[EXSCINDED]

PONE-D-19-17399

Prosthesis Design of Animal Models of Periprosthetic Joint Infection Following Total Knee Arthroplasty: A Systematic Review

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: Yes

Reviewer #3: N/A

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Current animal models of PJI are limited in their translational nature primarily because of their inability to recreate the periprosthetic environment. A clinically representative PJI model must involve an implant that recreates the periprosthetic space and be amenable to methodologies that identify implant biofilm as well as quantify the peri-implant bacterial load. Thus, there is an undoubted interest in improving PJI models to better understand the pathogenesis of this devastating clinical problem. Unfortunately, the work described in this manuscript only focuses in a single part of the animal models, namely the principles of implant design, and their data does not provide much novel insight.

Criteria for implant selection in order to reproduce the periprosthetic environment in animal models has being already described in the literature, where the most relevant existing models were presented and discussed in similar terms (implant stability, load-bearing, clinically relevant materials, separation of intra-articular and intramedullary spaces, etc.) as the authors did in the present manuscript (see reference: https://www.ncbi.nlm.nih.gov/pubmed/27707853).

In the present study, the authors provided examples of non-infected animal models, which might be suitable for infection models. However, only two of those models were mentioned in some more detail in the results section, with no deep discussion about their possible implementation to PJI models:

-Page 15 First paragraph: “The prosthesis showed great advantages in appearance, function, material science, stability, degree of matching, and so on. It can be used for reference in the design of the PJI animal model.”

In several occasions, the reference in the present study to bacterial biofilms is ambiguous or can lead to confusion:

-Page 8 Abstract’s conclusion and page 19 Conclusions: “…the surface of the prosthesis is smooth with the formation of biofilm…”

What do the authors mean by that sentence? Do they mean that the surface of the prosthesis should be smooth to allow (or avoid) biofilm formation?

-Page 16 Question 1: “…Other studies have shown that material can even form on an antibiotic-loaded bone cement [54, 55]…”

With the term “material” do the authors mean “biofilm”?

-Page 17 Question 4: “Karbysheva et al [54] supposed that the ability of bacterial adhesion and the formation of bacterial biofilm was different because of the diversity of biological materials.”

The sentence is not accurate. Karbysheva et al suggested that the microorganisms' ability to adhere and form a biofilm on different biomaterials of explanted joint prosthesis components might differs among biomaterials.

Incorrect reference to figures in pages 12-15.

The conclusion section would benefit of a brief reasoning for each mentioned criterion.

The manuscript is overall well written but it is suggested an English editing of the manuscript by a mother tongue speaker to correct spelling mistakes and improve the readability of numerous sentences.

Reviewer #2: This is a systematic review analyzing the prosthesis design used in animal models dealing with periprosthetic joint infection (PJI) following total knee arthroplasty (TKA). The review is well written and correctly follows the checklist PRISMA for systematic reviews. The aim of the study was to look at the different prosthesis designs in knee implants used in animal models of PJI. The authors have obviously the assumption that the design of the prosthesis used in the animal model is crucial for the imitation of human PJI. If this is indeed the case, the minimal infecting dose and the response to antimicrobial treatment should be closest to the human situation in the animal model using an implant which best imitates the human one. This clinically relevant part of the review is missing, because it can obviously not be extracted from the different studies. Thus, it may well be that other factors such as the pathogenesis of inoculation (exogenous during implantation vs hematogenous), the inoculum, the type of microorganism, the delay until antimicrobial therapy etc. are much more important for the precise simulation of the human situation than the design of the implant. The design of the prosthetic joint may be much more important in non-infectious situations, where factors such as function, aseptic loosening instead of susceptibility to infection are analyzed.

Specific comments

1.Abstract/Objectives. The aim of the study is to present criteria for the evaluation of a clinically representative model of PJI. Up to now, no PJI animal model perfectly simulates the design of a human TKA. Nevertheless, even with very crude imitations (see figure 2), all PJI animal models perfectly simulate the clinical situation in the sense that the minimal infecting dose is very low, the untreated PJI never spontaneously heals, and established biofilms cannot be eliminated by most antibiotics. Thus, the clinical relevance of the study objective can be contested.

2.Abstract/Results. Eight PJI animal models are presented in this review. Unfortunately, the manuscript is narrowly centered on a readership of orthopedic surgeons. Criteria which are important for Infectious Disease specialists are not reported. Among these are specifics regarding the minimal infecting dose, the spontaneous course of the infection (loosening? Sinus tract?), the expansion from PJI to concomitant osteomyelitis etc.

3.Introduction. The statement “…PJI is one of the catastrophic complications…” is clearly exaggerated, since in many cases, debridement, antibiotics and implant retention is a valuable strategy. Thus, PJI is a severe, but not a catastrophic complication.

4.Introduction. The authors state that “…the current design of PJI models is still dissatisfying.” In my view, it is correct, that none of the PJI animal model closely simulates the human situation. However, the authors should explain, why this is “dissatisfying”. Does this lead to wrong conclusions regarding pathogenetic, diagnostic or therapeutic concepts in human beings with PJI? The authors should cite such “dissatisfying” factors, in order to convince the reader that the PJI animal model should perfectly simulate the human situation.

5.Discussion/Question 1. The statement that cementless TKS is associated with higher loosening rates is not correct. Citation #48 is completely wrong. Drexler et al. state “…cemented fixation offered equivalent clinical outcomes and at least as good as, if not better, survival than uncemented fixation…”

6.Discussion/Question 1. The Charité group (citation #54) tested cobalt-chromium, titanium and polyethylene, but not bone cement.

7.Strenghts and limitations. The authors state that the strengths of their paper are “evident”. The individual strengths should be enumerated.

8.Strengths and limiations. The authors state “…most influencing factors are based on the prosthesis design, which determines the success or failure of the animal model…” However, they don’t show any examples of failed PJI animal models (cfr. #4 above). Thus, it remains unclear, whether the design is only important for non-infectious arthroplasty models, but also for PJI animal models.

Minor comment

1.Results. The authors cite 4 criteria for prosthetic design. However, they enumerate only the first two. Enumeration (3) and (4) should be added for the other two criteria.

Reviewer #3: The authors performed a systematic review aiming to summarize the prosthesis design of animal models of PJI following TKA. After a huge literature screening, they found a total of 12 studies (8 concerning models of infection, 4 non-infection models) and they summarized the different materials, animals, location and the presence/absence of cement, on order to find the best suitable prosthesis model for future animal model studies on PJIs.

Overall, the manuscript is well written and easy to read.

I have only minor comments:

- I would introduce the part concerning the different types of bacteria (gram postive vs gram negatives, inocolum) in the manuscript, not only in the tables.

- bacterial names should be written in Italic

- authors should check some spelling errors in english (i.e. tenses in the method section)

Figure2. Legend should be ameliorated. Does the figure refer to the used models in the literature of prosthesis for animal models?

- Tables: all the studies should be temporarly order

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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Prosthesis Design of Animal Models of Periprosthetic Joint Infection Following Total Knee Arthroplasty: A Systematic Review

PONE-D-19-17399R1

Dear Dr. Zeng,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

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Daniel Pérez-Prieto, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: N/A

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: In the revised version of the manuscript, the authors improved some linguistic problems and replaced references which did not support certain statements. Overall, the changes are minor but adequate. Most answers to the reviewers’ questions are defensive and do not resolve the indicated problem. Thus, the limitation remains, namely the very limited value of this manuscript for Infectious Disease clinicians. Nevertheless, this systematic review, which is methodologically correctly performed, may have a good value for orthopedic surgeons performing experimental work in the field of total knee arthroplasty.

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If you choose “no”, your identity will remain anonymous but your review may still be made public.

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Reviewer #2: No