Influence of chitosan and chitosan oligosaccharide on dual antibiotic-loaded bone cement: In vitro evaluations

Saran Tantavisut; Jiraporn Leanpolchareanchai; Amaraporn Wongrakpanich

doi:10.1371/journal.pone.0276604

Peer Review History

Original SubmissionMay 22, 2022
13 Jun 2022 Decision Letter - Syed Mahmood, Editor PONE-D-22-14809Influence of chitosan and chitosan oligosaccharide on dual antibiotic-loaded bone cement: in vitro evaluationsPLOS ONE Dear Dr. Wongrakpanich, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Jul 28 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. 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Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. [Note: HTML markup is below. Please do not edit.] 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 ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: N/A ****** 3. 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Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: No ****** 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: 1. Language and grammar need to be improved. Many sentences are missing adjectives, and articles are not properly formatted, making them difficult to understand. Also, a few references cited in the text are incomplete. 2. The following sentences seem repetitive. Authors are kindly advised to improve the sentence structure to avoid confusion and improve readability. Polymethylmethacrylate (PMMA) bone cement has many important roles in orthopaedics. It’s also played an imminent role in the treatment of orthopaedic infection. In the current practice, ALBC is used as a prophylaxis to prevent prosthetic joint infections (PJIs) in total joint arthroplasty. Moreover, ALBC is also used to treat orthopaedic infections such as PJIs and chronic osteomyelitis. 3. “To prepare the Ch and the ChO mixed bone cement samples, different amounts of Ch and ChO were added to the polymethylmethacrylate matrix with three concentrations (1%, 5%, and 10%)”. Authors kindly specify the basis for the selection of the aforementioned conditions. Also, comment on why only three concentrations were taken. 4. As mentioned in the introduction section manual mixing has several limitations. Still, the technique followed for the present work is manual mixing. Authors kindly justify why this is selected. 5. For antibacterial activity why only S. aureus and MRSA were considered. Are they predominant causative agents for orthopaedic infection? Authors kindly comment. 6. Why is it preferable to use a pre-warmed PBS for drug elution assay? ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: Yes: Zeenat Iqbal ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. Attachments Attachment Submitted filename: review comments.docx https://doi.org/10.1371/journal.pone.0276604.r001
Revision 1
20 Sep 2022 Author Response Reviewer #1 General comments: The submitted work is interesting as the author not only presented their work but has highlighted the limitations of the study. A few minor revisions were suggested. Specific comments/questions: 1. Language and grammar need to be improved. Many sentences are missing adjectives, and articles are not properly formatted, making them difficult to understand. Also, a few references cited in the text are incomplete. Response: We have corrected spelling, grammar, and punctuation errors in the document. We also rewrote a few sentences. All changes were tracked. We also thoroughly reviewed the references. 2. The following sentences seem repetitive. Authors are kindly advised to improve the sentence structure to avoid confusion and improve readability. Polymethylmethacrylate (PMMA) bone cement has many important roles in orthopaedics. It’s also played an imminent role in the treatment of orthopaedic infection. In the current practice, ALBC is used as a prophylaxis to prevent prosthetic joint infections (PJIs) in total joint arthroplasty. Moreover, ALBC is also used to treat orthopaedic infections such as PJIs and chronic osteomyelitis. Response: We agreed with the reviewer and changed the sentences to improve readability (Location page 4 line 60-61 and Location page 4 line 63-66). 3. “To prepare the Ch and the ChO mixed bone cement samples, different amounts of Ch and ChO were added to the polymethylmethacrylate matrix with three concentrations (1%, 5%, and 10%)”. Authors kindly specify the basis for the selection of the aforementioned conditions. Also, comment on why only three concentrations were taken. Response: Since there have been no existing studies on chitosan oligosaccharides and PMMA bone cement, we chose these parameters based on earlier works of chitosan by Dunne et al. (1), Tunney et al. (2), and Tan et al. (3). Incorporating new material into bone cement may impair its mechanical properties. Dunne et al. used three different concentrations of chitosan (1, 3, and 5% w/w) in bone cement. The mechanical properties of bone cements mixed with chitosan were significantly reduced after the degradation period, especially in the 5%w/w chitosan group (1). Tunney et al. also found that the mechanical properties of bone cement containing chitosan (5% w/w) were significantly reduced. According to Tan et al., although mixing chitosan (in the form of quaternised chitosan) with bone cement at the concentration of 20% w/w would reduce the mechanical properties, the bone cement mixtures still passed the ISO 5883-2002 (3). Considering these data, three concentrations of Ch and ChO were chosen, covering the concentration ranging from 1 to 10% w/w. Low concentrations (1 and 5% w/w) were concentrations that were used previously. High concentration (10% w/w) was in the middle between studies conducted by Dunne et al., Tunney et al. and Tan et al. 4. As mentioned in the introduction section manual mixing has several limitations. Still, the technique followed for the present work is manual mixing. Authors kindly justify why this is selected. Response: Despite the fact that various procedures, such as vacuum mixing, have been available for many years, surgeons continue to mix antibiotic-loaded bone cement (ALBC) by hand using only a mixing bowl and a spatula. In almost all cases, hand mixing is the primary technique used in operating rooms in Thailand. As a result, hand mixing was employed in this study to simulate real-life situations. In terms of manual mixing powder, this study requires hand-mixing chitosan or chitosan oligosaccharides with PMMA powder before mixing the powder with liquid. This is due to the lack of commercially available ALBC containing chitosan or chitosan oligosaccharides. 5. For antibacterial activity why only S. aureus and MRSA were considered. Are they predominant causative agents for orthopaedic infection? Authors kindly comment. Response: Yes, they are the most common pathogen in orthopaedic surgical site infections. According to a review by Saadatian-Elahi et al. (4), 20% of surgical site infections from studies found in the MEDLINE literature were primarily caused by S. aureus. In Germany, S. aureus caused approximately one-third of postoperative surgical site infections (5). With the widespread use of penicillin, S. aureus has developed antibiotic resistance. Latha et al. (6) found that among pathogens in orthopaedic infection, MRSA is the leading pathogen in India. MRSA is also a common pathogen associated with surgical site infection in Japan (7) and China (8). These details have been added to the manuscript to clarify the bacteria selection in the study (Location page 14, line 324-325). 6. Why is it preferable to use a pre-warmed PBS for drug elution assay? Response: The process of drug release varies depending on many factors, such as surface-area-to-volume ratio, drug/carrier interactions, and environmental factors (pH, temperature). Increasing the temperature of the system often increases drug release (9). For the drug elution assay, the temperature of the medium was set to body temperature (37°C). The PBS was removed and replaced with pre-warmed PBS (37°C) at a predetermined time. Although changing PBS at the volume of 1 mL in 30 mL was considered a small volume, replacing it with 1 mL of new PBS may cause the system temperature to change if the PBS was cold. To eliminate this potential variable, the PBS should be pre-warmed. References 1. Dunne N, Buchanan F, Hill J, Newe C, Tunney M, Brady A, et al. In vitro testing of chitosan in gentamicin-loaded bone cement: no antimicrobial effect and reduced mechanical performance. Acta Orthop. 2008;79(6):851-60. 2. Tunney MM, Brady AJ, Buchanan F, Newe C, Dunne NJ. Incorporation of chitosan in acrylic bone cement: effect on antibiotic release, bacterial biofilm formation and mechanical properties. J Mater Sci Mater Med. 2008;19(4):1609-15. 3. Tan H, Ao H, Ma R, Tang T. Quaternised chitosan-loaded polymethylmethacrylate bone cement: Biomechanical and histological evaluations. J Orthop Translat. 2013;1(1):57-66. 4. Saadatian-Elahi M, Teyssou R, Vanhems P. Staphylococcus aureus, the major pathogen in orthopaedic and cardiac surgical site infections: a literature review. Int J Surg. 2008;6(3):238-45. 5. Hardtstock F, Heinrich K, Wilke T, Mueller S, Yu H. Burden of Staphylococcus aureus infections after orthopedic surgery in germany. BMC Infect Dis. 2020;20(1):233. 6. Latha T, Anil B, Manjunatha H, Chiranjay M, Elsa D, Baby N, et al. MRSA: The leading pathogen of orthopedic infection in a tertiary care hospital, South India. Afr Health Sci. 2019;19(1):1393-401. 7. Fukuda H, Sato D, Iwamoto T, Yamada K, Matsushita K. Healthcare resources attributable to methicillin-resistant Staphylococcus aureus orthopedic surgical site infections. Sci Rep. 2020;10(1):17059. 8. Yang Z, Wang J, Wang W, Zhang Y, Han L, Zhang Y, et al. Proportions of Staphylococcus aureus and methicillin-resistant Staphylococcus aureus in patients with surgical site infections in mainland China: a systematic review and meta-analysis. PLoS One. 2015;10(1):e0116079. 9. Paarakh MP, Jose PA, Setty C, Christoper G. Release kinetics–concepts and applications. Int J Pharm Res Technol. 2018;8(1):12-20. Attachments Attachment Submitted filename: 220830 Response to reviewers_PLoSOne.docx https://doi.org/10.1371/journal.pone.0276604.r002
11 Oct 2022 Decision Letter - Syed Mahmood, Editor Influence of chitosan and chitosan oligosaccharide on dual antibiotic-loaded bone cement: in vitro evaluations PONE-D-22-14809R1 Dear Dr. Wongrakpanich, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Syed Mahmood Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0276604.r003
Formally Accepted
18 Nov 2022 Acceptance Letter - Syed Mahmood, Editor PONE-D-22-14809R1 Influence of chitosan and chitosan oligosaccharide on dual antibiotic-loaded bone cement: in vitro evaluations Dear Dr. Wongrakpanich: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Syed Mahmood Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0276604.r004

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