Intra-Articular Bone Marrow Aspirate Concentrate Injection in Patients with Knee Osteoarthritis

Round 1

Reviewer 1 Report

Thank you for the work you put into this study and manuscript, I appreciate the effort.

This paper is of interest to be published. However, a Major Revision to tackle some of the Points has to be done:

The range suggests that you included patients which were 16 years old. Is this correct? Did those patients have primary osteoarthritis?

Demographic data: which time points were the data assessed? This is important since the weight could have changed and is therefore a bias.

Figure 1: p < 0.05 indicates significant differences. But between which groups and at which time point are the differences?

Results:

Table 2:

• Which time points do the p-values stand for? Please indicate between which time points (preoperative vs 5 year?) significant differences were calculated.
• I can’t really see which tests were applied to which groups. You have 8 rows and 5 columns but only 3 p-values.
• Age: Here in both rows, age is 60. However, age is not a categorial variable unless you summarized specific ages into groups/categories. Did you mean < 60 and > 60?

Please write if you performed post-hoc testing. It seems that you performed a lot of statistical tests, the p-value might have to be adjusted.

Line 172f: If 12 patients underwent secondary operations, then of your entire cohort (n = 37), 32% of all patients have to be excluded since you can’t tell if the improvements can be regarded as a result of the bone marrow injection or the operative knee correction (TKA, HTO). This is a huge bias. Were these patients included in the results of the VAS scores etc.? It is logical that if a patient undergoes TKA VAS will improve.

Author Response

Manuscript No. applsci-888463-R1

Intra-articular Bone Marrow Aspirate Concentrate Injection in Patients with Knee Osteoarthritis

Applied Sciences

Dear Editors:

Thank you for taking your time to review our article. We deeply appreciate all of your thoughtful response as well as that of the reviewers. We have revised manuscript according to your valuable comments.

We have incorporated all your detailed edits in the manuscript and have addressed each of your questions or comments. We have also answered to each of comments of the reviewers in a point-by-point format using ‘Italicized text’, and have noted all changes/ additions in the manuscripts by using ‘Bolded text’. Then, we have highlighted the changes to revised manuscript using ‘Red colored text’. In addition, in order to provide the evidence for our answers to your questions, we cited the references according to the journal style and listed them at the end of the revision note.

We hope the revised manuscript will better meet the requirement of "Applied Sciences" for publication. Thanks again for all your insightful suggestion. We would be happy to make any further changes that you deem necessary.

Sincerely,

The Authors

Author Response File: Author Response.doc

Reviewer 2 Report

• Introduction is short, but well written and clearly describes the rationale. 
• Methods: 
  • it's unclear to me if patients had to sign an informed consent!
  • I suggest to insert table 1 (demographics) in the method section.
  • Did patients with a bilateral treatment receive this treatment at the same time? Clarify?
  • Did some patients get physiotherapy? Clarify?
• Results: 
  • You describe for the different variables nice figures. However, I suggest to indicate in which period you find statistical significant improvement? Is it in the first period (Pré-op --> 6 mo) or in another time interval? I suppose the most clear improvement is clear in the first year. 
  • Table 2: same remark: indicate in which period your statistical improvement is most important. 
  • Table 3 & 4: the p-value is unclear for me. What is analyzed here?
• Discussion: 
  • line 233: "The To date": remove "The"
  • Limitations: I suggest to add a paragraph about the possible side-effects of this treatment. This need somewhat more attention in my opinion. 

Author Response

Manuscript No. applsci-888463-R1

Intra-articular Bone Marrow Aspirate Concentrate Injection in Patients with Knee Osteoarthritis

Applied Sciences

Dear Editors:

Thank you for taking your time to review our article. We deeply appreciate all of your thoughtful response as well as that of the reviewers. We have revised manuscript according to your valuable comments.

We have incorporated all your detailed edits in the manuscript and have addressed each of your questions or comments. We have also answered to each of comments of the reviewers in a point-by-point format using ‘Italicized text’, and have noted all changes/ additions in the manuscripts by using ‘Bolded text’. Then, we have highlighted the changes to revised manuscript using ‘Red colored text’. In addition, in order to provide the evidence for our answers to your questions, we cited the references according to the journal style and listed them at the end of the revision note.

We hope the revised manuscript will better meet the requirement of "Applied Sciences" for publication. Thanks again for all your insightful suggestion. We would be happy to make any further changes that you deem necessary.

Sincerely,

The Authors

Author Response File: Author Response.doc

Round 2

Reviewer 1 Report

Patient selection:

Line 78-81: This belongs to the results section.

I can see now that you wrote "To eliminate bias, patients who underwent secondary operation during the follow-up period were excluded from clinical scoring". You changed graphs and tables, too. Nevertheless, you wrote in the section "2.2 Includion and Exclusion Criteria" that 37 patients were enrolled. This is absolutely not correct and misleading! In your study, your main message concerns the clinical outcome. And because of secondary operations, 12 patients dropped out. Therefore, n = 25 patients were enrolled. This has to be highlighted, and as already mentioned, this section belongs to the results.

Please present a flow chart depicting the patient selection process so that readers can see how many patients dropped out and which patients finally were included for the clinical outcome measures.

Statistics:

Again, I can not see if you adjusted p-values. Please report which adjustment method (e.g. Bonferroni) you used.

Author Response

Manuscript No. applsci-888463-R2

Intra-articular Bone Marrow Aspirate Concentrate Injection in Patients with Knee Osteoarthritis

Applied Sciences

Dear Editors:

Thank you for taking your positive responses to review our article. We deeply appreciate all of your thoughtful response as well as that of the reviewers. We have revised manuscript according to your valuable comments.

As in the previous version, we have incorporated all your detailed edits in the manuscript and have addressed each of your questions or comments. We have also answered to each of comments of the reviewers in a point-by-point format using ‘Italicized text’, and have noted all changes/ additions in the manuscripts by using ‘Bolded text’. Then, we have highlighted the changes to revised manuscript using ‘Red colored text’. In addition, in order to provide the evidence for our answers to your questions, we cited the references according to the journal style and listed them at the end of the revision note.

We hope the revised manuscript will better meet the requirement of "Applied Sciences" for publication. Thanks again for all your insightful suggestion. We would be happy to make any further changes that you deem necessary.

Sincerely,

The Authors

Reviewers’ Comments to Author:

Reviewer 1:

Patient selection:

Line 78-81: This belongs to the results section.

I can see now that you wrote "To eliminate bias, patients who underwent secondary operation during the follow-up period were excluded from clinical scoring". You changed graphs and tables, too. Nevertheless, you wrote in the section "2.2 Includion and Exclusion Criteria" that 37 patients were enrolled. This is absolutely not correct and misleading! In your study, your main message concerns the clinical outcome. And because of secondary operations, 12 patients dropped out. Therefore, n = 25 patients were enrolled. This has to be highlighted, and as already mentioned, this section belongs to the results.

Please present a flow chart depicting the patient selection process so that readers can see how many patients dropped out and which patients finally were included for the clinical outcome measures.

Response: We have fully agreed with your opinion. We have revised the sentences in the manuscript, and moved them to the result section. Moreover, we have also revised the demographic date according to changed number of enrolled patients. As your comments, we have added a flow chart depicting the patient selection process as a new Figure 1. Thank you.

Page 3-4, Line 135-145:

3.1. Characteristics of Enrolled Patients

In total, 41 patients (75 knees) with knee OA received an intra-articular BMAC injection into the knee. During the 5-year follow-up, four patients (5 knees) dropped out, and patients who underwent secondary operation were also excluded to eliminate bias. Finally, the remaining 25 patients (47 knees) were investigated in the present study (Fig. 1).

Figure 1. Study cohort.

Baseline data of the enrolled patients are presented in Table 1.

Table 1. Demographic data.

The time point at which the data assessed was when all patients had a minimum follow-up of 5 years after BMAC injection. Values are presented as mean ± standard deviation or median (range). BMI, body mass index; OA, osteoarthritis; K-L grade, Kellgren-Lawrence grade

Statistics:

Again, I can not see if you adjusted p-values. Please report which adjustment method (e.g. Bonferroni) you used.

Response: We have agreed with your opinion. We have revised the statistical analysis section. Moreover, we have added the statistical method used in the result section. Thank you.

Page 3, Line 123-130: Statistical evaluation was performed using the IBM SPSS software (Version 22, IBM Corp., Armonk, NY, USA. Continuous data are expressed as means with standard deviation. All dependent variables were tested for normality of distribution and equality of variances by using the Kolmogorov-Smirnov test. According to normality, parametric or non-parametric tests were utilized. Fisher’s exact test (or chi-square test) was used for categorical variables. Repeated measures ANOVA was used to analyze significant differences between the groups over the 5-year study period. Post hoc analysis was performed to using paired t-tests with significance set at P < 0.01 (=0.05/5) incorporating a Bonferroni correction to correct for multiple analysis.

Reviewer 2:

Authors answered my comments and suggestions. Thanks for that. 

Response: We deeply appreciate your thoughtful response.

Reviewer 2 Report

Authors answered my comments and suggestions. Thanks for that. 

Author Response

Authors answered my comments and suggestions. Thanks for that. 

Response: We deeply appreciate your thoughtful response.

Author Response File: Author Response.doc