A Self-Polymerizing Mesh of Nano-Tethers for the Mechanical Constraint of Degraded Intervertebral Discs—A Review of 25 Years of Pre-Clinical and Early Clinical Research

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have clinically evaluated the effect of genipin polymers on the mechanical properties of intervertebral discs, here. The paper has been well written but some issues need to be addressed before acceptance.

 

1.      The title of section 3.1, “ the mechanical property degradation…” is not a usual concept. It can be replaced by “ the mechanical strength deterioration..”.

2.      In section 3.2, the title is “biochemical studies review”, but the text explained the chemical reactions and polymerization process. It is supposed that based on the title, the biochemical reactions and phenomena should be discussed.

3.      It is suggested that the authors discuss the similar materials that are being used for the improvement of the mechanical strength of intervertebral discs in a separate section and explain the advantages and disadvantages of genipin.

Author Response

Thank you for your thoughtful review of the manuscript.  Detailed responses to each point of your review are found below.  The corresponding revisions/corrections can be seen by track changes in the revised manuscript.

1. Thank you for noting the unnecessary non-standard terminology in this heading, and thank you for suggesting a simpler and appropriate replacement.  We have changed the heading as suggested in the revised manuscript.
2. Thank you for noting that this subtitle is too general for the studies Included in this section.  We have changed the heading to Reaction Kinetics of Genipin in Collagenous Tissues to more precisely describe the studies that were included in this part of the reivew.  We also changed "biochemical studies review" to "reaction kinetics review" in the Introduction section (line 119).
3. We agree with you that a comparative review of other materials used for load support in the intervertebral disc, noting the strengths and weaknesses would enhance this review.  Therefore we have added two paragraphs and made other edits to the text in lines 257-292 including 3 additional references.

Reviewer 2 Report

Comments and Suggestions for Authors

This review article on ‘Intralink injection’ is very interesting with fine CG illustrations, which reinforces the degenerative intervertebral disc by self-polymerization of Genipine. It seems to be one of the best treatments for the low back pain with mechanical insufficiency of the disc. Please consider the following review comments to enhance the value of this article.

#1. Because the article title includes ‘a review of 25 years’, most readers expect long-term clinical results but the clinical research involves only 12 month follow-up as interrupted by covid19. Please avoid this misleading with some changes such as ‘A review of 25 years of preclinical research, and corroborative clinical research’.

#2. In the reviews of biomechanical studies and Mechanical effects, the author described the research outcomes by abstractive expressions. It is recommended to describe specific values of mechanical properties, such as Elastic modulus and deflection evaluated by mechanical testing.

#3. In clinical research, the injection procedure of the Intralink should be described in detail with the doses of the genipin powder and the aqueous buffer, gauge number of the needle, working time with injectable viscosity,

#4. The integer number is enough for the percent labels of the vertical axis in Figure 4 and 5.

 #5. It seems that clinical research in Malaysia and Australia was performed as a clinical trial. The author should describe the prospective or the present status of the Intralink treatment as an authorized clinical application. Many orthopedic clinicians and LBP patients would be waiting for such minimal invasive treatment.

 

 

Author Response

We are grateful to the reviewer for a thoughtful review of this manuscript. Please find responses below and the corresponding revisions in track changes in the resubmitted files.

#1 Thank you for alerting us to the possible misperception of the article based on the wording of the title.  Our clinical trials, including the preliminary work (protocol, informed consent, ethics reviews, site initiations, etc.) leading up to treating the first participant began in 2015.  So the clinical trial phase, albeit poorly funded and intercepted by COVID19, represents a 7-year period, and the preclinical phase was wrapping up after after 18 years of investigations.  Part of the story here, described very briefly in the first paragraph of the introduction, is that the novelty of this approach, combined with it being a materials-based approach - not having the glamour of a biological-based solution, worked against us from the beginning with regards to raising adequate funds to evaluate the merits and appropriateness of this solution for the biologically-limited disc.  That it took 25 dedicated, uninterupted years to get to the point of having 2-year data for 5 participants and 1-year data on 20, is probably not typical, but may be an important reference point for my younger peers contemplating their own innovation journey.  All that said (I apologize), we have changed the title to say: "... and Early Clinical Research".

#2 We have added specific percentage increases or decreases in strength, disc bulge, tear and delamination resistance, and joint instability characteristics with corrresponding p-values in lines 224 to 230. We agree that this detail gives a more robust sense of the effects of the genipin polymer mesh.

#3 Needle gauge, injection volume, genipin concentration and buffer description are now included in the text lines 315 to 318.

#4 This change has been made to figures 3 and 4.  Thank you.

#5 We have added statements regarding Intralink's current regulatory status in Europe and the US in lines 393 to 396.

Again thank you for your excellent suggestions.