The Computed Sinusoid

Round 1

Reviewer 1 Report

The manuscript by Boninsegna et al describes a computer simulation of hemodynamics in the hepatic sinusoids. The point of view is interesting and it is worthwhile that the manuscript includes comprehensive anatomical findings to date. However, the content is just descriptive and not coherent, and disappointing. I recommend authors to rewrite and resubmit the manuscript after considering following comments.  

1. Overall: Please explain your results with a narrative and lead clear and definite conclusion. It is not comprehensible what is new from the present manuscript.  

2. Conclusion in abstract: please provide specific values obtained from present work, as were shown in previous reports listed in Table 1.1.  

3. Results: Please extract only the data necessary for your story. Move supporting data from the main text to supplementary data.  

4. Iwata et al reported that blood flow is a key factor in liver function. They state implicitly that the point is a major hurdle of constructing bioartificial liver. Did authors consider the mechanical rigidity of the virtual sinusoids (= mesh in Figure 2.2) sufficient for each flow condition?  

Iwata H, Ueda Y. Pharmacokinetic Considerations in the Development of a Bioartificial Liver. Clin Pharmacokinet 2004;43(4):211-225 DOI: 10.2165/ 00003088-200443040-00001  

5. If you are resubmitting to the journal “Livers”, please format the manuscript according to instructions for authors. In addition, please organize the order of publication of the papers in Tables 1 and 2, for example, in chronological order, and complete all references (Henriksen & Lassen 1988 and Yoon 2013 in Table 1 are not listed).

Careful editing of English language by third person who is specialized in this field required. In addition, If you are resubmitting to the journal “Livers”, please format the manuscript according to instructions for authors.

Author Response

Reviewer 1

We thank reviewer 1 for her/his feedback, and have sought to address the issues raised in the following ways;

1 To address point 1: The manuscript has been edited to incorporate a legible narrative. We have restructured the discussion and conclusions to consist of these two only, with minor subheadings where appropriate.

2 To address point 2: we have added conclusions and specific values from the results to the abstract as suggested.

3 To answer point 3: we have moved flowline diagrams (Figures 3.7-3.9) into supplemental materials.

4 To answer point 4: we have not considered the mechanical rigidity of the model, compared with the flexibility of the organ in vivo, and have now added a comment on this in the discussion. Line 406-407. Blood flow is essential to liver function, and our model seeks to describe this at the ultrastructural level. Line 412.

5 To answer point five: The formatting of the article has been improved to follow the author guidelines for Livers. The articles in tables 1.1 and 1.2 have been sorted into chronological order, and missing references, Henriksen and Lassen ref no. 12, Yoon et al,. ref no. 13, have been filled in.

Reviewer 2 Report

The research of the present study aims to gain a deeper understanding on the physiology of liver sinusoids, crucial liver compartments that determine the blood pressure in this organ. Although the topic is of great interest because it could uncover important liver blood pressure changes during disease, the study remains preliminary and not ready for publication. The data are presented in preliminary form and explain the meaning of the findings only superficially. The way the work is written also lacks proof reading, for example, in section 3 (results), the formatting does not follow the journal's standards. Additionally, the word "modeling" sometimes is spelled as "modelling". Also, in some parts of the text the figures are mentioned as "see Figure...", whereas in other parts they are referred as "Figure..", again showing inconsistencies. The English form can be greatly improved by further proof reading or by professional editing. 

There are several points that are not clearly addressed in the manuscript:

1. How is sinusoid pressure currently measured in patients or in animal models?

2. How is the computational model here presented applied to animal models that mimic different liver diseases?

3. What liver disorders are the authors specifically addressing? The manuscript vaguely describes the applicability of this method to investigate sinusoidal pressure.

4. Why is the aim outlined at the beginning of the Introduction section?

5. What is the marker CD45 used for? There is no context presented when the authors mention this marker.

The English language would benefit from additional proof reading and/or professional editing.

Author Response

We thank reviewer 2 for her/his feedback, and seek to address the concerns raised therein,

1 To address point 1: we have added a sentence about in vivo measures of velocities and pressures in the sinusoids (the pressures can indeed not be directly measured, but must be inferred from terminal venule measurements). Line 65-67.

2 To address point 2: The model seeks to elucidate how the structure of the normal liver relates to its fluid dynamic parameters. The model or details from it can be applied to models with altered sinusoidal structure, such as in pathological states, where the normal state can be used as a baseline for comparison for example. We have further added a sentence about how liver sinusoidal ultrastructure is altered in disease, ageing and intoxication. Line 102-104.

3 To address point 3: this study did not seek to describe any pathology, but the normal functioning of the liver sinusoids in relation to their structure. Pathological boundary conditions (hypertensive pressure) were applied, to see if flow parameters would change markedly, however there was only a rescaling of the values, without further changes. Differences between low and high porosity models may be informative for conditions causing loss of fenestrations, but were not planned as such.

4 To address point 4: aims have been moved to the end of the introduction. Line 116-120.

5 To address point 5: the use of the marker CD45 is not material to this study, the reference to it has been struck from the manuscript.

Reviewer 3 Report

The paper is presenting a study on liver physiology by integrating AI in measurement of hepatic blood flow features on sinusoid level. Because of the small dimensions of the sinusoids direct measurement is not possible with current techniques.

It is in my opinion adequately covering the subject, the authors made complex computer-based calculations based on different parameters, like vessel size and shape and porosity and found that pressure and flow velocity in the sinusoids were entirely dependent on the shape and independent of the porosity of the vessel wall. For the space of Disse velocity was modulated by the qualities of porosity. 

The authors conclude that luminal flow and pressure depend on the overall shape of the vessel, while the quality of the fenestrations affect exclusively the flow in the space of Disse. 

The manuscript is in my opinion well structured. The cited references are relevant to the topic. The figures are technical.  

I find the conclusions are consistent with the argumentation.

The work is to my knowledge a novelty on the field, integrating AI in medicine progress and so providing new insights and opening perspectives for better understanding the pathophysiology of the human body and driving individualized medicine further. 

I suggest a minor revision of the language, with focus on the lines: 19—20, 95-97, 156-160, 169.

I suggest a minor revision of the language, with focus on the lines: 19—20, 95-97, 156-160, 169.

Author Response

We thank reviewer 3 for their feedback;

We have as suggested had a second native English speaker review the manuscript for legibility, and made corrections based on their feedback.

Round 2

Reviewer 1 Report

The content has been much improved. However, the Conclusion is too long and the Summary is duplicated at the end of the Conclusion. I think it would be better to remove the title "Conclusion" and make it a part of "General considerations and limitations:".

Author Response

We thank the reviewer for their time and consideration,

The repetitious summary section has been struck from the end of the manuscript, and the Conclusion section merged into Discussion under General considerations and limitations. 

Reviewer 2 Report

 The authors sufficiently addressed previous concerns. Now the manuscript shows clear improvements in its form and content and is suitable for publication.

Author Response

We thank the reviewer for their time and consideration.