An Effective and Safe Laser Treatment Strategy of Fractional Carbon Dioxide Laser for Chinese Populations with Periorbital Wrinkles: A Randomized Split-Face Trial

Abstract

Introduction

Ablative carbon dioxide fractional laser (CO₂ AFL) can alleviate static wrinkles; however, its use in East Asian populations can predispose them to postinflammatory hyperpigmentation (PIH). We aimed to explore the optimum energy and coverage parameters of CO₂ AFL for treating static periorbital wrinkles in a Chinese population and to minimize PIH incidence.

Methods

In total, 30 patients with static periorbital wrinkles were recruited. The PIH intervention side (1% hydroquinone cream every night on one periorbital area for each patient 1 month before and from the 8th day to 1 month after each treatment) and group (group A: 15‒20 mJ, 5%; group B: 10‒12.5 mJ, 15%; and group C: 12.5‒15 mJ, 10%) were determined randomly. The patients underwent two sessions of CO₂ AFL at 3-month intervals. Follow-ups were conducted until 6 months after the last treatment.

Results

Overall, 20 participants (48.1 ± 13.1 years) completed all follow-ups without any serious complications. The application of hydroquinone significantly reduced PIH (p = 0.02). Both the investigators’ and patients’ visual evaluations demonstrated a consistent efficacy rate of 68.2% without differences between groups. The Fitzpatrick wrinkle score significantly decreased compared with pre-treatment (p < 0.01); however, a significant reduction only in group B at 3 months (p = 0.016) and 6 months (p = 0.001) post-treatment was observed. Groups B and C demonstrated significant reductions in superficial and deep wrinkles and pigmentation (p < 0.01).

Conclusions

CO₂ AFL effectively reduced static periorbital wrinkles in the Chinese population. Low energy combined with high-density coverage was the most efficacious. The application of hydroquinone significantly reduced PIH incidence.

Trial Registration

Chinese Clinical Trial Registration no. ChiCTR2400087320 (date of trial registration: 25 July 2024).

Key Summary Points

Why carry out the study?

The optimum strategy of ablative carbon dioxide fractional laser for the treatment of static periorbital wrinkles has not been adequately assessed, and it is important to minimize the incidence of postinflammatory hyperpigmentation.

What was learned from the study?

The application of hydroquinone holds promise for the reduction of the incidence of postinflammatory hyperpigmentation. The ablative carbon dioxide fractional laser with low fluence combined with high-density coverage produces the best clinical efficacy for static periorbital wrinkles in Chinese populations; it provided evidence for best clinical practice of laser treatment for static wrinkles.

Introduction

Wrinkles are one of the main manifestations of skin aging, and their causes are complex. The treatment or alleviation of wrinkles is currently one of the most important and challenging topics in skin beauty science. The skin around the eyes is thin, only 0.2 mm in some patients [1]. Wrinkles and pigment changes around the eyes often appear around the age of 40 years or earlier, and genes, hormones, and environmental pressures can lead to aging performance [2]. Because the skin around the eyes is thin and close to the eyes, its unique anatomical structure and physiological characteristics make the treatment of the skin around the eyes challenging. Wrinkles around the eyes can be divided into dynamic and static wrinkles. Static wrinkles are related to the tension of muscles around the eyes and can be better relieved by the administration of botulinum toxin injection. The causes of static wrinkles around the eyes are more complicated, and the treatment is difficult. Currently, the treatment methods include fillers, chemical peeling, and photoelectric therapy [3]. Each method has its advantages and disadvantages. For example, the filler injection can effectively recover volume loss; however, it can only last for a short time. If the dosage and level of drug injection are not accurately mastered, it will easily lead to a more abnormal appearance [3, 4]. Therefore, a safe and efficient treatment to reduce the appearance of static wrinkles around the eyes would provide the greatest benefit to patients. In the past decades, devices based on energy conduction have been applied to the treatment of eye rejuvenation, which mainly include laser and radio frequency technology. Among all treatment methods, ablative fractional lasers (AFLs), such as the carbon dioxide (CO₂) (10,600 nm) [5] and erbium (Er: YAG) (2940 nm) lasers, have been found to have more remarkable curative effects [6]. CO₂ AFL uses coagulation thermal damage to reconstruct the skin surface to achieve rejuvenation, and thermal diffusion during the pulse is limited by the very short interaction time between the laser and tissue (< 1 ms) to avoid tissue carbonization [7]. Er: YAG AFL uses low energy, and there is almost no thermal damage when exfoliating the tissues [8]. However, the wavelength of Er: YAG (2940 nm) is closer to the absorption peak of water (3000 nm) than that of the CO₂ laser, and more energy is absorbed by the epidermis and dermal papillae when using the Er: YAG AFL. Therefore, although the recovery period after Er: YAG AFL treatment is shorter, the depth of epidermal exfoliation during treatment is also shallower [9]. Many studies have compared the efficacy and safety of CO₂ AFL and ER: YAG AFL in the treatment of static wrinkles around the eyes. The results showed that CO₂ AFL is more effective; however, the incidence of postoperative adverse reactions (such as postinflammatory pigmentation, erythema, itching, miliaria, and acne) is increasing [10–12]. The results obtained from the previous study in a white population with lighter skin color may differ from those obtained in the East Asian populations with Fitzpatrick skin types (FST), which are mostly type III or IV. The clinical efficacy of CO₂ AFL for the treatment of static periorbital wrinkles remains unclear. Therefore, this study aimed to investigate the treatment parameters of CO₂ AFL to treat static wrinkles around the eyes in the Chinese population to achieve the best degree of reduction and minimize the incidence of postinflammatory hyperpigmentation (PIH).

Methods

Study Design

This study was designed as a prospective, randomized, self-controlled clinical trial. A total of 30 patients with static periorbital wrinkles were recruited from the Department of Laser and Aesthetic Medicine at the Shanghai Ninth People’s Hospital between July 2022 and December 2023 (Fig. 1). The sample size was calculated by referring to previous literature, and the statistical power value of this sample size was verified by PASS software (α = 0.05, the power was 0.999, and the set loss rate was 20%) [13]. Inclusion criteria were the following: patients who met the indications for static periorbital wrinkles were aged 25‒65 years, regardless of sex; had never received other treatments for periorbital wrinkles; fully understood the treatment plan and risks; voluntarily signed the informed consent form; were willing to accept the self-controlled trial; and cooperated with the follow-up. The exclusion criteria were women with pregnancy preparation plans, allergies to topical anesthetics, wound or epidermal ulceration around the eyes, serious organic diseases, mental illnesses, and participation in other clinical trials.

Fig. 1.

Flow diagram of the clinical trial. PIH postinflammatory hyperpigmentation, CO₂ AFL carbon dioxide ablative fractional laser

Ethical Approval

This study was approved by the Ethics Committee of the Shanghai Ninth People’s Hospital (SH9H-2022-T135-1) and complied with the tenets of the Declaration of Helsinki. All subjects gave informed consent to participate in the clinical trial, cooperate with the treatment and follow-up during the study, and allow researchers to use all research—related materials (including but not limited to photographic data) for academic research and paper publication.

Randomization and Grouping

The treatment sequence was generated randomly. According to the order of enrollment, 30 patients were categorized into three groups (group A: high-energy and low-density; group B: low-energy and high-density; group C: medium-energy and medium-density; 10 people in each group). Thirty patients with periorbital wrinkles were divided into two groups for PIH intervention (15 patients in the left/right eye).

PIH Intervention

The sensitivity of 2% hydroquinone ointment (Qianbai™, Guangdong, China) was tested in the posterior ear area for 3 days before the intervention was performed for the first time. When there was no abnormality or only slight erythema but no itching, blisters, or other inflammatory reactions, the drug was considered applicable. Subsequently, 2% hydroquinone ointment was applied externally 1 month before each treatment and from 1 week to 1 month after treatment, once at night.

Treatment Protocol

A 10,600-nm carbon dioxide fractional laser (Ultrapulse™, Lumenis) was used to treat bilateral static periorbital wrinkles (group A: 15‒20 mJ, 5%, approximate depth: 0.45‒0.5 mm; group B: 10‒12.5 mJ, 15%, 0.3‒0.4 mm; group C: 12.5‒15 mJ, 10%, 0.4‒0.45 mm). The patients underwent two sessions of CO₂ AFL at 3-month intervals. The follow-up times were 1 week and 1 month after the first treatment and 1 week, 1 month, 3 months, and 6 months after the second treatment. Patients immediately used cold compresses after treatment and avoided contact with water in the treatment area within 72 h. From 1 month before laser treatment to the end of follow-up, the patients were instructed to strictly protect themselves from the sun. If postoperative discomfort occurred, increased application of moisturizing creams was recommended.

Subjective and Objective Assessment

A professional digital camera (60D camera; Canon, Tokyo, Japan) was used to capture standardized clinical photographs. The same light conditions, parameters, and patient angles were maintained during the shooting. The degree of wrinkle reduction was determined by two investigators and the patients themselves using the 5-point Global Aesthetic Improvement Scale (investigator (I)-GAIS and patient (P)-GAIS): 5 = very much improved, 4 = much improved, 3 = improved, 2 = no change, and 1 = worse [8], and the Fitzpatrick wrinkle score was based on the grading of wrinkling into three classes: I (mild, 1–3); II (moderate, 4–6); and III (severe, 7–9)[11]. Patients judged the comfort of the treatment using a 10-cm visual analogue scale (VAS) ranging from 0 (no pain) to 10 (extreme pain) after treatment.

The patients were also photographed using a CBS® multispectral dermoscope image processing workstation (Wuhan Boshi Electronics Co., Ltd) [14]. The feature counts of the skin texture, which were primarily an analysis of skin smoothness on both sides, were recorded.

The adverse effects, including blisters, purpura, hypopigmentation, hyperpigmentation, and scarring, were evaluated and recorded after each treatment session [15].

Data Analysis

Descriptive statistics were performed according to the intervention method, and continuous variables were described using the mean and standard deviation, while stratified variables were described using the median and quartiles. When comparing between groups, continuous variables with normal distribution were tested using the t-test, and continuous variables with non-normal distribution were tested using the Wilcoxon paired rank-sum test. The significance level of the above statistical methods was set at p < 0.05.

Results

Safety Assessment and PIH

During the study, ten patients failed to complete all treatments or follow-ups because of the influence of coronavirus disease 2019. In total, 20 people (1 male patient, 19 female patients; age 48.1 ± 13.1 years) completed the entire follow-up. No serious adverse reactions were observed during treatment. The VAS score was 3‒7 (72.7% of the patients scored < 4, 22.7% scored between 4 and 5, and one patient scored 7). In addition, two patients had solar lentigines around their eyes before treatment, which were reduced after treatment (Fig. 2). Moreover, three patients had melasma at baseline, and there was no aggravation on either side after treatment.

Fig. 2.

Control side (right): postinflammatory hyperpigmentation (PIH) was found 1 month after the second session (e) but faded away at last follow-up (g). Hydroquinone-applied side (left): no PIH but improvement on solar lentigines was found (d, f, h). (a, b, baseline; c, d, 1-month after first session; e, f, 1-month after second session; g, h 6-months after second session)

Five patients (six sides in total) thought that PIH appeared after treatment, and two independent evaluators found that one of them was actually a deepening of the overall skin color related to sun exposure. The other four patients appeared to have PIH 1 month after the second session in groups B and C, all of whom were not treated with hydroquinone. The PIH disappeared 6 months after postoperative follow-up. The incidence of PIH in patients treated with hydroquinone was significantly lower than that of those not treated with hydroquinone (Table 1, chi-squared test, p = 0.04).

Table 1.

Use of hydroquinone and occurrence of postinflammatory hyperpigmentation (PIH)

	Hydroquinone	No hydroquinone	Total
PIH	0	4	4
No PIH	20	16	36
Total	20	20	40

P-GAIS and I-GAIS

The investigators and patients visually evaluated the overall curative effects. Typical photographs with GAIS scores of 5, 4, and 3 are shown in Fig. 3. The investigator-GAIS (I-GAIS) and patient-GAIS (P-GAIS) are shown in Fig. 4a. The overall effective rate of P-GAIS and I-GAIS was the same (GAIS ≥ 3 is effective), both of which were 68.2%. There was moderate consistency between the investigators and patients in the GAIS scoring conclusions (z = 2.186, p = 0.029, kappa coefficient = 0.257).

Fig. 3.

Typical patient photos with GAIS (global aesthetic improvement scale) of 5, 4, and 3. Left, before (a–c); right, 6-months after second session (d–f)

Fig. 4.

a Investigator-GAIS (global aesthetic improvement scale, I-GAIS) and patient-GAIS (P-GAIS). The overall effective rate of P-GAIS and I-GAIS is the same (GAIS ≥ 3 is effective), both of which are 68.2%; b I-GAIS scores of different treatment parameter groups

The I-GAIS scores of different treatment parameter groups are shown in Fig. 4b; the effective rate in group A was the highest (6 sides in group A, the effective rate was 6/6 = 100%; 22 sides in group B, the effective rate was 16/22 = 72.7%, and 12 sides in group C, with an effective rate of 8/12 = 66.7%); however, there were no significant differences between these groups (one-way analysis of variance (ANOVA), p = 0.06).

Fitzpatrick Wrinkle Score

The Fitzpatrick wrinkle scores were significantly lower at all follow-up time points after treatment than before treatment (multi-way ANOVA and post hoc Bonferroni test). However, grouping analysis showed that only the Fitzpatrick wrinkle scores of group B were significantly lower 30 days (3.4 ± 1.2) and 6 months (2.9 ± 1.1) after treatments than before treatments (4.9 ± 0.9) (p = 0.016, p = 0.001). There were no significant differences between groups A and C before and after treatment.

CBS Analysis

The wrinkles and pigment index before and after treatment in the whole and each treatment group were compared and analyzed (Fig. 5). There were no statistical differences in the wrinkle and pigment indices in group A before and after treatment (p > 0.05).

Fig. 5.

CBS analysis which showed the improvements of wrinkles (a, b) and pigmented areas (c, d). Left, before; right, 6-months after second session. CBS is the trademark for a multispectral dermoscope image processing workstation

Both groups B and C showed marked reductions in superficial and deep wrinkles and the pigment index after treatment (paired t-test). No significant differences were observed in the pigment index between the sides coated with hydroquinone and those not coated with hydroquinone (p > 0.05).

Discussion

Recently, with the advancements in beauty repair technology, the aesthetic requirements of people have increased. The first part affected by aging is the periorbital region, and periorbital wrinkles are a problem faced by many middle-aged women. The periorbital skin lacks collagen, and the secretion of dermal sebaceous and sweat glands decreases. After the periorbital skin loses the support of the adipose tissue, the skin gradually becomes loose and rough [3]. With the popularization of laser skin replacement technology, ablative CO₂ lasers have become the first-line treatment method for white facial skin replacement. However, their further application is hindered by their long healing time, scarring, and postinflammatory pigmentation. To overcome the risk of complications, Manstein et al. proposed the theory of fractional photothermolysis (FP) for the first time in 2003 [16], and the designed CO₂ AFL has been widely used in clinics. The use of CO₂ AFL for the treatment of static periorbital wrinkles has been shown to be effective. Karsai used CO₂ AFL to treat periorbital rhytides, and the wrinkle depth and Fitzpatrick score were reduced by approximately 20% and 10% [11]. Our study showed that the investigators’ and patients’ visual evaluations demonstrated a consistent effectiveness rate of 68.2%.

Hantash et al. first reported the photothermal effects of an ablative CO₂ fractional laser on human skin in vitro and found that, in an ablative microarray, the center of the microthermal zone (MTZ) penetrated deep into the dermis, surrounding it with a circular zone of tissue coagulation [17]. This effectively promotes coagulation and hemostasis, while circular coagulation and tightening of collagen results in multiple small contractions, contributing to immediate, visible skin tightening, as well as long-term sustained tightening. In the same year, they also reported pathological changes following the application of an ablative CO₂ fractional laser to the human forearm skin [18]. The early response protein HSP72 was significantly upregulated 48 h after treatment, peaking at 2–7 days; HSP47 exhibited delayed expression, appearing at 7 days and lasting for at least 3 months, with diffuse expression throughout both the epidermis and dermis. Dermal remodeling extends well beyond the immediate MTZ area, which is particularly beneficial in treating static wrinkles that are typically caused by dermal atrophy and loss of skin elasticity. This pathological study further confirmed the intrinsic mechanisms underlying the clinical efficacy of CO₂ fractional laser.

Our findings suggest that low-energy, high-density CO₂ AFL parameters (10‒12.5 mJ, 15% density) are the most effective for treating static periorbital wrinkles, with patients continuing to show reductions even at 6 months post-treatment. The rationale behind using low energy with high density lies in achieving an optimal balance between efficacy and minimizing adverse effects, such as prolonged erythema and PIH. Notably, in our study, the energy of 10‒12.5 mJ was set as a relatively low grouping. However, the depth that this energy can penetrate is 0.3‒0.4 mm, and the depth of the whole skin layer of the lower eyelid is only approximately 0.5 mm, so it is enough to effectively stimulate the collagen production of the dermis [19]. However, the high-energy, low-density and medium-energy, medium-density groups were not as effective. There is a lack of relevant evidence on how to select the coverage rate when using fractional CO₂ laser for skin rejuvenation in Asian individuals. Typically, coverage rates reported for white populations range from 20–45% or even higher [20]. Nevertheless, such high coverage rates pose a significantly higher risk of PIH for Asian individuals with Fitzpatrick skin types III–V. Therefore, the maximum coverage rate used in this study was 15%, which has been found to strike a good balance between efficacy and safety. Using low-energy levels reduces the depth of penetration and thermal damage, decreasing the likelihood of PIH, whereas using a high density ensures sufficient coverage of the treatment area, leading to uniform collagen stimulation and skin resurfacing.

The long-term effectiveness observed at 6 months post-treatment can be attributed to the extended period required for collagen remodeling and skin maturation. Collagenesis is a gradual process that continues for several months after laser therapy, and the cumulative effects of two CO₂ AFL sessions likely contributed to sustained improvements in wrinkle reduction. This prolonged effect has been corroborated by other studies, such as that by Ross et al., who found that CO₂ induces collagen remodeling that persists for several months after post-treatment [21]. Ross et al. conducted a CO₂ laser study on the periorbital and perioral regions in 13 patients. Biopsies were obtained before treatment, immediately after treatment, and either 3 or 6 months after treatment to evaluate the degree of fibroplasia. Histologic examination demonstrated that the fibroplasia thicknesses after 3 and 6 months were 63 ± 41 um and 56 ± 45 um, respectively.

PIH is a common complication in darker skin types, particularly in East Asian patients, following CO₂ AFL treatments. Hydroquinone remains the gold standard for the treatment of PIH. It is a phenolic compound that inhibits tyrosinase, thereby reducing the conversion of dihydroxyphenylalanine (DOPA) to melanin [22]. Studies focusing on the prevention of PIH following CO₂ laser resurfacing have suggested that the use of sunscreen or hydroquinone combinations is a critical preventive strategy [23]. However, the efficacy of only hydroquinone in preventing PIH following CO₂ laser treatment remains unclear. In the largest clinical trial conducted, 100 participants were randomly assigned to receive pre-treatment on the face with either 10% glycolic acid cream, 4% hydroquinone cream, or 0.025% tretinoin cream, or no pretreatment for a maximum duration of 2 weeks before undergoing laser therapy. Analysis based on clinical photographs revealed no statistically significant differences in the incidence of PIH among the various treatment groups[24]. One of the critical findings of our study was the significant reduction in PIH when hydroquinone was applied before and after treatment (chi-squared test, p = 0.02). This finding highlights hydroquinone as an essential component of pre- and post-laser care in patients with darker skin tones. It should be noted that long-term use of hydroquinone and its potential side effects include skin irritation, exogenous ochronosis, carcinogenicity concerns, rebound hyperpigmentation, photosensitivity, and regulatory and safety precautions. However, short-term, supervised application at the lowest effective concentration, coupled with sun protection and periodic breaks, is critical to balancing efficacy and safety. Patients should be informed of risks and alternatives, particularly those with darker skin or requiring prolonged treatment.

This study had a limitation. The small sample size of this study may have reduced its statistical efficacy. It is necessary to include a larger number of patients and conduct a multicenter study to further confirm the research results. Indeed, a 6-month follow-up period is not exceptionally long. However, for conditions such as dynamic wrinkles, which are relatively easier to address by botulinum toxin, therapeutic effects are typically maintained for only 4–6 months. The causes of static wrinkles are multifaceted, involving not only atrophic factors due to collagen loss but also facial mimetic muscle movement, photoaging, gravitational effects, facial distortion during sleep, and others. Given that the improvement persisted for 6 months after just two sessions of treatment, patients were already highly satisfied with the outcomes. Therefore, we did not conduct follow-up longer than 6 months.

Conclusions

CO₂ AFL is an effective treatment for static periorbital wrinkles in Chinese populations, with an efficacy rate of 68.2%. The use of low-energy, high-density parameters not only maximizes treatment outcomes but also reduces the risk of adverse effects. The prolonged reduction in wrinkle appearance observed at 6 months post-treatment was likely due to ongoing collagen remodeling. In addition, the application of hydroquinone significantly reduced the incidence of PIH, making it an essential component of pre- and post-laser care for patients with darker skin tones. Our next phase of study will explore higher coverage rates and adjunctive therapies to further enhance the safety and efficacy of CO₂ AFL in various skin types.

Author contributions

Xianglei Wu—conceptualization, methodology, software, investigation, formal analysis, and writing—original draft; Qingqing Cen—data curation and writing—original draft; Jian Jin—visualization and investigation; Wei Gao—writing—review and editing; Ying Shang—resources and supervision; Linting Huang—software, validation, visualization, and writing—review and editing; Xiaoxi Lin—conceptualization, funding acquisition, resources, supervision, and writing—review and editing.

Funding

Our hospital covered the equipment maintenance charge and clinical research assistant labor costs for the clinical study. The rest of the funding has been provided by Lumenis Co. Ltd. The study sponsor is also funding the journal’s rapid service fees.

Data Availability

Dr. Xiaoxi Lin had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Conflict of Interest

The authors (Xianglei Wu, Qingqing Cen, Jian Jin, Wei Gao, Ying Shang, Linting Huang, and Xiaoxi Lin) declare that they have nothing to disclose.

Ethical Approval

This study was approved by the Ethics Committee of the Shanghai Ninth People’s Hospital (SH9H-2022-T135-1) and complied with the tenets of the Declaration of Helsinki. All subjects provided informed consent to participate in the clinical trial, cooperate with the treatment and follow-up during the study, and allow researchers to use all research—related materials (including but not limited to photographic data) for academic research and paper publication.