Optical clearing agent combined with hemoporfin-mediated photodynamic therapy for improved efficacy of port-wine stain patients: A pilot study

To the Editor: Photodynamic therapy (PDT) is an alternative treatment option for port-wine stains (PWSs) and offers several advantages over pulsed dye lasers (PDLs).[1] However, some patients still experience treatment resistance and significant side effects.[1] Optical clearing agent (OCA) has been shown to enhance light penetration in mouse models.[2] Therefore, we aimed to assess whether combined OCA pretreatment can improve clinical PDT therapy outcomes and investigate the effectiveness of different types of OCA, especially hyaluronic acid microneedles (HA-MNs), in enhancing PDT. This self-controlled comparative study was conducted at Wuhan Union Hospital from February 1, 2022, to October 31, 2023, and enrolled patients diagnosed with PWS. Lesions from each patient were divided into four parts and pre-treated with placebo, glycerol, HA-MN, or glycerol combined with ultrasound for 30 min, followed by PDT treatment. Measurements of ΔE (color change) for PWS sites were performed at baseline and 8 weeks post-treatment to evaluate treatment outcomes [Supplementary Methods, https://links.lww.com/CM9/C106]. The study was approved by the Ethics Committee of Wuhan Union Hospital (No. UHCT-IEC-SOP-016-03-01). Prior to participating, the patients have given written informed consent. Nine patients took part in the study, including four who were resistant to PDL and three who did not respond to regular PDT [Supplementary Table 1, https://links.lww.com/CM9/C106]. Seven patients received OCA adjuvant therapy once, while two underwent three sessions of OCA treatment. Pretreatment with OCA resulted in faster treatment attainment (mild purpura and greying), with reduced energy requirements (264.2 ± 207.2 J/cm2) and shorter light irradiation durations (2.17 ± 1.94 min)[Figure 1A]. Pain scores significantly decreased, as shown by a decline in the mean Visual Analog Scale pain score (7.17 ± 1.17 vs. 5.11 ± 1.17, P <0.05) [Figure 1B]. Among the OCA groups, the HA-MN group exhibited the highest therapeutic effect (ΔE improvement rate 9.42% [0.21–18.62%]) [Figure 1C and Supplementary Figures 1 and 2, https://links.lww.com/CM9/C106]. The glycerol and glycerol combined with ultrasound groups also showed improvement rates of 8.05% (0.79–15.32%) and 3.26% (−5.81% to 12.33%), respectively, compared to the placebo group [Figure 1D]. Notably, two patients in the HA-MN group who were previously predicted to have refractory PWS demonstrated an effective response to the third treatment.[1] No significant differences were observed in itching and edema; blisters were reported in the HA-MN area but resolved after two weeks of self-care [Figure 1B, C]. No permanent adverse events were observed.Figure 1: (A) Energy and time parameter in patients; (B) Side effects of pain and burn reported by patients; (C) Comparison of therapeutic effects in different areas and side effects of itch and edema reported by patients; (D) Comparison of chromameter results in different areas. Error bars represent the mean ± standard error of the mean. *P <0.05; ns: No significant difference.Although previous studies have reported the effectiveness of external OCA combined with PDT in inhibiting the growth of superficial tumors, the topical application of OCA has limited penetrability due to the dense stratum corneum.[2] In addition, the viscosity of glycerol may cause significant dehydration.[3] On the other hand, HA-MN-assisted PDT may offer better treatment outcomes because of its ability to penetrate the epidermis, leading to enhanced light energy penetration and faster therapeutic end-points.[4] The degree of side reaction blisters of HA-MN is mild, and its incidence is lower compared to the blister occurrence reported by Tang et al[5]. Surprisingly, the glycerol combined with ultrasound did not yield the expected results, despite the demonstrated transparency effects in the skin of healthy volunteer as measured by OCT.[6] This discrepancy can be ascribed to the short duration of action according to Supplementary Figure 3, https://links.lww.com/CM9/C106 and the difference in ultrasound devices used in the study by Genina et al[6]. The study’s constraints include a small sample size, necessitating expanded clinical observations with a larger sample size. In conclusion, our study suggests that OCA, particularly HA-MN, can enhance PDT efficacy and reduce energy, duration, and side effects in refractory PWS treatment. Further studies with larger sample sizes are needed to confirm these findings. Funding This work was supported by grants from the National Natural Science Foundation of China (Nos. 82203924, 82130089, and 82003366), Key Research Program of Hubei province (No. 2021BCA120), and China Postdoctoral Science Foundation (No. 2022M721265). Conflicts of interest None.