COMBINED PHOTODYNAMIC AND PULSED DYE LASER TREATMENT OF PORT WINE STAINS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 葡萄酒色斑(PWS)是一种先天性皮肤血管畸形，在美国有150万名患者。脉冲染料激光(PDL)是治疗这些病变的标准护理，通过选择性地靶向组织血管系统，减轻了一些PWS患者的这些病变。然而，很少有患者(&lt；10%)的皮损完全变白，通常需要多种治疗(5-30或更多)(1)。对于许多患者来说，限制PWS病变漂白的一个主要因素是PDL移除小血管(直径小于20m)的能力有限，这对这些胎记的临床表现有显著影响[2]。 另一种选择性靶向组织血管的高效方法是光动力疗法(PDT)，它利用化学光敏剂和光来产生单线态氧自由基。使用红光和血管特异性光敏剂的PDT已经在几个治疗PWS的小型试验中实施(4，5，6)。值得注意的是，病变减轻；然而，在某些情况下，由于使用长波红光引起的完全和深层次的血管破坏，也出现了轻微的疤痕。此外，患者还经历了长时间的光敏反应(30天)。 在过去的几年里，一种新的血管特异性光敏剂，苯并卟啉衍生物单酸环A(BPD-MA)，已经被美国食品和药物管理局(FDA)批准，用于治疗老年性黄斑变性和其他眼部指征，使用690米的吸收波段。BPD-MA在576 nm(黄光)处有一个额外的吸收峰，并且代谢迅速，将人类的光敏期限制在5天或更短。 我们计划使用BPD-MA和黄光来治疗PWS胎记。这种光敏剂和波长的组合将把血管损伤限制在真皮最浅的1毫米处。为了提供额外的安全边际，我们将使用阈值以下的PDT治疗来造成初始的血管损伤，然后使用PDL(波长=585 nm)来诱导光热效应，导致目标真皮浅1 mm区域的血管被移除。我们将使用光学多普勒血流计(ODT；见下文描述)来确定初始损伤发生的时间以及初始照射应停止的时间。 ODT结合了激光多普勒血流仪和光学相干断层扫描技术，可以获得高分辨率(10微米)的人体皮肤血流的原位和在线图像。ODT在记录治疗后PWS血流变化方面的作用已得到证实(7)。 我们研制了一台光纤迈克尔逊干涉仪，以加拿大魁北克AFC公司的超辐射二极管(SLD)为光源，波长为850 nm。输出功率为5 mW。从皮肤向后散射的光被耦合回光纤，并在光电探测器处形成干涉条纹。然后，计算机对数字化的条纹信号进行处理，以根据干涉条纹的复解析延拓生成常规的ODT图像。ODT测量不会对受试者构成风险。使用ODT仪器类似于用手电筒照射皮肤并测量后向散射光。在协议96-200中，完全相同的ODT仪器被批准用于评估。斯图尔特·纳尔逊博士是96-200的首席调查员，也是当前方案的联合调查员。 我们的目标是利用亚阈值光动力和标准光热破坏相结合的方法，安全地实现最大限度的临床相关PWS血管破坏。这项研究建议的中心假设是，与亚阈值光动力疗法或脉冲染料激光疗法相比，联合使用亚阈值光动力学和脉冲染料激光疗法可以安全地改善PWS皮损的减轻。在这项先导性研究中，我们将治疗成人小范围的非面部PWS，并比较我们的联合PDT/PDL方法与单独使用标准脉冲染料激光治疗和单独使用亚阈值PDT治疗的结果。 1.Kelly，K.M.，Nelson，J.S.《葡萄酒色斑临床治疗的最新进展》，《激光医学》，2000；15,220-226。 2.Edstom，D.W.，Hedblad，M-A，Ros，A-M闪光灯脉冲染料激光和氩气泵浦染料激光治疗鲜红斑痣的临床和组织学比较。BR J Derm 2002；146：285-289。 3.Nelson，J.S.，McCullough，J.L.，Berns，M.W.光动力疗法在皮肤科的原理和应用。收录于：Arndt K.A.，Dover J.E.，Olbricht S.A.(主编)，皮肤和美容外科的激光。费城，宾夕法尼亚州：利平科特-乌鸦出版社，1997；349-382。 4.姜力、顾永英、李晓霞、赵晓.、李杰、王凯、梁杰、潘永元、张永元。鲜红斑痣光动力治疗后皮肤血流灌注的变化。中华医学杂志1998；111：136-138。 5.林晓霞，王伟，吴绍芬，杨超，张春生。光化学疗法治疗毛细血管畸形(鲜红斑点)。《最后一次重建外科》1997；99：1826-1830。 6.KIMEL，S.，Svaasand，L.O.，Kelly，K.M.，Nelson，J.S.葡萄酒污渍的协同光动力和光热处理。提交出版《激光外科医学》。 7.Nelson J.S.，Kelly K.M.，赵勇，陈展。应用光学多谱勒断层成像技术原位和实时成像人体葡萄酒斑块中的血流。阿奇皮马托尔2001；137：741-744。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for 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.