Titanium Particle Impact on Immune Cells, Cytokines, and Inflammasomes: Helping to Profile Peri-Implantitis—A Systematic Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Dear authors,

I send my comments below:

1. Keywords:
- Keywords should be listed in alphabetical order

2. Methodology:
- The date of registration of the article in PROSPERO is missing
-  The abbreviation PROSPERO is not explained
- Line 104 does not specify the version of Zotero used
- Section 2.2 does not specify search restrictions such as language, search years, etc. If no restrictions were applied, this information should be provided
The PRISMA flow diagram should be included in the results section in accordance with the PRISMA checklist

3. Results
- Each table should have a list of abbreviations written out and expanded below it.

4. Discussion
- Should be divided into segments: general results, comparison to the literature (proper discussion), study limitations, and future implications.
- It is worth mentioning the use of carriers in the treatment of peri-implantitis, which could also be carriers for titanium particles - There are already studies on T-PRF. I recommend using this citation in relation to the use of PRF as carriers: DOI: 10.3390/ijms26052140

General comments:
- In vitro and in vivo should be written in italics

Best regards
Reviewer

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The study is relevant considering the benefits and risks of implants. The manuscript provides a detailed approach to the methodology and highlights the study's limitations. Some considerations could complement the manuscript, such as:

Materials and Methods:

1. Better highlight the tools used to assess the risk of bias.
2. In the PRISMA flowchart, better specify the number of in vitro and in vivo studies included in the review and their respective databases.

Results:

1. Check the numbering in Table 4, considering the separate numbering between Figures and Tables.

Discussion:

1. Add an approach on how the data from this review could be used to improve the success of implants in clinical practice.
2. Add perspectives for future studies.

Author Response

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Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

Minor Revision

• Some long sentences (especially in Introduction & Discussion) reduce clarity and should be broken up.
• Occasional grammar/typographical issues (e.g., “exacerbating” vs “exacerbate”, “P. Gingivalis” inconsistently capitalized).
• “Bio-tribocorrosion” is used frequently but not defined in lay terms for non-specialist readers.

Major Revision

• PECO formulation: While the PECO strategy is presented (Table 1), the Comparison element is weak — “implants without inflammatory signs” is too vague, and no consistent comparator is present across included studies.

• Search strategy transparency: Although PRISMA is followed, the exact search strings for each database are not fully disclosed, limiting reproducibility.

• Low in vitro methodological quality: As reported, median Modified CONSORT scores are 8/14, with missing details on randomization, blinding, and sample size. The review states this but does not sufficiently discuss how these weaknesses affect interpretation.

• Causality vs association: The review often implies causative effects of titanium particles (e.g., “stimulates chronic inflammation”) without clearly distinguishing from correlation in observational data.
• VEGF findings: The discussion acknowledges no histopathological pattern linking titanium particles and VEGF, but still suggests VEGF as a predictive biomarker without stronger evidence.
• Mixed results not fully reconciled: Conflicting findings (e.g., IL-8 role, MGNC presence) are noted but not synthesized into a coherent explanation or hypothesis.

• Some citations are slightly outdated in background context (e.g., peri-implantitis epidemiology could reference recent systematic reviews from 2023–2024).
• Reference style is inconsistent in a few entries (capitalization, punctuation).

 

Author Response

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Author Response File: Author Response.pdf

Reviewer 4 Report

Comments and Suggestions for Authors This systematic review addresses the role of titanium particle-induced inflammation in peri-implantitis. The topic is timely and clinically relevant. The manuscript is well-structured, adheres to PRISMA standards, applies a comprehensive search strategy, and presents the results in a generally clear manner. The number of included studies is sufficient. Overall, this is a solid and well-written paper. However, as only a few human in vivo studies were included, the clinical applicability remains somewhat limited. Below are my specific comments (recommendation: minor revision):

1. There are a few minor spelling or formatting issues that need correction. For example, “NRLP3” should be consistently written as “NLRP3” throughout the manuscript.
2. For consistency, Table 5c should include footnotes or explanatory notes similar to those provided for Tables 5a and 5b.
3. The inclusion and exclusion criteria are generally clear, but it would strengthen the methodology section to explain the rationale—particularly why animal studies and implant polishing studies were excluded, given that animal cell studies were included.
4. Although the PRISMA flowchart is well presented, it is not fully explained whether the search strategy ensured both sensitivity and specificity. Please clarify whether grey literature or manual searching (e.g., reference lists, conference abstracts) was performed to reduce the risk of publication bias.
5. The in vitro studies included in the review were generally rated as low quality. It is recommended to discuss the limitations this poses for interpreting the results and to avoid over-extrapolation to clinical scenarios.
6. Consider adding a brief summary in the Results section discussing the relationship between particle size and inflammatory response. This would help readers quickly grasp the key trends.
7. Some of the cited references are relatively old (around 2006); I suggest including more recent studies from the last three years, particularly those applying transcriptomic and single-cell approaches.

Author Response

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Author Response File: Author Response.pdf

Reviewer 5 Report

Comments and Suggestions for Authors

Dear Authors, 

Please find attached the comments. 

 

 

Comments for author File: Comments.pdf

Author Response

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Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I have no further comments

Reviewer 2 Report

Comments and Suggestions for Authors

The adjustments complemented the manuscript.

Reviewer 3 Report

Comments and Suggestions for Authors

It is publishable