A promising material for bone repair: PMMA bone cement modified by dopamine-coated strontium-doped calcium polyphosphate particles

Polymethyl methacrylate (PMMA) bone cement has been widely used in clinics as bone repair materials for its excellent mechanical properties and good injection properties. However, it also has defects such as poor biological performance, high temperature, and the monomer has certain toxicity. Our study tried to modify the PMMA bone cement by doping with various particle weight fractions (5, 10 and 15%) of SCPP particles and polydopamine-coated SCPP particles (D/SCPP) to overcome its clinical application disadvantages. Our study showed that all results of physical properties of samples are in accordance with ISO 5833. The 15% D/SCPP/PMMA composite bone cement had much better biocompatibility compared with pure PMMA bone cement and SCPP/PMMA composite bone cement due to the best cell growth-promoting mineralization deposition on the surface of 15% D/SCPP/PMMA composite bone cements and Sr2+ released from SCPP particles. Our research also revealed that the reaction temperature was found to be reduced with an increase in doped particles after incorporating the particles into composite bone cements. The novel PMMA bone cements modified by D/SCPP particles are promising materials for bone repair.


Recommendation?
Accept with minor revision (please list in comments)

Comments to the Author(s)
The manuscript describes coating of DOPA as an additional layer on SCCP/PMMA bone cements to improve biocomaptibility and stability issues of bone cements that can be used in bone repair. The production method and characterization data is satisfactory and the manuscript can be published in RSOS. However, there minor points to consider about the figures.

Do you have any ethical concerns with this paper? No
Have you any concerns about statistical analyses in this paper? No

Comments to the Author(s)
The novelty of this manuscript is sort of low. Authors lacked of tests in characterizing the synthesized materials and showing enough biological effects, leaving a superficial analysis far from completion. Animal models should be examined and included in this study as in vitro cell study could not convince the suitability of this materials for bone repair. For this reason, I do not see many novelty in this manuscript.

Review form: Reviewer 3 (Wenbo Zhou)
Is the manuscript scientifically sound in its present form? Yes 1. In the summary, "…the reaction temperature was found to reduce with an increase…" should be "…the reaction temperature was found to be reduced with an increase…". Please also check the grammar in the context. 2. In the introduction, the authors stated that 8% SCPP was used, while in the material section, 5%, 10%, 15% were tested. These information is inconsistent. 3. Image resolution needs improving. For example, it is difficult to ready the labels in Fig. 4. 4. The authors inferred that the D/SCPP/PMMA composite bone cements had better mechanical properties than the SCPP/PMMA composite bone cements. However, in Fig 5, their flexural strength/modolus is similar. 5. In the results, 15% doping was demonstrated to be the optimal for the biological activity. However, in the summary section, the authors stated that "the biological and physicochemical properties of this 8% SCPP particles/PMMA composite bone cement were systematically researched". The editor assigned to your manuscript has now received comments from reviewers. We would like you to revise your paper in accordance with the referee and Subject Editor suggestions which can be found below (not including confidential reports to the Editor). Please note this decision does not guarantee eventual acceptance.
Please submit your revised paper before 14-Aug-2019. Please note that the revision deadline will expire at 00.00am on this date. If we do not hear from you within this time then it will be assumed that the paper has been withdrawn. In exceptional circumstances, extensions may be possible if agreed with the Editorial Office in advance. We do not allow multiple rounds of revision so we urge you to make every effort to fully address all of the comments at this stage. If deemed necessary by the Editors, your manuscript will be sent back to one or more of the original reviewers for assessment. If the original reviewers are not available we may invite new reviewers.
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Once again, thank you for submitting your manuscript to Royal Society Open Science and I look forward to receiving your revision. If you have any questions at all, please do not hesitate to get in touch. ********************************************** RSC Associate Editor: Comments to the Author: (There are no comments.) RSC Subject Editor: Comments to the Author: (There are no comments.) ********************************************** Reviewers' Comments to Author: Reviewer: 1 Comments to the Author(s) The manuscript describes coating of DOPA as an additional layer on SCCP/PMMA bone cements to improve biocomaptibility and stability issues of bone cements that can be used in bone repair. The production method and characterization data is satisfactory and the manuscript can be published in RSOS. However, there minor points to consider about the figures.  Comments to the Author(s) The novelty of this manuscript is sort of low. Authors lacked of tests in characterizing the synthesized materials and showing enough biological effects, leaving a superficial analysis far from completion. Animal models should be examined and included in this study as in vitro cell study could not convince the suitability of this materials for bone repair. For this reason, I do not see many novelty in this manuscript.

Reviewer: 3
Comments to the Author(s) Review of "A promising material for bone repair: PMMA Bone Cement Modified by Dopaminecoated Strontium-doped Calcium Polyphosphate Particles" for Royal Society Open Science: This manuscript reported a new type of biofunctional composite composing DSCPP PAs and PMMA matrix, and evaluated its physicochemical properties and bio-activity. It requires some revisions before acceptance. Below are some of my comments.
1.In the summary, "…the reaction temperature was found to reduce with an increase…" should be "…the reaction temperature was found to be reduced with an increase…". Please also check the grammar in the context. 2.In the introduction, the authors stated that 8% SCPP was used, while in the material section, 5%, 10%, 15% were tested. These information is inconsistent. 3.Image resolution needs improving. For example, it is difficult to ready the labels in Fig. 4. 4.The authors inferred that the D/SCPP/PMMA composite bone cements had better mechanical properties than the SCPP/PMMA composite bone cements. However, in Fig 5, their flexural strength/modolus is similar. 5.In the results, 15% doping was demonstrated to be the optimal for the biological activity. However, in the summary section, the authors stated that "the biological and physicochemical properties of this 8% SCPP particles/PMMA composite bone cement were systematically researched".

Author's Response to Decision Letter for (RSOS-191028.R0)
See Appendix A.

Recommendation?
Accept as is Comments to the Author(s) After author corrections, the manuscript is appropriate to be published in Royal Society Open Science.

Dear Editor,
We would like to thank Royal Society Open Science for giving us the opportunity to revise our manuscript "A promising material for bone repair: PMMA Bone Cement Modified by Dopamine-coated Strontium-doped Calcium Polyphosphate Particles", ID: RSOS-191028. We thank the reviewers for their careful read and thoughtful comments on previous draft. We have carefully taken their comments into consideration in preparing our revision. The following are the responses to the comments.

Xixun Yu
Reviewer: 1 Major comments 1. Figure 4, 5, 8 is too small,statistically significant data sets are difficult to be observed. 2. Figure 7 is a SEM or confocal microscopy image? Scale bars are impossible to be seen.

Response
Thank you very much for your comments. Your comments are critical to this manuscript. Below are our responses to your valuable comments: 1. We are very sorry for this mistake. The size and resolution of all images have been revised, including Figure 4, 5, 8. 2. Figure.7 is the confocal microscopy image, not the SEM image. We wrote a wrong legend for this figure and it has been revised in revised manuscript. Each scale bar is 200um. The image size must be reduced due to limitations on space, therefore, the scale bar is also reduced and not easy to be seen.

Reviewer: 2 Major comments
The novelty of this manuscript is sort of low. Authors lacked of tests in characterizing the synthesized materials and showing enough biological effects, leaving a superficial analysis far from completion. Animal models should be examined and included in this study as in vitro cell study could not convince the suitability of this materials for bone repair. For this reason, I do not see many novelty in this manuscript.

Response
Thank you for your suggestion, all your suggestions are very important, they have important guiding significance for this manuscript and our future scientific research. Below are our responses to your valuable comments: 1. Although some ceramic particles (including hydroxyapatite, tricalcium phosphate, SiO 2 , etc.) are added into PMMA to improve the performance of PMMA, the biological effects of these particles are considerably lower than SCPP particles used in this study. Our previous studies showed that SCPP can greatly promote the growth of osteoblasts, and it also had a good stimulatory effect on the secretion of angiogenic growth factors (including VEGF and bFGF) by