Review of guidance for the selection of regenerative endodontics, apexogenesis, apexification, pulpotomy, and other endodontic treatments for immature permanent teeth.

This review guidance is a work in progress because the limitations of regenerative endodontics are still being discovered. The endodontic treatments for immature permanent teeth with a necrotic pulp can vary considerably among endodontic practitioners. Whereas, regenerative endodontic treatments are growing in popularity and are creating ever more complex treatment protocols, involving revascularization and/or autologous platelet-rich plasma and scaffolds to elicit host stem cell de novo tissue formation to reestablish the vitality of immature teeth for the purpose of continuing root maturation. Despite much evolving controversy about their potential benefits, risks, prognosis, and contraindications, this review is aimed to discuss how to ensure that regenerative endodontic treatments are successful, by strictly adhering to case selection criteria, and following precise steps to accomplish and monitor the success of the treatment. A review of the endodontic literature was performed, together with practical observations of the problems and outcomes of performing regenerative endodontic treatments. Traditionally, apexification has long been the treatment of choice provided to immature teeth with a necrotic pulp. Regenerative endodontics may be provided as an alternative to apexification, if the tooth and patient meet all the case selection criteria, and if there are no contraindications. Regenerative endodontics has the unique potential advantage of being able to continue the root development in immature permanent teeth, thereby potentially saving the teeth for the lifetime of the patient. Whereas, conventional endodontic root canal treatment, Cvek partial pulpotomy, apexogenesis, and apexification, should always be provided when these treatments are more likely to benefit the patient because they can be more successful than regenerative endodontics.

Methodological quality assessment criteria for the evaluation of laboratory-based studies included in systematic reviews within the specialty of Endodontology: A development protocol.

High-quality systematic reviews in the field of Dentistry provide the most definitive overarching evidence for clinicians, guideline developers and healthcare policy makers to judge the foreseeable risks, anticipated benefits, and potential harms of dental treatment. In the process of carrying out a systematic review, it is essential that authors appraise the methodological quality of the primary studies they include, because studies which follow poor methodology will have a potentially serious negative impact on the overall strength of the evidence and the recommendations that can be drawn. In Endodontology, systematic reviews of laboratory studies have used quality assessment criteria developed subjectively by the individual authors as there are no comprehensive, well-structured, and universally accepted criteria that can be applied objectively and universally to individual studies included in reviews. Unfortunately, these subjective criteria are likely to be inaccurately defined, unreliably applied, inadequately analysed, unreasonably biased, defective, and non-repeatable. The aim of the present paper is to outline the process to be followed in the development of comprehensive methodological quality assessment criteria to be used when evaluating laboratory studies, that is research not conducted in vivo on humans or animals, included in systematic reviews within Endodontology. The development of new methodological quality assessment criteria for appraising the laboratory-based studies included in systematic reviews within Endodontology will follow a three-stage process. First, a steering committee will be formed by the project leaders to develop a preliminary list of assessment criteria by modifying and adapting those already available, but with the addition of several new items relevant for Endodontology. The initial draft assessment criteria will be reviewed and refined by a Delphi Group (n = 40) for their relevance and inclusion using a nine-point Likert scale. Second, the agreed items will then be discussed in an online or face-to-face meeting by a group of experts (n = 10) to further refine the assessment criteria. Third, based on the feedback received from the online/face-to-face meeting, the steering committee will revise the quality assessment criteria and subsequently a group of authors will be selected to pilot the new system. Based on the feedback collected, the criteria may be revised further before being approved by the steering committee. The assessment criteria will be published in relevant journals, presented at national and international congresses/meetings, and will be freely available on a dedicated website. The steering committee will update the assessment criteria periodically based on feedback received from end-users.

PRILE 2021 guidelines for reporting laboratory studies in Endodontology: A consensus-based development.

Reproducible, skilfully conducted and unbiased laboratory studies provide new knowledge, which can inform clinical research and eventually translate into better patient care. To help researchers improve the quality and reproducibility of their research prior to a publication peer-review, this paper describes the process that was followed during the development of the Preferred Reporting Items for Laboratory studies in Endodontology (PRILE) 2021 guidelines and which used a well-documented consensus-based methodology. A steering committee was created with eight individuals (PM, RO, OP, IR, JS, EP, JJ and SP), plus the project leaders (PD, VN). The steering committee prepared an initial checklist by combining and adapting items from the modified Consolidated Statement of Reporting Trials checklist for reporting in vitro studies of dental materials and the Clinical and Laboratory Images in Publications principles as well as adding several new items. The steering committee then formed a PRILE Delphi Group (PDG) and PRILE Online Meeting Group (POMG) to provide expert advice and feedback on the initial draft checklist and flowchart. The members of the PDG participated in an online Delphi process to achieve consensus on the items within the PRILE 2021 checklist and the accompanying flowchart for clarity and suitability. The PRILE checklist and flowchart developed by the online Delphi process were discussed further by the POMG. This online meeting was conducted on 12 February 2021 via the Zoom platform. Following this meeting, the steering committee developed a final version of the PRILE 2021 guidelines and flowchart, which was piloted by several authors when writing up a laboratory study for publication. Authors are encouraged to use the PRILE 2021 guidelines and flowchart to improve the clarity, completeness and quality of reports describing laboratory studies in Endodontology. The PRILE 2021 checklist and flowchart are freely available and downloadable from the Preferred Reporting Items for study Designs in Endodontology website (http://pride-endodonticguidelines.org/prile/).

PRILE 2021 guidelines for reporting laboratory studies in Endodontology: explanation and elaboration.

Guidance to authors is needed to prevent their waste of talent, time and resources in writing manuscripts that will never be published in the highest-quality journals. Laboratory studies are probably the most common type of endodontic research projects because they make up the majority of manuscripts submitted for publication. Unfortunately, most of these manuscripts fail the peer-review process, primarily due to critical flaws in the reporting of the methods and results. Here, in order to guide authors, the Preferred Reporting Items for study Designs in Endodontology (PRIDE) team developed new reporting guidelines for laboratory-based studies: the Preferred Reporting Items for Laboratory studies in Endodontology (PRILE) 2021 guidelines. The PRILE 2021 guidelines were developed exclusively for the area of Endodontology by integrating and adapting the modified CONSORT checklist of items for reporting in vitro studies of dental materials and the Clinical and Laboratory Images in Publications (CLIP) principles. The process of developing the PRILE 2021 guidelines followed the recommendations of the Guidance for Developers of Health Research Reporting Guidelines. The aim of the current document is to provide authors with an explanation for each of the items in the PRILE 2021 checklist and flowchart with examples from the literature, and to provide advice from peer-reviewers and editors about how to solve each problem in manuscripts prior to their peer-review. The Preferred Reporting Items for study Designs in Endodontology (PRIDE) website (http://pride-endodonticguidelines.org/prile/) provides a link to the PRILE 2021 explanation and elaboration document as well as to the checklist and flowchart.

Platelet-Rich Plasma and Platelet-Rich Fibrin Can Induce Apical Closure More Frequently Than Blood-Clot Revascularization for the Regeneration of Immature Permanent Teeth: A Meta-Analysis of Clinical Efficacy.

The purpose of this review was to compare the clinical efficacy of platelet-rich plasma (PRP) and platelet-rich fibrin (PRF), vs. blood clot revascularization (BCR) for the regeneration of immature permanent teeth. A survey of the literature identified 222 cases of immature permanent teeth which had been given PRP, PRF or BCR regeneration treatment with at least a year-long follow-up in 12 different articles. A meta-analysis of the 222 immature permanent teeth after 1 year, were compared to assess the ability of PRP, PRF, and BCR to accomplish apical closure, a periapical lesion healing response, root lengthening, and dentinal wall thickening. The mean success rate for apical closure or reduction after 1 year was: PRP (85.1%) PRF (85.2%), and BCR (58.8%). The mean success rate for root lengthening after 1 year was: BCR (64.1%), PRP (64.2%), and PRF (74.1%). The periapical lesion healing response was 88.9% for BCR, 100% for PRP, and 100% for PRF. Dentinal wall thickening was 100% for BCR, 100% for PRP, and 100% for PRF. Apical closure occurred more frequently following PRP and PRF than with BCR (Fischer test, P < 0.0011), for all the other effects the PRP, PRF, and BCR treatments were similarly effective (Fischer tests, P > 0.05). In conclusion, the fractured or decayed immature permanent teeth of children and young adults aged 6 years to 28 which have a restorable crown, but thin dentinal walls may be regenerated by using a revascularization procedure which draws blood and stem cells into a disinfected root canal space. Although BCR is most common revascularization method, apical closure may occur more frequently if PRF and PRP are used instead of BCR for the regeneration of immature permanent teeth. The proper use of regenerative procedures can be very successful at the disinfection of bacteria from the periapical region of immature permanent teeth, which helps to heal localized lesions, and avoid the need for complex apical surgery, in addition to regenerating tissues to strengthen the structure of immature teeth, to help prevent tooth fracture and tooth loss.

Phase 1 study of APTO-253 HCl, an inducer of KLF4, in patients with advanced or metastatic solid tumors.

INTRODUCTION: This phase I, multicenter, open-label, single-arm, dose-escalation study evaluated the safety, pharmacokinetics and antitumor activity of APTO-253, an inducer of the transcription factor KLF4, in adults with advanced solid tumors. METHODS: APTO-253 was administered IV on days 1 and 2, and 15 and 16 of each 28 day cycle; the dose were escalated from 20 to 387 mg/m(2) in 9 cohorts until DLT was observed. RESULTS: Thirty-two patients were treated on this trial (50 % colon cancer, 22 % other gastrointenstinal malignancies and 18 % non-small cell lung cancer). Fatigue was the only drug-related treatment-emergent adverse event to occur in >10 % of patients. Dose-limiting toxicities of hypersensitivity reaction and transient hypotension despite prophylaxis occurred at 387 mg/m(2) which led to identification of 298 mg/m(2) as the MTD. Only 1 patient had any drug-related treatment-emergent grade 3 adverse event at or below 229 mg/m(2). A total of 21 patients underwent at least one restaging after 2 cycles; 11 patients discontinued prior to the end of cycle 2 due to adverse events (9) or disease progression (2). The best overall response was stable disease (SD) in 5 of these 21 (23.8 %) with durations ranging from 3.6 to 8.4 months. CONCLUSION: APTO-253 was well tolerated at the Phase 2 recommended dose and produced evidence of antitumor activity in the form of stable disease in patients with advanced solid tumors. Based on the drug levels achieved and the lower frequency of treatment-emergent adverse events encountered, 229 mg/m(2) was selected as the recommended Phase 2 dose. Overall APTO-253 was found to be well tolerated and to have favorable pharmacokinetics, and treatment was associated with stable disease in 5 of 21 (24 %) of patients with far advanced solid tumors.

Effectiveness of disinfection therapies and promotion of osteoblast growth on osseotite and nanotite implant surfaces.

OBJECTIVES: To evaluate the effectiveness of 4 procedures to disinfect implant surfaces intentionally inoculated with bacteria and afterward to evaluate osteoblast viability to the disinfected implant surfaces. MATERIALS AND METHODS: Eighty-eight commercially pure Osseotite and Nanotite titanium implant discs were inoculated with Porphyromonas gingivalis. The implant surfaces were disinfected with EDTA, tetracycline, citric acid, or neodymium-doped yttrium aluminum garnet (Nd:YAG) laser. The implant discs were then placed in cultures of osteoblast cells. RESULTS: Osseotite implant discs were easier to disinfect compared with the Nanotite implant discs. Citric acid and tetracycline were the most effective solutions for the disinfection of P. gingivalis from the Osseotite implant discs. CONCLUSION: The Nanotite implant discs were the most difficult to disinfect, likely because of their chemical and physical properties. Citric acid and tetracycline were most effective for disinfecting the Osseotite implant discs, and further clinical research is needed to verify these effects in vivo. The Nd:YAG laser was the weakest disinfection method, and it is not recommended for disinfecting implant surfaces until its effectiveness is improved.

A novel approach to evaluate the effect of medicaments used in endodontic regeneration on root canal surface indentation.

OBJECTIVES: The aim of this study was to investigate the capability of a novel reference point indentation apparatus to test the indentation properties of root canal surface dentine treated with three intracanal medicaments used in endodontic regeneration. MATERIALS AND METHODS: Immature human premolars were selected (n = 22). Four specimens were obtained from each root and randomly assigned to three treatment groups and a control group. Each specimen was exposed to one of the three treatment pastes (triple antibiotic (TAP), double antibiotic (DAP), or calcium hydroxide (Ca(OH)2)) or neutral deionized water (control) for 1 or 4 weeks. After each time interval, the indentation properties of the root canal dentine surfaces were measured using a BioDent reference point indenter. Two-way ANOVA and Fisher's protected least significant differences were used for statistical analyses. RESULTS: Significant differences in indentation parameters and estimated hardness between all groups at both time points were found. TAP-treated dentine had the highest significant indentation parameters, followed by DAP-treated dentine, untreated control dentine, and Ca(OH)2-treated dentine, respectively. Furthermore, TAP-treated dentine had the lowest significant estimated hardness, followed by DAP-treated dentine, untreated control dentine, and Ca(OH)2-treated dentine, respectively. CONCLUSION: BioDent reference point indenter was able to detect significant differences in indentation properties of root canal dentine treated with various medicaments. CLINICAL RELEVANCE: The use of a reference point indenter is a promising approach to characterize the indentation properties of root canal surfaces without any surface modification. This might provide an in vitro mechanical measurement that is more representative of the actual clinical situation.

Constructs and scaffolds employed to regenerate dental tissue.

Dental tissue injury and regeneration affects the daily lives of almost everyone. Tissue engineering is emerging as a promising therapy to regenerate missing teeth and dental tissues. The aim of regenerative dental therapies is to restore patients to full oral health. This means restoring normal function to missing or damaged tissue. Regeneration approaches use a combination of scaffolds, stem cells, growth factors, tissue engineering, organ tissue culture, transplantation, and tissue grafting. There are 8 key elements to create and use tissue constructs for tissue regeneration. These will be described in detail in this article.

A survey of dental residents' expectations for regenerative endodontics.

INTRODUCTION: The objective was to survey a group of dental residents regarding their expectations for using regenerative endodontic procedures as part of future dental treatments. METHODS: After institutional review board approval, the opinions of 32 dentists who were having postgraduate residency training to become specialists in a dental school were surveyed. The survey had 40 questions about professional status, ethical beliefs, judgment, and clinical practice. RESULTS: It was found that 83.9% of dentists had no continuing education or training in stem cells or regenerative endodontic procedures. Results showed that 96.8% of dentists are willing to receive training to be able to provide regenerative endodontic procedures for their patients. Of the total group, 49.1% of dentists already use membranes, scaffolds, or bioactive materials to provide dental treatment. It was determined that 47.3% of dentists agree that the costs of regenerative procedures should be comparable with current treatments. It was also found that 55.1% of dentists were unsure whether regenerative procedures would be successful. CONCLUSIONS: Dentists are supportive of using regenerative endodontic procedures in their dental practice, and they are willing to undergo extra training and to buy new technology to provide new procedures. Nevertheless, dentists also need more evidence for the effectiveness and safety of regenerative treatments before they will be recommended for most patients.

Recommendations for using regenerative endodontic procedures in permanent immature traumatized teeth.

The regeneration of immature permanent teeth following trauma could be beneficial to reduce the risk of fracture and loss of millions of teeth each year. Regenerative endodontic procedures include revascularization, partial pulpotomy, and apexogenesis. Several case reports give these procedures a good prognosis as an alternative to apexification. Care is needed to deliver regenerative endodontic procedures that maintain or restore the vitality of teeth, but which also disinfect and remove necrotic tissues. Regeneration can be accomplished through the activity of the cells from the pulp, periodontium, vascular, and immune system. Most therapies use the host's own pulp or vascular cells for regeneration, but other types of dental stem cell therapies are under development. There are no standardized treatment protocols for endodontic regeneration. The purpose of this article is to review the recent literature and suggest guidelines for using regenerative endodontic procedures for the treatment of permanent immature traumatized teeth. Recommendations for the selection of regenerative and conventional procedures based on the type of tooth injury, fracture type, presence of necrosis or infection, periodontal status, presence of periapical lesions, stage of tooth development, vitality status, patient age, and patient health status will be reviewed. Because of the lack of long-term evidence to support the use of regenerative endodontic procedures in traumatized teeth with open apices, revascularization regeneration procedures should only be attempted if the tooth is not suitable for root canal obturation, and after apexogenesis, apexification, or partial pulpotomy treatments have already been attempted and have a poor prognosis.

Proliferation of mature ex vivo human dental pulp using tissue engineering scaffolds.

INTRODUCTION: The purpose of this study was to measure and compare the proliferation of mature human dental pulp tissue using three types of tissue engineering scaffolds. METHODS: Mature human teeth were collected immediately after extraction for routine dental treatment reasons. Three types of tissue engineering scaffolds were investigated (1) open-polylactic acid (polymer) scaffolds, (2) bovine collagen (collagen) scaffolds, and (3) calcium phosphate bioceramic (calcium phosphate) scaffolds. The scaffolds were placed in direct contact with the dental pulp of the tooth slices from 7 to 30 days. Neutral-red dye was added to the culture media to stain metabolically active cells. The specimens were processed for histology. The numbers of proliferating cells were counted per unit area of scaffold according to ISO criteria. RESULTS: The proliferating dental pulp cells had a fibroblast phenotype, no cells of other phenotypes were observed, and none of the cells appeared to be mineralizing. The average rate of mature vital dental cell proliferation was 1.305 cells per day in the calcium phosphate scaffolds compared with 7.195 (a rate increase of 551%) in the collagen scaffolds and 13.885 (a rate increase of 1,064%) in the polymer scaffolds. CONCLUSIONS: Tissue engineering scaffolds can enhance the proliferation of mature dental pulp tissue. The rate of dental pulp proliferation is dependent on the chemical composition of the scaffold. Within the limitations of this study, the polymer scaffolds were more optimal than collagen or calcium phosphate scaffolds for mature dental pulp proliferation.

Dental pulp stem cell migration.

INTRODUCTION: The purpose of this in vitro study was to investigate the migration of dental pulp stem cells (DPSCs) in response to chemotactants and extracellular matrix proteins (EMPs). This DPSC signaling information is needed to help understand tooth regeneration after injury and to develop some future regenerative endodontic therapies. METHODS: DPSCs were released by trypsinization and plated on transwell filters. The chemotactants were recombinant sphingosine-1-phosphate (S1P), fibroblast growth factor (FGF), epidermal growth factor (EGF), or transforming growth factor beta-1 (TGF-ß1), and the EMPs were collagen-1, collagen-IV, laminin, and fibronectin. Data were analyzed by using analysis of variance (ANOVA) statistical tests for cell migration. RESULTS: S1P induced more vigorous DPSC migration in comparison with the other TGF- ß1, FGF, or EFG chemotactants (ANOVA, P < .05). Laminin induced more vigorous DPSC migration in comparison with the other EMPs (ANOVA, P < .05). CONCLUSIONS: The EMPs, particularly laminin, and chemotactants, particularly S1P and TGF-ß1, were found to be important promoters of DPSC migration. The interplay between the EMPs, blood lipid, serum, and chemotactants suggests that the migration of DPSC is highly regulated. Specific chemotactants and EMPs might mediate the process of pulp-dentin regeneration after tooth injury, and they could be used as part of regenerative endodontic therapy.

Diode laser debonding of ceramic brackets.

INTRODUCTION: Our objective was to investigate the effectiveness of debonding ceramic brackets with a diode laser. METHODS: Two types of ceramic brackets (monocrystalline and polycrystalline) were bonded to bovine maxillary central incisors. The diode laser was applied to brackets in the experimental groups for 3 seconds. Shear bond strength and thermal effects on the pulp chamber were assessed at 2 laser energy levels: 2 and 5 W per square centimeter. Analysis of variance (ANOVA) was used to determine significant differences in shear bond strength values. RESULTS: The diode laser was ineffective with polycrystalline brackets and effective with monocrystalline brackets in significantly (P <0.05) lowering the shear bond strength. There were no significant adhesive remnant index score differences between any groups tested. CONCLUSIONS: Diode laser use significantly decreased the debonding force required for monocrystalline brackets without increasing the pulp chamber temperature significantly. Diode lasers did not significantly decrease the debonding force required for polycrystalline brackets.

Effect of Aquatine Endodontic Cleanser on smear layer removal in the root canals of ex vivo human teeth.

OBJECTIVES: The purpose of this study was to measure and compare the root canal cleanliness and smear layer removal effectiveness of Aquatine Endodontic Cleanser (Aquatine EC) when used as an endodontic irrigating solution in comparison with 6% sodium hypochlorite (NaOCl). MATERIAL AND METHODS: Forty-five human teeth were randomly allocated to five treatment groups; the pulp chamber was accessed, cleaned, and shaped by using ProTaper and ProFile rotary instrumentation to an ISO size #40. The teeth were then processed for scanning electron microscopy, and the root canal cleanliness and removal of smear layer were examined. RESULTS: The most effective removal of smear layer occurred with Aquatine EC and NaOCl, both with a rinse of EDTA. CONCLUSIONS: Aquatine EC appears to be the first hypochlorous acid approved by the FDA to be a possible alternative to the use of NaOCl as an intracanal irrigant. Further research is needed to identify safer and more effective alternatives to the use of NaOCl irrigation in endodontics.

Effect of aquatine endodontic cleanser on smear layer removal in the root canals of ex vivo human teeth

OBJECTIVES: The purpose of this study was to measure and compare the root canal cleanliness and smear layer removal effectiveness of Aquatine Endodontic Cleanser (Aquatine EC) when used as an endodontic irrigating solution in comparison with 6 percent sodium hypochlorite (NaOCl). MATERIAL AND METHODS: Forty-five human teeth were randomly allocated to five treatment groups; the pulp chamber was accessed, cleaned, and shaped by using ProTaper and ProFile rotary instrumentation to an ISO size #40. The teeth were then processed for scanning electron microscopy, and the root canal cleanliness and removal of smear layer were examined. RESULTS: The most effective removal of smear layer occurred with Aquatine EC and NaOCl, both with a rinse of EDTA. CONCLUSIONS: Aquatine EC appears to be the first hypochlorous acid approved by the FDA to be a possible alternative to the use of NaOCl as an intracanal irrigant. Further research is needed to identify safer and more effective alternatives to the use of NaOCl irrigation in endodontics.

Osteogenic differentiation of stem cells derived from human periodontal ligaments and pulp of human exfoliated deciduous teeth.

Multipotent stem cells derived from periodontal ligaments (PDLSC) and pulp of human exfoliated deciduous teeth (SHED) represent promising cell sources for bone regeneration. Recent studies have demonstrated that retinoic acid (RA) and dexamethasone (Dex) induce osteogenesis of postnatal stem cells. The objective of this study was to examine the effects of RA and Dex on the proliferation and osteogenic differentiation of SHED and PDLSC and to compare the osteogenic characteristics of SHED and PDLSC under RA treatment. SHED and PDLSC were treated with serum-free medium either alone or supplemented with RA or Dex for 21 days. The proliferation of SHED and PDLSC was significantly inhibited by both RA and Dex. RA significantly upregulated gene expression and the activity of alkaline phosphatase in SHED and PDLSC. Positive Alizarin red and von Kossa staining of calcium deposition was seen on the RA-treated SHED and PDLSC after 21 days of culture. The influences of RA on the osteogenic differentiation of SHED and PDLSC were significantly stronger than with Dex. Supplementation with insulin enhanced RA-induced osteogenic differentiation of SHED. Thus, RA is an effective inducer of osteogenic differentiation of SHED and PDLSC, whereas RA treatment in combination with insulin supplementation might be a better option for inducing osteogenic differentiation. Significantly higher cell proliferation of PDLSC results in greater calcium deposition after 3-week culture, suggesting that PDLSC is a better osteogenic stem cell source. This study provides valuable information for efficiently producing osteogenically differentiated SHED or PDLSC for in vivo bone regeneration.