Optimal port wine stain treatment requires the selective absorption of light by the ectatic blood vessels. We investigated whether deeper blood vessels can be coagulated, without damaging other cutaneous structures, by varying the laser beam diameter. The penetration of the light was simulated with a random walk (Monte Carlo) program. Scattering of the light plays a major role: practically all light that is absorbed in a blood vessel in the dermis is scattered light. In the epidermis, where the distribution is more centered, a larger beam diameter does not increase the energy density as much as deeper within the dermis where the blood vessels lie and where the light is totally diffuse. Increasing the laser beam diameter from 200 microns to 1 mm or more, makes a typical blood vessel absorb 2.5 times more energy, while the energy absorbed by the epidermis remains the same. The larger the laser beam diameter the better the treatment.

J. C. Laser beam diameter for port wine stain treatment

Cancer is still a leading cause of death worldwide, while most chemotherapies induce nonselective toxicity and severe systemic side effects. To address these problems, targeted nanoscience is an emerging field that promises to benefit cancer patients. Gold nanoparticles are nowadays in the spotlight due to their many well-established advantages. Gold nanoparticles are easily synthesizable in various shapes and sizes by a continuously developing set of means, including chemical, physical or eco-friendly biological methods. This review presents gold nanoparticles as versatile therapeutic agents playing many roles, such as targeted delivery systems (anticancer agents, nucleic acids, biological proteins, vaccines), theranostics and agents in photothermal therapy. They have also been outlined to bring great contributions in the bioimaging field such as radiotherapy, magnetic resonance angiography and photoacoustic imaging. Nevertheless, gold nanoparticles are therapeutic agents demonstrating its in vitro anti-angiogenic, anti-proliferative and pro-apoptotic effects on various cell lines, such as human cervix, human breast, human lung, human prostate and murine melanoma cancer cells. In vivo studies have pointed out data regarding the bioaccumulation and cytotoxicity of gold nanoparticles, but it has been emphasized that size, dose, surface charge, sex and especially administration routes are very important variables.

Gold Nanoparticles as Targeted Delivery Systems and Theranostic Agents in Cancer Therapy.

A preliminary study of photoacoustic/ultrasound dual-mode imaging in melanoma using MAGE-targeted gold nanoparticles.

Glycosylated zinc phthalocyanine-gold nanoparticle conjugates for photodynamic therapy: Effect of nanoparticle shape.

https://escholarship.org/content/qt3wj7324f/qt3wj7324f.pdf?t=opqm4j

A two-temperature model for selective photothermolysis laser treatment of port wine stains

Background and Objective: Pulsed dye laser (PDL) is a commonly used treatment for Port Wine Stain birthmarks (PWS). However, deeper components of PWS are often resistant to PDL. Deeper penetrating lasers, including the long pulsed Neodymium:Yttrium Aluminum Garnet (Nd:YAG) laser have been used, but carry greater risk. This study evaluates the distinct blood vessel thermal responses to visible (595nm) and near infrared (1,064nm) lasers using animal and numerical models. Study Design/Materials and Methods: Blood vessels in the rodent dorsal skin chamber (DSC) were irradiated by a 595nm PDL and a long-pulsed 1,064nm Nd:YAG laser. Laser-induced immediate and 1-hour post-structural and functional changes in the vessels were documented. Numerical simulations were conducted using a 1,000mm depth SD mouse skin fold to simulate experimental conditions. Results: PDL irradiation produced immediate blood vessel hemorrhage. Modeling indicated this occurs due to preferential heating of the superior parts of large blood vessels. Nd:YAG irradiation resulted in blood vessel constriction; modeling indicated more uniform heating of vessel walls. Conclusion: PDL and Nd:YAG lasers result in distinct tissue responses. This supports different observable clinical treatment end points when using these devices. Vessel constriction associated with the Nd:YAG may be more difficult to observe and is one reason this device may carry greater risk. Lasers Surg. Med. 46:479–487, 2014. 2014 Wiley Periodicals, Inc.

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A Comparison of Microvascular Responses to Visible and Near-Infrared Lasers

Background and Objective
Port wine stains (PWS) are congenital vascular malformations that progressively darken and thicken with age. Laser therapy is currently the most effective way in clinical practice for PWS. A 1,064 nm Nd:YAG laser in the near-infrared band can achieve a deeper treatment depth compared to the current widely adopted pulsed dye laser. However, because of its relatively weak absorption by blood, single-pulse Nd:YAG laser requires high energy density to cause effective vessel damage, but may inflict undesirable burning to surrounding collagen. Multi-pulse laser has great potential in clinical treatment because it needs less energy density for each pulse. This paper presented an experimental and theoretical study of the transient thermal effects of low-energy multi-pulse Nd:YAG laser on blood vessels.

Study Design/Materials and Methods
In vivo experiments were performed on dorsal skin chamber. By using a high speed camera (up to 2,000 fps), the complete and dynamic thermal response of blood vessels during laser irradiation and between pulse intervals was obtained. In vitro experiment in capillary tubes and Numerical simulations by two-scale heat transfer model were also conducted to further explore the in vivo experimental findings.

Results
The complete and dynamic response of blood vessels were obtained, including vessel dilation, thrombus formation, partial vessel constriction, thread-like constriction, cavitation and bubbles, and hemorrhage. Thread-like constriction is the desirable treatment end point, which will only occur after thrombus completely occludes the vessel lumen. Cavitation can cause hemorrhage when thrombus fails to occlude the vessel lumen. In vitro experiment found that vessel constriction was due to the constriction of thrombus induced by laser irradiation. Theoretical investigation revealed that the mechanism for the effective reduction of energy density by multi-pulse Nd:YAG laser was due to enhanced light absorption of the blood with thrombus formation.

Conclusions
For multi-pulse treatment, laser parameters are recommended as repetition rate of 10 Hz and pulse number of 10. The incident energy in each pulse should be strong enough to induce blood coagulation through seven or eight pulses and should be lower than the threshold of blood cavitation. Lasers Surg. Med. 49:852–865, 2017. © 2017 Wiley Periodicals, Inc.

Experimental and numerical investigation on the transient vascular thermal response to multi-pulse Nd:YAG laser.

Pulsed dye lasers equipped with cryogen spray cooling (CSC) are now widely used to treat vascular malformation such as port wine stains (PWSs). This paper presents a new integrated model that can quantitatively simulate the cooling of the skin and the heating of the targeted blood vessels in PWSs during laser treatment. The new model is based on the classical homogeneous multi-layer skin model that treats PWS-containing dermis as a mixture of dermal tissue and homogeneously distributed blood. Light propagation in skin and PWSs is simulated by a Monte-Carlo method, which provides accurate description of the light scattering and absorption in the skin. Thermal response of a targeted vessel in the new model is then obtained from the thermal analysis of a Krogh-unit that consists of the vessel and the surrounding dermal tissues and is buried in PWSs. The results from the multi-layer skin model provide appropriate laser influence input as well as the initial thermal condition for the micro-model of the Krogh-unit. A general dynamic relation is also introduced on the surface of skin to quantify the convective cooling of CSC. The model is then applied to dye-laser treatment (wavelength of 585 nm) of PWSs with CSC. Numerical results demonstrate that the present model is able to quantify thermal response of a deeply buried blood vessel in PWSs as a discrete blood vessel does, with a more realistically estimate of the sheltering effect of the dermal tissue (scattering) and blood vessels (absorption) in front of the targeted vessel. To understand the poor response of PWSs in clinic, the thermal characteristics of a targeted vessel was simulated under various conditions. The effects of two morphological parameters, the vessel diameter and the burying depth of the vessel, are then systematically investigated under various pulse durations and fluences of laser. A threshold fluence for given vessel diameter and depth is then estimated quantitatively under the condition of the optimal laser pulse duration. The results indicate that significant high threshold fluence is needed for large vessels buried deeply in the dermis, explaining the physics of the difficulty in clinic of complete clearance of PWSs. The results provide guidance to the clinic selection of the laser pulse duration and laser energy fluence for given PWSs.

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A new model of selective photothermolysis to aid laser treatment of port wine stains

Background and objective Efficient photothermal conversion of gold nanoparticles with strong light absorption suggests their wide use as selective photothermal agents in biomedical fields. The aim of this study is to investigate the use of gold nanospheres (GNPs) as exogenous visible light absorbers to improve laser treatment of port-wine stains. Materials and methods Thiol-terminated methoxypolyethylene glycol modified GNPs (PEG-GNPs) with peak extinction matching the visible light wavelength of the laser being used were synthesized. An in vitro capillary experiment was prepared to investigate the thermal response of blood vessels with and without injection of 4.54 mg PEG-GNPs in mice prior to irradiation by a frequency-doubled Nd:YAG laser at a wavelength of 532 nm. Results The in vitro results demonstrated that the photocoagulation size in blood vessels after exposed to laser light increased with the increment of concentration of PEG-GNPs in blood within a certain range. However, the unwanted thermal response (i.e., cavitation) occurred when the concentration of PEG-GNPs in blood was larger than 2.5 mg/ml. The in vivo results suggested that more obvious blood thermal response can be induced by laser light after injection of PEG-GNPs. After injection of 4.54 mg PEG-GNPs, laser radiant exposure required for thread-like constriction of blood vessels decreased from 12.5 to 9.8 J/cm2 with the pulse duration of 10 ms, from 15 to 11.85 J/cm2 with the pulse duration of 30 ms, respectively. Conclusion This in vitro and in vivo experimental results show that PEG-GNPs combined with laser light could be a promising modality to reduce the radiant exposure required for obvious blood thermal response, thereby providing a potential strategy for improving the laser treatment of cutaneous vascular lesions. Lasers Surg. Med. © 2018 Wiley Periodicals, Inc.

Gold nanospheres enhanced photothermal therapy in a rat model

Laser has been widely used in the treatment of vascular skin diseases, such as port wine stain, due to the effect of selective photothermolysis in laser on biological tissue. The 755 nm alexandrite laser was expected to achieve better curative effect than the commonly used 585 or 595 nm pulsed dye laser (PDL) because of its deeper tissue penetration. In this study, the dorsal chamber model and microscopic visualization system were used to observe morphology changes on 42 blood vessels before and after irradiation with the 755 nm laser. Results showed that thermal effects of blood vessels intensified with the increase in energy, and high energy was required to produce the same thermal effect as the extension of pulse width. Different from 595 and 1064 nm lasers, partial vessel contraction was dominant thermal effect caused by the 755 nm laser. The bleeding injury rate and thermal effect of the 755 nm laser were between those of 595 nm PDL and 1064 nm Nd:YAG laser. The simulation results proved that 595 nm PDLs were effective for small and shallow target blood vessels. The 755 nm alexandrite lasers were effective in the treatment of hypertrophic and resistant blood vessels to PDL in the skin with low or moderate melanin concentration. The 1064 nm Nd:YAG laser was effective in the treatment of deeply buried and enlarged target blood vessels in the skin with high melanin concentration. The simulation results were supported by published clinical observations.

Zhaoxia Ying

Papers

A Comparison of Microvascular Responses to Visible and Near-Infrared Lasers

Experimental and numerical investigation on the transient vascular thermal response to multi-pulse Nd:YAG laser.

A new model of selective photothermolysis to aid laser treatment of port wine stains

Gold nanospheres enhanced photothermal therapy in a rat model

Experimental investigations on thermal effects of a long-pulse alexandrite laser on blood vessels and its comparison with pulsed dye and Nd:YAG lasers