https://doi.org/10.1007/s10103-023-03896-x ORIGINAL ARTICLE
The quantitative analysis of low‑concentration (2%) ALA‑PDT assisted with Q‑switch 1064‑nm Nd:YAG laser for acne vulgaris treatment
Yu‑Tsung Chen1,2 · Yun‑Jhen Lin3 · Chang‑Cheng Chang3,4,5,6 · Po‑Heng Liu7 · Yung‑Hsueh Huang7 · Jia‑Wei Shen5 · Meng‑En Lu5 · Hsiu‑Mei Chiang5 · Bor‑Shyh Lin4
Received: 26 May 2023 / Accepted: 25 September 2023
© The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature 2023
Abstract
Conventional 5‐aminolevulinic acid-photodynamic (ALA-PDT) therapy (10–20%) has been widely applied for moderate-to- severe acne. The aim of this study is to investigate the effects of non-ablative Q-switched 1064-nm Nd:YAG laser-assisted ALA-PDT with low concentration (2%) on the treatment of acne vulgaris. Enrolled patients were randomly assigned to 2 groups. One group received combined therapy of 2% ALA-PDT and non-ablative Q-switched 1064-nm Nd:YAG laser, and the other received only 2% ALA-PDT. Patients in each group had received 3-session treatments with 4-week intervals (week 0, 4, and 8). Sebum secretion, melanin index, erythema index, and transepidermal water loss (TEWL) were assessed at week 2, 8, 12, and 24. VISIA® skin image system score and global esthetic improvement scale (GAIS) were also evaluated.
Twenty-four participants were enrolled and evenly randomized to two groups. Significant improvement in sebum secre- tion was noted in combined therapy group compared to the monotherapy group at week 12 (37.5% versus 16.3%), and the improvement would still be noted until week 24 (18.3% versus 17.4%). Combined group also showed more severe melanin index and erythema index after treatment. For VISIA® skin analysis, patients in combined group had better percentile rank- ing in porphyrins and red-light images. There were no significant differences in GAIS at the end of the follow-up between each group, whereas higher proportion of satisfaction was noted in combined group at week 2. With the assistance of laser, low concentrations (2%) of 5-ALA can provide effective phototoxic reactions in treating acne vulgaris. The satisfaction of patients is high with acceptable adverse effects.
Keywords 5‐aminolevulinic acid · Photodynamic therapy · Nd:YAG laser · Acne
Introduction
Acne vulgaris, which affects more than 80% of young people, is a common chronic inflammatory disease of the pilosebaceous unit and is mainly caused by increased sebum production, altered keratinization, inflammation, and bac- teria colonization [1]. Furthermore, impaired skin barrier function plays a role in acne, including abnormal ceramide level and transepidermal water loss (TEWL) [2–4]. Acne can cause significant physical and psychological effects, including acne scar, anxiety, and overall impaired quality of life [5]. Common treatment of acne includes topical therapy (retinoids, benzoyl peroxide, antibiotics, and azelaic acid), systemic therapy (antibiotics, isotretinoin, contraceptives, spironolactone), chemical peels, laser therapy, and photo- dynamic therapy [6].
5‐aminolevulinic acid-photodynamic therapy (ALA-PDT) is a non-invasive technique that selectively creates a cytotoxic
* Chang-Cheng Chang [email protected]
1 School of Public Health, College of Public Health, Taipei Medical University, Taipei, Taiwan
2 Department of Dermatology, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan
3 School of Medicine, College of Medicine, China Medical University, China Medical University Hospital, Taichung, Taiwan
4 Institute of Imaging and Biomedical Photonics, National Yang Ming Chiao Tung University, Tainan, Taiwan
5 Department of Cosmeceutics, China Medical University, Taichung, Taiwan
6 Aesthetic Medical Center, China Medical University Hospital, Taichung, Taiwan
7 Four Seasons Clinic, Taichung, Taiwan
photodynamic reaction through the photochemical reaction by a photosensitizing agent [7]. Studies have revealed that ALA can be converted into PpIX in acne lesions which is a potential method in managing localized acne [8, 9]. ALA-PDT has been widely used in skin disease, including condyloma acuminate, actinic keratosis, Bowen’s disease, and squamous cell carci- noma. Studies have indicated that ALA-PDT can be effective as a management for moderate-to-severe and severe acne [10, 11] and may be used in combination with other forms of acne treatment. Hongcharu et al. [8] demonstrated that ALA-PDT results in a reduction of sebum secretion rate and suppression of follicular bacteria. However, effectiveness of ALA-PDT is related to skin delivery due to thickness of lesion, barrier func- tion of stratum corneum, and tight junction for permeation [12, 13]. To enhance the absorption of agent but no need of higher concentration of ALA, tape stripping, microneedling, iontophoresis, sonophoresis, radiofrequency, and laser have been employed. Laser resurfacing with fractional photolysis can precisely and superficially remove stratum corneum, and thus significantly increase drug permeation without produc- tion of biohazardous waste [14]. Studies revealed that laser- assisted drug delivery is effective in treating melasma, actinic keratosis, and skin cancers [15, 16]. Filippis et al. have also demonstrated that Q-switched 1064-nm Nd:YAG (neodym- ium-doped yttrium aluminum garnet) laser could straightly restore the skin barrier function, by increasing the expression of several molecules and modulating the proinflammatory cytokines [17].
In addition, the dose-dependent adverse effects of ALA, including pain, blistering, erythema, and dyspigmentation, usually last long and interrupt patient’s daily life. Conven- tional ALA-PDT with high concentration of ALA (10–20%) may significantly improve acne, while severity and duration of adverse effects are significantly positively correlated to the concentration of ALA [18]. Therefore, we used low-con- centration (2%) ALA-PDT combined with Q-switched 1064- nm Nd:YAG laser for minimizing thermal damage effects and optimizing the rate of pore clearance. To enhance patient acceptance of ALA-PDT, a lower concentration of ALA was selected to lower dose-dependent adverse effects. Addition- ally, fractional Nd:YAG laser was combined to enhance drug absorption and achieve equivalent therapeutic efficacy. The aim of this study is to investigate the effect of low-concen- tration (2%) ALA-PDT assisted with non-ablative Q-switch 1064-nm Nd: YAG laser for acne vulgaris treatment.
Materials and methods
Study design and patient selection
This prospective, randomized controlled trial was approved by the Institutional Review Board Ethical Committee (China
Medical University Hospital Ethics Committee No.110- REC1-102). From 1 September 2021 to 30 September 2022, 24 patients with mild-to-moderate acne vulgaris were enrolled in this study. None of the patients had a history of photosensitivity or autoimmune disease. Patients who had other acute or chronic skin disease on treatment area or received antibiotics, isotretinoin, oral contraceptive pills, hormone replacement therapy, laser and intense pulsed light in the preceding 6 months were excluded.
Treatment protocol
Enrolled patients were randomly assigned to 2 groups. One group (combined group) received combined therapy of 2%
ALA-PDT and non-ablative Q-switched 1064-nm Nd:YAG laser; the other group (monotherapy group) received only 2%
ALA-PDT. Each group received 3-session treatments with 4-week interval (week 0, 4, and 8). For combined therapy, patients were priorly treated with laser as a drug delivery system. Fluence of 2 J/cm2 with 7-mm spot size was applied.
Two percent ALA was applied for 40 min of incubation, fol- lowed by illumination with 633-nm red light (with energy density of 37 J/cm2 and power density of 105 mW/cm2) for 6 min. The parameters used for ALA-PDT were the same in two groups, and our treatment protocols were set based on our prior clinical experience.
Post‑treatment skin care
To minimize the adverse effects, patients were advised to apply adequate skin lotion for skin moisturizing and broad- spectrum sunscreen for sun protection if needed. Also, other topical bleaching agents were avoided during the follow-up.
Clinical evaluation
Patients from both groups were assessed before treatment at week 0 and post-treatment at week 2, 8, 12, and 24. Due to the potential similarity in post-treatment response between week 4 and week 8, the early assessment was conducted at week 2 instead of week 4. Sebum secretion, melanin index, erythema index, and transepidermal water loss (TEWL) were evaluated with MPA580 sebumeter (Germany). VISIA®
(Canfield Scientific, Parsippany, NJ) Complexion Analy- sis imaging system was used to evaluate two parameters including red areas and porphyrins over the forehead, nose, and cheeks. Red areas indicate inflammation while porphy- rins indicate bacterial secretion lodged in pores. A higher VISIA® score indicated better skin condition. Subjective assessments were conducted by both patients and physicians.
Participants were asked to self-evaluate the improvement in skin conditions according to Global Aesthetic Improvement Scale (GAIS). GAIS classifies clinical improvement into
“exceptional improvement,” “very improved,” “improved,”
“unaltered,” and “worsen.”
Statistical analysis
Data analysis was performed by using the SPSS Statistics (version 22; IBM, Armonk, NY) software. The deviation and percentage change in sebum secretion, melanin index, erythema index, and TEWL from baseline to post-treatment (week 0 to week 2, 8, 12, or 24) were compared using the Wilcoxon signed-rank test. GAIS between two groups was compared using chi-square test or Fisher’s exact test.
A two-sided p-value of < 0.05 was considered statistically significant.
Results
Twenty-four participants (7 men and 17 women, Fitzpat- rick III&IV) were enrolled, and they were evenly rand- omized to two groups (12 patients in combined group and 12 patients in monotherapy group). The average age for each group was 25.3 ± 7.6 and 23.8 ± 5.9 (Table 1). Compared to monotherapy group, more reduction in sebum secretion on the whole face average was noted in combined group.
At week 2, increased sebum secretion was noted in both groups, with a 14% increment in combined group and a 5%
increment in monotherapy group. Moreover, at weeks 8 and 12, significant improvement of sebum secretion was noted in both groups, and combined group showed more reduction compared to monotherapy group (Fig. 1; Table 1). In the combined group and monotherapy group, the improvement rates were 27.7% versus 9.2% at week 8 and 37.5% ver- sus 16.3% at week 12 (p < 0.05), respectively. The effect of sebum reduction was still noted until week 24. The improve- ment rates in combined group and monotherapy group were 18.3% versus 17.4% at week 24, respectively.
As for adverse effects, melanin, erythema index, and TEWL were measured (Fig. 2). A longer period of exacer- bation in melanin deposition was noted in combined group at weeks 2, 4, and 8. Eventually, the melanin deposition on the whole face average gradually subsided and improved in both groups at week 24, with 14.6% and 18.8% of reduction in combined group and monotherapy group, respectively. At week 2, combined group also resulted in higher erythema index than monotherapy group, especially on the cheeks.
In combined group and monotherapy group, the increment rates of erythema index were 11.1% versus 4.9% on cheeks at week 2, respectively. The erythema gradually subsided until week 24, and no significance was noted on the whole face average compared to the baseline. At week 24, there were only 4.1% and 2.7% increments of erythema index in combined group and monotherapy group, respectively. Both
groups had a similar deviation of TWEL until the end of fol- low-up. The VISIA® skin image analysis (Fig. 3) revealed improvement of porphyrins and red area in both groups. At the end of the follow-up, less porphyrin was noted in both groups compared to the beginning of the treatment. VISIA®
analysis also showed a better percentile ranking of red areas in combined group during the follow-up periods. For the subjective evaluation, we referred “exceptional improve- ment,” “very improved,” and “improved” as improved by using GAIS score and analyzed with Fisher’s exact test.
Patients in combined group had experienced satisfaction earlier at week 2, while there was no significant difference between patients in both groups during weeks 8, 12, and 24 except for one patient in monotherapy group (supplement Fig. 1).
For monotherapy group, the representative photographs of a 20-year-old female (Fitzpatrick III) who had completed treatment with ALA-PDT alone are shown in Fig. 4. At week 24, there were 28.1% reduction of sebum secretion and 6.4%
increment of erythema index in this patient, whereas no sig- nificant difference in melanin index and TWEL was noted compared to week 0. As for combined group, the clinical improvement photographs of a 21-year-old female (Fitzpat- rick III) who had received ALA-PDT and laser therapy are shown in Fig. 5. At week 24, there were 39.5% reduction of sebum secretion, 23.0% reduction of melanin deposition, and 6.0% increment of erythema index in this patient. Compared to baseline, there was no significant difference in TWEL at week 24. Both patients had improvement in GAIS score compared to week 0. Conclusively, significant reduction in acne nodules and improvement of skin texture were noted in both patients at the end of the follow-up. Almost no new acne lesion was observed. As for side effects, minimal to moderate erythema and melanin deposition were observed at week 2 to week 12 in both groups, but almost regressed within 24 weeks. Generally, compared to patients who received monotherapy, better skin texture with reduction of skin pore and less scar formation and inflammatory reaction were noted in patients who had received combined therapy.
Discussion
As a precursor of heme, ALA can penetrate the stratum cor- neum and is converted into the photoactive protoporphyrin IX (PpIX). The PpIX can be synthesized and accumulated in sebaceous glands, hair follicles, and other skin tissues after topical application of ALA [20]. Light sources includ- ing conventional, noncoherent light sources, and lasers can stimulate the excitation of photosensitizers [21, 22]. After the reaction between the photosensitizer and the light source, reactive oxygen species (ROS) is generated and up-taken by cells, resulting in cell death by apoptosis and necrosis
Table 1 Patient characteristics, mean value of sebum secretion, and its deviation from baseline (%) *p < 0.05 ALA-PDT + laserALA-PDT Age(yrs ± SD)25.3 ± 7.623.8 ± 5.9 Male25 Female107 Fitzpatrick III6 (50%)8 (67%) Fitzpatrick IV6 (50%)4 (33%) Average on faceNoseForeheadAverage on cheekAverage on faceNoseForeheadAverage on cheek Sebum (μg/cm2) Baseline85.9 ± 52.7117.0 ± 73.591.0 ± 59.067.9 ± 57.966.6 ± 43.689.8 ± 43.170.6 ± 40.253.0 ± 58.2 Week 299.9 ± 59.3138.1 ± 85.178.9 ± 68.891.3 ± 87.372.0 ± 56.399.3 ± 70.284.9 ± 69.651.9 ± 50.9 Week 858.3 ± 33.592.8 ± 60.757.2 ± 28.341.5 ± 34.257.4 ± 14.588.2 ± 24.762.7 ± 18.339.4 ± 18.4 Week 1248.5 ± 26.9 *76.6 ± 43.956.6 ± 27.430.4 ± 20.4 *50.3 ± 20.876.5 ± 37.347.7 ± 17.738.6 ± 30.9 Week 2470.2 ± 52.8120.5 ± 85.377.5 ± 91.641.3 ± 42.849.8 ± 20.969.0 ± 37.965.7 ± 22.732.3 ± 26.0 Deviation from baseline (%) Week 214.0 ± 52.321.1 ± 98.8 − 12.1 ± 82.523.4 ± 70.55.4 ± 68.69.5 ± 77.614.3 ± 70.7 − 1.1 ± 73.3 Week 8 − 27.7 ± 54.7 − 24.2 ± 87.9 − 33.8 ± 43.4 − 26.3 ± 61.5 − 9.2 ± 39.0 − 1.7 ± 51.0 − 7.9 ± 31.4 − 13.6 ± 50.3 Week 12 − 37.5 ± 49.1 − 40.4 ± 72.1 − 34.4 ± 50.9 − 37.5 ± 58.7 − 16.3 ± 42.6 − 13.3 ± 43.8 − 22.9 ± 38.3 − 14.4 ± 61.0 Week 24 − 18.3 ± 67.9 − 0.5 ± 116.1 − 13.6 ± 103.3 − 29.5 ± 71.2 − 17.4 ± 45.2 − 20.5 ± 62.4 − 5.5 ± 38.2 − 21.7 ± 62.6
Fig. 1 Significant improvement of sebum secretion in both groups
Fig. 2 Melanin, erythema index, and TEWL were measured
with minimal effects on surrounding tissues [23]. The effec- tiveness of several light sources with various wavelengths has been evaluated in ALA-PDT for the treatment of acne, including blue light, red light, and intense pulsed light source [8, 24–26]. Red light is the most widely used light source in the ALA-PDT for acne. The light source for acne treatment requires a longer wavelength to reach the seba- ceous gland which is located 0.5 to 1.0 mm deep from the skin surface. Compared to red lights, the wavelength of blue lights is shorter, which limits its penetration depth in super- ficial dermis [27]. Santos et al. [26] found ALA with intense pulsed light was beneficial in the management of acne vul- garis and could be used in combination with other acne treat- ments. Rojanamatin et al. [25] showed that combined ther- apy of topical ALA and intense pulsed light was effective in the treatment of inflammatory facial acne, and side effects were mild and reversible. Besides, Zhang revealed that red light offers the advantages of both accuracy and intensity, leading to improved efficacy through more effective pho- tobleaching of PpIX for the photodynamic treatment of acne vulgaris. Furthermore, patients demonstrated that obvious improvement and achieved acne clearance after undergoing fewer ALA-PDT treatment sessions with the utilization of red light. Above all, the red-light source has led to the best results in the long-term treatment of acne with ALA-PDT [28, 29].
In this study, we found that non-ablative Q-switched 1064 nm Nd:YAG laser-assisted ALA-PDT resulted in bet- ter control in sebum secretion than monotherapy group.
Although there was a slight increase in sebum secretion observed at week 2, this phenomenon was temporary and is expected to subside as the skin adjusts to the treatment.
Following skin adaptation and a reduction in inflammatory response, a noteworthy decrease in sebum production was noted due to photodamage to the sebaceous glands following the second treatment course. The effectiveness sustained for at least 16 weeks after the prior treatment. The shockwave induced by Nd:YAG laser creates a vacuolar reaction of sebocytes [30] and temporally disrupts the stratum corneum structure to enhance cutaneous drug delivery [31]. SEM reveals ultrastructural changes in skin surface after Nd:YAG laser emission [32]. Nd:YAG laser can also unplug sebum, cell debris, and desquamated keratinocytes that cover the pore, and thus increase the follicular delivery of ALA [32].
Therefore, as we expected, drug permeation is magnified with the assistance of Nd:YAG laser. Compared to con- ventional treatment, high concentration (10–20%) of ALA with long incubation time is not necessary, and equivalent therapeutic efficacy with mild side effects can be achieved (Table 2).
Erythema, edema, hyperpigmentation, and pain are major concerns of PDT. Painful, itching, and burning sensations usually start a few minutes after PDT and can become more severe with subsequent treatment. These adverse effects are usually dose-dependent [33]. The higher concentration of ALA and longer drug incubation time will enhance photo- toxic reactions for facial skin. The persistence of erythema and pigmentation can compromise patients’ acceptance to
Fig. 3 VISIA® skin image analysis
ALA-PDT and lead to patient drop-out. Zhang et al. dem- onstrated that decreased cumulative amount of ALA and increased irradiation time together can result in nearly painless treatment without jeopardizing therapeutic effect [34]. The purpose of this study was to focus on identifying treatments with reduced post-treatment side effects, such as
erythema, burning sensations, and peeling. Therefore, when compared to conventional therapy, the treatment could lead to improved patient acceptance and reduced patient drop- out. As a result, we used 2% concentration of ALA with 40 min of incubation time to minimize the acute adverse effects which could improve patients’ acceptance [19].
Despite potentially lower photosensitizer concentrations resulting in reduced drug penetration, our study revealed that patients still benefit from low concentrations of 5-ALA (2%), which could produce effective phototoxic reactions of acne skin. Moreover, with combination of Nd:YAG laser, reduc- tion of sebum secretion and the effects of pore clearance could be achieved, which led to higher treatment efficacy.
In previous studies, clinical images could potentially lead to bias, and the effect of reduced sebum secretion might not be clearly apparent in photographs, particularly in patients with mild to moderate acne vulgaris. Therefore, to over- come the limitation of depending on photographs alone to illustrate treatment efficiency, we predominantly relied on patient-reported outcomes and instrumental assessments, including the Global Aesthetic Improvement Scale (GAIS),
Fig. 4 Representative photographs of a 20-year-old female (Fitzpatrick III) who had completed treatment with ALA-PDT alone
Fig. 5 Clinical improvement photographs of a 21-year-old female (Fitzpatrick III) who had received ALA-PDT and laser therapy
the MPA580 sebumeter, and the VISIA® Complexion Analysis imaging system. As a result, these evaluations reflected patients’ real response and reported more objec- tive data to quantify treatment effectiveness. Additionally, our study included a long follow-up period of up to 24 weeks post-treatment to evaluate treatment efficacy and monitor any potential side effects. Nonetheless, our study did have certain limitations. To ensure more dependable outcomes, a larger sample size could have been enrolled. Also, patients were included consecutively during the study period without specific method of randomization. The difference between individual compliance of skin protection and modification after therapy, as well as different severity of acne vulgaris, may lead to sample bias. Additionally, patient education and treatment follow-up via phone calls were conducted to mitigate potential sample bias. Further research is required to confirm optimized parameters for the long-term efficacy of laser-assisted ALA-PDT. To reduce incubation time, treatment combined with other additional therapy includ- ing laser-induced optical breakdown or exosomes for drug delivery is necessary for further studies.
Conclusion
In this study, low concentrations 5-ALA combined with Nd:YAG laser are a desirable, effective, acceptable, and well-tolerated option for acne treatment. Recurrence is still a crucial challenge in acne, and repeated ALA-PDT treatment is needed. Although using lower concentration of 5-ALA can reduce unwanted adverse effects of 5-ALA, ice packing, sunscreen, and moisturizing lotion are still needed to help reduce adverse side effect and accelerate skin bar- rier function repairment. Therefore, given its advantages of high treatment efficacy and mild adverse reactions, low concentration ALA-PDT combined with Nd:YAG laser is the promising method to improve patients’ acceptability
by decreasing drug concentration and increasing drug permeation.
Supplementary Information The online version contains supplemen- tary material available at https:// doi. org/ 10. 1007/ s10103- 023- 03896-x.
Funding This was an industry-academy cooperation project and was funded by the CMU Research Fund, grant number 11042601.
Data availability The data that support the findings of this study are not openly available due to ethical restrictions and are available from the corresponding author upon reasonable request.
Declarations
IRB approval Reviewed and approved by Taipei Medical University Joint Institutional Review Board; approval #202002033.
Competing interests The authors declare no competing interests.
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