Progressive Platelet Rich Fibrin tissue regeneration matrix: Description of a novel, low cost and effective method for the treatment of chronic diabetic ulcers—Pilot study

Carlos José Saboia-Dantas; Paula Dechichi; Roberto Lichtsztejn Fech; Rafael Vilhena de Carvalho Furst; Rodrigo Daminello Raimundo; João Antonio Correa

doi:10.1371/journal.pone.0284701

Peer Review History

Original SubmissionDecember 7, 2022
6 Feb 2023 Decision Letter - Prabhakar Orsu, Editor PONE-D-22-32724Progressive Platelet Rich Fibrin tissue regeneration matrix: Description of a novel, low cost and effective method for the treatment of chronic diabetic ulcers - Pilot studyPLOS ONE Dear Dr. Raimundo, 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 Mar 23 2023 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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If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Does the manuscript report a protocol which is of utility to the research community and adds value to the published literature? Reviewer #1: Yes ******** 2. Has the protocol been described in sufficient detail? To answer this question, please click the link to protocols.io in the Materials and Methods section of the manuscript (if a link has been provided) or consult the step-by-step protocol in the Supporting Information files. The step-by-step protocol should contain sufficient detail for another researcher to be able to reproduce all experiments and analyses. Reviewer #1: Yes ****** 3. Does the protocol describe a validated method? The manuscript must demonstrate that the protocol achieves its intended purpose: either by containing appropriate validation data, or referencing at least one original research article in which the protocol was used to generate data. Reviewer #1: Yes ****** 4. If the manuscript contains new data, have the authors made this data 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 #1: Yes ****** 5. Is the article 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 highlight any specific errors that need correcting in the box below. Reviewer #1: 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 #1: The authors present a small case series in which patients with diabetic complex foot wounds were healed using a new type of second-generation PRF. I have just some minor comments to add to this well-written study. 1. Introduction: “…but the complexity of obtaining them (15,15) a…” Was there another reference to be inserted? 2. Introduction: “In addition, PRP offers limited benefits for the treatment of refractory ulcers as well as extensive and complex wounds (15).” I would say that is a little misleading. See for example: Meznerics FA, Fehérvári P, Dembrovszky F, Kovács KD, Kemény LV, Csupor D, Hegyi P, Bánvölgyi A. Platelet-Rich Plasma in Chronic Wound Management: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. J Clin Med. 2022 Dec 19;11(24):7532. 3. Introduction: “In addition to the cells, a three-dimensional, functional extracellular matrix must be present, functioning as a strong framework. With PRP, such conditions do not exist, limiting its use in the treatment of extensive and complex wounds (16,17).” It depends on whether it’s used in combination with a fibrin or other type of matrix. That should be mentioned. 4. Methods: UCMI. Please define this acronym. Please also check that all acronyms are spelled out at first usage. 5. Inclusion criteria: Were there any limitations in regard to area, depth, or type of tissue exposed? 6. Methods: Did the wounds need debridement after the initial treatment? 7. Methods: “The PRO-PRF, still in the fluid phase…” I might suggest gel phase because if the term fluid is used it suggests a liquid to most clinicians. 8. Methods: “At the beginning of the treatment, as well as in all the returns, the lesions were photographed, the wound dimensions were measured, local signs of infection and, depending on the evolution of the wound, a new application of PRO-PRF or conventional dressing with sunflower oil was chosen.” I might suggest: “At the beginning of the treatment, as well as in all subsequent patient visits…” Is the sunflower oil dressing a commercial product (if so, please state). If not, please describe how it was made. 9. Did any of the wounds need offloading (i.e., they were anatomically plantar wounds? 10. Results: I would suggest to use only one decimal place. 11. Discussion: “Our pilot study had a cost between $200 and $800.” Do these values represent the lowest and highest costs? What exchange rate (US dollars vs Brazilian Reals) was used? ****** 7. 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: Marissa Janine Carter ******** [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. https://doi.org/10.1371/journal.pone.0284701.r001
Revision 1
20 Mar 2023 Author Response Dear Reviewer We very much appreciate you for your highly constructive reviews to our submission. We have revised the material to eliminate the issues raised. The added or modified words, phrases, and sentences are in red. We hope the present version can be accepted. Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Does the manuscript report a protocol which is of utility to the research community and adds value to the published literature? Reviewer #1: Yes Answer: Thank you 2. Has the protocol been described in sufficient detail? To answer this question, please click the link to protocols.io in the Materials and Methods section of the manuscript (if a link has been provided) or consult the step-by-step protocol in the Supporting Information files. The step-by-step protocol should contain sufficient detail for another researcher to be able to reproduce all experiments and analyses. Reviewer #1: Yes Answer: Thank you 3. Does the protocol describe a validated method? The manuscript must demonstrate that the protocol achieves its intended purpose: either by containing appropriate validation data, or referencing at least one original research article in which the protocol was used to generate data. Reviewer #1: Yes Answer: Thank you 4. If the manuscript contains new data, have the authors made this data 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 #1: Yes Answer: Thank you 5. Is the article 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 highlight any specific errors that need correcting in the box below. Reviewer #1: Yes Answer: Thank you 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 #1: The authors present a small case series in which patients with diabetic complex foot wounds were healed using a new type of second-generation PRF. I have just some minor comments to add to this well-written study. 1. Introduction: “…but the complexity of obtaining them (15,15) a…” Was there another reference to be inserted? Answer: The reference has been corrected. “…but the complexity of obtaining them (15,16) a…” 2. Introduction: “In addition, PRP offers limited benefits for the treatment of refractory ulcers as well as extensive and complex wounds (15).” I would say that is a little misleading. See for example: Meznerics FA, Fehérvári P, Dembrovszky F, Kovács KD, Kemény LV, Csupor D, Hegyi P, Bánvölgyi A. Platelet-Rich Plasma in Chronic Wound Management: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. J Clin Med. 2022 Dec 19;11(24):7532. Answer: Thanks for the comment. The sentence has been rewritten and the reference has been included. “Currently, many Platelets Rich Plasma (PRP) methods are still commercialized and find applications in the treatment of skin wounds (15). PRP represents the first generation of blood concentrates, but the complexity of obtaining it (15,16) and the cost of application per treatment session make this technology inaccessible to most patients, however, PRP offers benefits for the treatment of ulcers refractory wounds, as well as extensive and complex wounds (15), is a safe and effective modality to improve wound healing and can improve the quality of life of these patients (17). A concept of broad versatility has been attributed to platelets, in addition to hemostatic activities, as indispensable structures for numerous physiological responses, including angiogenesis, inflammation, innate immunity and wound healing (9).” 3. Introduction: “In addition to the cells, a three-dimensional, functional extracellular matrix must be present, functioning as a strong framework. With PRP, such conditions do not exist, limiting its use in the treatment of extensive and complex wounds (16,17).” It depends on whether it’s used in combination with a fibrin or other type of matrix. That should be mentioned. Answer: Thanks for the comment. The sentence has been rewritten. In addition to the cells, a three-dimensional and functional extracellular matrix must be present, functioning as a strong structure. With PRP, such conditions do not exist, limiting its use in the treatment of extensive and complex wounds when used alone (16,18), however, this can be mitigated with the use in combination with a fibrin or another type of matrix (17). 4. Methods: UCMI. Please define this acronym. Please also check that all acronyms are spelled out at first usage. Answer: It was a typing error, thanks. “Patients over the age of 18 years, with chronic lower limb ulcer (CLLU) of diabetic etiology…” 5. Inclusion criteria: Were there any limitations in regard to area, depth, or type of tissue exposed? 6. Methods: Did the wounds need debridement after the initial treatment? Answer: Thanks for the comment. The sentence has been rewritten. “Patients over the age of 18 years, with chronic lower limb ulcer (CLLU) of diabetic etiology, without macroangiopathic ischemic disease, without active infection after debridement, without limitations in regard to area, depth or type of tissue exposed, and with sociocognitive ability to follow the treatment and care protocol were included in this study. Patients with ulcers of other etiologies were excluded.” 7. Methods: “The PRO-PRF, still in the fluid phase…” I might suggest gel phase because if the term fluid is used it suggests a liquid to most clinicians. Answer: Thanks for the comment. The term has been changed “The PRO-PRF, still in the gel phase, was immediately inoculated at the edges of the CLLU and deposited on the wound surface. In the subsequent step, the PRO-PRF membrane was implanted into the wound bed and fixed and stabilized using cyanoacrylate adhesive (Figure 2).” 8. Methods: “At the beginning of the treatment, as well as in all the returns, the lesions were photographed, the wound dimensions were measured, local signs of infection and, depending on the evolution of the wound, a new application of PRO-PRF or conventional dressing with sunflower oil was chosen.” I might suggest: “At the beginning of the treatment, as well as in all subsequent patient visits…” Answer: Thanks for the comment. The term has been changed. “The PVC cover remained on for 7 days and the secondary dressing was changed daily. The patients were followed up in the outpatient clinic weekly. At the beginning of the treatment, as well as in all subsequent patient visits,…” Is the sunflower oil dressing a commercial product (if so, please state). If not, please describe how it was made. Answer: Thanks for the comment. The description was made. “The PVC cover remained on for 7 days and the secondary dressing was changed daily. The patients were followed up in the outpatient clinic weekly. At the beginning of the treatment, as well as in all subsequent patient visits, the lesions were photographed, the wound dimensions were measured, local signs of infection and, depending on the evolution of the wound, a new application of PRO-PRF or conventional dressing with caprylic/capric triglyceride (typically sourced from coconut oil or sunflower) oil was chosen.” 9. Did any of the wounds need offloading (i.e., they were anatomically plantar wounds? Answer: Thanks for the comment. The sentence has been rewritten. Three cases, all male, were included in this pilot study. Their ages ranged from 51 to 57 years, with a mean of 54 years. They were treated in a period from May 2022 to August 2022. They had type II diabetes mellitus with diagnoses ranging from five to 16 years. All patients in the sample had chronic diabetic ulcers that were difficult to heal for a period ranging from 12 to 32 weeks. In this sample, all patients had a single wound, with a total of three ulcers. The ulcers were without infection and were previously treated with local care, systemic antibiotic therapy, and photodynamic therapy ranging from 2 to 4 sessions. The topography and dimensions of the initial lesions were right fourth polydactyl and right forefoot with an area of 37 cm2, left hallux amputation with an area of 15 cm2 and left metatarsal dorsal aspect of the foot with an area of 24 cm2. The treatment was performed over a period ranging from two to four weeks with an average treatment time of three weeks (Table 1). None of these three cases presented were offloading wound, however, this is not a contraindication of the technique. 10. Results: I would suggest to use only one decimal place. Answer: The manuscript has been revised and the decimal places have been changed “…15 cm2 and left metatarsal dorsal aspect of the foot with an area of 24 cm2” “… after the infection was eliminated, he started the proposed treatment with a 24 cm2 ulcer,..” “…After the first session the patients were reevaluated weekly and a reduction in the area of the wounds was observed. This reduction ranged from 20.4% to 54% with an average reduction of 36.6% of their area. After the second week, the reduction ranged from 17.6% to 25.6% with an average reduction of 22%. After the third week, this reduction ranged from 32% to 46% with an average reduction of 39%.” 11. Discussion: “Our pilot study had a cost between $200 and $800.” Do these values represent the lowest and highest costs? What exchange rate (US dollars vs Brazilian Reals) was used? Answer: We appreciate the comments. The discussion was reviewed by the authors Snyder and Ead (2020) conducted a study to analyze the cost-effectiveness of five advanced skin substitutes in the treatment of foot ulcers in patients with diabetes. The number of applications was also 12 weeks of treatment and the total cost ranged from $1245 to $7647. Our pilot study had a total cost (complete treatment) between $200 and $800 (depending on the number of sessions), which represents a low cost by Brazilian and international standards, even more so when compared to other regeneration matrices and industrialized dressings (33). 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: Marissa Janine Carter Answer: Dear Marissa Janine Carter. We very much appreciate you for your highly constructive reviews to our submission. We have revised the material to eliminate the issues raised. We hope the present version can be accepted. https://doi.org/10.1371/journal.pone.0284701.r002
6 Apr 2023 Decision Letter - Prabhakar Orsu, Editor Progressive Platelet Rich Fibrin tissue regeneration matrix: Description of a novel, low cost and effective method for the treatment of chronic diabetic ulcers - Pilot study PONE-D-22-32724R1 Dear Dr. Raimundo, 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, Prabhakar Orsu, PhD Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0284701.r003
Formally Accepted
25 Apr 2023 Acceptance Letter - Prabhakar Orsu, Editor PONE-D-22-32724R1 Progressive Platelet Rich Fibrin tissue regeneration matrix: Description of a novel, low cost and effective method for the treatment of chronic diabetic ulcers - Pilot study Dear Dr. Raimundo: 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. Prabhakar Orsu Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0284701.r004

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