**1. Introduction**

In permanent dentition, traumatic dental injuries (TDI) are a worldwide health issue and the most frequent cause of pulpal necrosis [1]. In 85% of TDIs, patients have injuries to the oral region [2]. Globally, around one billion people are affected by trauma [3], and one-third of these patients have injuries to their immature teeth that might cause pulp necrosis [4].

Pulp necrosis due to trauma or caries in children and adolescents may hinder permanent tooth root growth, resulting in thin dentinal walls, wide-open apices, and an insufficient crown:root ratio [5]. According to Cvek, the classification of root development in an immature necrotic permanent tooth can be at stage 1, where less than half of the root formation with open apex is present; stage 2 is where half of root formation with open apex is present; and stage 3 is when 2/3 of root development with open apex is present [6].

**Citation:** Panda, P.; Mishra, L.; Govind, S.; Panda, S.; Lapinska, B. Clinical Outcome and Comparison of Regenerative and Apexification Intervention in Young Immature Necrotic Teeth—A Systematic Review and Meta-Analysis. *J. Clin. Med.* **2022**, *11*, 3909. https://doi.org/10.3390/ jcm11133909

Academic Editors:

Emmanuel Andrès, Massimo Amato, Giuseppe Pantaleo and Alfredo Iandolo

Received: 28 May 2022 Accepted: 30 June 2022 Published: 5 July 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

In conventional root canal fillings, immature permanent teeth with necrotic pulps are difficult candidates and have an increased susceptibility to root fractures after treatment [7]. Hence, early intervention for non-vital immature teeth is critical. However, it is incredibly challenging, time-consuming and technically complex [8]. Apexification and regeneration are interventions routinely practiced in such cases [9]. RET is recommended in short roots with thin canal walls, a wide-open apex and for teeth lacking the potential for root formation, whereas apexification is done in the tooth which has nearly completed root formation with an open apex [5].

Apexification is a method to encourage the development of an apical barrier to close the open apex of an immature necrotic permanent tooth in which filling materials can be placed within the root canal space [10].

In contrast, RET or regenerative endodontic procedures (REPS) are biologically based procedures designed to replace damaged structures, such as the root and dentin, along with cells of the pulp–dentin complex [11]. The main aim of REPS is to establish a suitable environment (biomimetic microenvironment) in the root canal to facilitate mesenchymal stem cells such as osteo/odontoprogenitor stem cells, pulp tissue regeneration and continued root development.

The basic principles underlying both interventions involve removing necrotic pulp, debridement of the canal and control of infection with or without antiseptic medicament. Total treatment time may vary in multi-visit apexification, depending on the medicament used, the initial presence of periapical pathology [6], the frequency of medicament replacement [12], and the age of the patient [13].

This present review compares and assesses both interventions individually to manage immature necrotic young permanent teeth. This review aims to critically evaluate the outcome of regeneration and apexification procedure, which will impact clinical discussion making.

#### **2. Materials and Methods**

The review protocol was registered at PROSPERO (International Prospective Register of Systematic Reviews), bearing registration number CRD42021230284. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement guidelines [14].

#### *2.1. Search Strategy*

The following PICO components were established: Population (P)—systematically healthy patients with necrotic young, immature permanent tooth; Intervention (I)—regeneration procedure; Comparison (C)—apexification procedure; Outcomes (O)—clinical and radiographical successful outcome. The research question was: "Which intervention between and within the two that is regenerative and apexification, has a more successful outcome in the young permanent non-vital tooth?**"**

The electronic search strategy is described in Table 1. A comprehensive electronic search for relevant articles was performed in the PubMed, CENTRAL, EMBASE and ProQuest databases using the search keywords and combining the keywords using "AND" and "OR". For all these databases, Boolean operators (OR, AND) were used to combine and narrow down searches that included appropriate MeSH terms, keywords, and other terms following the syntax rules of each database. All references selected in the search were saved in Mendeley Desktop software to remove the duplicates.

A manual search was performed in the following dental journals: *International Endodontic Journal*; *British Dental Journal*; *Journal of Endodontics*; *Oral Surgery, Oral Medicine, Oral Pathology, and Oral Radiology*; and *Endodontics*. The search was supplemented by manual searching, citation screening and scanning all reference lists of the selected paper. Additional studies that were likely suitable for inclusion were screened from the bibliographies of potentially eligible clinical trials, case reports, case studies, and systematic reviews.

#### **Table 1.** Search strategy.

**Search Strategy**

#1 immature teeth/immature tooth/immature permanent tooth/immature permanent teeth/young permanent tooth/young permanent dentition

#2 pulp revascularization/pulp regeneration/pulp revitalization/PRF/PRP/blood clot

#3 apexification/calcific barrier/apical closure/root end closure/root apex closure/root end formation/root apex closure/apical plug/MTA plug

#4 survival rate/dentinal thickness/pulp vitality/root completion/successful rate/periapical healing/decrease in apical foramen width

#### *2.2. Study Selection*

The literature search was limited to articles available in English and to those published between January 2000 and April 2022. Each article was assessed carefully and in detail. Two independent reviewers (P.P. and L.M.) read abstracts and titles, and studies not about the research question were excluded. The remaining relevant studies' full texts were read and analyzed independently. In this selection, a third reviewer (S.G.) was called to achieve a consensus if there was a disagreement of opinions.

The selection of studies was performed with no restrictions on place or year of publication. However, a language restriction was applied, and only those articles written in English were included. Titles and abstracts were analyzed to determine whether they fulfilled the inclusion criteria. The inclusion and exclusion criteria are depicted in Table 2.

**Table 2.** Inclusion and exclusion criteria for selecting studies in the systematic review.


The relevant data of the included trials were extracted in detail using an Excel spreadsheet (Microsoft, Redmond, WA, USA) independently by two review authors (P.P., L.M.) and recorded in spreadsheets. In case of missing or unclear information, the authors of the included reports were contacted by email to provide clarification regarding data given or any missing information. The data of all included studies were entered in the characteristics of included studies tables in Review Manager (RevMan, Version 5).

#### *2.3. Study Quality Assessment*

Two review authors (P.P., L.M.) independently assessed the risk of bias in the included studies. In case of disagreement, a third review author (S.G.) was consulted. For the randomized control trials, the assessment was conducted following the instructions and the approach described in the Cochrane Handbook for Systematic Reviews of Interventions [15].

For each study, the following domains were considered: selection bias (random sequence generation and allocation concealment), performance bias (blinding of participants and personnel), detection bias (blinding of outcome assessment), attrition bias (incomplete outcome data addressed), and reporting bias (selective reporting).

For the non-randomized controlled trial, the risk of bias in included studies was assessed using the ROBINS-I risk of bias tool. The bias tool considered: bias due to confounding, selection of participants, classification of interventions, deviations from intended interventions, missing data, measurement of outcomes and selection of reported results.

The overall risk for individual studies was assessed as low, moderate, serious or critical based on the following criteria: low or moderate risk of bias if all domains were at low risk of bias; serious risk of bias if at least one domain was at serious risk of bias but not at critical risk of bias in any domain; critical risk of bias if one domain was at critical risk of bias.
