Fluid Dynamics Optimization of Microfluidic Diffusion Systems for Assessment of Transdermal Drug Delivery: An Experimental and Simulation Study

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors describe the physiological flow rates (lines 52-57), but the flow rates that they tested are much higher. Emphasis is needed on the justification of the selection of experimental conditions.

Line 319: “…Petrolatum basis ointment…” Do the authors mean “…Petrolatum based ointment…”? Nevertheless the formula they described are rather a cream not an ointment (please see the comment for line 333).

Line 331: ”The preservative was added to the preparation…” the presentative used and its percentage is not mentioned in the ingredient list (lines 319-326).

Line 333:” The prepared ointment was stored…” the formulation is a cream not an ointment. The water content of formulations described as ointment is usually ≤20%. This formulation contains ≥38% water so it cannot be classified as ointment.

Lines 349 and 350: what do the authors mean by the phrases “parallel exposures” and “parallel measurements”? Do they mean consecutive instead of parallel?

Lines 384-385: how was the thickness of the membranes measured?

Line 385: the procedure followed to obtain the skin should be described.

Lines 432-459: Please give the explanations of every symbol used in the equations.

Line 472: the viscosity unit should be Pa·s

Lines 473-474: These parameters are repeated elsewhere (lines 384-385) Many other unnecessary repetitions can be found in the text like lines 464 and 479 etc. These repetitions should be avoided.

The Discussion part is rather limited. This part should be expanded, and possible explanations of the results should be added. A conclusion is also needed.

Comments on the Quality of English Language

The quality of English Language is fine. Some minor but careful editing is needed throughout the text.

Author Response

The authors are grateful for the comments and suggestions of the Reviewers, which help to improve the quality of the manuscript and clarify the description of the experimental works.  The answers to the questions and comments are added to the attached file point by point.

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

Dear authors,

The manuscript is well written and structured, however some questions need to be answered before publication:

What are the driving factors behind the exponential growth of organ-on-a-chip technologies?

How do microfluidic devices contribute to the reduction of experimental animal use?

What are the key considerations in designing in vitro microfluidic devices for drug testing?

Can you describe the purpose of using different materials like cellulose acetate and polyester membranes in skin-on-a-chip models?

How does the flow rate affect the diffusion of substances in microfluidic diffusion chambers?

Why was a 40 µL/min flow rate found to be optimal for the diffusion of the hydrophilic model formulation?

In what way did Computational Fluid Dynamics simulation aid the analysis of the single-channel microfluidic system?

What does the consistency between the visualization and measured data suggest about the reliability of the microfluidic system?

How do the experimental findings support the advancement of microfluidic systems for penetration testing?

Author Response

The authors are grateful for the comments and suggestions of the Reviewers, which help to improve the quality of the manuscript and clarify the description of the experimental works.  The answers to the questions and comments are added to the attached file point by point.

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript entitled “Fluid Dynamics Optimization of Microfluidic Diffusion Systems for Assessment of Transdermal Drug Delivery―An Experimental and Simulation Study” compares in vitro release/permeation of caffeine from a O/W emulsions applied into three different microfluidic systems in which four different membranes were inserted (rat skin, cellulose-acetate, alginate scaffolds and  polyester).

The authors analyzed the results from single-channel microfluidic diffusion chambers using computational fluid dynamics simulations obtaining interesting information about the release process of caffeine through the investigated membranes.

The experimental protocol is well organized and the results are well presented and discussed.

Specific comments

Line 39. The meaning of the sentence “This fluid flow composed of the capillary microcirculation, the lymphatic microcirculation and 40 the movements in the extracellular fluids.” Is unclear. Please, rephrase.

Line 153. The authors partially attributed the obtained results to the presence of active transporter proteins in the skin cells. Excised skin consists of non-vital skin layers therefore no active transport can occur. Please, correct.

Line 320-322. Ingredients should be reported in English according the common nomenclature. Please, correct.

Line 331. Please, specify the preservative used (chemical name and source).

Comments on the Quality of English Language

English should be revised.

Author Response

The authors are grateful for the comments and suggestions of the Reviewers, which help to improve the quality of the manuscript and clarify the description of the experimental works.  The answers to the questions and comments are added to the attached file point by point.

Author Response File: Author Response.docx

Reviewer 4 Report

Comments and Suggestions for Authors

I suggest the authors continue the study in the future and complete it. The manuscript is well done and my suggestion is to publish this work in this journal after a minor revisions according to the few comments:

 1.      I suggest describe caffeine formulation in the manuscript in table form.

 2.      Describe model of spindle in the rheological measurements.

 3.      Do the authors perform flow curves in the rheological analyses? Please describe and introduce flow types (Newtonian or non-Newtonian) to improve section.

 4.      I suggest to the authors include this reference about PPG

www.ema.europa.eu/contact © European Medicines Agency, 2017.

 9 October 2017

EMA/CHMP/334655/2013

Committee for Human Medicinal Products (CHMP)

Propylene glycol used as an excipient

Report published in support of the ‘Questions and answers on propylene glycol used as an excipient in medicinal products for human use’ (EMA/CHMP/704195/2013).

 5.      Why have the authors chosen a caffeine cream model?

 6.      Line 82,472. Change Pas for Pa·s

 7.      Change minutes for min (line 345)

Author Response

The authors are grateful for the comments and suggestions of the Reviewers, which help to improve the quality of the manuscript and clarify the description of the experimental works.  The answers to the questions and comments are added to the attached file point by point.

Author Response File: Author Response.docx