal filling

(Economides et al. 2003, Felippe et al. 2006). On the other hand, MTA has numerous shortcomings
Accepted Article
including poor handling features, long setting time (3-4 hours) (Chng et al. 2005), the potential to

discolour teeth and high cost (Belobrov & Parashos 2011).

Comparative short-term clinical studies have reported a success rate for apexification

treatment with CH ranging between 73 and 100%, and for MTA with or without intermediary CH

dressing, a success rate between 70 and 100% (El-Meligy & Avery 2006, Pradhan et al. 2006, Damle

et al. 2012, Bonte et al. 2015).

The effect of the patients age on the outcome of apexification treatment is controversial. It has

been reported that apexification treatment is indicated in young children (Lin et al. 1986) and

provides more favourable results, as shown in an animal study (Weinstein & Goldman 1977).

However, successful biologic apexification with CH in adults has been reported in several case reports

(Rotstein et al. 1990, Gutmann & Fava 1992, Çalışkan & Türkün 1997), even in teeth previously

subjected to apical surgery (Çalışkan 2005). Until now, there is only one clinical study which

compared the outcome of CH treatment in patients between the ages of 8-20 years with the result

observed in patients between ages 27-40 years (Morfis & Siskos 1991). Other clinical apexification

treatment studies with MTA reported favourable results in immature teeth of different age groups

ranging from 6 to 82 years, and composed of mostly children (Simon et al. 2007, Witherpoon et al.

2008, Holden et al. 2008).

Additionally, in recent years, regenerative endodontic treatment (RET) has been proposed

as an alternative protocol to MTA or CH apexification treatment especially in young patients (Saoud

et al. 2014, Estefan et al. 2016, Lin et al. 2017), because RETs have the potential to promote further

root maturation of immature permanent teeth with a necrotic pulps and apical periodontitis. However,

the severity and duration of apical periodontitis, age of the patient, the stage of the root development,

follow up time and trauma are factors that may influence the success of RET (Saoud et al. 2014, Lin

et al. 2017, Kim et al. 2018).

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 In the literature, there is no published data prospectively comparing the effectiveness of MTA

and CH involving immature maxillary incisors with non-vital pulps and periapical lesions in adult
Accepted Article
patients. The aim of the present study was to evaluate and compare the influence of various predictors

on the outcomes of apexification treatment using either MTA or CH as an apexification material of

pulpless immature teeth with periapical lesions in adults.

Materials and Methods

All patients were referred for root canal treatment at the Department of Endodontics, School

of Dentistry, Ege University in Izmir, Turkey between 2015 and 2018. The study protocol was

approved by the Human Ethical Committee of Ege University, School of Medicine (No:14-12/2,

09.January.2015), in accordance with the principles of Helsinki (version 2008) and the trial was

registered on clinicaltrials.gov with ID: NCT03855501. This study was carried out on 90 adults with

ages ranging from 18 to 40 years. Immature 90 maxillary anterior teeth with necrotic pulps and

periapical lesions due to trauma, caries and dens invaginatus were enrolled. In cases with two or more

teeth treated, only one tooth was selected randomly for the analysis.

Patients were informed about the treatment options including apexification and regenerative

endodontic treatment, postoperative care, follow-up investigations, potential complications before

their participation in the present study. The patients who accepted only apexification treatment

options with MTA or CH were included. The inclusion criteria were as follows: patients without

systemic disease and compromised immune status, and had an immature maxillary anterior tooth with

periapical lesion without previous endodontic treatment. The exclusion criteria included patients with

advanced periodontitis (more than 5 mm periodontal attachment and bone loss), and teeth with

contraindications for endodontic treatment (root fracture, unrestorable tooth, replacement resorption

or previous surgical endodontic treatment). The diagnosis of the state of pulpal and periapical disease

prior to apexification treatment was established with standardized clinical and radiographical

examinations. The state of root development prior to treatment was recorded according to Cvek

(1992) who classified open apex teeth into 4 groups in relation to the level of root maturity (less than

half, half, 2/3rd and more than 2/3rd). Periapical status of each root visible on the digital radiographs

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 was scored with the periapical index (PAI) (Ørstavik et al. 1986) and the largest dimension of each

periapical lesion was measured and recorded.

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The treatment outcome predictors included patients’ age and gender, stage of root

development, preoperative signs and symptoms of apical periodontitis, and size of periapical lesion.

The patients were examined by an independent investigator who did not intervene in the

treatment of the patients and the randomization was performed as two groups in a 1:1 ratio by using

free online software (http://www.random.org). Following the randomization procedure, patients were

assigned sequential numbers in the order of enrollment and the operators were informed about the

treatment modality, either with CH or MTA as the apexification material, at the first appointment.

Group I included 45 teeth treated with MTA (White ProRoot MTA, Dentsply, Tulsa, OK,USA),

whereas Group II included 45 teeth treated with a pure CH paste (Merck, Whitehouse Station, NJ,

USA) mixed with saline. The apexification treatment was performed using a standardized technique

by experienced 2 endodontists. In teeth with symptomatic apical periodontitis, occlusal trauma was

eliminated and drainage was provided through the root canal. CH paste was applied in the root canal

only when active drainage finished. Except two cases with extraoral swelling, no antibiotics were

prescribed. The access cavity was restored temporarily with zinc oxide-eugenol cement (ZOE)

(Kemdent, Swindon, UK).

MTA group: Under local anaesthesia and rubber dam isolation, the working length was calculated

radiographically with K-files and recorded as the reference. The root canals were instrumented gently

with K-files and copious irrigation with 2.5% sodium hypochlorite (NaOCI) (Merck, Darmstadt,

Germany) by means of a 30 gauge endodontic irrigating needle (Sybron Endo, Crop, Orange, CA,

USA). After drying with large sterile paper points, CH powder was mixed with saline and applied to

the root canal with a lentulo spiral filler (Dentsply, Sirona Endodontics, Ballaigues, Switzerland) at

low speed. A cotton pellet was used to gently compress the CH into the root canal and its placement

was examined radiographically before placing ZOE as temporary restoration into the access cavity.

After one week, the CH was removed from the canal using both files and the irrigation with 2.5%

NaOCI and 17% ethylenediaminetetraacetic acid (EDTA) (Merck). A final irrigation was made with

2% chlorhexidine (CHX) (Klorhex, Drogsan, Turkey) before canal filling. Following drying of the

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 root canal with sterile paper points, MTA was placed with a MTA Endo Gun (Dentsply Sirona

Endodontics) into the apical portion of canals with a minimum 4-mm thickness and adapted to the
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canal walls with an endodontic hand plugger. Correct placement of the MTA plugs was verified with

a radiograph. After inserting MTA, a moist cotton pellet was placed in the canal in close contact with

MTA to facilitate its setting, and the access cavity was restored. One week later, the wet cotton pellet

and the temporary filling were detached and the setting of the MTA was with a hand plugger. All

procedures described above were performed under dental loupes (EyeMag Pro, Carl Zeiss,

Oberkochen, Germany). The remainder of the root canal was filled with gutta-percha in conjunction

with AH Plus sealer (Dentsply Sirona Endodontics) using lateral condensation. The coronal aspect of

the filling was completed with thermomechanical compaction by means of a heated-hand plugger

(Dentsply).The corono-radicular restoration was completed with a bonded resin composite (3M ESPE,

Dental Products, St. Paul, MN, USA) into the coronal third of the canal or a fibre post (Unicore Post,

Ultradent, Salt Lake City, UT, USA) was applied into the root canal with a self-adhesive resin cement

(3M ESPE) to support the coronal tooth structure.

CH group: After using the same biomechanical root canal preparation and irrigation protocol, the

root canal was filled to working length with CH paste (Merck, Whitehouse Station, NJ, USA). Both

clinical and radiographical examinations were performed to evaluate the apical barrier formation and

periapical healing. The root canal filling was postponed until a continuous hard tissue barrier was

observed apically on radiographs and was verified by clinical probing. The root canal was filled and

the coronal restorations were completed as for the MTA group.

Patients of both groups were recalled for clinical and radiographical examinations after the

first intervention at 1, 3, 6 and 12 months for the first year, every 6 months for the second year, and

every year thereafter until the end of the study. Periapical radiographs were taken using a paralleling

technique with a film holder (Hawe Super Bite; Kerr Hawe SA, Bioggio, Switzerland) by a digital

radiographic system at every recall visits. All digital radiographs were obtained under standard

exposure conditions (60 kVp, 7 mA, and 0.32 seconds) using a dental x-ray machine (Gendex GX,

Lake Zurich, IL, USA). Before the radiographic assessment, two independent investigators had been

calibrated regarding the use of PAI scoring system (Ørstavik et al. 1986) on 100 radiographs not

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 related to this study. Cohen’s kappa was utilized to measure the inter- and intraobserver agreement.

Each investigator analysed and scored the radiographs in both groups blindly, independently and
Accepted Article
repeated the radiographic scoring after 1 month to assess the intraobserver reliability. Any

disagreement on a PAI score for a particular tooth resulted in joint evaluation until an agreement was

reached.

The modified PAI radiographic healing criteria was used as introduced by (Holden et al. 2008).

The clinical and radiographic healing classification was as follows:

Healed – the tooth was asymptomatic and the radiograph showed PAI 1 or 2;

Healing – the tooth was asymptomatic and the radiograph showed PAI 3 or 4, with score improved at

follow up from immediate post-treatment radiograph;

Not healed – the tooth was either symptomatic or the tooth was asymptomatic but the radiograph

revealed no decrease or an increase in the size of the preexisting radiolucency at follow up from

immediate post-treatment radiograph (PAI 3-5).

Statistical analysis

An initial power analysis was performed according to the data of the effectiveness of the treatments at

12 months of Bonte et al. (2015) (100% for MTA group, 73.3% for CH group). The power calculation

based on data suggested a minimum sample size of 33 teeth in each group was required to have a 90%

power for detecting differences between the treatment methods with two-sided test (α = 0.05). To

ensure a minimum sample size of 33 at the end of the follow-up periods, 45 teeth per group were

included.

In all analyses, the dependent variable was “success at last follow-up”. In order to analyse the

cumulative success proportion and mean time, the Kaplan-Meier analyses and long-rank test were

utilized. Generalized logrank (GLR) statistic was used to describe prognostic clinical variables

(Mehrotra & Roth 2011). Fisher’s exact test was used for the evaluation of the healing and non

healing rates of both groups. A significance level of 0.05 was set to analyse the two-tailed hypothesis.

Statistical analysis were performed with statistical software packages SPSS 20.0 (IBM SPSS Inc.,

Chicago, IL, USA) and SAS 9.3 (SAS Institute, Cary, NC, USA).

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 Results

Ninety teeth were included in the study; however, 9 patients were not available for recall, 5 patients
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could not be reached and 3 patients refused to participate in the recall examination. Eighty-one

percent (73/90) of the teeth were available for recall (87% for MTA and 76% for CH)(Fig.1).Trauma

was evaluated as the most common aetiological factor in pulp death and the development of periapical

lesions (62 teeth), followed by either caries (7 teeth) or defective restorations (2 teeth) and dens

invaginatus (2 teeth). Sixty-two maxillary incisors had crown fractures that had been present for a

prolonged period approximately ranging between 8 to 30 years. The patient sample consisted of 40

males and 33 females and the age of the patients at the time of apexification treatment was between

18-40 years with a mean of 23.34 (±5.98) years.

The intra-and interexaminer weighted kappa value ranged from 0.908 to 1.00 revealing very good

reliability in the evaluation of the pre- and postoperative apical status.

The follow-up period was 12-48 months after apexification treatment with a mean period of 32.3

(±10.71) months; 37% teeth were followed for 12-24 months, and 63% teeth were followed for 25-48

months.

Of 73 apexified teeth, 67 teeth survived (92%) and 6 teeth (8%) failed. In the MTA group, 29

teeth (74%) revealed calcific barrier formation, with complete resolution of the periapical lesion, 7

teeth (18%) were healing, and 3 teeth (8%) were considered to have persistent disease (Table 1, Fig

2). In the CH group, 31 healed cases had calcific barrier formation in which 27 teeth (79%) had

complete healing of the periapical lesion and 4 teeth (12%) (developed an apical barrier allowing

canal filling) were healing, and the remaining 3 teeth (9%) was considered to have persistent disease

(Table 1, Fig 3). There was no significant difference between the healing and non healing rates of

both groups (P > 0.5).

Three cases in both groups were classified as failures according to combined clinical and

radiologic criteria. Apical surgery was undertaken for three cases, of which two had with continuous

clinical complaints and one with overfilling of the MTA plug. The remaining three cases were

extracted since two had recurrent periapical swelling and enlargement of the preexisting periapical

radiolucency or periodontal problems, and one had a further traumatic injury. The cumulative survival

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 rate after apexification treatment with MTA was 100% for 12 months, 94% for 24 months, 90% for 36

months and 90% for 48 months while CH yielded 94%, 91%, 91% and 91% survival rates after 12 to
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48 months, respectively (Fig 4). Overall, the 12-month survival was 97%, while 24- 36- and 48-month

survival rates were 92, 90 and 90%, respectively.

The overall healed rate of teeth of apexification treatment with MTA (92%) was similar to

that of apexification treatment with CH (91%) (hazard ratio [HR] = 1.2; 95% confidence interval [CI]

= 0.2-7.1; P>0.05). Of the tested clinical factors, none had a significant impact on the outcome of

apexification treatment with MTA and CH (P > 0.05). The evaluated clinical variables had no

significant effect on the outcome of apexification treatment with MTA (P > 0.05, Table 2) and none of

the investigated clinical variables had a significant effect on the outcome of apexification treatment

with CH (P > 0.05, Table 3). The survival rate of apexification treatment with MTA (90%) was

similar to the survival rate observed with CH (91%).

Discussion

The present study prospectively compared the effectiveness of MTA and CH involving

immature maxillary incisors with non-vital pulps and periapical lesions in adult patients. The effects

of various preoperative predictors on the outcome of apexification treatment were also examined by

comparing the results of previous prospective or retrospective short or long-term follow-up studies

that used MTA and/or CH (Morfis & Siskos 1991, Kleier & Barr 1991, Cvek 1992, Mackie et al.

1993, Finucane & Kinirons 1999, Dominguez Reyes et al. 2005, Simon et al. 2007, Witherpoon et al.

2008, Holden et al. 2008, Bonte et al. 2015).

The findings of this study revealed that neither the patient’s age nor gender affected the

outcome of apexification treatment with MTA or CH; this result is in accordance with previous

studies on the outcome of apexification with CH (Ghose et al. 1987, Mackie et al. 1988, Morfis &

Siskos 1991, Kleier & Barr 1991) or MTA (Sarris et al. 2008, Simon et al. 2007, Holden et al. 2008).

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 The diameter of the apical foramen has been considered as one of the determinants of

apexification treatment with CH (Mackie et al. 1988, Yates 1988). If the open apical foramen
Accepted Article
clinically measures smaller than a size 90 file, it is considered as a mature tooth and an intentional

ledge is created in the apical dentine wall and the canal is then treated by conventional root canal

therapy (Webber 1984). On the other hand, interestingly, some authors have reported that when the

apical foramen diameter is greater than size 60 (Sarris et al. 2008) or even size 40 (Mente et al. 2009,

2013), the tooth is suitable for apexification treatment with MTA. In order to clarify this confusion,

the selection of apexification treatment with CH and MTA in the present study was based on the lack

of resistance to a size 80 or larger endodontic file at the apical foramen, which may correspond to the

level of root maturity 2/3rd and more than 2/3rd according to Cvek (1992).

Removal of necrotic pulp tissue remnants and microorganisms from the root canal system and

canal disinfection are the primary factors required for successful apexification treatment (McCormick

et al. 1983). It is obvious that, due to the infectious nature of apical periodontitis, maximum bacterial

removal is essential. However, the antibacterial effect of biomechanical cleansing is weaker in young

teeth with immature roots when compared to mature teeth (Cvek et al. 1976). Therefore, an

antibacterial dressing to reinforce the elimination of bacteria resistant to instrumentation and irrigation

is necessary (Cvek 1992, Felippe et al. 2005).

Previously, many investigators used saline solution (Ghose et al. 1987, Yates 1988, Mackie et

al. 1988, 1993, Kinirons et al. 2001, Damle et al. 2012), hydrogen peroxide (Thater & Marechaux

1988), less concentrated 0.5% NaOCl (Dominguez Reyes et al. 2005) as irrigation solutions for the

disinfection of the root canal system during apexification with CH, so that the adverse effects of the

irrigation solution on periapical tissues could be avoided. Furthermore, some authors have declared

the success of CH apexification without even mentioning the irrigation solution used (Morfis &

Siskos 1991, Finucane & Kinirons 1999). Provided that these irrigation solutions have mild

antibacterial effects, CH paste was utilized in order to achieve both satisfactory bacterial elimination

and apical barrier formation. Additionally, direct contact between CH paste and the periapical tissues

was also considered important for a successful inductive action in apexification. The lack of this

contact may be another reason of the long time required for formation of apical barrier and periapical

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 healing (Webber 1984, Ghose et al. 1987, Rotstein et al. 1990). Due to these intraoperative

limitations, the duration of CH in the root canal might be prolonged between 5-20 months (Sheehy &
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Roberts 1997).

In contrast to above-mentioned studies, other irrigants are preferred for effective reduction of

intraradicular microorganisms and also to remove the smear layer particularly during apexification

treatment with MTA. NaOCl was used in clinical studies either as the only main irrigant as 3-5%

NaOCl (Simon et al. 2007, Mente et al. 2009, 2013), or in combination with 0.12% CHX in retreated

teeth with open apices (Mente et al. 2009, 2013) or as 5-6% NaOCl followed by 17% EDTA (Holden

et al. 2008, Witherspoon et al. 2008, Pace et al. 2014), and as 5-6% NaOCl with 17% EDTA and

additionally, with 2% CHX before canal filling (Witherspoon et al. 2008). Following irrigation, the

canal was filled with intermediary CH dressing for one week to provide further disinfection of the

root canal system and to prevent MTA extrusion into the periapical area (Al-Kahtani 2005, Pradhan et

al. 2006, Witherspoon et al. 2008, Holden et al. 2008, Pace et al. 2014).

Considering that MTA extrusion can occur in cases with wide-open apex, physical apical

barriers have been proposed to condense the MTA safely (Kratchman 2004). However, in many

previous studies (El-Meligy & Avery 2006, Beslot-Neveu et al. 2011 , Damle et al. 2012 , Bonte et

al. 2016 ), a physical apical barrier was not used and MTA was placed gently step by step with

radiographic examination, and the location of the MTA was checked immediately after placement. In

the present study, a similar protocol was utilized and careful radiographic examination was performed

during the placement of the MTA in order to prevent its extrusion.

Although there are four comparative studies with prospective design in mostly paediatric

patients aged from 6 to 18y (El-Meligy & Avery 2006, Pradhan et al. 2006, Damle et al. 2012, Bonte

et al. 2015), there were various flaws such as enrollment of teeth either with or without a preoperative

periapical lesion, and the lack of the clear treatment protocol (the use of saline or NaOCI as irrigation

solution or use of MTA with or without intermediary CH dressing) (El-Meligy & Avery 2006,

Pradhan et al. 2006, Damle et al. 2012, Bonte et al. 2015). In the present prospective randomized

comparative clinical study, in addition to strict patient enrollment criteria, a standardized clinical

treatment protocol was established as follows: care was taken not to overextend the instrumention,

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 disinfection of the root canal was provided with NaOCI, EDTA and finally CHX, CH paste was kept

in contact with the periapical tissues and changed until occurrence of apical barrier formation for CH
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group, while CH paste was used in MTA group for a week.

In the present study, preoperative signs and symptoms had no significant effect on

periapical healing in both groups, and this finding was consistent with these previous studies (Ghose

et al. 1987, Yates 1988, Mackie et al. 1993, Finucane & Kinirons 1999, Dominguez Reyes et al.

2005). Even though it may be inadequate to generalize the present findings due to the limited number

of failed cases, another study with larger patient sample reported similar results, revealing no impact

of preoperative signs and symptoms on the treatment outcome (Mente et al. 2013).

The success of the apexification treatment with MTA or CH has been related to absence and

presence of periapical lesions (Mente et al. 2013), and the size of the periapical lesions (Kleier & Barr

1991). For interpretation of periapical radiographs in endodontics, the PAI index had been validated

as a reproducible, unbiased method (Friedman 2008, Mente et al. 2009, 2013). In the present study,

preoperative lesion sizes were obtained between PAI 3 and PAI 5 score, corresponding to sizes ranged

between 3 and 15 mm. However, especially in immature teeth with large periapical lesions, the PAI

index was insufficient to allow precise scoring of 1 or 2 in a short follow up duration (Simon et al.

2007, Holden et al. 2008, Pace et al. 2014) since large preoperative apical lesions would need a longer

period of time to heal than small lesions (Sjögren et al. 1990, Çalışkan 2004, Pace et al. 2014).

Therefore, in this study, the modified PAI radiographic healing criteria was used as described by

(Holden et al. 2008).

There are limited long term studies about apexification treatment with CH (Cvek 1992,

Mackie et al. 1993); only two case series (Holden et al. 2008, Pace et al. 2014), and two clinical AT

with MTA studies (Mente et al. 2013, Witherspoon et al. 2008). It is reported that accurate evaluation

of treatment outcome can be assessed when the long follow-up period is completed (Cvek 1992,

Mackie et al. 1993, Holden et al. 2008, Witherspoon et al. 2008, Pace et al. 2014). In the present

comparative study, the median follow-up period was 32.3 months; the follow-up periods were

recorded as 12-24 months for 37% teeth, and 25-48 months for 63% teeth. At the final follow-up

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 controls, MTA and CH revealed similar overall success rates, 92% and 91%, respectively. The

findings were in accordance with above-mentioned studies.

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The frequent occurrence of cervical root fractures during and after AT with CH has been

attributed to the stage of root development and is one of the problems in managing immature teeth

with pulp necrosis. It has been revealed that the frequency of root fractures ranged from 77% with the

least root development to 27% with the most developed roots (Cvek 1992). This finding was

supported by a laboratory experimental study (Kahler et al. 2018). On the contrary, several laboratory

experimental studies suggested that dressing with CH for extended periods in apexification treatment

has been reported to be associated with a higher risk of cervical root fracture due to its ability to

denaturate and dissolute dentine proteins and increase the brittleness of the tooth (Andreasen et al.

2002, Sahebi et al. 2010).

On the other hand, among the previous clinical studies which reported successful outcome of

apexification treatment with CH, none has identified cervical root fracture as a reason of failure

(Webber 1984, Ghose et al. 1987, Yates 1988, Thater & Marechaux 1988, Morfis & Siskos 1991,

Kleier & Barr 1991, Mackie et al.1993, Finucane & Kinirons 1999, Kinirons et al. 2001, Dominguez

Reyes et al. 2005). This finding was similar to the results of the present study. In the literature, several

physical and biomechanical reasons have been considered responsible for reduced fracture strength of

teeth during and following root canal treatment such as the loss of coronal hard and pulp tissue from

trauma, caries, restorations combined with access preparation to the root canal system, excessive root

canal procedures, the use of various canal disinfectants (Sedgley & Messer 1992, Hülsmann et al.

2003, Al-Jundi 2004, Oliveira et al. 2007) and lack of providing adequate support with using

composite restorations extending into the root canal (Lawley et al. 2004, Wilkinson et al. 2007) or

fibre posts (Brito-Junior et al. 2014). In the present study, following the apexification treatment with

MTA or CH of immature teeth with stage of root development 3 and 4, the remainder of the root canal

was filled with gutta-percha and sealer. Finally, the access cavities were sealed with composite resin

extending into the coronal third of the canal or a fibre post with bonded composite material.

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 Randomization is an important step in clinical studies to ensure balance of sample size and to

eliminate selection bias. There are many randomization techniques, including tossing a coin (Singh &
Accepted Article
Garg 2012), selecting shuffled cards (Miçoğulları Kurt & Çalışkan 2018), throwing a die (Trope et al.

1999) and online randomization method (Rodriguez-Wong et al. 2016). In the present study,

online randomization method was performed as two groups in a 1:1 ratio by using a free online

software to prevent the selection bias and to insure against the accidental bias related to the operator

or patients. This method provided equal and random distribution of the patients to the groups.

Conclusion

The results of this clinical study demonstrated that apexification treatment with CH and MTA

had similar clinical and radiographical success rates in immature teeth of adults, and none of the

tested clinical predictors had significant impact on the overall treatment outcome. With these findings,

MTA may be advocated as a material for AT in immature teeth of adult patients because of the shorter

treatment time provided.

Acknowledgement

The authors would like to thank Assoc. Prof. Dr. Timur Köse from Ege University, Faculty of

Medicine, Department of Biostatistics and Medical Informatics for his valuable contributions in

statistical analyses and interpretations of data. The authors also thank Devan V. Mehrotra from

Clinical Biostatistics, Merck Research Laboratories for providing the codes used in generalized log

rank (GLR) statistic.

Conflict of Interest statement

The authors have stated explicitly that there are no conflicts of interest in connection with this article.

This article is protected by copyright. All rights reserved.

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 Figure Legends
Accepted Article
Figure 1 Patient flow chart of apexified teeth with MTA or CH. Consolitated Standards of Trials

Reporting (CONSORT) flow chart.

Figure 2 MTA apexification group: (a) The preoperative radiograph of an immature maxillary left

lateral incisor associated with large periapical lesion. (b) 24-month follow-up radiograph showing

reduced periapical radiolucency with no clinical sign and symptoms; The outcome is classified as

“healing”. Note significant reduction of radiolucency. (c) The preoperative radiograph of an immature

maxillary right central incisor associated with periapical radiolucency. (d) 36-month follow-up

radiograph showing the complete resolution of the periapical radiolucency; The outcome is classified

as “healed”.

Figure 3 CH apexification group: (a) The preoperative radiograph of an immature maxillary right

lateral incisor associated with dens invaginatus and large periapical lesion (b) 12-month follow-up

radiograph showing reduced periapical radiolucency with no clinical sign and symptoms: The

outcome is classified as “healing”. (c) The preoperative radiograph an immature maxillary left central

incisor associated with periapical radiolucency. (d) 24-month follow-up radiograph demonstrating the

complete resolution of the periapical radiolucency; The outcome is classified as “healed”.

Figure 4 The Kaplan-Meier survival curves with respect to tested AT materials.

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 Table 1 Outcomes of AT with CH and MTA related to follow-up periods
Accepted Article
Type of material and Follow-up period

Type of healing MTA (n = 39) CH (n = 34)

12-24 months 25-48 months 12-24 months 25-48 months

(n=13, %) (n=26, %) (n=14, %) (n=20, %)

Healed (PAI 1 or 2) 7 54 22 85 9 64 18 90

Healing (PAI 3 or 4, with score improved at follow-

4 31 3 11 3 22 1 5
up from immediate posttreatment radiograph

Nonhealed (PAI 3 or 5, with score not improved at

2 15 1 4 2 14 1 5
follow-up from immediate posttreatment radiograph

PAI, periapical index, AT apexification treatment

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 Table 2 Teeth and outcome across the various clinical predictors and estimated relative

success rates following AT with MTA.

Accepted Article
Variable Censored Failure, Total P value Hazard ratio

(n, %) (n, %) (95% CI)

Gender NS*

Male 25 (96) 1 (4) 26 1

Female 11 (85) 2 (15) 13 3.4 (0.2-55.5)

*
Age NA
*
18-25 y 27 (90) 3 (10) 30 NA

26-40 y 9 (100) 0 9 NA*

*
Root development NA

Stage III 7 (100) 0 7 NA*

Stage VI 29 (91) 3 (9) 32 NA*

Sign and symptoms NS*

Absent 33 (97) 1 (3) 34 1

Present 3 (6) 2 (4) 5 10.6 (0.7-163.9)

Lesion size NS*

3-7.9 mm 30 (94) 2 (6) 32 1

8-15 mm 6 (85) 1 (15) 7 1.9 (0.1-28.5)

CI, confidence interval; MTA, mineral trioxide aggregate; AT, apexification treatment.

NA* No statistics are computed because all cases are censored.

NS* Not significant

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 Table 3 Teeth and outcome across the various clinical predictors and estimated relative success rates

following AT with CH.

Accepted Article
Variable Censored Failure, Total P value Hazard ratio

(n, %) (n, %) (n, %) (95% CI)

Gender NS*

Male 13 (93) 1 (7) 14 1

Female 18 (90) 2 (10) 20 1.3 (0.1-22.1)

Age NS*

18-25 y 19 (90) 2 (10) 21 1

26-40 y 12 (92) 1 (8) 13 0.8 (0.1-13.0)

Root development NS*

Stage III 6 (86) 1 (14) 7 1

Stage VI 25 (93) 2 (7) 27 0.5 (0.03-8.3)

Sign and symptoms NS*

Absent 23 (92) 2 (8) 25 1

Present 8 (89) 1 (11) 9 1.5 (0.1-23.9)

Lesion size NS*

3-7.9 mm 21 (91) 2 (9) 23 1

8-15 mm 10 (91) 1 (9) 11 1.1 (0.1-16.8)

CI, confidence interval; CH, calcium hydroxide; AT, apexification treatment.

NS* Not significant

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