Efficacy and safety of sequential treatment with botulinum toxin type A, fractional CO2 laser, and topical growth factor for hypertrophic scar management: a retrospective analysis | Scientific Reports

Scientific Reports volume 14, Article number: 27233 (2024) Cite this article

Metrics details

Hypertrophic scars arise from aberrant wound healing and can lead to functional and aesthetic impairments. One of the common interventions for treating hypertrophic scars is fractional carbon dioxide (CO2) laser, which employs narrow laser beams to stimulate dermal collagen deposition. Recent studies and reports have suggested that combining laser therapy with other interventions such as botulinum toxin type A (BTX-A) and topical growth factors may enhance treatment outcomes. Here, we examine the efficacy and safety of a sequential combination of BTX-A, fractional CO2 laser, and topical growth factors, referred to as combined therapy, for treating hypertrophic scars compared with only using fractional CO2 laser and topical growth factors, referred to as monotherapy. Our retrospective study includes 128 patients with hypertrophic scars (56 underwent monotherapy and 72 underwent combined therapy), which were followed-up for up to 15 months after the initiation of treatment to collect demographic and clinical data. Our analysis showed that the combined therapy significantly outperformed monotherapy in improving Vancouver scar scale scores (P < 0.05) and in the reduction of scar thickness (P < 0.05), without increasing adverse complications. Repeated treatments further augmented the efficacy of the combined therapy. Subgroup analysis revealed that combined therapy was notably more effective in reducing Vancouver scar scale scores and scar thickness in early-stage scars compared to late-stage (P = 0.023 and P = 0.045, respectively). Our study suggests that including BTX-A treatment before fractional CO2 laser and topical growth factors offers superior efficacy in reducing hypertrophic scars. We encourage early intervention and repeated treatments for optimal treatment outcomes.

A hallmark of wound healing involves the secretion of collagen, which is essential for closing injuries1,2,3,4. However, irregulated collagen deposition can lead to the formation of excessive scars. Hypertrophic scar is a type of excessive scar often resulting from surgeries, burns, and trauma5. Its incidence varies by injury type6 and is affected by factors such as age, wound infection, gender, genetic background, site, and injury depth7. While hypertrophic scars are typically confined to the original site and may fade over time8,9, their undesirable appearance, itchiness, and possible recurrence still cause severe aesthetic concerns and psychological distress10,11. Conventional treatments for hypertrophic scars, including Pulsed Dye Laser, Nd: YAG Laser, compression therapy, silicone gels, topical and intra-lesional 5-fluorouracil, and steroid injections, are sometimes effective. However, their use is often limited to minimize side effects12,13,14,15,16,17. Hence, safe and effective medical interventions are in demand for the patient’s mental and physical health.

One promising approach for scar removal and skin rejuvenation is fractional CO2 laser therapy, which applies a laser at a wavelength of 10,600 nm to specifically target the epidermis or dermal papillary layer18,19. Recent studies have proven the effectiveness of the fractional CO2 laser, especially when applied in a combination of Deep and Active FX modes20,21. Despite these advancements, repeated use of this therapy may lead to complications such as post-inflammatory hyperpigmentation, prolonged erythema, skin swelling, and infection22,23. Thus, enhancing the efficacy of fractional CO2 laser without increasing adverse reactions, has become a critical research area in dermatology.

Including topical growth factors in fractional CO2 laser treatment can increase efficacy. These factors are a class of secreted polypeptide ligands widely used for the treatment of burns, chronic wounds, fresh wounds, and repair of corneal lesions24,25. One successful example is the usage of recombinant bovine basic fibroblast growth factor (rbFGF) and fractional CO2 laser in Acne Scars26.

Besides topical growth factors, antifibrotic agents have also been used to enhance the treatment of hypertrophic scars, particularly those that are thicker27,28. These agents includes Fluorouracil (5-FU)29,30, Verapamil Hydrochloride30, and Bleomycin31. Besides, this approach may also reduce side effects associated with fractional CO2 laser. For instance, triamcinolone, commonly used for treating skin itching and inflammation, has been successfully used with fractional CO2 laser for safer and more effective scar treatments32,33.

BTX-A is another agent showing promise when combined with a fractional CO2 laser34,35,36,37. It alleviates scar tension by causing muscle fiber atrophy38 and has shown effectiveness in treating muscle spasms, facial wrinkles, pathological scarring, and analgesia21,39. Recent studies have indicated that both topical and injected forms of BTX-A can be combined with laser therapy to offer improved therapeutic outcomes 34,35,36,37, 40,41,−42. However, there is uncertainty regarding the order and timing of BTX-A and laser therapy when given in combination, as evidence suggests there are no significant outcome differences whether BTX-A is administered before or after laser treatments40,41,43,44. A recent comprehensive review recommends using BTX-A before laser treatment to minimize the discomfort of injecting BTX-A into more sensitive skin following laser treatment45. Nevertheless, the effectiveness and safety of this sequential combined therapy in treating hypertrophic scars remain unexplored.

In this retrospective study, we evaluate the safety and efficacy of a sequential combination of BTX-A, fractional CO2 laser, and rbFGF, referred to as combined therapy, for treating hypertrophic scars in 128 patients compared with only using fractional CO2 laser and rbFGF, referred to as monotherapy. Our goal is to show the effect of the pre-treatment with BTX-A for hypertrophic scar treated with fractional CO2 laser and rbFGF.

This retrospective study was conducted at the General Hospital of Ningxia Medical University, Yinchuan, China, from January 2022 to February 2024. A total of 128 patients with hypertrophic scars from various causes were included: 56 received fractional CO2 laser monotherapy, while 72 underwent combined therapy with fractional CO2 laser and BTX-A. In the combined therapy group, intradermal injection of BTX-A was administered two weeks before each fractional CO2 laser session. Patients with various types of scars, including those caused by burns, surgical procedures, chemical agents, electricity, and other factors, were included without bias. Detailed patient information is provided in Table 1. No statistical differences were observed between the groups in terms of scar location, duration since injury, or history of previous injuries. Patients underwent one to three treatment sessions based on their individual improvement. Inclusion criteria were individuals aged 18 to 70 years without serious underlying conditions, while exclusion criteria included patients under 18 or over 70, those with a history of photosensitivity, skin tumors, or abnormal mental states.

All participants provided written informed consent (supplementary material). Demographic and clinical data such as age, gender, scar etiology, scar location, time since scar formation, number of treatments, and intervals between treatments were collected with the approval of the Ethics Committee of the General Hospital of Ningxia Medical University (No.: KYLL-2021-601). All methods were performed in accordance with the relevant guidelines and regulations.

Representative images of hypertrophic scars before and immediately after fractional CO2 laser treatments are provided in Supplementary Fig. 1. Prior to treatment, the scar area was cleansed and anesthetized with Lin compound lidocaine cream (Guoyao Zhunzi, H36022084, Beijing Unisplendour Pharmaceutical Co., Ltd.), formulated at 10 g:50 mg. After a 30-minute application, the cream was removed, and the area was disinfected. Fractional CO2 laser treatment was performed using the AcuPulse Fractional King device (Lumenis Medical Laser Company, USA). A preliminary scan was conducted using Deep FX mode, with settings of 15 to 20 mJ energy, a 10 mm spot diameter, and a spot density of 3–5%. Scars were categorized by thickness as mild, medium, or heavy, and treatment parameters were adjusted accordingly. Medium and heavy scars were treated with a 2 mm spot diameter, 100 mJ energy, and 40% spot density, while mild scars were treated with a 10 mm spot diameter, 15 to 20 mJ energy, and 10–15% spot density. This classification only determined laser parameters, following hospital standard procedures. Treatment duration ranged from 10 to 30 min.

After treatment, ice was applied to the treated area for 30 to 40 min, followed by recombinant bovine basic fibroblast growth factor (rbFGF) gel (Zhuhai Yisheng Biopharmaceutical Co., Ltd., approval number: S20020113) applied twice daily for a week to promote wound healing. Each application included 25,000 IU (50 µg) per 5 g. Patients were advised to keep the treated area clean and dry for the first three days, avoid facial washing, skincare products, makeup, and protect the skin from sun exposure. Patients underwent different sessions, from one to three, according to the improvement. The average interval between sessions is three months. The decision to schedule a subsequent treatment is contingent upon the evaluation of the results from the previous session.

Neuronox, supplied as a 100 U vacuum-dried powder in a single-use vial, was prepared by reconstituting with 2 ml of sterile, preservative-free 0.9% saline, achieving a concentration of 5 U/0.1 ml (#S10970037; 100 U; produced by Hengli, in Lanzhou, China). Lesions were treated with an intradermal injection of 5 IU/cm² at 2 weeks before each session of fractional laser treatment. The decision to inject BTX-A before laser treatment was made according to the recommendation of the recently published study to minimize the discomfort of injecting BTX-A into the more sensitive laser-treated skin45. A 2-week interval between treatments was selected to avoid potential inactivation of BTX-A by laser. The injection was administered intradermally at the periphery before targeting the body of the scar. Follow-ups were scheduled at one- and six months post-injection. The decision to use BTX-A was made by the dermatologist based on a comprehensive evaluation of the scar, the patient’s willingness, and any known allergies to the treatment.

Patients were followed up on an outpatient basis for up to 15 months with an average of 7.2 ± 2.2 months. Scar treatment was evaluated at 1 month after each treatment session. Scar treatment efficacy was gauged using the Vancouver scar scale, which includes pigmentation (0–3), vascularity (0–3), pliability (0–5), and height (0–4), for a maximum score of 15, and changes in scar thickness, measured by high-frequency ultrasound. To evaluate treatment safety, adverse events such as itching, pain, discharge, bleeding, and swelling were recorded after the completion of all treatment sessions.

Prior to the examination, the subject’s scar area was cleansed, followed by the initiation of a high-frequency ultrasound examination (ULTIMUS7P, VINNO). Initially, a trained medical professional applied a specialized ultrasound gel to the center of the scar. Subsequently, the skin ultrasound probe, operating at a frequency of 20 MHz and positioned perpendicular to the subject’s skin surface, was gently maneuvered over the scar area. Particular care was taken to ensure minimal pressure was applied to the subject’s skin during the procedure. For each part, three ultrasound images were captured. vascularity, the thickness of the scar, and pliability in each image were measured. The average value of these measurements was calculated. Next, the ultrasound images of both normal skin and scar tissue were processed using the DFY-1 ultrasound image diagnosis and analysis software to analyze the characteristics of the scar. Three distinct areas were selected within each image to measure the echo intensity, and the average value of these measurements was computed.

Subgroup analyses were conducted to examine variations in the efficacy and safety of combined therapy among scar patients at distinct stages. Patients were divided into early-stage (treatment within six months post-injury) and late-stage (treatment after six months post-injury) groups. The effectiveness and safety of the combined therapy in these distinct subgroups were then compared.

The statistical analysis in this study was conducted utilizing SPSS version 20.0. similar to previous studies46,47. Continuous variables were presented as mean with standard deviation (SD) \(\left( {\overline{\chi } \pm s} \right)\) . Comparisons between groups and subgroups were tested for significance using the two-tailed Mann-Whitney U test. Categorical data were presented as frequencies and percentages and assessed with chi-square \(\chi ^{2}\) tests. P value < 0.05 was considered indicative of statistical significance.

A total of 249 patients admitted for hypertrophic scar treatment were initially selected for this study (Fig. 1). Of those, 121 were excluded based on the predetermined criteria. Among the 128 patients included in the study, 56 received monotherapy while 72 received the combined therapy. Eighty-seven of the participants were male. The predominant cause of hypertrophic scars was burns. The most common locations for scars were the head and/or neck, followed by the extremities and trunk.

Trial profile. A sketch showing the patients involved in this study. Inclusion criteria: individuals aged between 18 and 70 years with no serious underlying conditions. Exclusion criteria: individuals under 18 or over 70 years of age, those with a history of photosensitivity, individuals with skin tumors, and those presenting with abnormal mental states.

A demographic overview of the mono- and combined therapy groups is summarized in Table 1. The average patient’ age was 32.3 ± 15.9 for the monotherapy group and 35.4 ± 16.7 for the combined therapy group. The average duration since scar formation was 7.1 ± 4.2 months for the monotherapy group and 6.3 ± 3.5 months for the combined therapy group. Treatment intervals were 3.0 ± 0.8 months and 2.7 ± 1.1 months for the mono- and combined therapy groups, respectively. In the monotherapy group, 29 participants underwent 1 treatment, 12 had 2 treatments, and 15 had 3 treatments. In the combined therapy group, 31 participants underwent 1 treatment, 25 had 2 treatments, and 16 had 3 treatments. Overall, no significant demographic differences were observed between the two groups (Table 1).

We first assess the efficacy of mono- versus combined therapy in shrinking hypertrophic scars. We employed the Vancouver scar scale score and measured changes in scar thickness. Both therapies demonstrated a significant reduction of hypertrophic scars, with P values of 0.042 for monotherapy and 0.001 for combined therapy (Table 2; Figs. 2 and 3). Before treatments, the two groups have no significant differences in scar scale and thickness (P > 0.05). However, after treatment, patients receiving combined therapy have notably smaller scars with reduced scale, pigmentation, vascularity, pliability, height, and thickness (P < 0.05) (Table 2). Accordingly, our result suggested combined therapy to be more effective in reducing hypertrophic scars (Fig. 4).

Representative pictures of hypertrophic scars before and after treatments. shown as representatives. (A) A 25 years-old male patient with a hypertrophic scar on his neck prior to monotherapy. (B) The picture of the same patient in (A) after 3 sessions of monotherapy. (C) A 30 years-old female patient with a hypertrophic scar on her neck prior to combined therapy. (D) The picture of the same patient in (C) after 3 sessions of combined therapy. (E) A 43 years-old female patient with a hypertrophic scar on her hand prior to monotherapy. (F) The picture of the same patient in (E) after 3 sessions of monotherapy. (G) A 55 years-old female patient with a hypertrophic scar on her hand prior to combined therapy. (H) The picture of the same patient in (G) after 3 sessions of combined therapy. Picture was taken at 1 month after the last treatment. Red arrows indicate the hypertrophic scars. Pictures in (A, C, E, G) were taken prior to the initial treatment. Pictures in (B, D, F, H) were taken at 1 month after the last treatment session. The use of pictures has been approved by the patients.

Representative pictures of ultrasound measurements before and after treatments. (A) Representative images showing the ultrasound measurements of vascularity, scar thickness, and pliability of the hypertrophic scar on the neck from a 25 years-old male patient before and after 3 sessions of monotherapy. (B) Representative images showing the ultrasound measurements of vascularity, scar thickness, and pliability of the hypertrophic scar on the neck from a 30 years-old female patient before and after 3 sessions of combined therapy. Pictures were taken either prior to the initial treatment (before) or at 1 month after the last treatment session (After). The use of pictures has been approved by the patients.

Bar plots showing the reduction in hypertrophic scar size and thickness after mono- and combined therapy. Data was presented as mean with standard deviation (SD). Comparisons were made between mono- and combined therapy groups. Statistical significance was tested as mentioned in the method section. *P < 0.05.

We then evaluate the safety of mono- and combined therapy by analyzing the incidence of adverse complications among patients (Table 3). Overall, there was no significant difference in the occurrence of adverse complications between patients receiving monotherapy (62.5%, 35 cases) and those undergoing combined therapy (68.1%, 49 cases). For both groups, the most common complication was pruritus (monotherapy, 21.5%; combined therapy, 23.6%), followed by seepage (monotherapy, 17.8%; combined therapy, 15.3%), bleeding (monotherapy, 12.5%; combined therapy, 13.9%), swelling (monotherapy, 5.3%; combined therapy, 8.3%), and pain (monotherapy, 5.3%; combined therapy, 6.9%). Taken together, these results indicate that combined therapy is as safe as monotherapy while demonstrating enhanced effectiveness in reducing hypertrophic scars.

To further evaluate the effectiveness of combined therapy, we assessed the performance of combined therapy over multiple treatment sessions. Our results indicate that patients receiving combined therapy typically showed a significant reduction in the Vancouver scar scale after two treatments, with improvements gradually increasing thereafter (Fig. 5A). On the other hand, the majority of the reduction in scar thickness occurred after the initial treatment (Fig. 5B).

Performance of combined therapy in multiple treatment sessions. (A) Changes in Vancouver scar scale after repeated treatments; (B) Changes in scar thickness after multiple treatments. Data was presented as mean with standard deviation (SD). Comparisons were by comparing each treatment to the baseline. Statistical significance was tested as mentioned in the method section. *P < 0.05; **P < 0.01.

We next evaluated the performance of combined therapy in early- and late-stage scars. We stratified patients receiving combined therapy into two subgroups: an early-stage subgroup and a late-stage subgroup based on the time after scar formation. Notably, there are no significant demographic differences between the two groups (Table 4).

To assess the performance of combined therapy in the two subgroups, we measured the changes in Vancouver scar scale and scar thickness. As expected, combined therapy significantly shrunk hypertrophic scars in both subgroups (Table 5). While the two subgroups have no significant differences in scar scale and thickness before treatment, early-stage patients exhibit much smaller scars, as demonstrated by lower scar scale and thickness, after treatment (Table 5). Similarly, early-stage patients demonstrated a larger reduction in scar scale and thickness (Fig. 6). Together, these results suggested that combined therapy is more effective at early-stage scars, and its performance is enhanced by repeat treatments.

Bar plots showing the reduction in hypertrophic scar size and thickness after combined therapy at early and late stages. Data was presented as mean with standard deviation (SD). Comparisons were made between early- and late-staged scars. Statistical significance was tested as mentioned in the method section. *P < 0.05.

In this study, we demonstrated that a sequential combination of BTX-A, fractional CO2 laser, and topical growth factors offers superior efficacy in reducing hypertrophic scars compared to only using fractional CO2 laser and topical growth factors. Our results suggest that combined therapy is particularly effective in the early stages (within 6 months) of scar formation, with its performance further enhanced by repeated treatments.

Fractional CO2 laser technology has been utilized in dermatology as a non-surgical approach for many years since 200748,49,50,51,52,53. Recently, there has been a trend towards integrating fractional CO2 laser treatment with other modalities to enhance its efficacy27. Huang et al. combined ablative fractional CO2 laser with 5-fluorouracil ethosomal gel29. While effective in a rabbit model, this combined therapy did not surpass monotherapy in human patients29. Conversely, our study indicated that sequential combining BTX-A, fractional CO2 laser, and rbFGF significantly surpasses monotherapy in human patients (Figs. 2, 3 and 4; Tables 2 and 3). This improvement may be due to BTX-A’s ability to alleviate scar tension by causing muscle fiber atrophy38,54,55,56,57.

Unexpectedly, patients receiving the combined therapy exhibited the same rate of pruritus complications as those receiving monotherapy, even though BTX-A has been reported to alleviate itching58. However, given the combined therapy did not increase any complications at least, we still recommend the use of the combined therapy over monotherapy for treating hypertrophic scars, where feasible.

Fibroblast growth factors play dynamic roles in fibrosis. In contrast to the long-held belief that growth factors stimulate fibroblast proliferation and activation to produce collagen, recent studies have suggested that many growth factors, such as FGF-259, FGF-960, and FGF-1860, inhibit fibroblast activation and collagen deposition in various organs61. Since fibrosis is primarily driven by the expression of pro-fibrotic genes28,62, one explanation for this dynamic is that different growth factors influence the expression of pro-fibrotic genes in distinct ways63. For example, FGF-2 has been shown to inhibit certain pro-fibrotic genes in both human and animal models63. Although the mechanism behind the antifibrotic effects of growth factors is not fully understood, many have proven effective in treating scars26. In this regard, we recommend the inclusion of growth factors, such as rbFGF, in the treatment of hypertrophic scars.

The performance of the combined therapy improves with repeated treatments. We observed a gradual reduction in the scar scale after at least two repeated treatments (Fig. 5A), which aligns with the published notion by Kemp Bohan et al.,64. Interestingly, scar thickness decreased dramatically after the initial treatment (Fig. 5B), which contrasts with findings that two laser treatments are necessary to reduce scar thickness64. This difference may be due to the incorporation of BTX-A and may warrant future investigation. Furthermore, we noted that combined therapy is more effective in patients within six months of scar formation. This finding is consistent with published research65. Based on these, we recommend clinicians apply at least two repeated treatments of combined therapy at early stages to achieve optimal outcomes.

Although our study shows promise, it is important to recognize certain limitations. First, the hypertrophic scars analyzed were caused by various etiologies, which might have influenced the effectiveness of therapies. Consequently, focused studies on hypertrophic scars with uniform etiology may be a better choice. However, such studies could be very challenging as limiting the study to a single etiology might significantly reduce the available sample size. Second, the majority of participants involved in the study received treatment within 12 months post-injury. Future studies may be needed to explore the performance of combined therapies on older scars.

The datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request.

Lin-Hui, L. et al. Recombinant human collagen type III improves hypertrophic scarring by regulating the ratio of type I/III collagen. J. Burn Care Res., irae040 (2024).

Rodrigues, M., Kosaric, N., Bonham, C. A. & Gurtner, G. C. Wound healing: A cellular perspective. Physiol. Rev. 99, 665–706 (2019).

Article CAS PubMed Google Scholar

Tottoli, E. M. et al. Skin wound healing process and new emerging technologies for skin wound care and regeneration. Pharmaceutics. 12, 735 (2020).

Article CAS PubMed PubMed Central Google Scholar

Frech, F. S. et al. Hypertrophic scars and keloids: Advances in treatment and review of established therapies. Am. J. Clin. Dermatol. 24, 225–245 (2023).

Article ADS PubMed Google Scholar

Bharadia, S. K., Burnett, L. & Gabriel, V. Hypertrophic scar. Phys. Med. Rehabilitation Clin. 34, 783–798 (2023).

Google Scholar

Limandjaja, G. C., Niessen, F. B., Scheper, R. J. & Gibbs, S. Hypertrophic scars and keloids: Overview of the evidence and practical guide for differentiating between these abnormal scars. Exp. Dermatol. 30, 146–161 (2021).

Article CAS PubMed Google Scholar

Ogawa, R. The most current algorithms for the treatment and prevention of hypertrophic scars and keloids: A 2020 update of the algorithms published 10 years ago. Plast. Reconstr. Surg. 149, 79e–94e (2022).

Article CAS PubMed Google Scholar

Tomtschik, J., Anand, N., Bustos, S. S., Martinez-Jorge, J. & Wyles, S. P. Practical management of hypertrophic scarring: The mayo clinic experience. Arch. Dermatol. Res. 316, 77 (2024).

Article CAS PubMed Google Scholar

Knowles, A. & Glass, D. A. Keloids and hypertrophic scars. Dermatol. Clin. 41, 509–517 (2023).

Article CAS PubMed Google Scholar

Nischwitz, S. P. et al. Evidence-based therapy in hypertrophic scars: An update of a systematic review. Wound Repair. Regeneration. 28, 656–665 (2020).

Article PubMed Google Scholar

Nischwitz, S. P. et al. Evidence-based therapy in hypertrophic scars: An update of a systematic review. Wound Repair. Regen. 28, 656–665. https://doi.org/10.1111/wrr.12839 (2020).

Article PubMed PubMed Central Google Scholar

Ramanauskaite, A., Fretwurst, T. & Schwarz, F. Efficacy of alternative or adjunctive measures to conventional non-surgical and surgical treatment of peri-implant mucositis and peri-implantitis: A systematic review and meta-analysis. Int. J. Implant Dentistry. 7, 1–61 (2021).

Article Google Scholar

Choi, C. et al. Management of hypertrophic scars in adults: A systematic review and meta-analysis. Australas. J. Dermatol. 63, 172–189 (2022).

Article PubMed Google Scholar

Worley, B. et al. Treatment of traumatic hypertrophic scars and keloids: a systematic review of randomized control trials. Arch. Dermatol. Res. 315, 1887–1896 (2023).

Article PubMed Google Scholar

Gianatasio, C., Abrouk, M. & Waibel, J. S. Treatment approaches for treating hypertrophic scars and keloids. Dermatological Reviews. 2, 11–22 (2021).

Article Google Scholar

Jiang, Z. Y. et al. Efficacy and safety of intralesional triamcinolone versus combination of triamcinolone with 5-fluorouracil in the treatment of keloids and hypertrophic scars: a systematic review and meta-analysis. Aesthetic Plast. Surg. 44, 1859–1868 (2020).

Article PubMed Google Scholar

Elsaie, M. L. Update on management of keloid and hypertrophic scars: A systemic review. J. Cosmet. Dermatol. 20, 2729–2738 (2021).

Article PubMed Google Scholar

Li, B. et al. Efficacy and adverse reactions of fractional CO2 laser for atrophic acne scars and related clinical factors: a retrospective study on 121 patients. J. Cosmet. Dermatol. 21, 1989–1997 (2022).

Article PubMed Google Scholar

Meynköhn, A. et al. Fractional ablative carbon dioxide laser treatment of facial scars: Improvement of patients’ quality of life, scar quality, and cosmesis. J. Cosmet. Dermatol. 20, 2132–2140 (2021).

Article PubMed Google Scholar

Zhang, N. et al. Fractional CO2 laser therapy for cesarean scar under the guidance of multiple evaluation methods: A retrospective study. J. Cosmet. Dermatol. 20, 2119–2124 (2021).

Article PubMed Google Scholar

Said, S. Z., Meshkinpour, A., Carruthers, A. & Carruthers, J. Botulinum toxin A: Its expanding role in dermatology and esthetics. Am. J. Clin. Dermatol. 4, 609–616 (2003).

Article PubMed Google Scholar

Oh, B. H., Hwang, Y. J., Lee, Y. W., Choe, Y. B. & Ahn, K. J. Skin characteristics after fractional photothermolysis. Ann. Dermatol. 23, 448 (2011).

Article PubMed PubMed Central Google Scholar

Metelitsa, A. I. & Alster, T. S. Fractionated laser skin resurfacing treatment complications: A review. Dermatol. Surg. 36, 299–306 (2010).

Article CAS PubMed Google Scholar

Luo, Y., Luan, X. L., Sun, Y. J., Zhang, L. & Zhang, J. H. Effect of recombinant bovine basic fibroblast growth factor gel on repair of rosacea skin lesions: A randomized, single-blind and vehicle-controlled study. Exp. Ther. Med. 17, 2725–2733. https://doi.org/10.3892/etm.2019.7258 (2019).

Article CAS PubMed PubMed Central Google Scholar

Luo, Y., Sun, Y. J., Zhang, L. & Luan, X. L. Treatment of mites folliculitis with an ornidazole-based sequential therapy: A randomized trial. Med. (Baltim). 95, e4173. https://doi.org/10.1097/MD.0000000000004173 (2016).

Article CAS Google Scholar

Yuan, C. et al. Therapeutic efficacy of bovine basic fibroblast growth factor combined with ultrapulsed fractional CO(2) laser in acne scars: Randomized controlled trial. Clin. Cosmet. Investig Dermatol. 16, 2813–2819. https://doi.org/10.2147/CCID.S428017 (2023).

Article CAS PubMed PubMed Central Google Scholar

Li, J., Wang, D., Wang, Y., Du, Y. & Yu, S. Effectiveness and safety of fractional micro-plasma radio-frequency treatment combined with ablative fractional carbon dioxide laser treatment for hypertrophic scar: A retrospective study. Annals Palliat. Med. 10, 9800809–9809809 (2021).

Google Scholar

Wu, J. et al. Glutamyl-Prolyl-tRNA synthetase regulates proline-rich pro-fibrotic protein synthesis during cardiac fibrosis. Circ. Res. 127, 827–846. https://doi.org/10.1161/CIRCRESAHA.119.315999 (2020).

Article CAS PubMed PubMed Central Google Scholar

Huang, J. et al. CO2 fractional laser combined with 5-fluorouracil ethosomal gel treatment of hypertrophic scar macro-, microscopic, and molecular mechanism of action in a rabbit animal model. Rejuven. Res. 24, 131–138 (2021).

Article CAS Google Scholar

Sabry, H. H., Abdel Rahman, S. H., Hussein, M. S. & Sanad, R. R. Abd El Azez, T. A. The efficacy of combining fractional carbon dioxide laser with verapamil hydrochloride or 5-fluorouracil in the treatment of hypertrophic scars and keloids: a clinical and immunohistochemical study. Dermatol. Surg. 45, 536–546. https://doi.org/10.1097/dss.0000000000001726 (2019).

Article CAS PubMed Google Scholar

Luo, Q. F. The combined application of bleomycin and triamcinolone for the treatment of keloids and hypertrophic scars: An effective therapy for treating refractory keloids and hypertrophic scars. Skin. Res. Technol. 29, e13389. https://doi.org/10.1111/srt.13389 (2023).

Article PubMed PubMed Central Google Scholar

Zhang, J., He, Z., Tang, Y., Xiao, X. & Yang, F. CO(2) fractional laser combined with triamcinolone acetonide injection for the hypertrophic scars: Which is first? Lasers Med. Sci. 38, 7. https://doi.org/10.1007/s10103-022-03693-y (2022).

Article PubMed Google Scholar

Zhou, J. et al. Treatment of hypertrophic scars with ablative fractional carbon dioxide laser assisted with different topical triamcinolone delivery ways. Heliyon 9, e22818. (2023). https://doi.org/10.1016/j.heliyon.2023.e22818

Zhou, B. R. et al. The effect of conditioned media of adipose-derived stem cells on wound healing after ablative fractional carbon dioxide laser resurfacing. BioMed Research International (2013). (2013).

Xu, X. et al. Adipose-derived stem cells cooperate with fractional carbon dioxide laser in antagonizing photoaging: a potential role of wnt and β-catenin signaling. Cell. Bioscience. 4, 1–11 (2014).

Article CAS Google Scholar

Erlendsson, A. M., Anderson, R. R., Manstein, D. & Waibel, J. S. Developing technology: Ablative fractional lasers enhance topical drug delivery. Dermatol. Surg. 40, S142–S146 (2014).

Article PubMed Google Scholar

Zhu, J. et al. The efficacy and safety of fractional CO 2 laser combined with topical type a botulinum toxin for facial rejuvenation: A randomized controlled split-face study. Biomed. Res. Int. 2, 1–7 (2016).

Google Scholar

Fagien, S. Botox for the treatment of dynamic and hyperkinetic facial lines and furrows: Adjunctive use in facial aesthetic surgery. Plast. Reconstr. Surg. 112, 40S–52S (2003).

Article Google Scholar

Alvarez, C. M. et al. Treatment of idiopathic clubfoot utilizing botulinum A toxin: A new method and its short-term outcomes. J. Pediatr. Orthop. 25, 229–235 (2005).

Article PubMed Google Scholar

Fan, X. et al. Clinical Assessment of the safety and effectiveness of nonablative fractional laser combined with transdermal delivery of botulinum toxin A in treating periocular wrinkles. Plast. Reconstr. Surg. Glob Open. 4, e1004. https://doi.org/10.1097/GOX.0000000000001004 (2016).

Article PubMed PubMed Central Google Scholar

Zimbler, M. S. et al. Effect of botulinum toxin pretreatment on laser resurfacing results: A prospective, randomized, blinded trial. Arch. Facial Plast. Surg. 3, 165–169. https://doi.org/10.1001/archfaci.3.3.165 (2001).

Article CAS PubMed Google Scholar

Cao, L. L. et al. A preliminary study on ultrasound techniques applied to evaluate the curative effect of botulinum toxin type a in hypertrophic scars. Heliyon. 10, e34723. https://doi.org/10.1016/j.heliyon.2024.e34723 (2024).

Article CAS PubMed PubMed Central Google Scholar

Yamauchi, P. S., Lask, G. & Lowe, N. J. Botulinum toxin type A gives adjunctive benefit to periorbital laser resurfacing. J. Cosmet. Laser Ther. 6, 145–148. https://doi.org/10.1080/14764170410023767 (2004).

Article PubMed Google Scholar

Semchyshyn, N. L. & Kilmer, S. L. Does laser inactivate botulinum toxin? Dermatol. Surg. 31, 399–404. https://doi.org/10.1111/j.1524-4725.2005.31105 (2005).

Article CAS PubMed Google Scholar

Chan, K. et al. Botulinum A Toxin and laser therapy: Evidence and recommendations for combination treatment. Aesthet. Surg. J. 43, NP811–NP814. https://doi.org/10.1093/asj/sjad217 (2023).

Article PubMed PubMed Central Google Scholar

He, W., Zhang, F., Jiang, F., Liu, H. & Wang, G. Correlations between serum levels of microRNA-148a-3p and microRNA-485-5p and the progression and recurrence of prostate cancer. BMC Urol. 22, 195 (2022).

Article CAS PubMed PubMed Central Google Scholar

Xia, G. et al. Correlation between severity of spinal stenosis and multifidus atrophy in degenerative lumbar spinal stenosis. BMC Musculoskelet. Disord. 22, 536 (2021).

Article CAS PubMed PubMed Central Google Scholar

Omi, T. & Numano, K. The role of the CO2 laser and fractional CO2 laser in dermatology. Laser Therapy. 23, 49–60 (2014).

Article PubMed PubMed Central Google Scholar

Shen, S., Cai, Y., Song, X. & Xiang, W. The efficacy of fractional carbon dioxide laser in surgical scars treatment: A system review and Meta-analysis. Aesthetic Plast. Surg. 47, 340–350 (2023).

Article PubMed Google Scholar

Zhang, M. X. et al. Evaluation of combining ultrapulse CO2 with fractional CO2 laser for the treatment of atrophic scars in asians. Lasers Med. Sci. 39, 1–7 (2024).

Article CAS Google Scholar

Grigoryan, K. V., Fusco, I., Ronconi, L. & Zingoni, T. Fractional CO2 laser therapy for effective treatment of Facial traumatic hypertrophic scar: A Case Report. Am. J. Case Rep. 25, e942706–e942701 (2024).

Article PubMed PubMed Central Google Scholar

Cai, Y., Tian, J., Li, J. & Deng, C. A novel combined technology for treating hypertrophic scars: adipose tissue extract combined with fractional CO2 laser. Front. Physiol. 14, 1284312 (2023).

Article PubMed PubMed Central Google Scholar

Makboul, M., Makboul, R., Abdelhafez, A. H., Hassan, S. S. & Youssif, S. M. Evaluation of the effect of fractional CO 2 laser on histopathological picture and TGF-β1 expression in hypertrophic scar. J. Cosmet. Dermatol. 13, 169–179 (2014).

Article PubMed Google Scholar

Guo, X., Song, G., Zhang, D. & Jin, X. Efficacy of botulinum toxin type A in improving scar quality and wound healing: A systematic review and meta-analysis of randomized controlled trials. Aesthetic Surg. J. 40, NP273–NP285 (2020).

Article Google Scholar

Elshahed, A. R., Elmanzalawy, K. S., Shehata, H. & ElSaie, M. L. Effect of botulinum toxin type A for treating hypertrophic scars: A split-scar, double‐blind randomized controlled trial. J. Cosmet. Dermatol. 19, 2252–2258 (2020).

Article PubMed Google Scholar

Zhou, N., Li, D., Luo, Y., Li, J. & Wang, Y. Effects of botulinum toxin type A on microvessels in hypertrophic scar models on rabbit ears. BioMed Research International (2020). (2020).

Liu, X. & Zhang, D. Evaluation of efficacy of corticosteroid and corticosteroid combined with botulinum toxin type A in the treatment of keloid and hypertrophic scars: a meta-analysis. Aesthetic Plast. Surg. 45, 3037–3044 (2021).

Article PubMed Google Scholar

Park, M. Y. & Ahn, K. Y. Scientific review of the aesthetic uses of botulinum toxin type A. Archives Craniofac. Surg. 22, 1 (2021).

Article Google Scholar

Koo, H. Y. et al. Fibroblast growth factor 2 decreases bleomycin-induced pulmonary fibrosis and inhibits fibroblast collagen production and myofibroblast differentiation. J. Pathol. 246, 54–66 (2018).

Article CAS PubMed PubMed Central Google Scholar

Joannes, A. et al. FGF9 and FGF18 in idiopathic pulmonary fibrosis promote survival and migration and inhibit myofibroblast differentiation of human lung fibroblasts in vitro. Am. J. Physiol. Lung Cell. Mol. Physiol. 310, L615–629. https://doi.org/10.1152/ajplung.00185.2015 (2016).

Article PubMed Google Scholar

Guzy, R. Fibroblast growth factor inhibitors in lung fibrosis: friends or foes? Am. J. Respir Cell. Mol. Biol. 63, 273–274. https://doi.org/10.1165/rcmb.2020-0156ED (2020).

Article CAS PubMed PubMed Central Google Scholar

Antar, S. A., Ashour, N. A., Marawan, M. E., Al-Karmalawy, A. A. & Fibrosis Types, effects, markers, mechanisms for Disease Progression, and its relation with oxidative stress, immunity, and inflammation. Int. J. Mol. Sci. 24 https://doi.org/10.3390/ijms24044004 (2023).

Dolivo, D. M., Larson, S. A. & Dominko, T. Fibroblast growth factor 2 as an Antifibrotic: antagonism of myofibroblast differentiation and suppression of pro-fibrotic gene expression. Cytokine Growth Factor. Rev. 38, 49–58. https://doi.org/10.1016/j.cytogfr.2017.09.003 (2017).

Article CAS PubMed PubMed Central Google Scholar

Bohan, P. M. K. et al. Fractionated ablative carbon dioxide laser therapy decreases ultrasound thickness of hypertrophic burn scar: A prospective process improvement initiative. Ann. Plast. Surg. 86, 273–278 (2021).

Article Google Scholar

Choi, K. J. et al. Fractional CO2 laser treatment for burn scar improvement: A systematic review and meta-analysis. Burns. 47, 259–269 (2021).

Article PubMed Google Scholar

Download references

None.

The study was supported by the Ningxia Natural Science Foundation (No: 2022AAC03534).

Jin Wang and Lijun Huang contributed equally to this work.

Department of Laser, General Hospital of Ningxia Medical University, Yinchuan, 750001, China

Jin Wang, Lijun Huang, Rui Xu, Tao Guo, Tong Huang, Yanping Wu & Li Liang

Pingluo County People’s Hospital, Shizuishan, 753400, China

Juan Li

Ningxia Medical University, Yinchuan, 750001, China

Yang Yang & Jiale Zhang

Department of Genetics, Stanford University , Stanford, 94304, USA

Feng Jiang

Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, 14620, USA

Huan Liu

Department of Vascular Surgery, General Hospital of Ningxia Medical University, 99 Fuan East Ln, Yinchuan, 750001, Ningxia Huizu, China

Lei Wang

Department of Vascular Surgery, General Hospital of Ningxia Medical University, Yinchuan, China

Lei Wang

You can also search for this author in PubMed Google Scholar

All authors (JW, LH, LL, and JL) contributed to the conception and study design. JW, LH, JL, RX, YY, TG, TH, YW, and JZ coordinated and managed all experiments of the study. CD carried out the literature search. JW, LH, JL, RX, YY, and JZ conducted data collection and performed preliminary data preparations. JW, LH, and JL conducted data analyses and all the authors contributed to the interpretation of data. FJ, HL, LL, and LW wrote the draft of the paper and all authors provided substantive feedback on the paper and contributed to the final manuscript. All authors have read and approved the final manuscript.

Correspondence to Li Liang or Lei Wang.

The authors declare no competing interests.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Below is the link to the electronic supplementary material.

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions

Wang, J., Huang, L., Li, J. et al. Efficacy and safety of sequential treatment with botulinum toxin type A, fractional CO2 laser, and topical growth factor for hypertrophic scar management: a retrospective analysis. Sci Rep 14, 27233 (2024). https://doi.org/10.1038/s41598-024-78094-y

Download citation

Received: 16 May 2024

Accepted: 28 October 2024

Published: 08 November 2024

DOI: https://doi.org/10.1038/s41598-024-78094-y

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative