A survey on the cosmetic use of injectable polynucleotide: The pattern of practice among Korean Dermatologists

Skin boosters denote injectables that promote global improvement of the skin which includes skin texture, elasticity, hydration, and overall appearance. Polynucleotide (PN) products have become popular, but there is surprisingly little guidance on their use. We aimed to maximize the safety and efficacy of injectable PN by providing information on their pattern of practice among board‐certified dermatologists.


| INTRODUC TI ON
Aging is a natural and inevitable process, and the skin is no exception.
Anti-aging treatment has come a long way, and with the increased preference for a "natural look," minimally invasive procedures are the new normal in the cosmetic industry.The term "skin booster" was first used interchangeably with small particle hyaluronic acid (HA) filler products but now includes a variety of substances that enhance the skin's overall condition. 1More specifically, it refers to injectables which can be placed directly into the skin.In Korea, the most popular "skin booster" at present is injectable polynucleotide (PN).
Polydeoxyribonucleotide (PDRN) is a mixture of low molecular weight DNA fragments acquired from Oncorhynchus mykiss (Salmon trout) or Oncorhynchus keta (Chum Salmon) sperm DNA. 2 By activating adenosine A2 receptors and the "salvage pathway," PDRN can help tissue repair and exert anti-inflammatory effect 3 and has been successfully applied to degenerative joints and diabetic foot ulcers. 4PN on the other hand, is a high molecular weight DNA chain extracted from salmon or trout gonads. 5It is more viscoelastic than PDRN, and by forming a three-dimensional porous structure, PN lasts longer and provides structural support, allowing it to be more suitable for skin rejuvenation. 6Currently, a number of PN injectables are available in different countries (i.e., NEWEST and PLINEST, Mastelli, Italy).However, REJURAN® (PharmaResearch Inc., Seoul, Korea) is the only commercial PN product in Korea that is allowed direct skin injection and represents the injectable PN mentioned throughout the survey.
Here, we have documented the current trend in Korean cosmetic practice, focusing on the practice pattern of injectable PN among Korean dermatologists.

| MATERIAL S AND ME THODS
A detailed questionnaire on the practice pattern of injectable PN was developed by the Korean Society of Anti-Aging Dermatology (KAAD) (Tables 1 and 2).The questionnaire was distributed to 1500 Korean Dermatologists who practice in various settings (primary, secondary, and tertiary hospitals).A web-based survey platform (http:// www.surve ymonk ey.com), accessed from August 29, 2022, to November 7, 2022) was adopted.The questionnaire link was sent through mobile phone text messages, and the respondents answered by accessing the site.A total of 235 Korean board-certified dermatologists familiar with skin boosters participated in the survey, of which 172 answered all questions (survey completion), and 63 showed partial response.This survey study was ethically approved by the Institutional Review Board (IRB) (IRB number: OC23QISI0049).

TA B L E 1
Questionnaire on the practice pattern of injectable PN (primary questionnaire).
Q1. How long have you been practicing as a board-certified dermatologist?
• Less than 1 year A total of 235 dermatologists knowledgeable of skin boosters responded.71 percent of the survey participants had at least 7 years of experience as a board-certified dermatologist, and 42% have been a specialist for 10 years and over (Figure 1A).

| Select the best indications to practice injectable PN (multiple choice, max 5)
The top 6 indications for injectable PN were fine lines on the cheek (63%) followed by infraorbital fine lines (56%), periorbital fine lines TA B L E 2 Questionnaire on the practice pattern of injectable PN (secondary questionnaire).
For each indication you selected (Primary questionnaire Q3), answer the following questions.

| Which device and setting do you prefer most when injecting PN? (choose one)
For fine lines (including those on the cheek, infraorbital and periorbital area, and forehead), the needle (74%) was the most preferred device for delivering PN, followed by the injector (23%) and cannula (3%).A 33G needle (54%), using the serial puncture technique (81%), targeting the dermis (85%) at a treatment interval of 4 weeks (75%) was the typical setting.

| Which injectable would you use alongside PN? And what would be its injection depth? (multiple choice)
For fine lines (including those on the cheek, infraorbital and periorbital area, and forehead), 55% of the survey respondents chose botulinum toxin to be injected alongside PN followed by non-cross-linked HA (33%), lightly cross-linked HA (15%), and PLA (8%).27 percent of the participants replied that they would inject PN alone.The injectables were most often targeted to the dermal layer (Figure 2A).
For uneven skin texture, botulinum toxin (44%) was the favorite injectable to combine with PN followed by non-cross-linked HA (43%), PLA (15%), and lightly crossed-HA (13%).25 percent of the respondents chose to inject PN alone.The preferred target layer was the intradermal layer (Figure 2B).

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What laser, light source, or skin care device would you combine with injectable PN? Also, would there be any modification in intensity when combined with PN? (multiple choice) For fine lines (including those on the cheek, infraorbital and periorbital area, and forehead), non-invasive RF (40%) was the most preferred laser/light source/skin care device to combine with PN followed by needle RF (27%), HIFU (26%), LIUS (16%) etc. 25 percent voted to inject PN alone.The survey participants preferred keeping the parameters the same regardless of PN injection (Figure 3A).
For uneven skin texture, 43% chose non-invasive RF to combine with injectable PN followed by needle RF (43%), LIUS (31%), Picosecond laser (26%), HIFU (19%), etc. 19 percent preferred PN injection only.The survey respondents mostly chose to keep the parameters the same as when they would use lasers or light sources alone (Figure 3B).

| DISCUSS ION
Among the various skin boosters, injectable PN is currently very popular in Korea.According to our survey, it was the participants' (expert dermatologists') top choice among different skin boosters, overtaking the popularity of small particle HA.The main advantage of this natural-origin, highly purified long-chain polynucleotide is its trophic action on dermal fibroblasts 7,8 as well as the high-water binding capacity. 9 Such features enable the plumping of the extracellular matrix with a boost in skin elasticity and turgor making PN ideal for facial fine lines and uneven and dry skin texture. 5,6,10,11tradermal PN injection with a 33G needle, and the use of the serial puncture technique is favored for most indications (Figure 4A), especially the lateral canthal lines which are prone to bruising. 12But for the fine lines on the cheeks, forehead, and the infraorbital area, cannula injection into the subdermal layer may also be considered as to fill-up the sunken area (infraorbital area) (Figure 4B) and to avoid the downtime ("bumps" associated with intradermal injection) in  In addition to the injector gun, a newer formulation of PN with HA and lidocaine has been introduced and is known to be noticeably less painful that the conventional PN product.
For a full-face treatment, it is best to inject 4 cc of PN while variable amounts can be applied for the different indications.A total of 3 sessions of treatment spaced 4 weeks apart is most often recommended.Since PN injection is performed to rejuvenate the skin, dermatologists often combine injectables or laser/light source/skin care devices with PN seeking a synergistic effect.Botulinum toxin works best for those with wrinkles and excessively oily skin, 13,14 and to minimize side effects such as the "frozen face," intradermal injection of botulinum toxin in tiny aliquots is preferred. 15It is important to note that PN injection is combined with botulinum toxin only once and the combination is not repeated in the subsequent sessions with the risk of antibody formation.On the contrary, combination of PN with non-cross-linked HA, lightly cross-linked HA, or PLA is often repeated.
7][18] Both induce denaturation of collagen and an inflammatory response which can be soothed by PN.Also, the rapid effect of PN complements the tightening effect of these devices which usually takes months before becoming visible.PN can either be injected before or after RF and HIFU treatment in cases where PN is injected first, the subsequent application of RF and HIFU can help reduce the "bumps" associated with intradermal PN injection.On the contrary, PN products with lidocaine makes treatment with the energy-based devices less painful.PN also alleviates skin dryness that is common after RF and HIFU treatment.
This expert survey illustrates the current trend in aesthetics, and the popularity of injectable PN in Korea.It also provides an outline on PN practice, including the major indications, mode of delivery, target layer, treatment interval, and ways to combine with other injectables and energy devices, which we hope will help dermatologists better understand and utilize injectable PN.

FU N D I N G I N FO R M ATI O N
This study was supported by PharmaResearch Products Co., Ltd.

CO N FLI C T O F I NTER E S T S TATEM ENT
Nark Kyoung Rho is on the advisory board of PharmaResearch Products Co., Ltd.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available on request from the corresponding author.The data are not publicly available due to privacy or ethical restrictions.

E TH I C S S TATEM ENT
Our survey has been performed in accordance with the principles stated in the Declaration of Helsinki.
highly sensitive individuals.PN injection accompanies a fair amount of discomfort, largely due to the introduction of a high molecular weight viscoelastic F I G U R E 2 Injectables chosen to be used alongside PN and its injection depth (A) for fine lines (including those on the cheek, infraorbital and periorbital area, and forehead) (n = 389), (B) for uneven skin tone (n = 67), (C) for dry skin (n = 66).F I G U R E 3 Laser, light source, or skin care device chosen to combine with injectable PN (A) for fine lines (including those on the cheek, infraorbital and periorbital area, and forehead) (n = 383), (B) for uneven skin tone (n = 68), (C) for dry skin (n = 66).F I G U R E 4 (A) Intradermal injection with a needle, (B) cannula injection into the subdermal layer, and (C) features of an injector gun (9 pins of 34G sterilized needles, insertion depth of 0.8 mm).

| 1251 RHO
et al.substance into the superficial layer of the skin.Much effort has been made to overcome this problem which includes the development of an injector gun.The injector gun is a medical device which administers PN automatically into the skin using 9 pins of 34G sterilized needles (Figure4C).Compared with the traditional syringe, it has the advantage of being less painful and can deliver PN into the exact targeted layer.The injector gun also saves time but there may be some leakage of PN at the needle port or vents.For the best outcome, we recommend using the injector gun on flat surfaced areas (i.e., central cheek and forehead) and applying the needle on the curvatures of the face (i.e., periorbital, infraorbital area).