Introduction A. Agrafioti, D.G. Giannakoulas*, C.G. Filippatos, E.G. Kontakiotis Teeth with necrotic pulp and open apex bring about several challenges to clinicians due to the lack of natural Department of , School of , National and apical constriction and the thin root walls that are Kapodistrian University of Athens, Athens, Greece prone to fracture [Trope, 2006, Camp, 2008]. In order *School of Dentistry, National and Kapodistrian University of to confine filling materials into the space and Athens, Athens, Greece prevent overfilling, the placement of an artificial apical barrier and/or the closure of the apex are necessary email: [email protected] before obturation of the root canal system [Trope 2006]. The traditional approach to handle cases with open apex DOI: 10.23804/ejpd.2017.18.04.03 is the multiple-visit treatment with the use of calcium hydroxide (CH) as intracanal medicament [Seltzer, 1988]. The frequency of changes of CH from the root canal constitutes a controversial topic as there are studies Analysis of clinical that propose that a single placement of this medicament is enough to achieve predictable outcomes [Chawla studies related 1986], whereas others claim that multiple replacements of CH could lead to a more rapid formation of a calcified to apexification tissue barrier [Abbot 1998]. The time required for the calcified tissue barrier to form varies from 5 to 20 months techniques [Sheehy and Roberts, 1996] and seems to be influenced by several factors such as opening of the apex, frequency of intracanal medication replacement, age of the patient and the presence of periapical radiolucency [Mackie et al., abstract 1988; Finucane and Kinirons, 1999; Kleier and Barr, 1991]. CH apexification has high clinical success rates and Aim The aim of this study was to gather all the clinical most of the teeth exhibit a calcified barrier at the blunt studies regarding apexification and artificial apical apex [Sheehy and Roberts, 1996; Mendoza et al., barrier techniques, point out the possible differences 2010]. However, despite the high success rate of CH of the clinical procedures and investigate how these apexification, several limitations led to seek for alternative are changing over time. treatment modalities. The long time for the apical barrier Materials and methods An electronic search to be formed, the multiple visits for completion of the was carried out in PubMed, covering the period from treatment, the possibility for coronal microleakage during March 1968 to July 2015. More articles were retrieved treatment as well as the lower resistance to fracture of by hand-searching or by the reference section of the the teeth are some of those disadvantages [Andreasen et included articles. Specific criteria were set in order to al., 2002; Andreasen et al., 2006; Rosenberg et al., 2007]. determine the relevance of each study. Torabinejad and Chivian [1999] proposed the use of Results One hundred and thirty eight articles were mineral trioxide aggregate (MTA) as an artificial apical included, 53% of them concerned apexification plug for the treatment of teeth with open apex. MTA with MTA plug. Long term apexification studies has the main advantages of inducing a hard tissue barrier demonstrated 13% for a single change of the intracanal in contact to its surface [Shabahang et al., 1999] and medicament and 85% for two or more. In 13% of the setting up in the presence of moisture [Torabinejad et al., studies concerning artificial apical plug, the procedure 1995]. MTA apexification treatment can be completed in included a single visit. Calcium hydroxide was left in a single visit or in two or more visits with the use of CH as the root canal for 3–12 months in 59% of the long intracanal medicament [Witherspoon et al., 2008; Nayar term apexification studies, for 12-24 in 42% and for et al., 2009]. In a systematic review of the literature, 24 months or more in 10%. Chala et al. [2011] report that the clinical success of Conclusion Both techniques can lead to favourable MTA plug apexification does not differ from that of CH clinical outcomes. There is a tendency for the artificial apexification. More recently, other biomaterials such as apical barrier apexification over the years, which Biodentine (Spetodont) and calcium-enriched mixture usually includes the use of intracanal medicament for (CEM) have also been used as artificial apical barriers in a short time. cases of pulpless teeth with open apex [Khetarpal et al., 2014; Asgary and Fazlyab, 2014]. Keywords Apexification; Calcium hydroxide; MTA; In recent years, regenerative endodontic procedures Open apex. (REPs) have been used to treat teeth with necrotic pulp and open apex [Kontakiotis et al., 2014]. Those techniques aim

European Journal of Paediatric Dentistry vol. 18/4-2017 273 Agrafioti A. et al.

to achieve healing of apical periodontitis, and thickening The criteria for the definitive inclusion of each article and/or lengthening of the root walls based on the core after full text retrieval were: principles of tissue engineering [Kontakiotis et al., 2015]. 1) clinical studies, case series or case reports that Since 2001, many studies have been published in the included calcium hydroxide apexification treatment literature presenting the use of REPs with signs of clinical or apexification procedure with the use of artificial success [Kontakiotis et al., 2014; Kontakiotis et al., 2015]. apical barriers in teeth with open apex; Apexification treatment has been implemented in teeth 2) adequate information with regard to the technique with open apex for more than 40 years. Several differences and the materials used; can be found among the relevant studies in the way the 3) outcome based on clear data from clinical and apexification procedures are carried out. Regardless the radiographic examination; type of apexification (long-lasting use of CH or use of 4) articles written in English language. artificial apical barriers), the type of apical barrier, the Exclusion criteria were: number of visits, the use of intracanal medicaments 1) articles irrelevant to apexification procedures; and its time of permanence in root canal, apexification 2) animal studies, reviews, in vitro or ex vivo studies; procedures appear to lead to favourable clinical 3) inadequate data regarding the application of the outcomes. Certainly, it is pretty important and helpful to treatment protocol; clinicians to gather and analyse the clinical articles related 4) articles written in languages other than English. to apexfication treatment via a systematic approach of The criteria were applied to each article independently the international literature. Regenerative endodontic by the reviewers for more reliable results. A consensus procedures were not taken into account in this review, as was achieved after discussion in cases of disagreement. there are already studies that have gathered the related The information selected from each article concerned: clinical articles and analysed the implemented protocols the type of each study, the cause of open apex, the type [Kontakiotis et al., 2014; Kontakiotis et al., 2015]. of apexification procedure (calcium hydroxide or artificial The purpose of this review was to retrieve all clinical apical barrier), the type of artificial apical barrier, the studies related to apexification treatment in teeth with number of visits for the completion of treatment, the open apex, point out the differences in treatment time that calcium hydroxide was left in the root canals, procedures among them, detect how these procedures the clinical success of the treatment as well as the apical are changing over time, as well as to survey the closure. In cases of clinical studies that included multiple percentages of clinical success and apical closure of the categories, all of them were counted. aforementioned techniques. Results Materials and methods One thousand two hundred and thirty-five (1235) An electronic search in PubMed database was results were found after the aforementioned electronic carried out covering the period from March 1968 to search, 1114 of which were not included in this review the second week of July 2015. Appropriate MeSH due to the exclusion criteria. The sample was formed at (Medical Subject Headings) terms for this search were 121 articles. Seventeen more studies were retrieved after formed: (((open[All Fields] AND ("Apex"[Journal] OR hand-searching in the specific journals or by the reference "apex"[All Fields])) OR (("calcium hydroxide"[MeSH section, so the final sample was 138 articles (Fig. 1). Terms] OR ("calcium"[All Fields] AND "hydroxide"[All The results of this study are shown in Table 1. Fifty-three Fields]) OR "calcium hydroxide"[All Fields]) AND percent of the studies included in this review referred to ("apexification"[MeSH Terms] OR "apexification"[All MTA apical plug technique, whereas in the last decade the Fields]))) OR (("pemetrexed"[Supplementary Concept] same percentage was 71%. The percentages regarding OR "pemetrexed"[All Fields] OR "mta"[All Fields]) AND the number of visits of CH apexification were 13% and apical[All Fields] AND plug[All Fields])) OR (("mineral 85% for two visits and multiple visits, respectively. As trioxide aggregate"[Supplementary Concept] OR "mineral far as the duration of the treatment is concerned, CH trioxide aggregate"[All Fields]) AND ("apexification"[MeSH remained in the root canal space for 3-12 months in 59% Terms] OR "apexification"[All Fields])). There was also of the studies, for 12-24 months in 42%, and 24 months a hand-search of 4 relevant dental journals: Journal of or more in 10% of the studies. Endodontics, International Endodontic Journal, Pediatric The apical plug technique was completed in one visit in Dentistry, and International Journal of Paediatric Dentistry. 13% of the studies; in two visits in 75% and in more than The reference section of each study included in this review two visits in 20%, whereas, the intracanal medicament was used as an additional article source. The relevance of was left for up to 3 weeks in 74% of the studies in which each article was initially evaluated by scanning its title and it was used. abstract. In cases of uncertainty for the article’s relevance, Long-term apexification presented higher percentages full texts were retrieved. of apical closure than artificial barrier apexification.

274 European Journal of Paediatric Dentistry vol. 18/4-2017 Pulp therapy for primary and young permanent teeth

Discussion

Pulp necrosis is caused by trauma or other insults, and it usually results in the arrest of root development of permanent immature teeth; immature pulpless teeth remain with open apex and thin and short root walls [Holden et al., 2008]. Other causes of open apex are: chronic periapical periodontitis that leads to apical resorption, apical resorption due to trauma, destruction of apical constriction during mechanical debridement, without use of root-end filling materials and horizontal root fracture [Kusgoz et al., 2009; Stefopoulos et al.; 2012; Mente et al., 2013]. In the case of immature teeth with open apex and fragile root walls, apart from the risk of extruding root filling materials in the periradicular tissues, there is also the risk of root fracture during or after the completion of treatment [Holden et al., 2008]. Two of the most popular techniques to confront fig. 1 PRISMA 2009 flow diagram. teeth with open apex are: the long-lasting apexification treatment with use of CH, and the apexification procedure with placement of artificial apical barriers at the blunt clear up their correlation with the treatment outcome. apex. The present study targeted clinical articles related According to the findings of the present study, all clinical to apexification procedures. The number of articles that articles published from 1976 to 2002 are related to CH complied with the inclusion criteria of this study was one apexification. However, it seems that in the last decade the hundred thirty eight. Gathering all these articles and use of artificial apical barriers has restricted the use of CH analysing in detail the treatment procedures is helpful technique, as in this decade 75 out of 105 relevant studies to uncover possible preferences to a specific treatment (71%) are related to MTA apical plug technique and, protocol or a specific biomaterial and to understand how additionally, there are a few cases of apical plug technique these preferences are changing over time as well as to in which Biodentine and calcium-enriched mixture (CEM)

Study Type of Cause of Barrier One or two Duration of Clinical Apical Recall Period study open apex visits CaOH success closure Umashetty et Case report Immature MTA 2 visits with 2 weeks 4/4 2/4 15 months

al, 2015 teeth Ca(OH)2 Yadav et al, Case report Immature MTA + PRF 2 visits with 1 week 1/1 0/1 2 years

2015 tooth membrane Ca(OH)2 Chalakkal et Case report Immature Mineralised 1 visit 1 year 0/1 1/1 1 year al, 2015 tooth tissue barrier (Metapex) Mente et al, Cohort Apicoectomy MTA 1 or 2 visits Not 20/23 Not 35 months 2015 clinical study (n=9) mentioned Mentioned Multiple visits (n=14)

with Ca(OH)2 Galhotra et Case report Immature Mineralised 1 visit 1 year Not clear Not clear 2 years al, 2015 tooth tissue barrier (Metapex) due to due to extrusion extrusion Kumar et al, Case report Immature MTA + PRF Multiple 3 weeks 1/1 1/1 1 year 2014 tooth membrane visits with triple antibiotic paste +

Ca(OH)2 Narang et al, Pilot clinical Immature MTA 2 visits Not 5/5 0/5 18 months 2015 study teeth with triple mentioned antibiotic paste Silva et al, Case report Immature Mineralised 4 visits with 9 months 1/1 1/1 6 years

2015 tooth tissue barrier Ca(OH)2 Immature MTA 2 visits with 3 weeks 1/1 1/1 tooth Ca(OH)2 Badole et al, Case report Immature MTA 2 visits with 1 week 2/2 0/2 1 year

2015 teeth Ca(OH)2

TabLE 1A Presentation of the data collected from the clinical studies on apexification techniques.

European Journal of Paediatric Dentistry vol. 18/4-2017 275 Agrafioti A. et al.

Study Type of study Cause of Barrier One or two Duration of Clinical Apical Recall open apex visits CaOH success closure Period Bonte et al, RCT Immature Mineralised 6 visits with 1 year 12/16 8/16 1 year

2015 teeth tissue Ca(OH)2 75% 50% barrier MTA 2 visits with 2 weeks 14/17 13/17 1 year

Ca(OH)2 82.4% 76.5% Kumar et al, Case report Immature MTA 2 visits with 2 weeks 2/2 2/2 8 months

2014 teeth Ca(OH)2 Khetarpal et Case report Immature Biodentine 2 visits with 1 week 1/1 1/1 18 months

al, 2014 tooth Ca(OH)2 Shekhar et Case report Immature MTA 2 visits with 1 week 1/1 1/1 6 months

al, 2014 tooth Ca(OH)2 Pace et al, Case series Immature MTA 2 visits with 1 week 15/16 Not 10 years

2014 teeth Ca(OH)2 mentioned Alobaid et Retro cohort Immature MTA Multiple Not 5/5 Not 22 months al, 2014 study teeth visits with mentioned mentioned

Ca(OH)2 Mineralised Multiple Not 7/7 Not tissue visits with mentioned mentioned

barrier Ca(OH)2 Asgary & Case report Immature C.E.M 1 visit - 1/1 1/1 2 years Fazlyab tooth 2014 Sinha et al, Case report Immature Biodentine 2 visits - 1/1 1/1 1 year 2014 tooth with triple antibiotic paste Chacko & Case report Immature Mineralised Multiple 2 years 1/1 1/1 2 years Pradhan tooth tissue visits with

2014 barrier Ca(OH)2 Ghosh et al, Comparative Immature Mineralised Multiple 7.6 months 44/51 37/51 7.6 months 2014 study teeth tissue visits with 86.3% 72.5%

barrier Ca(OH)2 Nayak & Case report Immature Biodentine 2 visits with 1 month 1/1 1/1 1 year

Hasan 2014 tooth + collagen Ca(OH)2 membrane Kumar et al, Case report Immature MTA 2 visits with 5 month 1/1 1/1 28 months

2014 tooth Ca(OH)2 Dixit et al, Case report Immature MTA 2 visits with 2 weeks 2/2 2/2 5 years

2014 teeth Ca(OH)2 mineralised 2 visits with 6 months

barrier Ca(OH)2 Nagy et al, RCT Immature MTA 2 visits Not 9/9 Not 18 months 2014 teeth with triple mentioned mentioned antibiotic paste Khetarpal et Case report Immature MTA + PRF 2 visits with 1& 2 weeks Inadequate Inadequate 3 months

al, 2013 tooth membrane Ca(OH)2 recall period recall period Cetenović et Case report Immature MTA 4 visits with 6 months 4/4 0/4 6 months

al, 2013 teeth Ca(OH)2 for the first (3 first)/ 3 3/ 4 months months for the other Gawthaman Case report Immature mineralised 2 visits with 3 months Inadequate 1/1 3 months

et al, 2013 tooth barrier Ca(OH)2 recall period MTA 2 visits with 5 days Inadequate Inadequate -

Ca(OH)2 recall period recall period Floratos et Case report Immature MTA 2 visits with 2 weeks 2/2 2/2 12&16

al, 2013 teeth Ca(OH)2 months Costa et al, Case report Immature mineralised Multiple 18 months 1/1 1/1 16 months 2013 tooth barrier + visits with

MTA Ca(OH)2 Shekhar & Case report Immature MTA 2 visits with 1 week 1/1 1/1 24 months

Shashikala tooth Ca(OH)2 2013 Chang et al, Case reports Immature MTA 2 visits 2 weeks 3/3 Not clear 11-24

2013 teeth Ca(OH)2 months 3 visits 3 weeks Not clear

Ca(OH)2 2 visits 1 week 1/1

Ca(OH)2

TabLE 1B Presentation of the data collected from the clinical studies on apexification techniques.

276 European Journal of Paediatric Dentistry vol. 18/4-2017 Pulp therapy for primary and young permanent teeth

Study Type of Cause of open apex Barrier One or two Duration of Clinical Apical Recall study visits CaOH success closure Period Fayazi et al, Case Immature tooth MTA 2 visits 1 week 1/1 1/1 6

2013 report Ca(OH)2 months Vijayran et Case Immature tooth MTA 2 visits 13 months Inadequate Inadequate -

al, 2013 report Ca(OH)2 recall period recall period Souza et al, Case Overinstrumentation Ca(OH)2 2 visits with 2 weeks 1/1 1/1 8 years

2012 report - destruction of AP plug Ca(OH)2 Paul et al, Case Immature tooth MTA 2 visits with 3 weeks 1/1 1/1 6

2012 report Ca(OH)2 months Mente et al, Retro Immature (12) MTA 2 or more Not 11/12 Not 1 year 2013 cohort visits with mentioned 92% mentioned

study Overinstrumentation Ca(OH)2 103/110 (110) 94% Root resorption due 89/105 to A.P. (105) 85% Root resorption Due 24/25 to trauma (25) 96% Silva & Zaia Case Immature tooth Mineralised Multiple 18 months 1/1 1/1 2 years 2012 report tissue visits with

barrier Ca(OH)2 de Jesus Case Immature tooth Mineralised 2 visits with 9 months 1/1 1/1 4 years

Soares et al, report tissue Ca(OH)2 2012 barrier Jeeruphan et Retro study Immature teeth MTA 1 visit - 13/19 Not >6 al, 2012 mentioned months Mineralised Multiple 17 months 17/22 Not tissue visits with mentioned

barrier Ca(OH)2 Stefopoulos Case Apicoectomy MTA 2 visits with 2 weeks 1/1 1/1 4 years

et al, 2010 report Ca(OH)2 Rudagi & Case Immature tooth MTA 2 visits with 1 week 1/1 1/1 1 year

Rudagi report Ca(OH)2 2012 Albadri et Case Immature teeth MTA 2 visits with Not 2/2 2/2 6-18

al, 2012 report Root fracture Ca(OH)2 mentioned 1/1 1/1 months Gunes & Case Immature teeth MTA 2 visits with 2 weeks 3/3 3/3 18

Aydinbelge report Ca(OH)2 months 2012 Aggarwal et Case Immature tooth Not clear Multiple 2 months 1/1 Not clear 24 al, 2012 report visits with months

Ca(OH)2 Points Bezgin et al, Prospect Immature tooth Mineralised Multiple 9.6 11/12 11/12 12 2012 Clinical tissue visits with months months study barrier Ca(OH)2 Points Mineralised Multiple 9.6 10/10 10/10 tissue visits with months barrier Ca(OH)2 Paste Asgary & Case Immature tooth MTA 2 visits with 2 weeks 1/1 1/1 7 years

Ehsani S report Ca(OH)2 2012 Nosrat et al, Case series Immature teeth CEM/MTA 2 visits with 2 weeks 7/7 7/7 12-24

2011 Resorption due to AP Ca(OH)2 6/6 6/6 months Yassen et al, Prospective Immature teeth Mineralised 2 (74%) 6-12 23/23 23/23 13 2012 study tissue 3 (22%) months months barrier 4 (4%) -visits with

Ca(OH)2 Ajwani & Case Immature tooth MTA 2 visits with 1 month 1/1 0/1 6

Saini 2011 report Ca(OH)2 months Paula-Silva Case Immature tooth MTA Multiple 14 months 1/1 1/1 12 et al, 2011 report visits with months

Ca(OH)2

TabLE 1C Presentation of the data collected from the clinical studies on apexification techniques.

European Journal of Paediatric Dentistry vol. 18/4-2017 277 Agrafioti A. et al.

Study Type of study Cause of open Barrier One or two Duration of Clinical Apical Recall apex visits CaOH success closure Period Beslot-Neveu RCT Immature teeth MTA 2 visits with 2 weeks Not Not 12

A et al, 2011 Ca(OH)2 mentioned mentioned months Mineralised 4 visits with 6-12

tissue barrier Ca(OH)2 months Shadmehr & Case report Immature tooth MTA+ Calcium 3 visits with 2 weeks 1/1 0/1 18

Farhad 2011 hydroxide plug Ca(OH)2 months Moore et al, Comparative Immature teeth MTA 2 visits with At least 1 21/22 14/22 23,4

2011 clinical study Ca(OH)2 week 95,5% 63,6% months Kumar et al, Case report Overi- MTA 2 visits with 1 week 1/1 0/1 6

2011 nstrumentation Ca(OH)2 months Kahler 2011 Case report Immature teeth MTA 2 visits with 1 month 2/2 0/2 12

Ca(OH)2 months Mohammadi Case report Immature tooth MTA Not Not 1/1 1/1 1 year & Yazdizadeh mentioned mentioned 2011 Warner & Al- Case report Immature tooth MTA 2 visits with 1 month 1/1 0/1 2

Salehi 2011 Ca(OH)2 months Asgary et al, Case report Immature teeth CEM 1 visit - 1/1 0/1 40 2011 without months

Ca(OH)2 2 visits with 6 weeks 1/1 0/1

Ca(OH)2 Mendoza et Clinical Immature teeth Mineralised Multiple 8,6+/- 3,36 28/28 28/28 24 al, 2010 Study tissue barrier visits with months months

Ca(OH)2 Cehreli et al, Case report Immature teeth MTA 2 visits Not 2/2 0/2 18 2011 without mentioned months

Ca(OH)2 Sridhar et al, Case report Immature teeth Mineralised 3 visits with 12 months 3/3 3/3 12 2010 tissue barrier Metapex® months

Chhabra et Case report Immature tooth MTA+ 2 visits with 2 weeks 1/1 0/1 24 al, 2010 Demineralized Metapex® months freeze-dried bone allograft Lee et al, Clinical Immature teeth Mineralised 4 visits with 10-14 32/32 32/32 Not

2010 study tissue barrier Ca(OH)2 weeks ment- ioned Vellore 2010 Case report Immature teeth Mineralised 3 visits with 3 months 2/2 2/2 -

tissue barrier Ca(OH)2 Araújo et al, Case report Apical resorption MTA+ Calcium 1 visit - 1/1 0/1 12 2010 sulphate without months

matrix Ca(OH)2 Khatavkar & Case report Immature tooth MTA+ Calcium 2 visits with 1 week 1/1 0/1 3

Hegde 2010 sulfate barrier Ca(OH)2 months Vanka et al, Case report Immature teeth MTA Multiple 16 months 1/1 0/1 6 2010 visits with months

Ca(OH)2 MTA+ 2 visits with 2 weeks 1/1 1/1 Not

absorbable Ca(OH)2 mentio- collagen ned sponge

Wang et al, Case report Immature tooth Mineralised Multiple 5 months 1/1 1/1 12 2010 tissue barrier visits with months

Ca(OH)2 Schmitz et al, Case report Immature teeth Mineralized Multiple 8 months / 2/3 2/3 38 2010 tissue barrier visits with 15 months months

Ca(OH)2 / 12 months Nayar et al, Clinical Immature teeth MTA Multiple Mean time 41/43 Not 10,67 2009 study visits with 20 weeks mentioned months

Ca(oH)2

TabLE 1d Presentation of the data collected from the clinical studies on apexification techniques.

278 European Journal of Paediatric Dentistry vol. 18/4-2017 Pulp therapy for primary and young permanent teeth

Study Type of Cause of open apex Barrier One or two Duration of Clinical Apical Recall study visits CaOH success closure Period Nuvvula et al, Case Immature tooth MTA Multiple 2 weeks 1/1 0/1 4 motnhs 2010 report visits with

Ca(OH)2 Annamalai et Clinical Immature teeth MTA 1 visit - 30/30 26/30 12 months al, 2010 study without 100% 86,6%

Ca(OH)2 Kusgoz et al, Case Apical resection MTA 3 visits with 6 weeks+ 1/1 0/1 30 months

2009 report Ca(OH)2 3 months (change (antibiotic every 2 paste) weeks+ 3 visits with triple antibiotic paste) Raldi et al, Case Immature teeth Mineralised Multiple 12 months 1/1 1/1 2 years 2009 report tissue barrier visits with

Ca(OH)2 MTA 2 visits with 2 weeks 1/1 1/1 5 years

Ca(OH)2 MTA 2 visits with 4 weeks 1/1 0/1 9 months

Ca(OH)2 Mente et al, RCT Overinstrumentation MTA 2 visits with Not 47/56 Not 30,9

2009 / Apical resorption Ca(OH)2 mentioned (84%) mentioned months Oktem et al, Case Apical resorption Mineralized Multiple 6 Months 1/1 1/1 24 months 2009 report tissue barrier visits with CHPP Bogen & Case Immature tooth MTA 2 visits with 1 week 1/1 1/1 18 months

Kuttler 2009 report Ca(OH)2 Kusgoz et al, Case Horizontal root MTA 2 visits with Not 3/3 0/3 24 2009 reports fracture Ca(OH)2 mentioned months/ 12months Ma et al, Case Immature tooth MTA 2 visits with 2 weeks Not 1/1 Not 2009 report Ca(OH)2 ment. mentioned Demartis et Case Immature tooth MTA 2 visits with 10 days 1/1 1/1 12 months al, 2009 report Ca(OH)2 Marcos Case Immature tooth Mineralised Multiple 18 months 1/1 1/1 7 years Jacobovitz et report tissue barrier visits with al, 2009 Ca(OH)2 Oliveira et al, Case Immature teeth MTA Multiple 6 months 2/2 0/2 15 months 2008 report visits with Ca(OH)2 Park & Lee Case Immature tooth MTA 2 visits with 1 week 1/1 1/1 24 months 2008 report Ca(OH)2 Witherspoon RCT Not mentioned MTA 1 visit with - 46/47 Not 19,4 et al, 2008 MTA mentioned months 2 visit with 3 weeks 26/31 Ca(OH)2 Holden et al, RCT Not mentioned MTA 2 visits with 1 week 17/20 Not 1 year 2008 Ca(OH)2 healed mentioned 1/20 healing

Deepti et al, Case Immature tooth Mineralised 3 visits with 13 months 1/1 1/1 Not 2008 report tissue barrier Ca(OH)2 mentioned Fregnani et Case Immature tooth IRM surgically Multiple 12 months 1/1 0/1 4 years al, 2008 report visits with Ca(OH)2 Zhu et al, Case Immature tooth MTA 2 visits with 2 weeks 1/1 0/1 30 months 2008 report Ca(OH)2 Erdem & Case Immature teeth MTA 2 visits with 1-6 weeks 4/5 4/5 24 months Sepet 2008 report Ca(OH)2 Soares et al, Case Immature tooth Mineralised 5 visits with 8 months 1/1 1/1 36 months 2008 report tissue barrier Ca(OH)2 Kristoffersen Case Immature tooth MTA 2 visits with 2 months 1/1 0/1 15 months et al, 2008 report Ca(OH)2 Ghaziani et Case Immature teeth MTA 2 visits with 2 weeks 1/2 0/2 24 months al, 2007 report Ca(OH)2 Sarris et al, Pilot Immature tooth MTA 3 visits Not 13/17 Not 12,53 2008 study without mentioned mentioned months Ca(OH)2 TabLE 1E Presentation of the data collected from the clinical studies on apexification techniques.

European Journal of Paediatric Dentistry vol. 18/4-2017 279 Agrafioti A. et al.

Study Type of study Cause of open Barrier One or two Duration of Clinical Apical Recall apex visits CaOH success closure Period De-Deus & Case report Immature tooth WPC (White 1 visit - 1/1 1/1 12 months Coutinho- Portland Filho, 2007 Cement) + resorbable collagen sponge D'Arcangelo Case report Immature teeth MTA + 2 visits with 2 weeks 2/2 0/2 12 months & D'Amario Absorbable Ca(OH)2 2007 gelatin sponge Gaitonde & Case report Immature tooth MTA 2 visits with 1 week 1/1 1/1 12 months Bishop 2007 Ca(OH)2 Simon et al, Prospective Not mentioned MTA 1 visit - 35/43 11/43 12 months 2007 study (81%) Pradhan et al, Clinical study Immature teeth MTA 2 visits with 1 week 100% 70% Not ment–

2006 Ca(OH)2 10/10 7/10 ioned Mineralised Multiple 7+/-2,5 100% 100% tissue barrier visits with months 10/10 10/10

Ca(OH)2 Sübay & Case report Immature tooth MTA (after 6 visits with 6 months 1/1 0/1 12 months

Kayataş surgery, Ca(OH)2 2006 because of no hard tissue barrier) Karp et al, Case report Immature tooth MTA canal 4 visits with 422 days 1/1 0/1 16 months

2006 obturation Ca(OH)2 + Ba(OH)2 El-Meligy & Comparative Immature teeth Mineralised Multiple 12 months 13/15 13/15 12 months Avery DR 2006 study tissue barrier visits with

Ca(OH)2 MTA 2 visits with 1 week 15/15 Not

Ca(OH)2 mentioned Ballesio et al, Case series Immature tooth Mineralised 2 visits with 6 months 15/15 15/15 7-13 years

2006 tissue barrier Ca(OH)2 Ghaziani et Case series Immature tooth MTA 2 visits with 1 week 38/41 Not 6 months

al, 2006 Ca(OH)2 92,7% mentioned Silberman et Case report Immature tooth MTA 3 visits with 6 months 1/1 0/1 9 months

al, 2006 Ca(OH)2 Dominguez Retrospective Immature teeth Mineralised Multiple 12,19 100% 100% Not ment– Reyes et al, study tissue barrier visits with months ioned

2005 Ca(OH)2 Kalaskar et Case report Immature tooth Mineralised 6 visitswith 6 months 1/1 1/1 6 months

al, 2004 tissue barrier Ca(OH)2 Pai et al, Case Report Immature tooth Mineralised Multiple 14 months 1/1 1/1 25 months 2004 tissue barrier visits with

Ca(OH)2 Jung 2004 Case report Immature tooth Mineralised Multiple 6 months 1/1 1/1 12 months tissue barrier visits with

Ca(OH)2 Hayashi et al, Case report Root- end MTA 2 visits with 2 weeks 2/2 0/2 24 months

2004 resection Ca(OH)2 Sedgley & Case report Apicectomy Mineralised 3 visits with 12 months 1/1 1/1 5 years

Wagner 2003 tissue barrier Ca(OH)2 Linsuwanont Case report Immature teeth MTA 2 visits with 8 months 2/2 1/2 12 months

2003 Ca(OH)2 Maroto et al, Case report Immature teeth Mineralised Multiple 2 years 1/1 1/1 12 months 2003 tissue barrier visits with

MTA Ca(OH)2 1/1 0/1 Giuliani et al, Case report Immature teeth MTA 2 visits with 1 week 3/3 0/3 12 months

2002 Ca(OH)2 Gupta S Case report Immature tooth Mineralised 2 visits with Not 3/3 3/3 Not ment–

1998 tissue barrier Ca(OH)2 mentioned ioned Selden 2002 Case report Immature tooth Mineralised 3 visits with 2 years 1/1 1/1 30 months tissue barrier Ca(OH)2 Kinirons et al, Retrospective Immature teeth Mineralised Multiple 26-52 107/107 107/107 Not ment– 2001 study tissue barrier visits with weeks ioned Ca(OH)2 Fava 2001 Case report Apicoectomy Mineralised 3 visits with 5 months 1/1 1/1 27 months tissue barrier Ca(OH)2

TabLE 1F Presentation of the data collected from the clinical studies on apexification techniques.

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Study Type of study Cause of open Barrier One or two Duration Clinical Apical Recall apex visits of CaOH success closure Period Kim 1999 Case report Not mentioned Mineralised 6 visits with 18 months 1/1 1/1 6 months

tissue barrier Ca(OH)2 Gentner Case report Immature tooth Mineralised 3 visits with 10 months 1/1 1/1 Not 1999 tissue barrier Ca(OH)2 mentioned Walia et al, Retrospective Immature tooth Mineralised Multiple visits Not 15/15 15/15 24 months 2000 study tissue barrier with Ca(OH)2 mentioned Gupta et al, Case report Immature tooth Mineralised 4 visits with 7 months 1/1 1/1 Not 1999 tissue barrier Ca(OH)2 mentioned Tarján & Case report Immature tooth Mineralised Multiple visits Not 1/1 1/1 24 months Rózsa 1999 tissue barrier with Ca(OH)2 mentioned Yeh et al, Case report Immature tooth Mineralised 3 visits with 6 months 1/1 1/1 10 months 1999 tissue barrier Ca(OH)2 Cotti et al, Case report Root resorption Mineralised Multiple visits 24 months 1/1 1/1 24 months 1998 tissue barrier with Ca(OH)2 Calişkan Case report Immature tooth Mineralised 4 visits with 9 months 1/1 1/1 15 months & Türkün tissue barrier Ca(OH)2 1997 Parashos Case report Apicectomy Mineralised 2 visits with 9 months 1/1 1/1 14 months 1997 tissue barrier Ca(OH)2 Harbert Case report Immature tooth Tricalcium 1 visit without - 1/1 1/1 7 years 1996 phosphate Ca(OH)2 as an apical plug Holtzman & Case report Immature tooth Mineralised 3 visits with 3 months 1/1 1/1 6 months Lezion 1996 tissue barrier Ca(OH)2 Gupta & Case report Immature tooth Mineralised 2 visits with 18 months 1/1 1/1 Not Sharma tissue barrier Ca(OH)2 mentioned 1996 Schumacher Case report Immature tooth Ca(OH)2 1 visit with - 1/1 0/1 1 year & Rutledge apical plug compensation 1993 of Ca(OH)2 and gutta- percha obturation Ohara & Case report Immature tooth Mineralised 3 visits with 11 months 1/1 1/1 Not Torabinejad tissue barrier Ca(OH)2 mentioned 1992 Su 1992 Case report Immature tooth Mineralised 4 visits with 15 months 1/1 1/1 4 years tissue barrier Ca(OH)2 Morfis & Clinical study Immature teeth Mineralised Multiple visits 12-24 31/34 30/34 Not Siskos 1991 tissue barrier with Ca(OH)2 months mentioned Yang et al, Case report Immature tooth Mineralised 4 visits with 12 months 1/1 1/1 18 months 1990 tissue barrier Ca(OH)2 Bal et al, Comparative Not mentioned Mineralised 4 visits with 6 months 12/12 9/12 6 months 1989 study tissue barrier Ca(OH)2 Morfis & Case report Immature tooth Mineralised 4 visits with 22 months 1/1 1/1 4 years Lentzari, tissue barrier Ca(OH)2 1989 Thäter & Follow up Immature teeth Mineralised Multiple visits 1-24 25/34 25/34 1-63 Maréchaux study tissue barrier with Ca(OH)2 months months 1988 Ghose et al, Clinical study Immature teeth Mineralised Multiple visits 3-10 49/51 49/51 Not 1987 tissue barrier with Ca(OH)2 months mentioned (Calasept) Ferguson et Case report Immature tooth Mineralised 3 visits with 12 months 1/1 1/1 5 months al, 1980 tissue barrier Ca(OH)2 Piekoff & Case report Immature tooth Mineralised Multiple visits 4 years 0/1 (fracture 1/1 Not Trott 1976 tissue barrier with Ca(OH)2 during post mentioned mixed with cementation) CPC TabLE 1 G Presentation of the data collected from the clinical studies on apexification techniques. were used as artificial barriers [Nosrat et al., 2011; Nayak analysis showed that this calcified tissue barrier consists of and Hasan, 2014]. In CH apexification treatment, CH is left distinct layers. The outer layer seems to be composed of a into the root canal for several months in order to induce a dense acellular cementum-like tissue, which surrounds a hard-tissue apical barrier that facilitates proper obturation of central mix of irregular dense fibrocollagenous connective root canal and prevents the passage of toxins and bacteria tissue [Baldassari-Cruz, 1998]. Laboratory observations into the periapical tissues [Rafter, 2005]. Histological that detected a decrease in fracture resistance of the root

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in which CH remained for a long period [Andreasen et al., of clinical signs and symptoms of periapical disease, 2002;Andreasen et al., 2006] as well as the long duration radiographic resolution of periapical lesion and induction of CH treatment and the difficulty to monitor patients for of a calcified tissue barrier at the apex. Both apexification several months, might be the reasons that brought about procedures present high percentages of clinical success. the need for alternative approaches [Torabinejad, 1999]. It However, looking at the findings of the present study, CH is noteworthy that in 59% of the relevant clinical studies, seems to be correlated with higher percentages of apical CH remained in the root canal for up to 12 months. Also, in closure. This could be considered as an advantage of the 10% of the studies it remained for more than 24 months. long-term apexification as the formation of this apical seal The frequency, as well as the number of changes of is a biological procedure, which enables the preservation the CH appear to be controversial topics. One placement and rehabilitation of the treated teeth. Regarding the of the intracanal medicament appeared to be enough lower percentages of apical closure that artificial apical for the induction of a hard-tissue apical barrier, [Chawla, barriers presented in the clinical studies compared with 1986; Chosack et al., 1997], whereas other studies claim CH apexification, it could be assumed that the follow-up that there is more to gain from multiple changes of CH, time in some cases of apical plug technique was possibly such as quicker induction of the apical [Abbot, not enough for the hard tissue to be visible in radiographs. 1998; Kinirons et al., 2001]. According to the findings of Moreover, there are no studies stating that non-formation the present study, 85% of the studies reported two or of a calcified apical barrier tissue constitutes a problem for more replacements of that intracanal medicament. So, it the prognosis of the treatment. is clear that clinicians preferred changing CH at least two times in order to obtain the desired outcome. As opposed to long-term CH apexification procedures, Conclusions apical plug technique with use of artificial barriers could be completed even in one visit. A biomaterial, such as Apexification treatment procedures are changed over MTA, Biodentine or CEM is placed apically in order to time and probably are influenced by observations of create an artificial seal that facilitates the compaction relevant laboratory, preclinical and clinical studies. There of gutta-percha on it. Although creation of hard tissue is a strong tendency towards one-visit apexification with at the apex after the placement of this material is well- the use of various artificial apical plugs. Both apexification documented [Nosrat et al., 2011; Umashetty et al., 2015], treatments lead to favorable treatment outcomes. The the primary goal of this technique is not to create a limited follow-up time, could not make explicit the biological closure of the apex [Rafter, 2005]. This is the effectiveness of artificial apical plugs regarding the reason for the short time that this treatment requires in induction of apical closure. order to be completed. The treatment can be finished in one visit without the use of an intracanal medicament Acknowledgements [Simon et al., 2007; Mente et al., 2009] or in two or more The authors deny any conflicts of interest related to this visits with the use of medication [Mente et al., 2009; study. Alobaid et al., 2014]. 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