TW202444316A - Device and method for dilation of a tubular anatomical structure - Google Patents

Abstract

Described is a method and device for dilating a tubular anatomical structure. The device and method can be useful for extracting a blood clot in an artery of a mammal by concentrically irradiating an inner wall of the occluded artery using an ultraviolet (UV) laser beam delivered by an optical fiber. Dilation results from photophysical production and release of nitric oxide from the cells lining the arterial wall when UV laser light is projected as a ring beam onto the inner arterial wall.

Description

Translated fromChinese

用於擴張管狀解剖結構的裝置和方法Devices and methods for dilating tubular anatomical structures

本發明涉及管狀解剖結構（例如管道或小管、動脈、細支氣管、輸尿管、脈管等）的擴張，使用紫外線（UV）雷射光来光物理地刺激一氧化氮從管狀解剖結構上內襯的平滑肌細胞中釋放，導致結構的鬆弛（徑向擴展）。更具體地，本發明涉及一種具有錐形尖端的光導纖維，用於將UV光的環形射束引導向管狀解剖結構的內表面。The present invention relates to dilation of tubular anatomical structures (e.g., ducts or tubules, arteries, bronchioles, ureters, veins, etc.) using ultraviolet (UV) laser light to photophysically stimulate the release of nitric oxide from smooth muscle cells lining the tubular anatomical structure, resulting in relaxation (radial dilation) of the structure. More specifically, the present invention relates to a light-guiding fiber having a tapered tip for directing an annular beam of UV light toward the inner surface of a tubular anatomical structure.

目前有四種方法用於治療閉塞性疾病。這四種方法包括： （1）使用高強度脈衝雷射藉由燒蝕或光聲衝擊（也使用直接超音波）來破壞血栓或栓子； （2）導管插入術、血管成形術和支架置入術，以物理地擴大動脈粥樣硬化導致收縮的血管腔； （3）施用溶栓劑或去血栓劑以化學解離血栓，通常隨後施用血小板抑制劑（也稱為抗血小板劑）以防止再形成血栓；和 （4）血栓切除術，其中藉由機械提取來去除閉塞性血栓，從而恢復血流。There are four approaches currently used to treat occlusive disease. These include:(1) the use of high-intensity pulsed lasers to disrupt thrombi or emboli by ablation or photoacoustic shock (direct ultrasound is also used);(2) catheterization, angioplasty, and stenting to physically dilate the lumen of vessels that have been constricted by atherosclerosis;(3) the administration of thrombolytic or thrombolytic agents to chemically dissociate the clot, usually followed by the administration of platelet inhibitors (also called antiplatelet agents) to prevent rethrombosis; and(4) thrombectomy, in which the occlusive clot is removed by mechanical extraction, thereby restoring blood flow.

這些目前可用的方法中的每一種都與對血管壁的潛在有害影響有關。例如，內皮損傷目前在血栓切除術中是不可避免的，並且在某些情況下療效差或恢復品質可疑。Each of these currently available methods is associated with potentially deleterious effects on the vessel wall. For example, endothelial injury is currently unavoidable during thrombectomy and in some cases results in poor efficacy or questionable recovery quality.

現在有兩種方法被認為對於在專門的臨床環境中去除血管障礙物是足夠有用的： （1）抽吸，其中在凝塊近端施加負壓，以及 （2）藉由支架取回器提取，其中擴展絲的網狀網絡被部署到凝塊中，導致當取回器被抽出時凝塊直接整合到網內，從而去除凝塊。Two approaches are currently considered sufficiently useful for removing vascular obstructions in a specialized clinical setting: (1) aspiration, in which negative pressure is applied proximal to the clot, and (2) retrieval by stent retriever, in which a mesh network of expanded wires is deployed into the clot, resulting in direct integration of the clot into the mesh when the retriever is withdrawn, thereby removing the clot.

抽吸法或支架取回器法都可能以不同但獨特的方式損傷動脈內皮層和動脈壁層，這預示著對動脈結構和功能來說未來的負面影響。在這一點上，主要的焦點是藉由這些機械手段快速去除凝塊，很少考慮局部或外周損傷，特別是對通常抗血栓內皮的損傷。對這些方法的所有改進都嚴格限於抽吸效率的機械改進，或支架取回器與凝塊的可整合性，以努力藉由裝置的一次應用（通過）來去除整個凝塊。儘管最近血栓切除術在去除動脈閉塞方面取得了明顯的成功，但目前的這些手術並不完善。在凝塊提取過程中，機械摩擦可以損傷動脈內皮。血管破裂是任何一種目前使用的介入手術（例如抽吸導管或支架取回器）的已知風險，並且在導管插入過程中（尤其是在進入分支動脈入口時），動脈壁穿孔可能發生。此外，目前血栓切除術手術後的患者恢復不是最佳的，尤其是在行為上。大約50%的患者展現出殘餘損傷的跡象，但這只在最近才成為關注的領域，因為從業者的主要焦點是凝塊提取的技術細節。在這種情況下，如果提取效率低下（需要多達五次通過，因此與血管壁有多得多的機械相互作用），則恢復就會受到影響。Either aspiration or stent retriever approaches may damage the arterial endothelium and arterial wall in different but unique ways, portending future negative effects on arterial structure and function. To this point, the primary focus has been on rapid clot removal by these mechanical means, with little consideration of local or peripheral injury, particularly to the normally thrombus-resistant endothelium. All refinements to these approaches have been strictly limited to mechanical improvements in aspiration efficiency or the integration of the stent retriever with the clot in an effort to remove the entire clot with a single application (pass) of the device. Despite the recent apparent success of thrombectomy in removing arterial occlusions, these current procedures are imperfect. During clot extraction, mechanical friction can damage the arterial endothelium. Vessel rupture is a known risk of any of the currently used interventional procedures (e.g., aspiration catheters or stent retrievers), and arterial wall perforation can occur during catheter insertion (especially when accessing branch arteries). In addition, patient recovery after current thrombectomy procedures is suboptimal, especially behaviorally. Approximately 50% of patients show signs of residual damage, but this has only recently become an area of concern because the main focus of practitioners has been on the technical details of clot extraction. In this case, recovery is compromised if the extraction is inefficient (requiring up to five passes and therefore many more mechanical interactions with the vessel wall).

已經提出了解決由先前已知的手術導致的損傷和風險問題的方法。例如，第6,539,944號美國專利描述了在有或沒有額外藥劑的情況下使用紫外線（UV）雷射光溶解動脈中的閉塞性血栓。換句話說，UV雷射光本身藉由其光物理產生凝血酶抑制劑一氧化氮（NO·）來促進血栓的溶解，一氧化氮是一種自由基，當從動脈壁中受照射的平滑肌細胞分泌時，使相鄰的血小板聚集體不穩定，成為單個血小板。本專利藉由引用以其整體併入本文。Methods have been proposed to address the problems of injury and risk caused by previously known surgeries. For example, U.S. Patent No. 6,539,944 describes the use of ultraviolet (UV) laser light with or without additional agents to dissolve occlusive clots in arteries. In other words, the UV laser light itself promotes the dissolution of clots by its photophysical generation of the thrombin inhibitor nitric oxide (NO·), which is a free radical that, when secreted from irradiated smooth muscle cells in the arterial wall, destabilizes adjacent platelet aggregates into single platelets. This patent is incorporated herein by reference in its entirety.

本領域需要的是一種裝置和方法，用於在治療患者期間擴張包含平滑肌細胞的管狀解剖結構，同時減輕和盡可能減少對解剖結構的損傷，並降低在進行醫療手術時對患者造成後果傷害的風險。根據本發明，這可以用擴張系統來完成。較佳地，本發明的系統可以盡可能減少系統的機械裝置和正被擴張的解剖結構之間的接觸，從而提供最小接觸擴張系統。例如，當藉由這樣的系統進行準備時，使用抽吸導管、支架取回器或其他機械血栓提取器的血栓切除術可以更容易地實現，並且內皮損傷更小，其中UV雷射光（而不是機械壓力）直接誘導閉塞的動脈擴張。以這種方式為隨後部署的血栓切除術裝置準備動脈，有助於減少摩擦和化學結合，從而減少在凝塊抽出之前、期間和之後對動脈壁的機械損傷。What is needed in the art is a device and method for dilating tubular anatomical structures containing smooth muscle cells during treatment of a patient while reducing and minimizing damage to the anatomical structure and reducing the risk of consequential injury to the patient when performing a medical procedure. In accordance with the present invention, this can be accomplished using a dilation system. Preferably, the system of the present invention can minimize contact between the mechanical device of the system and the anatomical structure being dilated, thereby providing a minimal contact dilation system. For example, thrombectomy using an aspiration catheter, stent retriever, or other mechanical clot extractor can be accomplished more easily and with less endothelial damage when primed by such a system, where UV laser light (rather than mechanical pressure) directly induces dilation of the occluded artery. Preparing the artery in this manner for a subsequently deployed thrombectomy device helps reduce friction and chemical bonding, thereby reducing mechanical damage to the arterial wall before, during, and after clot extraction.

本主題發明特別適用於使用能夠以環形雷射束的形式向動脈壁輸送UV光的光導纖維來擴張動脈，以逆轉與出血性中風一致的血管痙攣，或促進從脈管系統中去除血凝塊（血栓）。一種使用錐形尖端光導纖維產生環形形狀並將雷射束傳遞到管狀解剖結構內壁來擴張管狀解剖結構的方法也是本發明的一部分。The subject invention is particularly useful for dilating arteries using a fiber optic that delivers UV light in the form of an annular laser beam to the arterial wall to reverse vasospasm consistent with hemorrhagic stroke or to facilitate the removal of blood clots (thrombi) from the vascular system. A method of dilating a tubular anatomical structure using a tapered tip fiber optic to create an annular shape and deliver a laser beam to the inner wall of the tubular anatomical structure is also part of the invention.

該裝置和方法可以特別適用於對部分或完全閉塞的動脈進行的血栓切除術手術，特別適用於治療中風、心肌梗塞和其他血管閉塞性疾病（特別是在大腦脈管系統內形成的血栓）。它也可用於溶解已知發生在出血性中風中作為“早期腦損傷”表現的遠端微血管血栓。The device and method may be particularly useful for thrombectomy procedures on partially or completely occluded arteries, particularly for the treatment of stroke, myocardial infarction, and other vascular occlusive diseases (particularly thrombi formed within the cerebral vascular system). It may also be used to dissolve distal microvascular thrombi known to occur in hemorrhagic stroke as a manifestation of "early brain damage."

因此，本主題發明包括用於攜帶UV雷射光的鎔融二氧化矽光導纖維，其中，該光導纖維具有遠端，其中該遠端被配置為內翻錐體（即負錐透鏡）或外翻錐體，兩者都能夠發射作為錐形射束的UV雷射光。發射的UV雷射光的錐形射束撞擊在環狀或環形配置的管狀解剖結構的內壁上。Thus, the subject invention includes a fused silica optical fiber for carrying UV laser light, wherein the optical fiber has a distal end, wherein the distal end is configured as an inverted cone (i.e., a negative cone lens) or an outverted cone, both of which are capable of emitting UV laser light as a cone-shaped beam. The emitted cone-shaped beam of UV laser light impinges on the inner wall of a tubular anatomical structure in a ring-shaped or annular configuration.

光導纖維的錐形遠端可以設置為與光導纖維分離的尖端，即本身不是光導纖維的一部分，但是光學耦合（並且較佳地物理耦合）到光導纖維的遠端，並且與光導纖維的遠端的邊界連接，使得尖端與光導纖維光通信。較佳地，尖端被配置為具有形成為外翻錐體的遠端，該外翻錐體能夠發射作為錐形射束的UV雷射光。The tapered distal end of the optical fiber may be provided as a tip that is separate from the optical fiber, i.e., is not itself a part of the optical fiber, but is optically coupled (and preferably physically coupled) to the distal end of the optical fiber and is connected to a boundary of the distal end of the optical fiber so that the tip is in optical communication with the optical fiber. Preferably, the tip is configured to have a distal end formed as an everted cone that is capable of emitting UV laser light as a cone-shaped beam.

較佳地，本發明的光導纖維或與其耦合的尖端可以包括在其遠端的金剛石，以最佳化錐形射束的發射，例如，射束的尺寸、形狀、發射角度或強度可以藉由使用作為尖端的材料的金剛石或類金剛石材料（例如氧化鋯）來改變甚至改善。可替代地，尖端可以包括紫外線透明的聚合體材料，例如具有高折射率的特種塑膠。Preferably, the optical fiber of the present invention or the tip coupled thereto may include diamond at its distal end to optimize the emission of the pyramidal beam, for example, the size, shape, emission angle or intensity of the beam may be changed or even improved by using diamond or diamond-like materials (e.g., zirconium oxide) as the material of the tip. Alternatively, the tip may include a UV-transparent polymer material, such as a special plastic with a high refractive index.

本發明的光導纖維尖端的較佳實施例是內翻錐體（例如負軸錐）的形狀，能夠以從光導纖維的中心縱軸開始高達56°的發射角β向水中發射環形射束。外翻的錐形尖端可以以高達71.5°的角度β發射光。這些角度必然是近似的，因為雷射束的自然角散佈（spread）可能超過全內反射的臨界角，從而降低射束功率的某些部分。A preferred embodiment of the optical fiber tip of the present invention is in the shape of an inverted cone (e.g., a negative axis cone) capable of emitting an annular beam into water at an emission angle β of up to 56° from the central longitudinal axis of the optical fiber. An outward-turned cone tip can emit light at an angle β of up to 71.5°. These angles are necessarily approximate because the natural angular spread of the laser beam may exceed the critical angle for total internal reflection, thereby reducing some portion of the beam power.

斯涅耳定律允許的角度越大，則環形射束在所照射的表面上的投影越薄，雷射強度相應增加。較佳地，內翻錐形尖端能夠以從光導纖維的中心縱軸開始20°至56°的發射角β範圍向水中發射環形“環”射束；對於外錐體，發射角度範圍的極限是71.5°。利用該發射角度，本發明的光導纖維或尖端能夠將最大允許強度的環形射束髮射到管狀解剖結構的內壁上。The larger the angle allowed by Snell's law, the thinner the projection of the annular beam on the irradiated surface, and the corresponding increase in laser intensity. Preferably, the inverted cone tip is capable of emitting an annular "ring" beam into the water at an emission angle β ranging from 20° to 56° from the central longitudinal axis of the optical fiber; for the outer cone, the limit of the emission angle range is 71.5°. With this emission angle, the optical fiber or tip of the present invention is capable of emitting an annular beam of maximum allowed intensity onto the inner wall of a tubular anatomical structure.

本發明還涉及一種擴張系統，該擴張系統包括血管切除術導管，該血管切除術導管被修改為採用用於攜帶UV雷射光的光導纖維的系統，該光導纖維具有遠端或在其遠端包括尖端，其中光導纖維或尖端被構造成錐形，用於將UV雷射光作為具有錐形軌跡的射束髮射。本發明的包括光導纖維的擴張系統可以具有配置為內翻（向內凸出）錐體或向外突出錐體的光導纖維的遠端或尖端。本發明的包括光導纖維的擴張系統可以與抽吸血栓切除術導管或支架取回器結合使用。較佳地，本發明的擴張系統盡可能減小與擴張的解剖結構的物理接觸，但是仍然允許UV雷射光撞擊到該結構上。因為撞擊和由此產生的擴展可以是持續的（＞1天），所以本發明的較佳實施例被稱為“最小接觸持續擴張系統”。因此，該系統的較佳實施例包括“最小接觸持續擴張系統”。The present invention also relates to a dilation system including a vascular resection catheter modified to employ a system employing a fiberoptic light guide for carrying UV laser light, the fiberoptic light guide having a distal end or including a tip at its distal end, wherein the fiberoptic light guide or tip is configured to be tapered for emitting the UV laser light as a beam having a tapered trajectory. The fiberoptic light guide-included dilation system of the present invention may have a distal end or tip of the fiberoptic light guide configured as an inverted (inwardly bulging) cone or an outwardly bulging cone. The fiberoptic light guide-included dilation system of the present invention may be used in conjunction with an aspiration thrombectomy catheter or a stent retriever. Preferably, the dilation system of the present invention minimizes physical contact with the anatomical structure being dilated, but still allows the UV laser light to impinge on the structure. Because the impingement and resulting dilation can be continuous (>1 day), preferred embodiments of the present invention are referred to as "minimal contact continuous dilation systems." Accordingly, preferred embodiments of the system include "minimal contact continuous dilation systems."

在使用中，本發明的擴張系統可以用於擴張患者體內管狀解剖結構的方法。根據本主題發明的方法包括以下步驟： - 提供容納用UV透明釓基造影劑擴展的UV透明球囊的導管，在UV透明球囊中插入用於攜帶UV雷射光的光導纖維，其中光導纖維具有遠端或尖端，該遠端或尖端具有錐形構造；以及 - 通過球囊（其被釓造影劑擴展，以與管狀解剖結構的內壁的邊界連接）發射UV雷射光能，作為到達管狀解剖結構的內壁中的平滑肌細胞上的強度一致的環形射束。這將刺激從動脈平滑肌細胞中的亞硝酸鹽（NO₂^-）儲備中光物理產生和釋放一氧化氮（NO·），由此一氧化氮引起平滑肌細胞的鬆弛和管狀解剖結構的擴張。即使內皮被破壞也能實現擴張；藉由UV光曝光光物理產生的NO·在功能上複製了通常由內皮酶一氧化氮合酶產生的NO·。In use, the dilation system of the present invention can be used in a method for dilating a tubular anatomical structure in a patient. The method according to the subject invention includes the following steps: - providing a catheter containing a UV transparent balloon expanded with a UV transparent gadolinium-based contrast agent, inserting a light-conducting fiber for carrying UV laser light in the UV transparent balloon, wherein the light-conducting fiber has a distal end or tip having a conical configuration; and - emitting UV laser light energy through the balloon (which is expanded by the gadolinium contrast agent to connect with the boundary of the inner wall of the tubular anatomical structure) as a uniformly intense annular beam that reaches smooth muscle cells in the inner wall of the tubular anatomical structure. This stimulates the photophysical generation and release of nitric oxide (NO·) from nitrite (NO₂^- ) stores in arterial smooth muscle cells, whereby NO· causes relaxation of the smooth muscle cells and dilation of tubular anatomical structures. Dilation is achieved even if the endothelium is damaged; the NO· photophysical generation by UV light exposure functionally replicates the NO· normally generated by the endothelial enzyme nitric oxide synthase.

該方法可適用於或應用於血管內血栓切除術手術，還包括以下步驟： - 將UV光導纖維擴張系統定位在包含凝塊的動脈內距離凝塊約1-10倍血管直徑內； - 採用UV透明釓造影劑將UV透明球囊導管擴展至動脈內壁，足以停止血流，而不是藉由機械壓力擴張動脈； - 發射作為雷射束的UV光能爆發穿過採用釓擴展的球囊壁，到達動脈壁中的平滑肌細胞上，以刺激從平滑肌細胞中的亞硝酸鹽（NO₂^-）儲備中產生NO·，由此刺激並可以觀察到動脈的主動擴張；以及 - 機械地（例如，通過血栓切除術）去除凝塊，從而恢復動脈主幹及其分支的循環（再循環）。The method may be applicable or applied to an endovascular thrombectomy procedure and further comprises the following steps: - positioning a UV light-guided fiber dilation system within an artery containing a clot within about 1-10 vessel diameters of the clot; - dilating a UV transparent balloon catheter with a UV transparent gadolinium contrast agent to the inner wall of the artery sufficient to stop blood flow, rather than dilating the artery by mechanical pressure; - emitting bursts of UV light energy as laser beams through the wall of the balloon dilated with gadolinium to smooth muscle cells in the artery wall to stimulate the production of NO· from nitrite (NO₂^- ) stores in the smooth muscle cells, thereby stimulating and observable active dilation of the artery; and - Removing the clot mechanically (for example, by thrombectomy) thereby restoring circulation to the main artery and its branches (recirculation).

首先將UV透明球囊導管部署到管狀結構中，以使插入的光導纖維的錐形尖端居中，從而確保圍繞該結構的圓周的均勻照射強度。可以用UV透明釓造影劑將球囊擴展到管狀結構的內徑，以確保x射線檢查時的可視性。然後，UV照射穿過球囊流體進行，並進入壁內。A UV-transparent balloon catheter is first deployed into the tubular structure so that the tapered tip of the inserted light-guiding fiber is centered, thereby ensuring uniform irradiation intensity around the circumference of the structure. The balloon can be expanded to the inner diameter of the tubular structure with a UV-transparent gadolinium contrast agent to ensure visualization during x-ray examination. UV irradiation is then delivered through the balloon fluid and into the wall.

本發明的方法較佳藉由在離凝塊約1倍和約4倍血管直徑內將UV光引導到血管壁上來實施。該方法可以使用連續UV光發射來執行，或以脈衝寬度大於40奈秒的高頻（5-25 kHz）聲光調Q（脈衝）的UV光發射（由於雙光子吸收的最小化，以確保藉由二氧化矽光導纖維的傳輸）來執行，或作為具有皮秒脈衝寬度（例如，以100 MHz脈衝，脈衝寬度大於10皮秒）的準連續射束來執行，或作為持續至少2秒、至多15秒的方波來執行。在較佳實施例中，UV光以約180-400 nm的波長發射，更佳為以約300-400 nm的波長發射。一個較佳的實施例使用三倍頻的Nd:YAG雷射器發射UV光，該雷射器發射355nm的光（接近NO·釋放物質（例如S-亞硝基硫醇）的吸收最大值）。UV光的較佳入射強度在每平方釐米約3瓦特至約20瓦特之間。The method of the present invention is preferably implemented by directing UV light onto the vessel wall within about 1 and about 4 vessel diameters from the clot. The method can be performed using continuous UV light emission, or high frequency (5-25 kHz) acousto-optically Q-switched (pulsed) UV light emission with a pulse width greater than 40 nanoseconds (to ensure transmission through silicon dioxide photoconductive fibers due to minimization of two-photon absorption), or as a quasi-continuous beam with a picosecond pulse width (e.g., with a 100 MHz pulse, a pulse width greater than 10 picoseconds), or as a square wave lasting at least 2 seconds and at most 15 seconds. In a preferred embodiment, the UV light is emitted at a wavelength of about 180-400 nm, more preferably at a wavelength of about 300-400 nm. A preferred embodiment uses a frequency-tripled Nd:YAG laser to emit UV light, which emits light at 355 nm (near the absorption maximum of NO·-releasing substances such as S-nitrosothiol). The preferred incident intensity of the UV light is between about 3 watts and about 20 watts per square centimeter.

根據本文描述的方法，應當理解，在血栓切除術手術中使用的血管切除術導管可以是抽吸導管或通過其插入支架取回器的導管。In accordance with the methods described herein, it will be understood that the vascular resection catheter used in the thrombectomy procedure can be an aspiration catheter or a catheter through which a stent retriever is inserted.

本發明的目的是提供切入性或破壞性較小的方法，用於藉由非機械地打開用於切入性介入裝置以及用於抽出的血栓通過其排出的較大直徑路徑，從哺乳動物的動脈中提取血栓。本發明的這個目的和其他目的由本文描述的一個或更多個實施例提供。It is an object of the present invention to provide a less invasive or disruptive method for extracting thrombus from a mammalian artery by non-mechanically opening a larger diameter path for invasive interventional devices and for the extracted thrombus to be discharged therethrough. This object and other objects of the present invention are provided by one or more embodiments described herein.

本發明的目的是藉由降低對閉塞性凝塊的機械提取的摩擦或化學結合阻力來最佳化血栓切除術期間和之後的動脈完整性。本發明的裝置和方法包括當執行血栓提取技術時，當採用抽吸導管時，對凝塊近端的動脈內壁提供適當強度的UV雷射照射，或者當採用支架取回器時，對凝塊遠端的動脈內壁提供適當強度的UV雷射照射（儘管對遠端和近端都進行照射可能是有利的）。由其軸線與動脈共線的環狀射束進行的UV雷射照射誘導動脈壁在幾秒鐘內明顯擴張，其中擴張效應將向近端和遠端傳播，以削弱或釋放凝塊與壁的摩擦和/或化學結合。The present invention is directed to optimizing arterial integrity during and after thrombectomy by reducing frictional or chemical bonding resistance to mechanical extraction of occlusive clots. The apparatus and methods of the present invention include providing appropriate intensity UV laser irradiation to the inner wall of the artery proximal to the clot when an aspiration catheter is employed, or distal to the clot when a stent retriever is employed (although irradiation of both distal and proximal ends may be advantageous) when performing a thrombus extraction technique. UV laser irradiation by an annular beam whose axis is co-linear with the artery induces a marked dilation of the arterial wall within seconds, where the dilation propagates proximally and distally to weaken or release friction and/or chemical bonding of the clot to the wall.

本發明的另一個目的是提供抽吸導管或支架取回器，其還包括能夠將UV光攜帶到導管的遠端或尖端的光導纖維，其中，可以以短時間（例如在鹽水沖洗或球囊導管擴張期間的2-15秒）發射UV光，以從血管壁中清除血液（但不是機械擴張動脈），並因此將UV光引導到包括血管壁的平滑肌細胞。 一個具體實施例是通過血管內部署的光導纖維引入雷射束，該光導纖維包括凸出的（外部）錐形尖端，該錐形尖端藉由一次反射和一次折射實際上可以用作射束的發散透鏡（實際上是負軸錐）。這種設計將產生作為擴展的錐形環的圓周照射圖案，在射束被引導到的管狀解剖結構的壁上產生雷射光的環形射束。凸出的錐形輸出尖端較佳使用折射率（n）高於鎔融二氧化矽的UV透明材料製成，例如金剛石、氧化鋯或n＞2的定制聚合體材料（其可以光學耦合到二氧化矽）。隨著出射角β的增加，動脈擴張的射束強度和效率也隨著沿著動脈壁投射的射束寬度的減小（因為照射的環狀區域也減小）而增加。如果滿足強度標準，沿著動脈壁的任何投影長度都將引起擴張，但是較大的射束出射角有助於更大的強度，從而更高效地使用射束。Another object of the present invention is to provide an aspiration catheter or stent retriever further comprising a light-conducting fiber capable of carrying UV light to the distal end or tip of the catheter, wherein the UV light can be emitted for a short time (e.g., 2-15 seconds during saline flushing or balloon catheter dilation) to remove blood from the vessel wall (but not mechanically dilate the artery) and thereby direct the UV light to the smooth muscle cells comprising the vessel wall. A specific embodiment is to introduce the laser beam through a light-conducting fiber deployed within the blood vessel, the light-conducting fiber comprising a convex (external) conical tip that can actually act as a diverging lens for the beam (actually a negative axis cone) by primary reflection and primary refraction. This design will produce a circumferential illumination pattern as an expanding conical ring, producing an annular beam of laser light on the wall of the tubular anatomical structure into which the beam is directed. The convex conical output tip is preferably made of a UV transparent material with a refractive index (n) higher than fused silica, such as diamond, zirconia, or a custom polymer material with n>2 (which can be optically coupled to silica). As the exit angle β increases, the beam intensity and efficiency of arterial dilation also increases as the beam width projected along the arterial wall decreases (because the annular area illuminated is also reduced). Any projection length along the arterial wall will cause dilation if intensity criteria are met, but larger beam exit angles facilitate greater intensity, resulting in more efficient use of the beam.

動脈周圍的UV環形射束強度應保持恆定，以確保手術的可重複性。這是藉由採用UV透明球囊導管使光導纖維居中來促進的。如果結構是動脈，則擴展的球囊封閉血流，但擴展的球囊本身不會使動脈擴展。然後在與動脈最小接觸的情況下，通過球囊壁照射動脈壁。The intensity of the UV annular beam around the artery should be kept constant to ensure reproducibility of the procedure. This is facilitated by centering the light-guiding fiber using a UV-transparent balloon catheter. If the structure is an artery, the expanded balloon occludes blood flow, but the expanded balloon itself does not dilate the artery. The arterial wall is then irradiated through the balloon wall with minimal contact with the artery.

這些相同的考慮也適用於內翻錐形尖端，但是在金剛石中，最大發射角（例如，約56°）將小於來自外部尖端的發射角（例如，71.5°）。目的是提供兩種不同的方法來產生擴展環形狀的射束，其相對益處已經在上面描述過，並且可以評估用於臨床應用。These same considerations apply to the inverted tapered tip, but in the diamond the maximum emission angle (e.g., about 56°) will be less than the emission angle from the external tip (e.g., 71.5°). The goal was to provide two different approaches to producing an expanded toroidal beam whose relative benefits have been described above and can be evaluated for clinical application.

在本發明的另一個實施例中，用於發射UV雷射光的光導纖維設置在動脈導管中使用的導絲內。較佳地，該實施例包括形成為空心管的導絲，使得通過導絲的整個長度形成軸向空腔或管腔。根據本文描述的本發明，具有外部、內翻或蝕刻（衍射光學元件（DOE））錐形尖端的光導纖維可以設置在中空導絲的空腔內。光導纖維可以固定在導絲的空腔內，也可以從導絲的空腔中被去除。在一個實施例中，光導纖維可以被手動配置成“鎖定位置”（由此它被固定於導絲），以及被手動配置成“解鎖位置”（這允許導絲和光導纖維彼此獨立且分開地操作）。藉由消除導管插入術過程的某些步驟，設置在導絲內的光導纖維的組合可能是有利的。導絲和光導纖維的組合可以具有被配置成發射UV雷射光的錐形射束的遠端。In another embodiment of the invention, a light-conducting fiber for emitting UV laser light is disposed within a guidewire used in an arterial catheter. Preferably, the embodiment includes a guidewire formed as a hollow tube so that an axial cavity or lumen is formed through the entire length of the guidewire. According to the invention described herein, a light-conducting fiber having an external, inverted or etched (diffractive optical element (DOE)) tapered tip can be disposed within the cavity of a hollow guidewire. The light-conducting fiber can be fixed within the cavity of the guidewire or can be removed from the cavity of the guidewire. In one embodiment, the optical fiber can be manually configured into a "locked position" (whereby it is secured to the guidewire), and manually configured into an "unlocked position" (which allows the guidewire and optical fiber to be operated independently and separately from each other). The combination of an optical fiber disposed within a guidewire may be advantageous by eliminating certain steps of the catheterization process. The guidewire and optical fiber combination may have a distal end configured to emit a conical beam of UV laser light.

在一個實施例中，導絲和光導纖維的組合的遠端被配置為外錐體。在另一個實施例中，導絲和光導纖維的組合的遠端被配置為能夠發射UV雷射光的錐形射束的內翻錐體。在又一個實施例中，導絲和光導纖維的組合包括平坦的遠端，在該遠端上蝕刻有用作負軸錐透鏡的同心圓凹槽（DOE）。In one embodiment, the distal end of the guide wire and optical fiber combination is configured as an external cone. In another embodiment, the distal end of the guide wire and optical fiber combination is configured as an inverted cone capable of emitting a cone-shaped beam of UV laser light. In yet another embodiment, the guide wire and optical fiber combination includes a flat distal end on which concentric circular grooves (DOE) are etched to serve as negative axis cone lenses.

導絲和光導纖維的組合的遠端可以包括與光導纖維進行光通信的單獨的尖端。與光導纖維進行光通信的單獨的尖端可以是金剛石、氧化鋯或聚合體材料（例如，塑膠）。The distal end of the combination of the guide wire and the optical fiber may include a separate tip in optical communication with the optical fiber. The separate tip in optical communication with the optical fiber may be diamond, zirconia, or a polymer material (e.g., plastic).

本發明的一個方面涉及用於再灌注血栓遠端動脈血管的方法，其中，該方法包括以下步驟： i) 提供能夠攜帶UV雷射光的光導纖維； ii) 將光導纖維延伸通過血栓； iii) 從血栓遠端的光導纖維發射UV雷射光，以擴張血栓遠端的動脈血管；以及 iv) 去除血栓； 從而允許血液流向擴張的動脈微血管並使其再灌注。One aspect of the present invention relates to a method for reperfusing an artery distal to a thrombus, wherein the method comprises the following steps:i) providing a light-conducting fiber capable of carrying UV laser light;ii) extending the light-conducting fiber through the thrombus;iii) emitting UV laser light from the light-conducting fiber distal to the thrombus to dilate the artery distal to the thrombus; andiv) removing the thrombus;thereby allowing blood to flow to the dilated arterial microvessels and reperfuse them.

在一個實施例中，該方法包括在將光導纖維延伸通過血栓之前從血栓近端的光導纖維發射UV雷射光的步驟。在另一個實施例中，在從血栓遠端的光導纖維發射UV雷射光之後，可以將光導纖維抽出到血栓近端的位置，然後可以在血栓近端發射UV雷射光。在一個實施例中，該方法可以包括在將光導纖維延伸通過血栓之前和之後，從血栓近端的光導纖維發射UV雷射光。在一個實施例中，該方法包括作為閉塞性血栓的血栓。In one embodiment, the method includes the step of emitting UV laser light from a light-guide fiber proximal to the thrombus before extending the light-guide fiber through the thrombus. In another embodiment, after emitting UV laser light from a light-guide fiber distal to the thrombus, the light-guide fiber may be withdrawn to a position proximal to the thrombus and UV laser light may then be emitted proximal to the thrombus. In one embodiment, the method may include emitting UV laser light from a light-guide fiber proximal to the thrombus before and after extending the light-guide fiber through the thrombus. In one embodiment, the method includes the thrombus as an occlusive thrombus.

將光導纖維延伸通過血栓可以較佳地延伸到適合於UV照射遠端區域的距離，在該遠端區域中，可以藉由擴張來加強再灌注。在本文描述的過程中，UV雷射光的任何發射或脈衝都可以重複，以產生所需的動脈擴張效果。擴張並經歷再灌注的動脈血管較佳為小動脈。由發射的UV雷射光與平滑肌細胞相互作用產生的一氧化氮也可以解離（藉由脫血栓）或分解在血栓遠端的動脈或小動脈中形成的血小板凝塊，因為一氧化氮抑制凝血酶，而凝血酶是經由纖維蛋白原進行強血小板內結合所必需的。Extending the photoconductive fiber through the thrombus can preferably be extended to a distance suitable for UV irradiating a distal region in which reperfusion can be enhanced by dilation. In the process described herein, any emission or pulse of UV laser light can be repeated to produce the desired arterial dilation effect. The arteries that dilate and undergo reperfusion are preferably small arteries. Nitric oxide produced by the interaction of the emitted UV laser light with smooth muscle cells can also dissociate (by dethrombosis) or break down platelet clots formed in arteries or small arteries distal to the thrombus because nitric oxide inhibits thrombin, which is required for strong intraplatelet binding via fibrinogen.

在如本文所述的用於再灌注血栓遠端動脈血管的方法中，光導纖維可以與如上所述的中空導絲結合提供。In the method for reperfusing a thrombosed distal artery as described herein, the optical fiber may be provided in conjunction with a hollow guidewire as described above.

在根據本發明的用於建立閉塞動脈血管再循環或再灌注的方法中，較佳使用血栓切除術裝置進行去除血栓的步驟。用於去除血栓的血栓切除術裝置可以是支架取回器或抽吸導管。In the method for establishing recirculation or reperfusion of an occluded artery according to the present invention, the step of removing the thrombus is preferably performed using a thrombectomy device. The thrombectomy device used to remove the thrombus can be a stent retriever or an aspiration catheter.

本發明的另一個實施例涉及用於在不能通過血栓切除術直接治療的血栓遠端的小動脈分支中加強再灌注（即，恢復循環）的方法，其中，該方法包括以下步驟： i) 提供能夠攜帶UV雷射光的光導纖維； ii) 將光導纖維延伸通過阻塞主動脈幹的血栓； iii) 從血栓遠端的光導纖維發射UV雷射光，以擴張血栓遠端的小分支動脈；以及 iv) 去除血栓， 從而允許血流通過主動脈幹（即，再循環）並通過已擴張並且脫血栓的遠端小的動脈（small artery）和小動脈分支（例如小動脈（arteriole）（其不能藉由直接進行血栓切除術來治療））來建立再灌注。Another embodiment of the present invention relates to a method for enhancing reperfusion (i.e., restoring circulation) in small arterial branches distal to a thrombus that cannot be directly treated by thrombectomy, wherein the method comprises the following steps:i) providing a light-conducting fiber capable of carrying UV laser light;ii) extending the light-conducting fiber through the thrombus that occludes the aorta;iii) emitting UV laser light from the light-conducting fiber distal to the thrombus to dilate the small branch artery distal to the thrombus; andiv) removing the thrombus,thereby allowing blood flow through the aorta (i.e., recirculation) and through the dilated and dethrombusted distal small artery (small artery) and small arterial branches such as arterioles (which cannot be treated by direct thrombectomy) to establish reperfusion.

在一個實施例中，該方法包括在將光導纖維延伸通過血栓之前從血栓近端的光導纖維發射UV雷射光的步驟。在另一個實施例中，在從血栓遠端的光導纖維發射UV雷射光之後，可以將光導纖維抽出到血栓近端的位置，然後可以在血栓近端發射UV雷射光。在一個實施例中，該方法可以包括在將光導纖維延伸通過血栓之前和之後，從血栓近端的光導纖維發射UV雷射光。在一個實施例中，該方法包括作為閉塞血栓的血栓。In one embodiment, the method includes the step of emitting UV laser light from a light-guided fiber proximal to the thrombus before extending the light-guided fiber through the thrombus. In another embodiment, after emitting UV laser light from a light-guided fiber distal to the thrombus, the light-guided fiber may be withdrawn to a position proximal to the thrombus and UV laser light may then be emitted proximal to the thrombus. In one embodiment, the method may include emitting UV laser light from a light-guided fiber proximal to the thrombus before and after extending the light-guided fiber through the thrombus. In one embodiment, the method includes the thrombus as an occluding thrombus.

在本文描述的過程中，UV雷射光的任何發射或脈衝都可以重複，以產生所需的動脈擴張效果。擴張並經歷再灌注的動脈血管較佳為分支動脈和小動脈。還可以發射UV雷射光，以（藉由脫血栓）使在血栓遠端的動脈或小動脈中形成的血小板凝塊不穩定。In the process described herein, any shot or pulse of UV laser light can be repeated to produce the desired arterial dilation effect. The arteries that dilate and undergo reperfusion are preferably branch arteries and arterioles. UV laser light can also be emitted to destabilize (by dethrombosis) a platelet clot formed in an artery or arteriole distal to a thrombus.

在如本文所述的用於再灌注血栓遠端的小動脈分支的方法中，光導纖維可以與如上所述的中空導絲組合提供。In the methods for reperfusing small arterial branches distal to a thrombus as described herein, an optical fiber may be provided in combination with a hollow guidewire as described above.

在根據本發明的用於再灌注血栓遠端的小動脈分支的方法中，較佳使用血栓切除術裝置進行從主動脈幹去除血栓的步驟。用於去除血栓的血栓切除術裝置可以是支架取回器或抽吸導管。In the method for reperfusion of small arterial branches distal to a thrombus according to the present invention, the step of removing the thrombus from the aorta is preferably performed using a thrombectomy device. The thrombectomy device used to remove the thrombus can be a stent retriever or an aspiration catheter.

本發明涉及用於擴張管狀解剖結構（例如動脈）的裝置和方法，其中，藉由將適當強度的紫外線（UV）雷射束引導到管狀解剖結構的壁上來誘導擴張，這不會在功能上損傷該結構的細胞。本發明的裝置、系統或方法可用於解剖結構（例如解剖管、管道或小管、血管（例如動脈、細支氣管、輸尿管、脈管等））。The present invention relates to devices and methods for dilating tubular anatomical structures (e.g., arteries), wherein dilation is induced by directing an ultraviolet (UV) laser beam of appropriate intensity onto the wall of the tubular anatomical structure, which does not functionally damage the cells of the structure. The devices, systems, or methods of the present invention can be used on anatomical structures (e.g., anatomical tubes, ducts or tubules, blood vessels (e.g., arteries, bronchioles, ureters, veins, etc.)).

較佳實施例採用包括內翻錐形尖端的鎔融二氧化矽光導纖維。尖端較佳包括具有高折射率的UV透明材料，該UV透明材料與鎔融二氧化矽光導纖維光學接觸。對於尖端來說，具有高折射率的UV透明並且非常硬的材料（例如金剛石（在355 nm處的折射率為2.48）或氧化鋯（在355 nm處的折射率為2.3））或定制設計的高折射率（n＞2）聚合體材料是較佳的。這種尖端可以提供產生UV環形射束的高達56°（使用內翻錐形尖端）或71.5°（使用外翻的錐形尖端）的出射角（半錐形角）的能力，該內翻錐形尖端和外翻的錐形尖端均由金剛石製成。A preferred embodiment employs a fused silica optical fiber including an inverted tapered tip. The tip preferably comprises a UV transparent material having a high refractive index that is in optical contact with the fused silica optical fiber. For the tip, a UV transparent and very hard material having a high refractive index, such as diamond (refractive index of 2.48 at 355 nm) or zirconia (refractive index of 2.3 at 355 nm) or a custom designed high refractive index (n>2) polymer material is preferred. This tip can provide the ability to produce a UV annular beam with an exit angle (half-cone angle) of up to 56° (using the inverted tapered tip) or 71.5° (using the outverted tapered tip), both of which are made of diamond.

本發明的一個較佳實施例涉及直徑較佳為10-100 um（更佳為50-100 um）的光導纖維，該光導纖維用於將UV雷射光傳輸到光導纖維的遠端或尖端，並發射UV雷射光的錐形射束，該射束以擴展的環形環或環狀射束的形式撞擊在管狀解剖結構的內壁上。該光導纖維較佳為固體鎔融二氧化矽光導纖維。在較佳實施例中使用的固體光導纖維不是中空光導纖維，固體光導纖維也不包括作為任何部分或其延伸部分的中空光導纖維。A preferred embodiment of the present invention relates to an optical fiber having a diameter preferably of 10-100 um (more preferably 50-100 um) for transmitting UV laser light to the distal end or tip of the optical fiber and emitting a conical beam of UV laser light that impinges on the inner wall of a tubular anatomical structure in the form of an expanded annular ring or annular beam. The optical fiber is preferably a solid fused silica optical fiber. The solid optical fiber used in the preferred embodiment is not a hollow optical fiber, nor does the solid optical fiber include a hollow optical fiber as any part or extension thereof.

為了實現這種環形射束的形成，鎔融二氧化矽光導纖維的遠端可以形成錐形狀；例如，外錐形狀（向外突出），或者可以是內翻錐形狀（向內突出）。如使用具有位於微導管104內的外錐形尖端101的二氧化矽光導纖維的圖1A所示，雷射環形射束的z平面橫截面的上半部分被顯示為具有高斯強度分佈（G₀），該分佈G₀由具有錐體半頂角α的外錐形尖端的光導纖維產生。該分佈G₀撞擊在具有半徑R的動脈的內壁102上，以產生擴展的高斯射束輪廓G_w103。注意，射束具有極角散佈2θ_w。環形射束是圍繞光軸圓柱形對稱的，並且其中心最大值是以角度β發射的。在點“P”處G_w的強度是r_w= (z – z_o) sin β以及(z²+ R²)^1/2的函數。如圖所示，外錐形尖端101定位在血栓105（T）近端以供使用。To achieve this annular beam formation, the distal end of the fused silica optical fiber can be formed into a tapered shape; for example, an outer tapered shape (protruding outward), or can be an inverted tapered shape (protruding inward). As shown in FIG. 1A using a silica optical fiber with an outer tapered tip 101 located within a microcatheter 104, the upper half of the z-plane cross-section of the laser annular beam is shown as having a Gaussian intensity distribution (_G0 ) generated by the optical fiber with an outer tapered tip having a cone half-apex angle α. The distribution_G0 impinges on the inner wall 102 of an artery with_a radius R to produce an expanded Gaussian beam profile_Gw 103. Note that the beam has a polar angular spread 2θ_w . The annular beam is cylindrically symmetric about the optical axis and its central maximum is emitted at an angle β. The intensity of G_w at point "P" is a function of r_w = (z – z_o ) sin β and (z² + R² )^1/2 . As shown, the outer tapered tip 101 is positioned proximal to the thrombus 105 (T) for use.

圖1B是圖1A所示的具有外錐形尖端101的鎔融二氧化矽光導纖維的詳細視圖，示出了在凸出的（外部）錐形尖端光導纖維中的雷射軸向光線跟蹤。線（OO^*）描繪了在輸出端處具有錐形尖端（總頂角=2 α）的二氧化矽光導纖維中的理想的雷射光線的路徑。只要入射角θ₁大於在二氧化矽/水交界處的臨界角θ_crit（64.653°）（並且因此藉由觀察α ＜ 90° – θ_crit），並因此從點Q進入到水基介質內（θ_crit= 64.653°），則射束在點P處服從全內反射。當繞光軸旋轉時，由O^*定義的點的軌跡產生環形射束。N₁和N₂是錐體頂面和底面的法線。從圖上看，藉由觀察，α+θ₁=90°且ω=180°-2θ₁，因此δ = 3θ₁- 180° = 90° - 3α。同樣藉由觀察，環形射束軌跡是由角度β(α) = θ₁- α - γ(α)定義的圓錐曲面。γ(α)被表示為sin^-1{(n₁/n₂) cos 3α}。根據斯涅耳定律（Snell’s Law），β(α)現在可以根據纖維錐形尖端的半頂角α來確定。FIG1B is a detailed view of the fused silica optical fiber with an outer tapered tip 101 shown in FIG1A, showing the axial laser beam tracking in the convex (outer) tapered tip optical fiber. Line (OO^* ) depicts the path of an ideal laser beam in a silica optical fiber with a tapered tip (total tip angle = 2α) at the output end. As long as the incident angle_θ1 is greater than the critical angle_θcrit (64.653°) at the silica/water interface (and therefore by observing that α < 90° –_θcrit ), and therefore enters the water-based medium from point Q (_θcrit = 64.653°), the beam is subject to total internal reflection at point P. The trajectory of the points defined by O^* produces a toroidal beam when rotated about the optical axis._N1 and_N2 are the normals to the top and bottom of the cone. From the figure, by observation, α+_θ1 = 90° and ω = 180° -_2θ1 , so δ =_3θ1 - 180° = 90° - 3α. Also by observation, the toroidal beam trajectory is a cone defined by the angle β(α) =_θ1 - α - γ(α). γ(α) is expressed as sin^-1 {(_n1 /_n2 ) cos 3α}. From Snell's Law, β(α) can now be determined from the half-apex angle α of the fiber cone tip.

圖2A是根據本發明的光導纖維200的照片，示出了根據本發明實施例的36°全頂點錐形角（2α）鎔融二氧化矽纖維上的外錐形尖端201。FIG. 2A is a photograph of an optical fiber 200 according to the present invention, showing an outer tapered tip 201 on a fused silica fiber with a 36° full apex tapered angle (2α) according to an embodiment of the present invention.

圖2B示出了由圖2A所示的具有外錐形尖端的光導纖維在玻璃容器205內的水中產生的UV雷射環形射束。紫外雷射束被變換成擴展的環狀210，如圖2B示為熒光紙上的漫射環；然後，在使用鹽水注射或使用填充有UV透明釓基造影劑的UV透明球囊置換血液後，環形射束可以照射動脈的內圓周。Fig. 2B shows a UV laser annular beam generated by the optical fiber with an outer tapered tip shown in Fig. 2A in water in a glass container 205. The UV laser beam is transformed into an expanded annulus 210, as shown in Fig. 2B as a diffuse ring on fluorescent paper; the annular beam can then irradiate the inner circumference of the artery after blood is replaced using saline injection or using a UV transparent balloon filled with a UV transparent gadolinium-based contrast agent.

在此以下的表1根據纖維錐體半頂角α以及與一個全內反射和一個折射相關聯的角度（導致射束以角度β(α)離開尖端），提供了在鎔融二氧化矽外錐形尖端中射束的路徑範圍。環形射束沿動脈壁的橫截面（角寬2θ_w（參見圖1A））可以從高斯到超高斯“禮帽”輪廓變化，這是多模光導纖維的典型輸出圖案，其在最大值表達時意味著在環寬度上基本上恆定的強度。這些強度圖案對擴張的產生並不重要，但它們確實影響射束的平均功率和峰值功率及其上限。Table 1 below provides the range of paths of the beam in a fused silica outer tapered tip, based on the fiber cone half-apex angle α and the angles associated with a total internal reflection and a refraction that causes the beam to leave the tip at an angle β(α). The cross-section of the annular beam along the arterial wall (angular width 2θ_w (see Figure 1A)) can vary from a Gaussian to a super-Gaussian "top hat" profile, which is the typical output pattern of multimode optical fibers, which, when expressed at a maximum, means an intensity that is essentially constant over the annular width. These intensity patterns are not critical to the generation of dilation, but they do affect the average and peak powers of the beam and their upper limits.

在圖1A、圖1B、圖2A和圖2B中示出了根據本發明實施例的向外突出的錐形尖端。由二氧化矽製造的尖銳的外錐形尖端（全頂角＜40°，半錐形角＜20°（參見圖1和圖2A））可能會受制於血管內障礙（如果有的話）導致的斷裂和/或纏繞。最大鈍度的外部二氧化矽尖端（全頂角約50°）是較佳的（參見表2）。使用由非常硬的材料（例如金剛石、氧化鋯或高折射率（n＞2）聚合體材料（如塑膠））製成的尖端可以避免斷裂，但是纏繞仍然是可能的，這取決於所使用的互補器件的陣列。實際上，光導纖維是通過導管引入的，導管提供隔離，從而提供保護。An outwardly protruding tapered tip according to an embodiment of the present invention is shown in Figures 1A, 1B, 2A and 2B. Sharp outer tapered tips made of silica (full apex angle <40°, half taper angle <20° (see Figures 1 and 2A)) may be subject to breakage and/or entanglement caused by vascular obstructions (if any). The most blunt outer silica tip (full apex angle of approximately 50°) is preferred (see Table 2). Using a tip made of a very hard material (e.g., diamond, zirconia, or a high refractive index (n>2) polymer material (such as plastic)) can avoid breakage, but entanglement is still possible, depending on the array of complementary devices used. In practice, the optical fibers are introduced through conduits, which provide isolation and thus protection.

可替代地，錐形尖端可以在光導纖維的遠端內翻（向內突出），如圖3所示。較佳地，鎔融二氧化矽光導纖維301包括內翻金剛石錐形尖端310，因為這種設計可以避免被血管內障礙物截留，並且在插入或部署期間不太可能被損壞。這種尖端能夠使用金剛石尖端以高達56°的發射角向水中發射環形（環狀）射束（參見表3）。內翻的鎔融二氧化矽錐形尖端可以產生相對於光導纖維的中心縱軸20°至24°之間的發射角（參見表3）。擴張（和相關聯的凝塊溶解）過程的射束強度和效率隨著UV光的環形射束投射到管狀結構（即動脈）內壁上的發射角而增加，因此希望在UV透明、高折射率纖維尖端材料（鎔融二氧化矽、金剛石、氧化鋯或定制聚合體材料）允許的物理限制內使射束強度和效率最大化。尖端可以由耦合到常規光導纖維的UV透明、高折射率（n＞2）的材料製成，其中耦合的尖端和光導纖維彼此進行光通信。二氧化矽光導纖維的耦合錐形尖端可以從光導纖維的遠端向外突出（凸出），並以相對於光導纖維的縱軸高達約48°的角度（表1）發射無阻礙的環形射束。如果尖端由金剛石組成（表2），可以實現高達約71.5°的寬得多的發射角度的範圍。Alternatively, the tapered tip can be inverted (protruding inward) at the distal end of the optical fiber, as shown in FIG3. Preferably, the fused silica optical fiber 301 includes an inverted diamond tapered tip 310, because this design can avoid being entrapped by vascular obstructions and is less likely to be damaged during insertion or deployment. Such a tip can emit an annular (ring-shaped) beam into water at an emission angle of up to 56° using a diamond tip (see Table 3). The inverted fused silica tapered tip can produce an emission angle between 20° and 24° relative to the central longitudinal axis of the optical fiber (see Table 3). The beam intensity and efficiency of the dilation (and associated clot lysis) process increases with the angle of emission of the annular beam of UV light onto the inner wall of a tubular structure (i.e., an artery), so it is desirable to maximize the beam intensity and efficiency within the physical limitations allowed by the UV transparent, high refractive index fiber tip material (fused silica, diamond, zirconia, or custom polymer materials). The tip can be made of a UV transparent, high refractive index (n>2) material coupled to a conventional optical fiber, where the coupled tip and optical fiber are in optical communication with each other. The coupled conical tip of a silica fiber optic can protrude (bulge) outward from the far end of the fiber optic and emit an unobstructed annular beam at angles up to about 48° relative to the longitudinal axis of the fiber optic (Table 1). If the tip is composed of diamond (Table 2), a much wider range of emission angles up to about 71.5° can be achieved.

包括向外（外翻）或向內（內翻）突出的錐形尖端的光導纖維可用於本發明的最小接觸持續擴張系統中，例如，作為隨後部署的動脈血栓切除術導管系統的一部分。由本發明的光導纖維發射的環形（annular）或環形（ring）射束的寬度取決於錐形纖維的纖維半徑和角度α。該特徵可能是有利的，因為包括動脈在內的任何管狀解剖結構中的擴張效應是由射束強度驅動的，並且可以非常快地（＜1秒）發生，這取決於在管狀解剖結構（例如動脈壁）內襯的細胞中光物理產生的一氧化氮（NO·）濃度。在給定強度的輻射將引起相應的擴張，這種擴張可以藉由轉亞硝基化從環形射束接觸的區域向近端和遠端傳播。Light-guiding fibers including tapered tips that protrude outward (everted) or inward (inverted) can be used in the minimal contact sustained dilation system of the present invention, for example, as part of a subsequently deployed arterial thrombectomy catheter system. The width of the annular or ring beam emitted by the light-guiding fibers of the present invention depends on the fiber radius and angle α of the tapered fiber. This feature can be advantageous because the dilation effect in any tubular anatomical structure, including arteries, is driven by the beam intensity and can occur very quickly (<1 second), depending on the concentration of photophysically generated nitric oxide (NO·) in cells lining the tubular anatomical structure (e.g., the arterial wall). Radiation at a given intensity will cause a corresponding dilation that can propagate from the region contacted by the annular beam both proximally and distally by transnitrosylation.

在較佳實施例中，包括內翻錐形尖端或鈍的外翻錐形尖端的光導纖維可以與球囊導管一起使用，該球囊導管包括UV透明球囊和抽吸血栓切除術導管。較佳地，在閉塞近端的段中引入的導絲可以用UV透明球囊導管居中，並用UV透明釓基造影劑進行擴展，由此導絲被光導纖維替換。In a preferred embodiment, a light-guided fiber including an inverted tapered tip or a blunt outward tapered tip can be used with a balloon catheter including a UV transparent balloon and an aspiration thrombectomy catheter. Preferably, a guide wire introduced in the segment proximal to the occlusion can be centered with a UV transparent balloon catheter and expanded with a UV transparent gadolinium-based contrast agent, whereby the guide wire is replaced by the light-guided fiber.

另一個較佳實施例是本發明的擴張系統，包括與球囊導管結合的內翻錐形尖端或鈍的外翻錐形尖端，並依次與支架取回器一起使用。在該實施例中，導絲進行初始穿透，其中導絲必須位於擴展的球囊導管的中心，然後被光導纖維替換，以便UV環形射束以均勻的周向強度適當地撞擊內壁。Another preferred embodiment is a dilation system of the present invention comprising an inverted tapered tip or a blunt inverted tapered tip combined with a balloon catheter and in turn used with a stent retriever. In this embodiment, the guide wire makes the initial penetration, where the guide wire must be centered in the dilated balloon catheter and then replaced by the optical fiber so that the UV annular beam properly hits the inner wall with uniform circumferential intensity.

本發明的另一方面涉及一種用於進行血管內血栓切除術手術的方法，其中該方法包括以下步驟： - 提供與UV傳導光導纖維兼容的血管切除術導管； - 採用UV透明造影劑將UV透明球囊導管擴展至動脈內壁，足以停止血流，而不是藉由機械壓力擴張動脈； - 將UV光導纖維血管切除術導管定位在距離血管內所包含的凝塊一至四倍血管直徑內； - 將UV光能量作為環形射束髮射到動脈內壁的平滑肌細胞上，以誘導一氧化氮（NO·）的形成和釋放，從而引起動脈擴張，而不管內皮（NO·的通常來源）是否完整以及是否存在血液；以及 - 去除凝塊。Another aspect of the invention relates to a method for performing an intravascular thrombectomy procedure, wherein the method comprises the following steps: - providing a thrombectomy catheter compatible with a UV-conducting light-guided fiber; - dilating the UV-transparent balloon catheter to the inner wall of an artery with a UV-transparent contrast agent sufficient to stop blood flow, rather than dilating the artery by mechanical pressure; - positioning the UV-light-guided fiber-optic thrombectomy catheter within one to four vessel diameters of a clot contained within the vessel; - emitting UV light energy as a circular beam onto smooth muscle cells of the inner wall of the artery to induce the formation and release of nitric oxide (NO·), thereby causing arterial dilation, regardless of the integrity of the endothelium (the usual source of NO·) and the presence of blood; and - removing the clot.

上述手術可以在準備使用抽吸導管或支架取回器時進行。These procedures can be performed in preparation for the use of an aspiration catheter or stent retriever.

圖4A、圖4B和圖4C顯示了我們的光導纖維裝置的部署，以分別在三隻狗的基線處在基底動脈（BA）401、402和403中實施血管內355 nm UV雷射照射（每隻狗的BA起點用*表示）。隨後的UV照射引起的擴張是半局部的；對於長度約為40 mm的基底動脈，擴張可從相鄰（脊椎脊髓）動脈的環形射束照射軌跡散佈至高達60 mm（圖4B和圖4C）。圖4B和圖4C表示，在UV照射之前，脊椎脊髓動脈收縮阻止了纖維尖端進入基底動脈的嘴部。雖然對於狗A，纖維尖端411可以放置在BA起點遠端22%處（這是最佳的），但是對於狗B和狗C，纖維尖端421和431可以僅放置在BA起點（^*）近端相應BA長度的52%和34%內。照射強度為12-20瓦特/cm²，平均擴張從基線的78%開始後繼續到基線的94%，雖然在40 mm範圍內線性下降，但在BA末端仍觀察到擴張。Figures 4A, 4B, and 4C show the deployment of our optical fiber device to deliver intravascular 355 nm UV laser irradiation in the basilar arteries (BA) 401, 402, and 403 at baseline in three dogs, respectively (the origin of the BA in each dog is indicated by an *). The dilation induced by the subsequent UV irradiation was semilocal; for a basilar artery of approximately 40 mm in length, the dilation could spread up to 60 mm from the circular beam irradiation trajectory of the adjacent (spinal) artery (Figures 4B and 4C). Figures 4B and 4C show that prior to UV irradiation, the spondylospinal artery contraction prevented the fiber tip from entering the ostium of the basilar artery. While for dog A, fiber tip 411 could be placed 22% distal to the BA onset (which was optimal), fiber tips 421 and 431 could be placed only within 52% and 34% of the respective BA lengths proximal to the BA onset (^* ) for dogs B and C. Irradiation intensity ranged from 12-20 watts/^cm2 , and mean dilation started at 78% of baseline and continued to 94% of baseline, although it decreased linearly over 40 mm, but dilation was still observed at the end of the BA.

圖5顯示在UV雷射促進血栓切除術之前，球囊導管510在動脈閉塞（血栓）530附近插入的導絲520上的初始部署。球囊部分地膨脹（在此顯示為不接觸動脈540的內壁）。當球囊已膨脹或近似已膨脹時，導絲將有效地位於動脈中心。此時，UV發射光導纖維可以替換導絲，並且擴張阻礙性彎曲（如果存在的話），以降低對導絲的阻力，並且導絲可以暫時替換UV纖維，以便在重新插入UV光導纖維和隨後的血栓切除術裝置之前，進一步追蹤穿過動脈朝向血栓的最佳路線。FIG5 shows the initial deployment of a balloon catheter 510 over a guidewire 520 inserted near an arterial occlusion (thrombus) 530 prior to UV laser facilitated thrombectomy. The balloon is partially inflated (shown here as not touching the inner wall of the artery 540). When the balloon is inflated or nearly inflated, the guidewire will effectively be in the center of the artery. At this point, the UV emitting light guide fiber can replace the guidewire and the obstructive bend (if present) can be dilated to reduce resistance to the guidewire, and the guidewire can temporarily replace the UV fiber to further track the best route through the artery toward the thrombus before reinserting the UV light guide fiber and subsequent thrombectomy device.

圖6顯示了圖5的球囊導管510在導絲上完全膨脹，使其居中，並且導絲已被光導纖維610替換，該光導纖維610將從能夠以所需角度β產生環形射束620的錐形尖端發射UV雷射光。纖維的輸出端可以在球囊允許的情況下盡可能靠近血栓530放置，但是UV環形射束照射將引發從與血栓相距＜4個直徑開始至40個直徑的持續擴張。以3-20瓦特/cm²的射束強度，擴張將在數秒鐘內發生，並將延伸到形成血栓的段。然後抽出光導纖維，然後將血栓切除術裝置（例如，抽吸導管）安裝在已放氣的球囊微導管上，現在摩擦阻力較小，因為閉塞的動脈段已擴張。可替代地，為了部署支架取回器，導絲必須通過遠端穿透血栓，球囊在其上部署和其他步驟將如上該發生。在此，血栓遠端的UV誘導的擴張將允許支架取回器以更大的直徑部署，確保對血栓的最大攔截和完全提取，只要支架取回器的可整合性保持不變。FIG6 shows the balloon catheter 510 of FIG5 fully inflated over the guidewire, centered, and the guidewire replaced by a light-guided fiber 610 that will emit UV laser light from a tapered tip capable of producing an annular beam 620 at the desired angle β. The output end of the fiber can be placed as close to the thrombus 530 as the balloon will allow, but the UV annular beam exposure will induce a continuous dilation starting at <4 diameters from the thrombus to 40 diameters. At a beam intensity of 3-20 watts/cm², the dilation will occur within seconds and will extend to the thrombosed segment. The light guide is then withdrawn and a thrombectomy device (e.g., aspiration catheter) is then mounted over the deflated balloon microcatheter, now with less frictional resistance because the occluded arterial segment has been dilated. Alternatively, to deploy the stent retriever, the guidewire must penetrate the thrombus via the distal end, over which the balloon is deployed and the other steps will occur as above. Here, the UV-induced dilation of the distal end of the thrombus will allow the stent retriever to be deployed with a larger diameter, ensuring maximum interception and complete extraction of the thrombus, as long as the conformability of the stent retriever remains unchanged.

圖7給出了本發明應用於紫外雷射誘導擴張的血栓切除術中以便最大程度地減小由於機械摩擦引起的壁損傷所採用的步驟的圖示總結。圖7示出了使用圖5和圖6所示的球囊導管執行的本發明方法的步驟。在圖7的步驟A中，在部署本發明的血管切除術導管之前，血栓701顯示為在大腦中動脈702中。在球囊導管中通常採用的微導絲720被進給通過頸內動脈721，並定位在血栓701附近（步驟B）。在步驟C中，UV透明球囊730然後在微導絲720上進給（如在裝置的正常使用中），並且也定位在血栓701附近。步驟D示出了球囊導管然後膨脹740以接觸血管（動脈）721的內壁，使得血液流動在球囊和血管壁之間被顯著或完全阻礙。根據本文描述的方法部署UV雷射光，使得環形射束被發射以接觸血管的內壁，並且血管部分地擴張772（從UV雷射環形射束接觸的區域開始在兩個方向上傳播）。使用支架取回器或僅由步驟E中的示例所示的抽吸血栓切除術導管750的提取手術可以以其常規方式用於提取血栓701，在步驟F中顯示為該血栓701從大腦中動脈702中被去除。由UV雷射照射引起的擴張可以促進去除步驟。FIG7 provides a pictorial summary of the steps employed in the application of the present invention in a thrombectomy procedure using UV laser induced dilation to minimize wall damage due to mechanical friction. FIG7 shows the steps of the method of the present invention performed using the balloon catheter shown in FIGS. 5 and 6 . In step A of FIG7 , a thrombus 701 is shown in the middle cerebral artery 702 prior to deployment of the vascular resection catheter of the present invention. A microguidewire 720, commonly used in balloon catheters, is fed through the internal cervical artery 721 and positioned proximate to the thrombus 701 (step B). In step C, a UV transparent balloon 730 is then fed over the microguidewire 720 (as in normal use of the device) and also positioned proximate to the thrombus 701. Step D shows that the balloon catheter is then inflated 740 to contact the inner wall of the blood vessel (artery) 721, so that blood flow is significantly or completely blocked between the balloon and the vessel wall. UV laser light is deployed according to the methods described herein so that the annular beam is emitted to contact the inner wall of the vessel and the vessel partially dilates 772 (starting from the area contacted by the UV laser annular beam and propagating in both directions). An extraction procedure using a stent retriever or an aspiration thrombectomy catheter 750, shown by way of example only in step E, can be used in its conventional manner to extract the thrombus 701, which is shown in step F as being removed from the middle cerebral artery 702. The dilation caused by the UV laser irradiation can facilitate the removal step.

有利地，所描述的擴張方法可以提供減小的機械摩擦，從而最大程度地減小對動脈壁的損傷。另一個優點是凝塊的血小板成分也將擴張（參見美國專利6,539,944），並且最靠近動脈壁的部分部分地降解成單個血小板（藉由脫血栓），從而提供對壁的較少黏附，從而對提取過程的摩擦阻力較小。不會產生栓子。Advantageously, the dilation method described can provide reduced mechanical friction, thereby minimizing damage to the arterial wall. Another advantage is that the platelet component of the clot will also dilate (see U.S. Patent 6,539,944), and the portion closest to the arterial wall will partially degrade into single platelets (by dethrombosis), thereby providing less adhesion to the wall and thus less frictional resistance to the extraction process. No emboli will be generated.

在根據本發明的方法中，UV光可以持續短時間（例如2-15秒，較佳約5秒）連續發射，或者可以重複地發射，只要在任一情況下通過球囊接觸或藉由鹽水注射清除了光路中的血液。雷射照射間隔可以由連續波雷射束填充，或者由本身由多個連續的MHz鎖模脈衝（寬度約為10皮秒）組成的射束（稱為準連續射束）填充，或者由多個連續的（寬度高達100奈秒）5-25 kHz脈衝（稱為聲光調Q射束）填充。UV光較佳地被引導到距離血栓約20倍血管直徑內的血管壁上。更佳地，當使用球囊時，UV光被引導到距離血栓約4倍血管直徑內的血管壁上。在較佳的方法中，血管是被凝塊部分或完全閉塞的動脈。In the method according to the invention, the UV light can be emitted continuously for a short time (e.g. 2-15 seconds, preferably about 5 seconds), or can be emitted repeatedly, as long as the blood in the optical path is cleared in either case by balloon contact or by saline injection. The laser irradiation intervals can be filled by a continuous wave laser beam, or by a beam that itself consists of a plurality of continuous MHz mode-locked pulses (width of about 10 picoseconds) (called a quasi-continuous beam), or by a plurality of continuous (width up to 100 nanoseconds) 5-25 kHz pulses (called an acousto-optic Q-switched beam). The UV light is preferably directed to the vessel wall within about 20 vessel diameters from the thrombus. More preferably, when a balloon is used, the UV light is directed to the vessel wall within about 4 vessel diameters from the thrombus. In a preferred method, the vessel is an artery that is partially or completely occluded by the clot.

UV光以大約180-400 nm的波長發射，並且較佳以大約300-400 nm的波長發射。在一個較佳實施例中，使用發射355nm光的三倍頻Nd:YAG雷射器發射UV光。（也存在其他含Nd晶體（例如紫翠玉））。已經測量出在350納米處NO·的產量最大；然而，雷射UV光目前在350 nm波長不可用，並且可以使用355 nm的波長，而效率僅略有降低。新開發的349 nm和360 nm雷射器是存在的，但還不夠可靠，不能用於臨床。可與本發明一起使用的其他產生UV的雷射器（但未達到燒蝕點）包括XeF雷射器（351 nm）和連續波（CW）氬離子雷射器（351 nm、364 nm）。也可以使用任何二極管雷射器或染料雷射器，只要可以在非燒蝕性血管擴張效果所需的UV範圍內獲得輸出。目前，二極管雷射器不能產生處於最佳區域的波長。然而，如果克服了製造中的物理困難，也可以使用二極管雷射器，並且比上面提出的雷射器小得多。理論上，可以使用直接發射UV輻射或發射作為倍頻或三倍頻結果的UV輻射的任何雷射器。UV light emits at a wavelength of about 180-400 nm, and preferably at about 300-400 nm. In a preferred embodiment, the UV light is emitted using a frequency tripled Nd:YAG laser that emits 355 nm light. (Other Nd-containing crystals, such as alexandrite, also exist.) The maximum yield of NO· has been measured at 350 nm; however, laser UV light is currently unavailable at 350 nm, and a wavelength of 355 nm can be used with only a slight decrease in efficiency. Newly developed 349 nm and 360 nm lasers exist, but are not yet reliable enough for clinical use. Other lasers that produce UV (but do not reach the point of ablation) that can be used with the present invention include XeF lasers (351 nm) and continuous wave (CW) argon ion lasers (351 nm, 364 nm). Any diode laser or dye laser can also be used as long as the output can be obtained in the UV range required for the non-ablative vasodilation effect. At present, diode lasers cannot produce wavelengths in the optimal region. However, if the physical difficulties in manufacturing are overcome, diode lasers can also be used and are much smaller than the lasers proposed above. In theory, any laser that emits UV radiation directly or emits UV radiation as a result of frequency doubling or tripling can be used.

在本發明的裝置或方法中，UV光的平均入射強度在約3至約20瓦特/平方釐米（W/cm²）之間。In the apparatus or method of the present invention, the average incident intensity of the UV light is between about 3 and about 20 watts per square centimeter (W/cm² ).

本發明的裝置和方法可與預先施用有助於（纖維蛋白的）血栓溶解的藥學上可接受的溶栓劑結合使用。值得關注的是凝塊碎片的排放，這是我們的血小板脫血栓過程所避免的。血栓切除術的較佳過程是在沒有溶栓劑致碎裂的併發症的情況下去除凝塊。The devices and methods of the present invention can be used in conjunction with the prior administration of a pharmaceutically acceptable thrombolytic agent that aids in the lysis of (fibrin) clots. Of concern is the emission of clot fragments, which is avoided by our platelet ablation process. The preferred process of thrombectomy is to remove the clot without the complication of thrombolytic agent-induced fragmentation.

一個具體實施例是通過血管內部署的光導纖維引入雷射束，該光導纖維包括凸出的（外部）錐形尖端，該錐形尖端藉由一次反射和一次折射實際上可以用作射束的發散透鏡（即負軸錐透鏡）。這種設計將產生作為擴展的錐形環的圓周照射圖案，在射束被引導到的管狀解剖結構的壁上產生雷射光的環形射束。凸出的錐形輸出尖端較佳使用折射率高於鎔融二氧化矽的UV透明材料製成，例如金剛石、氧化鋯或n＞2的定制聚合體材料（例如塑膠）（其可以光學耦合到二氧化矽）。隨著射束出射角在斯涅耳定律施加的限制內增加，壁上的射束強度和動脈擴張的效率增加，因為到壁的距離、沿著動脈壁投射的射束的寬度以及因此照射的面積都減小了。One specific embodiment is to introduce the laser beam via an intravascularly deployed optical fiber that includes a convex (external) conical tip that can actually act as a diverging lens for the beam (i.e., a negative-axis conical lens) by primary reflection and primary refraction. This design will produce a circumferential illumination pattern as an expanding conical ring, producing a ring-shaped beam of laser light on the wall of the tubular anatomical structure into which the beam is directed. The convex conical output tip is preferably made of a UV transparent material with a higher refractive index than fused silica, such as diamond, zirconia, or a custom polymer material (e.g., plastic) with n>2 (which can be optically coupled to silica). As the beam exit angle increases within the limits imposed by Snell's law, the beam intensity at the wall and the efficiency of arterial dilation increase because the distance to the wall, the width of the beam projected along the arterial wall, and therefore the area irradiated, decreases.

這些相同的考慮也適用於內翻錐形尖端，但是最大發射角將小於來自外部尖端的發射角。目的是提供兩種不同的方法來產生擴展環形狀的射束，其相對益處已經在上面描述過，並且可以評估用於臨床應用。These same considerations apply to the inverted tapered tip, but the maximum emission angle will be less than that from the external tip. The goal was to provide two different approaches to producing an expanded toroidal beam whose relative benefits have been described above and can be evaluated for clinical application.

較佳的光導纖維尖端包括內翻的尖端配置（圖3），其在使用過程中不太可能被阻塞，然而其通過引導導管的部署應該避免這種可能性以及動脈穿孔的可能性。The preferred fiberoptic tip includes an inverted tip configuration (Fig. 3) that is less likely to become occluded during use, however its deployment via a guide catheter should avoid this possibility as well as the potential for arterial perforation.

另一個實施例是具有向外突出的尖端（圖1B）的鎔融二氧化矽光導纖維，其無阻礙的最大發射（半錐形）角約為48.4°（參見表2，但極限為50.3°）。當尖端尖時（全頂點錐形角小於40°，參見圖2A），如果使用易碎材料，它可能會因機械接觸而斷裂。這種情況可以用由具有高折射率的非常硬的材料（例如金剛石）製成的外錐形尖端來補救。外翻的金剛石錐形尖端將允許高達71.5°的射束出射角。當然，隨著鈍度的增加（全錐形頂角的增加），外部尖端（包括二氧化矽本身）將更能抵抗機械損傷。Another embodiment is a fused silica optical fiber with an outward protruding tip (FIG. 1B) with an unobstructed maximum emission (half-cone) angle of about 48.4° (see Table 2, but the limit is 50.3°). When the tip is sharp (full apex cone angle is less than 40°, see FIG. 2A), it may break due to mechanical contact if fragile materials are used. This situation can be remedied with an outward-conical tip made of a very hard material with a high refractive index, such as diamond. An outward-turned diamond cone tip will allow beam exit angles of up to 71.5°. Of course, as the bluntness increases (increase in the full cone top angle), the outer tip (including the silica itself) will become more resistant to mechanical damage.

當被動脈壁的平滑肌細胞中的亞硝酸鹽（NO₂^-）吸收時，UV光可以光物理地釋放一氧化氮（NO·），其濃度大於內皮在正常代謝期間維持的濃度。這導致血管的準暫時性（幾十分鐘到幾小時）和半局部擴張。從平滑肌細胞釋放的NO·藉由轉亞硝基化沿著距離UV光照射部位近端和遠端幾釐米的局部距離自我傳播。UV雷射器用於誘導閉塞附近的血管擴張，從而在部署血栓切除術裝置以提取血凝塊時減少與動脈壁的摩擦（或化學結合）。因此，血管的擴張可以促進凝塊與其黏附的血管壁分離，並且使用常規抽吸導管或支架取回器（藉由降低其與血管壁相互作用的強度和頻率）更容易和更安全地去除凝塊。本發明可以有利地減少對接受血栓切除術的閉塞動脈的內皮和內膜結構的結構和功能損傷的後期病理和行為後果。When absorbed by nitrite (NO₂^- ) in the smooth muscle cells of the arterial wall, UV light can photophysically release nitric oxide (NO·) in concentrations greater than those maintained by the endothelium during normal metabolism. This results in a quasi-temporary (tens of minutes to hours) and semi-local dilation of the vessel. NO· released from the smooth muscle cells propagates itself by transnitrosylation along local distances of a few centimeters proximal and distal to the site of UV light irradiation. UV lasers are used to induce dilation of vessels near the occlusion, thereby reducing friction (or chemical binding) with the arterial wall when a thrombectomy device is deployed to extract the blood clot. Thus, dilation of the vessel can promote the separation of the clot from the vessel wall to which it is adhered, and the clot can be removed more easily and safely using a conventional aspiration catheter or stent retriever (by reducing the intensity and frequency of its interaction with the vessel wall). The present invention can advantageously reduce the late pathological and behavioral consequences of structural and functional damage to the endothelial and intimal structures of occluded arteries undergoing thrombectomy.

血管的擴張增加了血管的直徑，這也有助於導管移動到位，即可以更容易地通過血管的彎曲（嚴重拐彎）或狹窄。Dilation of the blood vessels increases their diameter, which also helps the catheter move into place, allowing it to more easily pass through bends (severe bends) or narrowings in the blood vessels.

為了實現本發明的目的，一個新穎的方面涉及用於從光導纖維尖端或者通過光導纖維尖端發射UV輻射的光導纖維尖端的有益配置。例如，已經發現，採用包括非常硬但UV透明材料（例如金剛石）的外錐形尖端可以更容易地提供高達（相對於纖維軸）71.5°的外部（半錐形）發射角，以及伴隨的UV光的環形射束在內動脈壁上的更窄的投影。較佳的角度最好結合系統的其他部件（例如，用UV透明釓基造影劑擴展的UV透明球囊）來確定。To achieve the objects of the present invention, one novel aspect relates to a beneficial configuration of a light-guide fiber tip for emitting UV radiation from or through the light-guide fiber tip. For example, it has been found that the use of an outer conical tip comprising a very hard but UV transparent material (e.g., diamond) can more easily provide an outer (semi-conical) emission angle of up to 71.5° (relative to the fiber axis), and an accompanying narrower projection of the annular beam of UV light on the inner artery wall. The preferred angle is best determined in conjunction with other components of the system (e.g., a UV transparent balloon expanded with a UV transparent gadolinium-based contrast agent).

在本發明的另一個實施例中，光導纖維的遠端用內翻的錐形尖端覆蓋。內翻的錐形尖端較佳包括UV透明的高折射率材料（例如金剛石、氧化鋯或定制的聚合體材料（例如塑膠）），並且能夠以（從金剛石開始）相對於纖維縱軸高達56°的發射角發射環形射束。In another embodiment of the invention, the distal end of the optical fiber is covered with an inverted tapered tip. The inverted tapered tip preferably comprises a UV transparent high refractive index material such as diamond, zirconia or a customized polymer material such as plastic, and is capable of emitting an annular beam at an emission angle of up to 56° relative to the longitudinal axis of the fiber (starting from the diamond).

本發明的另一個目的是提供能夠傳輸由導管包圍的UV光的光導纖維，其中，該光導纖維包括內翻的錐形尖端，較佳由UV透明材料高折射率材料（例如金剛石、氧化鋯或能夠發射用於腦動脈的環形射束的定制聚合體材料（例如塑膠））組成。窄射束寬度將集中血管細胞吸收的能量的量，因此即使使用相對低功率的雷射，也將釋放有效量的NO·，以發生顯著的血管擴張。Another object of the present invention is to provide a light-conducting fiber capable of transmitting UV light surrounded by a catheter, wherein the light-conducting fiber includes an inverted tapered tip, preferably composed of a UV transparent material, a high refractive index material such as diamond, zirconia, or a custom polymer material such as plastic that can emit an annular beam for use in cerebral arteries. The narrow beam width will focus the amount of energy absorbed by the vascular cells, so even with a relatively low power laser, an effective amount of NO will be released to cause significant vasodilation to occur.

本發明的又一個目的是提供一種擴張系統，該擴張系統在最後一步中可以包括抽吸導管或支架取回器，在此之前是球囊導管，該球囊導管包含能夠將UV光攜帶到光導纖維遠端的鎔融二氧化矽光導纖維。較佳地，擴張系統包含用於UV照射的鎔融二氧化矽光導纖維，在光導纖維的遠端具有錐形尖端。較佳地，錐形尖端包括具有高折射率的UV透明材料，例如金剛石、氧化鋯或定制的聚合體材料（例如塑膠）。更佳地，錐形尖端是外翻的錐形尖端配置。可替代地，本發明的擴張系統的鎔融二氧化矽光導纖維部件包括血栓切除術抽吸導管或支架取回器系統，該抽吸導管或支架取回器系統包含光學接觸的內翻錐形尖端，該尖端包括紫外線透明的高折射率材料，例如金剛石、氧化鋯或定制的聚合體材料（例如塑膠）。Yet another object of the present invention is to provide a dilation system that may include an aspiration catheter or stent retriever in a final step, preceded by a balloon catheter that includes a fused silica light guide capable of carrying UV light to the distal end of the light guide. Preferably, the dilation system includes a fused silica light guide for UV irradiation, having a tapered tip at the distal end of the light guide. Preferably, the tapered tip includes a UV transparent material with a high refractive index, such as diamond, zirconia, or a customized polymer material (e.g., plastic). More preferably, the tapered tip is an everted tapered tip configuration. Alternatively, the fused silica optical fiber component of the dilation system of the present invention includes a thrombectomy aspiration catheter or stent retriever system, which includes an optically contacted inward-turned tapered tip, which tip includes a high refractive index material that is UV transparent, such as diamond, zirconia, or a customized polymer material (such as plastic).

本發明的再一個目的是提供一種包裹UV兼容光導纖維的UV透明球囊導管，該UV兼容光導纖維與抽吸血栓切除術導管相結合，作為整體擴張系統的一部分。較佳地，與抽吸血栓切除術導管或支架取回器結合的UV兼容光導纖維將在其遠端結合金剛石或氧化鋯（或高折射率聚合體材料）外翻的錐形尖端。Another object of the present invention is to provide a UV-transparent balloon catheter encapsulating a UV-compatible light-conducting fiber that is combined with an aspiration thrombectomy catheter as part of an overall dilation system. Preferably, the UV-compatible light-conducting fiber combined with the aspiration thrombectomy catheter or stent retriever will have an everted conical tip of alloyed granite or zirconia (or a high refractive index polymer material) at its distal end.

在一個較佳實施例中，可以使用UV透明的釓基造影劑流體來使球囊導管擴展；然後，球囊壁置換血液，從而為UV雷射光到達動脈內壁提供清晰的路徑。根據本發明，球囊為此目的而膨脹，並且也使錐形尖端居中；它不會膨脹以使血管壁的內徑擴展。釓造影劑定位於球囊，因此與血流隔離。在該實施例中，球囊材料和造影劑材料對UV光足夠透明，以允許UV光不受阻礙地穿過包裹導管和球囊。In a preferred embodiment, a UV transparent gadolinium-based contrast fluid can be used to expand the balloon catheter; the balloon wall then displaces blood, thereby providing a clear path for the UV laser light to reach the inner wall of the artery. According to the present invention, the balloon is inflated for this purpose and also centers the tapered tip; it does not inflate to expand the inner diameter of the vessel wall. The gadolinium contrast agent is localized to the balloon and is therefore isolated from the blood flow. In this embodiment, the balloon material and contrast agent material are sufficiently transparent to UV light to allow the UV light to pass through the wrapped catheter and balloon unimpeded.

本發明的進一步的目的是一種在需要血栓切除術的哺乳動物體內進行血栓切除術手術的方法，其中，該方法包括以下步驟： a) 提供如本文所述的擴張系統； b) 將UV光導纖維球囊導管定位於閉塞血管內在距凝塊1至4倍血管直徑內； c) 將連續或高重複率脈衝射束UV雷射光能的方波脈衝作為指定平均強度範圍內的射束髮射到在血管內壁內襯的平滑肌細胞上，以從細胞中釋放NO·，從而引起血管擴張；以及 d) 去除光導纖維並且引入血栓切除術裝置， e) 然後藉由機械提取來去除凝塊。A further object of the invention is a method of performing a thrombectomy procedure in a mammal in need of thrombectomy, wherein the method comprises the steps of:a) providing a dilation system as described herein;b) positioning a UV light-guided fiber balloon catheter within an occluded vessel within 1 to 4 vessel diameters of the clot;c) emitting a continuous or high repetition rate pulsed beam of square wave pulses of UV laser light energy as a beam within a specified average intensity range onto smooth muscle cells lining the inner wall of the vessel to release NO· from the cells, thereby causing vessel dilation; andd) removing the light-guided fiber and introducing a thrombectomy device,e) then removing the clot by mechanical extraction.

在一個實施例中，UV光導纖維擴張系統較佳地具有鎔融二氧化矽纖維，該纖維具有金剛石錐形尖端，能夠（對於外部尖端）以相對於纖維縱軸高達71.5°的角度發射環形射束。對於其他已知的高折射率材料（例如氧化鋯和定制的聚合體材料（例如塑膠）），該角度將會更小。In one embodiment, the UV light-guiding fiber expansion system preferably has fused silica fibers with diamond cone tips capable of emitting an annular beam at angles up to 71.5° relative to the longitudinal axis of the fiber (for the outer tip). For other known high refractive index materials such as zirconia and custom polymer materials (e.g., plastics), the angle will be smaller.

採用連續或脈衝形式的UV光能的爆發可以以約2-20秒（較佳為至少約5-15秒，更佳為約8-12秒）的照射間隔發射。10秒的爆發可以是發射UV光束的最佳持續時間，用於將血管擴張到足夠的直徑，以降低導管與血管彎曲或狹窄的摩擦相互作用，或者促進凝塊與血管壁的部分分離。Bursts of UV light energy in the form of continuous or pulsed can be emitted at an interval of about 2-20 seconds (preferably at least about 5-15 seconds, more preferably about 8-12 seconds). A 10 second burst can be an optimal duration for emitting a UV beam to dilate a vessel to a sufficient diameter to reduce frictional interaction of the catheter with a vessel bend or stenosis, or to promote partial separation of a clot from the vessel wall.

在較佳實施例中，本發明包括擴張系統，該擴張系統包括在準備期之後的抽吸導管或支架取回器，該準備期採用提供UV照射的環狀射束的錐形尖端光導纖維。光導纖維的錐形尖端可以從光導纖維的遠端向內或向外突出，這取決於所需的發射角度以及沿著所需路徑存在或不存在障礙物。In a preferred embodiment, the invention includes a dilation system that includes an aspiration catheter or stent retriever following a preparation period that employs a tapered tip light guide that provides an annular beam of UV radiation. The tapered tip of the light guide can protrude inwardly or outwardly from the distal end of the light guide, depending on the desired emission angle and the presence or absence of obstructions along the desired path.

在使用中，包括錐形尖端的光導纖維可以發射錐形射束軌跡，該射束軌跡以圍繞管狀結構的內圓周的環形或環狀射束的形式照射管狀解剖結構。可以用UV光擴張的管狀解剖結構是那些內襯有（平滑肌）細胞的結構，這些細胞能夠儲存一氧化氮（作為亞硝酸鹽）並釋放完全活性的一氧化氮（NO·）。這種擴張可以有利地用於在血栓附近的位置使動脈擴展或擴張，以藉由減少機械摩擦和與動脈的化學結合來促進更容易和更安全地去除血栓。血栓可以是閉塞性血栓或非閉塞性血栓。在血管內血栓的部位或血栓附近的血管擴張可以至少部分地鬆開血栓對血管壁的黏附或將血栓與血管壁分離，從而有助於藉由目前在醫學領域中使用的常規抽吸或支架取回器導管技術高效地去除血栓。在提取之前、期間和之後，應儘量減少對閉塞血管的外周損傷。In use, a light-guiding fiber including a tapered tip can emit a tapered beam trajectory that irradiates a tubular anatomical structure in the form of an annular or circular beam around the inner circumference of the tubular structure. Tubular anatomical structures that can be dilated with UV light are those that are lined with (smooth muscle) cells that are able to store nitric oxide (as nitrite) and release fully active nitric oxide (NO·). This dilation can be advantageously used to dilate or expand an artery at a location near a thrombus to facilitate easier and safer removal of the thrombus by reducing mechanical friction and chemical bonding to the artery. The thrombus can be an occlusive thrombus or a non-occlusive thrombus. Vascular dilation at or near the site of a thrombus within a vessel can at least partially loosen the adhesion of the thrombus to the vessel wall or detach the thrombus from the vessel wall, thereby facilitating efficient removal of the thrombus by conventional aspiration or stent retriever catheter techniques currently used in the medical field. Peripheral damage to the occluded vessel should be minimized before, during, and after extraction.

當在距血栓大約1、2、3、4、5、6、7、8、9、10、12、14、16、18、20、25或30倍的血管直徑內發生UV光照射時，能夠發生在血栓區域中的動脈擴張。如本文所用，術語“血管直徑”是指動脈的外徑。較佳地，在距血栓大約10倍血管直徑內照射血管。更佳地，在離血栓約1至4倍血管直徑之間照射血管。可以在血栓的近端或遠端照射血管。When UV light irradiation occurs within about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, or 30 vessel diameters from the thrombus, arterial dilation can occur in the area of the thrombus. As used herein, the term "vessel diameter" refers to the outer diameter of the artery. Preferably, the vessel is irradiated within about 10 vessel diameters from the thrombus. More preferably, the vessel is irradiated between about 1 and 4 vessel diameters from the thrombus. The vessel can be irradiated proximal or distal to the thrombus.

也可以藉由在距離主幹血栓約3、4、5、6、7、8、9、10、12、14、16、18、20、25或30倍血管直徑的距離處照射主幹血管來擴張分支動脈血管，因為UV誘導的血管擴張效應可以向遠端（以及向近端）傳播。這種現象在血栓切除術外科醫生無法可行地進入包含血栓並具有接近主幹動脈的近端通道的分支動脈或分支動脈中的小動脈的情況下特別有用。Branch artery vessels may also be dilated by irradiating the main trunk vessel at a distance of about 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, or 30 vessel diameters from the main trunk thrombus, as the UV-induced vasodilation effect can propagate distally (as well as proximally). This phenomenon is particularly useful in situations where the thrombectomy surgeon does not have feasible access to a branch artery or a small artery within a branch artery that contains a thrombus and has proximal access to the main trunk artery.

較佳地，藉由憑藉導管穿過放置在血管內的光導纖維傳輸的射束，UV光束被引導到管狀解剖結構（例如動脈）的內表面上。在照射之後（但幾乎緊接著，並且不超過用雷射束照射的幾秒鐘內），首先在受照射的部分處血管擴張，然後在近端方向和遠端方向上連續自我傳播幾釐米的距離。Preferably, the UV beam is directed onto the inner surface of a tubular anatomical structure (e.g., an artery) by transmitting the beam through an optical fiber placed in the blood vessel via a catheter. After irradiation (but almost immediately and within a few seconds of irradiation with the laser beam), the blood vessel first dilates at the irradiated portion and then continuously propagates itself over a distance of several centimeters in the proximal and distal directions.

在正常的生理條件下，擴張是由內皮產生的一氧化氮（NO·）介導的。相反，UV雷射介導的、NO·的光物理產生是由在動脈壁中未受損的平滑肌細胞中儲存的亞硝酸鹽（NO₂^-）的光切割產生的。無論內皮損傷的嚴重程度如何，甚至在內皮缺失（完全破壞）時，都可產生高達10 µM的局部NO·濃度。Under normal physiological conditions, dilation is mediated by nitric oxide (NO·) produced by the endothelium. In contrast, UV laser-mediated photophysical generation of NO· results from photocleavage of nitrite (NO₂^- ) stored in intact smooth muscle cells in the arterial wall. Local NO· concentrations of up to 10 µM can be generated regardless of the severity of endothelial damage, even when the endothelium is absent (completely destroyed).

平滑肌細胞中的亞硝酸鹽光解產生NO·、導致S-亞硝基硫醇（RNSO）的形成的硫醇的S-亞硝基化（RSH）、以及經由NO·或NO·從硫亞硝基鹽（RSNO）中的釋放的局部擴張；這些使其他硫醇轉亞硝基化，藉由NO·的更多釋放，在徑向上、遠端和近端傳播擴張。這是自我延續的連鎖過程。Photolysis of nitrite in smooth muscle cells produces NO·, S-nitrosylation of thiols (RSH) leading to the formation of S-nitrosothiols (RNSO), and local dilation via NO· or NO· release from sulfur-nitrosyl salts (RSNO); these transnitrosate other thiols, propagating dilation radially, distally, and proximally via further release of NO·. This is a self-perpetuating chain of processes.

光物理產生的一氧化氮可以刺激近端和遠端的擴張波。因此，可以在凝塊長度的某一部分上降低對凝塊去除的摩擦阻力。因此，可以用更小的力提取凝塊，因此，與目前觀察到的相比，對動脈的機械損傷更小，將來在該部位或其遠端甚至近端的併發症更少。Photophysically generated nitric oxide can stimulate dilation waves both proximally and distally. Therefore, the frictional resistance to clot removal can be reduced over a certain portion of the clot length. Therefore, the clot can be extracted with less force and, therefore, with less mechanical damage to the artery and fewer complications in the future at or distal to or even proximal to the site than has been observed to date.

用於擴張動脈從而治療閉塞血管的UV雷射束可以是連續的或脈衝的。使用脈衝雷射可以減少目標和周圍組織中的熱量積聚和隨之而來的損傷。如果使用非燒蝕脈衝雷射器（例如準連續或聲光調Q雷射器），則脈衝速率可以是與向目標組織輸送適當的時間平均照射強度一致的任何速率，同時避免如此高強度以至於持久損傷（即在生理相關時間框架（例如，幾小時至幾週的時間）內不可逆的損傷，導致目標組織或光導纖維急性損傷）的單個脈衝。UV laser beams used to dilate arteries and thereby treat occluded vessels can be either continuous or pulsed. The use of pulsed lasers can reduce heat accumulation and consequent damage in the target and surrounding tissues. If a non-ablative pulsed laser is used (e.g., a quasi-continuous or acousto-optic Q-switched laser), the pulse rate can be any rate consistent with delivering an appropriate time-averaged irradiation intensity to the target tissue while avoiding a single pulse of such high intensity that damage is lasting (i.e., irreversible damage over a physiologically relevant time frame (e.g., hours to weeks of time) resulting in acute damage to the target tissue or optical fibers).

UV光的波長較佳在180-400 nm的範圍內。更佳地，UV光在300-400 nm的範圍內。甚至更佳地，UV光為約340-370 nm，並且最佳為約350-360 nm。發射355 nm輻射的三倍頻Nd:YAG雷射器是特別較佳的。The wavelength of the UV light is preferably in the range of 180-400 nm. More preferably, the UV light is in the range of 300-400 nm. Even more preferably, the UV light is about 340-370 nm, and most preferably about 350-360 nm. A frequency tripled Nd:YAG laser emitting 355 nm radiation is particularly preferred.

可以與本發明一起使用（同時避免燒蝕）的其他UV雷射器包括XeF雷射器（351 nm）、CW氬離子（351、364 nm）或CW氪離子（351、356 nm）。也可以使用任何二極管雷射器或染料雷射器，只要可以在血管擴張效果所需的UV範圍內獲得非燒蝕輸出。理論上，可以使用直接發射UV輻射或發射作為倍頻或三倍頻結果的UV輻射的任何雷射器。Other UV lasers that can be used with the present invention (while avoiding ablation) include XeF lasers (351 nm), CW argon ions (351, 364 nm), or CW krypton ions (351, 356 nm). Any diode laser or dye laser can also be used, as long as non-ablative output can be obtained in the UV range required for the vasodilation effect. In theory, any laser that emits UV radiation directly or as a result of frequency doubling or tripling can be used.

對於355 nmUV雷射照射，在強度為7的寬動態範圍（強度為3~約20W/cm²）上刺激擴張，假設是高斯射束形狀。然而，擴張效應與射束形狀無關。在上限處，在平滑肌細胞中形成液泡，但功能未受損。擴張效應取決於平均強度。例如，具有5千瓦峰值功率的7 Hz 100奈秒脈衝序列可以以20W/cm²使用，而不會造成功能損傷。For 355 nm UV laser irradiation, dilation is stimulated over a wide dynamic range of intensities of 7 (intensities from 3 to about 20 W/cm² ), assuming a Gaussian beam shape. However, the dilation effect is independent of the beam shape. At the upper limit, vacuoles are formed in the smooth muscle cells, but function is not impaired. The dilation effect depends on the average intensity. For example, a 7 Hz 100 nanosecond pulse train with 5 kW peak power can be used at 20 W/cm² without causing functional impairment.

例如，在對血管壁或血栓進行照明之前，藉由將少量生理鹽水溶液沖洗通過射束即將從其離開的導管開口，可以將血液從雷射束的路徑中清除。For example, prior to illuminating a vessel wall or thrombus, blood can be cleared from the path of the laser beam by flushing a small amount of saline solution through the catheter opening from which the beam will exit.

較佳地，調節UV照明的強度，以提供在血栓切除術前所需時間範圍內實現所需血管擴張程度所需要的最小劑量。例如，使用三倍頻Nd-YAG雷射器，入射強度約為5瓦特/cm²在小動脈中產生約20-30%的擴張（這種擴張是可以藉由NO·抑制劑藥物逆轉的）。12-20瓦特/cm²的較高強度（相當於脈衝頻率為20赫茲的每脈衝高達1焦耳/cm²的能量通量）可使較大動脈（直徑約1.5 mm）的直徑類似地增加，但強度超過20瓦特/cm²可能改變血管壁結構（平滑肌組織中形成小液泡），但未觀察到功能損傷。Preferably, the intensity of UV illumination is adjusted to provide the minimum dose necessary to achieve the desired degree of vascular dilation within the time frame required prior to thrombectomy. For example, using a frequency-tripled Nd-YAG laser, an incident intensity of about 5 watts/^cm2 produces about 20-30% dilation in small arteries (this dilation is reversible with NO·inhibitor drugs). Higher intensities of 12-20 W/^cm2 (equivalent to energy fluxes of up to 1 J/^cm2 per pulse at a pulse frequency of 20 Hz) produce similar increases in diameter in larger arteries (about 1.5 mm in diameter), but intensities above 20 W/^cm2 may alter vessel wall structure (vacuoles formed in smooth muscle tissue), but no functional impairment has been observed.

然後，入射強度可以按增量增加（例如，2瓦特/cm²或更大的增量），直到在合理的時間內（例如在5秒內）觀察到血管的適當擴張。照射週期可以是連續的（即持續到擴張效應穩定），或者可以是間歇的（在這種情況下，一個或更多個照射週期的持續時間也可以以給定的入射強度變化，以便獲得適當的回應；已經引起的擴張將被保留和放大）。適當的血管擴張回應（即擴張的程度及其開始和持續的動力學）可以由使用者確定；然而，許多使用者通常認為在5-10秒內血管直徑增加20-40%範圍內的回應是合適的。The incident intensity may then be increased in increments (e.g., 2 Watt/^cm2 or greater increments) until adequate dilation of the vessel is observed within a reasonable time (e.g., within 5 seconds). The irradiation cycles may be continuous (i.e., continued until the dilation effect stabilizes) or may be intermittent (in which case the duration of one or more irradiation cycles may also be varied at a given incident intensity in order to obtain an adequate response; dilation already induced will be preserved and amplified). The appropriate vasodilatory response (i.e., the extent of dilation and its kinetics of onset and duration) may be determined by the user; however, many users generally consider a response in the range of 20-40% increase in vessel diameter within 5-10 seconds to be appropriate.

本發明的方法適用於治療涉及動脈閉塞的各種疾病狀況。這種狀況的示例包括中風、心肌梗塞和任何大或小的外周動脈的閉塞或痙攣。The methods of the present invention are suitable for treating a variety of disease conditions involving arterial occlusion. Examples of such conditions include stroke, myocardial infarction, and occlusion or spasm of any large or small peripheral artery.

在使用抽吸導管的本發明方法中，可以引入球囊導管，然後將抽吸導管引入導管正上方、球囊部分下方。當球囊擴張時，UV纖維可以被引入球囊。當UV透明球囊在曲折的拐彎或狹窄之前擴張到超過抽吸導管的直徑時，則UV纖維在動脈中居中，並且不流動的血液從投射的光路中移位。然後，UV射束可以閃爍幾秒鐘，以獲得足夠的擴張，從而允許在受試者擴張系統中使用的血栓切除術導管通過。這裡，球囊不推壓動脈以擴張動脈，而只是有助於在雷射環形射束遵循光學自由路徑以非機械方式擴張動脈時將血液從動脈中移走。球囊很常見，但如果過度膨脹，則會損傷組織。In the method of the invention using an aspiration catheter, a balloon catheter may be introduced, and then the aspiration catheter introduced just above the catheter and below the balloon portion. As the balloon expands, the UV fiber may be introduced into the balloon. When the UV transparent balloon expands to exceed the diameter of the aspiration catheter before a tortuous bend or stenosis, the UV fiber is centered in the artery and non-flowing blood is displaced from the projected light path. The UV beam may then be flashed for a few seconds to obtain sufficient dilation to allow passage of a thrombectomy catheter used in the subject's dilation system. Here, the balloon does not push on the artery to dilate it, but simply helps move blood away from the artery while the laser ring beam follows an optical free path to dilate the artery non-mechanically. Balloons are common, but can damage tissue if overinflated.

一旦UV光被發射到血管壁上並被吸收，血管就將擴張並傳播擴張，而不管隨後是否存在血液或血流。該過程可用於在到達凝塊的途中更容易地穿過曲折的拐彎或狹窄。因此，盡可能減少了從進入點到目標位置的結構和內皮損傷。一旦到達凝塊，則進行最後的照射（包括可選的鹽水沖洗），然後抽吸導管提取凝塊。Once the UV light is emitted to the vessel wall and absorbed, the vessel will dilate and propagate the dilation regardless of the subsequent presence of blood or blood flow. This process can be used to more easily navigate tortuous bends or strictures on the way to the clot. Thus, structural and endothelial damage from the entry point to the target site is minimized. Once the clot is reached, a final irradiation is performed (including an optional saline flush) followed by a suction catheter to extract the clot.

與支架取回器結合使用時，導絲穿透凝塊並剛好穿過凝塊一釐米或更多釐米。然後將球囊導管插入並剛好擴張到凝塊的遠端，用UV纖維替換導絲以照射遠端段。然後抽出UV纖維，支架取回器通過球囊導管，在凝塊位置替換UV纖維。球囊導管可以就在凝塊近端被抽出，支架取回器網在導管抽出過程中自發地或以受控的方式擴展到適合於均勻和對稱地提取凝塊的直徑，這使得它能夠更好地捕獲整個凝塊並確保提取效率。When used in conjunction with a stent retriever, the guidewire penetrates the clot and passes just one centimeter or more past the clot. A balloon catheter is then inserted and expanded just distal to the clot, and the guidewire is replaced with a UV fiber to irradiate the distal segment. The UV fiber is then withdrawn and the stent retriever is passed over the balloon catheter, replacing the UV fiber at the clot location. The balloon catheter can be withdrawn just proximal to the clot, and the stent retriever mesh expands spontaneously or in a controlled manner during catheter withdrawal to a diameter suitable for uniform and symmetrical extraction of the clot, which enables it to better capture the entire clot and ensure extraction efficiency.

另一個益處是能夠在導管難以向目標凝塊位置穿過的位置採用UV照射；這將有助於更安全地提取凝塊。在UV擴張後，在某些意想不到的點處仍然可以使用對動脈來說顯得太大的導管。如果一開始就錯誤地選擇了導管尺寸，則可以使用UV擴張來擴張動脈，而不必替換目前的導管。Another benefit is the ability to use UV irradiation in locations where it is difficult to pass a catheter toward the target clot site; this will facilitate safer clot extraction. A catheter that is too large for the artery may still be used at some unexpected point after UV dilation. If the catheter size was incorrectly selected at the outset, UV dilation may be used to dilate the artery without having to replace the current catheter.

開發了使用二氧化矽光導纖維的向外突出的錐形尖端的設計（α = 18^o（圖1A、圖1B和圖2A）），以用於經由微導管進行血管內部署。 表1：從採用外錐形尖端的二氧化矽光導纖維（n₁=1.475）發射到水（n₂=1.333）或空氣（n₂=1.00）中的355 nm光的發射角β(α)，單位為度；α=在錐形尖端頂點處的半頂角；β(α)=π/2-α-γ(α), δ=π/2-3α, 並且γ(α)=sin^-1{(n₁/n₂)cos 3α}。α           β(α_水)            δ(α_水)              γ(α_水)β(α_空氣)            γ(α_空氣)25         48.35              15                  16.64 22         41.62              24.0               26.38              31.13              36.87 21         39.27              27.0               29.73              26.96              42.04 20.5       37.63              28.5               31.87              24.77             44.73 20          36.89              30.0               33.11              22.48             47.52 19.5        35.18              31.5               35.32             20.08             50.42 19           34.48              33.0               36.52             17.55             53.45 18.5         33.27              34.5               38.23             14.84             56.66 18            32.04              36.0               39.96             11.89             60.11 17.5          30.81             37.5               41.69             8.61              63.89 17             29.56             39.0               43.44             4.84              68.16 16.48         28.26             40.55             45.26              ~ 0              73.52 16              27.02             42.0               46.98             TIR 注：α的極限為（90°-玻璃到水的臨界角64.653°）=25.347°。A design using an outwardly projecting conical tip of a silica photoconductor (α = 18^° (Fig. 1A, Fig. 1B, and Fig. 2A)) was developed for intravascular deployment via a microcatheter. Table 1: Emission angle β(α) of 355 nm light emitted from a silica photoconductor with an external conical tip (n₁ = 1.475) into water (n₂ = 1.333) or air (n₂ = 1.00), in degrees; α = half-apex angle at the apex of the conical tip; β(α) = π/2-α-γ(α), δ = π/2-3α, and γ(α) = sin^-1 {(n₁ /n₂ )cos 3α}.α β(α_water) δ(α_water) γ(α_water)β(α_air) γ(α_air) 25 48.35 15 16.64 22 41.62 24.0 26.38 31.13 36.87 21 39.27 27.0 29.73 26.96 42.04 20.5 37.63 28.5 31.87 24.77 44.73 20 36.89 30.0 33.11 22.48 47.52 19.5 35.18 31.5 35.32 20.08 50.42 19 34.48 33.0 36.52 17.55 53.45 18.5 33.27 34.5 38.23 14.84 56.66 18 32.04 36.0 39.96 11.89 60.11 17.5 30.81 37.5 41.69 8.61 63.89 17 29.56 39.0 43.44 4.84 68.16 16.48 28.26 40.55 45.26 ~ 0 73.52 16 27.02 42.0 46.98 TIR Note: The limit of α is (90° - the critical angle from glass to water 64.653°) = 25.347°.

為了增加β（從而減少環形射束所對的動脈壁的面積），一個短的（約0.5 mm）由具有較高折射率的UV透明材料製成的外翻錐形段必須光學黏合於二氧化矽纖維。最佳選項是金剛石，折射率為n_d=2.48。To increase β (and thus reduce the area of the arterial wall subtended by the annular beam), a short (about 0.5 mm) everted tapered segment made of a UV-transparent material with a higher refractive index must be optically bonded to the silica fiber. The best choice is diamond, with a refractive index of n_d = 2.48.

表2呈現了針對從外部金剛石尖端離開進入水中的射束的與上面相同的計算。 表2：從外部金剛石尖端二氧化矽光導纖維（n₁=2.48）發射到水（n₂=1.333）中的355 nm雷射光的發射角β(α)，單位為度（參見圖3）；β(α) = 90 - α - γ(α), δ = 90 - 3α, 且 γ(α) = sin^-1{(n₁/n₂) cos 3α，其中α=錐形尖端頂點處的半頂角。αβ(α_水)              δ(α_水)           γ(α_水)20.2                3.83              29.4             65.97 21                 11.37              27                57.63 22                 18.83              26                49.17 23                 25.19              21                41.81 24                 30.91              18                35.09 27                 46.08                9                16.92 29                 55.41                3                  5.59 30                 60                     0                   0 31                 64.87               -3                 -5.87 32.5              71.55               -7.5            -14.05 注：全內反射（金剛石到水）的臨界入射角為32.51°。Table 2 presents the same calculations as above for the beam exiting the external diamond tip into water. Table 2: Emission angle β(α) in degrees for 355 nm laser light emitted from an external diamond tipped silica optical fiber (n₁ =2.48) into water (n₂ =1.333) (see Figure 3); β(α) = 90 - α - γ(α), δ = 90 - 3α, and γ(α) = sin^-1 {(n₁ /n₂ ) cos 3α, where α = half apex angle at the apex of the conical tip.αβ(α_water) δ(α_water) γ(α_water) 20.2 3.83 29.4 65.97 21 11.37 27 57.63 22 18.83 26 49.17 23 25.19 21 41.81 24 30.91 18 35.09 27 46.08 9 16.92 29 55.41 3 5.59 30 60 0 0 31 64.87 -3 -5.87 32.5 71.55 -7.5 -14.05 Note: The critical angle of incidence for total internal reflection (diamond to water) is 32.51°.

表3顯示了從由二氧化矽和金剛石製成的內翻錐形尖端向動脈壁發射到水（鹽水）中的355 nm雷射光的路徑範圍。發射角β是內翻錐形半頂角α（如圖3所描繪）的函數。內翻錐形尖端設計可能是一些從業者較佳的，因為在障礙物（如果有的話）中對該尖端的截留比對外錐形尖端的截留的可能性小得多。 表3：根據斯涅耳定律計算出以度為單位的發射角β，作為向動脈壁發射到水中的環形射束的二氧化矽和金剛石尖端的內翻錐體半頂角α的函數（圖3）。α=90°-θ₁，其中θ₁=θ_g,d並且g=玻璃（二氧化矽），d=金剛石，θ₂=θ_水，和β=θ_水-θ_s,d。二氧化矽纖維n_玻璃金剛石尖端的二氧化矽纖維n_金剛石θ_玻璃θ_水α             β                       θ_金剛石θ_水α            β64.60            88.31       25.40      23.71                32.50        88.44        57.50      55.94 60.00            73.39       16.61      13.39                31.50        76.43        58.50      44.93 31.00        73.38        59.00      42.38 30.00        68.47        60.00      38.47Table 3 shows the range of paths for 355 nm laser light launched into the artery wall in water (saline) from inverted tapered tips made of silica and diamond. The launch angle β is a function of the inverted cone half-apex angle α (depicted in Figure 3). The inverted tapered tip design may be preferred by some practitioners because entrapment of this tip in an obstruction (if any) is much less likely than an outward tapered tip. Table 3: Launch angle β in degrees calculated from Snell's law as a function of the inverted cone half-apex angle α for silica and diamond tips launching annular beams into water into the artery wall (Figure 3). α = 90° - θ₁ , where θ₁ = θ_g,d and g = glass (silicon dioxide), d = diamond, θ₂ = θ_water, and β = θ_water - θ_s,d .Silica fibern_glassdiamond tip Silica fibern_diamondθ_glassθ_waterα β θ_diamondθ_waterα β 64.60 88.31 25.40 23.71 32.50 88.44 57.50 55.94 60.00 73.39 16.61 13.39 31.50 76.43 58.50 44.93 31.00 73.38 59.00 42.38 30.00 68.47 60.00 38.47

該計算補充了對外部金剛石錐形尖端所做的計算，並且顯示發射角β甚至更大，因此與內翻錐形尖端相比，在離外錐形尖端的距離減小時提供了增加的射束強度（兩者都比單獨的二氧化矽好得多）。然而，β對α非常敏感，這意味著輸入的射束必須很好地準直，以盡可能減少極角散佈2θw（參見圖1A），並且內部錐形尖端必須被非常精確地研磨，以確保表面高品質並因此盡可能減少射束散射。在此，θ_crit=θ_金剛石=32.51°並且β=57.49°。如果θ_金剛石=32.50°，則θ_水=88.44°，α=57.50°，並且β=55.94°（表3）。This calculation complements that done for the outer diamond tapered tip and shows that the launch angle β is even larger, thus providing increased beam intensity at decreasing distance from the outer tapered tip compared to the inverted tapered tip (both much better than silica alone). However, β is very sensitive to α, which means that the input beam must be well collimated to minimize polar angular spread 2θw (see Figure 1A) and that the inner tapered tip must be very accurately ground to ensure high surface quality and thus minimize beam scatter. Here, θ_crit = θ_diamond = 32.51° and β = 57.49°. If θ_diamond = 32.50°, then θ_water = 88.44°, α = 57.50°, and β = 55.94° (Table 3).

作為到目前為止顯示的產生環形射束的錐形尖端光學設計的替代方案，我們提出了衍射光學器件與光導纖維的組合。衍射光學器件涉及藉由幾種方法中的任何一種（例如，光刻、電子束蒸發）在平端光導纖維上蝕刻幾何圖案，平端光導纖維的尖端可以是鎔融二氧化矽本身或其他光學耦合的UV透明高折射率（n＞2）物質（例如氧化鋯、金剛石或定制設計的聚合體材料（例如，塑膠）），以獲得所需的衍射相位輪廓。纖維末端上的圖案類似於圓形對稱的淺浮雕——一系列深度和半徑可變的同心環形結構，因為必須精確去除材料才能獲得所需的衍射相位輪廓。所需的輸出是具有最小邊帶的非常清晰的環形貝塞爾射束（Bessel beam）。對於以β＞40°的角度離開尖端的射束，很可能使用高折射率物質，例如後三種（如已經說明的）。據我們所知，尚未產生藉由這種技術在任何介質中產生大於β=15°的環形射束，但是衍射光學器件的製造商願意考慮擴大它們的能力範圍。放置在合適的高折射率材料上的平端衍射圖案可能是該器件的最佳形式，該高折射率材料包括浸入水中的鎔融二氧化矽光導纖維的端蓋。As an alternative to the conical-tip optical designs shown so far for producing annular beams, we propose the combination of diffractive optics with optical fibers. Diffractive optics involve etching a geometric pattern on a flat-ended optical fiber, whose tip can be fused silica itself or other optically coupled UV-transparent high-refractive-index (n>2) materials such as zirconia, diamond, or custom-designed polymer materials (e.g., plastics), by any of several methods (e.g., photolithography, electron-beam evaporation) to obtain the desired diffractive phase profile. The pattern on the end of the fiber resembles a circularly symmetric shallow relief—a series of concentric annular structures of variable depth and radius, because material must be removed precisely to obtain the desired diffractive phase profile. The desired output is a very sharp annular Bessel beam with minimal sidebands. For beams leaving the tip at angles of β>40°, it is likely that a high index material such as the latter three (as already described) will be used. To our knowledge, annular beams greater than β=15° have not yet been produced by this technique in any medium, but manufacturers of diffractive optical devices would like to consider extending the range of their capabilities. A flat-ended diffraction pattern placed on a suitable high index material, including end caps of fused silica optical fibers immersed in water, is probably the best form of such a device.

外部或內部錐形尖端可以在與動脈壁成一定角度的範圍內產生環形射束，對於外部尖端，實際的上限對於二氧化矽為大約48°，對於金剛石為71.5°，但是較佳地將使用接近最大的角度。對於內部（內翻）金剛石錐形尖端，範圍可高達56°，這是較佳的。以最大銳角發射射束的直接益處是減小了環形射束寬度，從而提高了雷射強度。因為擴張過程完全取決於射束強度（在3到20瓦特/cm²之間），可以更高效地使用更低功率（並且很可能更緊湊）的雷射器。內部錐形尖端的設計是為了安全，因為在之前的工作中，我們注意到二氧化矽外部尖端可能會損壞。呈現出在藉由附接到任何其他裝置或組織部件插入時不會因而受損的裝置（這是由於避免了截留，並且保留了尖端結構）顯然是有益的。然而，這些效應不太可能發生於非常堅硬的材料，例如金剛石。External or internal tapered tips can produce an annular beam at a range of angles to the artery wall, with the practical upper limit being about 48° for silica and 71.5° for diamond for external tips, but it is preferred to use angles close to the maximum. For internal (inverted) diamond tapered tips, the range can be as high as 56°, which is preferred. The direct benefit of firing the beam at the most acute angle is a reduction in the annular beam width, which increases the laser intensity. Because the expansion process is entirely dependent on the beam intensity (between 3 and 20 watts/^cm2 ), a lower power (and likely more compact) laser can be used more efficiently. The design of the inner tapered tip is for safety, as in previous work we noted that silica outer tips can be damaged. It would be clearly beneficial to present a device that does not suffer damage during insertion by attachment to any other device or tissue component (this is because entrapment is avoided and the tip structure is preserved). However, these effects are unlikely to occur in very hard materials such as diamond.

鑒於本文提供的描述，本發明的這些和其他實施例和應用對技術人員來說將變得顯而易見。出血性中風的一個常見但難治的方面是大腦大動脈的血管痙攣（收縮）。從破裂的動脈瘤射入（例如）蛛網膜下腔的血液沿著動脈遷移，來自溶解的紅細胞的血紅蛋白進入動脈壁，並且清除一氧化氮，從而誘導痙攣。這種情況目前不能得到可靠的治療；全身性擴張藥物可以降低（並且已經降低）到發病點的血壓。另一個目前無法治療的方面是由大腦中血小板閉塞的微血管介導的早期腦損傷（即，前期血管痙攣）。儘管進行了大量的動物研究，但還沒有藥物可以溶解人體內的血小板血栓。UV雷射方法旨在明確治療這兩種極其困難的情況。我們已經在遭受出血性中風的狗中顯示了三天血管痙攣的逆轉。我們還表明，血小板凝塊確實可以被UV雷射誘導的一氧化氮溶解，因為一氧化氮抑制凝血酶，凝血酶是維持血小板間纖維蛋白原/血小板GPIIb-IIIa交聯所需的酶。These and other embodiments and applications of the invention will become apparent to those of skill in the art in view of the description provided herein. A common but intractable aspect of hemorrhagic stroke is vasospasm (contraction) of the large cerebral arteries. Blood ejected from a ruptured aneurysm into the subarachnoid space (for example) migrates along the arteries, and hemoglobin from lysed erythrocytes enters the arterial walls and scavenges nitric oxide, thereby inducing spasm. There is currently no reliable treatment for this condition; systemic vasodilators can (and have lowered) blood pressure to the point of onset. Another currently untreatable aspect is early brain damage mediated by platelet-occluded microvessels in the brain (i.e., pre-vasospasm). Despite extensive animal research, there are no drugs that can dissolve platelet clots in humans. The UV laser approach is designed to definitively treat both of these extremely difficult conditions. We have shown reversal of three-day vasospasm in dogs that suffered hemorrhagic stroke. We have also shown that platelet clots can indeed be dissolved by UV laser-induced nitric oxide, because nitric oxide inhibits thrombin, an enzyme required to maintain interplatelet fibrinogen/platelet GPIIb-IIIa crosslinks.

我們提出，由於一氧化氮的遠距離自我複製及其相關的血管擴張，對通向就其與遠端分支及其微血管床連接處近端的供血動脈的主幹進行UV照射，除了動脈再循環之外，還將允許並加強血液再灌注到不能通過血栓切除術直接治療的區域，從而提高組織存活的可能性。例如，腦動脈瘤破裂的患者將藉由標準護理介入裝置（例如線圈和支架）進行緊急治療。在動脈瘤被固定後，神經介入醫生可以繼續定位用於盤繞動脈瘤更遠端的微導管。微導管可以用UV透明球囊導管替換，並且微導絲可以用光導纖維替換。遠端UV照射將溶解血管區域中血小板栓塞閉塞的微血管，從而增強再灌注並改善患者的臨床結果。動脈瘤治療後的三至二十一天，腦血管痙攣可能導致血管收縮。同樣，使用UV透明球囊導管和光導纖維，血管收縮附近的UV照射將擴張動脈並將其恢復到其原始（或大於原始）直徑，從而恢復血液循環。We propose that UV irradiation of the main trunk of the feeding artery proximal to its connection with distal branches and their microvascular beds will, in addition to arterial recirculation, allow and enhance blood reperfusion to areas that cannot be treated directly by thrombectomy, thereby improving the likelihood of tissue survival due to the long-range self-replication of nitric oxide and its associated vasodilation. For example, patients with ruptured brain aneurysms would be treated acutely with standard of care interventional devices such as coils and stents. After the aneurysm is fixed, the neurointerventionalist can proceed to position a microcatheter that is used to coil the aneurysm more distally. The microcatheter can be replaced with a UV-transparent balloon catheter, and the microguidewire can be replaced with a light-guided fiber. Distal UV irradiation will dissolve microvessels occluded by platelet emboli in the vascular area, thereby enhancing reperfusion and improving the patient's clinical outcome. Three to twenty-one days after aneurysm treatment, cerebral vasospasm may cause vasoconstriction. Similarly, using a UV-transparent balloon catheter and light-guided fibers, UV irradiation near the vasoconstriction will dilate the artery and restore it to its original (or larger than original) diameter, thereby restoring blood circulation.

動脈粥樣硬化性血管疾病可由於斑塊的形成而導致動脈腔狹窄（stenosis 或narrowing (stricture)）。目前的方法要求通過球囊血管成形術擴大管腔，然後用支架植入術固定開口。血管成形術和支架植入術首先需要將微導絲穿過狹窄處以獲得遠端通路。當狹窄為中度至重度時，很難在不清除動脈粥樣硬化的情況下將導絲穿安全地穿過狹窄。在動脈粥樣硬化疾病的支架植入術手術期間，可以藉由用UV擴張動脈來促進導絲和裝置穿過斑塊（假設現有的疤痕組織將允許這種擴張）。如果斑塊鈣化，它可能會非常硬，並且不可壓縮。此外，球囊擴展可能導致鄰近的非動脈粥樣硬化段擴展和拉伸，甚至達到結構扭曲的程度。對這種創傷的常見反應是肥大，這是一種異常的癒合反應，已知其最終會堵塞支架形成的開口。我們提出，藉由一氧化氮途徑對動脈（即使是病變動脈）進行非機械性擴張，將極大地促進血管內裝置進入動脈粥樣硬化的遠端。NO途徑還將盡可能減少血管扭曲和癒合反應的過度表達，從而保留所需的管腔及其使用壽命。鄰近非動脈粥樣硬化段的內皮損傷也將減少。例如，在患有嚴重頸動脈粥樣硬化的患者體內，可以借助於微導絲將UV透明球囊導管定位在狹窄附近。導絲可以用光導纖維替換。隨後的UV照射將使動脈壁擴張，並且擴大狹窄間隙。然後，可以用微導絲替換光導纖維，並且導絲現在可以更容易地導航穿過加寬的狹窄，以獲得對遠端的進入。然後可以去除球囊導管，並且裝置輸送系統通過導絲，以用於治療斑塊。通常可以使用相同的系統來安全地放置支架，以確保通過狹窄的循環，除了現在支架可以放置在已擴張的血管中而不會引起通常的內皮損傷。這將避免再次狹窄（這是目前實施的支架部署的一種非常常見的併發症，並且需要在3-5年內替換支架）。Atherosclerotic vascular disease can lead to stenosis or narrowing (stricture) of the artery lumen due to plaque formation. Current approaches require dilation of the lumen with balloon angioplasty followed by stenting to stabilize the opening. Angioplasty and stenting first require passing a microwire through the stenosis to gain distal access. When the stenosis is moderate to severe, it is difficult to pass the wire safely through the stenosis without removing the atherosclerosis. During stenting procedures for atherosclerotic disease, passage of the wire and device through the plaque can be facilitated by dilating the artery with UV (assuming that the existing scar tissue will allow such dilation). If the plaque is calcified, it may be very stiff and incompressible. In addition, balloon dilation may cause adjacent nonatherosclerotic segments to dilate and stretch, even to the point of distorting the structure. The common response to this injury is hypertrophy, an abnormal healing response that is known to eventually occlude the stent-created opening. We propose that nonmechanical dilation of arteries, even diseased arteries, via the nitric oxide pathway would greatly facilitate the advancement of endovascular devices into the distal end of the atherosclerosis. The NO pathway would also minimize vessel distortion and overexpression of the healing response, thereby preserving the desired lumen and its lifespan. Endothelial damage adjacent to non-atherosclerotic segments will also be reduced. For example, in a patient with severe cervical atherosclerosis, a UV-transparent balloon catheter can be positioned near the stenosis with the aid of a microguidewire. The guidewire can be replaced with a light-guided fiber. Subsequent UV irradiation will dilate the arterial wall and widen the stenotic gap. The light-guided fiber can then be replaced with a microguidewire, and the guidewire can now be more easily navigated through the widened stenosis to gain access to the distal end. The balloon catheter can then be removed and the device delivery system passed over the guidewire for treatment of the plaque. The same system can often be used to safely place stents to ensure circulation through stenosis, except now the stent can be placed in an already dilated vessel without causing the usual endothelial damage. This will avoid restenosis (which is a very common complication of stent deployment as currently practiced and requires replacement of the stent in 3-5 years).

吸入一氧化氮可用於治療肺動脈高壓和急性呼吸窘迫症候群，尤其是在兒科患者中。吸入的氣體擴散通過肺泡——毛細血管膜並引起血管擴張，導致肺血管阻力降低和通氣肺段中血液灌注增加。這可能會改善患者體內的血氧。所提出的發明可能以更有針對性的方式用於擴張肺動脈的段和分支的血管。可以經由右心導管插入術經由股靜脈進入肺動脈及其分支。然後可以將球囊導管定位在目標肺動脈分支中。可以將光導纖維引入膨脹的球囊中，以便用環形射束照射動脈壁。由此產生的血管擴張將藉由轉亞硝基化從環形射束所接觸的區域向近端和遠端傳播。Inhaled nitric oxide can be used to treat pulmonary hypertension and acute respiratory distress syndrome, especially in pediatric patients. The inhaled gas diffuses through the alveolar-capillary membrane and causes vasodilation, resulting in a decrease in pulmonary vascular resistance and increased blood perfusion in the ventilated lung segments. This may improve blood oxygenation in the patient. The proposed invention may be used in a more targeted manner to dilate the blood vessels of segments and branches of the pulmonary arteries. The pulmonary arteries and their branches can be accessed through the femoral vein via right heart catheterization. A balloon catheter can then be positioned in the target pulmonary artery branch. A light guide fiber can be introduced into the inflated balloon in order to irradiate the arterial wall with a circular beam. The resulting vasodilation will propagate proximally and distally from the area contacted by the circular beam via transnitrosylation.

本發明的另一方面涉及一種可用於動脈導管插入術的改良導絲。典型地，導絲通過血管進給以到達目標位置，隨後將導管穿在導絲上以執行預期的過程，例如使用血栓切除術裝置（例如支架取回器或抽吸導管）的血栓切除術手術。本發明的過程包括從導管中去除導絲，並用光導纖維替換導絲，該光導纖維能夠發射UV雷射光作為具有足夠強度以使血管擴張的擴展環形射束。涉及去除導絲並用光導纖維替換導絲的步驟的替代方案是在導絲內提供光導纖維，作為導絲/光導纖維的組合。本發明這一方面的較佳實施例包括具有中空芯的導絲，使得在導絲的整個長度上形成軸向空腔或管腔，並且該軸向空腔或管腔被配置為柔性金屬管結構的形式。在導絲內所包含的是二氧化矽光導纖維，其尖端被設計成發射環狀射束，該尖端較佳由UV透明的高折射率材料（例如金剛石）製成。柔性金屬管結構可以由柔韌的金屬合金（例如鎳鈦諾）組成。光導纖維可以未固定於導絲，或者較佳地根據需要相對於中空導絲的內壁固定。在這種配置中（“鎖定位置”），導絲和光導纖維彼此是一體的，並且當被放置在血管內時作為單個單元一起工作。在一個實施例中，光導纖維可以被手動配置成“鎖定位置”（由此它被固定於導絲），以及被手動配置成“解鎖位置”（這允許導絲和光導纖維彼此獨立且分開地操作）。Another aspect of the invention relates to an improved guidewire that can be used in arterial catheterization. Typically, a guidewire is fed through a blood vessel to reach a target location, and a catheter is then threaded over the guidewire to perform the desired procedure, such as a thrombectomy procedure using a thrombectomy device (e.g., a stent retriever or an aspiration catheter). The process of the present invention includes removing the guidewire from the catheter and replacing the guidewire with a light guide fiber that is capable of emitting UV laser light as an expanded annular beam having sufficient intensity to cause blood vessel dilation. An alternative to the steps of removing the guidewire and replacing the guidewire with the light guide fiber is to provide the light guide fiber within the guidewire as a guidewire/light guide fiber combination. Preferred embodiments of this aspect of the invention include a guidewire having a hollow core such that an axial cavity or lumen is formed throughout the length of the guidewire and the axial cavity or lumen is configured in the form of a flexible metal tube structure. Contained within the guidewire is a silica optical fiber having a tip designed to emit an annular beam, the tip preferably being made of a UV transparent high refractive index material such as diamond. The flexible metal tube structure may be composed of a pliable metal alloy such as nickel titanium. The optical fiber may be unsecured to the guidewire or, preferably, secured relative to the inner wall of the hollow guidewire as desired. In this configuration ("locked position"), the guidewire and the optical fiber are integral to one another and work together as a single unit when placed within a blood vessel. In one embodiment, the optical fiber can be manually configured into a "locked position" (whereby it is secured to the guidewire), and manually configured into an "unlocked position" (which allows the guidewire and optical fiber to be operated independently and separately from one another).

整合或組合導絲和光導纖維實施例的遠端段在圖8A中以y平面（矢狀）橫截面的方式示出。圖8B、圖8C和圖8D描繪了不同的光導纖維尖端配置，其中每種配置都具有負軸錐透鏡的效果，將發散的雷射束投射到動脈內壁上。發散雷射束將導致光導纖維的輸出模式是多模或單模，這取決於纖維厚度。圖8A示出了中空導絲和光導纖維的組合800，其中根據預期的應用，外表面可以親水或疏水地塗覆。光導纖維802覆蓋有聚合體塗層803（包層），該聚合體塗層803確保全內反射，並且設置在柔性金屬導絲的中空芯801內。在一個實施例中，導絲的內部804包括包裹導絲中空芯的金屬線圈，使得可扭轉性、柔韌性、可成形性、形狀保持性和觸覺反饋的主要要求可以滿足所需的具體應用。光導纖維的遠端805（由其包層803的限制來限定）基本上與半球形導絲帽806的端部全等。帽806可以由柔軟的柔性材料製成，該材料旨在盡可能減少對其探測直到到達目標位置的空腔（例如動脈）的機械損傷。The distal end of an integrated or combined guidewire and optical fiber embodiment is shown in FIG8A in a y-plane (sagittal) cross-section. FIG8B, FIG8C, and FIG8D depict different optical fiber tip configurations, each of which has the effect of a negative axis cone lens, projecting a divergent laser beam onto the inner wall of the artery. The divergent laser beam will cause the output mode of the optical fiber to be multimode or single mode, depending on the fiber thickness. FIG8A shows a combination 800 of a hollow guidewire and an optical fiber, wherein the outer surface can be coated hydrophilically or hydrophobically, depending on the intended application. The optical fiber 802 is covered with a polymer coating 803 (cladding) that ensures total internal reflection and is disposed within the hollow core 801 of a flexible metal guidewire. In one embodiment, the inner portion 804 of the guidewire includes a metal coil that wraps around the hollow core of the guidewire so that the primary requirements of twistability, flexibility, formability, shape retention, and tactile feedback can be met for the specific application required. The distal end 805 of the optical fiber (defined by the confinement of its cladding 803) is substantially congruent with the end of a hemispherical guidewire cap 806. Cap 806 may be made of a soft, flexible material designed to minimize mechanical damage to the cavity (e.g., artery) it is probing until the target location is reached.

在較佳實施例中，導絲和光導纖維組合包括足夠長的固體鎔融二氧化矽光導纖維，以從其遠端發射UV雷射光而不受導絲帽806的阻礙，同時也不會延伸顯著超過導絲帽806，從而在移動和放置於目標位置時保護血管免受光導纖維尖端的影響。外錐形尖端的頂點可以被導絲屏蔽，直到放置在所需的位置。任何顆粒的積聚應當可以藉由鹽水沖洗導管來去除。In a preferred embodiment, the guidewire and optical fiber combination includes a solid fused silica optical fiber of sufficient length to emit UV laser light from its distal end without being obstructed by the guidewire cap 806, while not extending significantly beyond the guidewire cap 806, thereby protecting the blood vessels from the influence of the optical fiber tip during movement and placement at the target location. The apex of the outer tapered tip can be shielded by the guidewire until placed at the desired location. Any accumulation of particles should be removed by flushing the catheter with saline.

組合導絲和光導纖維的遠端可以包括與光導纖維進行光通信的單獨的尖端。與光導纖維進行光通信的單獨的尖端可以是金剛石、氧化鋯或聚合體材料（例如，塑膠）。例如，金剛石尖端可以光學耦合到二氧化矽纖維802，並以三種方式配置以產生雷射光的擴展射束。圖8B示出了具有外錐形尖端811的光導纖維。光線807被示出藉由一次全內反射進入和離開該纖維。顯示內反射角α和發射角β處於它們的最大值（分別為32.5°和71.5°）。在較佳實施例中，組合的導絲和光導纖維可以被配置在鎖定位置，使得尖端頂點可以稍微凸出，以穿過硬障礙物，例如鈣化的動脈粥樣硬化。在一個實施例中，光導纖維的遠端可以被配置為能夠發射如上所述的錐形射束中的UV光的外錐形尖端。The distal end of the combined guide wire and optical fiber can include a separate tip that is in optical communication with the optical fiber. The separate tip that is in optical communication with the optical fiber can be diamond, zirconium oxide, or a polymer material (e.g., plastic). For example, a diamond tip can be optically coupled to a silica fiber 802 and configured in three ways to produce an expanded beam of laser light. FIG. 8B shows an optical fiber with an outer tapered tip 811. Light 807 is shown entering and leaving the fiber by a total internal reflection. The internal reflection angle α and the emission angle β are shown to be at their maximum values (32.5° and 71.5°, respectively). In a preferred embodiment, the combined guide wire and optical fiber can be configured in a locked position so that the tip apex can be slightly protruded to pass through hard obstacles, such as calcified atherosclerosis. In one embodiment, the distal end of the optical fiber can be configured as an outer conical tip capable of emitting UV light in a conical beam as described above.

圖8C表示組合中空導絲和光導纖維，其中，光導纖維802具有與纖維光學接觸的內翻錐形尖端812。在一個實施例中，光導纖維的遠端可以被配置為能夠發射如上所述的錐形射束中的UV光的內翻錐形尖端。8C shows a combined hollow guidewire and optical fiber, wherein the optical fiber 802 has an inverted tapered tip 812 in optical contact with the fiber. In one embodiment, the distal end of the optical fiber can be configured as an inverted tapered tip capable of emitting UV light in a cone-shaped beam as described above.

圖8D顯示了在金剛石段的平坦的蝕刻尖端809上形成的衍射光學元件（DOE），該金剛石段光學耦合到二氧化矽主纖維，以從輸入TEM₀₀雷射束808產生UV雷射環形射束810，這類似於由負軸錐透鏡產生的射束。在這個快速發展的領域中，可以使用幾種已知方法中的任何一種，將TEM₀₀雷射束轉換成貝塞爾強度輪廓（環狀）。成形圖案可以包括在光導纖維的扁平輸出端上形成的同心斜面環（每個斜面環可以是具有連續厚度的薄扁平環的級聯），具有大約5 um的機械分辨率。在一個實施例中，環形射束可以對著至少90°的全錐形角。在較佳實施例中，環形射束可以對著120°或更大的全錐形發射角，以便增強擴張性紫外環形射束強度，從而需要更少的雷射輸入功率。纖維直徑、模式（可以是多模）和輸出環厚度對於產生操作上有效的環形射束輸出並不重要。在一個實施例中，光導纖維的遠端可以被配置為平坦遠端，該平坦遠端具有蝕刻在平坦遠端內的同心圓凹槽，其中平坦遠端是如上所述的衍射光學元件（DOE）。FIG8D shows a diffractive optical element (DOE) formed on the flat etched tip 809 of a diamond segment optically coupled to a SiO2 main fiber to produce a UV laser ring beam 810 from an input TEM₀₀ laser beam 808, similar to the beam produced by a negative axis cone lens. In this rapidly developing field, the TEM₀₀ laser beam can be converted into a Bessel intensity profile (ring shape) using any of several known methods. The shaped pattern can include concentric beveled rings formed on the flat output end of the optical fiber (each beveled ring can be a cascade of thin flat rings of continuous thickness) with a mechanical resolution of about 5 um. In one embodiment, the ring beam may subtend a full cone angle of at least 90°. In a preferred embodiment, the ring beam may subtend a full cone emission angle of 120° or greater to enhance the expanded UV ring beam intensity, thereby requiring less laser input power. The fiber diameter, mode (which may be multimode), and output ring thickness are not critical to producing an operationally efficient ring beam output. In one embodiment, the distal end of the optical fiber may be configured as a flat distal end having concentric circular grooves etched into the flat distal end, wherein the flat distal end is a diffractive optical element (DOE) as described above.

圖9A和圖9B示出了根據本發明的光導纖維的蝕刻端的實施例。圖9A顯示了光導纖維802的遠端的正視圖，該遠端蝕刻有在光導纖維中形成的V形凹槽的同心環，以產生衍射光學元件（DOE）。中央V形槽902在光導纖維的中心形成內翻錐體。中心外側的每個同心V形凹槽具有峰901a和谷901b。9A and 9B illustrate an embodiment of an etched end of an optical fiber according to the present invention. FIG. 9A shows a front view of the distal end of an optical fiber 802 etched with concentric rings of V-grooves formed in the optical fiber to create a diffractive optical element (DOE). The central V-groove 902 forms an inverted cone in the center of the optical fiber. Each concentric V-groove outside the center has a peak 901a and a valley 901b.

圖9B進一步示出了在圖8D的側視圖和圖9A的正視圖中所示的同心環V形凹槽圖案。在該視圖中，可以進一步理解光導纖維802的遠端平端中交替的峰901a和谷901b的圖案。較佳地，每個峰901a與其他峰901a具有相同的高度，並且每個谷901b與其他谷901b具有相同的深度。圖9B還示出了固體鎔融二氧化矽光導纖維。FIG9B further illustrates the concentric annular V-shaped groove pattern shown in the side view of FIG8D and the front view of FIG9A. In this view, the pattern of alternating peaks 901a and valleys 901b in the far flat end of the optical fiber 802 can be further understood. Preferably, each peak 901a has the same height as the other peaks 901a, and each valley 901b has the same depth as the other valleys 901b. FIG9B also illustrates a solid molten silicon dioxide optical fiber.

有利地，整合或組合的導絲和光導纖維實施例可以消除常規導管插入術手術的某些步驟。在常規導管插入術手術需要步驟（1）插入導絲，步驟（2）將導管放置在導絲上，然後步驟（3）從定位的導管中去除導絲，以及步驟（4）用光導纖維替換導絲以擴張血管的情況下，導絲內的組合光導纖維可以消除步驟（3）和步驟（4），因為導絲不需要從導管中被去除並由光導纖維替換。藉由消除步驟（3）和步驟（4）而節省的時間對於使用者和正在經歷該手術的患者是有利的。Advantageously, the integrated or combined guidewire and optical fiber embodiments can eliminate certain steps of a conventional catheterization procedure. Where a conventional catheterization procedure requires step (1) inserting the guidewire, step (2) placing a catheter over the guidewire, then step (3) removing the guidewire from the positioned catheter, and step (4) replacing the guidewire with an optical fiber to dilate the blood vessel, the combined optical fiber within the guidewire can eliminate step (3) and step (4) because the guidewire does not need to be removed from the catheter and replaced with the optical fiber. The time saved by eliminating step (3) and step (4) is advantageous to the user and the patient undergoing the procedure.

藉由消除上述手術中的步驟來節省時間，以促進再灌注，本發明的組合導絲/光導纖維可以降低與血栓切除術後相關的行為異常的發生率（約50%）和嚴重性。這些在TICI血流狀態的所有級別（甚至在3級時）都有證據，該證據表明主要閉塞動脈完全再通。然而，TICI沒有測量其分支動脈或小動脈中的血液回流，這些分支動脈或小動脈負責將營養物質直接輸送到組織。再灌注與既往再循環是獨立的，目前無法藉由血管造影技術觀察到。再灌注被定義為對不能通過血栓切除術進入或清除的動脈側分支和微血管中的正常血流進行恢復。儘管主動脈再通，但相對缺乏再灌注可能很好地解釋了行為恢復的可變性。這被認為是由於幾種機制，包括在原位或來自於所提取的閉塞血栓中釋放的栓子導致的在遠端血管中微血栓的形成或擴大。再灌注的目的是挽救半影組織，半影組織代謝靜止，但沒有死亡（梗塞），主要是由於側支循環的逆行充盈。然而，如果受試者區域已經梗塞，再灌注可以導致非常嚴重的出血後果，因為血管壁退化。因此，只有當判定半影組織可挽救，並且判定不太可能出血時，才應該使用UV雷射誘導的擴張。By eliminating the above steps in the procedure to save time and promote reperfusion, the combination guidewire/light guide fiber of the present invention can reduce the incidence (approximately 50%) and severity of behavioral abnormalities associated with post-thrombectomy. These are evidenced at all levels of TICI flow status (even at level 3), which indicates complete recanalization of the main occluded artery. However, TICI does not measure blood return in its branches or arterioles, which are responsible for delivering nutrients directly to the tissue. Reperfusion is independent of previous recirculation and cannot currently be observed by angiographic techniques. Reperfusion is defined as the restoration of normal blood flow in the collateral branches and microvessels of an artery that cannot be accessed or removed by thrombectomy. The relative lack of reperfusion despite recanalization of the main arteries may well explain the variability in behavioral recovery. This is thought to be due to several mechanisms, including the formation or expansion of microthrombi in distal vessels either in situ or from emboli released from the extracted occluding thrombus. The goal of reperfusion is to salvage penumbra tissue, which is metabolically quiescent but not dead (infarcted), primarily due to retrograde filling of the collateral circulation. However, if the subject area is already infarcted, reperfusion can result in very severe hemorrhagic consequences because of vessel wall degeneration. Therefore, UV laser-induced dilation should be used only when the penumbra tissue is judged to be salvageable and hemorrhage is judged unlikely.

本發明的一個方面涉及用於再灌注血栓遠端動脈血管的方法，其中，該方法包括以下步驟： i) 提供能夠攜帶UV雷射光的光導纖維；以及 ii) 將光導纖維延伸通過血栓；以及 iii) 從血栓遠端的光導纖維發射UV雷射光，以擴張血栓遠端的動脈血管；以及 iv) 去除血栓； 從而允許已擴張的動脈血管的再循環、血液流向以及再灌注，該血管包括通常不能通過血栓切除術治療的血管。One aspect of the present invention relates to a method for reperfusing an artery distal to a thrombus, wherein the method comprises the steps of:i) providing a light-conducting fiber capable of carrying UV laser light; andii) extending the light-conducting fiber through the thrombus; andiii) emitting UV laser light from the light-conducting fiber distal to the thrombus to dilate the artery distal to the thrombus; andiv) removing the thrombus;thereby allowing recirculation, blood flow, and reperfusion of the dilated artery, including vessels that are not normally treatable by thrombectomy.

將光導纖維延伸通過血栓可以較佳地延伸到適合於UV照射遠端區域的距離，在該遠端區域中，可以藉由擴張來加強再灌注。在本文描述的過程中，UV雷射光的任何發射或脈衝都可以重複，以產生所需的動脈擴張效果。本文所述的已擴張並經歷了再灌注的動脈血管較佳為小分支動脈以及小動脈。還可以發射UV雷射光來溶解、解離或分解在血栓遠端的動脈或小動脈中形成的血小板凝塊。Extending the optical fiber through the thrombus can preferably be extended to a distance suitable for UV irradiation of a distal region where reperfusion can be enhanced by dilation. In the process described herein, any emission or pulse of UV laser light can be repeated to produce the desired arterial dilation effect. The arterial vessels described herein that have been dilated and experienced reperfusion are preferably small branch arteries and small arteries. UV laser light can also be emitted to dissolve, dissociate or decompose platelet clots formed in arteries or small arteries distal to the thrombus.

在本發明的一個實施例中，在將光導纖維延伸通過血栓之前，用於再灌注血栓遠端的動脈血管的方法還包括從血栓附近的光導纖維（球囊導管內）發射UV雷射光的步驟。較佳地，用UV光照射血栓附近的動脈血管足夠溶解結合血小板層的時間。In one embodiment of the present invention, the method for reperfusing an artery distal to a thrombus further comprises the step of emitting UV laser light from the optical fiber (inside the balloon catheter) near the thrombus before extending the optical fiber through the thrombus. Preferably, the artery near the thrombus is irradiated with UV light for a time sufficient to dissolve the bound platelet layer.

在一個實施例中，該方法可以包括在將光導纖維延伸通過血栓之後，從血栓近端的光導纖維發射UV雷射光，以及抽出血栓近端的光導纖維。在另一個實施例中，該方法可以包括在將光導纖維延伸通過血栓之前和之後，用來自光導纖維的UV雷射光照射血栓附近。In one embodiment, the method may include emitting UV laser light from the optical fiber proximal to the thrombus after extending the optical fiber through the thrombus, and withdrawing the optical fiber proximal to the thrombus. In another embodiment, the method may include irradiating the vicinity of the thrombus with UV laser light from the optical fiber before and after extending the optical fiber through the thrombus.

在另一個實施例中，當光導纖維從血栓的遠端側抽出到血栓的近端側時，用UV光的至少一個爆發或幾個UV光照射間隔照射血栓遠端的動脈血管。血栓遠端的動脈血管較佳照射足夠溶解結合血小板層的時間。在較佳實施例中，連續或脈衝形式的UV光能爆發可以以約2-20秒（較佳為至少約5-15秒，更佳為約8-12秒）的照射間隔發射。In another embodiment, as the optical fiber is withdrawn from the distal side of the thrombus to the proximal side of the thrombus, the artery distal to the thrombus is irradiated with at least one burst of UV light or several UV light irradiation intervals. The artery distal to the thrombus is preferably irradiated for a time sufficient to dissolve the bound platelet layer. In a preferred embodiment, continuous or pulsed bursts of UV light energy can be emitted at an irradiation interval of about 2-20 seconds (preferably at least about 5-15 seconds, more preferably about 8-12 seconds).

在另一個實施例中，該方法可以包括發射UV雷射光以溶解或分解在血栓遠端的動脈或小動脈中形成的聚集的血小板凝塊的附加步驟。在一個實施例中，該方法包括作為閉塞血栓的血栓。In another embodiment, the method can include an additional step of emitting UV laser light to dissolve or decompose aggregated platelet clots formed in arteries or arterioles distal to the thrombus. In one embodiment, the method includes the thrombus as an occlusive thrombus.

在本發明的一個實施例中，用於再灌注血栓遠端的動脈血管的方法包括如上該設置在導絲內的光導纖維。In one embodiment of the present invention, a method for reperfusing an artery distal to a thrombus includes an optical fiber disposed within a guide wire as described above.

因為轉亞硝基化的鏈式過程產生全部沿著光導纖維的路徑的一氧化氮，其可以進入分支動脈，所以遠端段及其支流可以擴張，從而當血栓切除術影響再循環時，使分支動脈和小動脈準備好接受血液（再灌注）。Because the cascade of transnitrosylation generates nitric oxide all along the path of the optical fiber, it can enter the branch arteries so that the distal segment and its tributaries can dilate, thereby preparing the branch arteries and arterioles to receive blood (reperfusion) when thrombectomy affects recirculation.

在本發明的另一實施例中，用於再灌注血栓遠端動脈血管的方法包括使用血栓切除術裝置去除血栓的步驟。用於去除血栓的血栓切除術裝置可以是支架取回器。在部署支架取回器的情況下，UV雷射誘導的擴張為提供了用於部署的增加的空間，這可以增強凝塊的可整合性，並且對擴張的動脈壁損傷更小。可替代地，在本發明的另一個實施例中，血栓切除術裝置可以是抽吸導管。在抽吸導管部署的情況下，UV雷射誘導的擴張可以減少在凝塊兩端的摩擦，會降低遠端目前所需的線性壓力，從而抑制碎裂。所有這些過程方面都旨在以最少的通過次數提取凝塊，並且還確保遠端再灌注得到增強。In another embodiment of the present invention, a method for reperfusing a thrombosed distal artery includes the step of removing the thrombus using a thrombectomy device. The thrombectomy device for removing the thrombus can be a stent retriever. In the case of deploying the stent retriever, the UV laser-induced expansion provides increased space for deployment, which can enhance the conformability of the clot and cause less damage to the wall of the dilated artery. Alternatively, in another embodiment of the present invention, the thrombectomy device can be an aspiration catheter. In the case of aspiration catheter deployment, the UV laser-induced expansion can reduce friction at both ends of the clot, which can reduce the linear pressure currently required at the distal end, thereby inhibiting fragmentation. All of these procedural aspects are designed to extract the clot with a minimum number of passes and also ensure that distal reperfusion is enhanced.

上述揭露和示例總體上描述了本發明，並且是為了說明的目的而提供的，而不是為了限制本發明的範圍。本文描述的發明可以在沒有本文沒有具體揭露的任何一個或多個元件、一個限制或多個限制的情況下實施。因此，例如，在本文的每個實例中，術語“包括”、“基本上包含”和“包含”中的任何一個都可以用其他兩個術語中的任何一個來替換。術語和表達被用作描述術語而不是限制術語，並且在使用這些術語和表達時沒有排除所示和描述的特徵或其部分的任何等同物的意圖，而是認識到在所要求保護的發明的範圍內各種修改是可能的。因此，應該理解，雖然本發明已經藉由較佳實施例和可選特徵具體揭露，但是本領域技術人員可以求助於本文揭露的概念的修改和變化，並且這種修改和變化被認為是在由申請專利範圍限定的本發明的範圍內。The above disclosures and examples generally describe the present invention and are provided for the purpose of illustration, not for limiting the scope of the present invention. The invention described herein may be implemented without any one or more elements, one limitation or multiple limitations not specifically disclosed herein. Thus, for example, in each example herein, any of the terms "comprises," "substantially comprises," and "comprising" may be replaced with any of the other two terms. Terms and expressions are used as descriptive terms rather than limiting terms, and there is no intention to exclude any equivalents of the features shown and described or portions thereof when using these terms and expressions, but it is recognized that various modifications are possible within the scope of the claimed invention. Therefore, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, those skilled in the art may resort to modifications and variations of the concepts disclosed herein, and such modifications and variations are considered to be within the scope of the present invention as defined by the scope of the patent applications.

101、201:外錐形尖端 102:動脈的內壁 103:擴展的高斯射束輪廓 104:微導管 105、530、701:血栓 200、301、610、802:光導纖維 205:玻璃容器 210:擴展的環狀 310:錐形尖端 401、402、403:基底動脈 411、421、431:纖維尖端 510:球囊導管 520:導絲 540:動脈 620:環形射束 702:大腦中動脈 720:微導絲 721:頸內動脈 730:UV透明球囊 740:膨脹 750:抽吸血栓切除術導管 772:部分擴張的動脈壁 800:中空導絲和光導纖維的組合 801:中空芯 803:聚合體塗層 804:內部 805:光導纖維的遠端 806:導絲帽 807:光線 808:TEM₀₀雷射束 809:蝕刻尖端 810:雷射環形射束 811:外錐形尖端 901a:峰 901b:谷 902:中央V形槽101, 201: outer tapered tip 102: inner wall of artery 103: expanded Gaussian beam profile 104: microcatheter 105, 530, 701: thrombus 200, 301, 610, 802: optical fiber 205: glass container 210: expanded ring 310: tapered tip 401, 402, 403: basilar artery 411, 421, 431: fiber tip 510: balloon catheter 520: guide wire 540: artery 620: circular beam 702: middle cerebral artery 720: microguidewire 721: internal cervical artery 730: UV transparent balloon 740: inflation 750: aspiration thrombectomy catheter 772: partially dilated arterial wall 800: combination of hollow guidewire and fiber optic 801: hollow core 803: polymer coating 804: interior 805: distal end of fiber optic 806: guidewire cap 807: light 808: TEM₀₀ laser beam 809: etching tip 810: laser circular beam 811: outer conical tip 901a: peak 901b: valley 902: central V-groove

圖1A顯示了當雷射環形束撞擊到半徑為R的動脈內壁上以產生擴展的高斯射束輪廓G_w時具有高斯強度分佈G₀（由具有外錐形尖端的光導纖維產生，錐體半頂角為α）的雷射環形束的z平面橫截面的上半部分。注意，射束具有極角散佈2θ_w。環形射束是圍繞光軸圓柱形對稱的，並且其中心最大值是以角度β發射的。G₀的強度輪廓按1/9的比例繪製。在點“p”處G_w的強度是r_w=(z–z_o)sinβ以及(z²+ R²)^1/2的函數。 圖1B顯示了在凸出的（外部的或外翻的）錐形尖端光導纖維中的雷射軸向光線跟蹤。虛線（OO*）描繪了在輸出端處具有錐形尖端（總頂角=2 α）的二氧化矽光導纖維中的理想的雷射光線的路徑。只要入射角θ₁大於在二氧化矽/水交界處的臨界角θ_crit（64.653°）（並且因此藉由觀察α ＜ 90° – θ_crit），並因此從點Q進入到水基介質內（θ_crit= 64.653°），則射束在點P處服從全內反射。當繞光軸旋轉時，由O*定義的點的軌跡產生環形射束。N₁和N₂是錐體頂面和底面的法線。從圖上看，藉由觀察，α+θ₁=90°且ω=180°-2θ₁，因此δ = 3θ₁- 180° = 90° - 3α。同樣藉由觀察，環形射束軌跡是由角度β(α) = θ₁- α - γ(α)定義的圓錐表面。γ(α)被表示為sin^-1{(n₁/n₂) cos 3α}。根據斯涅耳定律（Snell’s Law），β(α)現在可以根據纖維錐形尖端的半頂角α來確定。 圖2A示出了根據本發明實施例的在36°全頂點錐形角（2 α）鎔融二氧化矽纖維上機加工的外錐形尖端。 圖2B示出了由圖2A所示的外錐形尖端在水中產生的UV雷射環形射束。表1顯示了純二氧化矽光導纖維的α、β(α)值以及反射角和折射角的值，表2顯示了當尖端是光耦合金剛石時的β(α)。與二氧化矽本身（高達48.4°）相比，金剛石β(α)的範圍和值（高達71.5°）顯著增加。 圖3顯示了內翻錐形尖端光導纖維的光學特性，顯示了具有內翻錐形尖端或由金剛石製成的尖端的鎔融二氧化矽纖維中的反射和折射雷射光（從右側進入）的路徑，並且該射束出射進入水（鹽水）中，到達內動脈壁上。從金剛石進入水的最大發射角β(α)約為56°，遠遠超過從二氧化矽進入水的最大發射角（僅25.4°）；參見表3。 圖4A、圖4B和圖4C限制了在三隻狗的基底動脈（BA）中放置光導纖維尖端和血管內UV照射。UV照射引起的擴張是半局部的；對於長度約為40 mm的基底動脈，擴張甚至可從相鄰（脊椎脊髓）動脈的環形射束照射軌跡散佈高到60 mm。 圖5顯示了在UV雷射促進血栓切除術之前，在插入動脈閉塞（血栓）附近的導絲（深灰色）上的球囊導管的初始部署。球囊部分地膨脹了。當球囊已膨脹或近似已膨脹時，導絲將有效地位於動脈中心。在這一點上，導絲可以被收回並用UV發射光導纖維替換，以便擴張阻礙彎曲（如果存在的話）以降低導絲進一步插入的阻力，以便進一步追蹤UV發射光導纖維以及然後的血栓切除術裝置通過動脈的最佳路線。 圖6顯示了圖5的球囊導管，其已經在居中的導絲上完全膨脹，並且導絲被抽出並被光導纖維（白線）替換，該光導纖維將從錐形尖端發射UV雷射，該錐形尖端被合成以在閉塞（血栓）附近以期望的角度β產生環形射束（標記的橢圓軌跡）。纖維的輸出端可以在球囊允許的情況下盡可能靠近血栓放置，但是UV環形射束照射將引發從與血栓相距＜4個直徑開始至40個直徑的持續動脈擴張。以3-20瓦特/cm²的射束強度，擴張將在數秒鐘內發生，並將延伸到形成血栓的段。然後抽出光導纖維，然後將血栓切除術裝置安裝在已放氣的球囊上。在這種配置中，將會引入抽吸導管來抽出血栓，現在摩擦阻力更小，因為閉塞的動脈段已擴張。為了部署支架取回器，導絲必須穿透血栓（可能在邊緣附近），球囊部署在導絲上，其他步驟將會如上該發生。在此，血栓遠端的擴張將允許支架取回器以更大的直徑部署，確保最大程度地攔截和完全提取血栓並且伴隨著更少的碎裂，只要支架取回器的可整合性得以保持。類似地，考慮到碎裂的可能性，抽吸手術可能受益於遠端照射和近端照射，因為抽吸力不是沿著血栓均勻分佈的。 圖7給出了紫外雷射誘導擴張應用於血栓切除術以便最大程度地减小機械摩擦引起的壁損傷的圖示總結。 圖8A表示中空導絲和光導纖維的組合，其中光導纖維設置在中空導絲內。 圖8B表示中空導絲和光導纖維的組合，其中設置在中空導絲內的光導纖維具有外錐形尖端。 圖8C表示中空導絲和光導纖維的組合，其中設置在中空導絲內的光導纖維具有內翻錐形尖端。 圖8D表示中空導絲和光導纖維的組合，其中設置在中空導絲內的光導纖維具有作為負軸錐透鏡的蝕刻尖端（即衍射光學元件（DOE））。 圖9A顯示了光導纖維遠端的正視圖，該遠端蝕刻有在光導纖維中形成的V形凹槽的同心環，以產生作為負軸錐透鏡的衍射光學元件（DOE）。 圖9B顯示了圖9A的光導纖維的橫截面透視圖。Figure 1A shows the upper half of a z-plane cross section of a laser ring beam with a Gaussian intensity distribution G₀ (generated by a fiber optic with an outer conical tip, with a cone half-apex angle of α) when the laser ring beam impinges on the inner wall of an artery of radius R to produce an expanded Gaussian beam profile G_w . Note that the beam has a polar angular spread 2θ_w . The ring beam is cylindrically symmetric about the optical axis and its central maximum is emitted at an angle β. The intensity profile of G₀ is drawn at a scale of 1/9. The intensity of G_w at point “p” is a function of r_w = (z–zo₀ )sinβ and (z² + R² )^1/2 . FIG1B shows axial laser beam tracking in a convex (external or inside-out) tapered tip fiber. The dashed line (OO*) depicts the path of an ideal laser beam in a silica fiber with a tapered tip (total tip angle = 2α) at the output end. As long as the angle of incidence_θ1 is greater than the critical angle_θcrit (64.653°) at the silica/water interface (and thus by observing that α < 90° –_θcrit ), and thus enters the water-based medium from point Q (_θcrit = 64.653°), the beam is subject to total internal reflection at point P. The trajectory of the point defined by O* produces a toroidal beam when rotated about the optical axis. N₁ and N₂ are the normals to the top and bottom of the cone. From the figure, by inspection, α+θ₁ = 90° and ω = 180° - 2θ₁ , so δ = 3θ₁ - 180° = 90° - 3α. Also by inspection, the annular beam trajectory is a cone surface defined by the angle β(α) = θ₁ - α - γ(α). γ(α) is expressed as sin^-1 {(n₁ /n₂ ) cos 3α}. From Snell's Law, β(α) can now be determined from the half-apex angle α of the fiber cone tip. FIG2A shows an outer tapered tip machined on a fused silica fiber at a 36° full apex tapered angle (2α) according to an embodiment of the present invention. FIG2B shows a UV laser ring beam generated in water by the outer tapered tip shown in FIG2A. Table 1 shows the values of α, β(α) and the values of the reflection and refraction angles for pure silica optical fibers, and Table 2 shows β(α) when the tip is optically coupled diamond. The range and value of β(α) for diamond (up to 71.5°) is significantly increased compared to silica itself (up to 48.4°). Figure 3 shows the optical properties of an inverted tapered tip fiberoptic light guide, showing the path of reflected and refracted laser light (entering from the right side) in a fused silica fiber with an inverted tapered tip or a tip made of diamond, and the beam exiting into water (saline) to the wall of an internal artery. The maximum emission angle β(α) from diamond into water was approximately 56°, far exceeding the maximum emission angle from silica into water (only 25.4°); see Table 3. Figures 4A, 4B, and 4C limit the placement of fiberoptic light guide tips and intravascular UV irradiation in the basilar artery (BA) of three dogs. The dilation induced by UV irradiation is semilocal; for a basilar artery of approximately 40 mm in length, dilation can even be spread as high as 60 mm from the circular beam irradiation trajectory of the adjacent (spinal) artery. Figure 5 shows the initial deployment of a balloon catheter over a guidewire (dark gray) inserted near an arterial occlusion (thrombus) prior to UV laser-facilitated thrombectomy. The balloon is partially inflated. When the balloon is inflated or nearly inflated, the guidewire will effectively be in the center of the artery. At this point, the guidewire can be withdrawn and replaced with a UV emitting light guide in order to dilate the obstruction bend (if present) to reduce resistance to further insertion of the guidewire in order to further track the optimal route of the UV emitting light guide and then the thrombectomy device through the artery. Figure 6 shows the balloon catheter of Figure 5 which has been fully inflated over the centered guidewire and the guidewire withdrawn and replaced with the light guide (white line) which will emit UV laser from a tapered tip that is synthesized to produce a ring-shaped beam (marked elliptical trajectory) at the desired angle β near the occlusion (thrombus). The output end of the fiber can be placed as close to the thrombus as the balloon will allow, but the UV annular beam irradiation will induce sustained arterial dilation starting at <4 diameters away from the thrombus and extending to 40 diameters. At beam intensities of 3-20 watts/cm², dilation will occur within seconds and will extend to the thrombosed segment. The light-guided fiber is then withdrawn and the thrombectomy device is then mounted over the deflated balloon. In this configuration, an aspiration catheter will be introduced to aspirate the thrombus, now with less frictional resistance because the occluded arterial segment is dilated. To deploy the stent retriever, the guidewire must penetrate the thrombus (probably near the edge), the balloon is deployed over the guidewire, and the other steps will occur as above. Here, expansion of the distal end of the thrombus will allow the stent retriever to be deployed at a larger diameter, ensuring maximum interception and complete extraction of the thrombus with less fragmentation, as long as the integrity of the stent retriever is maintained. Similarly, given the possibility of fragmentation, aspiration procedures may benefit from distal irradiation as well as proximal irradiation because the aspiration force is not evenly distributed along the thrombus. Figure 7 provides a pictorial summary of the application of UV laser-induced expansion in thrombectomy to minimize wall damage caused by mechanical friction. Figure 8A shows a combination of a hollow guidewire and a fiber optic, wherein the fiber optic is disposed within the hollow guidewire. FIG8B shows a combination of a hollow wire and an optical fiber, wherein the optical fiber disposed in the hollow wire has an external tapered tip. FIG8C shows a combination of a hollow wire and an optical fiber, wherein the optical fiber disposed in the hollow wire has an inverted tapered tip. FIG8D shows a combination of a hollow wire and an optical fiber, wherein the optical fiber disposed in the hollow wire has an etched tip that serves as a negative axis cone lens (i.e., a diffractive optical element (DOE)). Figure 9A shows a front view of the distal end of a fiber optic having concentric rings of V-shaped grooves etched therein to produce a diffractive optical element (DOE) that is a negative axis cone lens. Figure 9B shows a cross-sectional perspective view of the fiber optic of Figure 9A.

101:外錐形尖端101: External conical tip

102:動脈的內壁102: Inner wall of artery

103:擴展的高斯射束輪廓103: Expanded Gaussian beam profile

104:微導管104: Microcatheter

105:血栓105: Blood clots

Claims (17)

Translated fromChinese

一種導絲和能夠攜帶UV雷射光的光導纖維的組合體，其中，該導絲形成為一中空管，並且具有設置在該中空管內的該光導纖維，該光導纖維用於攜帶來自一UV雷射光源的UV雷射光。A combination of a guide wire and an optical fiber capable of carrying UV laser light, wherein the guide wire is formed into a hollow tube and has the optical fiber arranged in the hollow tube, and the optical fiber is used to carry UV laser light from a UV laser light source.如請求項1所述的導絲和能夠攜帶UV雷射光的光導纖維的組合體，其中，該中空導絲和能夠攜帶UV雷射光的光導纖維彼此固定。A combination of a guide wire and an optical fiber capable of carrying UV laser light as described in claim 1, wherein the hollow guide wire and the optical fiber capable of carrying UV laser light are fixed to each other.如請求項1所述的導絲和能夠攜帶UV雷射光的光導纖維的組合體，其中，能夠攜帶UV雷射光的光導纖維具有一遠端，該遠端被配置成發射UV雷射光的一錐形射束。A combination of a guide wire and an optical fiber capable of carrying UV laser light as described in claim 1, wherein the optical fiber capable of carrying UV laser light has a distal end configured to emit a conical beam of UV laser light.如請求項1所述的導絲和能夠攜帶UV雷射光的光導纖維的組合體，其中，能夠攜帶UV雷射光的光導纖維具有被配置為一外部椎體的一遠端，以發射UV雷射光的一錐形射束。A combination of a guide wire and an optical fiber capable of carrying UV laser light as described in claim 1, wherein the optical fiber capable of carrying UV laser light has a distal end configured as an external cone to emit a conical beam of UV laser light.如請求項1所述的導絲和能夠攜帶UV雷射光的光導纖維的組合體，其中，能夠攜帶UV雷射光的光導纖維具有被配置為一內翻椎體的一遠端，以發射UV雷射光的一錐形射束。A combination of a guide wire and an optical fiber capable of carrying UV laser light as described in claim 1, wherein the optical fiber capable of carrying UV laser light has a distal end configured as an inverted cone to emit a conical beam of UV laser light.如請求項1所述的導絲和能夠攜帶UV雷射光的光導纖維的組合體，其中，能夠攜帶UV雷射光的光導纖維具有一平坦的遠端，該平坦的遠端包括蝕刻在該平坦的遠端內的同心圓凹槽。A combination of a guide wire and an optical fiber capable of carrying UV laser light as described in claim 1, wherein the optical fiber capable of carrying UV laser light has a flat distal end, and the flat distal end includes concentric circular grooves etched into the flat distal end.如請求項3所述的導絲和能夠攜帶UV雷射光的光導纖維的組合體，其中，能夠攜帶UV雷射光的該光導纖維的遠端被設置為與該光導纖維進行光通信的獨立尖端。A combination of a guide wire and an optical fiber capable of carrying UV laser light as described in claim 3, wherein the distal end of the optical fiber capable of carrying UV laser light is configured as an independent tip for optical communication with the optical fiber.如請求項7所述的導絲和能夠攜帶UV雷射光的光導纖維的組合體，其中，與該光導纖維進行光通信的該獨立尖端包括金剛石。A combination of a guide wire and an optical fiber capable of carrying UV laser light as described in claim 7, wherein the independent tip in optical communication with the optical fiber comprises diamond.如請求項7所述的導絲和能夠攜帶UV雷射光的光導纖維的組合體，其中，與該光導纖維進行光通信的該獨立尖端包括氧化鋯。A combination of a guide wire and an optical fiber capable of carrying UV laser light as described in claim 7, wherein the independent tip in optical communication with the optical fiber comprises zirconium oxide.一種用於再灌注一血栓遠端的動脈血管的方法，該方法包括下列步驟： - 將能夠攜帶UV雷射光的一光導纖維延伸通過該血栓； - 從該血栓遠端的該光導纖維發射UV雷射光，以擴張該血栓遠端的動脈血管； - 去除該血栓； 從而允許血液流向該擴張的動脈血管並使其再灌注。A method for reperfusing an artery distal to a thrombus, the method comprising the following steps: - extending a light-conducting fiber capable of carrying UV laser light through the thrombus; - emitting UV laser light from the light-conducting fiber distal to the thrombus to dilate the artery distal to the thrombus; - removing the thrombus; thereby allowing blood to flow to the dilated artery and reperfuse it.如請求項10所述的方法，還包括下列步驟： - 在將該光導纖維延伸通過該血栓之前，從該血栓近端的該光導纖維發射UV雷射光。The method as claimed in claim 10 further comprises the following steps: - before extending the optical fiber through the thrombus, emitting UV laser light from the optical fiber proximal to the thrombus.如請求項10所述的方法，還包括下列步驟： - 在從該血栓遠端的該光導纖維發射UV雷射光以擴張該血栓遠端的該動脈血管之後，將該光導纖維抽出到該血栓近端的一位置，並且從該血栓近端的該光導纖維發射UV雷射光。The method as described in claim 10 further comprises the following steps: - After emitting UV laser light from the optical fiber distal to the thrombus to dilate the artery distal to the thrombus, the optical fiber is withdrawn to a position proximal to the thrombus, and UV laser light is emitted from the optical fiber proximal to the thrombus.如請求項10所述的方法，其中，使用一血管切除術導管執行去除該血栓的步驟。A method as described in claim 10, wherein the step of removing the thrombus is performed using a vascular resection catheter.如請求項13所述的方法，其中，該血管切除術導管是一抽吸導管。A method as described in claim 13, wherein the vascular resection catheter is a suction catheter.如請求項13所述的方法，其中，該血管切除術導管是一支架取回器。The method of claim 13, wherein the vascular resection catheter is a stent retriever.如請求項10所述的方法，其中，該動脈血管包括小動脈。A method as described in claim 10, wherein the arterial blood vessels include arterioles.如請求項10所述的方法，其中，該血栓是一閉塞的血栓。The method of claim 10, wherein the thrombus is an occluded thrombus.