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 Table of Contents  
RESEARCH ARTICLE
Year : 2020  |  Volume : 5  |  Issue : 2  |  Page : 9-13

Treating periodontal intrabony defects using guided tissue regeneration and Bio-Oss® with platelet-rich fibrin: study protocol for a self-controlled trial


1 Department of Periodontology, Peking University School and Hospital of Stomatology, Beijing, China
2 Department of Cariology and Endodontology, Peking University School and Hospital of Stomatology, Beijing, China

Date of Submission18-Jun-2020
Date of Decision20-Jun-2020
Date of Acceptance29-Jun-2020
Date of Web Publication15-Jul-2020

Correspondence Address:
Bing Han
Department of Cariology and Endodontology, Peking University School and Hospital of Stomatology, Beijing, China

Zhi-Bin Chen
Department of Periodontology, Peking University School and Hospital of Stomatology, Beijing, China

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2542-4157.289237

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  Abstract 

Background and objective: Guided tissue regeneration (GTR) has been widely used for periodontal regeneration after intrabony defects, and Bio-Oss® can be used together with GTR for the stability of the space under the GTR membrane. Platelet-rich fibrin (PRF), as a kind of platelet concentrate with rich autologous biologic agent, has been also used to treat periodontal intrabony defects for periodontal regeneration. However, whether PRF can enhance the regenerative effect of GTR and Bio-Oss® is not reported.
Subjects and methods: This is a randomized self-controlled trial. Fourteen patients with periodontal intrabony defects who will receive treatment in the Department of Periodontology, Peking University School and Hospital of Stomatology, China will be included in this study. The left or right intrabony defects of each patient will be randomly randomized to a test group and a control group. In the test group, GTR, Bio-Oss® and PRF will be used for the treatment of periodontal intrabony defects. In the control group, GTR and Bio-Oss® will be used for the treatment of periodontal intrabony defects. PRF used in the trial will be liquid PRF, which can form Bio-Oss®-PRF mixture with Bio-Oss®, making the use of PRF easier in periodontal surgery. This study was approved by the Ethics Committee of Peking University School and Hospital of Stomatology (PKUSSIRB-201629066) on November 4, 2016.
Outcome measures: The primary outcome is clinical attachment level, which will be measured at baseline, as well as 6, 12 and 24 months after surgery. The secondary outcomes include (1) depth of intrabony defect, (2) vertical bone loss, (3) probing depth, (4) bleeding index and (5) time of bone graft filling in the surgery. Radiographic evaluation will be accomplished at baseline and at 12 and 24 months after surgery. Probing depth and bleeding index assessments will be performed at baseline, and at 6, 12 and 24 months after surgery.
Discussion: If the regenerative effects of GTR, Bio-Oss®, and PRF in combination are superior to those of GTR combined with Bio-Oss®, then the trial results will provide clinical evidence for the treatment of periodontal intrabony defects.
Trial registration: Chinese Clinical Trial Registry, ID: ChiCTR1900027581. Registered on November 19, 2019.

Keywords: Bio-Oss®; double-masked; guided tissue regeneration; intrabony defect; periodontitis; platelet-rich fibrin; protocol; randomized self-controlled trial; split-mouth


How to cite this article:
Liu KN, Huang Z, Chen ZB, Han B, Ouyang XY. Treating periodontal intrabony defects using guided tissue regeneration and Bio-Oss® with platelet-rich fibrin: study protocol for a self-controlled trial. Clin Trials Orthop Disord 2020;5:9-13

How to cite this URL:
Liu KN, Huang Z, Chen ZB, Han B, Ouyang XY. Treating periodontal intrabony defects using guided tissue regeneration and Bio-Oss® with platelet-rich fibrin: study protocol for a self-controlled trial. Clin Trials Orthop Disord [serial online] 2020 [cited 2020 Aug 6];5:9-13. Available from: http://www.clinicalto.com/text.asp?2020/5/2/9/289237


  Introduction Top


Periodontitis, with the feature of loss of tooth-supporting tissues caused by periodontal inflammation, may lead to impaired chewing function or even tooth loss, and is a great public health problem.[1] The goal of periodontal treatment is to restore periodontal stability with acceptable function and esthetics by eliminating inflammation and controlling predisposing factors.[1] If indicated, periodontal regeneration is also an important goal of periodontal therapy.[1],[2],[3] Guided tissue regeneration (GTR) has been widely used for periodontal regeneration. Since the stability of the space under the GTR membrane is of vital importance for successful regeneration,[4] GTR can be accomplished together with bone grafts, and Bio-Oss® is frequently utilized. In addition to GTR and bone grafts, clinical application of biologic agents may have positive influence on periodontal regeneration, since biologic agents induce the differentiation, chemotaxis and proliferation of cells.[3]

Platelet-rich fibrin (PRF) is a kind of platelet concentrate, which is a rich reservoir of autologous biologic agents.[5] PRF has been shown to induce the migration, proliferation, and differentiation of different periodontium-related cells (e.g. gingival fibroblasts, periodontal ligament cells, osteoblasts, and alveolar bone marrow stem cells).[6],[7],[8] Thus, PRF has been widely used to achieve regeneration in the treatment of periodontal intrabony defects. Compared with open flap debridement (OFD), combination of PRF and OFD is more effective in probing depth (PD) reduction, clinical attachment level (CAL) gain and bone fill, indicating better regeneration in periodontal intrabony defects.[9],[10],[11] PRF was also reported to augment the regenerative effects of different bone graft materials (e.g., demineralized freeze-dried bone allograft,[12],[13] nanocrystalline HA alone,[14] Bio-Oss®,[15] and bioactive glass[16]) in intrabony defects. Besides, the adjunctive use of a resorbable collagen membrane with PRF was verified to be more effective than using the membrane alone in periodontal regeneration in intrabony defects.[17]

Previous studies have shown that using Bio-Oss® together with PRF could also promote the regenerative effects of PRF alone,[18],[19] indicating that it was better to use Bio-Oss® and PRF together than Bio-Oss® or PRF alone. Hitherto, the adjunctive use of GTR, bone grafts and PRF was only reported in a case report,[20] and no such clinical studies were reported. In a case report,[20] resorbable collagen membrane, Bio-Oss® and PRF were used together to treat severe intrabony defects in a maxillary right lateral incisor, and improvements were achieved both clinically and radiographically 15 months after the surgery.

The major hypothesis in this study is that the adjunctive use of GTR, Bio-Oss® and PRF in combination might be more effective than GTR combined with Bio-Oss® in treating intrabony defects, which will be tested in the present double-blinded randomized controlled trial.


  Methods/Design Top


Overview

The present study is a double-blinded randomized self-controlled clinical trial. Fourteen periodontitis patients having at least one intrabony defect with the depth ≥ 3 mm on each side will be recruited. The recruitment, treatments and follow-ups will be accomplished in the Department of Periodontology, Peking University School and Hospital of Stomatology, China. A trial flowchart is shown in [Figure 1]. The study protocol followed the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidance for protocol reporting (Additional file 1[Additional file 1]).
Figure 1: Consolidated Standards of Reporting Trials (CONSORT) diagram.

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Inclusion criteria

  1. Aged ≥ 18 years.
  2. Stage IV grade C periodontitis diagnosed based on 2017 consensus classification of periodontal and peri-implant diseases and conditions.[21]
  3. At least one intrabony defect with the depth ≥ 3 mm on each side according to intraoral periapical radiographs.
  4. PD and bleeding index (BI)[22] on intrabony defect sites will be ≥ 5 mm and ≥ 2 after initial periodontal therapy, respectively.


Exclusion criteria

  1. Smokers.
  2. Participants with systemic diseases such as cardiovascular and endocrine diseases.
  3. Pregnant or lactating women.


Recruitment

Before recruitment, each patient will be subjected to initial periodontal therapy, which consists of oral hygiene instructions, full mouth scaling and root planning. Hand curettes (Hu-Friedy, Chicago, IL, USA) and an ultrasonic device (Dentsply, Charlotte, NC, USA) will be used in the therapy. Root planning will be finished under local anesthesia. According to the reevaluation 6 weeks after initial periodontal therapy, the need of periodontal surgery will be judged. If the need exists, the study information will be explained to the patients. Only the patients who would like to participate in the trial and agree to sign written informed consent will be enrolled. The procedures of the trial are shown in the CONsolidated Standards Of Reporting Trials (CONSORT) flow chart (Figure 1).

Randomization and blinding

The left or right intrabony defects of each patient will be randomized into a test group and a control group by a periodontist using a coin flipping method. In the test group, PRF will be used together with Bio-Oss® (Geistlich, Switzerland) and a resorbable collagen membrane (B type, ZH-Bio, China) to treat intrabony defects. In the control group, only Bio-Oss® and resorbable collagen membrane will be used in the periodontal surgery. All the surgeries will be finished by the same periodontist who was blinded to clinical examination and data analysis. Similarly, the examiner and data analyst will be also blinded to all the other procedures in the trial.

Interventions

All patients will receive periodontal surgeries, which will be carried out by an experienced operator. Periodontal surgery will be performed on the left side first, no matter the left side served as test group or control group. Under local anesthesia by 4% aticaine containing 1:100,000 epinephrine, sulcular incisions will be followed by elevation of mucoperiosteal flaps. In the test group, after the elevation of flaps, 10 mL whole blood from the antecubital vein will be collected in sterile tubes without any anticoagulant. The blood will be centrifuged (TDL-80-2B, Anke, Shanghai, China) at 700 r/min for 3 minutes, and the upper layer will be liquid PRF. The liquid PRF will be mixed with Bio-Oss®. Meanwhile, complete debridement will be finished using hand curettes (Hu-Friedy). After the debridement of intrabony defects, the Bio-Oss®-PRF mixture will become a kind of gelatinous material and will be filled into the defects. A resorbable collagen membrane will be used to cover the defects, the flaps will be sutured using 5-0 nylon sutures, and a periodontal dressing will be used to cover the surgical areas. The time of the step that bone graft is filled into each intrabony defect will be recorded respectively. After the surgery, amoxicillin (0.5 g every 8 hours for 7 days) and 0.2% chlorhexidine gluconate rinses (twice a day) will be prescribed. The only difference of the surgery in the control group will be that the intrabony defects will be filled with Bio-Oss® alone before being covered by a resorbable collagen membrane. To make the participants blinded to the different treatments, when performing surgery on the control side, blood will be also obtained but PRF will not be prepared. The periodontal dressing and sutures will be removed 2 weeks postoperatively. All patients will be recalled for follow-up every 3–6 months after the surgery. Personalized oral hygiene instructions and supportive periodontal therapy will be performed at each time point during the follow-up.

Examination

On admission, patient’s PD, CAL and BI at the intrabony defect sites will be recorded as baseline clinical data. At each intrabony defect site, the buccal and lingual clinical parameters (PD, CAL and BI) will be recorded respectively. In addition, the intrabony defects will be examined using intraoral periapical radiographs.

All patients will be reevaluated 6, 12 and 24 months after surgery. At each reevaluation, the same clinical examination will be performed. At 12 and 24 months after surgery, intraoral periapical radiographs will also be obtained. All the clinical examinations will be accomplished by a self-calibrated examiner. Another clinician will finish all radiographical analyses and data analyses.

Outcome measures

The primary outcome is clinical attachment level, measured using a University of Michigan ‘‘O’’ probe with Williams markings. The secondary outcomes include (1) depth of intrabony defect, (2) vertical bone loss, (3) PD, (4) BI and (5) time of bone graft filling during the surgery. Both depth of intrabony defect and vertical bone loss are radiographic parameters. Depth of intrabony defect will be calculated as distance from alveolar crest to the base of intrabony defect/the length of root. Vertical bone loss will be calculated as cemento-enamel junction to the base of intrabony defect/the length of root. PD will be measured using a University of Michigan ‘‘O’’ probe with Williams markings. BI will be evaluated 30 seconds after periodontal probing according to the criteria reported by Mazza et al.[22] [Table 1] summarizes the assessment schedule.
Table 1: The schedule of the trial

Click here to view


Sample size and power

The sample size will be calculated according to the formula:



In previous reports[13],[23] in which the influences of bone grafts with and without PRF on clinical attachment level were compared, σ/δ was about 0.7. The inspection level (α) and the power value (1–β) will be set at 0.05 and 0.9, respectively. Thus, at least 11 subjects will be needed according to the calculation. Since the missing rate will be set as 20%, 14 participants will be enrolled.

Data collection

For the reliability of measurement, all the data collections will be accomplished by the same examiner. All data collected will be stored both on paper and digitally. Besides, the data will also be uploaded in the Chinese Clinical Trials Registry (http://www.chictr.org.cn/).

Statistical analysis

Before analysis, normality will be tested using the Shapiro-Wilk test, and variance equality will be tested using the Levene variance homogeneity test. Normally distributed data will be shown as the mean ± standard deviation, otherwise as median (lower to upper quartile). Only if both normality and variance equality can be verified, the differences between the two groups will be compared using Student’s t-test. Otherwise, the Mann-Whitney U test will be utilized. Statistical analyses will be accomplished using SPSS 11.5 (SPSS Inc., Chicago, IL, USA). Statistical significance will be accepted when P < 0.05.

Withdrawal

All participants can withdraw from this study whenever they want, and no reason is needed. The withdrawal will not have any influence on subsequent patient treatments in Peking University Hospital of Stomatology, China.

Data monitoring

Progression of the trial, adverse events, and data quality will be monitored by an Independent Data (and Safety) Monitoring Board (IDMB). The IDMB is the Ethics Committee of Peking University School and Hospital of Stomatology, which is independent of the trial sponsors.

Audits

An inspector will review the incoming data every 3 months. The process will be independent from the investigators and the sponsors. The inspector will review whether each electronic case report form is completed accurately. All discrepancies in the electronic case report form will be corrected by the principal investigator.

Harms

There will be no harms caused by the trial. As for the regenerative periodontal surgery itself, there is a possibility that the surgery might fail. All the surgeries will be finished by the same experienced periodontist, and all necessary measures will be taken to minimize the possibility.

Ethics and dissemination

The study was approved by the Ethics Committee of Peking University School and Hospital of Stomatology (PKUSSIRB-201629066) on November 4, 2016 (Additional file 2 [Additional file 2]). All patients will provide written informed consent prior to their participation in the trial (Additional file 3 [Additional file 3]). After the research, the results will be published in an international peer-reviewed scientific journal.


  Discussion Top


GTR and Bio-Oss® are widely used in periodontal regeneration. As a rich source of autologous growth factors such as platelet-derived growth factor, transforming growth factor β1, epidermal growth factor that can induce the migration, proliferation, and differentiation of different periodontium-related cells,[5],[6],[7],[8] PRF is also used in periodontal regeneration. However, whether combination of GTR, Bio-Oss® and PRF is advantageous over GTR and Bio-Oss® has not been reported.

Besides the growth factors in PRF, there are another two reasons why PRF is attractive in periodontal regeneration: (1) Since platelets are of importance in periodontal immune defense through platelet-leukocyte aggregates and the regulation of the interaction between endothelial cells and leukocytes,[24],[25],[26] quantities of platelets in PRF[8] might be beneficial to periodontal regeneration after surgery. (2) There is also a large amount of leukocytes in PRF, which are also involved in periodontal immune defense and might be associated with better periodontal outcome. However, PRF is gelatinous but not liquid, and how to mix PRF with bone graft material evenly is challenging. In the previous reports,[15],[19],[20] PRF was minced into small pieces before mixed with bone grafts. These extra steps will enhance the complexity and extend the time of the regenerative surgery, which is not favorable. What is worse, the exposure of alveolar bone in the air too long will lead to bone resorption.[27] Thus, the simplification of using PRF is needed, and Bio-Oss®-PRF mixture might be a good choice.

It was reported that the clinical advantages of regenerative periodontal therapy over open flap debridement could be maintained for as long as 10 years, but the differences between different regenerative periodontal therapies were unneglectable during the long-term follow-up.[28] However, there are no studies in which PRF was used in regenerative periodontal therapy with the follow-up over 1 year. In the present trial, the follow-up will last 2 years, and might shed light on the long-term effects of PRF in periodontal regeneration.

Thus, this split-mouth randomized controlled clinical trial was designed to compare the effects of GTR and Bio-Oss® with and without PRF in treating intrabony defects in vivo. In addition, the way of using PRF as Bio-Oss®-PRF mixture is simple and innovative, and is worth studying. Findings from this trial will provide evidence to determine whether GTR and Bio-Oss® with PRF is more effective in the treatment of periodontal intrabony defects than GTR and Bio-Oss® without PRF.

Trial Status

The trial was registered with the Chinese Clinical Trials Registry (ID: ChiCTR1900027581) on November 19, 2019. The enrollment started in October 2016. Analysis of the primary outcome measure will be completed in September 2020 and the study will end in September 2020. This research plan refers to protocol V2.0.

Additional files

Additional file 1: SPIRIT checklist.

Additional file 2: Ethical Approval Documentation.

Additional file 3: Model consent form.

Author contributions

Conceptualization, methodology, investigation, original draft writing, and funding acquisition: KNL. Investigation: ZH. Conceptualization, methodology, investigation, project administration: ZBC. Conceptualization, methodology, formal analysis, supervision, project administration, review writing and editing, funding acquisition: BH. Investigation and formal analysis: XYO. All authors approved the final submission for publication.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Financial support

This work was supported by the Program for New Clinical Techniques and Therapies of Peking University School and Hospital of Stomatology (No. PKUSSNCT-16B04, to KNL) and the National Natural Science Foundation of China (No. 81400562, to BH).

Institutional review board statement

The study was approved by the Ethics Committee of Peking University School and Hospital of Stomatology (PKUSSIRB-201629066) on November 4, 2016. Registered in the Chinese Clinical Trials Registry, ID: ChiCTR1900027581.

Declaration of patient consent

The authors certify that they will obtain all appropriate patient consent forms. In the forms the patients will give their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Reporting statement

This study followed the CONsolidated Standards Of Reporting Trials (CONSORT) statement.

Biostatistics statement

The statistical methods of this study were reviewed by the biostatistician of Peking University School and Hospital of Stomatology in China.

Copyright license agreement

The Copyright License Agreement has been signed by all authors before publication.

Data sharing statement

The results of statistical analyses will be uploaded to Chinese Clinical Trials Registry as soon as the trial ends. The clinical data of the individual participants will be available between 9 months and 36 months following article publication. The radiographic data of the individual participants will not be available, because the shapes of teeth are recognizable on X-ray images.

Plagiarism check

Checked twice by iThenticate.

Peer review

Externally peer reviewed.

Open access statement

This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

Funding: This work was supported by the Program for New Clinical Techniques and Therapies of Peking University School and Hospital of Stomatology (No. PKUSSNCT-16B04, to KNL) and the National Natural Science Foundation of China (No. 81400562, to BH).

C-Editor: Zhao M; S-Editor: Li CH; L-Editors: Song LP, Wang L; T-Editor: Jia Y

 
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