Low-Temperature Spine-Specific PMMA Enhances Bone Regeneration via Localized Thermal Necrosis in an Osteoporotic Rat Model
, Md Abdul Khaleque, Ga-Hyun Kim, Sang-Eun Park, Hwan-Hee Lee *,†and Young-Yul Kim *,†Round 1
Reviewer 1 Report
Comments and Suggestions for Authors- The abstract states that spine-specific PMMA enhances bone regeneration via localized thermal necrosis but does not explicitly define the novelty compared to existing low-temperature PMMA formulations. Clarify how this formulation differs from prior products (e.g., composition, polymerization kinetics).
- While osteoporosis and PMMA limitations are well-discussed, the rationale for choosing spine-specific PMMA over other bioactive cements (e.g., calcium phosphate) is insufficient. Justify its selection with references to prior comparative studies.
- The sample size (n=8 per group) is small for in vivo studies？ Include a power analysis to validate statistical reliability or acknowledge this limitation. Is it reasonable?
- The study focuses on 12-week outcomes but omits long-term safety (e.g., chronic inflammation, PMMA degradation). Acknowledge this gap in the Discussion.
- The peak polymerization temperature of spine-specific PMMA is stated as "below 100°C" but not quantified. Provide exact temperature measurements during curing.
- No direct comparison is made between spine-specific PMMA and conventional PMMA in the same model. Include a control group with traditional PMMA to highlight its advantages.
- While the results are promising, the Discussion lacks a roadmap for clinical trials (e.g., dosage optimization, large-animal studies). Propose specific next steps.
- The study presents a compelling case for spine-specific PMMA as a dual-functional biomaterial. Addressing these points will strengthen mechanistic insights, methodological rigor, and translational relevance.
- The latest article about “"Spine-specific PMMA formulations have been developed to control exothermic reactions and reduce the peak polymerization temperature to below 100∘C." (Page 2)" should be cited for great correlations with the discusses about the statement connects to the development of fluorine-free, bioinspired anti-corrosion coatings because both studies focus on material engineering to optimize thermal/chemical properties—here, controlling exothermic reactions in PMMA parallels the design of hydrophobic coatings through nanoparticle modification to achieve desired functional outcomes.------ “Robust, fluorine-free, bioinspired PU superhydrophobic composite coating based on modified ceramics nanoparticle: Preparation, characterization and mechanism[J]. Progress in Organic Coatings, 2025, 204: 109226.”
Author Response
Dear Editor-in-Chief
International Journal of Molecular Sciences,
On behalf of all authors, I would like to express our sincere gratitude for the insightful comments and suggestions regarding our manuscript (ID: ijms-3625781) entitled “Low-Temperature Spine-Specific PMMA Enhances Bone Regeneration via Localized Thermal Necrosis in an Osteoporotic Rat Model.”
We have thoroughly revised the manuscript based on the reviewer’s feedback. All changes and additions have been clearly marked in colored text in the revised Word document for your convenience.
Thank you for your thoughtful consideration.
Sincerely,
Young-Yul Kim
May 9, 2025
Reviewer-1
Reviewer Comments: The abstract states that spine-specific PMMA enhances bone regeneration via localized thermal necrosis but does not explicitly define the novelty compared to existing low-temperature PMMA formulations. Clarify how this formulation differs from prior products (e.g., composition, polymerization kinetics).
Author’s response: Thank you for your valuable feedback. We have incorporated this information into our abstract to the best extent possible
Reviewer Comments: While osteoporosis and PMMA limitations are well-discussed, the rationale for
choosing spine-specific PMMA over other bioactive cement (e.g., calcium phosphate) is insufficient. Justify its selection with reference to prior comparative studies
Author’s response: we appreciate your valuable comments. Spine-specific PMMA was chosen due to its clinically proven mechanical strength and lower exothermic reaction, offering better handling and reduced thermal damage compared to calcium phosphate cements
Reviewer Comments: The sample size (n=8 per group) is small for in vivo studies？ Include a power analysis to validate statistical reliability or acknowledge this limitation. Is it reasonable?
Author’s response: We sincerely appreciate your constructive feedback. We are committed to minimizing animal use whenever possible and ensured that no samples were wasted, which we believe justifies our approach
Reviewer Comments: The study focuses on 12-week outcomes but omits long-term safety (e.g., chronic inflammation, PMMA degradation). Acknowledge this gap in the Discussion
Author’s response: Thank you for your valuable comments. We have addressed this section in accordance with your suggestions.
Reviewer Comments: The peak polymerization temperature of spine-specific PMMA is stated as "below 100°C" but not quantified. Provide exact temperature measurements during curing.
Author’s response: We appreciate your insightful comments and have revised this section accordingly based on your suggestions.
Reviewer Comments: No direct comparison is made between spine-specific PMMA and conventional PMMA in the same model. Include a control group with traditional PMMA to highlight its advantages.
Author’s response: Thank you for your insightful comments. We have completed our current projects; however, we have a secondary plan involving PMMA, which we aim to explore in our upcoming project.
Reviewer Comments: While the results are promising, the Discussion lacks a roadmap for clinical trials (e.g., dosage optimization, large-animal studies). Propose specific next steps.
Author’s response: Thank you for your comments. We have tried to address and incorporate your suggestions in our discussion.
Reviewer Comments: The study presents a compelling case for spine-specific PMMA as a dual-functional biomaterial. Addressing these points will strengthen mechanistic insights, methodological rigor, and translational relevance.
Author’s response: Thank you for your comments. We have incorporated your suggestion into the manuscript.
Reviewer Comments: The latest article about “"Spine-specific PMMA formulations have been developed to control exothermic reactions and reduce the peak polymerization temperature to below 100∘C." (Page 2)" should be cited for great correlations with the discusses about the statement connects to the development of fluorine-free, bioinspired anti-corrosion coatings because both studies focus on material engineering to optimize thermal/chemical properties—here, controlling exothermic reactions in PMMA parallels the design of hydrophobic coatings through nanoparticle modification to achieve desired functional outcomes.------ “Robust, fluorine-free, bioinspired PU superhydrophobic composite coating based on modified ceramics nanoparticle: Preparation, characterization and mechanism[J]. Progress in Organic Coatings, 2025, 204: 109226.
Author’s response: Thank you for your valuable comment. We have included relevant information in our manuscript as suggested. However, upon thorough review, we found that the specific focus and context of the referenced paper differ from the scope of our study. As a result, we believe it may not be appropriate to directly cite this particular article. Nonetheless, we appreciate the suggestion and its relevance to material engineering approaches.
Reviewer 2 Report
Comments and Suggestions for Authors
General characteristics and evaluation of the reviewed scientific article:
The article addresses an important clinical problem in the treatment of osteoporotic vertebral fractures and presents a novel approach using a low-temperature variety of PMMA cement. The authors conducted in vivo studies in a rat model using molecular, imaging and histopathological methods to evaluate the effect of spine-specific PMMA on bone regeneration. The results suggest that moderate thermal necrosis can induce an osteogenic response. Although the paper has great cognitive value and translational potential, it contains significant methodological, interpretive and linguistic shortcomings.
The paper is interesting, written generally correctly, its structure corresponds to the typical structure of scientific papers, but the article requires major corrections and additions to both content and references before further processing and acceptance for publication. Below are my detailed comments and observations.
Minor comments:
The introduction lacks discussion of several critical factors affecting the mechanical properties of PMMA bone cements. Key variables—such as mixing methods, typical surgical contaminants (e.g., blood, bone fragments, saline), and slight deviations in component ratios—can significantly influence performance.
Additionally, biological responses, including bone–cement interactions and adaptive mechanisms like osseointegration and remodeling, are essential for long-term success and should be addressed. The role of solid-phase additives (e.g., ceramic particles, bioactive glass), which enhance mechanical strength and osteointegration, also warrants mention.
These aspects are thoroughly examined in the following series: The effect of various additives on selected mechanical properties of medium-viscosity bone cements: Part 1, 2 and 3, which should be cited to ensure a more balanced and complete introduction.
The article relies on the hypothesis of local thermal necrosis as a mechanism to induce osteogenesis, but no direct temperature measurements during cement polymerization in vivo are presented. The authors should add temperature measurements in bone tissue during PMMA application in an animal model or refer to previous studies with specific temperature values and exposure times. I would also recommend expanding the discussion with a discussion of factors that can lower the temperature without disrupting the cement polymerization process such as solid admixtures or the use of saline rinses.
The authors used rat tail vertebrae, which do not correspond to the biomechanical conditions of the human spine. I recommend discussing in detail the translational limitations of the model in a broader biomechanical context and suggesting future research on models more similar to humans (e.g., the lumbar spine of large animals).
The article often refers in general terms to osteoblast activation by heat stress, but does not provide mechanistic depth (e.g., analysis of HSP70, ERK, Wnt in vivo is missing). The discussion section should be expanded to include analysis of potential signaling pathways and, if possible, supplement the study with expression levels of HSP70 or ERK/Wnt proteins.
The study used small experimental groups (n = 8), which limits the statistical power of the results. Consideration should be given to expanding the study to include a larger number of animals or conducting power analysis (power analysis) for the data presented.
Observations were terminated after 12 weeks, which does not allow assessment of the stability of the biological and mechanical effects of PMMA. Further long-term studies are needed, taking into account, for example, inflammatory reactions, fibrosis and potential material degradation. Please expand on the description of limitations and plans for further research.
In many places, the text contains stylistic and syntactic errors in English (e.g., repetitions, unclear wording, incorrect syntax). The article should undergo professional language proofreading before publication.
I congratulate the authors on their interesting study and wish you continued success.
Comments on the Quality of English Language
In many places, the text contains stylistic and syntactic errors in English (e.g., repetitions, unclear wording, incorrect syntax). The article should undergo professional language proofreading before publication.
Author Response
Dear Editor-in-Chief
International Journal of Molecular Sciences,
On behalf of the authors of Manuscript ID: ijms-3625781, titled “Low-Temperature Spine-Specific PMMA Enhances Bone Regeneration via Localized Thermal Necrosis in an Osteoporotic Rat Model,” I would like to express my sincere appreciation for the valuable comments and suggestions provided by the reviewer.
In response to the reviewer’s feedback, we have carefully revised the manuscript accordingly. All modifications and additions have been highlighted in colored text within the revised Word document for clarity.
Thank you for your kind consideration.
Sincerely,
Young-Yul Kim
May 09, 2025
Reviewer-2
Reviewer Comments: The introduction lacks discussion of several critical factors affecting the mechanical properties of PMMA bone cements. Key variables—such as mixing methods, typical surgical contaminants (e.g., blood, bone fragments, saline), and slight deviations in component ratios—can significantly influence performance.
Author’s response: Thank you for your valuable feedback. We have included the suggested information in our manuscript accordingly.
Reviewer Comments: Additionally, biological responses, including bone–cement interactions and adaptive mechanisms like osseointegration and remodeling, are essential for long-term success and should be addressed. The role of solid-phase additives (e.g., ceramic particles, bioactive glass), which enhance mechanical strength and osteointegration, also warrants mention.
Author’s response: We appreciate your thoughtful feedback. The recommended information has been incorporated into our manuscript accordingly.
Reviewer Comments: These aspects are thoroughly examined in the following series: The effect of various additives on selected mechanical properties of medium-viscosity bone cements: Part 1, 2 and 3, which should be cited to ensure a more balanced and complete introduction.
Author’s response: Thank you for your constructive feedback. We have updated our manuscript to include the suggested information.
Reviewer Comments: The article relies on the hypothesis of local thermal necrosis as a mechanism to induce osteogenesis, but no direct temperature measurements during cement polymerization in vivo are presented. The authors should add temperature measurements in bone tissue during PMMA application in an animal model or refer to previous studies with specific temperature values and exposure times. I would also recommend expanding the discussion with a discussion of factors that can lower the temperature without disrupting the cement polymerization process such as solid admixtures or the use of saline rinses.
Author’s response: Thank you for your helpful feedback. We have revised the manuscript to reflect the suggested additions
Reviewer Comments: The authors used rat tail vertebrae, which do not correspond to the biomechanical conditions of the human spine. I recommend discussing in detail the translational limitations of the model in a broader biomechanical context and suggesting future research on models more similar to humans (e.g., the lumbar spine of large animals).
Author’s response: Thank you for your valuable comments. We have provided a future research direction and suggested an animal model that closely resembles human physiology.
Reviewer Comments: The article often refers in general terms to osteoblast activation by heat stress, but does not provide mechanistic depth (e.g., analysis of HSP70, ERK, Wnt in vivo is missing). The discussion section should be expanded to include analysis of potential signaling pathways and, if possible, supplement the study with expression levels of HSP70 or ERK/Wnt proteins.
Author’s response: Thank you for your comments. We made an effort to find relevant information that is incorporated in vivo, but unfortunately, we were unable to locate any.
Reviewer Comments: The study used small experimental groups (n = 8), which limits the statistical power of the results. Consideration should be given to expanding the study to include a larger number of animals or conducting power analysis (power analysis) for the data presented.
Author’s response: We greatly appreciate your constructive feedback. We are dedicated to minimizing animal use whenever feasible and have ensured that no samples were wasted, which we believe supports the validity of our approach.
Reviewer Comments: Observations were terminated after 12 weeks, which does not allow assessment of the stability of the biological and mechanical effects of PMMA. Further long-term studies are needed, taking into account, for example, inflammatory reactions, fibrosis and potential material degradation. Please expand on the description of limitations and plans for further research.
Author’s response: Thank you for your comments. We have included the long-term effects as per your suggestion.
Reviewer Comments: In many places, the text contains stylistic and syntactic errors in English (e.g., repetitions, unclear wording, incorrect syntax). The article should undergo professional language proofreading before publication.
Author’s response: Thank you for your comments. We have made efforts to improve our English and address other errors.
