Abstract
SIGNIFICANCE: Port-wine stains (PWSs) are congenital capillary malformations with the incidence of in newborns of ∼ 0.8% to 2.1%. Hematoporphyrin monomethyl ether-mediated photodynamic therapy (HMME-PDT) has been widely applied in China for PWS. However, there remains substantial room for improvement in both the phototherapeutic selectivity coefficient (PSC) and pain management. AIM: We investigated the feasibility of modulating transcutaneous oxygen delivery during photodynamic therapy of PWS to enhance therapeutic efficacy and reduce pain. APPROACH: A three-dimensional (3D) computational biophysical model was employed to elucidate the mechanisms through which transcutaneous oxygen modulation enhances the therapeutic efficacy of HMME-PDT and improves pain management. The model was constructed to simulate the light propagation, photosensitizer kinetics, oxygen diffusion, and reactive oxygen species (ROS) generation. A treatment optimization strategy based on epidermal oxygen regulation was proposed and evaluated in computational studies. The spatiotemporal distributions of singlet oxygen under normoxic, hypoxic, and anoxic conditions were evaluated, and their effects on treatment-induced pain and lesion-targeted cytotoxicity were analyzed. RESULTS: Computational analysis showed that compared with normoxic conditions, hypoxia and anoxia significantly enhanced PSC, with improvements of 48% and 61%, respectively. Furthermore, these oxygen-modulated regimens attenuated treatment-associated pain, reducing photochemical pain duration of 17% (hypoxia) and 30% (anoxia). Choosing the right combination of light source irradiance and surface oxygen supply rate amplified therapeutic performance and patient comfort, achieving a 213% increase in PSC and a 57% reduction in photochemical pain duration. These findings establish a mechanistic framework for advancing precision PDT protocols with minimized iatrogenic discomfort. CONCLUSIONS: Established in this computational study, strategic epidermal oxygen restriction critically augments PDT PSC while improving patient tolerance. Computational modeling demonstrates that controlled epidermal hypoxia spatially redistributes oxygen gradients, thereby suppressing superficial ROS generation in nontargeted epidermal layers and selectively concentrating ROS within PWS vasculature. This dual mechanism-simultaneously enhancing therapeutic precision and attenuating treatment-induced pain-presents a pioneering strategy centered on an active oxygen control strategy for enhancing HMME-PDT clinical outcomes. Future research will progress from preclinical validation in animal models to clinical studies to evaluate the therapeutic efficacy and translational potential of this strategy.