A Dissolving Microneedle Design for Poorly Water-Soluble Drugs for Enhanced Skin Permeation and Transdermal Delivery Fabricated Using 3D Printing

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript investigates stereolithography (SLA)-printed microneedle (MN) masters, assessing printing angle effects on tip resolution and comparing three geometries (conical, pyramidal, star) for insertion and transdermal permeation using flurbiprofen (FLU) as a model drug. While the experiments are competently executed, the principal findings largely confirm already well-documented phenomena, and the paper does not sufficiently articulate what fundamentally new insight it contributes beyond prior art.

 

1. Printing-angle optimization duplicates established SLA/DLP findings
   The conclusion that printing at ~45° maximizes tip sharpness and insertion falls within an already known design space for SLA/DLP MNs. Prior studies have shown that increasing build orientation (e.g., 40–60°) improves effective layer area at the tip and yields sharper apices and better penetration; e.g., Choo et al. (2022) identified 60° as optimal for tip resolution in SLA, and other reports demonstrate bevel/tip control by adjusting the print direction (Ref. 26).  In addition, Fitaihi et al., 2024 also considered angle dependence (Ref. 23); Jeong et al., 2023 controlled the bevel angle by the printing direction (Ref. 48). Hence, the present “45° optimum” is not a substantive advance over these established results. 
   
   
2. The manuscript’s central claim—that multi-vertex (star) bases concentrate stress at edges and therefore enhance insertion and transdermal delivery—is consistent with prior experimental demonstrations. In particular, De Martino et al. (2022) systematically compared circular, triangular, square, and star bases and showed decisively that star-shaped MNs achieve the greatest insertion depth owing to vertex-driven stress concentration (Ref. 47). The present work largely confirms this trend rather than providing a new mechanism or design rule.  Furthermore, the “star-type” microneedle is insufficiently defined. A star shape can vary widely (vertex number, vertex angle, edge sharpness), and insertion performance strongly depends on these parameters, as shown by De Martino et al., 2022. Without specifying the exact geometry, the claim that “the star-type is superior” is not reproducible or generalizable.
   
   
3. Drug choice offers limited novelty Flurbiprofen (FLU) is a widely studied NSAID in MN delivery; recent reports have explored cross-linked gelatin MNs for postoperative pain and broader transdermal NSAID strategies. Consequently, the drug choice—while reasonable for demonstration—does not confer novelty at the pharmacological level.  (https://doi.org/10.1007/s12274-024-6751-x,https://doi.org/10.13140/RG.2.2.30099.55843, https://doi.org/10.3390/pr13030907)
   
   
4. Parafilm® M insertion is a recognized in vitro surrogate, but its translational value benefits from explicit calibration against ex vivo depth (e.g., via OCT/sectioning) or model-to-model correlations. The manuscript would be stronger with a quantitative mapping (layers → μm depth) cross-validated on tissue, as proposed by Larrañeta et al. and emphasized in later comparative method papers. (https://doi.org/10.1016/j.ijpharm.2014.05.042)
   
   
5. Cumulative percent permeation over 12 h is informative but incomplete. Reporting steady-state flux , lag time, and simple Fickian fits, and quantifying drug loading/distribution in tip vs. backing would strengthen causal links between geometry, microchannel formation, and transport. Recent reviews highlight how geometry (tip radius, base width, spacing) governs penetration and flux; leveraging that framework here would enable more generalizable conclusions. (https://doi.org/10.1208/s12249-025-03246-w)
   
   
6. If star-shaped MNs are the preferred architecture, the angle–geometry interaction should be mapped explicitly for the star design as well (0–60°), ensuring internal consistency between optimization and conclusions. 

Author Response

1. I appreciate so much your comments.
2. Indicated the revised parts with red color in this revised manuscript.

 

Reviewer #1

 

The manuscript investigates stereolithography (SLA)-printed microneedle (MN) masters, assessing printing angle effects on tip resolution and comparing three geometries (conical, pyramidal, star) for insertion and transdermal permeation using flurbiprofen (FLU) as a model drug. While the experiments are competently executed, the principal findings largely confirm already well-documented phenomena, and the paper does not sufficiently articulate what fundamentally new insight it contributes beyond prior art.

 

Response: I appreciate the reviewer’s suggestion. While this study aligns with certain findings from previous literature, its primary contribution lies in the incorporation of poorly soluble drugs into microneedle systems. I believe it is important to examine how microneedle design parameters influence the skin permeability of these substances is crucial. Accordingly, we have revised the manuscript to more explicitly highlight our findings in contrast with previously published data.

 

Point 1.  Printing-angle optimization duplicates established SLA/DLP findings

The conclusion that printing at ~45° maximizes tip sharpness and insertion falls within an already known design space for SLA/DLP MNs. Prior studies have shown that increasing build orientation (e.g., 40–60°) improves effective layer area at the tip and yields sharper apices and better penetration; e.g., Choo et al. (2022) identified 60° as optimal for tip resolution in SLA, and other reports demonstrate bevel/tip control by adjusting the print direction (Ref. 26).  In addition, Fitaihi et al., 2024 also considered angle dependence (Ref. 23); Jeong et al., 2023 controlled the bevel angle by the printing direction (Ref. 48). Hence, the present “45° optimum” is not a substantive advance over these established results.

 

Response 1: While acknowledging that our study shares commonalities with prior research, we contend that the investigation into SLA 3D printing angles provides a significant practical advancement. By focusing on the structural integrity and design efficiency of microneedles for poorly soluble drug delivery, we address a key gap in scalable manufacturing. My empirical data, derived from Parafilm-based permeability assays, confirms that the printing angle is a decisive factor in delivery performance. I have updated the text to highlight these contributions and included comparative data from related studies.

 

Added “Previous studies have demonstrated that --- for the delivery of poorly soluble compounds.” in line 280-295.

 

Point 2.  The manuscript’s central claim—that multi-vertex (star) bases concentrate stress at edges and therefore enhance insertion and transdermal delivery—is consistent with prior experimental demonstrations. In particular, De Martino et al. (2022) systematically compared circular, triangular, square, and star bases and showed decisively that star-shaped MNs achieve the greatest insertion depth owing to vertex-driven stress concentration (Ref. 47). The present work largely confirms this trend rather than providing a new mechanism or design rule.  Furthermore, the “star-type” microneedle is insufficiently defined. A star shape can vary widely (vertex number, vertex angle, edge sharpness), and insertion performance strongly depends on these parameters, as shown by De Martino et al., 2022. Without specifying the exact geometry, the claim that “the star-type is superior” is not reproducible or generalizable.

 

Response 2: I agree with the reviewer’s assessment and appreciate the opportunity to clarify the scope of our work. As previously noted, the primary significance of this study lies in validating the efficacy of specific microneedle architectures for enhancing the skin permeability of poorly soluble drugs. In accordance with your feedback, I have extensively revised the manuscript to incorporate a more comprehensive review of previous literature and have added detailed characterizations of the microneedle structures used. I believe these additions provide a clearer context for our findings and better highlight the technical advancements of our proposed fabrication method.

 

Added “Table 1” and Revised “Figure 1”.

 

Point 3.  Drug choice offers limited novelty Flurbiprofen (FLU) is a widely studied NSAID in MN delivery; recent reports have explored cross-linked gelatin MNs for postoperative pain and broader transdermal NSAID strategies. Consequently, the drug choice—while reasonable for demonstration—does not confer novelty at the pharmacological level.  (https://doi.org/10.1007/s12274-024-6751-x,https://doi.org/10.13140/RG.2.2.30099.55843, https://doi.org/10.3390/pr13030907)

 

Response 3: I appreciate the reviewer’s comment regarding the distinction between my work and previous literature. Prior studies involving flurbiprofen-loaded microneedles have often overlooked the drug’s inherent physicochemical challenges, particularly its poor aqueous solubility. My study specifically addresses this gap by evaluating microneedle architectures tailored to these characteristics.

Unlike existing approaches that utilize genipin-cross-linked gelatin or incorporate poorly soluble drugs in nanoparticulate forms, my research focuses on a homogenous polymer matrix system. This structure constitutes a dissolvable microneedle, and my primary objective was to investigate how the microneedle's physical design influences delivery performance within this specific matrix. In response to your feedback, the manuscript has been thoroughly revised to highlight these methodological departures and to provide a more detailed comparative analysis with existing studies

 

Added “Several studies have previously investigated --- the structural advantages of the MN system.” in line 389-401.

 

Point 4.  Parafilm® M insertion is a recognized in vitro surrogate, but its translational value benefits from explicit calibration against ex vivo depth (e.g., via OCT/sectioning) or model-to-model correlations. The manuscript would be stronger with a quantitative mapping (layers → μm depth) cross-validated on tissue, as proposed by Larrañeta et al. and emphasized in later comparative method papers. (https://doi.org/10.1016/j.ijpharm.2014.05.042)

 

Response 4: I fully acknowledge the reviewer’s point regarding the importance of validating permeability in actual biological tissues. I agree that such experiments would provide further insight into the clinical translatability of my system. However, due to current institutional resource constraints and the specific scope of this fundamental study, further ex vivo or in vivo verification was not feasible at this stage.

In this research, Parafilm was employed as a validated mechanical simulant to quantitatively assess the differences in microneedle structural integrity (insertion force) resulting from varying printing angles. My subsequent skin permeation assays further confirmed that these structural variations significantly dictate the delivery efficiency of poorly soluble drugs. I have added a discussion section to the revised manuscript, acknowledging these experimental limitations and outlining my plans for future tissue-based validation. I hope the reviewer understands that the current findings provide a solid foundational framework for the optimized fabrication of these systems.

 

Added “While Parafilm® M insertion assays --- and transdermal drug delivery efficiency.” in line 362-368.

 

Point 5.  Cumulative percent permeation over 12 h is informative but incomplete. Reporting steady-state flux , lag time, and simple Fickian fits, and quantifying drug loading/distribution in tip vs. backing would strengthen causal links between geometry, microchannel formation, and transport. Recent reviews highlight how geometry (tip radius, base width, spacing) governs penetration and flux; leveraging that framework here would enable more generalizable conclusions. (https://doi.org/10.1208/s12249-025-03246-w)

 

Response 5: I am grateful for your constructive feedback and helpful advice. I have carefully revised the manuscript to address all the points raised, and I believe these updates have significantly strengthened the quality of our work.

 

Added “All permeation tests were conducted in triplicate --- to the initial drug concentration loaded on the donor side.” and “As summarized in Table 2, --- 8.5 times higher than that of the control film.”  in lines 218-227 and 407-416.

 

Added “Table 2”

 

Point 6. If star-shaped MNs are the preferred architecture, the angle–geometry interaction should be mapped explicitly for the star design as well (0–60°), ensuring internal consistency between optimization and conclusions.

 

Response 6: Thank you for your valuable insights. I have carefully revised the manuscript in accordance with your feedback.

 

Added “Furthermore, consistent with the results observed --- for optimizing penetration performance across different geometric designs” in line 381-385.

 

Added “Figure S2”

 

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

In this manuscript, the authors present 3D-printed microneedles with three different tip geometries: cone-type, pyramid-type, and star-type. PDMS molds were fabricated from the printed masters and subsequently used to produce PVA microneedles. The microneedles were evaluated for skin penetration performance at different 3D-printed angles ranging from 0° to 60°. The effect of aspect ratio (AR) on penetration behavior was also investigated. Finally, the three types of microneedles were assessed for drug delivery performance in an in vivo rat model, with a 12-hour delivery study conducted for each microneedle design. Overall, the study is interesting and presents valuable insights into the development of wearable microneedle-based systems. However, several important points require clarification and further discussion, as outlined below:

1. The geometric dimensions of the microneedles are inadequately described. Critical parameters, including tip diameter, base diameter, and total microneedle length, are not clearly specified for each microneedle geometry (cone-, pyramid-, and star-type). The authors should explicitly report all dimensional parameters, preferably in a summarized table and supported by schematic diagrams or SEM images with scale bars. Furthermore, the effect of different 3D-printing angles on the resulting tip diameter and tip sharpness should be systematically analyzed and discussed, as variations in printing angle may significantly influence penetration behavior.
2. The manuscript lacks a discussion of skin recovery and post-treatment effects following microneedle application. While penetration performance is emphasized, penetration efficiency alone is insufficient to evaluate microneedle safety and practical applicability. The authors should assess and discuss the skin recovery rate after microneedle removal, including evidence of skin closure and healing over time. Importantly, the optimal microneedle design should demonstrate a balance between high penetration efficiency and minimal skin damage.
3. The study would be significantly strengthened by a more comprehensive investigation of the 3D-printing parameters. Currently, the printing angles are limited to a range of 0° to 60°, which restricts the generalizability of the conclusions. Extending the printing angle range to 90° would provide a more complete understanding of how printing orientation influences microneedle geometry, tip sharpness, and penetration performance. In addition, the manuscript does not adequately address the effect of inter-microneedle spacing (distance between microneedles), which is a critical design parameter influencing mechanical strength, skin deformation, and overall penetration efficiency. The authors should consider evaluating multiple spacing configurations and discussing their impact on penetration behavior and drug delivery performance.

Author Response

1. I appreciate so much your comments.
2. Indicated the revised parts with red color in this revised manuscript.

 

Reviewer #2

 

In this manuscript, the authors present 3D-printed microneedles with three different tip geometries: cone-type, pyramid-type, and star-type. PDMS molds were fabricated from the printed masters and subsequently used to produce PVA microneedles. The microneedles were evaluated for skin penetration performance at different 3D-printed angles ranging from 0° to 60°. The effect of aspect ratio (AR) on penetration behavior was also investigated. Finally, the three types of microneedles were assessed for drug delivery performance in an in vivo rat model, with a 12-hour delivery study conducted for each microneedle design. Overall, the study is interesting and presents valuable insights into the development of wearable microneedle-based systems. However, several important points require clarification and further discussion, as outlined below:

 

Point 1.  The geometric dimensions of the microneedles are inadequately described. Critical parameters, including tip diameter, base diameter, and total microneedle length, are not clearly specified for each microneedle geometry (cone-, pyramid-, and star-type). The authors should explicitly report all dimensional parameters, preferably in a summarized table and supported by schematic diagrams or SEM images with scale bars. Furthermore, the effect of different 3D-printing angles on the resulting tip diameter and tip sharpness should be systematically analyzed and discussed, as variations in printing angle may significantly influence penetration behavior.

Response 1: Thank you for your insightful suggestions. We have added new microscopic images and comparative tables (refer to Figure 1, Table 1, and Table S1) as requested. These additions offer a more comprehensive visualization of the microneedle structures, addressing the concerns you raised.

 

Added “Additionally, as summarized in Table S1, --- enhances the mechanical penetration performance of the MNs.” in line 274-278.

 

Revised “Figure 1”. Added “Table 1 and Table S1”

 

 

Point 2.  The manuscript lacks a discussion of skin recovery and post-treatment effects following microneedle application. While penetration performance is emphasized, penetration efficiency alone is insufficient to evaluate microneedle safety and practical applicability. The authors should assess and discuss the skin recovery rate after microneedle removal, including evidence of skin closure and healing over time. Importantly, the optimal microneedle design should demonstrate a balance between high penetration efficiency and minimal skin damage.

 

Response 2: I sincerely appreciate your valuable insight regarding the safety of microneedles, which is indeed a critical factor for clinical development. However, the primary objective of this study was to establish the fundamental correlation between microneedle structural parameters and skin permeability.

While the current work focuses on these mechanistic aspects, I fully acknowledge that in vivo efficacy and biocompatibility assessments are essential prerequisites for further application. Accordingly, these evaluations are planned as a key component of our future research. In response to your comment, we have revised the manuscript to explicitly state these limitations and clarify the intended scope of this foundational study.

 

Added “For future clinical translation, comprehensive in vivo safety evaluations --- compromise skin integrity or provoke adverse biological responses.” in line 430-434.

 

Point 3.  The study would be significantly strengthened by a more comprehensive investigation of the 3D-printing parameters. Currently, the printing angles are limited to a range of 0° to 60°, which restricts the generalizability of the conclusions. Extending the printing angle range to 90° would provide a more complete understanding of how printing orientation influences microneedle geometry, tip sharpness, and penetration performance. In addition, the manuscript does not adequately address the effect of inter-microneedle spacing (distance between microneedles), which is a critical design parameter influencing mechanical strength, skin deformation, and overall penetration efficiency. The authors should consider evaluating multiple spacing configurations and discussing their impact on penetration behavior and drug delivery performance.

 

Response 3: I sincerely appreciate your insightful comments. Regarding the 90° printing angle, we have removed the preliminary data from the main results as it proved unfeasible for consistent structural fabrication. However, we have added a brief explanation in the revised manuscript to clarify this technical limitation and justify the selected range of printing angles.

Furthermore, I agree that inter-needle spacing is a critical parameter influencing mechanical insertion. However, the primary focus of this study was to isolate the impact of microneedle geometry on the skin permeability of poorly soluble drugs. I have acknowledged the role of spacing as a limitation of the current work and have updated the text to include this as a key consideration for future optimization. I hope these revisions adequately address your concerns and thank you for your professional understanding.

 

Added “Attempts were made to fabricate MNs at a 90° orientation, --- were not included in the presented results.” and “Furthermore, additional design parameters beyond the scope of this study---for further optimization in MN-based drug delivery systems.” in line 247-249 and 368-372.

 

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

1. Fig S1: The layout is poor and needs to be reorganized.
2. The manuscript mentions optimizing the needle tip morphology by adjusting the printing angle, but it does not explain how 45° was determined as the optimal angle. It is recommended that the authors provide experimental evidence or optimization curve data to enhance methodological transparency and reproducibility.
   3. The 12-hour Franz diffusion cell experiments show clear differences in permeation among microneedles of different geometries, but the manuscript does not discuss the drug’s cumulative release rate, local concentration gradients, or potential drug retention. It is suggested to include kinetic analysis and permeation curve fitting to more comprehensively evaluate delivery efficiency.
3. The manuscript states that star-shaped microneedles have high penetration efficiency, but the explanation of stress distribution and penetration mechanism is rather superficial. It is recommended to include finite element simulations or mechanical analysis to quantitatively explain why an increased number of vertices leads to higher penetration efficiency.
4. The manuscript emphasizes that PVP enhances the solubility of hydrophobic drugs, but lacks quantitative data on drug loading and release efficiency. It is suggested to provide data on drug loading in the needles and release rates at the needle tips to support functional conclusions.
5. Some method descriptions are lengthy and repetitive, such as multiple descriptions of the vacuum-casting process. It is recommended to streamline the text and focus on key steps and parameters.

Author Response

1. I appreciate so much your comments.
2. Indicated the revised parts with red color in this revised manuscript.

 

Reviewer #3

 

 

Point 1.  Fig S1: The layout is poor and needs to be reorganized.

 

Response 1:  Figure S1 has been modified.

 

Point 2.  The manuscript mentions optimizing the needle tip morphology by adjusting the printing angle, but it does not explain how 45° was determined as the optimal angle. It is recommended that the authors provide experimental evidence or optimization curve data to enhance methodological transparency and reproducibility.

 

Response 2: I appreciate your valuable guidance throughout the review process. The suggested information has been fully integrated into the revised manuscript, and I hope the updated version now meets with your approval.

 

Added “Additionally, as summarized in Table S1, the tip diameter exhibited --- enhances the mechanical penetration performance of the MNs.” in line 274-278.

 

Added “Table S1”

 

Point 3.  The 12-hour Franz diffusion cell experiments show clear differences in permeation among microneedles of different geometries, but the manuscript does not discuss the drug’s cumulative release rate, local concentration gradients, or potential drug retention. It is suggested to include kinetic analysis and permeation curve fitting to more comprehensively evaluate delivery efficiency.

 

Response 3: I appreciate your valuable guidance throughout the review process. The suggested information has been fully integrated into the revised manuscript, and I hope the updated version now meets with your approval.

 

Added “As summarized in Table 2, --- than that of the control film.” in line 407-416.

 

Added “Table 2”

 

 

Point 4.  The manuscript states that star-shaped microneedles have high penetration efficiency, but the explanation of stress distribution and penetration mechanism is rather superficial. It is recommended to include finite element simulations or mechanical analysis to quantitatively explain why an increased number of vertices leads to higher penetration efficiency.

 

Response 4: I appreciate your valuable guidance throughout the review process. The suggested information has been fully integrated into the revised manuscript, and I hope the updated version now meets with your approval.

 

Added “Furthermore, as summarized in Table 1, --- with smaller or more optimized base geometries.” in line 358-362.

 

Added “Table 1”

 

Point 5.  The manuscript emphasizes that PVP enhances the solubility of hydrophobic drugs, but lacks quantitative data on drug loading and release efficiency. It is suggested to provide data on drug loading in the needles and release rates at the needle tips to support functional conclusions.

 

Response 5: I sincerely appreciate your valuable feedback regarding the drug delivery profile. In response to your suggestion, I have incorporated new parameters evaluating the release efficiency and the residual drug amount remaining within the microneedles after application.

These additional data points provide a more comprehensive understanding of the delivery performance and ensure a rigorous mass balance analysis of the loaded flurbiprofen. The revised manuscript now includes these results in Table 2, further validating the effectiveness of our proposed polymer matrix system.

 

Added “Furthermore, as the drug was primarily localized within the needle tips,--- were observed across the different geometric designs.” in line 416-418.

 

Added “Table 2”

 

 

Point 6.  Some method descriptions are lengthy and repetitive, such as multiple descriptions of the vacuum-casting process. It is recommended to streamline the text and focus on key steps and parameters.

 

Response 6: Thank you for your insightful advice. We have meticulously audited the text to eliminate repetitive descriptions and unnecessary details. We believe this streamlined version significantly enhances the readability and ensures that the emphasis remains on the novel aspects of our microneedle design.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I appreciate the authors’ revisions in v2—most notably the explicit geometric definition for the star‑type microneedles (vertex count and angle in Table 1) and the addition of permeation kinetics (J_ss, lag time, retention; Table 2). These changes improve clarity relative to the original submission. Nevertheless, the novelty remains insufficiently demonstrated in the manuscript text as currently written. In their response, the authors argue that the key contribution lies in embedding a poorly water‑soluble drug into a homogeneous polymer matrix system (PVP/PVA) and showing enhanced permeation; however, the methods, analysis, and positioning in the main text do not yet make this contribution clear or distinguish it from established literature. In particular, homogeneous PVP/PVA‑type dissolving microneedles for poorly soluble drugs are already widely reported, and the present study must therefore articulate what is fundamentally new beyond that platform. 

 

The revised manuscript reiterates that the work is novel because it focuses on a homogeneous polymer matrix (PVP/PVA) for a poorly soluble API (flurbiprofen, FLU). However, the field already contains numerous examples of homogeneous dissolving microneedles using PVP/PVA or PVA‑sucrose matrices for low‑solubility drugs(https://doi.org/10.1063/5.0247733, https://doi.org/10.1063/5.0247733). As such, the choice of a homogeneous matrix by itself does not sufficiently establish novelty. The authors should explicitly position their contribution relative to this prior art and state what new design rule, mechanism, or performance envelope is revealed that could not be inferred from existing studies.

 

The manuscript now claims that FLU “inherent solubility” increased from 1.1 to 15.3 µg/mL in PVP (≈14‑fold), but the measurement conditions are not specified (pH, ionic strength, temperature, equilibration time with excess solid, filtration, analytical method). Given that FLU is a weakly acidic BCS Class II compound with marked pH‑dependent solubility, the current description is insufficient to verify whether the reported values reflect thermodynamic equilibrium solubility or transient supersaturation. Please provide (a) a standardized solubility protocol, (b) pH‑resolved equilibrium solubility (e.g., pH 1.2/4.5/6.8 at 25/37 °C), and (c) replicate statistics. Without these, the central claim that this is a “poorly water‑soluble drug” study leveraging a homogeneous matrix remains methodologically under‑supported in the text

Author Response

I appreciate the authors’ revisions in v2—most notably the explicit geometric definition for the star‑type microneedles (vertex count and angle in Table 1) and the addition of permeation kinetics (Jss, lag time, retention; Table 2). These changes improve clarity relative to the original submission. Nevertheless, the novelty remains insufficiently demonstrated in the manuscript text as currently written. In their response, the authors argue that the key contribution lies in embedding a poorly water‑soluble drug into a homogeneous polymer matrix system (PVP/PVA) and showing enhanced permeation; however, the methods, analysis, and positioning in the main text do not yet make this contribution clear or distinguish it from established literature. In particular, homogeneous PVP/PVA‑type dissolving microneedles for poorly soluble drugs are already widely reported, and the present study must therefore articulate what is fundamentally new beyond that platform.

 

Response: I am grateful for your continued guidance. I have carefully integrated your feedback into the latest version of the manuscript. I hope that these further enhancements address all remaining concerns and meet the high standards of the journal.

 

Point 1.  The revised manuscript reiterates that the work is novel because it focuses on a homogeneous polymer matrix (PVP/PVA) for a poorly soluble API (flurbiprofen, FLU). However, the field already contains numerous examples of homogeneous dissolving microneedles using PVP/PVA or PVA‑sucrose matrices for low‑solubility drugs (https://doi.org/10.1063/5.0247733, https://doi.org/10.1063/5.0247733). As such, the choice of a homogeneous matrix by itself does not sufficiently establish novelty. The authors should explicitly position their contribution relative to this prior art and state what new design rule, mechanism, or performance envelope is revealed that could not be inferred from existing studies.

 

Response 1: I sincerely appreciate your insightful feedback regarding the novelty of my work. While numerous studies have utilized polymer matrices for microneedle fabrication, research focusing specifically on enhancing both the solubility and skin permeability of poorly soluble drugs remains notably sparse. I believe my manuscript offers significant novelty by demonstrating how strategic structural optimization—specifically the geometric design of the microneedles—can effectively overcome the inherent delivery challenges associated with poorly soluble drugs. I have refined the manuscript based on your feedback, further clarifying these original contributions and highlighting the differences between my approach and existing polymer-based systems.

 

Added “While previous studies utilizing polymer matrices --- penetration efficiency of poorly water-soluble drugs.” in line 306-315.

 

Added one reference

 

Point 2.  The manuscript now claims that FLU “inherent solubility” increased from 1.1 to 15.3 µg/mL in PVP (≈14‑fold), but the measurement conditions are not specified (pH, ionic strength, temperature, equilibration time with excess solid, filtration, analytical method). Given that FLU is a weakly acidic BCS Class II compound with marked pH‑dependent solubility, the current description is insufficient to verify whether the reported values reflect thermodynamic equilibrium solubility or transient supersaturation. Please provide (a) a standardized solubility protocol, (b) pH‑resolved equilibrium solubility (e.g., pH 1.2/4.5/6.8 at 25/37 °C), and (c) replicate statistics. Without these, the central claim that this is a “poorly water‑soluble drug” study leveraging a homogeneous matrix remains methodologically under‑supported in the text.

 

Response 2: I sincerely appreciate your insightful feedback regarding the solubility evaluation methodology. As you correctly pointed out, our initial description of the criteria and experimental protocols was insufficient. Accordingly, I have completely revised the paper to include more detailed methods for measuring drug solubility. I believe these revisions provide a more solid foundation for interpreting permeation data.

 

Added “2.7. Solubility test” in line 229-238.

 

Revised “By incorporating the drug within the PVP matrix, --- potentially maintaining a supersaturated state that drives enhanced transdermal flux.” in line 415-420.

 

Reviewer 2 Report

Comments and Suggestions for Authors

The author has satisfactorily addressed all of my questions, and I recommend the article for publication.

Author Response

The author has satisfactorily addressed all of my questions, and I recommend the article for publication.

Response: I am grateful for the time and effort you dedicated to reviewing my manuscript. Your expert feedback has been instrumental in refining my methodology and discussion, leading to a much-improved final version. Thank you for your professional contribution to my research.

Round 3

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript has been sufficiently revised to be of sufficient quality to be published in Micromachines.