Recent Advances in Microneedling-Assisted Cosmetic Applications

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Dears authors:

Thank you for submitting your manuscript to Journal of Cosmetics. I have received your manuscript entitled “Recent Advances in Microneedling-Assisted Cosmetic Applications”

 

The article is good in general, it is written in good language and well arranged, and highlights a modern and important technique in cosmetic treatments. but it does not include clinical trials or treatments on patients or experimental animals, and not even statistical studies. It is as if it were a book or a theoretical review of the use of microneedling in treatments and its types and methods...

 

However, I have some questions:

1.The mechanism of microneedling has not been discussed?

2.In treating skin cancer with microneedling, there is no fear of the spread of cancer cells during microneedling treatment?

3.Melasma and vitiligo are two opposite conditions on the skin.... The first is the presence of hyperpigmented spots on the skin and the second is the presence of hypopigmented areas of the skin... Can we really treat both conditions with microneedling and how is the skin reaction different in each disease using the same technique...? Do the cells responsible for wound healing have this intelligence to increase or decrease melanocytes depending on the clinical situation?

4. Mechanism and effectiveness of microneedling on surgical scars?

5.The use of microneedling with radiofrequency has not been reported!?

Comments for author File: Comments.pdf

Author Response

Response to reviewers

We would like to thank the reviewers for the careful and thorough reading of this manuscript and for the thoughtful comments and constructive suggestions, which helped to improve the quality of this manuscript. Kindly find our response to the reviewers. We have been able to incorporate changes to reflect most of the suggestions provided by the reviewers. Please let me know if there are any questions or if it is unclear. Here is a point-by-point response to the reviewers’ comments and concerns.

Reviewer 1

[Cosmetics] Manuscript ID: cosmetics-2894722 - Review Request

Type of manuscript: Review

Title: Recent Advances in Microneedling-Assisted Cosmetic Applications

Special Issue: 10th Anniversary of Cosmetics—Recent Advances and

Perspectives.

Dears authors:

Thank you for submitting your manuscript to Journal of Cosmetics. I have received your manuscript entitled “Recent Advances in Microneedling-Assisted Cosmetic Applications”

The article is good in general, it is written in good language and well arranged, and highlights a modern and important technique in cosmetic treatments. but it does not include clinical trials or treatments on patients or experimental animals, and not even statistical studies. It is as if it were a book or a theoretical review of the use of microneedling in treatments and its types and methods...

We thank the reviewer for pointing this out. The manuscript reported several studies that discussed the clinical treatments of microneedles applied to patients. Please check for example [1-6].

However, I have some questions:

1.The mechanism of microneedling has not been discussed?

We thank the reviewer for pointing this out. Two mechanisms of microneedling have been added to the revised manuscript (page 4, lines 132-149).

Two mechanisms have been proposed for microneedling [7]. The first mechanism suggests that microneedling leads to the release of growth factors that stimulate collagen and elastin formation in the papillary dermis. Briefly, the needles penetrate the SC and create small holes (micropunctures) without damaging the epidermis. These micro-injuries lead to minimal superficial bleeding, inducing the wound-healing cascade and activating the platelets and neutrophils to release the growth factors (transforming growth factor (TGF)-alpha, TGF-beta, and platelet-derived growth factor) and stimulate the production of collagen and elastin in the papillary layer of the dermis. This ultimately results in the deposition of collagen by fibroblasts [7-9]. Moreover, micropores created by microneedling enhance the permeation of skin care formulations, thus boosting their efficacy [10]. The second mechanism suggests that microneedling generates a demarcation current rather than physical wounds when microneedles penetrate the skin. This current triggers a cascade of growth factors that facilitate the healing process. This mechanism based on the concept of bioelectricity, where epidermal injury alters the electric potential within cells to a negative electric potential of -70 mV, compared to the epidermis which has a positive potential. It is anticipated that the change in the potential stimulates the migration and proliferation of fibroblasts to the site of injury, leading to collagen deposition at the injury site [7, 11].

2.In treating skin cancer with microneedling, there is no fear of the spread of cancer cells during microneedling treatment?

We thank the reviewer for pointing this out. The elective microneedling for cosmetic purposes is not advised for cancer patients, exactly like any abrasive procedure. While microneedling has proven efficacy in treating skin cancer, there are concerns regarding the potential spread of cancer cells if microneedling performed over a cancer skin lesion affected by cancer. Nevertheless, to the best of our knowledge there are currently no published studies that definitively confirm the spread of skin cancer through microneedling (page 12, line 452-456).

3. Melasma and vitiligo are two opposite conditions on the skin.... The first is the presence of hyperpigmented spots on the skin and the second is the presence of hypopigmented areas of the skin... Can we really treat both conditions with microneedling and how is the skin reaction different in each disease using the same technique...? Do the cells responsible for wound healing have this intelligence to increase or decrease melanocytes depending on the clinical situation?

We thank the reviewer for pointing this out. The use of microneedling in treating vitiligo and melasma has been discussed in details in Sections 2.1.2 and 2.1.4, respectively. The discussion focusses on using a combination therapy of microneedling and topical therapies for these skin conditions. The following paragraph highlights the mechanism of action of microneedling in melasma and vitiligo (page 10, line 364-378).

Microneedling shows promise in treating melasma (hyperpigmentation) and vitiligo (hypopigmentation) to varying degrees with different mechanisms [9, 12]. The skin reaction to microneedling differs between melasma and vitiligo due to their distinct pathophysiology [13]. In melasma, microneedling may help by stimulating collagen production and facilitating the penetration of topical medications, potentially leading to improvement in hyperpigmented spots [12, 14]. Additionally, microneedling may induce controlled injury, triggering a healing response that could lead to melanocyte activation and pigment dispersion [15]. Whereas, in vitiligo, microneedling may not directly address the underlying cause of depigmentation but could potentially aid in promoting melanocyte and keratinocytes proliferation and their migration to the hypopigmented areas, potentially aiding repigmentation [16, 17]. As for the intelligence of wound-healing cells in modulating melanocytes, research suggests that fibroblasts, keratinocytes, and immune cells play critical roles in regulating melanocyte function and distribution. These cells release factors such as cytokines, growth factors, and extracellular matrix components, which influence melanocyte behavior in response to stimuli, including wound healing processes [18].

4. Mechanism and effectiveness of microneedling on surgical scars?

We thank the reviewer for pointing this out. The following paragraph has been added to the revised manuscript to discuss the role of microneedling in surgical scars (page 8, line 245-251).

Microneedling is a widely used procedure for improving the final appearance of surgical scars [19]. Microneedling creates controlled micro-injuries to the skin, which stimulate the natural wound-healing response of the body. The healing process leads to the production of new collagen and elastin, resulting in the remodeling of scar tissues that ultimately improves the texture, color, and overall appearance of the scars [20]. Several studies have demonstrated the effectiveness of microneedling in treating various types of scars, including surgical scars [21-23].

5.The use of microneedling with radiofrequency has not been reported!?

We thank the reviewer for pointing this out. The use of microneedling with radiofrequency was reported under Skin Rejuvenation, Section 2.1.5. Nevertheless, more discussion has been added about the use of microneedling with radiofrequency (page 11, line 405-424).

Microneedling was combined with a radiofrequency (RF) energy to stimulate the production of collagen [24]. The radiofrequency microneedling (RFM) is used to treat various skin conditions such as acne scars, acne vulgaris, and skin rejuvenation [25]. The RFM devices are composed of an energy system of 50 W output and a disposable tip with 49 insulated gold-plated needles. The depth of the needles can be adjusted from 0.5 to 3.5 mm [26]. The RF energy heats the skin up to 65-70º C, without thermally damaging the epidermis [25, 27]. The insulated needles penetrate the epidermis with minimal heating while effectively delivering the desired energy to predetermined depths [27]. The adjustable needles’ depths allows distinct electrothermal coagulation at different dermis layers [26]. Several studies showed that fractional radiofrequency is safe and effective for treating moderate and severe acne scars in different skin types [26, 28, 29]. Kim et al. [30] reported the findings of a pilot study on the effect of an antioxidant topical formulation containing L-ascorbic acid, vitamin E, and ferulic acid on facial photo-aging after microneedling treatment with radio-frequency (FMRF). In this study, all patients were treated using a pulse-type fractional microneedle FMRF device (SylfirmTM, Seongnam, Korea) with 25 non-insulated microneedles in 5 x 5 arrays. Patients were instructed to apply four to five drops of the topical formulation to one side of the face immediately after FMRF treatment. Results showed that the laser-assisted delivery of the antioxidant formulation following FMRF was the safe and effective adjuvant approach for the treatment of photo-damaged skin.

 References

1. Ali, B.; N. ElMahdy , and N.N. Elfar. Microneedling (Dermapen) and Jessner’s solution peeling in treatment of atrophic acne scars: a comparative randomized clinical study. J. Cosmet. Laser Ther. 2019, 21(6), 357-363.
2. KIM, S.-K.; Y.-H. JANG; Y.-H. SON; C.-S. LEE; J.-Y. BAE , and J.-M. PARK. Management of Hypertrophic Scar after Burn Wound Using Microneedling Procedure (Dermastamp (R)). J. Korean. Burn. Soc. 2009, 121-124.
3. Mina, M.; L. Elgarhy; H. Al‐saeid , and Z. Ibrahim. Comparison between the efficacy of microneedling combined with 5‐fluorouracil vs microneedling with tacrolimus in the treatment of vitiligo. J. Cosmet. Dermatol. 2018, 17(5), 744-751.
4. Yang, G.; Q. Chen; D. Wen; Z. Chen; J. Wang; G. Chen; Z. Wang; X. Zhang; Y. Zhang , and Q. Hu. A therapeutic microneedle patch made from hair-derived keratin for promoting hair regrowth. ACS Nano. 2019, 13(4), 4354-4360.
5. Hong, C.; G. Zhang; W. Zhang; J. Liu; J. Zhang; Y. Chen; H. Peng; Y. Cheng; X. Ding , and H. Xin. Hair grows hair: Dual-effective hair regrowth through a hair enhanced dissolvable microneedle patch cooperated with the pure yellow light irradiation. Appl. Mater. Today. 2021, 25, 101188.
6. Yang, H.; S. Kim; M. Jang; H. Kim; S. Lee; Y. Kim; Y.A. Eom; G. Kang; L. Chiang; J.H. Baek; J.H. Ryu; Y.E. Lee; J. Koh , and H. Jung. Two-phase delivery using a horse oil and adenosine-loaded dissolving microneedle patch for skin barrier restoration, moisturization, and wrinkle improvement. J. Cosmet. Dermatol. 2019, 18(3), 936-943.
7. Majid, I.; G. Sheikh , and P. September. Microneedling and its applications in dermatology. Prime Int J Aesthetic Anti-Ageing Med. Healthcare. 2014, 4(7), 44-9.
8. Doddaballapur, S. Microneedling with dermaroller. J. Cutan. Aesthet. Surg. 2009, 2(2), 110-111.
9. Iriarte, C.; O. Awosika; M. Rengifo-Pardo , and A. Ehrlich. Review of applications of microneedling in dermatology. Clin. Cosmet. Investig. Dermatol. 2017, 10, 289-298.
10. Dsouza, L.; V.M. Ghate , and S.A. Lewis. Derma rollers in therapy: the transition from cosmetics to transdermal drug delivery. Biomed. Microdevices. 2020, 22(4), 1-11.
11. Fabbrocini, G.; N. Fardella; A. Monfrecola; I. Proietti , and D. Innocenzi. Acne scarring treatment using skin needling. Clin. Exp. Dermatol. 2009, 34(8), 874-879.
12. Lima, E.d.A. Microneedling in facial recalcitrant melasma: report of a series of 22 cases. An. Bras. Dermatol. 2015, 90, 919-921.
13. Speeckaert, R.; V. Bulat; M.M. Speeckaert , and N. van Geel. The Impact of Antioxidants on Vitiligo and Melasma: A Scoping Review and Meta-Analysis. Antioxidants. 2023, 12(12), 2082.
14. Arenas-Soto, C. Microneedles: a therapeutic alternative in melasma. J. Dermat. Cosmetol. 2018, 2, 207-210.
15. Ogbechie-Godec, O.A. and N. Elbuluk. Melasma: an up-to-date comprehensive review. Dermatol. Ther. 2017, 7, 305-318.
16. Aust, M.C.; D. Fernandes; P. Kolokythas; H.M. Kaplan , and P.M. Vogt. Percutaneous collagen induction therapy: an alternative treatment for scars, wrinkles, and skin laxity. Plastic and reconstructive surgery. 2008, 121(4), 1421-1429.
17. Roohaninasab, M.; K. Gandomkar , and A. Goodarzi. Microneedling in vitiligo: A systematic review. Surg. Cosmet. Dermatol. 2022, 14, e20220123.
18. Gao, F.L.; R. Jin; L. Zhang , and Y.G. Zhang. The contribution of melanocytes to pathological scar formation during wound healing. Int J Clin Exp Med. 2013, 6(7), 609-13.
19. Claytor, R.B.; C.G. Sheck , and V. Chopra. Microneedling outcomes in early postsurgical scars. Plast. Reconst. Surg. 2022, 150(3), 557e-561e.
20. Singh, A. and S. Yadav. Microneedling: Advances and widening horizons. Indian Dermatol. Online J. 2016, 7(4), 244-254.
21. Ramaut, L.; H. Hoeksema; A. Pirayesh; F. Stillaert , and S. Monstrey. Microneedling: Where do we stand now? A systematic review of the literature. J. Plast. Reconstr. Aesthet. Surg. 2018, 71(1), 1-14.
22. Juhasz, M.L. and J.L. Cohen. Microneedling for the treatment of scars: an update for clinicians. Clin. Cosmet. Investig. Dermatol. 2020, 997-1003.
23. Lima, E.; M. Lima; E. Lima , and M. Lima. Correcting Post-surgical Scar Using PCI. Percutaneous Collagen Induction With Microneedling: A Step-by-Step Clinical Guide. 2021, 133-139.
24. Dayan, E.; C. Chia; A.J. Burns , and S. Theodorou. Adjustable depth fractional radiofrequency combined with bipolar radiofrequency: a minimally invasive combination treatment for skin laxity. Aesthet. Surg. J. 2019, 39(Suppl 3), S112.
25. Hidajat, D. and S. Murlistyarini. Successful treatment of rare adverse event after radiofrequency microneedle on Fitzpatrick skin type IV: a case report. J. Cosmet. Laser. Ther. 2024, 1-5.
26. Chandrashekar, B.S.; R. Sriram; R. Mysore; S. Bhaskar , and A. Shetty. Evaluation of microneedling fractional radiofrequency device for treatment of acne scars. J. Cutan. Aesthet. Surg. 2014, 7(2), 93-97.
27. Baek, G.; M.H. Kim , and M.S. Jue. Efficacy of microneedle radiofrequency therapy in the treatment of senile purpura: A prospective study. Skin Res. Technol. 2022, 28(6), 856-864.
28. Eubanks, S.W. and J.A. Solomon. Safety and efficacy of fractional radiofrequency for the treatment and reduction of acne scarring: a prospective study. Lasers. Surg. Med. 2022, 54(1), 74-81.
29. Li, J.; F. Duan , and J. Kuang. Meta‐analysis of fractional radiofrequency treatment for acne and/or acne scars. J. Cosmet. Dermatol. 2022, 21(12), 6754-6766.
30. Kim, J.; S.M. Kim; B.K. Jung; S.H. Oh; Y.-K. Kim , and J.H. Lee. Laser-assisted Delivery of a Combined Antioxidant Formulation Enhances the Clinical Efficacy of Fractional Microneedle Radiofrequency Treatment: A Pilot Study. Medical Lasers; Engineering, Basic Research, and Clinical Application. 2021, 10(3), 161-169.

 

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

A well written and organized review on microneedle based cosmetic applications. 

Please review and fill in data for Table 2. The best comparison of microneedles is their number (array or single) length, and width. Some rows are missing these informations.

Please elaborate on line 744-745. What type of microneedles are referred to. Solid material based ones can be removed with ease.

Formatting recommendations:

Table 1 on page 6 has a distorted formatting, missing column headers and maybe the 3 columns are not present.

Table 2 is not centered on page.

minor formatting differences: line: 89 letter size, lines 439 - 444 letter size and typeface.

please note: silicon and silicone are two different materials ( line 124 and Table 4)

Please review References, some are missing exact bibliography data:

Refs: 6, 36, 46, 99, 167.

Please check for duplicates: e.g. Ref 46 is identical with Ref. 185.

Author Response

Response to reviewers

We would like to thank the reviewers for the careful and thorough reading of this manuscript and for the thoughtful comments and constructive suggestions, which helped to improve the quality of this manuscript. Kindly find our response to the reviewers. We have been able to incorporate changes to reflect most of the suggestions provided by the reviewers. Please let me know if there are any questions or if it is unclear. Here is a point-by-point response to the reviewers’ comments and concerns.

Reviewer 2

A well written and organized review on microneedle based cosmetic applications. 

Please review and fill in data for Table 2. The best comparison of microneedles is their number (array or single) length, and width. Some rows are missing these information.

We thank the reviewer for pointing this out. The information compiled in Table 2 has been compiled from many studies with the most accessible information on the FDA-approved microneedling devices for cosmetic applications. Nevertheless, the number, length, and width of microneedling devices were reported in the manuscript whenever these data were available.   

Please elaborate on line 744-745. What type of microneedles are referred to. Solid material based ones can be removed with ease.

We thank the reviewer for pointing this out. The type of microneedles (polymeric microneedles) has been added to the revised manuscript (page 23, line 834).

Formatting recommendations:

Table 1 on page 6 has a distorted formatting, missing column headers and maybe the 3 columns are not present.

We thank the reviewer for pointing this out. Table 1 has been checked. Nothing is missing, however, Dermaroller and Dermapen shared similar specifications including Microneedling setup and Recovery of the skin barrier function.  

Table 2 is not centered on page.

We thank the reviewer for pointing this out. Table 2 has been centered on page.

minor formatting differences: line: 89 letter size, lines 439 - 444 letter size and typeface.

We thank the reviewer for pointing this out. Formatting differences have been corrected.

please note: silicon and silicone are two different materials (line 124 and Table 4)

We thank the reviewer for pointing this out. This has been corrected to “silicone”.

Please review References, some are missing exact bibliography data:

Refs: 6, 36, 46, 99, 167.

We thank the reviewer for pointing this out. All references have been reviewed.

Please check for duplicates: e.g. Ref 46 is identical with Ref. 185.

We thank the reviewer for pointing this out. All references have been reviewed.

 

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

The paper aims to provide a comprehensive overview of the recent advancements in microneedling technology and its applications in the field of cosmetic dermatology. The main contributions of the paper include a detailed comparison of microneedling devices such as dermaroller and dermapen, the safety and regulatory considerations of microneedling, and the potential applications of microneedling in delivering cosmetic agents for various skin conditions.

The manuscript is presented in a clear and organized manner, making it a valuable resource for researchers and practitioners in the field. Overall, the document is well-structured, relevant, and provides a comprehensive overview of microneedling-assisted cosmetic applications.

The article touches on the safety and regulatory aspects of microneedling devices, mentioning FDA classifications and concerns. However, the discussion on the safety regulations related to microneedling products could be expanded to include more specific guidance on the approval process, especially for new microneedling devices entering the market.

The authors should address the potential for adverse effects more thoroughly, including the risk of infection, skin irritation, and allergic reactions, and provide recommendations for minimizing these risks.

The article mentions the importance of needle sharpness and the materials used in fabricating microneedles. However, there is a lack of in-depth discussion on the material science behind microneedle fabrication, which is crucial for understanding their safety and efficacy. The authors should elaborate on the types of materials used, their biocompatibility, and how they influence the performance of microneedling devices.

The authors should format the tables (font size) and the text wrapping and also the font size for line 439-444.

The conclusion briefly mentions the limitations of the clinical application of fabricated microneedle patches, such as their limited coverage area and loading capacity. The authors should explore these limitations in greater detail and discuss ongoing research and potential innovations that may overcome these challenges.

 

Author Response

Response to reviewers

We would like to thank the reviewers for the careful and thorough reading of this manuscript and for the thoughtful comments and constructive suggestions, which helped to improve the quality of this manuscript. Kindly find our response to the reviewers. We have been able to incorporate changes to reflect most of the suggestions provided by the reviewers. Please let me know if there are any questions or if it is unclear. Here is a point-by-point response to the reviewers’ comments and concerns.

Reviewer 3

The paper aims to provide a comprehensive overview of the recent advancements in microneedling technology and its applications in the field of cosmetic dermatology. The main contributions of the paper include a detailed comparison of microneedling devices such as dermaroller and dermapen, the safety and regulatory considerations of microneedling, and the potential applications of microneedling in delivering cosmetic agents for various skin conditions.

The manuscript is presented in a clear and organized manner, making it a valuable resource for researchers and practitioners in the field. Overall, the document is well-structured, relevant, and provides a comprehensive overview of microneedling-assisted cosmetic applications.

The article touches on the safety and regulatory aspects of microneedling devices, mentioning FDA classifications and concerns. However, the discussion on the safety regulations related to microneedling products could be expanded to include more specific guidance on the approval process, especially for new microneedling devices entering the market.

We thank the reviewer for pointing this out. The safety and regulatory aspects of microneedling devices were discussed in the original manuscript (Sections: Safety of microneedling and Regulations related to microneedling products). Nevertheless, more specific guidance on the approval process, especially for new microneedling devices entering the market has been added to the revised manuscript (page 23, line 896-912).

Additionally, according to FDA guidance, for a new microneedling device entering the market, the manufacturers should demonstrate a significant equivalent of their device to those legally available in the market. Based on the special controls described in 21 CFR 878.4430, the health risks associated with microneedling devices should be mitigated. These health risks include adverse tissue reaction or tissue damage, cross-contamination and skin infection, electrical shock, nerve and blood vessel damage, scarring, hyper/hypopigmentation, mechanical failure, or software failure. For new microneedling devices, FDA may request clinical data and non-clinical testing, if needed. The clinical data should describe the following: 1) clinical study protocol and representative subjects enrolled for the intended use of the device, 2) safety data collection to support the safe use of the device, 3) the proposed effectiveness endpoint of the new microneedling device, and 4) follow-up period that ensures a reasonable assessment of the short-term and long-term performance of the device, including the safety and effectiveness of the device [1]. Nevertheless, the special controls in 21 CFR 878.4430 might differ based on the specific features of the new microneedling device, where a wireless microneedling device would require additional controls to mitigate electrical shock hazard that is not essential in a roller with fixed needles [1].

The authors should address the potential for adverse effects more thoroughly, including the risk of infection, skin irritation, and allergic reactions, and provide recommendations for minimizing these risks.

We thank the reviewer for pointing this out. More adverse effects of microneedling have been added to the revised manuscript, including skin infection, irritant and allergic contact dermatitis, hyperpigmentation, abnormal scarring, and irritant and allergic granulomas [2] (Page 22, line 816-818).

To minimize the side effects of microneedling, patients with recent sun exposure are recommended to delay the microneedling procedure until all traces of suntan have faded to avoid post-microneedling dyspigmentation. In addition, patients with oral herpes labialis might be at high risk for viral reactivation post-microneedling. Moreover, microneedling over inflammatory or active acne lesions may lead to bacterial microabscesses or granulomas. Furthermore, skin preparation and hygiene before microneedling procedure is important, where proper skin cleansing removes makeup and debris from the skin’s surface and reduces the risk of introducing bacteria into the deeper skin layers, decreasing superficial skin infections [3] (Page 23, line 825-833).

The article mentions the importance of needle sharpness and the materials used in fabricating microneedles. However, there is a lack of in-depth discussion on the material science behind microneedle fabrication, which is crucial for understanding their safety and efficacy. The authors should elaborate on the types of materials used, their biocompatibility, and how they influence the performance of microneedling devices.

We thank the reviewer for pointing this out. A discussion on the material science used in the fabrication of MNs has been added to the revised manuscript (Page13-14, line 467-497).

Silicon, metals, ceramic, and polymeric materials are employed in the fabrication of MNs [4]. The first introduced MNs were silicon-made. Multiple shapes and types of MNs could originate from silicon owing to its flexible nature, which makes it a preferable material. However, a variety of drawbacks limit the usage of silicon in MN fabrication including high cost, time-consuming, complex procedure, and high skin fracture potential which may lead to skin infections. For handling such concerns, a compatible, biodegradable nano-structured porous silicon has been developed on the MNs’ tip. Thus, even if the tip is fractured and persists within the skin, it will be degraded in a few weeks. The manufacturing of silicon MNs with nano- and porous features significantly affects the skin’s permeability and results in improved drug delivery [5]. Metals, mainly stainless steel and titanium, exhibit decent mechanical characteristics; hence they are prevalent in the production of MNs [6]. Before titanium, stainless steel was the first metal used in the manufacturing of MNs. It has been utilized over a few decades due to its biocompatibility under expanded clinical use and patient compliance [5]. Metallic materials are more rigid and difficult to fracture relative to silicon [7]. Although metal MNs are capable of penetrating skin, their application may lead to allergic response [7]. Porous titanium MNs, which are relatively novel developments, have been investigated for various biomedical transdermal delivery systems, including the loading and delivery of macromolecule compounds like insulin [8]. Ceramic materials, such as alumina, calcium sulfate dihydrate, and calcium phosphate dihydrate, have been employed in the manufacturing of MNs owing to their valuable chemical characteristics, reliable resistance to compression, and biocompatibility [7]. On the other hand, the lower tensile strength is represented by these materials, particularly alumina which is fragile and readily broken within the patient’s body [9]. Currently, alumina is frequently utilized to fabricate micro- or nano-scale porous MNs for delivering fluids [9]. Polymers have gained a lot of interest in MNs fabrication due to their biocompatibility, biodegradability, cost-effective, and distinct mechanical properties, such as their capacity to resist higher bending stresses without breaking down [10]. However, they are weaker than metals and silicon [11]. A variety of polymers, including poly (methyl methacrylate) (PMMA), polylactic acid (PLA), poly (carbonate), polystyrene, and SU-8 photoresist, were utilized to fabricate MNs [7, 12].

The authors should format the tables (font size) and the text wrapping and also the font size for line 439-444.

We thank the reviewer for pointing this out. The font size of the tables and text wrapping has been adjusted.

The conclusion briefly mentions the limitations of the clinical application of fabricated microneedle patches, such as their limited coverage area and loading capacity. The authors should explore these limitations in greater detail and discuss ongoing research and potential innovations that may overcome these challenges.

We thank the reviewer for pointing this out. To overcome the limitations of the clinical application of fabricated MN patches, alternative materials with desirable MNs’ attributes such as better mechanical properties (strength and flexibility) and biocompatibility should be explored. In addition, new fabrication methods for MNs that can improve the delivery of several types of MNs for different therapeutic applications should be investigated. In future research, novel materials, new fabrication methods, and commercialization will be discussed in details to ensure medical efficiency, cost-effectiveness, and mass production of fabricated MNs. In addition, advanced applications of MNs including disease detection, management, monitoring, diagnostic, and personalized medicine will be explored (page 14, line 930-938).

 

 References

1. FDA. Regulatory considerations for microneedling products. Guidance for Industry and Food and Drug Administration Staff 2020; November 10, 2020.:[Available from: https://www.fda.gov/media/107708/download.
2. Cary, J.H.; B.S. Li , and H.I. Maibach. Dermatotoxicology of microneedles (MNs) in man. Biomed. Microdevices. 2019, 21, 1-8.
3. Alster, T.S. and P.M. Graham. Microneedling: a review and practical guide. Dermatol. Surg. 2018, 44(3), 397-404.
4. Luo, X.; L. Yang , and Y. Cui. Microneedles: materials, fabrication, and biomedical applications. Biomed. Microdevices. 2023, 25(3), 20.
5. Waghule, T.; G. Singhvi; S.K. Dubey; M.M. Pandey; G. Gupta; M. Singh , and K. Dua. Microneedles: A smart approach and increasing potential for transdermal drug delivery system. Biomed. Pharmacother. 2019, 109, 1249-1258.
6. Dharadhar, S.; A. Majumdar; S. Dhoble , and V. Patravale. Microneedles for transdermal drug delivery: a systematic review. Drug Dev. Ind. Pharm. 2019, 45(2), 188-201.
7. Aldawood, F.K.; A. Andar , and S. Desai. A Comprehensive Review of Microneedles: Types, Materials, Processes, Characterizations and Applications. Polymers. 2021, 13(16), 2815.
8. Sargioti, N.; T.J. Levingstone; E.D. O’Cearbhaill; H.O. McCarthy , and N.J. Dunne. Metallic microneedles for transdermal drug delivery: applications, fabrication techniques and the effect of geometrical characteristics. Bioengineering. 2022, 10(1), 24.
9. Bao, L.; J. Park; G. Bonfante , and B. Kim. Recent advances in porous microneedles: Materials, fabrication, and transdermal applications. Drug Deliv. Transl. Res. 2022, 12, 395-414.
10. Ebrahiminejad, V.; Z.F. Rad; P.D. Prewett , and G.J. Davies. Fabrication and testing of polymer microneedles for transdermal drug delivery. Beilstein J. Nanotechnol. 2022, 13(1), 629-640.
11. Al-Japairai, K.A.S.; S. Mahmood; S.H. Almurisi; J.R. Venugopal; A.R. Hilles; M. Azmana , and S. Raman. Current trends in polymer microneedle for transdermal drug delivery. Int. J. Pharm. 2020, 587, 119673.
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Author Response File: Author Response.pdf