Lubricant Strategies in Osteoarthritis Treatment: Transitioning from Natural Lubricants to Drug Delivery Particles with Lubricant Properties

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review provides an overview of joint physiology, followed by an indepth examination of the most recent advancements in lubricant-based therapies for OA. Authors make comprehensive review on lubricant strategies to treat OA. However, several improvements are recommended.

1.      Drug delivery is not the mainly concentrated topic. It is suggested to list the characteristics of each liposome sphere (e.g., friction coefficient). Comparisons are preferred rather than just listing article results. There are few perspectives and no discussion part in manuscript, and we suggest authors expressing personal prospects on the topic of review.

2.      Authors demonstrated a good view on Lubricant Strategies to Osteoarthritis, and views from the article (Applications of hydrogels in osteoarthritis treatment, Biomedicines, 2024, 12(4), 923) can be referred to improve the academic level of the review.

3.      Improvement of academic English writing is recommended.

Comments on the Quality of English Language

Improvement of academic English writing is recommended.

Author Response

Comments and Suggestions for Authors

This review provides an overview of joint physiology, followed by an indepth examination of the most recent advancements in lubricant-based therapies for OA. Authors make comprehensive review on lubricant strategies to treat OA. However, several improvements are recommended.

1. Drug delivery is not the mainly concentrated topic. It is suggested to list the characteristics of each liposome sphere (e.g., friction coefficient). Comparisons are preferred rather than just listing article results. There are few perspectives and no discussion part in manuscript, and we suggest authors expressing personal prospects on the topic of review.

Authors thank the reviewer for the overall evaluation of the work. We enriched the discussion portion of each of the paragraphs presenting different Drug Delivery Systems (DDS) with authors opinion and considerations on every specific topic:

• Non-HA based Hydrogels with superior Lubricant features.
• Micro-gels and Nano-gels.
• Innovative Liposomes based strategies for drug delivery and lubrication.

As for the main topic we would like to respectfully point out that the general aim of this work is to highlight the possible transition from the use of natural lubricants to the design of drug delivery systems with biolubricant features for restoring homeostasis in OA. Biolubrication is broadly recognized as essential to treat OA, but it’s often not sufficiently efficacious. Therefore, DDS with lubricant features can make the treatment more complete by granting at the same time the needed lubrication and the release of different payloads directly at the joint level. Of course, we also need to present natural lubricants, both as a starting point and as a possible parallel solution which is being anyway currently object of research and development. In summary, since both macro areas (biolubricants and DDS based lubricants) are currently object of research, we deliberately reported both to give a broad view on the main field in which research is moving with promising results. We personally believe the application of DDS could give a significant progression to find novel solution, some of the modification of the text are specifically finalized to strengthen our vision.

As for liposomes friction coefficient:

• In some papers there are no information on the friction coefficients and so it was not possible to report them. This is mainly due to the nature of the works, since many of them focus more on the in vivo outcome rather than on the formulation aspect.
• We included in the text all the information found in the cited papers which report data on friction coefficients (new ref 112, and new ref 114).
• For new ref 113 (which also reports friction coefficients) we preferred including the overall finding since the many comparisons the authors of the study made cannot be all reported into a review.

As for the liposomes characterization information we included the information available in the manuscripts we cited, we integrated the surface charge of liposomes in new reference 108.

2. Authors demonstrated a good view on Lubricant Strategies to Osteoarthritis, and views from the article (Applications of hydrogels in osteoarthritis treatment, Biomedicines, 2024, 12(4), 923) can be referred to improve the academic level of the review.

The suggested review was added to the manuscript references.

3. Improvement of academic English writing is recommended.

We thank the reviewer for the suggestion, the manuscript underwent a language revision by a mother tongue researcher.

 

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript summarised the advancement of lubricants development for osteoarthritis. Part of the content of this review overlapped with the recent review (DeMoya CD, Joenathan A, Lawson TB, Felson DT, Schaer TP, Bais M, Albro MB, Mäkelä J, Snyder BD, Grinstaff MW. Advances in viscosupplementation and tribosupplementation for early-stage osteoarthritis therapy. Nat Rev Rheumatol. 2024 Jul;20(7):432-451. doi: 10.1038/s41584-024-01125-5. Epub 2024 Jun 10. PMID: 38858605.), it is suggested that the authors highlight what this review could bring to the field compared to the published one.

Here are some comments for the authors’ consideration:

1.        As the authors summarized many studies in tables, but no information on the timing of intervention is mentioned. Could the authors provide more information or comments on when the intervention is administrated? Because the effectiveness of injection would be different in the early OA and late OA.

2.        Line 110, “MLS, derived from bone marrow myeloid precursors, are phagocytic cells characterized by numerous lysosomes…”. However, recent studies indicated that the synovial macrophages could be derived from primitive macrophages present in the yolk sac, which is different from the infiltrating macrophages derived from bone marrow myeloid precursors.  See reference “Bai LK, Su YZ, Wang XX, Bai B, Zhang CQ, Zhang LY, Zhang GL. Synovial Macrophages: Past Life, Current Situation, and Application in Inflammatory Arthritis. Front Immunol. 2022 Jul 26;13:905356. doi: 10.3389/fimmu.2022.905356. PMID: 35958604; PMCID: PMC9361854.”

3.        In tables 5 and 6 "Name an nanoparticle structure” should be "Name and nanoparticle structure"?

Author Response

Rev2:

The manuscript summarised the advancement of lubricants development for osteoarthritis. Part of the content of this review overlapped with the recent review (DeMoya CD, Joenathan A, Lawson TB, Felson DT, Schaer TP, Bais M, Albro MB, Mäkelä J, Snyder BD, Grinstaff MW. Advances in viscosupplementation and tribosupplementation for early-stage osteoarthritis therapy. Nat Rev Rheumatol. 2024 Jul;20(7):432-451. doi: 10.1038/s41584-024-01125-5. Epub 2024 Jun 10. PMID: 38858605.), it is suggested that the authors highlight what this review could bring to the field compared to the published one.

Authors thank the reviewer for the comment. It is authors’ opinion that beside the introduction, which has necessarily some common point on providing an overview of joint physiopathology, the two manuscripts present several important differences:

• With our review we aim to underline the chances arising from the possible introduction of Drug Delivery Systems (DDS) (elsewhere indicated as particles) in the development of lubricants. It’s our first objective to present how recently developed DDS with lubricant features might make OA treatment more complete by granting at the same time the needed lubrication and the release of different payloads directly at the joint level. In the suggested manuscript the portion about particles is more confined.
• Another important point of difference is represented by the fact that we did not focus specifically on the treatment of early-stage OA. Indeed, our aim was to report the more recent and innovative pharmacological approaches for a complete treatment of OA by coupling the need of joint's lubrication and the controlled release of active drugs to tackle inflammation and friction at the same time. An example is the work reported from Chen et al., who proposed poly PMPC-grafted MSNs (MSNs-NH2@PMPC) as a good candidate for the treatment of both early- and late-stage OA (new ref 94).
• Finally, with respect to the indicated review, our general approach on the articular cartilage lubrication topic was mainly focused on the technological point of view, more specifically on the recent advancements in preclinical studies involving DDS.

Here are some comments for the authors’ consideration:

1. As the authors summarized many studies in tables, but no information on the timing of intervention is mentioned. Could the authors provide more information or comments on when the intervention is administrated? Because the effectiveness of injection would be different in the early OA and late OA.

Where available in the papers we cited this information was integrated in the text of the new version of the manuscript.

2. Line 110, “MLS, derived from bone marrow myeloid precursors, are phagocytic cells characterized by numerous lysosomes…”. However, recent studies indicated that the synovial macrophages could be derived from primitive macrophages present in the yolk sac, which is different from the infiltrating macrophages derived from bone marrow myeloid precursors.  See reference “Bai LK, Su YZ, Wang XX, Bai B, Zhang CQ, Zhang LY, Zhang GL. Synovial Macrophages: Past Life, Current Situation, and Application in Inflammatory Arthritis. Front Immunol. 2022 Jul 26;13:905356. doi: 10.3389/fimmu.2022.905356. PMID: 35958604; PMCID: PMC9361854.”

The authors appreciate the reviewer’s insightful comment. We acknowledge that recent research has indeed revealed that MLS, previously believed to originate mainly from monocytes differentiated from hematopoietic stem cells (HSCs) in the bone marrow, were recently found to derive from primitive macrophages present in the yolk sac or fetal liver. We amended the text according to reviewer comment to reflect this updated finding and we included the reference provided by the reviewer.

3. In tables 5 and 6 "Name an nanoparticle structure” should be "Name and nanoparticle structure"?

The text was corrected accordingly in the new version of the manuscript.

 

Reviewer 3 Report

Comments and Suggestions for Authors

This review paper reported the recent research recent advancements in lubricant-based therapy for OA, focusing on natural, bioinspired, and alternative products. The paper is very carefully arranged and indicates the important research progress in lubricant-based therapy for OA. They also provided the background of the OA. The conclusion is well written supported by future direction. Thus, I will accept this manuscript for further publication

Some Minor point that needs to address 

1. Line 280-282: Authors mentioned that “In this manuscript authors demonstrated that when human synovial fibroblasts (derived from OA patients) were treated with exogenous HA, they started synthesizing new HA depending on its specific MW [59]”. This might be unclear to the readers. It appears that human synovial fibroblasts are synthesizing new HA depending on its specific MW, which is not the case. This sentence could be improved for clarity, and the reference should be 60, instead of 59. Please double-check all the references.

2. In Table 6. Name and nano particle structure instead of “Name an nanoparticle structure”.

 

Author Response

Rev3:

This review paper reported the recent research recent advancements in lubricant-based therapy for OA, focusing on natural, bioinspired, and alternative products. The paper is very carefully arranged and indicates the important research progress in lubricant-based therapy for OA. They also provided the background of the OA. The conclusion is well written supported by future direction. Thus, I will accept this manuscript for further publication

Authors thank the reviewer for the overall evaluation of the work

Some Minor point that needs to address 

1. Line 280-282: Authors mentioned that “In this manuscript authors demonstrated that when human synovial fibroblasts (derived from OA patients) were treated with exogenous HA, they started synthesizing new HA depending on its specific MW [59]”. This might be unclear to the readers. It appears that human synovial fibroblasts are synthesizing new HA depending on its specific MW, which is not the case. This sentence could be improved for clarity, and the reference should be 60, instead of 59. Please double-check all the references.

Authors thank the reviewer for pointing out this unclear point. We revised the sentence in the new version of the manuscript.

In addition, we respectfully would like to underline that the reference 59 (new ref 60) is the correct one. In reference 60 (new ref 61) the scientist running this project run some in vivo test revealing a partial restoration of synovial cell metabolism and the normalization of HA bio-synthesis in OA models treated with 500 – 1000 KDa HA.

2. In Table 6. Name and nano particle structure instead of “Name an nanoparticle structure”.

The text was corrected accordingly in the new version of the manuscript.

 

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

All comments are addressed.