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Publication numberCN1191793 C
Publication typeGrant
Application numberCN 98803827
PCT numberPCT/US1998/000706
Publication date9 Mar 2005
Filing date14 Jan 1998
Priority date31 Jan 1997
Also published asCA2282635A1, CN1251508A, EP1006902A1, EP1281367A2, EP1281367A3, US6056738, US6251100, US6315772, US6387059, US6419642, US6425873, US6443945, US20020133147, US20030045867, US20030097123, US20040127815, US20040143248, US20050010198, WO1998033444A1
Publication number98803827.7, CN 1191793 C, CN 1191793C, CN 98803827, CN-C-1191793, CN1191793 C, CN1191793C, CN98803827, CN98803827.7, PCT/1998/706, PCT/US/1998/000706, PCT/US/1998/00706, PCT/US/98/000706, PCT/US/98/00706, PCT/US1998/000706, PCT/US1998/00706, PCT/US1998000706, PCT/US199800706, PCT/US98/000706, PCT/US98/00706, PCT/US98000706, PCT/US9800706
Inventors斯蒂芬T弗洛克, 凯文S马尔基托, 查尔斯H维斯塔尔, 保罗莱曼
Export CitationBiBTeX, EndNote, RefMan
External Links: SIPO, Espacenet
CN 1191793 C
Abstract  translated from Chinese
本发明提供一种激光器,包括箱体;位于箱体内的激光元件,其中激光元件选自Er:YAG、脉冲CO The present invention provides a laser, comprising housing; laser element located in cabinets, in which a laser element is selected from Er: YAG, pulsed CO
Claims(12)  translated from Chinese
1.一种激光器,其包括:箱体;位于所述箱体内的激光元件,其中所述激光元件选自Er:YAG、脉冲CO2、Ho:YAG、Er:YAP、Er/Cr:YSGG、Ho:YSGG、Er:GGSG、Er:YLF、Tm:YAG、Ho/Nd:YAlO3、钴:MgF2、HF试剂、DF试剂、一氧化碳、深UV激光器、二极管激光器、增至三倍频率的Nd:YAG激光器和它们的所有组合,并且所述激光元件发射一束或多束激光束到病人皮肤上,所述一束或多束激光束具有0.2-10微米的波长,0.03-9.6J/cm2的能量流量,和1飞秒至1000微秒的脉冲宽度,其特征在于,当所述激光元件发射的所述一束或多束激光束施加到病人皮肤上时,所述一束或多束激光束使皮肤上出现了改变位点或消融位点;和递送装置,其安装到所述箱体上、适于将物质递送到改变或消融位点。 A laser, comprising: a housing; cabinets located in said laser element, wherein said laser element is selected from Er: YAG, pulsed CO2, Ho: YAG, Er: YAP, Er / Cr: YSGG, Ho : YSGG, Er: GGSG, Er: YLF, Tm: YAG, Ho / Nd: YAlO3, cobalt: MgF2, HF reagent, DF reagent, carbon monoxide, deep UV lasers, diode lasers, frequency tripled Nd: YAG laser and all combinations thereof, and the laser element emitting a laser beam or beams onto the skin of the patient, the one or more beams of laser beam having a wavelength of 0.2 to 10 micrometers, the energy flow 0.03-9.6J / cm2 of , and 1 to 1000 microseconds femtosecond pulse width, wherein the laser element when the one or more beams emitted from the laser beam is applied to the skin of the patient, the one or more beams so that the laser beam It appeared on the skin to change the site or the site of ablation; and a delivery device, which is mounted on the housing, adapted to deliver substance to change or ablation site.
2.权利要求1的激光器,其中所述递送装置包括:容器,以容纳一些所述物质。 2. The laser of claim 1, wherein said delivery device comprising: a container to accommodate some of the substances.
3.权利要求1的激光器,其中所述递送装置安装到所述箱体上以接触皮肤并使得由所述激光元件发射的一束或多束激光束从中通过。 3. The laser of claim 1, wherein the delivery device is mounted on the housing for contacting the skin and allow the laser element by the one or more beams emitted from the laser beam to pass therethrough.
4.权利要求2的激光器,其中所述容器处于正压下。 4. The laser of claim 2, wherein said container is under positive pressure.
5.权利要求1的激光器,其中激光元件适于发射一束或多束具有预定能量的激光束,由此,皮肤的角质层至少被部分消融。 5. The laser of claim 1, wherein the laser device is adapted to emit a beam or a laser beam having a predetermined energy, whereby at least the stratum corneum of the skin is partially ablated.
6.权利要求5的激光器,其中所述激光元件还适于发射一束或多束具有预定能量的激光束,由此,皮肤的角质层被辐照,而不辐照皮肤的毛细管层。 6. The laser of claim 5, wherein said element is further adapted to emitting a laser beam or a laser beam having a predetermined energy, whereby the stratum corneum of the skin is irradiated, without a capillary layer of irradiated skin.
7.权利要求1的激光器,其中所述激光元件还适于产生直径为0.5微米-5.0毫米的改变位点。 7. The laser of claim 1, wherein said laser device is further adapted to generate change sites diameter of 0.5 m -5.0 mm.
8.权利要求1的激光器,其中所述激光元件还适于发射一束或多束波长为2.94微米的激光束。 8. The laser of claim 1, wherein said laser device is further adapted to transmit one or more beams having a wavelength of 2.94 micron laser beam.
9.权利要求1的激光器,其中所述激光元件还适于同时向病人皮肤上发射大量激光束。 9. The laser of claim 1, wherein said laser device is further adapted to the patient's skin at the same time a large number of laser beam emitted.
10.权利要求9的激光器,还包括:分光器,其位于箱体内以产生所述大量激光束。 10. The laser of claim 9, further comprising: a splitter, located cabinets to generate said plurality of laser beam.
11.权利要求2的激光器,其中所述递送装置包括:雾化器,其与所述容器相连以通过将所述物质喷到皮肤上而将所述物质递送到所述改变位点。 11. The laser of claim 2, wherein said delivery device comprising: a nebulizer, which is connected to the container by spraying the substance into the skin and deliver the substance to the site of the change.
12.权利要求2的激光器,其中所述递送装置包括:辊,其与所述容器相连,在该辊从皮肤上滚过时,通过将所述物质沉积到皮肤上而将所述物质递送到所述改变位点。 12. The laser of claim 2, wherein said delivery device comprising: a roller, which is connected to the container, when the roller from rolling over the skin, by depositing the material to the skin and the substance is delivered to the He said changing the site.
Description  translated from Chinese
激光器 Lasers

本申请是在1997年1月31日申请的未决的USSN08/792,335的部分继续申请,USSN08/792,335本身是在1993年9月24日申请的美国专利5,643,252的部分继续申请,美国专利5,643,252是1992年10月28日申请的USSN07/968,862的部分继续申请,所有这些引入本文作为参考。 This application is a continuation application in part January 31, 1997 filed pending USSN08 / 792,335 of, USSN08 / 792,335 itself to continue to apply in part of U.S. Patent September 24, 1993 filed 5,643,252, and US Patent No. 5,643,252 in 1992 section on October 28 filed USSN07 / 968,862 is to continue to apply, all of which are incorporated herein by reference.

技术领域 Technical Field

本发明属于医学操作领域,即用于将麻醉剂或药品递送到患者、或从患者处去除流体、气体或其它生物分子的激光器。 The present invention is in the field of medical procedures, namely for delivering drugs or anesthetics to the patient, or the removal of fluids, gases or other biomolecules laser from the patient.

背景技术 Background

从患者处收集少量的流体、气体或其它生物分子的传统方法是利用尖锐的器械例如金属小刀或针将皮肤机械穿孔。 Small amounts of conventional methods fluids, gases or other biomolecules collected from the patient using a sharp instrument such as a metal knife or a needle piercing the skin mechanically. 另外,使用麻醉剂或其它药物的传统方法是通过使用针。 In addition, the use of anesthetics or other drugs is through the use of traditional needles.

这一步骤有许多缺点,包括可能由用于穿孔皮肤的尖锐器械引起的健康护理工作者和大众感染,以及操作和处理生物危险废物的费用。 This procedure has many disadvantages, including the possibility of a sharp instrument used by the perforation of the skin caused by infection of health care workers and the general public, as well as bio-hazardous waste handling and disposal costs.

当皮肤被尖锐设备例如金属小刀或针刺穿,就由患者的血液和/或组织产生“明显”污染的形式的生物废物。 When the skin is a sharp device such as a metal knife or needle through, then have a "significant" pollution in the form of biological waste from the patient's blood and / or tissues. 如果患者被源于血液的病原体,例如人免疫缺乏病毒(HIV)、乙肝病毒或其它任一病原体感染,污染的利刃就对可能接触到它的其它人造成严重的威胁。 If the patient is derived from the blood of pathogens such as human immunodeficiency virus (HIV), hepatitis B virus or any other pathogen infection, contaminated sharp can pose a serious threat to the possibility of other people exposed to it. 例如,许多医疗工作者由于与污染的利刃意外接触而感染上HIV。 For example, many health workers due to accidental contact with contaminated sharp and infected with HIV.

污染利刃的使用后处理对最终使用者造成后勤和财政的负担。 The use of post-processing contamination razor logistical and financial burden on the end user. 这些费用作为不适当处理的社会后果而征税。 These costs, as the social consequences of improper handling and tax. 例如,在二十世纪八十年代在众多场合的公共海滩冲洗的不适当处理生物废物。 For example, in the 1980s the public beach on numerous occasions flushing inappropriate treatment of biological waste. 不适当的处理也使得其它的人,例如静脉内药物使用者能获得污染的针和并得上传染病。 Inappropriate treatment also makes the other person, such as intravenous drug users and can get contaminated needles and get on infectious diseases.

使用针来施用麻醉剂或药物以及抽取流体、气体或其它生物分子的传统方法还存在一个缺点。 Administered using a needle or anesthetic drugs and the traditional method of extraction fluids, gases or other biomolecules there is a drawback. 尖锐器具带来的刺痛是一个使人精神受伤的步骤,尤其对儿科患者,能在患者中引起显著的紧张和焦虑。 Sharp implements sting is a step makes the spirit of injuries, especially for pediatric patients, can cause significant stress and anxiety in patients. 而且,对于抽取流体、气体或其它的生物分子,在获得足够的样品前经常必须重复多次刺穿步骤。 Further, for extracting fluids, gases or other biomolecules, before sufficient samples often must be repeated several times piercing step.

不使用针进行局部麻醉的的现有技术一般包括(a)局部的利多卡因(lidocaine)混合物,(b)离子电渗疗法,(c)改善角质层或者药物的化学特性的化合物制作的载体或赋形剂,及(d)涉及用超声改变角质层的屏障功能的声渗疗法(sonophoresis)。 Without using local anesthesia needle prior art generally include (a) partial lidocaine (lidocaine) mixture, (b) iontophoresis, (c) improved chemical properties of the stratum corneum or pharmaceutical compound produced vector or excipients, and (d) relates to a change in the barrier function of the stratum corneum using ultrasound acoustic therapy permeability (sonophoresis). 通常使用一种含利多卡因的药膏,尤其对儿科患者更是如此,但这需要使用长达60分钟,造成的麻醉深度仅有约4mm深。 Usually containing lidocaine cream, especially for pediatric patients especially, but this requires the use of up to 60 minutes, the depth of anesthesia caused only about 4mm deep. 由于表皮层的屏障功能利多卡因缺乏渗透性。 Since the barrier function of the epidermis lidocaine lack of permeability. 离子电渗疗法的固有问题包括递送系统的复杂性,费用,以及长时间暴露在电流下的未知的毒性。 Problems inherent iontophoresis include the complexity, cost, and prolonged exposure to unknown toxicity current delivery system. 另外,载体和赋形剂的使用涉及另外的化合物,这些化合物可能改变所关心的药物的药代动力学或令人不快。 In addition, the carriers and excipients used to refer to other compounds that may alter the concerned drug pharmacokinetics or unpleasant.

因而,为了去除流体、气体或其它生物分子或施用麻醉剂或其它药物,需要存在不需要尖锐设备的一种技术。 Thus, in order to remove fluids, gases or other biomolecules or to administer anesthetic or other drugs, does not require a sharp technique requires the presence of equipment. 本文公开的技术和设备满足了这一需要,避免了对被污染器械的处理,从而降低了被感染的危险性。 Technology and equipment disclosed herein meets this need, to avoid contamination of the process equipment, thereby reducing the risk of infection.

近年来,激光被用作一些外科操作中使用的高效精确的工具。 In recent years, some of the laser is used as efficient precise tool for use in surgical operations. 在可用于激光放射的潜在的新原料中,在医学上最能引起人们注意的是稀土元素。 The potential of the new material can be used in the laser radiation in medicine can cause the most attention is a rare earth element. 这些稀土元素中最有前途的之一是用铒(Er)离子掺杂的YAG(钇、铝、石榴石)晶体。 One of the most promising of these rare earth elements are doped YAG (yttrium aluminum garnet) crystals with erbium (Er). 使用这种晶体,有可能建立一种铒:YAG(Er-ARG)激光,将这种激光设定以一定波长(2.94微米)发射电磁能,该波长能被水和其它物体强烈吸收。 Using this crystal, it is possible to establish an Erbium: YAG (Er-ARG) laser, this laser is set to a certain wavelength (2.94 microns) emit electromagnetic energy, the wavelength can be strongly absorbed by water and other objects. 当主要由水组成的组织在这一波长或附近被照射,就能将能量传递到组织中。 When an organization mainly composed of water is irradiated at or near this wavelength, it will be able to deliver energy to the tissue. 如果照射强度足够,就引起迅速加热,然后组织蒸发。 If the irradiation intensity sufficient to cause rapid heating, and then organize evaporated. 另外,这种能量的沉积能引起组织的光学机械破坏。 In addition, the deposition of this energy can cause tissue damage optomechanical. 在牙科学、妇科学和眼科学的健康护理规程中描述了一些医用Er:YAG激光,见,例如,Bogdasarov,BV等,“Er:YAG激光照射对固体和软组织的影响”,预印本266页,普通物理研究所,莫斯科,1987;BOL'shakov,EN等,“Er:YAG在牙科学应用的实验基础”,SPIE 1353:160-169,激光和医药(1989)(本文引用的这些和其它所有的文献引入本文,就好象在此处将它们全部阐明)。 Described in the health care regulations dentistry, gynecology and ophthalmology in some medical Er: YAG laser, see, for example, Bogdasarov, BV, etc., "Er: Effect of YAG laser irradiation on solid and soft tissue," Preprint 266 Institute of General Physics, Moscow, 1987; BOL'shakov, EN, etc., "Er: YAG dental experimental basis in scientific applications", SPIE 1353: 160-169, laser and Medicine (1989) (herein incorporated these and other all incorporated herein as if set forth herein them all).

尤其是,专利公开WO94/09713描述了现有技术的激光设备。 In particular, Patent Publication WO94 / 09713 describes a prior art laser device. 该设备发射出被描述为适合穿透病人皮肤的光波。 The device emits is described as suitable for light waves penetrate the skin of the patient. 该设备能够用于促进各种目的的血液撤回,并准备用于后续药物递送的皮肤。 The device can be used to promote blood withdrawn for various purposes, and prepared for subsequent drug delivery skin.


本发明应用一种激光器来穿孔或改变患者的皮肤以去除流体、气体或其它生物分子或施用麻醉剂或其它药品。 Application of a laser of the present invention to perforate or alter the skin of a patient to remove fluids, gases or other biomolecules or the administration of anesthetics or other pharmaceuticals. 通过用激光的电磁能脉冲照射目标组织的表面。 By surface electromagnetic energy pulse irradiation target tissue with laser light. 在处理前,护理员适当选择波长、能量通量(脉冲能量除以照射面积)、脉冲瞬时宽度和照射点大小以精确穿孔或改变目标组织到选择的深度,避免对健康的临近组织不希望的破坏。 Before treatment, care workers appropriately selected wavelength, energy fluence (pulse energy divided by the irradiated area), pulse temporal width and irradiation spot size to precisely perforate or alter the target tissue to a depth of selected healthy adjacent tissue to avoid unwanted destruction.

本发明的第一方面(方面1),提供了一种激光器,其包括:箱体;位于所述箱体内的激光元件,其中所述激光元件选自Er:YAG、脉冲CO2、Ho:YAG、Er:YAP、Er/Cr:YSGG、Ho:YSGG、Er:GGSG、Er:YLF、Tm:YAG、Ho/Nd:YAlO3、钴:MgF2、HF试剂、DF试剂、一氧化碳、深UV激光器、二极管激光器、增至三倍频率的Nd:YAG激光器和它们的所有组合,并且所述激光元件发射一束或多束激光束到病人皮肤上,所述一束或多束激光束具有0.2-10微米的波长,0.03-9.6J/cm2的能量流量,和1飞秒至1000微秒的脉冲宽度,其特征在于,当所述激光元件发射的所述一束或多束激光束施加到病人皮肤上时,所述一束或多束激光束使皮肤上出现了改变位点或消融位点;和递送装置,其安装到所述箱体上、适于将物质递送到改变或消融位点。 The first aspect of the present invention (aspect 1), there is provided a laser, comprising: a housing; laser element in said box body, wherein the laser device is selected from Er: YAG, pulsed CO2, Ho: YAG, Er: YAP, Er / Cr: YSGG, Ho: YSGG, Er: GGSG, Er: YLF, Tm: YAG, Ho / Nd: YAlO3, cobalt: MgF2, HF reagent, DF reagent, carbon monoxide, deep UV lasers, diode laser , frequency tripled Nd: YAG lasers and all combinations thereof, and the laser element emitting a laser beam or beams to the patient's skin, the laser beam having one or more bundles of 0.2-10 microns wavelength, energy fluence 0.03-9.6J / cm2, and 1000, and 1 microsecond to femtosecond pulse width, wherein the laser element when said one or more beams emitted from the laser beam is applied to the skin of the patient when the said one or more bundles of the laser beam so that there has been change in the ablation site or sites on the skin; and a delivery device, which is mounted on the housing, adapted to deliver substance to change or ablation site.

方面2、方面1的激光器,其中所述递送装置包括:容器,以容纳一些所述物质。 Aspect 2, aspects of laser 1, wherein said delivery device comprising: a container to accommodate some of the substances.

方面3、方面1的激光器,其中所述递送装置安装到所述箱体上以接触皮肤并使得由所述激光元件发射的一束或多束激光束从中通过。 3 aspects, aspects of laser 1, wherein said delivery device is mounted on the housing for contacting the skin and allow the laser element by the one or more beams emitted from the laser beam to pass therethrough.

方面4、方面2的激光器,其中所述容器处于正压下。 Aspect 4, the aspects of the laser 2, wherein said container is under positive pressure.

方面5、方面1的激光器,其中激光元件适于发射一束或多束具有预定能量的激光束,由此,皮肤的角质层至少被部分消融。 Aspect 5, one aspect of the laser, wherein the laser device is adapted to emit one or more beams having a predetermined energy laser beam, whereby the stratum corneum of the skin is at least partially ablated.

方面6、方面5的激光器,其中所述激光元件还适于发射一束或多束具有预定能量的激光束,由此,皮肤的角质层被辐照,而不辐照皮肤的毛细管层。 6 aspects, aspects of laser 5, wherein said laser device is further adapted to transmit one or more beams having a predetermined energy laser beam, whereby the stratum corneum of the skin is irradiated, without a capillary layer of irradiated skin.

方面7、方面1的激光器,其中所述激光元件还适于产生直径为0.5微米-5.0毫米的改变位点。 7 aspects, aspects of laser 1, wherein said laser device is further adapted to generate change sites diameter of 0.5 m -5.0 mm.

方面8、方面1的激光器,其中所述激光元件还适于发射一束或多束波长为2.94微米的激光束。 8 aspects, aspects of laser 1, wherein said laser device is further adapted to transmit one or more beams having a wavelength of 2.94 micron laser beam.

方面9、方面1的激光器,其中所述激光元件还适于同时向病人皮肤上发射大量激光束。 9 aspect, the aspect of a laser, wherein the laser device is further adapted to the patient's skin at the same time a large number of laser beam emission.

方面10、方面9的激光器,还包括:分光器,其位于箱体内以产生所述大量激光束。 10, lasers 9 aspect, further comprising: a splitter, located cabinets to generate said plurality of laser beam.

方面11、方面2的激光器,其中所述递送装置包括:雾化器,其与所述容器相连以通过将所述物质喷到皮肤上而将所述物质递送到所述改变位点。 11 aspects, aspects of laser 2, wherein said delivery means comprises: nebulizer, which is connected to the container by spraying the substance into the skin and deliver the substance to the site of the change.

方面12、方面2的激光器,其中所述递送装置包括:辊,其与所述容器相连,在该辊从皮肤上滚过时,通过将所述物质沉积到皮肤上而将所述物质递送到所述改变位点。 12 aspects, aspects of laser 2, wherein the delivery device comprises: roller, which is connected to the container, when the roller from rolling over the skin, by depositing the material to the skin and the substance delivered to the He said changing the site.

通过参考附图本发明可被更好地理解,其优点更能为本技术领域人员所认识。 Can be better understood by reference to the accompanying drawings of the present invention, its advantages better recognized by those skilled in the present. 其中:附图简述图1示出的是有其电源、高压脉冲形成网络、闪光灯、激光棒、镜子、外壳和聚焦透镜的激光器。 Wherein: BRIEF DESCRIPTION OF DRAWINGS Figure 1 is shown in its power supply, high voltage pulse forming network lasers, flash, laser rod, mirrors, housing and focusing lens.

图2示出的是一个可选的装有弹簧的联锁器和可选的加热施用器。 Figure 2 shows an optional spring-loaded interlock and optionally heated applicator.

图3示出的是一种使用二极管激光器激发激光棒的可选方法。 Figure 3 shows an alternative method of using diode laser excitation laser rod.

图4示出的是另一种的聚焦机制。 Figure 4 shows another focusing mechanism.

图5A和5B示出的是用来产生多重同时穿孔的可选分光镜。 5A and 5B illustrate the multiple simultaneous perforations are used to generate an optional beam splitter.

图6示出的是用来消毒照射部位的一个小块。 Figure 6 shows a portion of a piece of irradiation for sterilization.

图7A和7B示出的是用来消毒和/或递送药物,和/或收集流体、气体或其它生物分子的另一种小块。 7A and 7B shows are used to disinfect and / or another small drug delivery and / or collection of fluids, gases or other biomolecules.

图8示出的是一个可选的容器装置,用来收集流体、气体或其它生物分子、消融组织和/或从照射装置部位释放的其它东西,以及降低激光和患者组织相互作用造成的噪声。 Figure 8 shows an optional container unit for collecting fluids, gases or other biomolecules, ablated tissue, and / or other things released from the irradiation apparatus parts, as well as to reduce the interaction between the laser and the patient's tissue caused by noise.

图9示出的是一个插头和插头穿透中央。 Figure 9 shows a plug and plug through the center.

图10示出的是一个可选的容器装置,用来收集消融的组织和/或从照射装置部位释放的其它东西,以及降低激光和患者组织相互作用造成的噪声。 Figure 10 shows an optional container means for collecting ablated tissue and / or other thing released from the irradiation device location, as well as reduce noise caused by the interaction of laser and the patient's tissue.

图11示出的是递送麻醉剂和药物的滚抹设备。 Figure 11 shows the delivery of anesthetics and drugs roll-on devices.

图12示出的一个是对固态激光晶体元件的支架,对固态激光晶体元件每一端有可选的镀膜表面。 Figure 12 shows a solid-state laser crystal device is a stent, for each end of the solid-state laser crystal element with an optional coating surface.

图13示出的是一个晶体棒的例子,环绕晶体棒整个外周有一层不光滑的镀层。 Figure 13 shows an example of a crystal rod around the entire periphery of crystal rods with a layer of matte coating.

图14示出的是一个晶体棒的例子,环绕晶体棒整个外周三分之二有一层不光滑的镀层。 Figure 14 shows an example of a crystal rod around two-thirds of the entire periphery of crystal rods with a layer of matte coating.

图15示出的是一个晶体棒的例子,沿晶体棒经向有一层不光滑的条纹。 Figure 15 shows an example of a crystal rod, along with a layer of crystal rods through the matte stripes.

图16示出的是一个晶体激光棒元件的横截面图,这个晶体激光棒元件被折射指数大于棒的折射指数的材料包绕。 Figure 16 shows a cross-sectional view of a crystal laser rod element, the crystal laser rod element is a refractive index greater than the refractive index of the material rod wrapped.

图17A-17G示出的是容器装置的多个例子。 Figure 17A-17G shows a plurality of examples of the container means.

图18示出的是一个递送麻醉剂和药物的喷雾器。 Figure 18 shows a nebulizer delivery of narcotics and drugs.

图19示出的是与激光器一起使用的容器装置的一个例子。 19 shows an example of the container means for use with the laser.

图20示出的是有面罩的透镜的例子。 Figure 20 shows an example of the mask is a lens.

图21一个表明对在77mJ和117mJ下使用皮质酮表现出增强的渗透性(比对照高)的研究图。 Figure 21 shows that the use of an corticosterone in 77mJ and 117mJ exhibit enhanced permeability (higher than the control) study Fig.

图22示出的是活体使用多种激光脉冲能皮肤阻抗的降低。 Figure 22 shows a laser pulse can be reduced using a variety of skin impedance of a living body.

图23-24示出的是氚水(3H2O)在能量从50mJ(1.6J/cm2)到1250mJ(40J/cm2)下以激光照射的人的皮肤的渗透研究。 Figure 23-24 shows a tritiated water (3H2O) from 50mJ (1.6J / cm2) to 1250mJ (40J / cm2) lower energy laser irradiation of human skin penetration studies.

图25示出的是照射在150到300mJ下人的皮肤的组织切片图。 Figure 25 shows a 150 to 300mJ servant irradiated skin tissue slices.

图26是一个表明对在150mJ和300mJ下照射DNA表现出增强的渗透性的研究图。 Figure 26 is a show for the 150mJ and 300mJ irradiated DNA showed enhanced permeability of graphs.

图27表明激光脉冲能量(J)相对于活体上透过人的皮肤的水的损失。 Figure 27 shows that the laser pulse energy (J) with respect to the living body through the human skin water loss.

图28是一个表明对正常水合(66%)的人角质层的DSC扫描,和用接近消融脉冲能量60mJ的Er:YAG激光的扫描图图29-31是表明对用不同的方法处理的角质层的DSC图谱的三个峰热转化(μJ)、转化中心(℃)和转化(℃)的半峰全长的图。 FIG. 28 is a show that normal hydration (66 percent) cuticle DSC scan, and with close ablation pulse energy 60mJ of Er: YAG laser scanning Figure 29-31 is to show the cuticle of different treatment methods The DSC pattern of three peaks thermal conversion (μJ), Transfer Center (℃) and conversion (℃) half peak full-length diagram.

图32-33是对照和激光角质层的FTIR图谱的图。 32-33 is a control and laser FTIR chart of the stratum corneum.

图34表明作为角质层处理一个作用的氨基化合物I带(Amide I band)的位置(cm-1)。 Figure 34 shows that the position of acting as a cuticle treatment with amino compound I (Amide I band) of (cm-1).

图35表明作为角质层处理一个作用的CH2的振动位置(cm-1)。 Figure 35 shows that a treatment effect as the stratum corneum of the CH2 vibration position (cm-1).

图36示出的是照射在80mJ下鼠的皮肤的组织切片图。 Figure 36 shows a 80mJ irradiated skin tissue sections under the rat FIG.

图37示出的是照射在80mJ下人的皮肤的组织切片图。 Figure 37 shows that irradiation 80mJ Human skin tissue slices.

图38示出的是体外漂白试验结果。 Figure 38 shows the results of in vitro tests bleaching.

图39-41示出的是γ-干扰素、胰岛素和利多卡因在体外经人皮肤的渗透。 Figure 39-41 shows a γ- interferon, insulin and lidocaine infiltration in vitro human skin.

图42示出的是适合进行同时照射多个部位的分光镜的例子。 Figure 42 illustrates an example of a suitable irradiation of multiple sites simultaneously spectroscope.

图43是示出使用分光镜的一种可能的穿孔或改变部位的模式。 FIG 43 is a diagram showing a possible use of dichroic mirrors perforation or alteration site model.


根据本发明的实施方案,激光器发射一束脉冲激光束,为了穿孔或改变目标组织在一个小点聚焦。 According to an embodiment of the present invention, the laser emits a pulsed laser beam to perforate or alter the target tissue is focused to a small spot. 通过调节激光的输出,激光器操作者可以按所需控制穿孔或改变的深度、宽度和长度。 By adjusting the output of the laser, the laser operator can control the desired perforation or alteration of the depth, width and length.

在另外一个实施方案中,可以使用连续波或二级管激光器达到脉冲激光的效果。 In another embodiment, it is possible to use a continuous-wave diode laser or a pulsed laser to achieve the effect. 对这些激光通过门控其输出进行调节,或如果是二极管激光器,通过变动在二极管激光器的激光激发电流进行调节。 These laser is adjusted by gating their output, or if it is a diode laser, by changes in laser diode laser excitation current regulation. 总的效果是达到短暂的照射,或一系列短暂的照射,这样产生如脉冲激光相同的组织渗透效果。 The overall effect is to achieve irradiation, or a series of short-term transient irradiation, so as to generate the same laser pulse effect tissue penetration. 在此处使用的术语“调制的激光”是指这种复制的脉冲激光束。 As used herein, the term "modulated laser" means that copying of the pulsed laser beam.

在此处使用的术语“穿孔”是指消融角质层,从而减弱或除去其屏障功能。 As used herein, the term "perforation" refers to the ablation of the stratum corneum, and thus reduce or remove its barrier function. 在此处使用的术语角质层的“改变”是指在角质层的一种变化,这种变化减弱或除去角质层的屏障功能,并在不消融或仅仅极少部分消融角质层自身下增加渗透性。 As used herein, the term cuticle "change" means a change in the stratum corneum, such changes weaken or remove the barrier function of the stratum corneum, and in no or only a very small portion of the ablation catheter ablation itself under increased penetration of the stratum corneum sex. 红外激光照射的脉冲或脉冲束在接近消融的能量下,例如,60mJ(使用TRANSMEDIATM国际公司的照射能为波长2.94微米、脉冲200μs(微秒)、点大小2mm的(“TRANSMEDIATM”)Er:YAG激光)将改变角质层。 Pulse or pulse infrared laser beam energies near the ablation, for example, irradiation 60mJ (international companies can use TRANSMEDIATM 2.94 micron wavelength, pulse 200μs (microseconds), point size ("TRANSMEDIATM") Er 2mm in: YAG laser) will change the stratum corneum. 这一技术可以用于经皮肤的药物递送或从身体取得样品、流体、气体或其它生物分子。 This technique may be used for transdermal drug delivery or obtained samples, fluids, gases or other biomolecules from the body. 激光照射的波长不同或能量水平低于或大于60mJ也也可以产生增强的渗透性效果而不消融皮肤。 Different wavelengths of laser radiation or energy level less than or greater than 60mJ also be produced enhanced skin penetration effect without ablation.

角质层的这一改变的机制并不确定。 This change of the stratum corneum mechanism is uncertain. 它可能包括脂类或蛋白特性或功能的改变,或归因于皮肤的干燥或次于传播压力波或空穴泡的机械改变。 It may include changes in lipid or protein features or functionality, or due to the drying of the skin or inferior to alter the propagation of mechanical pressure waves or holes bubble. 通常认为局部应用的药品所采取通过角质层的途径要通过细胞和/或绕过它们,也通过毛囊。 Generally considered the drug for topical application route taken through the stratum corneum through the cell and / or bypass them, but also through the hair follicles. 皮肤对局部应用的药品的不渗透性取决于细胞与细胞的紧密连接,以及细胞膜和胞内环境的生物分子组成。 Skin for topical application of drugs not dependent on cell-cell permeability of tight junctions and cell intracellular biomolecules and environmental components. 不管是组成细胞膜或胞内环境的分子的任何改变,还是角质层或毛囊的机械结构完整性的改变,都会导致屏障功能的降低。 Regardless of any change in the composition of cell membranes intracellular molecules or environmental change or cuticle or hair follicles mechanical structural integrity, will result in reduced barrier function. 据认为用Er:YAG激光产生的照射能照射皮肤会引起热特性可测量的变化,这通过角质层的微分扫描热量计(DSC)图谱和傅立叶变换红外(FTIR)图谱得到证实。 It is believed that with the Er: YAG laser irradiation energy generated by the thermal characteristics of exposure to the skin can cause measurable changes, which through the stratum corneum differential scanning calorimeter (DSC) and Fourier transform infrared spectra (FTIR) spectra confirmed. DSC和FTIR图谱的变化是分子或大分子结构,或围绕这些分子或结构的环境的改变的结果。 Changes DSC and FTIR spectra of molecular or macromolecular structure, or change the result around the structure of these molecules or the environment. 不希望束缚在任何特定的理论中,我们可暂时将这些观察归因于用电磁照射照射分子引起的在角质层的脂类、水和蛋白质的改变,这些改变既通过直接改变分子也通过产生也能改变分子的热和压力波引起。 Not wishing to be bound to any particular theory, these observations we can temporarily be attributed in lipids, water and protein changes of the stratum corneum is irradiated with electromagnetic radiation caused by the molecule, these changes either by directly changing molecules are also produced by heat and pressure waves cause molecules to change.

穿孔和改变都能在某种意义上改变皮肤的渗透参数,使得药物的通路增加,以及流体、气体或其它生物分子穿过角质层。 Perforation and change can penetrate the skin, in a sense change parameters, so that the drug increased passage, and a fluid, gas or other biological molecules through the stratum corneum.

因而,本发明的一个目的是提供一种能穿孔或改变患者角质层的方法而不引起出血。 Accordingly, an object of the present invention is to provide a method capable of perforating or altering the stratum corneum of the patient without causing bleeding. 例如,在目标组织产生的穿孔或改变是通过应用穿过角质层或角质层和真皮的激光束完成的,因而能降低或消除角质层的屏障作用。 For example, the perforations or change the target tissue is by applying through the stratum corneum or the stratum corneum and dermis of the laser beam is completed, which can reduce or eliminate the barrier function of the stratum corneum. 这一步骤允许经皮肤施用麻醉剂或其它药物以及去除流体、气体或其它生物分子。 This step allows the transdermal administration of anesthetic or other drugs as well as removal of fluids, gases or other biomolecules. 而且,这一步骤允许对门诊患者长期连续施用药品。 Furthermore, this procedure allows for outpatient long-term continuous administration of drugs. 因而对于透过皮肤较慢或不能透过的药品,药品的递送速度和/或效率得到提高。 Thus for slow or through the skin impermeable drugs, the drug delivery rate and / or efficiency is improved.

本发明的另一个目的是提供一种施用药品的供选择的方法,否则这些药品需要使用其它方法,例如口服或注射,因而提高患者的合作性和降低患者的不安。 Another object of the present invention to provide a method for administering a drug selected, otherwise these drugs need to use other methods, such as oral or injected, thus improving cooperation between patients and reduce patient anxiety.

本发明另外一个目的是允许测定多种流体成分例如葡萄糖,或对气体进行测定。 Another object of the present invention is to allow the determination of a variety of fluid ingredients such as glucose, or the gas is measured.

本发明还有一个目的是避免使用利刃。 Another object of the present invention is to avoid the use of a sharp knife. 不使用污染的利刃将消除意外伤害的危险,以及消除其带来的对健康护理工作者、患者以及可能与利刃接触的其它人的危险。 Do not use contaminated sharp will eliminate the risk of accidental injury, and the elimination of the risks to their health care workers, patients and others who may come into contact with the cutting edge. 不使用利刃又避免了处理生物危险废物的需要。 Do not use a sharp knife and avoid the need to deal with bio-hazardous waste. 因而,本发明提供了一种生态上合理的使用麻醉剂和其它药物以及去除流体、气体或其它生物分子的方法。 Thus, the present invention provides a reasonable use of anesthetics and other drugs as well as the removal of fluids, gases or other biomolecules on an ecological approach.

在另一个实施方案中将一部普通的激光器改造以包括一个容器装置。 Another embodiment will be in an ordinary laser modified to include a container means. 增加这一容器装置能:(1)提高收集流体、气体或其它生物分子的效率;(2)降低激光束穿透患者组织时产生的噪音;和(3)收集被消融的组织。 This can increase the container means: (1) improve the collection of fluids, gases or other biomolecules efficiency; (2) reduce the noise generated when the laser beam penetrates the patient's tissue; and (3) collect the ablated tissue. 可任选的容器装置是被经常清空,以加速收集释放的物质例如流体、气体或其它生物分子。 The container means may optionally be emptied frequently, in order to accelerate the release of substances such as collecting fluids, gases or other biomolecules. 该容器也能用于只收集消融的组织。 The container can also be used to collect only ablated tissue. 激光与患者皮肤相互作用产生的噪声可能引起患者的焦虑。 Noise laser interaction with the patient's skin may cause patient anxiety. 可任选的容器装置降低噪声强度并缓解患者的焦虑和紧张。 Optional container unit to reduce noise intensity and alleviate patient anxiety and tension. 容器装置也能使交叉污染的危险降至最低,并保证收集的样品无菌。 Container means also enables to minimize the risk of cross contamination, and to ensure that the samples were collected aseptically. 在本发明的使用中容器装置的安置是非常独特的,它覆盖用激光束照射时要照射的组织,因此能收集当穿孔或改变发生时流体、气体或其它生物分子样品和/或消融组织。 In the use of the present invention positioned container unit is very unique in that it covers the tissue to be irradiated with a laser beam irradiation, so they can collect the perforation or alteration occurs when a fluid, gas or other biomolecule sample and / or ablation of tissue. 可以对容器进行改造以容纳物质,例如可能在照射前、时和后使用的药品。 It can be modified to accommodate the container material, e.g., drugs may be prior to irradiation, during and after use of.

用于本发明的普通的激光器不需特殊的使用技能。 Common lasers used in the present invention without the use of special skills. 它可以很小,轻便并能使用常规电池或充电电池。 It can be small, lightweight and can use conventional or rechargeable batteries. 激光器越容易携带和便于使用,本发明在多种环境例如医院的房间、诊所或家中的利用越大。 The easier to carry and easy to use lasers, such as the larger hospital room, clinic or home use in a variety of environments present invention.

安全特性能结合到激光上,这种激光不需要激光器操作者、患者或在使用时激光附近的任何人佩带特殊的安全眼镜。 Security features can be incorporated into the laser on, this laser does not require laser operator, patients or in the use of laser anyone near to wear special safety glasses.

本发明提供一种穿孔或改变皮肤的方法,用于对流体、气体或其它生物分子进行取样或用于施用麻醉剂或其它药物。 The present invention provides a method of perforation or skin changes, for fluids, gases or other biomolecules for sampling or administration of anesthetic or other drugs. 本发明利用一束在合适的波长特别聚焦并照射的激光束,以在患者皮肤上产生小的穿孔或改变。 The present invention utilizes a bunch of special focus and exposure at the appropriate wavelength of the laser beam on the skin of the patient to produce a small perforation or alteration. 在优选的实施方案中,激光束的波长约0.2到10微米之间。 In a preferred embodiment, the wavelength of the laser beam is from about 0.2 to 10 microns. 优选的是该波长在约在1.5到3.0微米之间。 It is preferred that the wavelength between about 1.5 to 3.0 microns. 更优选的该波长为约2.94微米。 More preferably, the wavelength of about 2.94 microns. 在一个实施方案中,激光束用透镜聚焦以在皮肤上产生照射点,照射点大小约为直径0.5微米到5.0厘米。 In one embodiment, the laser beam is focused to produce a spot on the skin is irradiated, the irradiation spot size of about 0.5 microns to 5.0 cm in diameter lens. 可任选的,点可以是狭缝状的,宽约0.05到0.5mm,长度可达到2.5mm。 Optionally, the point may be a slit-shaped, width of 0.05 to 0.5mm, the length can reach 2.5mm.

护理员可以考虑限定激光束的几个因素,包括波长、能量通量、脉冲瞬时宽度和照射点大小。 Caregiver may consider defining a laser beam on several factors, including wavelength, energy fluence, pulse temporal width and irradiation spot size. 在优选的实施方案中,能量通量在0.03-100,000J/cm2。 In a preferred embodiment, the energy flux in 0.03-100,000J / cm2. 更优选的是,能量通量在0.03-9.6J/cm2。 More preferably, the energy flux in 0.03-9.6J / cm2. 激光束的波长部分取决于激光材料,例如Er:YAG。 Part of the laser beam depends on the wavelength of the laser material, such as Er: YAG. 脉冲瞬时宽度是由例如一组电容器、闪光灯和激光棒材料产生的脉冲宽度的结果。 Pulse temporal width is a bank of capacitors such as pulse width, flash, and the laser rod material produced results. 脉冲宽度优选在1fs(飞秒)到1000μs。 Pulse width is preferably in 1fs (femtosecond) to 1000μs.

根据本发明的方法,激光产生的穿透或改变不需用激光器的单一脉冲产生。 The method according to the present invention, the penetration or change a single pulse of laser produced without the use of laser generation. 在优选的实施方案,护理员通过使用多个激光脉冲在角质层产生穿孔或改变,每一个都只穿孔或改变目标组织厚度的小部分。 In a preferred embodiment, the caregiver using a plurality of laser pulses produced by perforation or changes in the stratum corneum, each perforation or only a small change in the thickness of the portion of the target tissue.

为了达到这一目的,将单个脉冲的能量除以所需的脉冲数,就能粗略地估计用多个脉冲穿孔或改变角质层所需的能量。 To achieve this, the single pulse energy divided by the number of pulses required can be roughly estimated by a plurality of pulses required to perforate or alter the stratum corneum energy. 例如,假如一个特定大小的点需要1J的能量以在整个角质层产生穿孔或改变,则使用10个每个脉冲具有该能量的1/10的脉冲,就能产生性质上类似的穿孔或改变。 For example, if a specific point size 1J energy required to produce perforations in the stratum corneum or the entire change, using 10 of the pulse energy of each pulse having a 1/10, can produce a similar change in the nature or perforations. 因为要求患者在照射中不移动目标组织(人的反应时间在约100ms),在每一脉冲产生的热不能显著扩散,在优选的实施方案中激光的脉冲重复速率应在少于100ms的时间产生完全的穿孔。 Because they require the patient does not move the target tissue irradiation (human reaction time is about 100ms), the heat generated at each pulse not significantly diffuse laser pulse repetition rate should be produced in less than 100ms time In a preferred embodiment, complete perforation. 可选择的是,目标组织和激光的定向能机械选定,这样在长时间的照射中目标组织的定位就不能发生改变。 Alternatively, the target tissue, and directed-energy laser machine is selected, so that prolonged exposure in locating the target tissue can not be changed.

为了以不引起出血的方式穿透皮肤,就从皮肤外表面例如角质层穿孔或改变,但不深及毛细血管层。 In order not to cause bleeding in a manner to penetrate the skin, the stratum corneum on the surface, such as perforation or change from outside the skin, but not as deep as the capillary layer. 激光束在皮肤上精确定位,在皮肤上产生的束的直径在0.5微米到5.0cm。 Precise positioning of the laser beam on the skin, the diameter of the beam on the skin produced in 0.5 micron to 5.0cm. 宽度可以是任何尺寸,通过要照射的解剖面积以及使用的药物、或要去除的流体、气体或其它生物分子所需的渗透速率控制。 Width can be any size, by the anatomical area to be irradiated, and drug use, or fluid, gas or other biomolecule to be removed the desired permeation rate control. 聚焦透镜的焦距可以是任何长度,但在一个实施方案中它是30cm。 The focal length of the focusing lens can be of any length, but in one embodiment it is 30cm.

通过改变波长、脉冲长度、能量通量(是激光能量输出(焦耳)和在焦点的束的大小(cm2)的作用,以及照射点大小,有可能使皮肤上的效果在消融(穿孔)和非消融或部分消融(改变)中变化。角质层的消融和非消融都引起随后应用的药物的渗透、或流体、气体或其它生物分子去除效果的提高。 By changing the wavelength, pulse length, energy fluence (laser energy output (J) and the focus of the beam size (cm2) of action, and the irradiation spot size, it is possible to make the effect on the skin ablation (perforation) and non- ablation or partial ablation (change) the changes of the stratum corneum ablation and non-ablation are caused by penetration of the subsequent application of drugs or fluids, gases or other biomolecules removal increased effectiveness.

例如,通过减少脉冲能量同时维持其它参数恒定,有可能在消融和非消融组织效果之间改变消融效果。 For example, by reducing the pulse energy while maintaining the other parameters constant, there may be between the ablation and non-ablation of tissue ablation effect change effect. 使用脉冲长度约300μs的TRANSMEDIATMEr:YAG激光器,用单脉冲或照射能,在2mm点的皮肤上照射,脉冲能大于约100mJ引起部分或完全消融,而任何低于约100mJ的脉冲能量引起角质层部分消融或不消融。 TRANSMEDIATMEr pulse length of approximately 300μs: YAG laser irradiation with a single pulse or in 2mm point skin exposure, greater than about 100mJ pulse can cause partial or complete ablation, and no less than about 100mJ pulse energy causes the stratum corneum section ablation or ablation. 可任选的,通过使用多脉冲,增强药品物递送所需的阈值脉冲能量被降低的倍数约等于脉冲的数量。 Optionally, approximately equal to the number of pulses by using a multi-pulse, to enhance delivery of the drug was required to reduce the threshold pulse energy is multiple.

可选择地,通过降低点的大小同时维持其它参数恒定,也可能在消融和非消融组织效果之间改变消融效果。 Alternatively, while maintaining the other parameters constant by reducing the size of the point, it may change the effect of ablation and non-ablation of tissue between the ablation effect. 例如,减半点面积将引起产生同样效果的能量减半。 For example, halving the point area will cause the energy to produce the same effect by half. 例如,通过将激光的照射输出耦合到显微镜的物镜(例如,可从Nikon公司,Melville,纽约),能获得低于0.5微米的照射。 For example, by irradiating the laser output is coupled to the microscope objective (e.g., available from Nikon Corporation, Melville, New York), the irradiation can be obtained less than 0.5 microns. 在这种情况下,有可能将光束以显微镜的分辨率极限级向下聚焦到点,这可能是在0.5微米的数量级。 In this case, it is possible to focus the beam down to the resolution limit of the microscope stage to the point, which may be in the order of 0.5 microns. 实际上,假如光束图谱是高斯型的,受影响的照射面积的大小能小于测量的光束大小,并能超过显微镜的成像精确度。 Indeed, if the pattern is a Gaussian beam, the size of the affected irradiated area can be less than the measured beam size and can exceed the microscope imaging accuracy. 对这时非去除型的改变组织,使用3.2J/cm2的能量通量将是适合的,对于半微米点大小,将需要脉冲能量是约5nJ。 At this type of change in the non-removal of tissue using a 3.2J / cm2 energy flux would be suitable for half-micron spot size, will need pulse energy is about 5nJ. 这一低的脉冲能量从二极管很容易达到,也可以从例如Er:YAG激光器通过用吸收滤光器例如玻璃减弱光束。 This low pulse energies from diode is easy to reach, but also from such as Er: YAG laser beam, such as glass weakened by absorbing filter.

可任选地,变化照射能的波长同时维持其它参数恒定,有可能在消融和非消融组织效果之间改变消融效果。 Optionally, the change in the wavelength of irradiation while maintaining the other parameters constant, there may be between the ablation and non-ablation of tissue ablation effect change effect. 例如,使用Ho:YAG;(钬:2.127微米)代替Er:YAG(铒:2.94微米)激光器,将导致组织吸收的能量更少,产生较弱的穿孔或改变。 For example, using Ho: YAG; (holmium: 2.127 microns) in place of Er: YAG (erbium: 2.94 micrometers) laser, would result in less absorption of energy tissue produce weaker perforation or alteration.

激光器产生的皮秒和飞秒脉冲也能用于在皮肤上产生改变和消融。 Picosecond and femtosecond pulses generated by the laser can also be used to produce change and melt on the skin. 这可以用调节二极管激光器或相关的微芯片激光器来完成,这些激光器将以1飞秒到1微秒的范围传送单脉冲。 This can be adjusted by a diode laser or related microchip lasers to accomplish, these lasers will be a range of 1 microsecond to femtosecond single pulse transmission. (见D.Stern等人,“通过纳秒、皮秒和飞秒激光在532和625nm下消融角膜”,107卷,587-592页(1989),通过引用结合在此,其公开了长度低于1飞秒的脉冲的使用)。 (See D.Stern et al., "By nanosecond, picosecond and femtosecond laser ablation at 532 and 625nm cornea", vol. 107, 587-592 (1989), incorporated by reference herein, which discloses low length Use in a femtosecond pulses).

根据本发明的一个实施方案,在激光照射后可以立即施用麻醉剂或药物。 According to one embodiment of the present invention, the laser irradiation can be administered anesthetic or drugs immediately. 本发明的两个实施方案结合喷雾器(图18)或滚抹设备(图11)。 Two embodiments of the present invention bind sprayer (Figure 18) or roll-on device (Figure 11). 如果是滚沫设备,激光束穿过与滚沫设备的球164结合的孔162。 If the device is a roll-on, roll-on and the laser beam passes through the device bore 162 of the ball 164 binding. 可选地,滚沫设备可以定位在激光束通过一次性使用的施用器的路径附近。 Alternatively, the roll-on device can be positioned in the vicinity of the laser beam through a disposable applicator path. 照射后,滚沫设备滚过照射部位,从而施用所希望的麻醉剂或药物。 After irradiation, the roll-on device rolled over the irradiated site, thereby applying a desired anesthetic or drugs. 如果是喷雾器设备,通过使用压缩气体从药品储存器166使用麻醉剂。 If the sprayer equipment, compressed gas through the use of the drug reservoir 166 from the use of anesthetics. 照射后,触发含压缩气体(例如,二氧化碳)的汽缸168在照射部位喷射规定量的麻醉剂或药品。 After irradiation, the trigger cylinder containing compressed gas (eg, carbon dioxide) in the irradiated area 168 a predetermined amount of anesthetic injection or drugs.

或者,对药品储存器应用正压从而将药品推向皮肤,或者在收集储存器使用负压,从而促进分析物扩散出皮肤。 Alternatively, the application of pressurized drug reservoir to the skin so that the drugs, or the use of a negative pressure in the collection bin, thus contributing to the analyte to diffuse out of the skin. 环境的大气压力是760mmHg,或一个大气压。 Ambient atmospheric pressure is 760mmHg, or one atmosphere. 因为在直立个体的流体静压,在头部相对颈部水平测量的参照值的压差可以是10mmHg,头部比足部高90mmHg。 Because in an upright individual hydrostatic head relative to the neck at the level of the reference value of the differential pressure measurement can be 10mmHg, head over feet high 90mmHg. 相对于臂部高8-35mmHg。 With respect to the arm high 8-35mmHg. 另外注意到因为跳动的心脏,在循环系统中有80-120mmHg的动态压力(在正常的健康的个体)。 Also noted as the beating heart of dynamic pressure 80-120mmHg in the circulatory system (in normal, healthy individuals). 因而,为了使药物透过皮肤(如在臂部的皮肤)大于约(760mm+35mm)的正压是适合的。 Thus, in order to make the drug through the skin (such as skin in the arm) is greater than about (760mm + 35mm) are suitable positive pressure. 稍大于一个大气压的压力适合于增强药品的渗透,而因血流的动态压力不能渗透到血流中。 Slightly larger than an atmospheric pressure suitable for enhanced drug permeation, while the dynamic pressure due to the blood flow can not penetrate into the blood stream. 稍高的压力有利于扩散到血液。 Higher pressure conducive to the spread into the bloodstream. 然而,然而,长时间远大于约5个大气压的确能产生副作用。 However, however, much greater than about 5 atmospheres for a long time indeed to produce side effects.

在本发明的另一个实施方案中,使用一个墨水喷嘴或标记来标记照射部位。 In another embodiment of the present invention, the use of an ink nozzle or marker to mark irradiated sites. 对肉眼而言,照射部位不总是容易看到的,因而保健员可能不能精确知道照射后在那里施用麻醉剂或药物。 To the naked eye, the irradiation area is not always easy to see, so health workers may not know precisely where after irradiation or administration of anesthetic drugs. 本发明还提供一种标记皮肤的技术以使照射部位明显。 The present invention also provides a technique to mark the skin so that the irradiation portion obvious. 例如,在激光照射前、照射中或刚刚激光照射后,先用墨水喷嘴标记(类似与喷墨打印机)。 For example, before the laser irradiation, laser irradiation or immediately after irradiation, the first mark with ink nozzles (similar to an ink jet printer). 另外,可以沿消融部位画一个圆圈,或使用一系列全指向消融部位的线。 In addition, you can draw a circle along the ablation site, or using a series of lines omnidirectional ablation site. 或者,用一种染料标记一次性使用的安全涂药头/施用器的末端(触到患者皮肤的末端)。 Or, the security applicator head with a dye-labeled single-use / applicator tip (end touches the patient's skin). 在激光照射前、时或完成后马上将施用器和皮肤接触,从而使皮肤照射部位产生标记。 Before the laser irradiation, or completed immediately after the applicator and skin contact, making the skin produce labeled irradiated sites.

为了一定的目的,使皮肤同时或以很快的顺序产生多个穿孔或改变是有利的。 For some purposes, so that the skin simultaneously or in sequence to produce a plurality of perforations quickly or change is advantageous. 为了完成这一点,可任选地在激光器中加一个分光镜,或快速脉冲激光器例如二极管或相关的微芯片激光器。 To accomplish this, a beam splitter can optionally be added in the laser, the pulsed laser such as a diode or fast or related microchip lasers. 同时产生的或依次产生的多个照射部位,将导致药品吸收比单照射部位增强(即摄取的增加与消融部位的总数成正比)。 Sequentially generating a plurality of irradiation sites or simultaneously generated, the drug will lead to enhanced absorption than a single irradiation site (i.e., increase uptake is proportional to the total number of ablation site). 与一个激光器一起使用的适合进行同时照射位点分光镜48的例子见图42。 And a laser suitable for use with dichroic mirror sites simultaneously irradiated example is shown in Figure 42 48. 使用这一技术可以在皮肤上产生任何几何图案的点。 Using this technique can produce any geometric dot pattern on the skin. 因为局部施用的药品扩散进皮肤近乎是对称的,进行局部药品递送的照射点的有利图案将是(这样在尽可能大的面积里产生均匀的浓度)定位在交错矩阵型彼此等距的每一点。 Since topically applied drug diffusion into the skin is nearly symmetrical, be advantageous to design the local delivery of the drug would be irradiation spot (as large as possible so that in the area to create a uniform concentration) in a staggered matrix positioned equidistant from each other at every point .

或者,使用扫描器能产生多照射部位,或任意大小或形状的照射面积。 Alternatively, the scanner can produce multiple irradiation area, or the irradiated area of any size or shape. 例如,反射激光照射能量束的震荡镜可被操作以作为扫描器。 For example, the reflected laser beam irradiation energy shock mirrors may be operated as a scanner.

对应用激光设备进行麻醉剂或药物递送,以及流体、气体或其它生物分子的去除,激光器的操作方式应使一部分患者皮肤被定位在施用器内激光聚焦的部位。 Of the laser device or anesthetic drug delivery and removal of fluids, gases or other biomolecules, such that operation of the laser part of the skin of the patient is positioned in the focus of the laser applicator portion. 对穿孔或改变进行麻醉剂或药物递送,以及流体、气体或其它生物分子的去除与硬物或污染源较少联系的皮肤区域是优选的,但不是必需的。 Perforations or alterations of anesthesia or drug delivery agents, as well as fluids, gases or other biomolecules or removing hard skin contact area sources are less preferred, but not essential. 例如在臂部、腿部、腹部或背部的皮肤。 Such as skin in the arm, leg, abdomen or back. 可任选地,在这时触发皮肤加热元件以减少改变或消融角质层所需的激光能量。 Optionally, the skin heating element is triggered at this point in order to reduce or alter the stratum corneum ablation laser energy required.

最好提供一种具有与光学系统的焦平面符合的孔的支架。 Preferably to provide a focal plane of the optical system in line with the bracket holes. 可任选地,如图2所示,将装有弹簧的联锁器36与支架相连,这样,当患者对联锁器施加少量的压力时,使它凹进焦点,开关关闭,激光器激发照射脉冲。 Optionally, as shown, the spring-loaded interlock 36 is connected to the bracket shown in Figure 2, so that when a small amount of pressure applied to the patient interlock, it recessed focus switch is turned off, the laser excitation irradiation pulse. 在这一设备中,只有压下末端时,束的焦点才与支架的末端在一条直线上。 In this device, only when pressing the end, the focus of the beam before the end of the stent in a straight line. 在极不可能的情况下,激光器在激光施用器末端正确定位前偶然发出激光,光学构件将产生的能量通量非常低,因而对无意的目标产生的影响可以忽略。 In the extremely unlikely case, the laser before the end of the correct positioning of the laser applicator occasionally emitting a laser, an optical component will have a very low energy density, and thus impact on unintended targets generated can be ignored.

本发明方法的效能可以通过使用具有一种波长的激光器而得到提高,该波长被可强烈影响皮肤的渗透性所关心的皮肤成分(例如水、脂质或蛋白质)特定性的吸收。 Effectiveness of the method of the present invention by using a laser having a wavelength which is improved, the wavelength can be strongly influenced by the permeability of the skin the skin components of interest (e.g., water, lipids or protein) of the specific absorption. 然而,选择能发射强烈吸收的波长的激光是不需的。 However, the choice can be strongly absorbed emission wavelength of the laser light is not required. 改变角质层的脂质可允许渗透增强,同时避免影响蛋白质和水所必需的较高的能量。 Changes in the stratum corneum lipids may allow enhanced penetration while avoiding the impact of high energy protein and water are required.

使用不同于Er:YAG的特定激光器进行角质层消融或改变是有利的。 Unlike the use of Er: YAG lasers were given stratum corneum ablation or change is advantageous. 例如,二极管激光器发射的波长810nm(0.8微米)的照射能量是较低廉的,但这种波长的照射仅仅被组织很差地吸收。 For example, the wavelength of 810nm (0.8 microns) radiation energy emitted by the laser diode is relatively inexpensive, but rays of this wavelength is absorbed only by poor organization. 在本发明的另一个实施方案中,在吸收这一照射波长的皮肤表面使用染料,或者在完整的角质层上使用,或者在Er:YAG激光处理的部位使用(这样能产生深层的染料渗透)。 In another embodiment of the present invention, in the absorption wavelength of the irradiated surface of the skin using a dye, or the complete cuticle, or Er: YAG laser treated site of use (this will produce deep dye penetration) . 例如,靛氰绿(ICG),一种用于内质网血管学和肝清除研究的无害染料当在血浆中时在810nm具有最大吸收(Stephen Flock和StevenJacques,“使用靛氰绿和脉冲紫翠石激光在鼠皮瓣窗室中血管的热损伤:可行性研究”,激光医学科学,8,185-196,1993)。 For example, indocyanine green (ICG), a harmless dye endoplasmic reticulum angiography and hepatic clearance for research in plasma when a maximum absorption at 810nm (Stephen Flock and StevenJacques, "the use of indocyanine green and purple pulse emerald stone laser mouse skin flap window chamber thermal damage blood vessels: a feasibility study "Laser Medical Sciences, 8,185-196,1993). 这一染料,当在角质层时,预计吸收二极管(例如,GaAlAs激光)激光的810nm照射能,因而升高组织的温度,随后引起消融和分子改变,导致屏障功能减弱。 The dye, when in the stratum corneum, the expected absorption diode (for example, GaAlAs laser) 810nm laser irradiation, thereby raising the temperature of the tissue and subsequently cause ablation and molecular changes, leading to weakened barrier function.

或者,有可能化学改变皮肤的光学特性以增强随后的激光照射吸收,而在激光照射时实际上不存在化学药品。 Alternatively, it is possible to chemically alter the optical properties of the skin to enhance subsequent absorption of laser irradiation, laser irradiation and in the chemical does not actually exist. 例如,5-氨基乙酰丙酸(5-ALA)是卟啉的前体,它是一种参与血红蛋白生成和活动的分子。 For example, 5-aminolevulinic acid (5-ALA) is a precursor of porphyrin, which is a molecule involved in hemoglobin production and activity. 卟啉是光的强吸收剂。 Porphyrin is a strong absorber of light. 施用5-ALA刺激在细胞中产生卟啉,但在这一过程中他自己消耗。 Administration of 5-ALA stimulates the production of porphyrins in cells, but in the process of his own consumption. 随后,在这一组织卟啉中在吸收的波长(例如400nm或630nm)照射能量吸收增强。 Subsequently, this organization porphyrin absorption wavelengths (eg 400nm or 630nm) irradiation energy absorption enhancement.

增强角质层吸收照射能量而不添加外源吸收化合物的另一方法是通过在激光照射前在皮肤上应用闭合屏障水化角质层。 Enhanced absorption of the stratum corneum without the addition of another method of irradiating energy absorption of exogenous compounds by laser irradiation prior to the application on the skin hydration of the stratum corneum barrier is closed. 在这种情况下,在体内自身产生的水继续扩散到角质层并穿过皮肤上的孔,但因闭合屏障而避免了蒸发。 In this case, the water produced in the body itself continues to spread to the stratum corneum and through the hole on the skin, but closed barrier to avoid evaporation. 因而,可以利用湿气进一步饱和角质层。 Thus, you can use the moisture saturation of the stratum corneum. 因为Er:YAG发射的照射能量被水强烈吸收,这一步骤将增加角质层的吸收系数,所以引起在角质层增强局部药品递送所需的改变或消融需要的能量更少。 Because the Er: YAG irradiation energy emitted is strongly absorbed by water, this step will increase the absorption coefficient of the stratum corneum, thus causing localized in the stratum corneum to enhance the delivery of drugs or ablation desired changes require less energy.

另外,激光消融部位最终因能有效愈合消融处的角质化细胞和角蛋白的渗透(约两周完成)而愈合,或通过血清向消融部位的扩散形成有效愈合消融处的凝块(焦痂)而愈合。 In addition, the final result of the laser ablation site can effectively heal keratinocytes and keratin ablation at penetration (approximately two weeks to complete) and healing, or the formation of the diffusion of the ablation site by serum effective at healing clot ablation (eschar) and healing. 对长期局部递送药品,或多步施用局部药品,保持消融部位长时间开放是有利的。 Long-term local delivery of drugs, or multi-step topical drugs, keeping open the ablation site for a long time is advantageous.

因而,在本发明的另一个实施方案中,通过保持照射处潮湿来使消融或非消融部位开放。 Thus, in another embodiment of the present invention, by maintaining the irradiation of the wet to make ablation or ablation site open. 这通过使空气与消融部位接触最小和/或提供流体保持消融部位潮湿和/或保持与角质层生化相似而完成。 This provides fluid to keep the ablation site moist and / or maintain the stratum corneum biochemical similarity and complete ablation site through the air in contact with the minimum and / or. 在该部位上应用补片(含,例如药膏例如凡士林油或含氢化可的松的凡士林油)有助于其保持开放。 On the site of patch application (including, for example, such as petroleum jelly or cream containing hydrocortisone Vaseline oil) help keep it open. 水凝胶补片能用来提供必需的湿气。 The hydrogel patch can be used to provide the necessary moisture. 另外,细胞毒素药品例如顺氯氨铂(cisplatin)、争光霉素、阿霉素(doxorubicin)和氨甲喋呤,如在低浓度局部使用将局部防止细胞和伤口修复。 In addition, cytotoxic drugs such as cisplatin (cisplatin), bleomycin, adriamycin (doxorubicin) and methotrexate, such as at low concentrations for topical use to prevent local cell and wound repair. 而且,在照射后使用维生素C(抗坏血酸维生素)或其它黑色素产生的抑制剂,将有助于防止在处理后额外的皮肤着色。 Also, after irradiation using an inhibitor of vitamin C (ascorbic acid) or other melanin production, after the treatment will help prevent additional skin coloring.

连续波(Cw)激光扫描在机器或微处理器的控制下,有可能在目标组织上扫描激光束(连续波或脉冲波),将对表皮或解剖部位临近组织的热损伤降至最低或消除。 Continuous wave (Cw) laser scanning at the machine or microprocessor control, it is possible to scan a laser beam (continuous wave or pulsed wave) in the target tissue, the skin will close or anatomic site to minimize thermal damage tissue or eliminate .

例如,可以制造一种扫描器(由光电或机械部件制成)在使用者确定的区域上连续移动激光术。 For example, you can create a scanner (made of photoelectric or mechanical parts) on the user defined area continuously moving the laser surgery. 这一区域可以是任意大小或形状。 This area can be any size or shape. 扫描途径可以是螺旋状的或光栅的。 Scanning approach can be spiral or grating. 假如激光是脉冲的或调制的,就可能成一个离散的随机图案,其中,扫描光学元件机械引导光束到皮肤的部位,激光器发射激光,然后,扫描光学元件机械引导光束到不同的部位(最好不靠近第一个点,这样在临近的皮肤点被加热前皮肤有时间冷却)。 If the laser is pulsed or modulated, it may become a discrete random pattern where the scanning optics direct the beam to the mechanical parts of the skin, the laser emits laser light, and then guide the beam scanning optical element to a different mechanical parts (preferably not close to the first point, this point in the adjacent skin is heated before the skin has time to cool).

在以前已用铜汽化物激光(用于处理端口—深红斑)使用这一扫描技术,并且与CO2激光一起使用用于表面重修。 In previously been vaporized with copper laser light (for handling port - deep erythema) using the scanning technology, and used in conjunction with the CO2 laser for resurfacing. 前者以皮下血管作为目标,而在后者中,约100微米的组织沿每一激光途径被蒸发和熔化。 The former subcutaneous blood vessels as a target, and in the latter, about 100 microns along each laser pathway tissue is vaporized and melted.

麻醉剂的递送可以用激光沿外表面例如角质层穿孔或改变皮肤,但不深及毛细血管层,以使局部麻醉剂被局部施用。 Anesthetic may be delivered by a laser, for example along the outer surface of the stratum corneum piercing or skin changes, but not as deep as the capillary layer, such that the local anesthetic is administered topically. 局部施用的麻醉剂必须穿过角质层才能发挥效能。 Topical application of anesthetic must pass through the stratum corneum can play performance. 目前,用于作为药品载体的化合物被用于帮助一些药品的跨皮扩散。 Currently, the compounds are useful as pharmaceutical carriers are used to facilitate the transdermal diffusion of some medicines. 这些载体有时改变药品的状态或自身有毒性。 These carriers sometimes alter the state or the drug itself toxic.

在其它参数设定下,激光激发源的大小决定激光脉冲的强度,而脉冲强度又决定产生的穿孔或改变的深度。 In other parameter settings, the laser excitation source size determines the intensity of the laser pulse, the pulse intensity and determine the depth of the perforation produced or altered. 因此,可以调节激光的多种设定以使角质层有不同深度的穿孔和改变。 Therefore, you can adjust various settings of the laser so that the stratum corneum piercing and changes at different depths.

可任选地,光束清除(beam-dump)应以不妨碍激光用于末端的穿孔和改变这一方式来定位。 Optionally, a beam-dump (beam-dump) shall be without prejudice to the laser for perforation and changing the way the end of the positioning. 光束清除将吸收所有的不能被组织吸收的从光束发出的离散的电磁照射,因而避免任何的散射光线引起损伤。 The beam-dump will absorb all the discrete electromagnetic radiation emitted from the beam can not be absorbed by the tissue, thus avoiding any damage caused by the scattered light. 光束清除可设计或在当光束清除妨碍身体部分被安置在施用器上的情况下,能容易去除。 Beam clear design or in the case when the beam is cleared hinder part of the body is placed on the applicator can be easily removed.

这一递送麻醉剂的方法在被照射的组织产生非常小的区域,并且在非常小的区域产生热坏死。 This method of delivery of anesthetic a very small area in the tissue is irradiated, and generating heat necrosis in a very small area. 可行的圆照射点直径可从0.1到5.0cm,而狭缝型的孔宽可从0.05到0.5mm,长可达近2.5mm,尽管其它大小和长度的狭缝也可使用。 Possible irradiation spot diameter circle from 0.1 to 5.0cm, and slit-type hole width from 0.05 to 0.5mm, length up to nearly 2.5mm, although other sizes and lengths of the slits may be used. 因此,与用尖锐器具刺穿皮肤相比愈合较快或愈合一样快。 Therefore, compared with a sharp instrument to pierce the skin to heal faster or heal as fast. 在照射后可直接向皮肤施用麻醉剂或药学可接受的制剂例如膏剂、油膏、洗液或斑点。 After irradiation may be administered anesthetic directly to the skin or a pharmaceutically acceptable formulations such as creams, ointments, lotions or spots.

另外,递送区能通过照射点关键的定位和使用多位点而放大。 In addition, the delivery area through the irradiation point positioning and use of a number of key points and amplification. 例如,皮肤的区域可用脉冲激光通过第一次扫描所需的区域而麻醉,并使每一脉冲都足以引起穿孔或改变。 For example, the skin of the area available pulse laser by first scanning the desired area and anesthesia, and each pulse is sufficient to cause perforation or alteration. 这能通过调制的二极管或相关的芯片激光器完成,这些激光器以1飞秒到1毫秒的瞬时宽度递送单脉冲。 This can be related to the modulation of the diode chip or laser is completed, the laser is a femtosecond to 1 ms width instantaneous delivery of a single pulse. (见D.Stern等,“通过纳秒、皮秒和飞秒激光在532和625nm下消融角膜”,107卷,587-592页(1989),通过引用结合在此,其公开了长度低至1飞秒的脉冲的使用)。 (See D.Stern et al., "By nanosecond, picosecond and femtosecond laser ablation at 532 and 625nm cornea", vol. 107, 587-592 (1989), incorporated by reference herein, which discloses a length up to 1 femtosecond pulses used). 然后将麻醉剂(例如10%的利多卡因)施加到被处理的区域以完成该区域的麻醉。 Then anesthetics (e.g., 10% lidocaine) is applied to the area to be treated in the region to complete anesthesia.

本方法能用来运输多种麻醉剂。 This method can be used to transport a variety of anesthetics. 这些麻醉剂在其全身和局部毒性上、产生的麻醉的程度、麻醉开始的时间、麻醉发作的时间长度、生物干扰和副作用上不同。 The extent to which these different anesthetic in its systemic and local toxicity, produced anesthesia, anesthesia start time, the length of time the onset of anesthesia, biological disturbances and side effects. 可以在Fitzpatrick RE,Williams B.Goldman MP的“在激光表面重修时的术前麻醉和术后考虑”,Semin.Cutan.Med.Surg.15(3):170-6,1996中找到用激光进行面部皮肤表面重修的局部麻醉的例子。 In Fitzpatrick RE, Williams B.Goldman MP of "In the laser resurfacing preoperative anesthesia and postoperative considerations", Semin.Cutan.Med.Surg.15 (3): 170-6,1996 found with a laser Examples of local anesthesia in facial skin resurfacing. 部分名单由下列组成:可卡因、普鲁卡因、嘧哌凡卡因、依替卡因、罗匹凡卡因(ropivacaine)、布比卡因、利多卡因、丁卡因、普鲁卡因胺、哌罗卡因、MEGX(去乙基利多卡因)和PPX(哌吡卡因二甲代苯胺)。 A partial list consists of the following components: cocaine, procaine, ethyl piperazine where the cocaine, etidocaine, Luo horses where Cain (ropivacaine), bupivacaine, lidocaine, tetracaine, procaine amine, piperazine Roca because, MEGX (go ethyl lidocaine) and PPX (piperazine bupivacaine xylidine). 在Rudolph de Jong的“局部麻醉”,Mosby-Year书,圣路易斯,1994中可以发现有关局部麻醉的参考。 In Rudolph de Jong "local anesthesia", Mosby-Year Book, St. Louis, 1994 can be found information about local anesthesia.

药物的递送本发明也能用于以类似于上述递送麻醉剂的方式递送药物。 Drug delivery of the present invention can also be used to deliver anesthetic to the above-described manner analogous to deliver the drug. 通过改变功率水平,和/或激光束的点大小,就能使穿孔或改变不深及毛细血管层。 By changing the power level, and / or spot size of the laser beam can cause perforation or alteration not as deep as the capillary layer. 这些穿孔或改变就能只穿过外表面,例如角质层或角质层和表皮。 These perforations or alterations can only pass through the outer surface, such as the cuticle, or cuticle and skin. 可任选地,可以使用光学光束分光器或多脉冲激光以在所需的部位进行单穿孔或多穿孔。 Optionally, you can use the optical beam splitter or a pulsed laser to a desired site in a single perforation or perforation. 在穿孔或改变后,药物可直接被施用在皮肤上或以药学上接受的配剂例如膏剂、油膏、洗液或修补的形式施用。 In the perforation or alteration, the pharmaceutical can be applied directly to the skin or a pharmaceutically acceptable formulation, for example in the form of ointments, ointment, lotion or patch administration.

本方法能用于多种全身作用的药物的递送。 This method can be used for a variety of systemically acting drug delivery. 例如硝化甘油和止吐药例如东莨碱;抗生素例如四环素、链霉素、磺胺类药物、卡那霉素、新霉素、青霉素和氯霉素;多种激素,例如副甲状腺素、生长激素、促性腺激素、胰岛素、ACTH、生长激素抑制因子、促乳激素、胎盘催乳激素、黑素细胞刺激素、促甲状腺素、副甲状腺素、降血钙素、脑啡肽和血管紧缩素;类固醇或非类固醇消炎剂和全身性的抗生素、抗病毒或抗真菌剂。 Such as nitroglycerin and antiemetics such as East buttercup base; antibiotics such as tetracycline, streptomycin, sulfonamides, kanamycin, neomycin, penicillin and chloramphenicol; a variety of hormones, such as parathyroid hormone, growth hormone gonadotropin, insulin, ACTH, somatostatin, prolactin, placental lactogen, melanocyte stimulating hormone, thyroid-stimulating hormone, parathyroid hormone, calcitonin, enkephalins and angiotensin; steroids or non-steroidal anti-inflammatory agents, and systemic antibiotic, antiviral or antifungal agents.

局部作用的药物的递送激光辅助的穿孔或改变为药物局部吸收到所需部位提供了一种独特的位点。 Local effect of the drug delivery laser-assisted perforation or alteration of local drug absorbed into the desired site provides a unique site. 因而,药物可以达到高的局部浓度,这是利用在施用点附近的有限稀释从而在照射点附近区域起效。 Thus, the drug can achieve high local concentration, which is limiting dilution use in the vicinity of the point of application so that the onset of irradiation spots around the area. 本发明的这一实施方案提供了一种方法用于处理局部疼痛或感染,或直接向小的特定区域应用药物,因而避免了通过口服或静脉注射产生高的可能的全身毒性量。 This embodiment of the present invention provides a method for treating local pain or infections, or direct application to a specific area of small drugs, thus avoiding the injection produces a high amount of possible systemic toxicity by oral or intravenous. 局部施用的药物例如前列地尔(alprostadil)(例如Pharmacia & Upjohn的Caverject),多种抗生素、抗病毒或抗真菌剂,或化学疗法或抗癌剂,能使用这一方法递送到临近递送部位的处理区域。 Topical administration of drugs such as alprostadil (alprostadil) (such as Pharmacia & amp; Upjohn's Caverject), a variety of antibiotics, anti-viral or anti-fungal agents, or chemotherapy or anti-cancer agents that can be delivered using this method to close the site of delivery processing region. 基于生物药物的蛋白质或DNA也能用这种方法递送。 Based biopharmaceutical protein or DNA can also use this method of delivery.

免疫象药物的递送一样,从病毒、细菌或其它刺激免疫反应的作用物衍生的抗原能被施用穿过皮肤用于免疫目的。 Immunization as drug delivery as, from a virus, bacteria or other immune response stimulating effect was derived antigen can be administered through the skin for immunization purposes. 使穿孔或改变穿过皮肤的外层,或者是单个的,或者是多个的,并在适当的免疫原剂型中提供免疫原。 Perforation or alteration through the outer layer of skin, or single, or multiple, and provides an immunogen in an appropriate immunogen dosage form. 对于提高免疫,其递送经一定时间能增加免疫反应,可以一种剂型提供免疫原,这种剂型免疫原能缓慢通过穿孔或改变,但速度比穿过非穿孔或非改变的皮肤快。 To improve immunity, its delivery by a certain time can increase the immune response, it may provide a dosage form immunogen immunogen can slow the dosage form by punching or changed, but faster than through a non-perforated or change skin.

这种方法为临床医师提供了一种免疫的新方法,解决了用其它使用途径(例如许多疫苗制剂通过口腔或静脉途径不很有效)遇到的一些问题。 This method provides a new method for clinicians immune solved by using other ways (such as many vaccine formulations through the oral or intravenous route is not very effective) some of the problems encountered. 而且,对侵入的微生物来说,皮肤往往是第一道防线,在皮肤的免疫反应部分象粘液膜那样由免疫球蛋白A(IgA)抗体组成。 And, of invading microbes, the skin is often the first line of defense, as the immunoglobulin A (IgA) antibodies composed in part of the skin's immune response as mucus membrane. 科学家长期以来寻求使用多种疫苗制剂诱导粘膜免疫的途径。 Scientists have long sought ways to use a variety of vaccine formulations induce mucosal immunity. 不幸的是他们只取得了有限的成功,因为,为了产生IgA反应,必需将疫苗制剂递送至肠或窦的粘膜,用标准制剂很难到达这些地方。 Unfortunately, they only had limited success because, in order to produce IgA response is necessary to deliver the vaccine formulation or sinus intestinal mucosa, with a standard preparation of these places are difficult to reach. 通过皮内免疫,可以产生独特的抗体群体,包括IgA,这是粘膜免疫的关键成分。 By intradermal immunization, can produce a unique population of antibodies, including IgA, which is the key component of mucosal immunity. 因而这种激光辅助的皮内抗原呈现方法可以用作产生一种针对侵入有机体的IgA的抗体。 Thus this laser-assisted intradermal antigen presenting method can be used to produce one for invasive organisms IgA antibodies.

过敏源的递送传统的过敏检测要求过敏症专科医师在患者的皮肤上做多个刺出点,并施用特定的免役原进行测定皮内超敏性。 Delivery of traditional allergy to detect allergens requirements allergist on the patient's skin to make multiple stab a point, and the original immunizations were administered within a specific measuring skin hypersensitivity. 本发明的方法能用于递送免疫原进行过敏性测定,结果具有重现性。 The method of the present invention can be used to deliver immunogens allergic measurement results reproducible. 多重穿孔或改变能穿过皮肤的外层而不刺到毛细血管水平。 Multiple perforations or alterations can not pass through the outer layer of skin stuck to the capillary level. 这样就能将多种免疫源应用到皮肤上作为皮肤斑点检测。 This will be more immune to detect the source application to the skin as a skin spots. 这一方法的一个益处是角质层屏障功能减弱程度(即激光照射)比用锐器刺更相为一致。 One benefit of this approach is that the stratum corneum barrier function reduced level (ie laser irradiation) than with a sharp thorn more consistent phase.

渗透增强剂的递送某些化合物可以用来增强物质向穿孔或消融的角质层下的渗透。 Penetration enhancers can be used to enhance the delivery of certain compounds to penetrate the material perforation or ablation of the stratum corneum under. 这些增强剂包括DMSO、醇类和盐类。 These enhancers include DMSO, alcohol and salt. 其它化合物基于特定的效果例如通过增加消融或通过抑制发炎(即水杨酸)提高毛细血管流动来特异性地辅助渗透。 Other compounds, such as by increasing the ablation or by suppressing inflammation (ie salicylic acid) increase capillary flow to specifically assist penetration based on a specific effect. 本发明的方法能用来递送这些渗透增强剂。 The method of the present invention can be used to deliver these permeation enhancers. 多或单穿孔或改变能穿过皮肤外层而不刺到毛细血管水平。 Multiple or single perforations or alterations can pass through the outer layer of skin and not stuck to the capillary level. 继而,多种渗透增强剂能施用到照射部位,例如在皮肤斑点。 Then, a variety of permeation enhancers can be applied to the irradiated site, e.g. blotchiness.

消炎剂的递送可以使镇痛剂和其它非类固醇类消炎剂,以及类固醇类消炎剂渗透过穿孔或改变的角质层以在照射部位附近局部影响组织。 Delivery of anti-inflammatory agents may make analgesics and other non-steroidal anti-inflammatory agents, steroids and anti-inflammatory agents to permeate through the perforation or alteration of the stratum corneum to nearby parts of the local impact of tissue irradiated. 例如,消炎剂例如Indocin(Merck & Co.),一种非类固醇类药品,当口服时是治疗风湿性关节炎的有效药剂,然而有时会发生使胃肠衰弱的作用。 For example, anti-inflammatory agents such as Indocin (Merck & amp; Co.), a non-steroidal drugs, when taken orally is an effective agent for treating rheumatoid arthritis, but debilitating gastrointestinal effects may occur. 在激光辅助的穿孔或改变部位施用这种药剂,就可以避免这些危险的并发症。 In laser-assisted perforation or alteration site administration of such agents can avoid these dangerous complications. 而且,相对于口服时产生的全身浓度,在照射部位更容易达到高的局部药剂浓度。 Moreover, with respect to the whole body concentration generated when administered orally, at the irradiated site easier to achieve high local drug concentration.

吸取流体、气体或其它生物分子可以用一种激光器穿孔或改变皮肤的外表层,例如角质层,但不深及毛细血管层,以使得能够收集流体、气体或其它生物分子。 Absorb fluids, gases or other biomolecules can be changed in a laser perforation or outer surface of the skin, such as the stratum corneum, but not as deep as the capillary layer, to enable the collection of fluids, gases or other biomolecules. 流体、气体或其它生物分子能被用于很多种检测。 Fluid, gas or other biomolecule can be used for a wide variety of detection. 在其它参数设定下,激光泵源的大小将决定激光脉冲的强度,而激光脉冲的强度又决定产生的穿孔和改变的深度。 In other parameter settings, the size of the laser pump source will determine the intensity of the laser pulse, and the intensity of the laser pulse in turn determines the depth of the perforation produced and changed. 因此,在激光器上能调节多种预设值以使得不同厚度的皮肤穿孔。 Thus, the laser can be adjusted in a variety of presets such skin perforation different thicknesses.

可任选地,以不阻碍使用激光器在肢体上进行穿孔或改变的方式定位光束清除,光束清除将吸收所有的不能被组织吸收的从光束发出的离散的电磁照射,因而避免任何的散射光线引起损伤。 Optionally, in order to not hinder the use of laser perforation on the limb or altered positioned beam Clear, beam-dump will absorb all of the discrete electromagnetic radiation emitted from the light beam can not be absorbed by the tissue, thus avoiding any stray light caused damage. 光束清除可被设计成当光束清除妨碍身体部分在施用器上安置的情况下,能容易去除。 The beam-dump can be designed to purge the case when the beam prejudice body part disposed on the applicator can be easily removed.

这一吸取流体、气体或其它生物分子的方法在被照射的组织上产生非常小的区域,并且在非常小的区域产生热坏死。 This drawing fluids, gases or other biomolecules have a very small area on the tissue being irradiated and thermal necrosis in a very small area. 例如,实际上的圆照射点直径可从0.1到1mm,而狭缝型的孔宽可从0.05到0.5mm,长可达近2.5mm。 For example, the actual irradiation spot diameter circle from 0.1 to 1mm, and a slit-type hole width from 0.05 to 0.5mm, length up to nearly 2.5mm. 因此,与用尖锐器具刺穿皮肤相比愈合较快或愈合一样快。 Therefore, compared with a sharp instrument to pierce the skin to heal faster or heal as fast.

可以将流体、气体或其它生物分子收集进合适的容器中,例如小试管或毛细管,或在上述的激光器和组织之间放置的容器单元中。 You can be fluids, gases or other biomolecules collect into a suitable container, such as a small test tube or a capillary tube, or container unit between the laser and the tissue is placed in. 这一步骤不需要接触。 This step is not necessary contacts. 因而,不管是患者、要吸取的流体、气体或其它生物分子,还是产生穿孔或改变的器械都不会被污染。 Thus, regardless of the patient, to draw fluids, gases or other biomolecules, or a pinhole or altered instrument will not be contaminated.

本发明的技术可以用来对胞外流体取样以定量葡萄糖等。 Technology of the present invention can be used to quantitate extracellular fluid samples such as glucose. 葡萄糖在胞外存在的浓度与在血管中的相同(或成已知的一定比例)(例如,LonnrothP.Strindberg L.用于原位微透析管的“内参比技术”的确定,ActaPhysiological Scandinavica,153(4):37580,1995年四月)。 Determining the concentration of glucose in the extracellular presence of the same (or a certain percentage of known) in the blood vessels (eg, LonnrothP.Strindberg L. for in situ microdialysis tube "internal reference technology", ActaPhysiological Scandinavica, 153 (4): 37580, April 1995).

角质层的穿孔或改变引起经皮肤的水损失局部增加(指跨皮水损失,或TEWL)。 Perforation or alteration caused by water loss through the stratum corneum of the skin of a local increase (of transdermal water loss, or TEWL). 如图27所示,随着激光能量通量(J/cm2)的增加,水的损失相应增加。 As shown in Figure 27, with the laser energy fluence (J / cm2) is increased, a corresponding increase in water loss. 贴条剥离(tape stripe)实验结果是一个正对照,证明这一测量方法的确对皮肤水蒸发的的增高敏感。 Stickers peeling (tape stripe) results is a positive control, increased sensitivity of this measurement, proof indeed evaporation of water on the skin.

在图27使用的两个能量,27、40mJ和80mJ(1.27和2.55J/cm2)是非消融的,因而它表明非消融能量使得角质层的屏障功能改变,从而导致跨皮水分损失的增强,而这会提供胞外流体的诊断样品。 In Figure 27 both energy usage, 27,40mJ and 80mJ (1.27 and 2.55J / cm2) is non-ablation, so it indicates that the non-ablation energy such that changes of the stratum corneum barrier function, leading to enhancement of transdermal water loss, and This will provide diagnostic sample of extracellular fluid.

除了葡萄糖,其它的化合物和病理剂也能在细胞外流体中检测出。 In addition to glucose, other compounds and pathological agents also can be detected in the extracellular fluid. 例如,HIV在胞外存在可以根据本方法测定。 For example, HIV can be measured in the presence of extracellular according to this method. 不用锐器不取血,获得样品进行HIV分析的益处是显然的,这样就不能感染保健护理人员。 Benefits do not take sharp blood, to obtain a sample for HIV analysis is obvious, so it can not infect health care provider. 另外,本发明能用来使用非消融激光器而减少或消除人体中非皮肤类屏障的屏障特性,例如血脑交界面的膜、例如位于脑第三室和视丘下部的膜、眼巩膜或其它粘膜组织、例如在口腔中的膜。 Further, the present invention is the use of non-ablative lasers can be used to reduce or eliminate the barrier properties of human skin class barrier of Central Africa, such as the blood-brain interface of the film, for example, in the third chamber and the hypothalamus of the brain membranes, sclera, or other mucosal tissue, such as a membrane in the mouth.

改变而不消融改变而不消融角质膜的技术有很多优势。 Ablation change without changing the cuticle without ablation technique has many advantages. 在优选的实施方案中,皮肤被改变,但不消融,这样其结构和生化组成允许药物的渗透。 In a preferred embodiment, the skin is changed, but not melt, so its structure and biochemical composition allows the penetration of the drug. 这一实施方案的结果是:(1)在照射后皮肤的屏障功能虽然降低,但依然对病毒和化学毒素呈现一个的屏障;(2)比消融角质层需要的能量少,因而能使用更小和便宜的激光器;并且(3)出现较少的组织损伤,因而导致愈合的更快和有效。 The results of this embodiment are: (1) skin barrier function after irradiation, although lower, but still against viruses and chemical toxins present a barrier; (2) less than the energy required for ablation of the stratum corneum, which can use a smaller and cheap lasers; and (3) appear less tissue damage, resulting in faster and effective healing.

照射能对激光照射能激光器发射的照射能具有连贯、单色、平行和(一般地)强烈的特性。 Irradiation energy of the laser irradiation energy emitted by the laser irradiation can have a coherent, monochromatic, parallel, and (usually) a strong feature. 然而,为了增强跨皮的药品递送或收集流体/气体或生物分子,使用的照射能不必具有这些特性,或具有所有这些特性之一,但也能被非激光光源产生。 However, in order to enhance transdermal drug delivery or collection of the fluid / gas or biomolecule irradiation energy used need not have these properties, having one or all of these features, but can also be a non-laser light source.

例如,脉冲氙闪光灯的脉冲光输出能用光学滤光器或其它波长选择设备过滤,从照射能量输出中选出一定范围的波长。 For example, pulsed xenon flash lamp light output can be pulsed optical filter or other wavelength selection filter device, a wavelength selected from a range of the irradiation energy output. 而这种配置的非连贯和近单色输出不能象连贯照射能那样向下聚焦到一个小点上,因为前述的目的这是不重要的,因为它能向下聚焦到毫米级的点上。 And this configuration incoherent and nearly monochromatic radiant energy output is not as coherent as the focus down to a small point, because the purpose of the foregoing it is not important, because it can focus down to the millimeter point. 假如需要的话这种光源可以用于一种连续波模式。 If desired, such a light source can be used in a continuous wave mode.

白炽光的红外输出比可见光的输出显著,假如这种光源被适当过滤以除去不能降低屏障功能的不希望的能量,就能用于这一目的。 Infrared light output incandescent significant than visible light output, if such a light source is appropriately filtered to remove the barrier function can not reduce undesired energy can be used for this purpose. 在本发明的另一实施方案中,有可能利用强烈的白炽光(例如卤灯),用光学滤光器或类似设备过滤它,使用连续波照射能输出以降低角质层的屏障功能而不引起消融。 In another embodiment of the present invention, it is possible to use a strong incandescent light (e.g. halogen lamp), filter it with an optical filter or similar device, using the continuous-wave radiant energy output to decrease the barrier function of the stratum corneum without causing ablation. 所有这些照射能源能用于产生脉冲或连续波照射能。 All of these can be used to produce energy irradiating pulsed or continuous wave irradiation energy.

激光设备已经发现本发明的实施能通过多种激光器有效进行;例如,TRANSMEDIATMEr:YAG激光穿孔器,或Schwartz电—光Er-YAG激光。 Laser device embodying the present invention has been found through a variety of laser effectively; for example, TRANSMEDIATMEr: YAG laser perforator, or Schwartz - The light Er-YAG laser. 优选地,任何产生在组织中被强烈吸收的能量的脉冲激光器都可以用于实施本发明,产生在非消融波长、脉冲长度、脉冲能量、脉冲数和脉冲速率下相同的结果。 Preferably, any produce energy in tissue is strongly absorbed by the pulsed laser may be used in the practice of the present invention, produced in a non-ablation wavelength, pulse length, pulse energy, pulse number and pulse rate of the same results. 然而,产生不能被组织强烈吸收的能量的激光器也可以用于本发明的实践中,只是效率较低。 However, the energy produced can be strongly absorbed by tissue may also be used in the practice of the laser of the present invention, is less efficient. 另外,如本文所述,连续波激光器也可以用于本发明的实践中。 In addition, as described herein, a continuous wave laser may also be used in the practice of the invention.

图1和图2是表示能用于本发明的一般的激光器的图。 Figure 1 and Figure 2 is a general diagram of the laser can be used in the present invention. 如图1和图2所示,典型的激光器含有电源线路,这可以是标准的电源10或可任选的充电电池组12,为安全目的可任选电源联锁器开关14;高压脉冲形成网16;含激光棒20,优选的是Er:YAG,的激光泵空腔18;激发激光棒的设备,优选的是在激光泵空腔中支撑的闪光灯22;一个由位于激光棒后部的高反射镜24和位于激光棒前端的输出藕联镜26组成的光学共振器;一个位于输出藕联镜后的传播聚焦透镜28;一个可任选的位于输出藕联镜和传播聚焦透镜之间的第二聚焦圆柱型透镜27;用来将患者皮肤定位在激光束焦平面上的施用器30,施用器30可任选地用例如用电热加热器32加热,连接在激光器罩34上;位于施用器和动力电源之间的联锁器36;和可任选的具有指尖触及口40的连接到施用器上的激光消除38。 1 and 2, a typical laser comprises two power lines, which can be a standard power supply 10 or the optional rechargeable battery pack 12, for security purposes may optionally power interlock switch 14; high voltage pulse forming network 16; with the laser rod 20, preferably Er: YAG, laser pump cavity 18; equipment excitation laser rod, preferably in the laser pump cavity 22 flash support; a laser rod located in the rear by a high the mirror 24 and the front end of the laser rod output - coupled mirror 26. The optical resonator; one in the mirror after linking output dissemination lotus focusing lens 28; an optional on the output mirror and dissemination - coupled between the focusing lens a second focusing cylindrical lens 27; for the skin of a patient positioned on the focal plane of the laser beam applicator 30, applicator 30 may optionally be used with an electric heater 32 is heated, for example, attached to the laser housing 34; administration located and the power supply interlock between 36; and optionally attached to the applicator has a finger touch laser port 40 to eliminate 38.

一般地,激光器从标准110V或220V交流电源10(单相、50或60Hz)获得能量,交流电源被整流并用来对包括高压脉冲形成网16的一组电容器库充电。 In general, the laser energy from a standard 110V or 220V AC power supply 10 (single-phase, 50 or 60Hz), AC power is rectified and used to include a group of high-voltage pulse forming network 16 charging capacitor library. 任选地,换之以充电电池组12。 Optionally, replace it with a rechargeable battery pack 12. 该电容组经高输出闪光灯22建立了一个高直流电压。 The capacitor bank via a high-output flash 22 establishes a high DC voltage. 可选地提供一个动力联锁器14,例如按键开关,这将避免电容器的意外充电,因而避免意外的激光激发。 Optionally a power interlock 14, such as a key switch, which will prevent accidental charging of the capacitor, thus avoiding accidental laser excitation. 还可以在施用器上向激光器上加一个联锁器,例如装有弹簧的联锁器36,这样需要两个联锁器电容器才能放电。 You can also add an interlock device to the laser on the applicator, for example a spring-loaded interlock 36, this requires two interlocking capacitor to discharge.

当按下开关,为了使闪光灯通电,通过闪光灯在已经存在的电压上叠加脉冲电压,结果引起闪光灯进行激发闪光。 When you press the switch, in order to make the flash is powered by the flash is superimposed on an existing voltage pulse voltage, the results were challenged cause flash fires. 从闪光灯发出的光能施用器位于激光空腔18中,这个激光空腔具有一定的形状,这样大多数光能被有效导到激光棒20,激光棒吸收光能,并去激活随之发出激光。 Light emitted from the applicator flash of the laser cavity 18, the laser cavity having a certain shape, so most of the light can be effectively conducted to the laser rod 20, the laser rod absorbs light energy, and subsequent deactivation lase . 低反射率26和高反射率28的激光空腔镜,与激光棒的长轴位于一条直线上,适合于放大和调整激光束。 Low reflectivity laser cavity mirror 26 and the high reflectivity of 28, with the long axis of the laser rod located on a straight line, adapted to amplify and adjust the laser beam.

可任选地,如图12所示激光空腔镜含镀层124、126,这两层镀层被涂到晶体元件的末端,并具有期望的反射率特性。 Optionally, the laser cavity mirror 12 containing coating 124, the reflectance of the coating layers which are applied to the end of the crystal element, and having the desired properties. 在优选的实施方案中,Er:YAG晶体是生长在直径两英寸长五英寸的梨型人造宝石中。 In a preferred embodiment, Er: YAG crystal is grown two inches in diameter of five inches long boule in. 梨型人造宝石被中心转孔产生一个直径5-6毫米长5英寸的棒。 Boule is generated centering around a diameter of 5-6 mm long hole five inches of the rod. 晶体的末端被研磨和抛光。 End crystals are ground and polished. 输出端,即此处激光束从该元件射出的末端,在5弧分内垂直于棒的中心轴。 Output terminals, namely where a laser beam emitted from the end of the element, since the beginning of the 5 arc perpendicular to the central axis of the rod. 输出端的平面性在90%的孔上,是1/10波长(2.9微米)。 Plane of the output of the 90% of holes, 1/10 wavelength (2.9 microns). 高反射端,即与输出端相反的一端,含有一个半径两米的凸球。 High reflectance end, that is the opposite end of the output terminal, comprising a convex spherical radius of two meters. 抛光端被抛光所以每军用规格Mil-013830A有平均十个擦伤和五个凹坑。 Polishing end is polished so every military specification Mil-013830A an average ten scrapes and five pits. 如美国军用标准规定的抓痕和擦伤是测定大表面的缺陷的能见度的一个主观测量方法。 Such as scratches and abrasions US military standard is to measure a large surface defect subjective measurements visibility. 等级由两个数字组成,第一个是擦伤的能见度,后一个是凹坑(小的凹陷)的数目。 Grade consist of two digits, the first is the visibility of scratches, the latter is the number of pits (small depressions) are. 一个#10的擦伤看起来与10微米宽的标准擦伤一样,而一个#1的凹陷看起来与一个0.01mm直径的标准凹坑一样。 Scratch a # 10 standard scratch looks like 10 microns wide, and a # 1 seems depressed and a 0.01mm diameter as standard pit. 为了校准激光束,通常使用优于40-20擦伤—凹坑等级的光学器件。 In order to calibrate the laser beam, usually better than 40-20 scratch - pit grade optics.

从Rocky Mountain Instruments,Colorado Springs,Colorado可以购得许多镀料。 From Rocky Mountain Instruments, Colorado Springs, Colorado can be purchased in many coating material. 然后在末端真空沉积上镀层。 Then the end of the vacuum-deposited coating. 对一个2.9微米的波长,后反射表面124的反射率应大于99%。 For a 2.9 micron wavelength, the reflectivity of the back reflector surface 124 should be greater than 99%. 相反,输出端表面的镀层反射率应在93%到95%之间,但反射率象80%那么低的其它的反射表面才是有用的。 In contrast, the reflectivity of the output end surface coating should be between 93% to 95%, but the reflectance of as low as 80% of the other reflecting surface is useful. 与其它激光波长一起使用时其它具有已知的反射特性的真空沉积的金属镀层普遍可以使用。 When used in conjunction with other laser wavelengths other vacuum deposited metal coating having a known reflection characteristics can be widely used.

定义在激光空腔中粒子数群反转极限必需的镜子的反射率的一般方程是:R1R2(1-aL)2exp((g21-α)2L)=1其中,R1和R2是镜子的反射率,aL是通过空腔的每一通路的总散射损失,g21是增益系数,也就是激发光横截面与粒子群反转强度的比率,α是激光器空腔的长度上照射的吸收,L是激光空腔的长度。 Defines the number of particles in the laser cavity inversion population necessary to limit the reflectivity of the mirror general equation is: R1R2 (1-aL) 2exp ((g21-α) 2L) = 1 wherein, R1 and R2 are the mirror reflectivity , aL is the total scattering losses through each passage of the cavity, g21 is the gain coefficient, which is a cross-section of the excitation light intensity ratio reversal particle group, α is the absorption length of the laser cavity is irradiated, L is the laser the length of the cavity. 使用上述方程,可以从下面的参考文献中选择一个有合适的光谱反射率的镀层。 Using the above equation, you can choose a suitable spectral reflectance coating from the following references. W.Driscoll和W.Vaughan,“光学手册”,第8章,McGraw-Hill编:纽约(1978);M.Bass等,“光学手册”,第35章,McGraw Hill编:纽约(1995)。 W.Driscoll and W.Vaughan, "Optics Handbook", Chapter 8, McGraw-Hill series: New York (1978); M.Bass et al., "Optical Handbook", Chapter 35, McGraw Hill State: New York (1995).

可任选地,也如图12所示,晶体元件可以是非刚性装配的。 Optionally, also as shown in FIG crystal element assembly 12 may be non-rigid. 在图12中在位于晶体元件的高反射端的激光器端部装配罩120中的狭缝中有弹性体材料的O-形圈130。 In FIG. 12 with an elastomeric material of O- rings crystal element 130 located in a highly reflective laser end fitting end cap 120 of the slit. O-形圈通过同心接受所示的元件将晶体元件连接。 O- ring shown by concentric receiving element crystal element connection. 然而,只要能对元件(直接或间接)提供弹性体支持从而允许元件的热膨胀,任何形状的弹性体材料都可以使用。 However, for as long as the element (directly or indirectly) providing an elastomeric support member so as to allow thermal expansion of the elastomeric material of any shape can be used. 可任选地,闪光灯22也可以是非刚性装配的。 Optionally, the flash 22 may be a non-rigid assembly. 图12示出的是在激光器端部装配罩中各在自己的狭缝中的弹性体O-形圈134、136。 Figure 12 shows that each in its own slit elastomeric O- rings 134, 136 in the laser end fitting cover. 然而,可以通过其它形状的弹性体材料,包括没有开口的形状支撑闪光灯。 However, the elastomeric material may be other shapes, including shapes without openings flash support.

可任选地,如图3所示,可以使用产生与激光晶体长轴同线的泵激束二极管激光器42代替闪光灯来激发晶体。 Optionally, as shown in Figure 3, it can be used to generate the same lines of the long axis of the laser crystal pump diode laser beam 42 to excite the crystal in place of the flash. 用校准镜44校准这一激光器的泵激束,并通过高反射红外镜45传输至初始激光棒。 The calibration of the laser alignment mirror 44 pump beam, and through the high reflectance infrared mirror 45 is transmitted to the primary laser rod. 高反射镜允许二极管泵激激光束传播,同时反射来自原来激光的红外光。 High reflection mirror allows the diode pumped laser beam propagation, while reflecting infrared light from the original laser light.

Er:YAG发射激光材料是激光棒的优选材料,因为从这一激光器发出的电磁能波长,2.94微米,非常接近于水的峰值吸收波长(近3微米)。 Er: YAG laser emitting material is a preferred material for the laser rod because the electromagnetic energy emitted from the laser wavelength of 2.94 microns, very close to the peak water absorption wavelength (near 3 microns). 因而,这一波长被水和组织强烈吸收。 Thus, this wavelength is strongly absorbed by water and tissue. 水和组织的快速加热引起皮肤穿孔或改变。 Rapid heating of water causes skin and tissue perforation or alteration.

其它有用的发射激光材料是,当诱发发出激光,发射出被组织例如被水、核酸、蛋白质或脂类强烈吸收的波长的任何材料,并随后引起皮肤(尽管不需要强烈吸收)穿孔或改变。 Other useful lasing material, when induced to lase, emits a wavelength of any material is organized e.g. by water, nucleic acids, proteins or lipids strongly absorbed and subsequently cause the skin (although strong absorption is not required) perforation or alteration. 激光能有效消融或改变表现出吸收系数是10-10,000cm-1的组织。 Laser ablation or change effectively exhibiting the absorption coefficient of the tissue 10-10,000cm-1. 发射激光的元件例如脉冲CO2激光器、Ho:YAG(钬:YAG),Er:YAP,Er/Cr:YSGG(铒/铬:钇、钪、镓、石榴石;2.796微米),Ho:YSGG(钬:YSGG;2.088微米),Er:GGSG(铒/钇、钪、镓、石榴石),Er:YLF(铒:钇、锂、氟化物;2.8微米),Tm:YAG(铥:YAG;2.01微米),Ho:YAG(钬:YAG;2.127微米),Ho/Nd:YAlO3(钬/钕:钇,铝酸盐,2.85-2.92微米),钴:MgF2(钴:氟化镁;1.75-2.5微米),HF试剂(氟化氢;2.6-3微米),DF试剂(氟化氘;3.6-4微米),一氧化碳(5-6微米),低UV激光,和增至三倍频率的Nd:YAG(钕:YAG,其中激光束通过使频率增至三倍的晶体)。 Lasing element e.g. pulsed CO2 lasers, Ho: YAG (holmium: YAG), Er: YAP, Er / Cr: YSGG (erbium / chromium: yttrium, scandium, gallium, garnet; 2.796 microns), Ho: YSGG (holmium : YSGG; 2.088 microns), Er: GGSG (erbium / yttrium, scandium, gallium, garnet), Er: YLF (erbium: yttrium, lithium, fluoride; 2.8 microns), Tm: YAG (thulium: YAG; 2.01 microns ), Ho: YAG (holmium: YAG; 2.127 microns), Ho / Nd: YAlO3 (holmium / neodymium: yttrium, aluminate, 2.85-2.92 microns), cobalt: MgF2 (cobalt: magnesium fluoride; 1.75-2.5 microns ), HF reagent (hydrogen fluoride; 2.6-3 microns), DF reagent (deuterium fluoride; 3.6-4 microns), carbon monoxide (5-6 microns), low UV lasers, and frequency tripled Nd: YAG (Neodymium : YAG, where the laser beam is increased by three times the frequency of the crystal).

利用目前的技术一些激光材料另外具有尺寸小的益处,允许激光器很小并便携。 Some current technology utilizing laser material additional benefit of having a small size, allowing the laser is small and portable. 例如,除了Er:YAG外,Ho:YAG激光器也能提供这些有利条件。 For example, in addition to Er: YAG outside, Ho: YAG lasers also provide these advantages.

固态激光器,包括但不限于上面所列出的这些,可以使用抛光的滚磨晶体棒。 Solid-state lasers, including but not limited to those listed above, you can use the tumbling polished crystal rods. 棒表面也可含如图13所示的糙面精整。 Stick surfaces may matte finish containing as shown in Figure 13. 然而,这两个配置在环绕中央输出光束引起光晕线。 However, the two arranged around a central output beam halo rays cause. 而且,虽然糙面精整相对于抛光棒可降低光晕线,但这会导致总激光能量输出有相对大的下降。 Moreover, while matte finish relative to the polishing stick can reduce halos line, but this will lead to the total laser energy output is relatively large decline. 为了降低光晕线并以另一种方式影响光束模式,可以在沿棒带状提供糙面精整,每一个带绕棒的整个圆周扩展。 To reduce the Halo line and in another way influence the beam pattern, matte finish can be provided in the strip along the rod, each with a stick around the entire circumference of the extension. 或者,可以仅在棒的部分外周上提供条状糙面精整。 Or it can provide strip matte finish only in part on the outer periphery of the rod. 图14示出了一种激光晶体元件,其中沿元件整个外周的长度三分之二提供糙面精整。 Figure 14 shows a laser crystal element, wherein the length of the entire periphery of the two-thirds along element provides a matte finish. 作为选择,如图15所示,沿元件整个棒的纵向提供糙面精整。 Alternatively, as shown in Figure 15, provides a matte finish along the entire rod longitudinal member. 纵向条纹可以沿棒部分长度交替存在,例如以各种长度的条纹形。 Alternating vertical stripes may exist along the length of the rod portion, for example, a stripe shape in a variety of lengths. 可以使用前述技术的组合影响束的形状。 You can use a combination of the foregoing techniques affect the shape of the beam. 其它图案的变化也可以用于所需的光束形状中。 Other changes may also be used to pattern the beam shape desired. 按照所需的最终光束形状和能量水平,根据从100%抛光元件发出的光束的起始构型可以确定特定的图案。 According to the desired final beam shape and energy levels, according to the initial configuration sent from 100% polished element beam can identify a specific pattern. 完全糙面精整的元件也可以用作起始的参照点。 Completely matte finish elements may also be used as a starting reference point.

为了控制光束的形状,任何大于30微米的表面精整都被认为是不光滑的。 In order to control the shape of the beam, any surface finish of greater than 30 microns it is considered to be not smooth. 一微英寸等于一英寸的一百万分之一(0.000001),是用来建立标准的粗糙单位值的常用测量单位。 A micro-inch equals one millionth of an inch (0.000001), it is used to establish a standard unit of value used rough measurement units. 使用高于或低于平均参照线距离的微英寸数的方根平均值,对这些距离的平方和的平均值求方根计算粗糙度。 Above or below the average root mean distance between the reference line of micro number of inches, the average value of the square of the distance and of those seeking root calculation roughness. 虽然大于500微英寸的粗糙表面可被用于影响光束形状,但这种精整极大地降低进入晶体棒的光能的量,从而降低激光能量。 Although more than 500 microinches rough surface can be used to affect beam shape, but the finishing greatly reduces the amount of light entering the crystal rod, thereby reducing the laser energy.

为了去掉光束的光晕,环绕Er:YAG激光棒全长三分之二提供约50微英寸的不光滑区域。 To remove the beam halo around Er: YAG laser rod provided two-thirds of the full-length matte area of about 50 micro-inches. 棒的光滑区域少于10微英寸。 Stick smooth area of less than 10 micro inches. 可以首先进行非光滑棒的基线检验以确定基线光束的形状和棒的能量。 Baseline testing may be first non-smooth rod to determine baseline energy beam shape and bars. 然后通过弄粗抛光晶体激光棒获得不光滑的区域,例如用钻石磨或喷粗砂机。 Then get matte region get through the rough polishing crystal laser rod, for example, diamond grinding grit or spray machine. 不光滑的特定图案由所需的光束形状和所需的光束能量水平决定。 Matte specific pattern determined by the desired beam shape and beam energy level required. 这就导致大大降低光束的光晕。 This results in greatly reduced beam halo. 也可以通过中心钻孔梨型人造宝石晶体制造棒而留下一个糙面精整,然后抛光所需的区域,或通过精制部分糙面、部分抛光的梨型人造宝石达到所需的图案。 You can also drill through the center of boule crystal manufacturing stick while leaving a matte finish and polish the desired area, or through the refining section matte, partially polished boule achieve the desired pattern.

晶体激光棒元件的光束形状可以选择为如图16通过环绕在对激发光透明但反射指数大于棒的材料160中的棒20那样改动。 Beam shape crystal laser rod element 16 may be selected to surround the excitation light through transparent but reflective index greater than the rod material 160 as the rod 20 changes. 这一改动通过增加在晶体内偏离轴的光子的逃逸可能性,可以减少光束的光晕。 This change by increasing the deviation in the crystal axis of photons escape the possibility to reduce the beam halo. 这一步骤也可以用来代替或附加在前面的糙面步骤中。 This step can also be used instead of or in addition to the foregoing matte procedure.

使用聚焦透镜28发射激光束聚焦至毫米或亚毫米大小的点。 Use the focus lens 28 emits a laser beam focused to spot mm or sub-mm size. 考虑到激光的安全问题,将使用短焦距聚焦透镜以保证能量通量速率(W/cm2)除在透镜焦点外较低,要穿孔或改变的组织样品在焦点处定位。 Taking into account the security concerns of the laser, the use of short focal length focusing lens to ensure energy fluence rate (W / cm2) in addition to lower tissue sample to be perforated or change the positioning of the lens at the focal point of focus. 这样,激光束的危害就将至最低。 Thus, the harm of the laser beam on approaching a minimum.

为了通过使用圆柱形的聚焦透镜组27产生狭缝形的穿孔或改变,激光被聚焦的方式为被聚焦在一个轴线比其它的轴更窄。 Order by using a cylindrical focusing lens group 27 generates a slit-shaped perforation or alteration, the laser light is focused in a manner to be focused more narrow than the other axis of the shaft. 这一透镜组,沿一个轴向会聚光束,与透射聚焦透镜28连续放置。 This lens group along an axial convergent beam focusing lens 28 and the transmission placed consecutively. 当穿孔或改变是狭缝形的时,穿孔或改变产生的患者不适或疼痛就显著降低。 When the perforation or alteration is slit-shaped perforation or alteration resulting patient discomfort or pain will be significantly reduced.

可任选地,光束可以被加宽,例如在通过聚焦透镜28聚焦前使用一个凹面发散透镜46(图4)。 Optionally, the beam can be widened, for example, prior to focusing through the focusing lens 28 using a concave diverging lens 46 (FIG. 4). 这一加宽的激光束导致激光束在焦点上的一个较短的距离的能量通量更低,因而降低危害水平。 This widened the focus of the laser beam results in a shorter distance between the laser beam energy flux lower, thereby reducing the level of hazard. 进而,这一光学安排在处理位置的激光点减少了光学偏差,从而导致更精确的穿孔或改变。 Furthermore, this optical arrangement in the position of the laser spot treatment to reduce the optical deviation, resulting in a more precise perforation or alteration.

也可任选地,激光束能依靠分光镜分开,以产生同时或近乎同时穿孔或改变的多光束。 Also optionally, the laser beam can rely spectroscope split to produce simultaneous or near-simultaneous multi-beam perforation or alteration. 图5提供了两种形式的有用的分光镜。 Figure 5 provides a useful spectroscope two forms. 在一个形式中在光束聚焦后可以提供多分光镜例如部分镀银镜、二色镜、或分光棱镜。 In one form may be provided after the beam is focused multi-beam splitter e.g. partially silvered mirrors, dichroic mirrors or dichroic prism. 或者,可以提供一个声光调节器52,用调制的高压驱动调节器52并弯曲光束。 Or it can provide a sound and light modulator 52, with modulated high voltage drive actuator 52 and bend the beam. 这一调节器在激光空腔之外。 The regulator outside the laser cavity. 从而它迅速起到以多种角度偏转激光束的功能以激发多激光束的产生。 In more rapidly so that it plays the function of angular deflection of the laser beam to generate multiple excitation laser beams.

便携性当前,使用一个便携TRANSMEDICATMEr:YAG激光器,装置每20-30秒放电一次。 Portability Currently, using a portable TRANSMEDICATMEr: YAG laser, the discharge means once every 20-30 seconds. 这可通过添加电池和电容和冷却系统以获得更快的周期而得到提高。 This is accomplished by adding a battery and a capacitor and cooling systems for faster cycles and improved. 多电容能排在一起以使放电速率降到每5或10秒一次(顺序充电电容组)。 More capacitance can be discharged together with the discharge rate down to one (sequence charging capacitor group) every 5 or 10 seconds. 因此,比用单电容达到更高的循环速率。 Therefore, to achieve higher circulation rate than with a single capacitor.

TRASMEDIATMEr:YAG激光器结合一个闪光灯,其输出通过充电电容器库产生的电高压脉冲激发。 TRASMEDIATMEr: YAG laser combined with a flash, high-voltage pulse electric output generated by the charging capacitor library excitation. 由于高压需要激发闪光灯,并因为涉及的激光器型式要结合干电池工作(因而充电电流比墙上插头能提供的更小),则,电容需用20秒充分充电。 Due to the high pressure needed to stimulate the flash, because the laser and the type of work involved to combine the battery (hence the charging current is smaller than the wall plug can provide), then, 20 seconds required to fully charge the capacitor. 这样,如果需要的脉冲循环频率为1脉冲/20秒,使用能够顺序充电的多电容器组将是适合的(即当一个电容器组起动闪光灯时,另一个电容器组重新充电、起动,诸如此类)。 Thus, if desired pulse cycle frequency of 1 pulse / 20 seconds, using a multi-capacitor banks can charge would be appropriate order (that is, when a flash start capacitor, another capacitor pack recharges, start, and so on). 这样,脉冲的循环频率仅受装置中使用的电容器组的数目所限(也受激光器空腔的废热排除速率所限)。 Thus, the number of devices used in the capacitor bank limited (the laser cavity is also affected by the rate of heat exclude limited) by the frequency of the pulse cycle only.

小加热器如热电加热器32可任选地位于激光器施用器末端最接近于穿孔的位置处。 Small heater thermoelectric heater 32 may optionally be located at the end of the laser applicator closest to the perforation. 加热器在激光照射前升高预穿孔或改变的组织处的温度。 Before the laser irradiation heater elevated temperature or change pre-punched at the organization. 当本装置用于该目的时,这会增加收集的液体的体积。 When the unit used for this purpose, which will increase the volume of the liquid collected. 尽管任何能引起血管扩张并导致血流加速,但不会改变血液化学性质的温度都是合适的,但仍然建议皮肤温度的范围是36EC-45EC。 Although any can cause blood vessels to dilate and cause blood flow to accelerate, but does not change the nature of the temperature of the blood chemistry it is appropriate, it is recommended that skin temperature range is 36EC-45EC.

容器装置容器装置68可任选地安装于激光器罩内最接近于穿孔或改变的位置处。 Container means the container means 68 can optionally be attached to a position closest to the perforation or alteration within the laser housing. 容器装置能降低当激光束穿透或改变患者的组织时产生的声音的强度,提高流体、气体或其它生物分子的收集效率,并收集消融的组织和其它由于穿孔释放出的物质。 The container unit can reduce the intensity when the laser beam penetrates the patient's tissue or change the sound and improve the collection efficiency of fluids, gases or other biomolecules, and collecting ablated tissue and other substances due to the release of the perforation. 容器装置的形状要便于容易插入激光器罩内并在激光器罩内提供摩擦配合。 Shape of the container to facilitate the easy insertion of the device within the laser housing and to provide a friction fit within the laser housing. 图8表示一般的容器装置插入激光器罩内并放于穿孔位点上方。 Figure 8 shows the general container means is inserted into the laser housing and placed in a position above the point of perforation.

容器装置68包括一个主接受器82,该主接受器包括一个透镜84。 Container means 68 comprises a main receptacle 82, the main receptacle includes a lens 84. 主接受器收集流体、气体或其它生物分子样品、消融的组织、和/或由于穿孔释放出的其它物质。 Main receptacle to collect tissue fluid, gas or other biomolecule sample, ablation, and / or other substances due to the release of the perforation. 透镜的放置使激光束可透过透镜到达穿孔位置,但穿孔释放出的物质不会溅回到施用器上。 The lens is placed so that the laser beam through the lens to reach the puncture site, but the substance is not released by the perforation splash back onto the applicator. 容器装置还可选择包括一个基托86,附着于接受器。 Selecting means further comprises a container base plate 86, attached to the receptacle. 基托可选择形状为能插入施用器中断开激光器的安全装置,从而容许激光束的发射。 Base plate can be selected as the shape of the applicator is inserted in the laser safety device is disconnected, thereby allowing the laser beam emitted.

如图17所示,容器装置68的形状和尺寸要便于放置于施用器旁边或插入其中,并可以收集流体、气体或其它生物分子样品、消融的组织、和/或其它由于穿孔或改变释放出的物质。 17, the shape and size of the container means 68 to facilitate the administration placed next to or inserted, and can collect fluid, gas or other biomolecule samples, ablated tissue, and / or other perforation or alteration due to the release of substances. 主接受器可采用的形状的实例包括圆柱形、子弹形、圆锥形、多面体或任意的形状。 Examples of the shape of the main receptacle may be used include cylindrical, bullet-shaped, conical, polyhedral or arbitrary shape. 优选容器装置含有主接受器,其体积为大约1-2毫升。 Preferably container means containing the main receptacle, the volume of about 1-2 ml. 然而,较大和较小的接受器也能起到合适的作用。 However, larger and smaller receiver can also play a proper role.

透镜84允许激光束透过而阻止生物物质或其它物质溅回到施用器上,它至少是部分透明的。 Lens 84 allows the laser to prevent biological substances and other substances or splash back onto the beam through the applicator, it is at least partially transparent. 构成该透镜的物质能传播所用激光波长。 Constituting the lens material can be spread, the laser wavelength. 透镜位于激光束经过的路径,在容器装置末端最接近于激光束的位置处。 Lens of the laser beam path through which, in the end of the container means at a position closest to the laser beam. 传播物质可为石英,但其它合适的红外线传播物质的实例包括岩盐、锗、玻璃、晶体蓝宝石、聚氯乙烯和聚乙烯。 Propagation material for quartz, but other suitable infrared materials include rock salt spread, germanium, glass, sapphire crystal, PVC and polyethylene. 然而,这些物质应当不合有会吸收激光束能量的杂质。 However, these materials should not contain impurities absorbing the laser beam energy. 如图20所示,透镜可任选地包括一层非透射性物质85的掩膜,这样透镜可定形传送到穿孔位点的光束部分。 20, the lens may optionally include a layer of material non-transmissive mask 85, so that the lens can be shaped to a beam transmitting portion the perforation site.

主接受器82是由透镜和壁88形成的,优选在基本上离开透镜的周围向外延伸。 Main receptacle 82 is formed by the lens and the wall 88 is preferably substantially extends outwardly around the left lens. 主接受器的开口端或边90邻近于穿孔或改变位点。 Open end or side of the main receptacle 90 adjacent to the perforation or alteration site. 因此由透镜、主接受器的壁和穿孔和改变点所决定的区域在激光器操作过程中实质上是封闭的。 So area by the lens, and the perforated wall of the main receptacle and the decision to change the points during the laser operation is essentially closed.

基托86是容器装置的一部分,可任选地插入施用器。 Base plate 86 is a part of the container means may optionally be inserted into the applicator. 基托可包括一个圆柱体、一个多元支架或其它结构。 Underpinning may include a cylinder, a multi-arm, or other structures. 基托可选择含有穿线。 Underpinning optionally contain threading. 当基托完全插入时,可任选地切断激光器的安全装置,允许激光束的发射。 When the base plate is fully inserted, optionally laser cutting safety device, which allows the laser beam is emitted.

典型的容器装置可包括一个圆柱形主接受器82,一个圆柱形基托86和一个位于主接受器的基托之间的至少部分透明的圆形透镜84。 A typical container unit can comprise a cylindrical main receptacle 82, is at least partially transparent circular lens 86 and a base plate of a cylindrical main receptacle located between the base plate 84. 透镜可任选地包括一层定形穿孔组织的光束的掩膜。 Lens may optionally include a layer of amorphous mask perforated tissue beam. 主接受器的内部可任选地被抗凝剂和/或防腐化合物涂布。 Inside the main receptacle may be optionally anticoagulants and / or anti-corrosion coating compound. 容器装置可由玻璃或塑料构成。 Container means may be formed of glass or plastic. 容器装置为可任选地为一次性使用的。 Container means to be optionally be disposable.

图19表示使用具有容器装备的激光器以吸取流体、气体或其它生物分子或施用药物的例子。 Figure 19 shows the use of a laser to draw a container equipped example fluids, gases or other biomolecules or the administration of the drug. 在这一实施方案中,施用器30被罩34包围。 In this embodiment, the applicator 30 is housed 34 siege. 容器装置插入施用器30并成一直线,以便于能够消除联锁器36的作用。 Container means 30 and inserted into the applicator in a straight line, so as to be able to eliminate the role of the interlock 36. 在本实施方案中,容器装置的基托86位于施用器30内,而接受器82的边90邻近于预穿孔的组织。 In the present embodiment, the base plate 86 of container means 30 located within the applicator, and the receptacle 82 adjacent to the edge 90 pre-perforated tissue.

此外,容器装置可为真空的。 In addition, means may be a vacuum container. 容器装置内可任选的真空比组织液或血液中的气压对穿孔或改变位点的作用小,因此提高了流体、气体或其它生物分子的收集效率。 Container means may optionally vacuum than in the tissue or blood pressure perforation or alteration site effects on small, thus increasing the collection efficiency of fluids, gases or other biomolecules. 容器装置可选择被抗凝剂和/或防腐化合物涂布。 The container unit may be optionally anticoagulants and / or anti-corrosion coating compound. 容器装置的末端可用塞70密封。 The end of the container means available plug 70 seals. 塞子是由具有适当弹性的物质构成,并与穿孔位点的轮廓一致(例如,手指)。 Stopper is a substance having a suitable elastic structure, and outline agreement (for example, finger) and perforation site. 需要的穿孔或改变位点用塞子牢牢压住。 Perforation or alteration site needed with a plug firmly pressed. 塞子的材料优选不能透过气体的。 The stopper material is preferably gas impermeable. 而且,塞子的材料要薄至激光能穿透该物质并穿透皮肤。 Moreover, the plug material is thin to the laser can penetrate the material and penetrate the skin. 塞子可由例如橡胶构成。 It may be e.g. rubber stopper.

如图9所示,塞子穿孔中心74优选由薄橡胶材料构成。 As shown in Figure 9, the plug perforation center 74 is preferably made of a thin rubber material. 塞子的厚度要能使塞子在穿孔前保持真空,并且激光能穿透塞子和邻近塞子的组织,当使用Er:YAG激光器时,塞子的厚度可为约100-500微米。 The thickness of the plug allows the plug to maintain the vacuum prior to perforation, and the laser can penetrate the stopper and the stopper adjacent tissue, when using Er: YAG laser, when the thickness of the stopper may be about 100-500 microns.

塞子穿孔中心74要大到能盖住穿孔或改变位点。 Plug perforation center 74 should be large enough to cover the perforation or alteration site. 穿孔位点可任选地是圆形孔,大约的直径范围是0.1-1mm,或为缝隙,宽度约0.05-0.5mm,长度约2.5mm。 Perforation site is optionally circular holes, the diameter range of about 0.1-1mm, or slit width of about 0.05-0.5mm, a length of about 2.5mm. 这样,塞子穿孔中心就足够大至能覆盖这些尺寸的穿孔位点。 Thus, the plug perforation center is sufficiently large to cover perforation sites of these sizes.

如图10所示,容器装置68可包括孔76,激光从孔中通过。 10, the container device 68 may include an aperture 76, through the hole from the laser. 在本实施方案中,容器装置可选择地只收集消融的组织。 In this embodiment, the container means selectively collect only ablated tissue. 在其它实施方案中,照射位点是用容器装置牢牢地压住。 In other embodiments, the irradiation site is firmly pressed against container means. 容器装置可选择包括一个最接近于穿孔位点的塞子,然而,由于并不需要保持真空,因次这并非是必要的。 It means optionally includes a container is closest to the perforation site plug, however, as they do not need to maintain a vacuum, it is not necessary dimensionless. 容器装置降低激光束和患者组织间相互作用产生的噪音,并因此减轻患者的焦虑和压力。 The container unit to reduce noise between the laser beam and the patient's tissue interaction, and thus reduce patient anxiety and stress.

容器还可改变为可通过开口容纳或接受药物或其它物质,这些物质随后在照射同时或照射后被不久即释放出。 The container may also be changed to accommodate the openings or by receiving drug or other substances that then irradiated simultaneously or shortly after irradiation release. 图11表示一个实施方案,具有容器和内置式药物储存器和输送用的滚装装置。 Figure 11 shows an embodiment having a container and a built-in drug reservoir and delivery device in accordance with Ro. 图18表示一个容器和施用器,还含一个与高压汽缸连接的喷雾器。 Figure 18 shows a container and applicator, further comprising a high-pressure sprayer cylinder connection.

容器装置可选择是一次性的,这样容器装置和塞子可在用后扔掉。 Alternatively container unit is disposable, so that the container unit and plug can be discarded after use.

为了在穿孔或改变前给皮肤消毒,可选择将消毒乙醇浸泡的纸片或其它薄材料放于预穿孔的位点。 In order to change the skin before perforation or sterilization, disinfection choose to ethanol soaked paper or other thin material placed on the site of a pre-perforated. 这种材料还可防止穿孔释放出的烟缕中的可能被感染的物质被吹走。 This material also prevents the plume released by the perforation of the material may be infected to be blown away. 该材料必需对激光束的波长具有总吸收低的特性。 The material required for the wavelength of the laser beam has an overall low absorption characteristics. 这种材料的实例包括,但不限于,薄层玻璃、石英、云母或蓝宝石。 Examples of such materials include, but are not limited to, a thin layer of glass, quartz, mica, or sapphire. 换句话说,薄层塑料如聚氯乙烯或聚乙烯薄膜可放于皮肤上。 In other words, a thin layer of plastic such as polyvinyl chloride or polyethylene film can be placed on the skin. 尽管激光束可穿透皮肤,但是塑料能够防止大多数烟缕飞走,并因此减少了由于感染组织造成的任何可能污染的危险。 Although laser beams penetrate the skin, but can be prevented most plastic plume fly away, and thus reduces any possible risk of infection due to contamination caused by the tissue. 换句话说,可将一层有粘性的无菌物质如凡士林加到透明材料或塑料膜上,以增加透明物质或塑料膜对皮肤的附着,并进一步减低烟缕污染。 In other words, a layer of viscous sterile substance such as Vaseline is applied to a transparent material or plastic film, in order to increase transparency material or plastic film attached to the skin, and to further reduce contamination plume. 此外这样的片可用于传递过敏原、局部麻醉剂或其它下述的药物。 Also such sheet can be used to deliver allergens, local anesthetics, or other drugs described below.

图6和7中给出了这种贴片的实施方案。 Figures 6 and 7, and given the embodiment of such a patch. 在图6中,乙醇浸泡的纸片54被临时性的粘合带58环绕。 In Figure 6, the ethanol soaked paper 54 is surrounded by a temporary adhesive tape 58. 两种任选其一的贴片的测试图列于图7,其中消毒乙醇、抗生素软膏、过敏原或药物存在于贴片60的中心区域。 Choose one of the two test patches shown in Figure 7, wherein the disinfecting alcohol, antibiotic ointment, allergen, or pharmaceutical is present in the central region 60 of the patch. 这种物质被纸片或塑料膜62保留在该位置,可选择与激光透明材料64一起。 This material is paper or plastic film 62 remains in this position, the transparent material 64 optionally together with a laser. 这种物质的实例包括,但不限于,云母、石英或蓝宝石,这些都是对激光束透明的并位于贴片中央。 Examples of such materials include, but are not limited to, mica, quartz or sapphire, which are transparent to the laser beam and the center of the patch located. 然而,这种物质不需完全透明。 However, this substance without completely transparent. 可用粘合剂66将贴片放到皮肤上。 Available 66 adhesive patch placed on the skin.

调制激光除了上述脉冲激光,也可用调制激光复制脉冲激光以增强表面药物的传送,同时增强流体、气体或其它生物分子的排除。 In addition to the above-mentioned modulated laser pulse laser, the laser can also be modulated pulsed laser copy transfer surface to enhance the drug, while enhancing fluids, gases or other biomolecules excluded. 这可通过机械调制或可选择其它方式如饱和吸收器使连续波激光的输出断开来实现(见:例如Jeff Hecht,“激光器指南,”McGraw-Hill:N Y,1992)。 This can be modulated by mechanical or other means such as a saturable absorber selectively enables the output of a continuous wave laser disconnection is achieved (see: e.g., Jeff Hecht, "Laser Guide," McGraw-Hill: NY, 1992). 连续波激光的实例包括CO2其发射出激光的范围在9-11微米(例如EdinburghInstruments,Edinburgh,UK),钕:YAG、铥:YAG(Tm:YAG)其发射出2.1微米的激光(例如CLR Photonics Inc.,Boulder CO),半导体(二极管)激光器发射出激光的范围是1.0-2.0微米(SDL Inc.,San Jose,CA)。 Examples include continuous wave CO2 laser which emits laser light in the range of 9-11 microns (e.g. EdinburghInstruments, Edinburgh, UK), Nd: YAG, Tm: YAG (Tm: YAG) which emits a laser 2.1 microns (e.g. CLR Photonics Inc., Boulder CO), semiconductor (diode) laser emits a laser range is from 1.0 to 2.0 microns (SDL Inc., San Jose, CA).

断开激光输出(例如,用Stanford Research Instruments Inc.,SunnyvaleCA的机械斩波器)会更好地导致从毫秒的十分之几到纳秒或皮秒短暂间隔的不连续阶段照射。 Disconnect the laser output (for example, with Stanford Research Instruments Inc., SunnyvaleCA mechanical chopper) will result in better phase discontinuity illuminated from a few tenths of milliseconds to nanoseconds or picoseconds short intervals. 换句话说,对二极管激光器的情况下,产生激光的过程可用调制激光器的激发电流进行调制。 In other words, a diode lasers, the procedure can be used to generate the laser excitation current modulated laser modulation. 激光二极管电源的调制器可从SDL Inc.,San Jose,CA处购得。 Power laser diode modulator from SDL Inc., San Jose, CA at commercially. 换句话说,连续波束可选用例如光电电池(例如得自New Focus nc.,Santa Clara,CA)或来自GeneralScanning,Inc.,Watertown MA的扫描镜进行调制。 In other words, a continuous beam can be used, for example a photovoltaic cell (e.g. from New Focus nc., Santa Clara, CA) or from GeneralScanning, Inc., Watertown MA modulated scanning mirror.

使用二极管激光器可发挥多重穿孔的加和效应。 Diode laser can serve multiple perforations additive effect. 由SDL Corporation(San Jose,CA)提供的激光器二极管发射出1.8-1.96微米波长照射能的连续波束。 By a laser diode SDL Corporation (San Jose, CA) to provide continuous beam emitted irradiation energy of 1.8-1.96 micron wavelength. 这些二极管在相当于500mW的输出功率下操作,并可结合起来累计产生更高能量用于角质层消融。 These diodes at the equivalent of 500mW output power operation, and can be combined to produce a total of more energy for the ablation of the stratum corneum. 例如,一个二极管棒可含有十个这样的二极管结合起来产生5mJ/ms的脉冲能。 For example, a diode bar may contain such diode ten combined to produce 5mJ / ms pulse energy. 已经证明,将仅有25mJ这么低的能量传送到1mm直径的点上,就可看到消融效应。 We have demonstrated that the only 25mJ such a low energy transmitted to the point 1mm in diameter, you can see the ablation effects. 因此,这种类型的二极管激光器的五个5毫秒脉冲或二十五个1毫秒脉冲在相同时间内就具有和一个25mJ脉冲基本相当的消融效果。 Therefore, this type of diode laser pulse 5 ms or twenty five to five 1-millisecond pulse at the same time having a pulse and a roughly equal 25mJ ablation effect.

下列实施例描述了使用激光器增加角质层的通透性,从而排出流体、气体或其它生物分子以及输送药物。 The following examples describe the use of a laser to increase the permeability of the stratum corneum, thereby discharging the fluid, gas or other biomolecule and drug delivery. 这些实施例并不限制本发明的范围,而仅仅是实施方案。 These examples are not intended to limit the scope of the invention, but merely embodiments.

实施例1激光器包括一个闪光灯泡(PSC灯,Webster,NY),一个铒:YAG晶体(Union Carbide Crystal Products,Washagoul,WA),光学共振镜(CVILaser Corp.,Albuquerque,NM),一个红外传送透镜(Esco Products Inc.,Oak Ridge,NJ)和多个标准电子元件如电容器、电阻、电感器、晶体管、二极管、可控硅整流器、保险丝和开关,这些均可从任何电子元件供应公司买到,如Newark Electronics,Little Rock,AR。 Example 1 comprises a laser flash bulb (PSC lamp, Webster, NY), an Er: YAG crystal (Union Carbide Crystal Products, Washagoul, WA), optical resonator mirror (CVILaser Corp., Albuquerque, NM), an infrared transmitting lens (Esco Products Inc., Oak Ridge, NJ), and a plurality of standard electronic components such as capacitors, resistors, inductors, transistors, diodes, silicon controlled rectifiers, fuses and switches, which are available from any electronics supply company to buy, such as Newark Electronics, Little Rock, AR.

实施例2红外激光发射脉冲是使用固态脉冲型铒:YAG激光器并通过将激光束聚焦的方式来形成的,这种激光器是由两个平共振器镜、一个铒:YAG晶体作为活性介质、一个电源组成的。 Example 2 infrared laser emitting pulses embodiment using solid state pulsed Erbium: YAG laser and the laser beam is focused by the way the formation, this laser is composed of two flat resonator mirrors, an Er: YAG crystal as an active medium, a power component. 激光束的波长是2.84微米。 The wavelength of the laser beam is 2.84 m. 使用单脉冲。 Use single pulse.

操作参数如下:每次脉冲的能量是40、80或120mJ,焦点处激光束的尺寸是2mm,产生能量通量1.27、2.55或3.82J/cm2。 Operating parameters are as follows: energy per pulse is 40, 80 or 120mJ, the size of the focal point of the laser beam is 2mm, creating an energy fluence 1.27,2.55 or 3.82J / cm2. 脉冲间的短暂间隔是300μs,产生能量通量速率为0.42、0.85或1.27104W/cm2。 Short interval between pulses is 300μs, creating an energy fluence rate of 0.42,0.85 or 1.27 104W / cm2.

经上皮丢失的水分(TEWL)是通过志愿者前臂手掌外观进行测定。 Transepithelial water loss (TEWL) was measured by a volunteer forearm palm appearance. 随后将前臂放于激光器的焦点处并将激光器放电。 Then put in the forearm and the focal point of the laser laser discharge. 随后收集照射位点的TEWL测量值,其中要减去未照射的对照的测量值。 TEWL measurements are then irradiated sites collect, where to subtract the measured values of the non-irradiated control. 结果(列于图27)表明脉冲能量是40、80和120mJ时,角质层的屏障功能减小并且导致的水分丢失分别测定为131、892和1743gm/m2/hr。 The results (presented in Figure 27) indicates the pulse energy is 40, 80 and 120mJ, the stratum corneum barrier function and reduce moisture loss caused were determined to 131,892 and 1743gm / m2 / hr. 测定贴条剥离正对照(将25片Scotch穿孔贴条连续敷贴并快速从一块皮肤上取走)是9.0gm/m2/hr,大于未触及的对照;这样激光器在降低角质层的屏障功能方面比贴条剥离更为有效。 Peeling stickers measurement control (the 25 continuous strip of Scotch perforation applicator and quickly removed from the piece of skin) is 9.0gm / m2 / hr, more than untouched control; this laser to reduce the stratum corneum barrier function more effective than peeling stickers.

照射后24小时进行临床评估。 24 hours after irradiation clinical evaluation. 在高能量照射的位点仅有一块明显的小焦痂,不存在皮下水肿。 At the site of high-energy radiation is just a small piece of clear eschar, there is no subcutaneous edema. 无志愿者受过辐射或需要医疗。 Volunteers received no radiation or need medical treatment.

实施例3红外激光发射脉冲是使用固态脉冲型铒:YAG激光器并通过将激光束聚焦的方式来形成的,这种激光器是由两个平共振器镜、一个铒:YAG晶体作为活性介质、一个电源组成的。 3 infrared laser emitting pulses embodiment is the use of a solid state pulsed Erbium: YAG laser and the laser beam is focused by the way the formation, this laser is composed of two flat resonator mirrors, an Er: YAG crystal as an active medium, a power component. 激光束的波长是2.94微米。 The wavelength of the laser beam is 2.94 m. 使用单脉冲。 Use single pulse.

操作参数如下:每次脉冲的能量是60mJ,焦点处激光束的尺寸是2mm,产生能量通量1.91J/cm2。 Operating parameters are: energy per pulse is 60mJ, size at the focal point of the laser beam is 2mm, creating an energy fluence 1.91J / cm2. 脉冲间的短暂间隔是300μs,产生能量通量速率为0.64104W/cm2。 Short interval between pulses is 300μs, creating an energy fluence rate of 0.64 104W / cm2.

将志愿者前臂的手掌部分放于激光器的焦点处并将激光器放电。 The forearm palm some volunteers put in the focal point of the laser and the laser discharge. 消融位点用30%利多卡因溶液表皮给药两分钟。 Ablation site with 30% lidocaine solution administered topically two minutes. 随后将一根26G-0.5针插入激光器消融位点,无可见的疼痛。 Followed by an 26G-0.5 needle into laser ablation site, no visible pain. 另外在6分钟麻醉处理后,将一根22G-1针完全插入激光器消融位点,无可见的疼痛。 In addition, after six minutes of anesthesia treatment, a 22G-1 pin is fully inserted into the laser ablation site, without visible pain. 志愿者未受过辐射且不需医疗。 Volunteers have not received radiation and does not require medical treatment.

实施例4消融阈能:在两层显微镜载玻片间正常水合(66%)角质层是层状,并曝露到铒:YAG激光器发射的单脉冲下。 Example 4 ablation threshold energy: in between two glass microscope slides properly hydrated (66%) of the stratum corneum is layered, and exposure to the Er: YAG laser emits a single pulse under. 将样品靠近灯看是否在照射位置处有任何角质层脱落,借此测定消融痕迹。 The sample near the lamp in a position to see whether there is any stratum corneum irradiated, thereby measuring the ablation traces. 从这一试验中,测定出照射阈能(对于2mm照射点而言)是约90-120mJ。 From this test, the measured threshold energy irradiation (irradiation point for 2mm terms) is about 90-120mJ. 由于将角质层从其粘着的表皮上除去要消耗能量,当角质层仍覆盖在表皮上以及在正常皮肤的情况下,阈可能会更高。 Because the cuticle is removed from its adhesive skin to consume energy when the cuticle is still covered in the epidermis and in the case of normal skin, the threshold may be higher.

实施例5差示扫描量热法(DSC):图28表示正常水合(66%)人角质层的DSC扫描,以及使用60mJ的亚消融脉冲能量的铒:YAG激光器照射角质层的扫描。 Example differential scanning calorimetry (DSC) 5: DSC scan of human stratum corneum, and the use of pulse energy 60mJ alkylene ablation erbium FIG. 28 shows the normal hydrated (66%): YAG laser irradiated stratum corneum scanning. 在约65、80和92℃定义热转化峰,我们测定了转化热(μJ),转化(℃)中心和转化(℃)半峰处的全宽(图29-31)。 At about 65,80 and 92 ℃ thermal conversion defined peak, we determined the conversion of heat (μJ), conversion (℃) center and transformation (℃) full width at half maximum (29-31). 显示的结果是在正常66%水合角质层、脱水33%角质层、蒸汽加热的角质层、铒:YAG激光照射的角质层或浸泡在氯仿—甲醇(一种液体溶剂)或β-巯基乙醇(一种蛋白变性剂)中的角质层。 The results showed that 66% of the normal hydration of the stratum corneum, dehydrated 33% stratum corneum, steam heated stratum corneum, Er: YAG laser irradiated stratum corneum, or soaked in chloroform - methanol (a liquid solvent) or β- mercaptoethanol ( a protein denaturing agent) in the stratum corneum. 激光照射在角质层上的效果与由于热损害(即用蒸汽加热)引起的可见变化和脱脂是一致的(取决于你所看的转化1、2或3)。 The effect of laser irradiation with visible changes in the stratum corneum and skim damage due to the heat (ie steam heating) cause is the same (depending on the conversion you see 1, 2 or 3). 3H2O的渗透性和以同样方式在皮肤上作的穿皮阻抗试验表明这些处理的结果(热、溶剂或变性剂)导致了渗透性增加。 3H2O penetration and in the same manner as the wear on the skin skin impedance test results show that these treatments (heat, solvent or denaturant) resulted in increased permeability. 这样,这些处理诱导的角质层的变化、与在激光照射的角质层中可见的变化相一致的变化、以及不会导致角质层消融的变化一起导致了渗透性增加。 Thus, treatment-induced changes in the stratum corneum, the stratum corneum is consistent with the laser irradiation of visible change changes, and will not lead to changes in the stratum corneum ablation, result in increased permeability.

实施例6傅立叶变换红外(FTIR)光谱:用傅立叶光谱研究与上述DSC试验相同方式处理的角质层,除了使用的能量是53-76mJ。 Example 6 Fourier transform infrared (FTIR) spectroscopy: cuticle Fourier spectra of the above DSC test process in the same way, except energy use is 53-76mJ. 广谱(见例如图32-33)表明当角质层被照射后由于水、蛋白和脂质产生的吸收带改变了。 Broad-spectrum (see example in Figure 32-33) shows that when the cuticle is irradiated due to water, protein and lipid absorption band changed. 其中一些变化是与非激光处理的角质层(例如脱水、热损伤、脂质溶液化或蛋白变性)的可见变化一致的。 Some of these changes are non-laser treated with the stratum corneum (e.g. dehydration, thermal damage, lipid solubilization or protein denaturation) visible changes in the same. 例如,由于蛋白质(最可能是角蛋白,其组成了角质层蛋白的大部分)的存在产生的酰胺I和II带移动至较大的波数,与单独变性的影响是一致的(对酰胺II带而言)或与脱水和β-巯基乙醇处理是一致的(对酰胺II带而言)(见例如图34)。 For example, since the proteins (most likely keratin, which constitute most of the stratum corneum protein) produced by the presence of amide I and II to move with a large wave number, and the individual effects are consistent with denatured (amide II band of terms) or with dehydration and β- mercaptoethanol is consistent (with the terms of the amide II) (see for example Figure 34). CH2振动带(由于脂质的存在而产生)经总是迁移到较小的波数表明邻近的脂质分子间的联系被打乱了,和/或脂质分子周围的环境以改变分子振动行为的方式改变了(见例如图35)。 CH2 vibration band (due to the presence of lipids generated) by the always migrate to a smaller wave number show contact between adjacent lipid molecules are disrupted, and / or lipid molecules surroundings to alter the behavior of molecular vibrations It changed the way (see for example Figure 35).

实施例7组织学:已在老鼠和人身上做了大量体内试验。 Example 7 Histology: much has been done in vivo experiments in mice and humans. 通常,用铒:YAG激光器选择特殊脉冲能量对皮肤2mm点进行照射,然后立即或24小时后对照射部位进行组织检查。 Typically, Er: YAG laser pulse energy selecting specific points on the skin is irradiated 2mm, and then immediately or 24 hours after irradiation parts of the tissue examination. 典型结果的两个实例列于图36和37。 Two examples of typical results are shown in Fig. 36 and 37. 图36表示以80mJ照射老鼠皮肤,这一能量足够使皮肤成为可透过性(例如对利多卡因)而并无任何角质层消融的迹象。 Figure 36 shows in 80mJ irradiated mouse skin, the energy is sufficient to make the skin become permeable (eg lidocaine) and there were no signs of the stratum corneum ablation. 图37描绘了以80mJ照射后24小时时的人皮肤。 Figure 37 depicts the human skin 24 hours after irradiation is 80mJ. 在这种情况下,角质层表观发生了一些变化(也许是几层角质层凝固成暗黑色的单层),而角质层仍大部分是完整的且未被消融。 In this case, the apparent undergone some changes of the stratum corneum (stratum corneum layers may be solidified into dark black monolayer), while the stratum corneum is still largely intact and not ablated. 在活体内照射人皮肤并随后在解剖显微镜下检查,表明在亚消融能量下(小于约90-120mJ),角质层仍存在于皮肤上。 Irradiated human skin in vivo and subsequently examined under a dissecting microscope, indicating that Asian ablation energies (less than about 90-120mJ), the stratum corneum is still present on the skin. 在活体内照射的皮肤略微变白,这可能是脱水或角质层从其下的组织上分离的证据。 Slightly whitened in vivo irradiation of the skin, which may be evidence of isolated stratum corneum of the tissue from dehydration or under.

实施例8量化角质层屏障功能的减少的一种方法是测量由于激光照射导致的皮肤阻抗的减少。 Example 8 A method for reducing quantization stratum corneum barrier function due to the reduction embodiment is to measure skin impedance caused by laser irradiation. 在这一试验中,用铒:YAG激光器的单脉冲照射能量对志愿者前臂手掌部分上分开的2mm点进行照射,该激光器使用能量域。 In this test, with the Er: YAG laser irradiation energy single pulse to separate the palm portion of the forearm of volunteers 2mm irradiating point, the use of laser energy regions. 然后在同一前臂的照射位点和20cm远处未照射的位点各放一个ECG电极。 Then put on an ECG electrode in the same forearm irradiation site and 20cm distant sites unirradiated. 然后用1伏特全幅值数量级的100Hz正弦波测量皮肤的阻抗。 Then 1 volt full magnitude 100Hz sine wave amplitude measurement of skin impedance. 一系列测量的结果列于图22,该图表明使用拟合后的曲线内插数据,象10mJ那么低的照射能量照射皮肤,皮肤的阻抗降低,。 Results of a series of measurements are shown in Figure 22, which shows that the use of the inner curve fitting is inserted after the data, as 10mJ so low irradiation energy exposure to the skin, the skin impedance decreases.

实施例9将人皮肤块放入渗滤池中,并用铒:YAG激光器产生的单脉冲照射能进行照射。 9 cases of human skin into the diffusion cells block the implementation and use Er: YAG laser produces a single pulse irradiation can be irradiated. 点的大小是2mm且脉冲能是用校准的电度表测量的。 The spot size is 2mm and the pulse can be measured with a calibrated meter. 照射后,将渗滤池放入37℃加热装置中。 After irradiation, the diffusion cell placed in 37 ℃ heating device. 将磷酸缓冲盐水加入皮下受体室,并将一根小搅拌棒插入受体室保持流体的持续混合。 The phosphate buffered saline was added subcutaneous receptors room, and a small stir bar inserted into the receptor chamber maintain continuous mixing of the fluid. 对照皮肤是未经照射的。 It is the non-irradiated control skin. 然后将小容量放射性标记的化合物(皮质酮或DNA)加入供体室并在移走前保留15分钟(对皮质酮而言)或在试验全过程中一直保留(对DNA而言)。 Then the small capacity radiolabeled compound (corticosterone or DNA) was added and the donor room 15 minutes before removing the reservations (for corticosterone) or the remains (for DNA) that at trial the whole process. 然后在使用了试验化合物后的不同时间,将样品从受体室中取出并用闪烁计数器或γ计数器测量。 Then at different times after the test compound, the samples were removed and measured with a scintillation counter or γ counter from the receptor chamber. 本试验的结果列于图21和26。 The results of this experiment are shown in Figures 21 and 26. 结果说明在亚消融激光脉冲能量下可发生渗透性增加(见皮质酮的77mJ/脉冲数据)。 The results described in the sub-ablation laser pulse energies increased permeability may occur (see corticosterone 77mJ / pulse data). 尽管在DNA试验中使用的能量可能是消融型的,但是当使用较低能量时仍能增加渗透性。 Although the energy used in the DNA tests may be melt type, but when using a lower energy still increase permeability.

实施例10对在体内或体外照射的老鼠和人皮肤进行的组织学研究表明,当使用的铒:YAG激光器脉冲能量小于100-200mJ,几乎没有或没有消融。 Histological study of 10 pairs of in vivo or in vitro exposure of mouse and human skin example shows that when using erbium: YAG laser pulse energy is less than 100-200mJ, little or no ablation. (见例如图25)。 (See for example Figure 25). 重复这一研究显示与前述研究相同的结果。 Repeat this study shows the same results with the previous study. 使用氚水(3H2O)的体外的渗透研究,对确定的(图23和24)50mJ(1.6J/cm2)到1250mJ(40J/cm2)的能量激光照射皮肤,可以看到比低至5J/cm2的渗透性增加,而这这种渗透性或多或少是不变的。 Permeation studies using tritiated water (3H2O) in vitro, and to determine (Fig. 23 and 24) 50mJ (1.6J / cm2) to 1250mJ (40J / cm2) of the energy of the laser irradiation the skin, you can see the ratio as low as 5J / cm2 increased permeability, which is more or less unchanged this permeability. 这表明当亚消融性的能量下,激光照射诱导渗透性增加(氚水)。 This means that when the next energy sub-ablative laser irradiation induced increased permeability (HTO).

实施例11铒:YAG激光器的输出激光穿过一个孔以限制其直径为2mm。 Example 11 Er: YAG laser output of a laser passes through an aperture to limit a diameter of 2mm. 将从皮肤库购买的人皮肤放在Franz渗滤池中。 Library purchased from the skin in Franz diffusion cells of human skin. 池的受体室中装入0.9%缓冲盐水。 Cell receptor compartment was charged with 0.9% buffered saline. 用标准能量的单脉冲照射不连续渗滤池中的皮肤。 Skin standard single pulse irradiation energy discontinuous diafiltration pool. 对照皮肤是未照射的。 Control skin is not illuminated. 当测验利多卡因的渗透性时,使用254mJ脉冲并照射多个样品。 When lidocaine penetration test using 254mJ pulse and multiple samples were irradiated. 在测验γ-干扰素的情况下,使用285mJ脉冲并照射多个样品。 In the case of test γ- interferon, the use of a plurality of samples irradiated with 285mJ pulses and. 在测验胰岛素的情况下,使用274mJ脉冲并照射多个样品。 In the case of insulin test, using 274mJ pulse and multiple samples were irradiated. 在测验可的松的情况下,使用77mJ或117mJ脉冲并照射多个样品。 In the case of test cortisone using 77mJ or 117mJ pulses and irradiate a plurality of samples. 在测验γ-干扰素的情况下,使用285mJ脉冲并照射多个样品。 In the case of test γ- interferon, the use of a plurality of samples irradiated with 285mJ pulses and. 照射后将一块搅拌磁石放入渗滤池的受体室中并将池放入加热装置中,保持温度为37℃。 After irradiation a stirring magnet into the diffusion cell receptor chamber and the cell into the heating device, maintained at a temperature of 37 ℃. 放射性标记的利多卡因、γ-干扰素和胰岛素用缓冲盐水稀释,将得到的100μl溶液倒入不连续的渗滤池的供体室中。 Radiolabeled lidocaine, γ- interferon and insulin diluted with buffered saline, 100μl solution was poured into a discontinuous diafiltration pool of donor chamber. 在试验过程中将供体留在皮肤上。 In the test process in the donor left on the skin. 在施药后的多次将样品从受体室中取出,并用γ-计数器或液体闪烁计数器测定所含药物的数量。 The samples were removed after application in a number from the recipient chamber and γ- counter or liquid scintillation counters measure the amount of contained drug. 得到的数据图表列于图39、40和41。 The data obtained are shown in chart 39, 40 and 41 in FIG. 从这些数据和相似的数据可导出渗透性常数并列于下文:药物渗透性常数,kp(10-3cm/hr) These data and similar data can be exported from the permeability constant listed in the following: drug permeability constant, kp ( 10-3cm / hr)

利多卡因 2.62+/-6.9γ-干扰素 9.74+/-2.05胰岛素 11.3+/-0.93实施例12在同样的试验中收集这一数据作为TEWL结果(见实施例2和图27)。 Lidocaine 2.62 +/- 6.9γ- interferon insulin 11.3 +/- 9.74 +/- 2.05 0.93 Example 12 to collect this data in the same test as the TEWL results (see Example 2 and Figure 27). 在漂白测定中,用Minolta CR-300氯量计(Minolta Inc.,NJ)测定每个点的原始皮肤色泽(红色)。 Bleaching assay to measure each point of the original skin color (red) with the Minolta CR-300 chlorine meter (Minolta Inc., NJ). 然后使用铒:YAG激光器在一只前臂上消融六个2mm点,使用能量为40、80和120mJ。 Then use the Erbium: YAG laser ablation of six points on a forearm 2mm, using the energy of 40, 80 and 120mJ. 与激光照射的点直接相邻的点(负量热器对照)保持不接触。 And the laser irradiation point directly adjacent to the point (negative calorimeter control) remain in contact. 随后将1%氢化可的松的薄膜涂布到处理臂上的六个照射点上。 The film is then coated with a 1% hydrocortisone to the processing arm of the six irradiation point. 对侧臂上一个未接触的点用一薄层Diprolene(β-methasone),这是一种强类固醇,可以足够引起可测的皮肤漂白的量渗透无损伤的角质层。 A pair of arms, the point is not in contact with a thin layer Diprolene (β-methasone), which is a potent steroid, may be sufficient to cause a detectable amount of penetration of skin bleaching intact stratum corneum. 将一块由简单的塑料包装组成的闭合片用纱布和皮肤带固定在双臂所有的位点上,并放置2小时,之后用棉签将施用的类固醇轻轻抹去。 A piece by a simple piece of plastic packaging consisting of a closed fixed with gauze and tape on the arms of all skin sites, and for two hours, followed by a cotton swab to gently wipe the steroid administered. 照射后2、4、8、10、12和26小时用量热计测量每个未照射和照射的点,结果列于图38。 2,4,8,10,12 and 26 hours the amount of heat measured at each point non-irradiated and irradiated after irradiation, the results are shown in Figure 38. 最后,对皮肤进行临床评估作为照射26小时后评估的根据。 Finally, the skin clinical assessment as a basis for 26 hours after exposure assessment.

量热计测量的结果表明出现一些皮肤红斑(变红),但由于漂白渗透的氢化可的松的相反作用,变红点要少于未接受氢化可的松处理的对照点所见的红斑。 Results calorimeter measurements show some skin erythema (reddening), but because of the opposite effect penetration of the bleaching hydrocortisone, red point to control point received no less than hydrocortisone treatment erythema seen. Diprolene对照证实了测量的有效性并且在26小时评估时志愿者无问题发生,尽管在一些情况下照射位置明显为一个小红点。 Diprolene control proved the validity of the measurement and assessment of the volunteers at 26 hours no problem, although in some cases irradiation position clear as a red dot.

实施例13将铒:YAG激光器的照射输出用光学器件聚焦并校准,从而在皮肤表面产生大小为例如5mm的点。 Example 13 Er: YAG laser irradiation output by the focusing optics and alignment, resulting in the skin surface, for example, point size of 5mm. 将患者的皮肤患病处或靠近患病处的位置肉眼检查有任何东西可能影响将要施用的药的药代动力学(例如,显著的红斑或角质层完整性大范围的丧失)。 The skin of the patient sick or diseased location close visual inspection at the pharmacokinetics of the drugs may affect anything to be administered (e.g., significant erythema or loss of integrity of the stratum corneum large range). 这一点,就是要照射的点,被轻轻地净化以去除所有的碎片和任何的外来的化合物例如香水或体油的组成。 This point is to be irradiated, the composition is purified to remove all debris and any foreign compounds such as perfume or body oil gently. 在照射前将一个连接在激光器上的一次性端头压在皮肤上,用来包含所有的消融生物碎片,以及包含所有由激光器发出的漂移的照射能。 Disposable tip in front of irradiating a laser attached to the pressure on the skin, is used to contain all of the ablated biological debris, as well as containing all emitted by laser irradiation can drift. 用950mJ的单个激光脉冲(约350μs长)照射这一点。 This irradiation with 950mJ single laser pulse (approximately 350μs long). 结果是角质层的屏障功能降低或消除。 The result is the stratum corneum barrier function is reduced or eliminated. 随后,将一定量的药品例如氢化可的松涂在照射点上。 Subsequently, the amount of drugs such as hydrocortisone coated on the irradiated point. 药物可以是膏状,这样就能保留在照射位点。 The drug may be a paste, so that we can remain in the irradiated site. 可选地,将一个闭塞片放在药品上以使它保留在照射点处。 Optionally, a closing piece on the drug so that it remains in the irradiated point.

实施例14通过使用由两个平谐振镜组成的固态脉冲Er:YAG晶体激光器、作为有效介质的Er:YAG晶体、电源供应、和一种会聚激光束的方法形成红外激光照射脉冲。 Example 14 by using a solid state pulse Er consisting of two flat resonator mirrors consisting of: YAG crystal lasers, as an effective medium of Er: YAG crystal, power supply, and a method of forming a convergent laser beam infrared laser pulses. 激光束的波长是2.94微米。 The wavelength of the laser beam is 2.94 m. 脉冲的宽度为约300μs。 The pulse width is about 300μs. 点的大小是约2mm,能量通量是5J/cm2。 The spot size of about 2mm, the energy flux is 5J / cm2. 使用单脉冲。 Use single pulse.

在松弛的阴茎上制造三个2mm直径的点。 Manufacturing three 2mm diameter spots on the relaxation of the penis. 消融后把前列地尔(alprostadil)(购于Pharmacia & Upjohn,Kalamazoo,MI)药物制剂涂到由薄纸组成的小片上。 After the ablation of the alprostadil (alprostadil) (available from Pharmacia & amp; Upjohn, Kalamazoo, MI) pharmaceutical formulations applied to the small piece of tissue paper composed. 然后将片用到在松弛阴茎的皮肤的多穿孔区域,用胶带固定45分钟。 The sheet is then used in a multi-perforated region flaccid penis skin, taped 45 minutes. 在约35分钟后,患者能够勃起,勃起维持1小时多。 In about 35 minutes later, the patient can erection, erection for 1 hour more.

这一给药途径的好处是不痛。 The benefits of the route of administration is not painful. 施用前列地尔的通常途径包括将化合物用皮下注射针注射深入海绵体中。 Usual route of administration of alprostadil include the compound with a hypodermic needle injection depth corpus cavernosum. 这一步骤不仅疼痛,而且也会导致利刃可能的传染性污染。 This step is not only pain, but also lead to the cutting edge of possible infectious contamination.

实施例15通过使用由两个平谐振镜组成的固态脉冲Er:YAG晶体激光器、作为有效介质的Er:YAG晶体、动力供应、和一种会聚激光束的方法形成红外激光照射脉冲。 Example 15 by using a solid state pulse Er consisting of two flat resonator mirrors consisting of: YAG crystal lasers, as an effective medium of Er: YAG crystal, power supply, and a method of forming a convergent laser beam infrared laser pulses. 激光束的波长优选是2.94微米。 The wavelength of the laser beam is preferably 2.94 microns. 脉冲的宽度优选为约300μs。 The pulse width is preferably about 300μs. 点的大小优选是约2mm,用约150mJ的脉冲能量产生约5J/cm2的能量通量。 The spot size is preferably about 2mm, with a pulse energy of about 150mJ produces about 5J / cm2 energy flux.

从TRANSMEDICATMEr:YAG发出的单脉冲的照射能量,按上述参数操作,优选用来照射在显示出头发脱落的头皮2mm直径的点。 From TRANSMEDICATMEr: single pulse irradiation energy emitted YAG, operating according to the above parameters, it is preferable to irradiate at showing some hair loss on the scalp 2mm diameter. 可以使用多照射点,在照射后,可以在头皮接近空隙的地方涂上米诺地尔(minoxidil)(例如购自Pharmacia & Upjohn,Kalamazoo,MI的Rogaine),使得药物刺激毛囊比只是跨皮吸收的量更大。 You can use the multi-point irradiation, after irradiation, can close the gap on the scalp where applying minoxidil (minoxidil) (such as those available from Pharmacia & amp; Upjohn, Kalamazoo, MI's Rogaine), so that the drug across the skin to stimulate hair follicles than just a greater amount of absorption. 作为选择,在消融后,可以通过激光器消融位点施用雄性激素抑制剂。 Alternatively, after ablation, androgen inhibitors may be administered by laser ablation site. 这些雄性抑制剂能起到抵消雄性激素对头发脱落处的影响。 These inhibitors can play to offset the impact of male hormones on the male hair loss at.

实施例16皮肤表面重修获得广泛的应用,并是一个通常要求的化妆步骤,其中用激光器产生的照射能通过消融约400微米的皮肤上去掉(一般是这样)患者脸上的皱纹(Dover JS,Hruza GJ,“激光皮肤重修”,Simen,Cutan,Med.Surg.,15(3):177-88,1996)。 Example rebuilt skin surface 16 is widely used, and is a make-up steps normally required, which is irradiated by a laser ablation to remove generated (usually the case) in patients with wrinkles (Dover JS skin on about 400 microns, Hruza GJ, "laser skin rebuilt", Simen, Cutan, Med.Surg, 15 (3):. 177-88,1996). 处理后通常向照射区域涂上一层由水凝胶制成的“掩膜”,以提供冰凉感,并防止处理皮肤不期望的干燥和体液的“渗漏”。 After the treatment is generally coated with a layer of the irradiated region from a hydrogel made of "mask" to provide cold feeling, and to prevent undesirable drying treatment of the skin and body fluids. "Leak."

如果不使用局部或全身麻醉剂,这一步骤产生的疼痛将是令人无法忍受的。 If you do not use local or general anesthetic, the pain generated by this step would be intolerable. 一般地,在照射皮肤前完成多重(约到30)局部注射利多卡因。 In general, perform multiple skin prior to irradiation (about 30) local injection of lidocaine. 这些注射自身花大量的时间作用,而且它们自身也是相对引起疼痛的。 These injections of their own to spend a lot of time to effect, and they are themselves relatively pain caused.

在皮肤表面重修前优选使用从TRANSMEDIATMEr:YAG激光器发出的单脉冲照射能照射要求多施用利多卡因的脸部上2mm直径的点。 Skin resurfacing before preferred to use from TRANSMEDIATMEr: single pulse irradiation energy emitted from a YAG laser irradiation requires more applied point of lidocaine face 2mm diameter. 在每个激光脉冲使用的能量优选是150mJ。 In the use of the energy of each laser pulse is preferably 150mJ. 照射后,使用利多卡因作全身麻醉剂。 After irradiation, the use of lidocaine as a general anesthetic. 进而,通过把利多卡因(优选地是利多卡因—盐酸亲水型)结合到水溶胶或其它片或胶保存方法中,并在激光照射前把这些复合物(以“面膜”的物理形式)涂到到患者的脸上,而后用Er:YAG激光器消融处理部位矩阵点的角质层,对这一能无痛进行的步骤能产生充分的麻醉。 Furthermore, by lidocaine (preferably lidocaine - hydrochloride hydrophilic) binding to water sol or other sheet or plastic storage method and, before the laser irradiation of these complexes (the "Mask" physical form ) applied to the patient's face, and then use the Er: YAG laser ablation treatment site matrix point cuticle, this step can be a pain to produce adequate anesthesia. 将止痛剂结合在水溶胶中进而为担心医疗步骤的患者准备也是有利的。 The analgesic in aqueous sol and then to worry about preparing patient medical procedure is also advantageous. 可选地,能将“面膜”分割成几个麻醉单元适于对脸上的特殊激光处理区域单独应用。 Alternatively, can "mask" is divided into several anesthesia unit adapted to special laser processing region face alone. 最后,另一个结合有用药物的“面膜”,例如抗生素(例如杆菌肽、Neosporin、Polysporin和Sulphadene)或长期局部或全身止痛剂,例如芬太尼(fentanyl)或demeral,能在皮肤表面重修后涂到患者身上。 Finally, another combination of useful drugs "mask", such as antibiotics (e.g. Bacitracin, Neosporin, Polysporin, and Sulphadene) or long term topical or systemic analgesics, such as fentanyl (fentanyl) or demeral, can be applied to the skin resurfacing to the patient.

实施例17在鼻孔中毛发的生长是一个常见的化装问题。 Example 17 nostril hair growth is a common problem in disguise. 目前的治疗方法,是将毛发用镊子拔出,疼痛而且不持久。 Current treatments, is to pull out hair with tweezers, but not lasting pain. 通过使用由两个平谐振镜组成的固态脉冲Er:YAG晶体激光器、作为有效介质的Er:YAG晶体、电源供应、和一种会聚激光束的方法形成红外激光照射脉冲。 By using a solid state pulse Er consisting of two flat resonator mirrors consisting of: YAG crystal lasers, as an effective medium of Er: YAG crystal, power supply, and a method of forming a convergent laser beam infrared laser pulses. 激光束的波长优选是2.94微米。 The wavelength of the laser beam is preferably 2.94 microns. 脉冲的宽度优选为约300μs。 The pulse width is preferably about 300μs. 点的大小优选是约2mm,用约150mJ的脉冲能量产生约5J/cm2的能量通量。 The spot size is preferably about 2mm, with a pulse energy of about 150mJ produces about 5J / cm2 energy flux.

优选使用从TRANSMEDICATMEr:YAG发出的单脉冲的照射能量,按上述参数操作,在显示出化装不美观的毛发生长的鼻粘膜上2mm直径的点照射。 Preferred to use from TRANSMEDICATMEr: single pulse irradiation energy emitted YAG, operating according to the above parameters, the show 2mm diameter spot irradiation disguise unsightly hair growth on the nasal mucosa. 可以使用多照射点。 You can use multiple irradiation points. 照射自身足够改变组织从而抑制随后的毛发生长,因而照射自身足够改变组织从而抑制随后的毛发生长。 Irradiating tissue itself sufficient to inhibit subsequent change hair growth, thus irradiating tissue itself sufficient to inhibit subsequent change of hair growth. 作为选择,在照射后,可以涂上一种染料,例如靛氰绿,它能吸收照射的不同波长。 Alternatively, after the irradiation, it can be coated with a dye, for example indocyanine green, it can absorb different wavelengths of radiation. 在染料被鼻孔吸收后,可以使用从二极管激光器(GaAlAs激光器)发出的810nm的照射能量升高周围组织的温度。 After the dye is absorbed by the nose, you can use the radiation energy emitted from 810nm diode laser (GaAlAs laser) raising the temperature of the surrounding tissue. 这能起到选择性破坏与染料接触的毛囊的作用。 It can play a role in the selective destruction of hair follicles in contact with the dye. 结果鼻组织就被改变不再生出毛发,或至少不象手工去除毛发那样重生得那么快。 Results nasal tissue was no longer give birth to change hair, or at least not like that kind of rebirth manually removing hair so fast.

在示出和描述本发明的多种应用时,对本领域技术人员而言很明显所述技术的许多改变也是可能的,而不偏离本文的发明概念。 In the illustrated and described in various applications of the invention, the person skilled in the art that many changes in terms of the technology is obviously possible without departing from the inventive concepts herein.

International ClassificationA61B17/00, A61M37/00, A61B18/20, A61B18/00, A61B10/00, A61B19/00, A61N5/06, A61B17/34, A61B5/145
Cooperative ClassificationA61B2090/395, A61M2037/0007, A61B5/150022, A61B2218/008, A61B18/20, A61B2017/00765, A61B5/411, A61M37/00, A61B18/203, A61B5/150099, A61B2017/00057, A61B5/150076, A61B5/15138, A61B2010/008, A61B2018/00452, A61B17/3476, H04R25/75
European ClassificationA61B5/41B, H04R25/75, A61B18/20H, A61M37/00, A61B18/20
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