Systematic Review and Meta-Analysis of the Use of Hyaluronic Acid Injections to Restore Interproximal Papillae

Round 1

Reviewer 1 Report

General comments

 

Overall, page 1 to page 3 is describing mainly on the significance of Hyaluronic Acid (HA) and interproximal papillae along with the details of their search strategy in conducting this systematic review and meta-analysis. While in page 3 until 7, the authors describe on the efficiency of HA in restoring interproximal papillae by discussing the findings from the five articles that they have chosen. The introduction was concise for the purpose of a systematic review, but the importance of the research question could be expounded a little beyond one line referencing studies 2-4 (page 1 line 37 and 38).

 

Specific comments

 

Page 1 line 28- “AH” should be corrected to HA 

Page 2 line 41-42 – Consider paraphrasing.

Page 2 line 51 – It is better to use “Therefore, it is highly possible” instead of “In this way, it has also been possible”.

Page 2 line 62 – Consider “We have identified and considered”.

Page 3 Figure 1 – The Prisma P used is not the latest. Kindly use Prisma P 2020. Details of the reasons to exclude need to be explained in more details. Eg. What does the author mean by ‘excluded by summary’?  Is it because the summary does not contain relevant information to the searching criteria?  This is similar to other reasons of exclusion.

Page 3 line 77 – More detail selection studies should be provided. This includes the type of articles included in the systematic review. Eg. research articles, review paper, case report etc.

Page 4 line 100 – There should be “A total of five articles with one randomised control trial and four clinical trials”.

Page 4 line 114- “..but has less weight than the previous study” should be corrected to “but had less weight than the previous study..”

Page 5 Figure 3 – The figure should be centralized.

Page 5 Table 2 – The colour coded (red, green and yellow) and symbols should be explained.

Result section should also mention the Kappa score among the authors’ agreement.

Discussion could include comparison to other techniques available for reconstructing interproximal papilla deficiency and their effectiveness.

Page 8 line 268 – Contribution of co-authors in the systematic review should be explained. 

Author Response

We would like to thank the reviewers for careful and thorough reading this manuscript and for the thoughtful comments and constructive suggestions, which helped to improve the quality of this manuscript.

 

Below follow point-by-point responses to the reviewer´s comments (the reviewer´s comments are in red).

 

Reviewer 1

General comments

Overall, page 1 to page 3 is describing mainly on the significance of Hyaluronic Acid (HA) and interproximal papillae along with the details of their search strategy in conducting this systematic review and meta-analysis. While in page 3 until 7, the authors describe on the efficiency of HA in restoring interproximal papillae by discussing the findings from the five articles that they have chosen. The introduction was concise for the purpose of a systematic review, but the importance of the research question could be expounded a little beyond one line referencing studies 2-4 (page 1 line 37 and 38).

Answer:

We appreciate the reviewer's suggestion and have expanded the importance of the review by adding the following paragraph:

Page 1 lines 39-41: “The importance of the subject lies in knowing the fields of application of HA in clinical terms, its indications and its limitations. For which we have reviewed the existing literature in order to provide recommendations based on previously published studies.”

 

Specific comments

Page 1 line 28- “AH” should be corrected to HA

Answer:

Thanks for the recommendation. We have corrected the misprint "AH" instead "HA"

Page 2 line 41-42 – Consider paraphrasing.

Answer:

We have paraphrasing:

"In an attempt to reconstruct the interdental papilla, many surgical techniques have been developed, although the results of these techniques can be unpredictable" being replaced by the following "Reconstruction of the interdental papilla has been approached from various techniques. Most of them include surgical techniques with not always predictable results. The minimally invasive HA approach has the potential advantage of being effective, predictable, and minimally invasive with only slight injury.”

Page 2 line 51 – It is better to use “Therefore, it is highly possible” instead of “In this way, it has also been possible”.

Answer:

We accept the reviewer's suggestion and have changed “In this way, it has also been possible”. By "Therefore, it is highly possible"

Page 2 line 62 – Consider “We have identified and considered”.

Answer:

We have replaced the paragraph “Through the PICO process, we identified and considered the studies for this systematic review” by the following “The focused question was structured according to the PICO format”

Page 3 Figure 1 – The Prisma P used is not the latest. Kindly use Prisma P 2020. Details of the reasons to exclude need to be explained in more details. Eg. What does the author mean by ‘excluded by summary’? Is it because the summary does not contain relevant information to the searching criteria?  This is similar to other reasons of exclusion.

Answer:

We used the previous guide because, at the time of starting the study, the current one had not yet been published. The causes of exclusion are reflected in figure 1 Basically there were 4 duplicate articles, 1060 discarded due to the title, 3 excluded after reading the abstract, 1 impossible to obtain, 2 were animal studies, 1 article was discarded due to the sample size and 2 due to the impossibility of extracting the necessary data.

 

Page 3 line 77 – More detail selection studies should be provided. This includes the type of articles included in the systematic review. Eg. research articles, review paper, case report etc.

Answer:

We have included the type of article finally selected as " A total of five articles with one randomised control trial and four clinical trials (case series) "

 

Page 4 line 100 – There should be “A total of five articles with one randomised control trial and four clinical trials”.

Answer:

We appreciate the reviewer's suggestion and have included their phrase “A total of five articles with one randomised control trial and four clinical trials”.

 

Page 4 line 114- “but has less weight than the previous study” should be corrected to “but had less weight than the previous study”

Answer:

We accept the reviewer's suggestion and have changed “but has less weight than the previous study”. By “but had less weight than the previous study”

 

Page 5 Figure 3 – The figure should be centralized.

Answer:

All figures have been centralized

Page 5 Table 2 – The colour coded (red, green and yellow) and symbols should be explained.

Answer:

We agree with the reviewer and have added the colour codes such as low risk of bias = green (+), Unclear risk of bias = yellow (¿?), High risk of bias = red (-)

Result section should also mention the Kappa score among the authors’ agreement.

Answer:

We have included the value of the in the results.

“To assess the validity of the review, the Kappa coefficient was used. Kappa is a measure of agreement proposed by Cohen in 1960, which is based on comparing the agreement observed in a set of data, with respect to what could occur by mere chance. The agreement obtained in our study was 0.824”

Discussion could include comparison to other techniques available for reconstructing interproximal papilla deficiency and their effectiveness.

Answer:

This consideration is very relevant, however, it exceeds the intentions of the authors who were to determine the scope of application of HA in published cases in order to clarify its indications and limitations.

We add the following sentence in the text: “Reconstruction of the interdental papilla has been approached from various reconstruction techniques. Most of them include surgical techniques with not always predictable results. The minimally invasive HA approach has the potential advantage of being effective, predictable, and minimally invasive with only slight injury as compared to surgical treatments. In addition, it has few side effects. Although its application is limited to small defects.”

 

Page 8 line 268 – Contribution of co-authors in the systematic review should be explained. 

Answer:

We have followed the journal's instructions when establishing the contribution of all authors. All of them have participated in the exposed phases, and are represented with their initials to maintain anonymity during the review phase.

• TRV was our graduate student who had the idea to evaluate the extent to which HA could represent a treatment option for the loss of the papilla and its limitations. She wrote the work under the supervision of ASP.
• ASP carry out all the checks of the study. I also review all phases of the work, directing the rest of the work components. He gave the go-ahead to the investigation and has been the author for the correspondence.
• AJG and CNC supervise all the disagreements and review the final version of the work.
• CNC He was the second critical reader of the studies and who also extracted the data from them
• BMJ and AJG They performed all the validations and supervised the statistical analysis. Likewise, they refined the final wording of the writing.

 

Reviewer 2 Report

The loss of the interdental papilla is a very common problem. Currently there are several techniques with multiple fills to solve this problem. Recent studies suggest the use of HA as a possible help in the non surgical reconstruction of the interdental papilla. This article has an interesting theme, but it has many failures:

• A literature review is carried out between 2009-2019, considering that we are in the end of 2021, all works published in 2020 and early 2021 are missing here, ie this work is not up to date. On the other hand, with the large number of works published, choosing only 5 (studies included in the review) is too little.
• Must be described the most appropriate protocol of HA injection and identify if necessary one pretreatment
• What is the advantage of this reconstruction technique with HA relative to other techniques.

 

Author Response

We would like to thank the reviewers for careful and thorough reading this manuscript and for the thoughtful comments and constructive suggestions, which helped to improve the quality of this manuscript.

 

Below follow point-by-point responses to the reviewer´s comments (the reviewer´s comments are in red).

 

Reviewer 2

Comments and Suggestions for Authors

The loss of the interdental papilla is a very common problem. Currently there are several techniques with multiple fills to solve this problem. Recent studies suggest the use of HA as a possible help in the non surgical reconstruction of the interdental papilla. This article has an interesting theme, but it has many failures:

• A literature review is carried out between 2009-2019, considering that we are in the end of 2021, all works published in 2020 and early 2021 are missing here, ie this work is not up to date. On the other hand, with the large number of works published, choosing only 5 (studies included in the review) is too little.

Answer:

 

The review of the published literature involves a time lag due to the process of identification, selection, reading, data extraction, analysis, writing and editing of the systematic review.

Updating the current bibliography from 2020/1/1 to 2021/9/30 means the appearance of a total of 1786 new articles. Its processing would imply a delay in the publication of the data equivalent to that currently presented in this review (Table 1, Figure 1).

 

Year	Papers
2020	955
2021	831
Total	1786

 

Table 1: Total number of bibliography from 2020/1/1 to 2021/9/30

Figuer 1: Bibliography from 2020/1/1 to 2021/9/30 with columns pertaining to 2021 and 2020 highlighted

As an example, we present a systematic review published in 2020 and that its search covers from 2010 to 2016. (reference 1)

Reference 1: Ficho AC, de Souza Faloni AP, Pennisi PRC, Borges LGF, de Macedo Bernadino Í, Paranhos LR, Queiroz TP, Santos PL. Is interdental papilla filling using hyaluronic acid a stable approach to treat black triangles? A systematic review. J Esthet Restor Dent. 2021 Apr;33(3):458-465. doi: 10.1111/jerd.12694. Epub 2020 Dec 17. PMID: 33332683.

• Must be described the most appropriate protocol of HA injection and identify if necessary one pretreatment..

Answer:

 

Although each author has carried out their own treatment protocol, as a general rule the treatment is carried out as: The local anaesthetic is injected and then, in each session, a single dose per 0.1 ml to 0.2 ml HA was used with a maximum of five applications or until black triangles were no longer visible. The time interval between applications was 3 weeks.

No pre-treatment was used except good oral hygiene.

 

We have included this paragraph in the conclusions of the study.

 

• What is the advantage of this reconstruction technique with HA relative to other techniques.

Answer:

The advantages of this technique lie in the ease of use, a fast learning curve and its few side effects (especially in cases of failure where the original defect will not be increased). This cannot be generalized to other surgical techniques. On the other hand, its effectiveness is limited to small defects (less than 1mm).

We have included this paragraph in the discussion.

 

 

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

The authors have made the amendments according to the previous comments.  The current version is ready for publication at Applied Sciences.

Author Response

Thank you for your time and effort in improving our work.

Reviewer 2 Report

I appreciate the explanations that the authors provided, but I am of the opinion that a complete review is necessary. The manuscript bibliography must also include recent studies, the must up-to-date as possible, that justify the work carried out. It is a essential that the research review is updated to avoid criticism about the importance of the work. So I am of the opinion that the article should have the bibliographic review updated to be published.

Author Response

We are pleased to submit a revised version of our manuscript untitled  “Systematic Review and Meta-Analysis of the Use of Hyaluronic Acid Injections to Restore Interproximal Papillae”

 

On behalf of my colleagues, I would like to thank you for the valuable comments made on our investigation. We are looking forward to having this revised manuscript considered now for publication in the Journal

 

A new update of the bibliographic search was carried out from January 2019 to September 2021. A total of 1786 new articles were found. What supposes a renewed interest by this topic.

 

Of these, 15 were selected by title.

 

1. Efficacy Evaluation of Hyaluronic Acid Gel for the Restoration of Gingival Interdental Papilla Defects. Ni J, Shu R, Li C. J Oral Maxillofac Surg. 2019 Dec;77(12):2467-2474. doi: 10.1016/j.joms.2019.06.190. Epub 2019 Jul 5. PMID: 31445036
2. Interproximal attachment gain: The challenge of periodontal regeneration. Rasperini G, Tavelli L, Barootchi S, McGuire MK, Zucchelli G, Pagni G, Stefanini M, Wang HL, Giannobile WV. J Periodontol. 2021 Jul;92(7):931-946. doi: 10.1002/JPER.20-0587. Epub 2020 Nov 23. PMID: 33152103
3. Clinical outcomes of the entire papilla preservation technique with and without biomaterials in the treatment of isolated intrabony defects: A randomized controlled clinical trial. Aslan S, Buduneli N, Cortellini P. J Clin Periodontol. 2020 Apr;47(4):470-478. doi: 10.1111/jcpe.13255. Epub 2020 Feb 3. PMID: 31925811 Clinical Trial.
4. Subperiosteal Papilla Augmentation With a Non-Animal-Derived Hyaluronic Acid Overlay Technique. Spano SJ, Ghilzon R, Lam DK, Goldberg MB, Tenenbaum HC. Clin Adv Periodontics. 2020 Mar;10(1):4-9. doi: 10.1002/cap.10075. Epub 2019 Oct 4. PMID: 31520457
5. Minimally invasive procedures for deficient interdental papillae: A review. Zhang Y, Hong G, Zhang Y, Sasaki K, Wu H. J Esthet Restor Dent. 2020 Jul;32(5):463-471. doi: 10.1111/jerd.12608. Epub 2020 Jun 9. PMID: 32519508 Review.
6. Exosome-like vesicles derived from Hertwig's epithelial root sheath cells promote the regeneration of dentin-pulp tissue. Zhang S, Yang Y, Jia S, Chen H, Duan Y, Li X, Wang S, Wang T, Lyu Y, Chen G, Tian W. Theranostics. 2020 Apr 27;10(13):5914-5931. doi: 10.7150/thno.43156. eCollection 2020. PMID: 32483427 Free PMC article.
7. Interdental papilla reconstruction using injectable hyaluronic acid: A 6-month prospective longitudinal clinical study. Alhabashneh R, Alomari S, Khaleel B, Qinawi H, Alzaubi M. J Esthet Restor Dent. 2021 Apr;33(3):531-537. doi: 10.1111/jerd.12680. Epub 2020 Nov 10. PMID: 33174355
8. Effect of Flap Design for Enamel Matrix Derivative Application in Intraosseous Defects. Trombelli L, Simonelli A, Quaranta A, Tu YK, Li H, Agusto M, Jiao XJ, Farina R. JDR Clin Trans Res. 2021 Apr;6(2):184-194. doi: 10.1177/2380084420934731. Epub 2020 Jun 19. PMID: 32559395
9. Is interdental papilla filling using hyaluronic acid a stable approach to treat black triangles? A systematic review. Ficho AC, de Souza Faloni AP, Pennisi PRC, Borges LGF, de Macedo Bernadino Í, Paranhos LR, Queiroz TP, Santos PL. J Esthet Restor Dent. 2021 Apr;33(3):458-465. doi: 10.1111/jerd.12694. Epub 2020 Dec 17. PMID: 33332683 Review.
10. Modified minimally invasive surgical technique plus Bio-Oss Collagen for regenerative therapy of isolated interdental intrabony defects: study protocol for a randomised controlled trial. Zhang C, Zhang H, Yue Z, Miao L, Han Y, Liu K, Hou J. BMJ Open. 2020 Dec 10;10(12):e040046. doi: 10.1136/bmjopen-2020-040046. PMID: 33303446 Free PMC article.
11. Reconstructive surgical treatment of isolated deep intrabony defects with guided tissue regeneration using entire papilla preservation technique: A prospective case series. Aslan S, Buduneli N, Cortellini P. J Periodontol. 2021 Apr;92(4):488-495. doi: 10.1002/JPER.20-0288. Epub 2020 Sep 8. PMID: 32822062
12. Pocket resolution in regenerative treatment of intrabony defects with papilla preservation techniques: A systematic review and meta-analysis of randomized clinical trials. Aimetti M, Fratini A, Manavella V, Giraudi M, Citterio F, Ferrarotti F, Mariani GM, Cairo F, Baima G, Romano F. J Clin Periodontol. 2021 Jun;48(6):843-858. doi: 10.1111/jcpe.13428. Epub 2021 Apr 5. PMID: 33476402 Review.
13. Periodontal reconstructive surgery of deep intraosseous defects using an apical approach. Non-incised papillae surgical approach (NIPSA): A retrospective cohort study. Moreno Rodríguez JA, Ortiz Ruiz AJ, Caffesse RG. J Periodontol. 2019 May;90(5):454-464. doi: 10.1002/JPER.18-0405. Epub 2018 Nov 28. PMID: 30421495
14. Interdental Papillae Loss and Multiple RT2 and RT3 Gingival Recession Defects: A Case Report of a Combined Surgical Treatment Approach. Littarru C, Orgeas GV. Int J Periodontics Restorative Dent. 2021 Mar-Apr;41(2):177-185. doi: 10.11607/prd.4547. PMID: 33819320
15. . Interdental papilla loss: treatment by hyaluronic acid gel injection: a case series.Awartani FA, Tatakis DN Clin Oral Investig. 2016 Sep;20(7):1775-80. doi: 10.1007/s00784-015-1677-z. Epub 2015 Nov 27. PMID: 26613740.

 

After reading the abstract, 6 articles were eventually selected in order a critic read.

 

1. Efficacy Evaluation of Hyaluronic Acid Gel for the Restoration of Gingival Interdental Papilla Defects. Ni J, Shu R, Li C. J Oral Maxillofac Surg. 2019 Dec;77(12):2467-2474. doi: 10.1016/j.joms.2019.06.190. Epub 2019 Jul 5. PMID: 31445036
2. Minimally invasive procedures for deficient interdental papillae: A review. Zhang Y, Hong G, Zhang Y, Sasaki K, Wu H. J Esthet Restor Dent. 2020 Jul;32(5):463-471. doi: 10.1111/jerd.12608. Epub 2020 Jun 9. PMID: 32519508 Review.
3. Awartani FA, Tatakis DN. Interdental papilla loss: treatment by hyaluronic acid gel injection: a case series. Clin Oral Investig. 2016 Sep;20(7):1775-80. doi: 10.1007/s00784-015-1677-z. Epub 2015 Nov 27. PMID: 26613740.
4. Subperiosteal Papilla Augmentation With a Non-Animal-Derived Hyaluronic Acid Overlay Technique. Spano SJ, Ghilzon R, Lam DK, Goldberg MB, Tenenbaum HC. Clin Adv Periodontics. 2020 Mar;10(1):4-9. doi: 10.1002/cap.10075. Epub 2019 Oct 4. PMID: 31520457.
5. Interdental papilla reconstruction using injectable hyaluronic acid: A 6 month prospective longitudinal clinical study. Alhabashneh R, Alomari S, Khaleel B, Qinawi H, Alzaubi M. J Esthet Restor Dent. 2021 Apr;33(3):531-537. doi: 10.1111/jerd.12680. Epub 2020 Nov 10. PMID: 33174355.
6. Is interdental papilla filling using hyaluronic acid a stable approach to treat black triangles? A systematic review. Ficho AC, de Souza Faloni AP, Pennisi PRC, Borges LGF, de Macedo Bernadino Í, Paranhos LR, Queiroz TP, Santos PL. J Esthet Restor Dent. 2021 Apr;33(3):458-465. doi: 10.1111/jerd.12694. Epub 2020 Dec 17. PMID:33332683 Review.

 

2 were ruled out due to insufficient sample size (9 patients and 3 patients)

2 were discarded because they were reviews (1 narrative and 1 systematic)

2 articles met the inclusion criteria (42 new patients and 148 papillae) and was included in the study.

 

Interdental papilla reconstruction using injectable hyaluronic acid: A 6 month prospective longitudinal clinical study. Alhabashneh R, Alomari S, Khaleel B, Qinawi H, Alzaubi M. J Esthet Restor Dent. 2021 Apr;33(3):531-537. doi: 10.1111/jerd.12680. Epub 2020 Nov 10. PMID: 33174355

 

Efficacy Evaluation of Hyaluronic Acid Gel for the Restoration of Gingival Interdental Papilla Defects. Ni J, Shu R, Li C. J Oral Maxillofac Surg. 2019 Dec;77(12):2467-2474. doi: 10.1016/j.joms.2019.06.190. Epub 2019 Jul 5. PMID: 31445036

 

Multiples sentences and new graphics were included in the text, to be able to update the text with the new contrib utions. The summary of the main data obtained is represented in the embedded summary table (table 1)

Table 1: Summary of the data obtained with the mean, standard deviation and weight of the included studies.

 

We are looking forward to hearing from you.

 

Sincerely

Author Response File: Author Response.pdf

Round 3

Reviewer 2 Report

The revised manuscript is ok for me