|Year : 2021 | Volume
| Issue : 2 | Page : 129-141
Effectiveness of various scaffolds on the success of endodontic tissue regeneration: A systematic review and meta-analysis of randomized controlled trials
Amal Sroor Alrashidi1, Durre Sadaf2, Raghad S Alabdulrazaq1, Abdulaziz S Alrashidi1, Muneera A Alajlan1, Areen A Aljuhani1
1 Department of Dentistry, College of Dentistry, Qassim University, Buraydah, Qassim, Saudi Arabia
2 Department of Conservative Dentistry, College of Dentistry, Qassim University, Buraydah, Qassim, Saudi Arabia
|Date of Submission||15-Jul-2020|
|Date of Decision||15-Aug-2020|
|Date of Acceptance||26-Sep-2020|
|Date of Web Publication||8-May-2021|
Dr. Amal Sroor Alrashidi
Department of Dentistry, College of Dentistry, Qassim University, Buraydah, Qassim, P. O. Box: 1162
Source of Support: None, Conflict of Interest: None
Introduction: This systematic review was planned to summarize and quantitatively assess the effect of various tissue regenerative scaffolds on the success of regenerative endodontic techniques in nonvital immature permanent teeth.
Materials and Methods: An organized electronic search was conducted through multiple databases. Only randomized controlled trials in patients with nonvital immature teeth were included. The main outcomes were the healing of periapical radiolucency, apical closure, and an increase in root length. The Cochrane risk of bias assessment tool was used for evaluating the risk of bias in the included studies. The quality of each outcome was assessed through the use of the Grading of Recommendations, Assessment, Development, and Evaluation approach. A random-effects model was used for meta-analysis.
Results: Sixteen studies involving 153 patients were included, and the overall risk of bias in these studies was moderate. A comparison between blood clot (BC) and platelet-rich plasma (PRP) showed that BC had the greater healing of periapical radiolucency, with an odds ratio (OR) of 3.99; 95% confidence interval (CI): 1.073–14.79; P = 0.04; I2 = 0% (certainty of evidence = moderate), as well as greater root length development, with an OR of 2.94; 95% CI: 1.34–6.48; P = 0.007; I2 = 83% (certainty of evidence = moderate). However, no significant difference in apical closure had been found between the BC and PRP groups, with an OR of 1.73; 95% CI: 0.53–5.70; P = 0.36; I2 = 46% (certainty of evidence = moderate).
Conclusions: Moderate quality evidence showed that BC and platelet-rich fibrin are equally effective in the healing of apical radiolucency, apical closure, and an increase in root length of nonvital immature permanent teeth during tissue regeneration. BC scaffold performs better than PRP. Additional well-designed randomized controlled trials on other scaffolds are recommended.
Keywords: Blood clot, endodontic regeneration, immature teeth, nonvital tooth, platelet-rich fibrin, platelet-rich plasma, scaffold
|How to cite this article:|
Alrashidi AS, Sadaf D, Alabdulrazaq RS, Alrashidi AS, Alajlan MA, Aljuhani AA. Effectiveness of various scaffolds on the success of endodontic tissue regeneration: A systematic review and meta-analysis of randomized controlled trials. Saudi Endod J 2021;11:129-41
|How to cite this URL:|
Alrashidi AS, Sadaf D, Alabdulrazaq RS, Alrashidi AS, Alajlan MA, Aljuhani AA. Effectiveness of various scaffolds on the success of endodontic tissue regeneration: A systematic review and meta-analysis of randomized controlled trials. Saudi Endod J [serial online] 2021 [cited 2021 Jun 17];11:129-41. Available from: https://www.saudiendodj.com/text.asp?2021/11/2/129/315644
| Introduction|| |
The treatment of immature nonvital teeth in endodontic practice is a major clinical problem. The lack of apex closure and the thin dentinal walls make the tooth difficult to obturate and more vulnerable to fracture. Regenerative endodontic treatment can be described as a biologically based procedure designed to replace damaged structures, including dentin and root structures, as well as the cells of the pulp–dentin complex. Regenerative endodontic treatment is dependent on the idea of tissue engineering, which requires three basic elements: stem cells, growth factors, and scaffolds. Scaffolds are considered to be one of the most important requirements of tissue engineering. A scaffold forms a three-dimensional physical environment that organizes and provides support to the individual cells for growth and differentiation. Various biodegradable biological and artificial scaffolds have been used in the regeneration process. Biological scaffolds – which include scaffolds such as blood clot (BC), platelet concentrate, collagen, hyaluronic acid, silk, Emdogain, chitin, and polysaccharidic materials – provide better biocompatibility and bioactivity proprieties, whereas synthetic scaffolds such as polylactic acid, polyglycolic acid, poly-lactic-co-glycolic acid (PLGA), and hydroxyapatite provide better biodegradation and mechanical properties.,,
BC is the most commonly used scaffold in regenerative endodontics. The advantages of the BC scaffold are that it is technically simple and does not require any additional technology. Furthermore, the regeneration provided by BC helps to avoid the possibility of immune rejection and infection., However, in clinical practice, it might not always be possible to promote sufficient bleeding in the root canal space, so researchers are continuing to examine other possible scaffolds. The most well-known platelet concentrates used in clinical practice are platelet-rich plasma (PRP) and platelet-rich fibrin (PRF). PRP is a first-generation platelet concentrate with elevated platelet concentrations; these qualities increase the level of various growth factors, which aid in the differentiation of stem cells in order to encourage healing and tissue regeneration., PRF is a second-generation platelet concentrate that can be considered to be biomaterial; it works over a period of 7–14 days, acting as a reservoir for active biochemicals, which are released slowly and continuously., A platelet pellet (PP) is an autologous platelet concentrate with a higher platelet concentration than PRP. Collagen scaffold use in regenerative endodontics is desirable because it increases operating comfort and ensures the positioning of the sealing material., Injectable scaffolds, such as hydrogels, have the ability to be noninvasive and easy to carry into a root canal space., Chitosan is nontoxic, easily bioabsorbable, shows antibacterial activity, and demonstrates fibroblast and odontoblastic proliferation. Synthetic polymers such as PLGA are nontoxic, biodegradable, and allow for the precise manipulation of their physicochemical properties.,,
The objective of this systematic review was to evaluate the effect of various regenerative scaffolds on the success of tissue regeneration in the form of the healing of apical radiolucency, apical closure, and an increase in root length in immature nonvital teeth. A search through the existing literature revealed that there are currently no systematic reviews comparing the effectiveness of different scaffold materials. This review aimed to provide the best available evidence regarding the outcomes of different scaffold materials in order to critically appraise the available publications and to run the meta-analysis on the literature when applicable.
| Materials and Methods|| |
This systematic review was performed under the guidance of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-S guidelines, as well as the Cochrane Handbook for Systematic Reviews of Interventions. The comprehensive documentation of the systematic review protocol is available online on the PROSPERO International Prospective Register of Systematic Reviews with the ID CRD42020184385. PICOS is defined by the following characteristics: population – immature nonvital teeth; intervention – various regenerative scaffolds; comparison – all scaffolds were compared with each other; and outcome – the main outcomes were the healing of apical radiolucency, apical closure, and an increase in root length. Additional outcomes were the elimination of clinical symptoms, an increase in root thickness, and the response to a pulp test.
A well-organized electronic search and reference list screening were undertaken until May 30, 2020. The following databases were searched for the appropriate literature: MEDLINE (using the PubMed search engine), Scopus, ScienceDirect, Cochrane Central Register of Controlled Trials (CENTRAL), the Wiley Online Library, Web of Science, and Ovid. Unpublished literature was also electronically searched on ClinicalTrials.gov (www.clinicaltrials.gov), the National Research Register (www.controlled-trials.com), and the Networked Digital Library of Theses and Dissertations. Gray literature databases were also consulted, including HealthInfonet (http://www.healthinfonet.ecu.edu.au), OpenGrey (http://www.opengrey.eu), the GlaxoSmithKline Study Register, and Google Scholar; all were searched within the parameters of English-language articles. The following search queries in each database were based on PICO components combined with the Boolean operators and restricted to clinical trials for humans: (((regenerative endodontics) OR (endodontic revascularization) OR (endodontic revitalization)) AND ((immature permanent tooth) OR (immature permanent teeth) OR (open apex) OR (immature apex) OR (incompletely developed tooth))). The reference list of the screened reviews and of the included studies was also searched for possible additional studies not identified by the electronic search.
Inclusion and exclusion criteria
The inclusion criteria included the following: (1) publications in the English language with no restriction on date of publication; (2) randomized clinical trials (RCTs) with regenerative endodontic treatment performed on immature nonvital teeth in a comparative design regarding scaffold types; (3) at least 6 months of follow-up data; and (4) outcomes based on clinical and radiographic interpretation. The exclusion criteria were as follows: (1) studies that did not follow the inclusion criteria; (2) necrotic mature teeth; (3) lack of information about scaffold type; (4) participant dropout rate higher than 30%; (5) study designs other than RCTs; and (6) animal studies.
All records were imported to EndNote X8 (Clarivate Analytics, Philadelphia, PA). After the removal of duplicates, the studies that met the eligibility criteria were selected in the first screening based on the titles and abstracts by two independent researchers. In case of disagreement in opinion, consensus was achieved through the opinion of a third reviewer. The full text of the articles was then examined in order to assess whether they met the inclusion criteria. Eventually, the suitable studies that have been included were subject to data extraction, risk bias assessment, and data synthesis and analysis.
Data extraction was independently conducted by two observers. Data extraction from all detected studies was performed using a standardized form that included the following informations: the authors, year and place of publication, type of publication, age and gender of the patients, sample size, type of scaffold, type of tooth, etiology of pulp necrosis, protocol used in treating these cases (irrigation and its concentration, intracanal medicaments and its duration, sealing materials, and permanent restoration), follow-up interval, radiographic tool assessment, and outcomes (clinical and radiographic). If multiple treatment groups were presented in a study, the data were collected that exclusively conformed to PICOS.
Quality of evidence
The quality of each RCT was assessed according to the Cochrane risk of bias tool. The corresponding authors were contacted for clarification regarding missing information. This tool assesses the risk of bias based on seven key domains: random sequence generation, allocation concealment, blinding (participants and personnel), blinding (outcome assessment), incomplete outcome data, selective outcome reporting, and other biases. The judgment was based on key domains and categorized as a “low” risk of bias when more than half of all key domains were low. A study was categorized as having a “high” risk of bias when there were at least two “high” key domains. Apart from these criteria, the overall result was considered to be “unclear.”
All included studies have been statistically described by summarizing the demographic data, clinical protocols, percentage of successful cases, and any complications. In order to standardize the possible different scores used to evaluate the outcomes (usually scored as excellent, good, fair, satisfactory, or unsatisfactory), as well as to conduct a proper statistical analysis, the outcomes were dichotomized. A meta-analysis was performed in order to analyze the results of studies with similar exposures including BC, PRP, and PRF with similar outcome measures (periapical healing, apical closure, and increase in root length); these studies also needed follow-up data from at least 6 months. The Mantel–Haenszel method used for the binary data (healing of periapical radiolucency and apical closure) was based on the odds ratio (OR) with a random-effects analysis model. In order to combine dichotomous and continuous outcomes (root length), the effect size and standard error were calculated for all studies. Then, the inverse variance-weighted average method was used to pool the effect sizes from all studies using a random-effects model. A standard Chi-square test and I2 test were used in order to evaluate the heterogeneity. The results of the included studies were combined to estimate the pooled effect estimate in the form of OR and the 95% confidence interval (CI) using RevMan 5.3 (Review Manager, Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014).
Certainty of evidence assessment
The strength of the evidence was evaluated according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach, using tables of summary findings constructed using GRADEpro Guideline Development Tool software (Evidence Prime, Inc., Seattle, WA). Each GRADE criterion was assessed individually and then computed for the certainty of the evidence. In order to achieve transparency and implicity, the GRADE approach classifies the certainty of evidence into one of the following four grades: high, moderate, low, or very low.
| Results|| |
Search and selection of studies
Through the search, 5,588 studies were accessed and included in the first electronic search. Of these, 3581 studies were found to be duplicates. The remaining 2007 studies were screened by reading the title and abstract, and a total of 99 articles were subjected to full-text review. A total of 83 studies were excluded for various reasons. Finally, 16 randomized controlled studies were selected for the qualitative analysis,,,,,,,,,,,,,,,, and 9 studies underwent quantitative synthesis and meta-analysis.,,,,,,,, The Preferred Reporting Items Reviews and Meta-Analyses flowchart summarizing the systematic review process is provided in [Figure 1].
|Figure 1: Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart summarizing the systematic review process in the identification of the included studies|
Click here to view
Characteristics of included studies
Sixteen randomized controlled studies were selected for the final review.,,,,,,,,,,,,,,, All of the included studies were randomized controlled studies with parallel designs, except for two studies that used the split-mouth design., The participants in 12 studies were reported to be 44.6% of males and 35.1% of females, whereas the remaining 21.3% of participants' data were missing regarding gender. The mean age of participants was 17 years. The maxillary central incisor was the most common reported tooth for regeneration, and trauma is the most common cause for pulp necrosis. In all involved studies, 11 types of scaffold were used: BC (n = 157), PRP (n = 124), collagen (n = 29), PRF (n = 73), placentrex (n = 4), chitosan (n = 4), injectable scaffold (n = 10), PRF gel (n = 19), PRF membrane (n = 19), PLGA (n = 4), and PP (n = 17). A summary of characteristics of the involved studies is found in [Table 1].,,,,,,,,,,,,,,,
Quality of evidence
The detailed risk of the bias description of the included articles is provided in [Figure 2]. Four studies were judged to be at a high risk of bias.,,, The remaining studies were judged as a low or unclear risk.,,,,,,,,,,, A high risk of bias was found in the domain of the blinding of participants and personnel. A low risk of bias was associated with random sequence generation, the blinding of outcomes assessment, and incomplete outcome data.
Summary of main outcomes
Healing of the periapical radiolucency and apical closure was reported in the studies and evaluated using different radiographic assessment. Most of the scaffolds reported the complete healing of radiolucency and apical closure, except for placentrex and PLGA, which have less successful outcomes. Increasing root length was higher in the following scaffolds: injectable, PP, PRF, PRP, BC, and collagen. The placentrex scaffold showed a moderate increase, while PLGA scaffold and chitosan showed a less increase in root length. [Figure 3] shows how these were distributed among the selected studies.
Summary of additional outcomes
The resolution of clinical signs and symptoms was high across studies irrespective of the scaffold type. Regarding the increase of dentin thickness, better outcomes were associated with the chitosan, injectable, PP, PRF, BC, collagen, and PRP scaffolds. PLGA has a less increase in dentin compared to other scaffolds, while placentrex showed no improvement in root dentin thickness. An increase in root dentin thickness was not reported in the PRF gel and PRF membrane. Most studies that assessed pulp vitality showed lower percentages of positive response, and this may be due to the short follow-up time and the thick layers of mineral trioxide aggregate (MTA) (3–4 mm) and glass-ionomer cement (2 mm), followed by permanent restoration.,,,,,,,, [Figure 4] shows how these were distributed among the selected studies.
Data from three comparisons (BC vs. PRP, BC vs. PRF, and PRF vs. PRP) were analyzed using a meta-analysis for ORs with a 95% CI.
Comparison of blood clot versus platelet-rich plasma
Six studies with 153 participants compared BC with PRP.,,,,, The pooled OR of the healing of apical radiolucency was estimated as 3.99 [95% CI: 1.07–14.79; P = 0.04; I2 = 0%; [Figure 5]], with a statistically significant greater healing of apical radiolucency in the BC scaffold than in the PRP scaffold.
|Figure 5: Forest plots of the odds ratio of blood clot versus platelet-rich plasma scaffolds|
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The increase in root length was three times higher in the BC scaffold than in the PRP scaffold, with a pooled OR of 2.94 [95% CI: 1.34–6.48; P = 0.007; I2 = 83%; [Figure 5]]. However, there were no significant differences between these two scaffolds in relation to apical closure, with a yielded pooled OR of 1.73 [95% CI, 0.53–5.70; P = 0.36; I2 = 46%; [Figure 5]].
Comparison of blood clot versus platelet-rich fibrin
Six studies with 121 participants compared the BC scaffold and the PRF scaffold.,,,,, The meta-analysis showed no significant difference in the healing of apical radiolucency, apical closure, or an increase in root length between the BC and PRF scaffolds, and the pooled ORs were estimated as follows, respectively: OR = 0.93; 95% CI, 0.34–2.51; P = 0.88; I2 = 0% [Figure 6], OR = 1.34; 95% CI, 0.55–3.26; P = 0.52; I2 = 0% [Figure 6], and OR = 1.44; 95% CI, 0.70–3.00; P = 0.32; I2 = 0% [Figure 6].
|Figure 6: Forest plots of the odds ratio of blood clot versus platelet-rich fibrin scaffolds|
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Comparison of platelet-rich fibrin versus platelet-rich plasma
Three studies with 84 participants compared the PRF and PRP scaffolds.,, The results were not statistically significant between the two scaffolds. The estimated pooled OR was 0.38 [95% CI, 0.04–3.55; P = 0.39; I2 = 31%; [Figure 7]]. The increase in root length was higher in the PRP scaffold than PRF scaffold, although it was not statistically significant, with a pooled OR of 1.89 [95% CI, 0.81–4.43; P = 0.14; I2 = 17%; [Figure 7]]. The apical closure was almost the same between the PRF and PRP scaffolds, with no statistically significant differences between the scaffolds. The pooled OR was 1.12 [95% CI, 0.40–3.17; P = 0.83; I2 = 0%; [Figure 7]].
|Figure 7: Forest plots of the odds ratio of platelet-rich fibrin versus platelet-rich plasma scaffolds|
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Side effects and complications were diversely reported across the various articles. The most commonly reported complications were pulp canal obliteration, and tooth discoloration,,,,,, which were reported to be caused using tetracycline (included in triple antibiotic) or MTA. Internal resorption was reported in one study.
Certainty of evidence
The GRADE approach was used in order to assess the certainty of the evidence obtained from meta-analysis, comparing the efficacy of the investigated scaffolds. The total success of the outcomes was graded as a moderate grade of evidence based on the imprecision due to small sample sizes and the risk of bias related to the blinding of participants and personnel [Table 2], [Table 3], [Table 4].
|Table 2: Summary of findings blood clot scaffold versus platelet-rich plasma|
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|Table 3: Summary of findings blood clot scaffold versus platelet-rich fibrin|
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|Table 4: Summary of findings platelet-rich fibrin scaffold versus platelet-rich plasma|
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| Discussion|| |
A qualitative and quantitative analysis was conducted in order to evaluate the effect of BC, PRP, and PRF on the overall success of the regenerative procedure in nonvital immature permanent teeth. Moderate quality evidence showed that the radiographic healing of apical periodontitis was 3.99 times greater, and the increase in root length was 2.68 times more in BC scaffolds when compared to PRP. However, apical closure was equally observed in both the BC and PRP scaffolds. A moderate quality of evidence showed no difference between BC scaffolds and PRF in the healing of apical radiolucency, increase in root length, and apical closure. A moderate quality of evidence showed no significant difference between PRP and PRF in the healing of apical radiolucency, increase in root length, and apical closure. Pulp canal obliteration, tooth discoloration, and internal resorption are the most common complications associated with regenerative procedures, regardless of the type of scaffold that was observed in this systematic review. Looking through various publications, a high variety of scaffolds can be found, for example, PRP, PRF, collagen, PP, hydrogels, chitosan, and PLGA. However, there is an absence of high levels of evidence that compare the outcome of these scaffolds, which made it difficult to perform a meta-analysis for all of the scaffolds that were present. Through the literature, the collagen and PRF scaffolds were found to be better than those of placentrex, chitosan, BC, and PLGA., Jiang et al. suggest that the use of the collagen membrane did not directly improve the success rate but did increase convenience in operation and ensured the positioning of the sealing material. Nagy et al. used BC and an injectable scaffold impregnated with basic fibroblast growth factor and found that the use of the injectable scaffold was not essential for repair. When comparing the PRF membrane to PRF gel, the PRF membrane was found to be easier and less time-consuming, while PRF gel provided fast results. Ulusoy et al. found that the PP, PRP, and PRF groups had significantly faster initial response times to sensitivity tests than the BC group, and this was explained by the higher platelet level of these biological scaffolds. Scaffolds such as collagen, injectable, placentrex, chitosan, PRF gel, PRF membrane, PLGA, and PP are still new materials used in individual studies with small sample sizes, which prevent a final decision regarding their benefits, as they still need further investigation. Even the present studies have high variation regarding clinical protocols and outcome assessment. Most studies evaluated the radiographic outcomes based on two-dimensional radiograph, while only two studies, used cone-beam computed tomography, which may affect the accuracy of findings. The underlying discrepancies between the included studies might present certain limitations. Routinely, the recommended protocol for regeneration is to induce bleeding into the pulp space by over-instrumentation, which creates a BC that acts as a biologic scaffold. Apical bleeding can introduce stem cells from the apical papilla that are capable of initiating ectopic, progressive deposition of hard tissues on root walls, with the added advantages of being inexpensive and acceptable by patients. The formation of the BC into the canal is not always achievable. In fact, the concentration of growth factors in the BC is lower and more unpredictable. Because of this possibility, the need for another scaffold emerged. Platelet concentrate was considered a suitable alternative for BC but still had some disadvantages, including its need for the extraction of blood from the patient – most of whom are children – as well as the need for more equipment for the preparation, which is responsible for the high cost of the treatment. The findings of this literature closely correspond with another systematic review of platelet concentrations in the regeneration of immature nonvital teeth, which showed that PRP or PRF was not significantly better than BC in terms of increasing the root length or the width in regenerative endodontic treatment. The same results are shown by Shivashankar et al., who compared the PRF, PRP, and BC techniques, concluding that it would be wise to consider the induced bleeding technique as the standard endodontic procedure for the regeneration of nonvital immature permanent teeth. On the other hand, Verma and Elsheshtawy et al. concluded that no significant difference was observed in the outcome between BC and PRP., When PRF is compared to PRP, no significant difference is established in the meta-analysis, and this result agrees with the findings of Rizk et al., which compared PRF and PRP and concluded that PRF as a scaffold shows no significant difference in primary and secondary outcomes.
The overall risk of bias was low for 12 studies because of the prevalence of other low-risk key domains.,,,,,,,,,,, The remaining four studies are judged to be high risk due to the presence of more two high-risk dominions.,,, Most of the high-risk domains were associated with the blinding of participants and personnel because it was difficult to achieve blindness with PRP and PRF, since it required blood extraction from the patients. Two studies showed a high risk of bias due to incomplete outcome data., The analysis of the meta-evidence using the GRADE approach showed that the quality of the evidence was moderate for most of the comparisons due to imprecision and the risk of bias in the blinding of both participants and personnel.
In this systematic review, an extensive literature search was conducted, quality and certainty of evidence were evaluated, and statistically combined data were provided in the form of a meta-analysis. Less heterogeneity among studies was found in this systematic review, which implies its internal validity. The limitation of this review is that it contains a low number of studies that compare different scaffolding materials; even the available studies still have varying clinical protocols with different follow-up times, making them difficult in terms of producing an accurate comparison. There could also be a possibility of missing studies regarding this topic. Thus, future research should focus on performing RCTs that include large sample sizes and long-term follow-up data. Future studies should also follow a standard clinical protocol and radiographic assessment.
| Conclusions|| |
The followings could be satisfactorily concluded:
- A moderate quality of evidence showed that BC and PRF are equally effective in the healing of apical radiolucency, apical closure, and in the increase in the root length of nonvital immature permanent teeth during tissue regeneration
- There is no significant difference when comparing PRP and PRF
- The BC scaffold performs better than PRP
- Further well-designed randomized controlled trials on other scaffolds are recommended.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2], [Table 3], [Table 4]