Journal of Pharmacy And Bioallied Sciences
Journal of Pharmacy And Bioallied Sciences Login  | Users Online: 3235  Print this pageEmail this pageSmall font sizeDefault font sizeIncrease font size 
    Home | About us | Editorial board | Search | Ahead of print | Current Issue | Past Issues | Instructions | Online submission

 Table of Contents  
Year : 2021  |  Volume : 13  |  Issue : 5  |  Page : 36-42  

Regenerative endodontic therapy in the management of nonvital immature permanent teeth: A systematic review and meta-analysis

1 DMD Student, Rutgers School of Dental Medicine, Newark, New Jersey, USA
2 Dental Surgeon, Guru Nanak Dev Dental College and Research Institutes, Sunam, Punjab, India
3 Dental Surgeon, Narayana Dental College and Hospital, Nellore, Tamil Nadu, India
4 Dental Surgeon, Sri Ramakrishna Dental College and Hospital, Coimbatore, Tamil Nadu, India
5 Dental Surgeon, Sibar Institute of Dental Sciences, Guntur, Andhra Pradesh, India
6 Dental Surgeon, AME'S Dental College, Raichur, Karnataka, India
7 Department of OMFS, Narsinhbhai Patel Dental College and Hospital, Sankalchand Patel University, Visnagar, Gujarat, India

Date of Submission06-Dec-2020
Date of Decision08-Dec-2020
Date of Acceptance09-Dec-2020
Date of Web Publication05-Jun-2021

Correspondence Address:
Izaz Shaik
Rutgers School of Dental Medicine, Newark, New Jersey
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jpbs.JPBS_807_20

Rights and Permissions

This meta-analysis is intended to evaluate the reliability of evidences published in current regenerative endodontic publications in a critical way. This meta-analysis is used to summarize and analyze the various clinical and radiographic findings associated with nonvital immature permanent teeth which have been treated with regenerative endodontic techniques. We also intend to significantly evaluate the worth of facts provided in the previous published literature. A structured electronic search by authors was undertaken in August 2020 using MEDLINE and PubMed search engine. The chosen parameters studied in this systematic review were presented in flowcharts and were summarized. We observed a good accomplishment rates in terms of survival of the treated tooth and also in resolution of any associated pathology in the apical areas; on contrary, our results in relation to apex closure along with constant root development, our findings from various studies were quiet variable. Regenerative endodontic procedures are constantly being restructured and enhanced to benefit present-day dentistry in all likely ways. Still, many factors that are important for the success of regenerative endodontic treatment outcomes still remain unexplained. There are still numerous gaps in our expertise at the present stage of this study.

Keywords: Meta-analysis, outcome measures, regenerative endodontic therapy, scope

How to cite this article:
Shaik I, Tulli M, Unnam P, Karunakaran S, Vaddi DS, Jabeen R, Tiwari RV. Regenerative endodontic therapy in the management of nonvital immature permanent teeth: A systematic review and meta-analysis. J Pharm Bioall Sci 2021;13, Suppl S1:36-42

How to cite this URL:
Shaik I, Tulli M, Unnam P, Karunakaran S, Vaddi DS, Jabeen R, Tiwari RV. Regenerative endodontic therapy in the management of nonvital immature permanent teeth: A systematic review and meta-analysis. J Pharm Bioall Sci [serial online] 2021 [cited 2022 Nov 30];13, Suppl S1:36-42. Available from:

   Introduction Top

Regenerative endodontic (RE) procedures are described as biologically based techniques intended to restore damaged tooth structures, comprising dentin and along with other root structures, and even cells of the pulp-dentin complex.[1] The source for these RE techniques is to make use of the principles of tissue engineering. In the process of regeneration, we not only require the cells to secrete new tissue for regeneration, but at the same time, we also require sufficient molecular and cellular signaling to occur so as to stimulate the cells to secrete new tissue responsible for regeneration. It is now evident that the dentin matrix comprises a varied mixture of growth factors and cytokines that can be released from the matrix during caries which can contribute considerably to the regenerative process. In the present era, various researchers plan to create improved regenerative treatment procedures that have the potential beyond existing limits to regenerate new tissues. This process entails new protocols using stem cells, scaffolds, and growth factors to be created. To regenerate the various tissues required to produce a tooth and its supporting tissues, many approaches relating stem cells, different scaffolds, and growth factors can be united. Presently, areas of RE are persistently developing in managing nonvital immature teeth. With numerous available prospective studies, together with recently published randomized controlled studies regenerative endodontic treatment (RET) is being reported as one of the feasible treatment alternatives in the treatment of nonvital, immature permanent teeth. Hence, its well-timed for the current literature to re-evaluate this shifting landscape of the feasible treatment alternatives for nonvital immature permanent teeth in young individuals.[2] Hereby in this analysis, we aimed to evaluate the reliability of data published in the current literature regarding RE treatment in a critical way. This meta-analysis is used to summarize and analyze the various clinical and radiographic findings for infected immature permanent teeth which are treated using RE techniques and importantly also to evaluate the quality of facts provided in the already published literature.

   Materials and Methods Top

A structured electronic search by authors was undertaken in August 2020 using MEDLINE and PubMed search engine. Unpublished literature was electronically searched on Clinical Trials. gov ( and the National Research Register ( The search strategy comprised a combination of different key words along with some Medical Headings relatable to RET. The chosen parameters studied in this systematic review were presented in flowcharts and were summarized as given in [Figure 1].
Figure 1: Flowchart summarizing the chosen reporting parameters studied in systematic reviews and meta-analysis

Click here to view

Outcome measures of data analysis

The challenge begins with every clinical procedure as we try to describe what a good result is in terms of outcome of revascularization procedures. Evidence of root development and root formation is taken into account. It is essential to restore the pulpal function to measuring the effectiveness of therapy. The data reviewed in this analysis was analyzed, and the primary outcome measures which were analyzed were as follows: (1) Survival of the tooth, (2) Clinical and radiographic signs of healing if pathology in periapical areas, (3) Results of constant root formation as seen according to the decreased size of apical foramen, evidence of root lengthening, and formation of root dentin.

   Results Top

Various clinical studies on RET have been conducted since 2001. The clinical concerns for regenerative endodontic procedures of the American Association of Endodontists (2016) describe performance across three measures:

  1. Primary objective (essential): Symptom removal and proof of bony healing
  2. Secondary (desirable) target: Increased thickness of the root wall and/or increased root length
  3. Tertiary target: Positive response to checking for vitality.

The main objective of resolving the clinical signs of infection and bone healing is usually attainable,[3] while disinfection procedures and limited filing have been related to failed cases as earlier established. In two recent systematic reviews by Tong et al. 2017[4] and Torabinejad et al. 2017[5] showed that the primary objective of RET could be reliably accomplished.

Study design

In this analysis, three studies[6],[7],[8] were seen to estimate the outcomes of the technique, based on types of intracanal medicaments used. Four studies evaluated the results of RET based on different scaffolds used in the studies,[9],[10],[11],[12] 8 studies reported the results based on different treatment options like that of Ca (OH) 2 for apexification or the use of MTA apical plug technique[6],[7],[8],[10],[11] and included 3 failed cases as well.[13],[14],[15]

Primary outcome

Clinical outcome

The two primary clinical outcomes measures as studied included firstly survival of the tooth and secondly clinical signs of healing. Except 2 studies, 100% positivity in tooth survival was reported in all other studies evaluated.[7],[8]

Radiographic outcomes

The parameters included in the evaluation of radiographic outcomes included are firstly the resolution of apical pathology, secondly the amount of apical closure, thirdly the evaluation of increase in root length, and finally, the thickening of root due to dentine deposition. Eight researchers have used computerized tools and image correction, along with measurement analysis. Among these, two studies further studied radiographic results using the measurement of relative radiographic field.[8],[9] Periapical healing and Apical Closure: In the meta-analysis, almost all 100% studies evaluated reported periapical pathology resolution success rates. Apical closure was reported in 11 studies with variability and apical closure success rates ranging within 76%–91%.[4],[5],[9],[16],[17],[18],[19] Root length and root dentin thickness: four studies evaluated in this meta-analysis mentioned on the success rates of root lengthening and root dentin formation.[12],[18],[19],[20] The results of estimated success rates for both ranged from 80% to 94%.

Secondary outcomes

Two studies in this meta-analysis were found to report that no consistency in achieving root maturation.[14],[21] Hence, these outcomes seem to be more variable. In addition, some long-term potential studies have also reported outcomes even past 18 months.[4] Hence, long-lasting retention of RET treated teeth is still questionable. Secondary outcomes included late-stage effects and side effects, which were conflicting through different researches studied. Two most common observed late-stage effects included obliteration of the pulp canals and the presence of tooth discoloration. Discoloration was observed in almost 50% of studies.[8],[9],[20],[22],[23] Details of different study characteristics and their outcome measures are hereby tabulated in [Table 1] and [Table 2].
Table 1: Primary and secondary outcome measures

Click here to view
Table 2: Failed regenerative endodontic treatment papers studied

Click here to view

   Discussion Top

A data analysis of the RET clinical protocol found that RET protocols differed greatly across all trials. Different treatment protocols may lead to different outcomes of treatment. Therefore, in the literature, it is not viable to assess the exact treatment outcome of RET. Nevertheless, the largely most favorable outcome considered for RET clinically is the continuation of root development and apex closure.

An immature permanent tooth

Young immature permanent teeth with wide-open apex permit both cellular and molecular mechanism of the innate and adaptive immunity to be effectively carried to the canal space by pulp blood circulation. As a result, young, immature permanent teeth are supposed to be more challenging than mature permanent teeth to carious infections or trauma. As a result, if such teeth are affected by caries or trauma, it may take probably more time for the pulp to become fully necrotic and present with apical periodontitis. This hypothesis was based on the findings studied during this meta-analysis with cases comprising of young permanent teeth with such pulpal and periapical pathological conditions. These were clinically diagnosed with when the canals were probed, bleeding occurred, or patients encountered pain with hand files.

Microenvironment and tissue repair mechanisms

In developmental biology, the microenvironment is described as a precise location that maintains the stem cell. Micro-environmental signals, such as stromal cells, extracellular matrix, adhesion molecules, growth factors and cytokines, decide the fate of stem cells.[24],[25],[26] If the microenvironment is altered, the fate of stem cells is also said to be will also be altered. The pulpal tissue is enclosed within canal room's sterile microenvironment. This microenvironment should be preserved as similar as practicable to the original sterile microenvironment of the pulp canal but it is altered when the teeth become contaminated due to the accumulation of biofilm on the canal walls, by bacterial toxins and by resorption. Even after intracanal irrigation and medication, this microenvironment is also altered. The stem cell fate in the treated canals and sterile canals may therefore be distinct. This may be the possible reason as to why it becomes tough to regenerate pulp tissue with infected/necrotic pulp after RET, in accordance with the immature permanent teeth.[27] In this meta-analysis, Most studies have stated that RET has the potential to facilitate canal wall thickening and/or continued root growth of immature permanent teeth with necrotic pulps. It was suggested by various researchers that cells from the remnants of pulp or the cells obtained from the papilla may relocate within the disinfected pulpal canal space, hereby to deposit secondary dentine on the canal walls and the root apex, and helps in increasing the thickness of the canal walls and root length. Histologically, results of various studies suggest from this meta-analysis, that evidence of both Hard and soft connective tissue formation was observed in the root canal space after RET even after disinfection. The tissues which were formed in the canal space of these treated immature teeth were characterized as bone, cement-and periodontal ligament-like tissue in consequent animal study models as well.[4],[5] The findings of this meta-analysis showed that periapical pathology resolution success rates past RET were equivalent to MTA or apexification therapy. This indicates that for bacterial removal, together, disinfection methods have identical efficiency. We observed that the accomplishment rates for apical closure, enlargement in root length, and the formation of dentin were higher in the case of RET in contrast to the normal. It is been suggested that a 20% increase in the root length may be associated with a clinically significant change, according to these studies.[28] Substantial heterogeneity was observed in the reporting of results between studies studied in the analysis. This includes reporting of pre- and postoperative clinical features and also the quantification of radiographic interpretations. Thus it was observed that, due to deficient data regarding the standardized conclusion of presently accessible data, it has mostly affected the best possible application and combination of these outcomes, which are necessary for accurate interpretation of factors affecting the successful outcome of RET.

Side effects

There was comparatively less reporting of multiple adverse effects such as decoloration, pulp canal obliteration, anomalies in root morphology during the growth process, absence of apical seal/closure, and eventually loss of pulp/tooth vitality after apical closure. In 50% of studies, tooth decoloration after RET treatment has been identified. The discoloration is commonly reported to be associated with minocycline, even though calcium hydroxide has also been reported to be associated with tooth discoloration.[20] MTA can also cause tooth discoloration, specifically Bismuth oxide in MTA, which has shown to cause crown discoloration. Consequently, after contact with blood, materials exhibit greater color changes, which has consequences in RET as they are put in close contact with the BC scaffold. With the use of present-day filling materials such as composites and bonding agents, reduced interaction between antibiotics and hemosiderin with dentinal walls is observed. In different studies, though this approach has been implemented, its usefulness is unpredictable. The use of Biodentine instead of MTA to minimize the possibility of discoloration has been reported in several studies. In general, bleaching of decolored teeth is effective in improving the esthetic result.[21],[29] We observed a good accomplishment rates in terms of survival of the treated tooth and also in the resolution of any associated pathology in the apical areas; on the contrary, our results in relation to apex closure along with constant root development, our findings from various studies were quiet variable. We observed that at present, there is a lack of well-documented, longitudinal studies in the literature which can focus on long-term outcomes of the treated teeth. The interpretation of the processes underlying angiogenic reactions to dental pulp is still not yet fully understood. In relation to the production of new therapies required to regenerate the pulp tissue, revascularization is important. Hence, regulation and expression of growth factors such as vascular endothelial growth factor and fibroblast growth factor, new therapeutic technique may be applied to revascularize the pulp tissue of traumatized teeth. Regenerative endodontic techniques have tremendous potential to be an effective, healthy, and biological way of preserving teeth that have damaged structural integrity if the problems discussed above are addressed. To advance regenerative therapeutics to the next stage, significant research and development efforts are needed.

   Conclusions Top

Regenerative endodontic procedures are constantly being restructured and enhanced to benefit present-day dentistry in all likely ways. Still, many factors which are important for the success of RET outcomes still remain unexplained. There are still numerous gaps in our expertise at the present stage of this study.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Vacanti JP, Langer R. Tissue engineering: The design and fabrication of living replacement devices for surgical reconstruction and transplantation. Lancet 1999;354:SI32-4.  Back to cited text no. 1
Bansal R, Jain A. Current overview on dental stem cells applications in regenerative dentistry. J Nat Sci Biol Med 2015;6:29-34.  Back to cited text no. 2
Chen YP, del Mar JS, Sheth CC. Is revascularization of immature permanent teeth an effective and reproducible technique? Dent Traumatol 2015;34:429-36.  Back to cited text no. 3
Tong HJ, Rajan S, Bhuujel N, Kang J, Duggal M, Nazzal H. Regenerative endodontic therapy in the management of nonvital immature permanent teeth: A systematic review – Outcome evaluation and meta-analysis. J Endod 2017;43:1453-64.  Back to cited text no. 4
Torabinejad M, Nosrat A, Verma P, Udochukwu O. Regenerative endodontic treatment or mineral trioxide aggregate apical plug in teeth with necrotic pulps and open apices: A systematic review and meta-analysis. J Endod 2017;43:1806-20.  Back to cited text no. 5
Bose R, Nummikoski P, Hargreaves K. A retrospective evaluation of radiographic outcomes in immature teeth with necrotic root canal systems treated with regenerative endodontic procedures. J Endod 2009;35:1343-9.  Back to cited text no. 6
Jeeruphan T, Jantarat J, Yanpiset K, Suwannapan L, Khewsawai P, Hargreaves KM, et al. Mahidol study 1: Comparison of radiographic and survival outcomes of immature teeth treated with either regenerative endodontic or apexification methods: A retrospective study. J Endod 2012;38:1330-6.  Back to cited text no. 7
Alobaid AS, Cortes LM, Lo J, Nguyen TT, Albert J, Abu-Melha AS, et al. Radiographic and clinical outcomes of the treatment of immature permanent teeth by revascularization or apexification: A pilot retrospective cohort study. J Endod 2014;40:1063-70.  Back to cited text no. 8
Bezgin T, Yilmaz AD, Celik BN, Kolsuz ME, Sonmez H. Efficacy of platelet-rich plasma as a scaffold in regenerative endodontic treatment. J Endod 2015;41:36-44.  Back to cited text no. 9
Nagy MM, Tawfik HE, Hashem AA, Abu-Seida AM. Regenerative potential of immature permanent teeth with necrotic pulps after different regenerative protocols. J Endod 2014;40:192-8.  Back to cited text no. 10
Narang I, Mittal N, Mishra N. A comparative evaluation of the blood clot, platelet-rich plasma, and platelet-rich fibrin in regeneration of necrotic immature permanent teeth: A clinical study. Contemp Clin Dent 2015;6:63-8.  Back to cited text no. 11
[PUBMED]  [Full text]  
Jadhav G, Shah N, Logani A. Revascularization with and without platelet-rich plasma in nonvital, immature, anterior teeth: A pilot clinical study. J Endod 2012;38:1581-7.  Back to cited text no. 12
Peng C, Yang Y, Zhao Y, Liu H, Xu Z, Zhao D, et al. Long-term treatment outcomes in immature permanent teeth by revascularisation using MTA and GIC as canal-sealing materials: A retrospective study. Int J Paediatr Dent 2017;27:454-62.  Back to cited text no. 13
Linsuwanont P, Sinpitaksakul P, Lertsakchai T. Evaluation of root maturation after revitalization in immature permanent teeth with nonvital pulps by cone beam computed tomography and conventional radiographs. Int Endod J 2017;50:836-46.  Back to cited text no. 14
Lin LM, Kim SG, Martin G, Kahler B. Continued root maturation despite persistent apical periodontitis of immature permanent teeth after failed regenerative endodontic therapy. Aust Endod J 2018;44:292-9.  Back to cited text no. 15
Kahler B, Mistry S, Moule A, Ringsmuth AK, Case P, Thomson A, et al. Revascularization outcomes: A prospective analysis of 16 consecutive cases. J Endod 2014;40:333-8.  Back to cited text no. 16
Fang Y, Wang X, Zhu J, Su C, Yang Y, Meng L. Influence of apical diameter on the outcome of regenerative endodontic treatment in teeth with pulp necrosis: A review. J Endod 2018;44:414-31.  Back to cited text no. 17
Estefan BS, El Batouty KM, Nagy MM, Diogenes A. Influence of age and apical diameter on the success of endodontic regeneration procedures. J Endod 2016;42:1620-5.  Back to cited text no. 18
Cehreli ZC, Isbitiren B, Sara S, Erbas G. Regenerative endodontic treatment (revascularization) of immature necrotic molars medicated with calcium hydroxide: A case series. J Endod 2011;37:1327–30.  Back to cited text no. 19
Nagata JY, Gomes BP, Rocha Lima TF, Murakami LS, de Faria DE, Campos GR, et al. Traumatized immature teeth treated with 2 protocols of pulp revascularization. J Endod 2014;40:606-12.  Back to cited text no. 20
Silujjai J, Linsuwanont P. Treatment outcomes of apexification or revascularization in nonvital immature permanent teeth: A retrospective study. J Endod 2017;43:238-45.  Back to cited text no. 21
McTigue DJ, Subramanian K, Kumar A. Case series: Management of immature permanent teeth with pulpal necrosis: A case series. Pediatr Dent 2013;35:55-60.  Back to cited text no. 22
Chen MY, Chen KL, Chen CA, Tayebaty F, Rosenberg PA, Lin LM, et al. Responses of immature permanent teeth with infected necrotic pulp tissue and apical periodontitis/abscess to revascularization procedures. Int Endod J 2012;45:294-305.  Back to cited text no. 23
Li L, Xie T. Stem cell niche: Structure and function. Annu Rev Cell Dev Biol 2005;21:605-31.  Back to cited text no. 24
Scadden DT. The stem-cell niche as an entity of action. Nature 2006;441;1075-9.  Back to cited text no. 25
Jones DL, Wagers AJ. No place like home: Anatomy and function of stem cell niches. Mol Cell Biol 2008;9:11-21.  Back to cited text no. 26
Fouad AF, Nosrat A. Pulp regeneration in previously infected root canal space. Endod Top 2013;28:24-37.  Back to cited text no. 27
Saoud TM, Zaazou A, Nabil A, Moussa S, Lin LM, Gibbs JL, et al. Clinical and radiographic outcomes of traumatized immature permanent necrotic teeth after revascularization/revitalization therapy. J Endod 2014;40:1946-52.  Back to cited text no. 28
Kirchhoff AL, Raldi DP, Salles AC, Cunha RS, Mello I. Tooth discolouration and internal bleaching after the use of triple antibiotic paste. Int Endod J 2015;48:1181-7.  Back to cited text no. 29


  [Figure 1]

  [Table 1], [Table 2]

This article has been cited by
1 Use of scaffolds and regenerative materials for the treatment of immature necrotic permanent teeth with periapical lesion: Umbrella review
Javier Caviedes-Bucheli, Hernan D. Muñoz-Alvear, Luis F. Lopez-Moncayo, Angela Narvaez-Hidalgo, Lorena Zambrano-Guerrero, José F. Gaviño-Orduña, Ricardo Portigliatti, Jose F. Gomez-Sosa, Hugo R. Munoz
International Endodontic Journal. 2022;
[Pubmed] | [DOI]
2 Outcomes reporting in systematic reviews on revitalization: A scoping review for the development of a core outcome set
Siobhan Cushley, Conor McLister, Mark J. Lappin, Marc Harrington, Venkateshbabu Nagendrababu, Henry F. Duncan, Ikhlas El karim
International Endodontic Journal. 2022;
[Pubmed] | [DOI]
3 Tooth Bleaching of Discolorations Caused by Hydraulic Cements in Regenerative Endodontic Treatment: A 3-Year In Vitro Study
Carmen Llena, Manuel Iglesias-Diaz, Paula Ciscar-Muñoz, Ana Belén Bataller-Martínez, María Melo, José Luis Sanz
Materials. 2022; 15(21): 7845
[Pubmed] | [DOI]


    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

  In this article
    Materials and Me...
    Article Figures
    Article Tables

 Article Access Statistics
    PDF Downloaded204    
    Comments [Add]    
    Cited by others 3    

Recommend this journal