Efficacy and safety of ablative CO2 fractional laser and narrowband intense pulsed light for the treatment of hypertrophic scars: a prospective, randomized controlled trial

Abstract Background and Objectives Hypertrophic scarring is a complex process, and numerous methods have been introduced to treat scars. This study aims to evaluate the effect of combined CO2 fractional laser and narrowband intense pulsed light (IPL) compared to IPL alone in the treatment of hypertrophic scars. Materials and Methods This was a prospective, randomized controlled study enrolled 138 patients with hypertrophic scars. The participants were randomly divided into two groups: CO2-IPL and IPL group, and received three sessions at 10–14-week intervals for 3-month follow-up. Two independent plastic surgeons evaluated the treatments using the Patient and Observer Scar Assessment Scales (POSAS). Overall satisfaction was evaluated using the Patient Satisfaction Scale (PSS). Results 101 subjects completed the study. Compared to single IPL, the combination CO2-IPL group showed a significant improvement in itching, color, stiffness, thickness, and irregularity, except for pain, and an enhancement in vascularization, pigmentation, thickness, relief, and pliability of the scar, assessed by POSAS (p < .01). 100% patients in the combination group were satisfied compared to 84% in IPL alone. Conclusion The combination of CO2 fractional laser and narrowband IPL efficiently improved the appearance and profile of hypertrophic scars, offering a comprehensive and reliable approach for scar therapy.


Introduction
Skin wound healing involves a series of pathophysiological processes that defend against harmful injuries, protect against infection, and maintain skin integrity.Typically, normal wound healing occurs in three stages: inflammation, proliferation, and remodeling (1).However, when the injury affects the dermis or deep tissues, it can trigger an abnormal inflammatory response, increased vessel density, excessive collagen deposition, and ultimately result in pathological scars such as hypertrophic scars (HTS) and keloid (2,3).In the clinical setting, HTS is often caused by burns, surgery, trauma, infection, and other severe skin diseases.It tends to be restricted to the margins of the initial wound, unlike keloid.HTS can present with clinical symptoms such as pain, itching, redness, thickness, stiffness, and poor appearance, even leading to deformity and dysfunction, which can result in physiological and psychological issues (4).
Various therapeutic methods have been extensively utilized for hypertrophic scars, including silicone gel sheeting, pressure garments, intralesional corticosteroid injections, cryotherapy, surgery and photoelectric therapy (5).While surgery can resolve joint contractures and reduce scar tension, it is ineffective for addressing itching, erythema, and unsightly appearance.Pressure therapy is also challenging to apply to certain body parts, such as the neck and face.Additionally, other methods have drawbacks, including low efficacy, dyspigmentation, and high recurrence rates.Photoelectric therapy has rapidly developed and has been proven effective for hypertrophic scars, with minimal invasiveness and excellent outcomes (6).
In photoelectric technology, laser therapy has been used for the treatment of hypertrophic scars for decades, based on the principle of photothermolysis.The CO 2 laser was initially invented for this purpose, but it was found to cause high rates of pigmentation, erythema and burning.In 2006, the revolutionary concept of fractional laser therapy was introduced, whereby microscopic thermal treatment zones (MTZs) are created and surrounded by untreated tissue, in order to stimulate collagen remodeling and regeneration of skin tissue (7).Nowadays, ablative fractional CO 2 laser treatment has been found to be highly beneficial and safe for the treatment of hypertrophic scars (8)(9)(10).Compared to laser, the intense pulsed light (IPL) is a non-coherent broadband light with the spectrum between 400-1200 nm.IPL system has high versatile conditions based on specific targets with various parameters such as wavelength, pulse width and interval time (11).Narrowband IPL, evolved from IPL, λ = 500-600 nm, can be effectively absorbed by hemoglobin because of 542 and 577 nm oxyhemoglobin absorption peaks with minimized skin damage.Narrowband IPL system has numerous applications including vascular malformations, acne vulgaris, rejuvenation, sensitive skin, melasma, telangiectasias and hypertrophic scars.Recent studies have reported that narrowband IPL can improve hypertrophic scars on itching, erythema, and suppress scar excessive proliferation (12,13).
Although photoelectric technologies, such as ablative fractional CO 2 laser and narrowband IPL, have shown promise in the treatment of hypertrophic scars, past studies have provided limited comparisons between combination therapy and single therapy.As a result, we have designed a prospective, randomized controlled trial to evaluate the efficacy and safety of combined CO 2 -IPL versus single IPL.

Study design
This was a prospective, observer-blinded, randomized controlled study.It was approved by the Ethic Board of Shanghai Ninth People's Hospital, Shanghai Jiaotong University of Medicine, China (2017-343-T252) and registered at Chinese Clinical Trial Registry (ChiCTR-ONH-17012350).Informed consents were obtained from all patients before enrollment.

Patients
From August 2017 to January 2021, a total of 138 patients with hypertrophic scars were recruited for this study from the Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital.The inclusion criteria were patients aged between 16 and 55 with Fitzpatrick skin types II-IV who developed hypertrophic scars due to burns, surgeries, or trauma that were at least 2 cm in length and had been present for over 8 weeks.Exclusion criteria included pregnancy and lactation, patients diagnosed with keloids, serious skin disorders, or systemic diseases, as well as those who had undergone laser, intralesional treatment, or dermabrasion for hypertrophic scars in the past 3 months.To randomly assign patients to either the CO 2 -IPL group or the IPL group, A or B were generated through a computer-generated process prior to the study.

Treatment
Each patient received three sessions with intervals of 10-14 weeks and a follow-up of 3 months.Prior to therapy, each patient's scar area was cleaned with 70% alcohol and dried using sterile gauzes.The same photographer took photos of the patients before each session and again 3 months after the final session in fixed position and lighting, using a digital camera (D750, Nikon, Japan) and the VISIA Skin Analysis System (Canfield Scientific, USA).During photoelectric treatment, physicians should wear specialized glasses and ensure that patients' eyes are protected.
For narrowband IPL therapy, 2-3 mm of ultrasound gel was evenly applied to the scar surface.The area was then irradiated using a commercial IPL (λ = 500-600 nm, spot size = 3 cm 2 , fluence = 6-8 J/cm 2 , pulse width = 12 ms, 2 passes) (Alma Laser, Caesarea, Israel).For CO 2 -IPL therapy, a topical anesthetic cream (Compound Lidocaine Cream, Beijing Ziguang, China) was applied to the scar and occluded for 30-60 min.The cream was then removed and the IPL treatment was conducted according to the above protocol.Next, the clinician used the Ultrapulsed Fractional CO 2 Laser (Deep FX mode, Lumenis, Santa Clara, CA, USA) with a parameter of 17.5-25 mJ/cm 2 for one pass at a density of 5%.The endpoint was determined by the appearance of thermal ablation, mild erythema, and edema.To avoid bias, patients in both groups applied ice bags to the scar area for 20-30 min to reduce thermal damage.Following the procedure, antibacterial ointment and moisturizer were applied topically twice a day for one week.The treated region was instructed to remain sterile, and patients were advised to avoid intense exercise and saunas for one week.Additionally, patients were instructed to protect themselves from the sun during the entire therapy by wearing protective clothing, hats, and using sunscreen cream.

Clinical Assessment
The Patient and Observer Scar Assessment Scales (POSAS) are a reliable and feasible scar evaluation scale that have been modified from the Vancouver Scar Scale.The scale comprises a combination of a patient scale and an observer scale, with the former assessing pain, itching, color, stiffness, thickness, and irregularity.The observer scale reflects vascularization, pigmentation, thickness, relief, and pliability.Each characteristic is scored on a scale of 1-10, with one representing normal skin and ten indicating the worst possible situation.Before each treatment and three months after the last session, two independent plastic surgeons assessed each characteristic of the POSAS.Additionally, overall satisfaction was assessed by Patient Satisfaction Scale (PSS) with the range of 1 (very satisfied), 2 (satisfied), 3 (unsatisfied) and 4 (very unsatisfied) after the follow-up.

Statistical Analysis
The statistical software (SPSS version 24.0, IBM, Chicago, USA) was used for performing the statistical analyses.The paired Student's t-test was used to analyze significant changes between baseline and follow-up, whereas the non-parametric Mann-Whitney test was used to compare statistical differences between two groups for demographic data (age, scar duration), POSAS scores, and PSS scores.Pearson's chi-square test was used for other characteristics of patients (gender, scar location, scar source).A statistically significant difference was defined as p < .05 at a 95% confidence level.

Results
The consort flow chart is illustrated in Figure 1.Out of the 138 patients who were recruited, a total of 122 patients with hypertrophic scars were randomized into either the CO 2 -IPL group or the IPL group.Ultimately, a total of 101 participants (43 male and 58 female) successfully completed the study.Nine patients were unable to complete the three interventions while another nine were lost to follow-up due to scheduling conflicts or other reasons.The age range of the patients was between 16 and 52 years old with a mean scar duration of 6.4 months (ranging from 2-15 months).The hypertrophic scars were located on the face (30.7%), neck (11.9%), trunk (19.8%), and extremities (37.6%).The majority of scars were caused by burns (57.4%), while others resulted from surgery (34.7%) and trauma (7.9%).No significant differences were observed between the CO 2 -IPL and IPL groups in terms of gender, scar duration, scar location, and source (p < .05)(Table 1).
The POSAS scores from clinical assessments were measured after photoelectric therapy and are presented in Table 2.At 3 months after three sessions, the total POSAS scores were significantly lower in the CO 2 -IPL group (38.58 ± 4.71) compared to the IPL group (44.04 ± 5.07) (p < .0001).Both PSAS and OSAS scores showed significant improvement in the CO 2 -IPL group compared to the IPL group.For PSAS, improvements in itching, color, stiffness, thickness, and irregularity were significantly greater in the CO 2 -IPL group than in the IPL group (p < .01),except for pain (p = .4205).In the OSAS, significant differences were observed in vascularization, pigmentation, thickness, relief, and pliability after CO 2 -IPL treatment compared to IPL intervention (p < .01).
At the final follow-up of the study, the patients were told to provide satisfaction scale scores based on their previous therapy.Results from the CO 2 -IPL group showed that 28 patients (54%) were very satisfied with the combined phototherapy, while 24 patients (46%) were satisfied.No patients were unsatisfied or very unsatisfied.In the IPL group, 41 patients (84%) reported being

Discussion
This study was a prospective, randomized controlled trial that aimed to assess the efficacy and safety of combined CO 2 -IPL and single light IPL in treating hypertrophic scars.The clinical curative   effect was evaluated using POSAS, and patient satisfaction was assessed using PSS.In comparison to single IPL, the combined CO 2 -IPL treatment demonstrated lower POSAS scores.Independent observers found the combined treatment to be more effective in terms of vascularization, pigmentation, thickness, relief, and pliability, while patients reported reduced pruritus, lighter color, thinner scars, and more regular shape.Moreover, 100% of patients in the CO 2 -IPL group expressed satisfaction with the treatment outcome.Of the satisfied group, 54% were very satisfied and wished to continue follow-up treatment.The IPL group obtained an overall satisfaction rate of 84%, but none were very satisfied with the therapy.Furthermore, 16% expressed dissatisfaction with the scar improvement.
Although the exact mechanism behind the formation of hypertrophic scars (HTS) is not fully understood, it is widely believed that trauma triggers the degranulation of platelets, activation of vascular endothelial cells (EC), and increased vascular permeability.This leads to the aggregation of immune cells, inflammatory waterfall, and neovascularization.Inflammatory cytokines stimulate fibroblasts to over-proliferate and transform into myofibroblasts, which express α smooth muscle actin (α-SMA), secrete collagen, and promote the deposition of extracellular matrix, scar growth, and contracture (14,15).As a result, microvasculature and collagen play crucial roles in HTS formation, which is characterized by two important clinical features: redness and thickening.Therefore, targeting microvasculature and collagen is pivotal in the prevention and treatment of HTS (16).
Gradually, laser and light therapy are becoming central to the field.Photoelectric treatments are minimally invasive or noninvasive, less painful, and have excellent therapeutic efficacy with short downtime and rare side effects.They can be applied to a large area in a single session.The methods are most commonly used to destroy local vessels and reduce blood supply by targeting oxyhemoglobin, including IPL (400-1200nm) and Pulsed Dye Laser (PDL) (585 nm or 595 nm).To successfully close blood vessels, it is required that the pulse duration is shorter than the heat relaxation time of hemoglobin (17).
IPL is a non-laser light source that targets both oxyhemoglobin and melanin, delivering low-level light to the epidermis and dermis layers.IPL can simultaneously coagulate microvasculature, eliminate melanin, and stimulate collagen regeneration.The researches had shown that IPL irradiation can promote fibroblast proliferation and increase the expression levels of procollagen I and III mRNA without affecting the levels of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP) (18,19).In one study, 109 patients with hypertrophic scars underwent eight IPL treatment sessions, and 92.5% of patients showed significant improvement in scar height, erythema, and hardness (20).Previous studies have demonstrated IPL's excellent effects on the pliability and pigmentation of surgical and traumatic scars.Importantly, IPL is suitable for almost all skin types, including darker skin, and can be combined with other therapies (21,22).PDL is capable of targeting oxyhemoglobin and coagulating microvessels, making it effective in the treatment of port wine stains and other hemangiomas.Additionally, it can decrease collagen III deposition and reduce the thickness, pigmentation, and vascularity of scar tissue (23).However, in this study, we opted to use narrowband IPL instead of PDL to target scar vessels.PDL treatment often results in purpura, which can cause new injury to the thin scar skin and trigger excessive inflammatory reactions, neovascularization, and even new scarring.Moreover, PDL has a smaller hand tool spot size (15 mm), while the larger 3 × 1 cm footprint of IPL is better suited for treating large areas of hypertrophic scars.Narrowband IPL (500-600 nm) is filtered from IPL and effectively targets erythema and melanin without harming the epidermis, making it a safer choice for darker skin types with minimal downtime (24,25).
Based on fractional photothermolysis, the fractional CO 2 laser (10600 nm) creates less than 500 μ MTZs surrounded by remaining skin tissue, which allows for rapid repair without new scarring.The CO 2 laser can be absorbed by water and penetrate deeper into the skin with high energy, causing skin vaporization and collagen denaturation (26,27).Burn scars have been treated with fractional CO 2 laser and studies have shown molecular changes, including increased collagen III, TGF-β3, and MMP-1, as well as reduced collagen I (28,29).In 2017, Julian treated ten patients with hypertrophic burn scars using fractional CO 2 laser.After six months of treatment, it was observed that surface relief improved, the firmness of scars decreased, and the Vancouver Scar Scale (VSS) and POSAS scores showed significant improvement (30).Additionally, the authors proved that the texture and color of hypertrophic post-burn scars improved noticeably after fractional CO 2 laser treatment.No scarring or dyspigmentation was reported (31).
In this study, fractional CO 2 laser and narrowband IPL were selected for the treatment of hypertrophic scars.The combined CO 2 -IPL therapy demonstrated significant improvement in overall scar assessment, as compared to IPL therapy alone, according to the POSAS evaluation.This improvement in scars was due primarily to the photothermolysis of tissue collagen by fractional CO 2 , rather than narrowband IPL targeting scar vessels.No serious side effects were noted from the combination therapy.Results showed that the combination CO 2 -IPL therapy had a higher potential for benefits, with shorter treatment sessions than single IPL therapy.In a separate randomized controlled trial, 23 patients with large hypertrophic scars received CO 2 ablative fractional laser (AFL) and IPL treatment over four sessions.Compared to control and CO 2 laser alone, combined IPL and CO 2 AFL resulted in higher improvements, as assessed by Manchester Scar Scale (MSS) and POSAS.This demonstrates the importance of applying multiple phototherapies, including CO 2 AFL and IPL, for the effective treatment of hypertrophic scars (32).However, this clinical study had a small sample size and did not have IPL therapy as a control, considering its excellent efficacy on scar vessels.Our study analyzed 101 patients with hypertrophic scars, providing strong evidence for the photoelectric combination therapy as the potential benefits of combination CO 2 -IPL therapy over IPL alone were demonstrated.Thus, the results emphasize the crucial role of combining phototherapies in the treatment of hypertrophic scars.
Our study has certain limitations.Firstly, it is a single-center study, and to strengthen the level of evidence, a multi-center clinical study involving multiple regions and ethnic groups should be conducted in the future.Secondly, more objective tests such as ultrasound should be applied.However, our study unequivocally demonstrates the efficacy of combination CO 2 -IPL therapy and offers a dependable approach for treating hypertrophic scars.

Conclusion
The use of a fractional CO 2 laser in combination with narrowband IPL has been found to achieve substantial results in the management of hypertrophic scars.This combination offers a safe and dependable alternative for multi-photoelectric therapies.

Disclosure statement
No potential conflict of interest has been reported by the authors.

Figure 2 .
Figure 2. a 21-year-old burn female with hypertrophic scars on lower limbs received three co 2 -iPl treatments showing marked improvement in color, thickness and texture.

Figure 3 .
Figure 3. a 26-year-old burn male with hypertrophic scars on face at (a) baseline and (B) 3 months after three co 2 -iPl treatments showing great improvement in vascularization, pliability and thickness.

Figure 4 .
Figure 4. a 28-year-old female with hypertrophic scars from surgery on face at (a) baseline and (B) 3 months after three co 2 -iPl treatments showing excellent improvement in thickness, color, stiffness and texture.

Figure 5 .
Figure 5. a 32-year-old burn female with hypertrophic scars from on lower limbs at (a) baseline and (B) 3 months after three iPl treatments showing good changes in vascularization and thickness.

Figure 6 .
Figure 6. a 29-year-old female with hypertrophic scars from skin graft surgery on lower limbs at (a) baseline and (B) 3 months after three iPl treatments showing good improvement in vascularization and stiffness.

Table 2 .
comparison of PoSaS scores before and after treatment.