Toward Long-Term Implantable Glucose Biosensors for Clinical Use

Round 1

Reviewer 1 Report

Well, to be honest I did not learn much with this paper. It is not really a review and there are only 2h figures (2 figure and one table). The first figure is just here to justify the need for continuous monitoring blood glucose. It is not real measurments just a drawing to show that fingerpricking is not enough to detect dangerous variation of the the glucose concentration. To be honest, even for healthy patient there is a nycteremal fluctuation regarding to the lunch time, physical activities and son on... So, what is the upper and lower glucose concentrations that should be detected by the new generation of biosensor, I did not find the answer after reading this article. Moreover the "zone evaluation" of glucose biosensor that is poposed in this article is not clear. Why the authors never speak about reproducibility, reproductibility, standard deviation and the conclusion about subcutaneaous  electrochemical sensors is rather disturbing since the authors fianlly say that the quality of the glucose concentration measurement could be troubled by biocompatibility issues that may vary from one patient to another. The principle of Clarck electrode is not even given and the optical method based of the photochemistry of fluorescent hydrogel is poorly discussed at the end of the paper. We did not learn much about the medium and long term biocompatibility of diboronic acids gels.

To conclude this article did not give me a clear vision of what has been done and what could be improve in the future aroung blood glucose concentration. I suggest to give time to the authors to improve this review by giving a more constructive scientific discussion and by adding more revelant figures.

Author Response

1. Well, to be honest I did not learn much with this paper. It is not really a review and there are only 2h figures (2 figure and one table). The first figure is just here to justify the need for continuous monitoring blood glucose. It is not real measurments just a drawing to show that fingerpricking is not enough to detect dangerous variation of the the glucose concentration. To be honest, even for healthy patient there is a nycteremal fluctuation regarding to the lunch time, physical activities and son on... So, what is the upper and lower glucose concentrations that should be detected by the new generation of biosensor, I did not find the answer after reading this article.

                                                                                                            

Figure 1 schematically explains the difference between intermittent and continuous glucose monitoring. Blood glucose concentrations of healthy people fluctuate, but the concentrations stay in normal glucose concentrations (3.9−7.1 mmol/L or 70−130 mg/dL) (R1). Repeating episodes of abnormal glycemia can lead diabetic complications. High glycemic variability is also known as a reason to induce diabetic complications. Thus, diabetic patients have to maintain their blood glucose concentrations in a normal range. To control blood glucose concentrations, people with diabetes firstly understand their blood glucose concentrations.

 

[R1] Brynes, A.E., Adamson, J., Dornhorst, A. and Frost, G.S., 2005. The beneficial effect of a diet with low glycaemic index on 24 h glucose profiles in healthy young people as assessed by continuous glucose monitoring. British journal of nutrition,93(2), pp.179-182.

 

We revised the manuscript as below:

Line 26-38

Diabetes mellitus is a chronic disease that affects more than 400 million people worldwide [1]. Since high or low blood glucose concentration episodes and high glycemic variability can cause diabetic complications (e.g., diabetic retinopathy, kidney failure, heart disease, diabetic neuropathy and diabetic foot disease) and even lead to death; it is crucial for diabetic patients to maintain their blood glucose concentration in a normal range and to decrease glycemic variability [2-5]. To maintain blood glucose concentration in the normal level and reduce blood glucose variability, people with diabetes first understand their blood glucose concentrations. Blood glucose concentration measurement accompanies with painful finger-pricking. Such intermittent monitoring is not only painful but also ineffective to prevent abnormal blood glucose concentrations between measurement points [6]. Alternately, continuous glucose monitoring (CGM) is proposed. CGM can constantly measure blood glucose concentrations and give users alarm when abnormal blood glucose concentration occurs (Fig. 1). Thus, CGM enables to reduce occurrence of hypo or hyperglycemia and high glycemic variability [7, 8].

 

2. Moreover the "zone evaluation" of glucose biosensor that is poposed in this article is not clear.

 

We added the figure that explains error grid analysis zones to help readers understand zone evaluation. Now, authors order the electric figure to get copyright from the journal.

3. Why the authors never speak about reproducibility, reproductibility, standard deviation and the conclusion about subcutaneaous  electrochemical sensors is rather disturbing since the authors fianlly say that the quality of the glucose concentration measurement could be troubled by biocompatibility issues that may vary from one patient to another.

 

We mentioned that the recent electrochemical sensors can reduce user calibration that may fix variation one from another patient, since electrochemical sensors manufacturing provides reproducibility of glucose oxidase deposition on working electrode and uniformity of glucose limiting membrane coating (Line 147-155). The exact number of reproducibility is unknown. But, even without calibration, the “factory-calibrated” CGMS sensors have low errors (less than 10%) (Table 2) that is sufficient to Zone A (less than 20% error). (Section 2.2.1)

 

4. The principle of Clarck electrode is not even given and the optical method based of the photochemistry of fluorescent hydrogel is poorly discussed at the end of the paper. We did not learn much about the medium and long term biocompatibility of diboronic acids gels.

 

We focus onto CGMSs for clinical use rather than discussing principles of sensors. The principles of enzymatic electrode and diboronic acids are well explained in other several articles including the author’s previous publication. We include them into the references to help readers who want to obtain further information about principles of sensors.

 

5. To conclude this article did not give me a clear vision of what has been done and what could be improve in the future aroung blood glucose concentration. I suggest to give time to the authors to improve this review by giving a more constructive scientific discussion and by adding more revelant figures.

 

We added the figure that explains error grid analysis zones to help readers understand zone evaluation.

Author Response File: Author Response.pdf

Reviewer 2 Report

The review describes the long-term implantable glucose biosensors for clinical use. The topic of this work is quite interesting, the use of implantable glucose biosensor with continuous glucose monitoring is a powerful tool to manage blood glucose. The advances in this field will provide new strategies for effective diabetic management. Moreover, the manuscript is well organized and discussed, however I request for the following suggestions before acceptance:

Some misspellings must be corrected:

The year of Reference 17 publication should be 2018

Please, revise and improve the quality and organization of Tables 1 and 2

 

Author Response

1. Some misspellings must be corrected:

 

The year of Reference 17 publication should be 2018

 

We revised the manuscript as below:

Line 340-342

[17] Shah, V.N., Laffel, L.M., Wadwa, R.P. and Garg, S.K. Performance of a factory-calibrated real-time continuous glucose monitoring system utilizing an automated sensor applicator. Diabetes Technol Ther 2018, 20, pp.428-433.

 

2. Please, revise and improve the quality and organization of Tables 1 and 2

 

We revised tables 1 and 2 to increase readability.

Author Response File: Author Response.pdf

Reviewer 3 Report

The manuscript is a well written document. The authors have carried out a thorough research on this topic. There are few points / suggestions that will improve the readability of the document. Following are the reviewer’s suggestions:

1.       Line 77: Please define MARD

2.       Line 96: Please included a table or a schematic explaining the Clarke’s error grid, since the authors go in to greater details in the following paragraphs.

If these changes are made, then the manuscript is fit for publication.

Comments for author File: Comments.docx

Author Response

The manuscript is a well written document. The authors have carried out a thorough research on this topic. There are few points / suggestions that will improve the readability of the document. Following are the reviewer’s suggestions:

 

1.       Line 77: Please define MARD

 

We revised the manuscript as below:

Line 77

9% mean absolute relative difference (MARD)

 

2.       Line 96: Please included a table or a schematic explaining the Clarke’s error grid, since the authors go in to greater details in the following paragraphs.

 

We added the figure that explains error grid analysis zones to help readers understand zone evaluation. Now, we order the electric figure to get copyright from the journal.

Author Response File: Author Response.pdf