This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Port wine stains (PWS) are congenital vascular malformations of the skin present in 1.5 million patients in the United States. The pulsed dye laser (PDL) is the standard of care for treatment of these lesions and by selectively targeting tissue vasculature, lightens these lesions in some PWS patients. However, few patients (< 10%) achieve complete blanching of their lesion and multiple treatments (5 -30 or more) are generally required (1). One primary factor limiting PWS lesion blanching for many patients is the limited ability of the PDL to remove small (less than 20 m diameter) superficial vessels, which contribute significantly to the clinical appearance of these birthmarks (2). Another highly effective method for selectively targeting tissue vasculature is photodynamic therapy (PDT), which utilizes a chemical photosensitizer and light to generate singlet oxygen radicals (3). PDT using red light and vascular specific photosensitizers has been implemented in a few small trials for PWS treatment (4,5,6). Impressive lesion lightening was noted; however, mild scarring also occurred in some cases as a result of total and deep vascular destruction induced by the use of long wavelength red light. Further, patients experienced prolonged photosensitivity (30 days). In the last few years, a new, vascular specific photosensitizer, benzoporphyrin derivative monoacid ring A (BPD-MA), has been developed and approved by the Food and Drug Administration for treatment of age-related macular degeneration and other ocular indications using an absorption band at 690 m. BPD-MA has an additional absorption peak at 576 nm (yellow light) and is rapidly metabolized, limiting the photosensitivity period in humans to 5 days or less. We plan to use BPD-MA and yellow light to treat PWS birthmarks. This photosensitizer and wavelength combination will limit vascular injury to the most superficial 1mm of the dermis. In order to provide an additional margin of safety, we will use sub-threshold PDT treatment to create an initial vascular injury and then use the PDL (wavelength = 585 nm) to induce photothermal effects, resulting in removal of vessels in the targeted superficial 1 mm region of the dermis. We will use optical Doppler flowmetry (ODT; see description below) to determine when the initial injury has occurred and initial irradiation should be stopped. ODT combines laser Doppler flowmetry with optical coherence tomography to obtain high resolution (10 microns) images of blood flow in human skin in-situ and on-line. The utility of ODT for documenting the change of PWS blood flow in response to therapy has been demonstrated (7). We developed an ODT instrument, which uses a fiber optic Michelson interferometer with an AFC Inc. (Quebec, Canada) superluminescent diode (SLD) at a wavelength of 850 nm as the light source. The output power is 5 mW. Light backscattered from the skin is coupled back into the fiber and forms interference fringes at the photodetector. The digitized fringe signal is then processed by a computer to generate conventional ODT images from complex analytic continuation of the interference fringes. ODT measurements pose NO RISK to subjects. Use of the ODT instrument is similar to shining a flashlight on the skin and measuring the backscattered light. The exact same ODT instrument is approved for evaluations in protocol 96-200. Dr. Stuart Nelson is the principal investigator for 96-200 and a co-investigator in the current protocol. Our goal is to safely achieve maximum clinically relevant PWS vessel destruction utilizing the combined approach of sub-threshold photodynamic together with standard photothermal destruction. The central hypothesis of this research proposal is that combined sub-threshold photodynamic and pulsed dye laser therapy can be used to safely achieve improved PWS lesion lightening as compared to either sub-threshold photodynamic therapy or pulsed dye laser therapy alone. For this PILOT STUDY, we will treat small areas of non-facial PWS in adults and compare the results of our combined PDT/PDL approach to standard pulsed dye laser treatment alone and sub-threshold PDT alone. 1. Kelly, K.M., Nelson, J.S. An update on the clinical management of port wine stains, Lasers Med Sci 2000; 15,220-226. 2. Edstom, D.W., Hedblad, M-A., Ros, A-M. Flashlamp pulsed dye laser and argon-pumped dye laser in the treatment of port-wine stains: a clinical and histological comparison. Br J Derm 2002; 146:285-289. 3. Nelson, J.S., McCullough, J.L., Berns, M.W. Principles and applications of Photodynamic Therapy in dermatology. In: Arndt K.A., Dover J.E., Olbricht S.A. (eds.), Lasers in Cutaneous and Aesthetic Surgery. Philadelphia, PA: Lippincott-Raven, 1997;349-382.4. Jiang, L., Gu, Y., Li, X., Zhao, X., Li, J., Wang, K., Liang, J., Pan, Y., Zhang, Y. Changes of skin perfusion after photodynamic therapy for port wine stain. Chin Med J 1998;111:136-138.5. Lin, X.X., Wang, W., Wu, S.F., Yang, C., Chang, T.S. Treatment of capillary vascular malformation (port-wine stains) with photochemotherapy. Plast Reconstr Surg. 1997;99:1826-1830.6. Kimel, S., Svaasand, L.O., Kelly, K.M., Nelson, J.S. Synergistic photodynamic and photothermal treatment of port wine stains. Submitted for publication Lasers Surg Med. 7. Nelson J.S., Kelly K.M., Zhao Y., Chen Z. Imaging blood flow in human port wine stain in-situ and In real-time using optical doppler tomography. Arch Dermatol 2001;137: 741-744.

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General Clinical Research Centers Program (M01)
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University of California San Diego
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