Efficacy of a novel microneedle patch for rejuvenation of the nasolabial fold

Skin rejuvenation plays a significant role in the esthetic medicine market. Microneedle patches have been developed for a wide range of applications based on the principles of transdermal drug delivery; however, clinical trials of microneedle patches for skin rejuvenation remain limited.


INTRODUCTION
Aging skin is a visible sign of physical aging. 1 Wrinkles gradually appear as collagen, and elastic fibers decrease over time, 2 and loss of subcutaneous fat and skin moisture accelerates the process. 3 Thus, there is an increasing demand for skin rejuvenation with both surgical and nonsurgical procedures, the favorability of which depends upon minimal invasiveness and downtime. Currently, there are various kinds of noninvasive cosmetics available on the market; however, their limited efficacy is often attributed to the low skin penetration of active compounds due to the stratum corneum, which serves as an external barrier. 4 The microneedle patch has been newly introduced for drug delivery through the skin 5 and has been used to improve transdermal delivery of active agents, such as drugs and vaccines, in various medical fields. 6 Since clinical trials of microneedle patches for skin rejuvenation remain limited, the purpose of this study was to measure the efficacy of a newly designed microneedle patch combined with hyaluronic acid (HA) for the improvement of the nasolabial fold.

Study design
The study was designed as an investigator-blinded, randomized controlled trial. The protocol was developed in accordance with the principles of good clinical practice and is within the appli-

Participants
Twenty-three Thai women aged 30-60 years were recruited as vol-

Microneedle patch and HA solution
The microneedle patches were prepared by the nanoneedle research team, responsive material and nanosensor research Group, National Nanotechnology Center, Thailand. The microneedle array was fabricated on the fabric substrate via the photo-polymerization technique.
Each microneedle was designed with a four-point star shape, as shown in Figure 1A. This four-point star structure is also shown from the side in Figure 1B, with a fin along each side of a microneedle. The average height (h) and base diameter (w) of the microneedles were 1100 and 280 μm, respectively. The distance between the tip of the microneedles (d) was 900 μm. The density of the microneedle array in this study was 265 needles/cm 2 . The shape of the microneedle patch was designed to cover the nasolabial fold area, and the total area of the microneedle array in the patch was 7.5 cm 2 . The active ingredient delivery mechanism of the microneedle array in the patch is presented in Figure 2. The fins of each four-point star-shaped microneedle formed a gap or channel between the microneedle grooves and tissue when it was punctured into skin. As seen in the schematic structure in Figure 3 (inset), a reservoir was attached to the patch, which was provided to each participant in group 1.

Intervention
A microneedle patch with HA was applied to the nasolabial fold area of right side of the participant's face, as shown in Figure 3, while the microneedle patch alone was applied to the other side once every 2 weeks for a total of 8 weeks. All applications were performed after the face was washed, and no topical anesthetics were administered during the clinical trial. Participants were instructed to massage the patch on each side for 5 min and then remove it. Moisturizers were provided to each participant.

Quantitative evaluation of wrinkle improvement
The severity of wrinkles was assessed before patch application and again at 2, 4, 8, 12, and 16 weeks.

2.6
Subjective and objective assessments of wrinkle improvement

Safety and product preference
Patients were surveyed for development of any adverse effects, such as erythema, edema, itching, and irritation, at each visit. No adverse effects were reported.

Statistical analysis
All data are presented as mean ± SD. Statistical significance was set at p < 0.05. All statistical analyses were performed using Statistical Package for the Social Sciences software (Chicago, IL, USA). Generalized estimating equations were used for intragroup and intergroup comparisons.

Patient characteristics
The average age of the 23 participants who participated in this study was 50.78 ± 6.41 years. Nine people (39.13%) were in their 40s, 12 (52.17%) were in their 50s, and two (8.69%) were in their 60s. All participants were women.
F I G U R E 4 Nasolabial fold wrinkle grade assessed by independent blinded dermatologists (*p < 0.05 compared within groups)

F I G U R E 5
The change in nasolabial fold wrinkle grade assessed by independent blinded dermatologists between groups (*p < 0.05 compared within groups)    Figure 7. Clinical photographs are shown in Figures 8 and 9.

Safety end points
No adverse effects were reported by the participants during the application period of the test product, and no skin abnormalities were observed on physical examination by the dermatologist. In the survey for the microneedle patch preference, 100% of participants answered "no" when asked about pain induced by the patch.

CONFLICT OF INTEREST
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.

ETHICS STATEMENT
The authors confirm that the ethical policies of the journal, as noted on the journal's author guidelines page, have been adhered to, and the appropriate ethical review committee approval has been received.
The Institutional Review Board of the Human Research Ethics Committee of Thammasat University (Medicine) approved all study protocols (number: MTU-EC-OO-0-078/64, November 25, 2021) and relevant supporting data. Written informed consent was obtained from all participants.