WO2013056497A1 - 一种血管内植入装置包和植入装置的制备方法 - Google Patents

一种血管内植入装置包和植入装置的制备方法 Download PDF

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Publication number
WO2013056497A1
WO2013056497A1 PCT/CN2011/084143 CN2011084143W WO2013056497A1 WO 2013056497 A1 WO2013056497 A1 WO 2013056497A1 CN 2011084143 W CN2011084143 W CN 2011084143W WO 2013056497 A1 WO2013056497 A1 WO 2013056497A1
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stent
derivatives
implant device
film
membrane
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PCT/CN2011/084143
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English (en)
French (fr)
Inventor
谢志永
康亚红
金巧蓉
陈冰
张久礼
吕健
徐晓红
王森
罗七一
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上海微创医疗器械（集团）有限公司
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Priority to EP11874217.0A priority Critical patent/EP2769701A4/en
Publication of WO2013056497A1 publication Critical patent/WO2013056497A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
    • A61F2/06—Blood vessels
    • A61F2/07—Stent-grafts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/86—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
    • A61F2/90—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/94—Stents retaining their form, i.e. not being deformable, after placement in the predetermined place
    • A61F2/945—Stents retaining their form, i.e. not being deformable, after placement in the predetermined place hardenable, e.g. stents formed in situ
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
    • A61F2/06—Blood vessels
    • A61F2/07—Stent-grafts
    • A61F2002/072—Encapsulated stents, e.g. wire or whole stent embedded in lining

Definitions

  • the invention relates to the field of medical devices. More specifically, the present invention relates to an intravascular implant device package and a method of preparing the implant device.
  • the device can be used for implanting blood vessels to treat vascular malformations such as aneurysms, especially intracranial aneurysms. Background technique
  • the vessel wall may have local abnormalities under the influence of internal and external factors such as mechanical injury, hardening of the arteries, hypertension, proliferation of vascular smooth muscle cells, bacterial or viral infection, induction of venous valve disease, and blood flow impact. Dilatation or bulging, called an aneurysm.
  • Aneurysms can occur in different parts of the body, most commonly abdominal aortic aneurysms and intracranial aneurysms.
  • An intracranial aneurysm is a cystic dilatation of the intracranial vessel wall.
  • An aneurysm grows under the impact of blood flow, causing symptoms around the surrounding brain tissue; its greatest risk is that the aneurysm ruptures due to increased blood pressure or other factors.
  • Intracranial aneurysms are extremely important. Lack of support around the intracranial artery, with thin wall, more vascular gyrus, more branches, sensitive to stimuli. Intracranial aneurysms occur mostly in the branches, bifurcations, and bends of blood vessels. Mainly due to the hemodynamic factors of the site, that is, the axial blood flow impinges on the blood vessel, causing the destruction of the elastic layer of the blood vessel, forming a saclike protrusion, and then growing into an aneurysm.
  • Methods of treatment of aneurysms typically include both surgical and vascular interventional procedures.
  • Surgery is the closure of an aneurysm that has already formed, including the cutting and ligation of the aneurysm's mother artery and the clamping of the aneurysm neck with an aneurysm clip to block the impact of blood on the aneurysm.
  • this method is time consuming and traumatic, high risk and high complications.
  • endovascular intervention has gradually become the preferred method for the treatment of aneurysms. This method can be divided into two types according to the different treatment methods:
  • embolic devices to embolize aneurysms for endovascular intervention.
  • various embolic materials are used to deliver embolic agents into the aneurysm lumen through microcatheters to achieve embolization of the aneurysm to achieve therapeutic effects.
  • the embolic materials used are detachable coils, microwire loops, detachable balloons, and curable liquids such as NBCA, Glubran, Onyx glue, and the like.
  • embolization of an aneurysm with a coil-like solid embolic material tends to have a low embolic rate and is prone to form a wide range of thrombi and cause cerebral infarction.
  • liquid embolic materials are either severely stuck, easy to bleed when extubating, or use toxic organic solvents. The operation is complicated, the operation time is long, and the recurrence rate is high, which is not an ideal means.
  • the second is intravascular interventional stent implantation.
  • the stent graft has been used as a vascular intervention for the treatment of intracranial aneurysms.
  • the membrane is used to form a closed conduit in the diseased blood vessel to block the impact of blood flow on the aneurysm, so that the blood flow in the lesion is completely isolated from the normal blood circulation, and the purpose of curing the aneurysm is achieved.
  • due to the numerous branches of the intracranial arteries once the covered stent covers the important branches, the corresponding nerve function will be lost. It is also reported that the aneurysm is treated with the flow-Diverter, which works on the lesion.
  • the stent mesh When the vessel is fully open, the stent mesh is small enough to alter the hemodynamics of the aneurysm neck, causing thrombosis within the aneurysm; and due to the difference in fluid pressure, the vessel with the dense mesh stent can still retain it.
  • the patency of the branch vessels is extended relative to the scope of application of the stent graft.
  • blocking the aneurysm and keeping the branch open is a contradiction. It is difficult to balance both, and the method is difficult to treat the ruptured aneurysm.
  • Liu Jianmin et al. discloses a vascular remodeling stent.
  • the vascular remodeling stent has a mesh tubular structure and has a plurality of meshes formed by interlacing a plurality of silk chains.
  • each of the chains is continuous, and the nodes of the mesh are movable.
  • the vascular remodeling stent of the invention is highly flexible and flexible, and can pass through a tortuous and fine cerebral blood vessel to reach a target lesion, and conforms to a tortuous blood vessel to maintain a lumen passage of the blood vessel.
  • the stent has a high-density mesh that can significantly alter the flow of blood in the aneurysm to cause it to form blood clots and organic solids.
  • Sun Yikui et al see Journal of Interventional Radiology, 2010, Vol. 19, No. 4
  • preliminary results provide that Willis stent-grafts are effective and have good compliance with CICA aneurysms.
  • the Willis stent graft is a non-local stent graft.
  • Jonita et al. (Proc Soc Photo Opt Instrum Eng. 2009 January 1; 7262: 72621H1-72621H10) uses a novel polyurethane asymmetric vascular stent to treat animal model aneurysms.
  • the stent is a vascular stent partially covered with a polyurethane patch for closing the neck of the aneurysm, thereby blocking blood flow into the aneurysm.
  • the results showed that the proximal end was completely cured, while the distal end was closed.
  • the treatment of aneurysm remains to be further studied.
  • Tian Xia et al. discloses a vascular embolization agent and a preparation method thereof, which are prepared from ⁇ -cyanoacrylate n-octyl acrylate, strontium powder and lipiodol (or iodophenyl ester).
  • the volume percentage of the three can be 80-85: 1-5: 10-15, and 83.75:2.5: 13.75 is better, the one-component stability is good, and the use is convenient.
  • decyl cyanoacrylate is a classic liquid embolic material with good embolization effect; on the other hand, collagen egg
  • the white water absorption can rapidly expand, and the cell endothelial factor growth can be induced after embolization, which not only makes the embolization body low in density, but also has good flexibility, and can achieve the purpose that the permanent embolization does not recur.
  • the disclosure of this application is incorporated herein by reference.
  • Kerber et al. (US 2009/0137981 A1) discloses a method of treating blood vessels.
  • the method includes providing at least one operable tool at a blood vessel to deposit a non-solid polymerizable material to a vascular deposition zone, wherein the polymerizable liquid solidifies over time upon contact with blood in the blood vessel, and is cured by an operating tool
  • the shape of the polymerizable material changes.
  • the implant device package is used for preparing a partially covered intravascular stent, which comprises two parts: one is a membrane to be coated, can be delivered into an aneurysm through a microcatheter, rapidly solidifies in blood, and has A certain degree of adhesion, can be adhered to any part of the stent to form a dense membrane to prevent blood flow into the aneurysm; the second is a stent with sufficient mesh density as a skeleton of the partial membrane.
  • the stent is capable of traversing a tortuous cerebral blood vessel to a target lesion and is capable of conforming to a tortuous vessel to maintain a lumen lumen.
  • the combination of the two not only can accurately and quickly block the neck of the tumor, but also maintain branch opening, and can significantly improve the occupancy effect, thus achieving a true cure of the aneurysm.
  • the invention provides a preparation method of a partial membrane implantation device, comprising the following steps: placing a microcatheter for transporting a membrane material into a tumor cavity, and then implanting the stent into a vascular lesion through a delivery system, releasing the stent, and injecting a membrane The material, as well as the film, forms a film on the surface of the stent at the neck of the neck.
  • the invention also provides a method for preparing another partial film implant device, comprising the following steps:
  • the stent is delivered to the vascular lesion site, the stent is released, and then the membrane is delivered through the microcatheter through the stent mesh into the tumor cavity, and the membrane is formed on the stent surface at the neck of the tumor.
  • the main component of the film is decyl cyanoacrylate, and its structure is as shown in the following formula (1):
  • the decyl cyanoacrylate contains a cyano group and a carboxyl group, and has a double electron withdrawing action to make the a carbon atom susceptible to rapid polymerization and solidification in the environment.
  • the blood is rich in anions, so it is easy to cause membrane bonding during the operation to achieve on-site filming.
  • the film material further includes a developer, a polymerization inhibitor, and/or a plasticizer in addition to the #1 base.
  • the polymerization inhibitor allows 3 ⁇ 4 to be stored in an emergency, and may be selected from the group consisting of m-methoxyphenol, hydroquinone, phosphoric acid, phosphorus pentoxide or sulfur dioxide.
  • the plasticizer ensures that the film is soft and tough, and the film is convenient, and may be selected from dimethyl phthalate, diethyl phthalate, dibutyl phthalate, butyl benzyl phthalate. , acetyl tributyl citrate, benzoate or tricresyl phosphate.
  • the contrast agent of the angiography is mixed in the membrane to be suitable for the visual observation of the film condition during the surgery and after the fluorescent radiography.
  • the developer includes an iodide such as 6-triiodoformic acid, sodium 6-triiodobenzoate, iodine titanic acid, acetaminophen, iodine acid, iodoic acid, iopakaic acid, iohexol, and iodine.
  • Terpenoids such as antimony trioxide; barium sulfate; metal powders such as barium powder, gold powder, etc.; and other common developers and any mixtures thereof.
  • the developer is iodide, gold powder, platinum powder, strontium powder, titanium powder, tungsten powder or barium sulfate.
  • the present invention has no particular requirement for the amount of the polymerization inhibitor, the plasticizer and the contrast agent to be added, and is preferably added in an amount well known to those skilled in the art.
  • the film and the degradable polymer are used in combination at the time of film formation.
  • the degradable polymer is selected from the group consisting of polylactic acid, polyglycolide, polycaprolactone, polycaprolactone, polyanhydride, poly 1,2-propylene fumarate, polyphosphazene, L-case Acid-derived polymer, polyorthoester, amino acid polymer, chitin and its derivatives, chitosan and its derivatives Bio, hyaluronic acid and its derivatives, chondroitin sulfate and its derivatives, collagen and its derivatives, gelatin and its derivatives, agar and its derivatives, fibrin and its derivatives, and silk proteins and their derivatives One or several of them.
  • the degradable polymer is collagen or polylactic acid.
  • the stent is a laser machined tubular mesh stent or a braided stent woven from a continuous filament chain.
  • the mesh density of the stent is asymmetrically changed in the axial direction.
  • the material of the stent is selected from the group consisting of biocompatible metal materials or/and polymeric materials, or the above-described degradable polymers.
  • the membrane Before or after the stent is transported, the membrane can be transported by a microcatheter, catheter or dedicated conveyor through the tortuous vessel to the target;
  • Figure 1 shows a stent with a non-uniform grid structure in which a portion of the stent with a higher mesh density (i.e., greater metal coverage) covers the aneurysm neck of the parent artery, and the other stents have a lower mesh density ( That is, a smaller metal coverage).
  • Figure 2 shows a stent of a non-uniform grid structure in which a higher mesh density covers a portion of the neck of the tumor and a lower mesh density covers the vessel branch.
  • Figure 3 shows a bracket of a uniform grid structure.
  • the microcatheter conveying the membrane is placed in the tumor cavity, and then the stent is implanted into the lesion of the aneurysm through the delivery system, the stent is released, the membrane is injected, and the membrane is solidified at the neck of the tumor and adhered to the stent to form a layer.
  • a dense membrane to achieve partial coverage allows precise positioning of the stent.
  • the microcatheter that transports the membrane material can also reach the tumor cavity through the stent mesh after the stent is released, and then form a membrane at the neck of the tumor.
  • the implant device of the present invention consists of a stent and a membrane (1-0) that is coated at the surgical site by microcatheter delivery (see Figure 1).
  • the film (1-0) is formed by polymerizing and curing a film comprising n-octyl cyanoacrylate and cerium powder.
  • the film (1-0) can also be polymerized and cured from a mixture of a film comprising cyanoacrylate n-octyl acrylate and strontium powder, and the specific steps are as follows: First, 0.5 mol of collagen is granulated by a bubbling bed. (See Zhao Jiang, equivalent to the “Optimization of the Process for Producing Protein Powder by Boiling Bed Spraying Lecithin Granulation Technology” published in Food Research and Development in 2007. The collagen particles with a particle size of about 50 mesh are obtained, and then added. In the monomer of 3 mol of n-octyl cyanoacrylate, ultrasonic dispersion allows the collagen particles to be uniformly dispersed in the monomer.
  • the brackets may be brackets of a non-uniform grid structure, that is, different parts have different metal coverage.
  • the part of the higher mesh density (1-2) covers the aneurysm (1-6) of the tumor-bearing artery (1-1) to maximize the blood flow in the aneurysm.
  • the low mesh density (1-3) structure attaches the support to the normal vessel wall (1-4), maintains a smooth lumen and minimizes the coverage of the branches (1-5).
  • the present invention can also cover a portion of the neck neck and a lower mesh density at a higher mesh density.
  • the treatment of aneurysms is also achieved when covering the branches (see Figure 2); it can also be a stent with a uniform grid structure, as long as the branch blood flow can be ensured and the aneurysm can be completely treated (see Figure 3).
  • the above device can accurately and quickly block the neck of the aneurysm, prevent the blood flow from attacking the aneurysm, and maintain the blood flow of the normal arterial branch, and significantly improve the occupying effect, thereby realizing the true healing of the aneurysm.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Cardiology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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Abstract

一种血管内植入装置包和一种植入装置的制备方法。该植入装置为一种局部覆膜的血管内支架，可用于植入血管治疗血管病变，如动脉瘤等，特别是颅内动脉瘤。该植入装置包包括待涂覆的膜材和网孔支架，其中膜材的主要成分为氰基丙烯酸烷基酯。该制备方法直接使植入装置在瘤颈口现场成膜，不但能够精确、快捷地封堵瘤颈口，而且能保持分支开通，并可显著改善占位效应，从而实现动脉瘤的真正治愈。

Description

一种血管内植入装置包和植入装置的制备方法 技术领域
本发明涉及医疗器械领域。 更具体而言， 本发明涉及一种血管内 植入装置包和植入装置的制备方法。 该装置可用于植入血管治疗血管 畸形病变， 如动脉瘤等， 特别是颅内动脉瘤。 背景技术
血管壁， 特别是动脉血管壁， 可能在机械损伤、 血管硬化、 高血 压、 血管平滑肌细胞的增生、 细菌或病毒感染、 静脉瓣疾病的诱导和 血流冲击等内外因素的作用下发生局部异常的扩张或凸起， 称之为动 脉瘤。 动脉瘤可发生在身体的不同部位， 最常见为腹主动脉瘤和颅内 动脉瘤。 颅内动脉瘤是颅内血管壁的囊性扩张， 动脉瘤在血流的冲击 下不断生长， 压迫周围脑组织引起症状； 其最大的危险性就是会因血 压增高或其他因素引起动脉瘤破裂， 发生急剧的出血， 有人称其为 "不 定时炸弹" 。 每次破裂出血死亡率约 1/3， 不经针对性处理， 短期内会 再次出血， 存活的可能性极小， 故及时、 正确处理颅内动脉瘤极为重 要。 颅内动脉周围缺乏支撑， 具有壁薄， 血管迂回弯曲多、 分支多、 对刺激敏感等特点。 颅内动脉瘤多发生在血管分支、 分叉、 弯曲部位。 主要由于该部位的血流动力学因素， 即轴向血流冲击血管， 导致血管 弹力层的破坏， 形成囊状突起， 进而生长成动脉瘤。 动脉瘤治疗的方法通常包括外科手术和血管介入治疗两种。 外科 手术是对已经形成的动脉瘤进行封堵， 包括针对动脉瘤母动脉的剪断、 结扎和采用动脉瘤夹将动脉瘤颈夹住， 从而阻断血液对动脉瘤的冲击。 但是， 这种方法耗时较长且具有创伤性、 高风险性及高并发症。 近年来， 随着血管影像学的发展， 血管内介入治疗逐渐成为动脉 瘤治疗的首选方法， 该方法按照其治疗方式的不同可分为两种：
一是利用栓塞材料栓塞动脉瘤的血管内介入治疗， 通常使用各种 栓塞材料通过微导管将栓塞剂运送至动脉瘤腔内实现动脉瘤的栓塞而 达到治疗效果。 所用的栓塞材料有可脱卸弹簧圈、 微金属丝圈、 可解 脱球囊及可固化液体如 NBCA、 Glubran、 Onyx胶等。 然而采用弹簧圈 类的固体栓塞材料栓塞动脉瘤时往往栓塞率较低， 且容易形成大范围 的血栓而引起大脑梗塞。 而目前上市的液体栓塞材料， 要么粘管严重， 拔管时容易再出血， 要么使用的是有毒性的有机溶剂， 操作复杂， 手 术时间漫长、 复发率高， 并非理想手段。
二是血管内介入治疗支架植入术。 目前覆膜支架作为血管介入治 疗颅内动脉瘤已有使用。 其利用覆膜在病变血管中形成一个封闭的管 道， 遮挡血流对动脉瘤的冲击， 使病变部位血流与正常血循环完全隔 绝， 达到治愈动脉瘤的目的。 但由于颅内动脉分支众多， 覆膜支架一 旦覆盖重要分支， 将丧失相应神经功能； 也有报道用密网支架一一血 流导向装置 （Flow-Diverter) 治疗动脉瘤， 其工作原理是支架在病变血 管处完全打开时， 支架网孔小到足以改变动脉瘤颈部的血流动力学， 从而引起动脉瘤内的血栓形成； 同时由于流体压力差存在， 装有密网 支架的血管仍可以保留其分支血管的通畅性， 相对覆膜支架应用范围 得到扩展。 但封堵动脉瘤和保持分支开通本就一对矛盾， 难以两者都 兼顾， 并且该法对已破裂的动脉瘤救治很困难。 临床上也有人为了得 到更好地封堵效果， 采用 "双支架" 或 "多支架" 技术， 增加瘤颈处 网孔密度， 通过支架交错叠加相对降低瘤颈处支架网孔大小， 来治疗 颅内动脉瘤。 但此方法存在封堵分支血管的风险。 目前， 密网孔支架 的这些缺陷主要是设计与工艺受限， 网孔较大， 网孔密度难以提高， 且无法实现仅在瘤颈处具有更高网孔密度和更小网孔大小、 在分支处 实现较低网孔密度和较大网孔大小的设计。 也有研究报道预制成局部 覆膜的支架， 其在支架的某一局部涂覆有聚氨酯基材的膜， 目的是用 该覆膜的局部掩盖动脉瘤瘤颈从而阻断进入动脉瘤的血流。 但如何将 已压缩的支架在迂曲复杂的血管里精准释放使得该部位恰好定位在瘤 颈口却难以实现。 关于支架， 刘建民等 （参见 CN101991477A) 公开了一种血管重 构支架。 所述血管重构支架呈网管状结构， 具有通过多根丝链相互交 错编织形成的多个网孔。 其中， 每根丝链是连续的， 所述网孔的节点 是可移动的。 该发明的血管重构支架高度柔软、 灵活， 能够穿越曲折 纤细的脑血管到达靶病变， 并顺应迂曲的血管保持血管内腔通道。 该 支架具有高密度网孔， 可以显著改变动脉瘤内血流流动使其滞留形成 血凝块和有机化固体物。 关于覆膜支架， 孙贞魁等 （参见 《介入放射学杂志》 2010 年 19 卷 4期） 提供的初步结果显示， Willis覆膜支架治疗 CICA动脉瘤有效 且具有良好的柔顺性。 Willis覆膜支架为非局部覆膜支架 Jonita等（Proc Soc Photo Opt Instrum Eng. 2009 January 1 ; 7262: 72621H1-72621H10 ) 采用新型聚氨酯不对称血管支架治疗动物模型动脉瘤。 该支架为一种 部分覆盖有聚氨酯片材 （patch) 的血管支架， 用于封闭动脉瘤颈口， 从而堵塞血液流入动脉瘤。 结果表明， 近端完全治愈， 而远端封闭残 留， 对动脉瘤治疗尚待进一步研究。 另外， 该局部覆膜支架存在定位 不准、 微导管在其内难以实现三维旋转等缺陷。 关于栓塞材料， 田霞等 （CN86107191 ) 公开了一种血管栓塞剂及 其制备方法， 所述栓塞剂由 α-氰基丙烯酸正辛酯、 钽粉和碘油 （或碘 苯酯） 配制而成， 三者的体积百分比可为 80-85: 1-5 : 10-15， 而以 83.75:2.5: 13.75为更佳， 单组份稳定性好， 使用方便。在体内聚合迅速， 发热量小， 聚合体柔软， 不会被血液或组织液吸收降解而失效， 能在 X 光照射下， 体内聚合体显影的永久性血管栓塞材料。 中国专利申请 No. 2011 10172325.4 也公开了一种基于胶原蛋白的新型液体栓塞材料， 其 中所含的氰基丙烯酸垸基酯和胶原蛋白在栓塞时以自组装的方式形成 多连接点聚合体从而制得栓塞材料体系。 一方面， 氰基丙烯酸垸基酯 作为经典的液体栓塞材料、 具有良好的栓塞效果； 另一方面， 胶原蛋 白吸水能迅速膨胀， 栓塞后可诱导细胞内皮因子生长， 不但使得栓塞 体密度低， 柔韧性好， 并可达到永久栓塞不再复发之目的。 该申请的 公开内容并入在此引作参考。 另外， Kerber等 （US 2009/0137981 A1 ) 公开了一种治疗血管的 方法。 所述方法包括在血管处提供至少一个可操作工具， 将非固体可 聚合材料沉积至血管沉积区， 其中可聚合液体在与血管中的血液接触 时随时间固化， 以及固化的同时通过操作工具使得可聚合材料的形状 改变。 发明内容
为了解决上述的现有技术问题，本发明提供一种植入装置包（kit)。 该植入装置包用于制备一种局部覆膜的血管内支架， 包括两部分： 其 一为要涂覆的膜材， 可通过微导管输送至动脉瘤内， 在血液中迅速固 化， 并具有一定的粘附性， 能够在支架的任何部位粘合形成一层致密 的膜阻止血流进入动脉瘤内； 其二为具有足够网孔密度的支架， 作为 局部覆膜的骨架。 所述支架能够穿越曲折纤细的脑血管到达靶病变， 并能顺应迂曲的血管保持血管内腔通道。 两者相互配合， 不但能够精 确、 快捷地封堵瘤颈口， 而且能保持分支开通， 并可显著改善占位效 应， 从而实现动脉瘤的真正治愈。 本发明提供一种局部覆膜的植入装置的制备方法，包括下列步骤: 将输送膜材的微导管置于瘤腔内， 然后通过输送系统植入支架至 血管病变部位， 释放支架， 注射膜材， 以及膜材在瘤颈口处的支架表 面成膜。 本发明还提供另一种局部覆膜的植入装置的制备方法， 包括下列 步骤：
将支架输送至血管病变部位， 释放支架， 然后通过微导管经由支 架网孔将膜材输送至瘤腔内， 膜材在瘤颈口处的支架表面成膜。 根据本发明， 所述膜材的主要成分为氰基丙烯酸垸基酯， 其结构 如下式 (1)示：
I I
' ( 1 )
其中 l n 12， 优选 4 n 10， 最优 5 n 8。 该类氰基丙烯酸垸基酯中含有氰基和羧基， 其具有的双重吸电子 作用可使 a碳原子易受环境中的阴离子催^迅速聚合固化。 血液中 富含阴离子， 因此在手术过程中极易引发膜 合而实现现场覆膜。
H2C C C OCnH2n+1 根据本发明， 所述膜材除 #1基丙 i:^^基酯之外， 还包括显影剂、 阻聚剂和 /或增塑剂。 所述阻聚剂使得 ¾ 急定存放， 可选自间甲氧基 苯酚、 对苯二酚、 磷酸、 五氧化二磷或二氧化硫等。 所述增塑剂确保 膜柔软有韧性， 使覆膜方便， 可选自邻苯二甲酸二甲酯、 邻苯二甲酸 二乙酯、 邻苯二甲酸二丁酯、 邻苯二甲酸丁苄酯、 乙酰柠檬酸三丁酯、 苯甲酸酯或磷酸三甲酚酯等。 膜材中混合血管造影术的造影剂， 以适 于外科手术期间和之后荧光 X射线照相术， 使肉眼可见地观察覆膜情 况。所述显影剂包括碘化物， 如 6-三碘甲酸、 6-三碘苯甲酸钠、碘钛酸、 甲泛影酸、 碘达酸、 碘克酸、 碘帕酸、 碘海醇和碘曲仑等； 铋类化合 物， 例如三氧化二铋； 硫酸钡； 金属粉末， 例如钽粉， 金粉等； 以及 其他常见的显影剂和它们的任意混合物。 优选的， 所述显影剂为碘化 物、 金粉、 铂粉、 钽粉、 钛粉、 钨粉或硫酸钡。 本发明对所述阻聚剂、 增塑剂和造影剂的添加量没有特殊要求， 优选为本领域技术人员熟知 的添加量。 在本发明的优选技术方案中， 所述膜材与可降解聚合物在成膜时 混合使用。 所述可降解聚合物选自聚乳酸、 聚乙交酯、 聚己内酯、 聚 己酸内酯、 聚酐、 聚 1，2-亚丙基富马酸酯、 聚膦腈、 L-酪氨酸衍生高分 子、 聚原酸酯、 氨基酸类聚合物、 甲壳素及其衍生物、 壳聚糖及其衍 生物、 透明质酸及其衍生物、 硫酸软骨素及其衍生物、 胶原蛋白及其 衍生物、 明胶及其衍生物、 琼脂及其衍生物、 纤维蛋白及其衍生物和 丝蛋白及其衍生物中的一种或几种。 优选的， 所述可降解聚合物为胶 原蛋白或聚乳酸。 根据本发明， 所述支架是激光加工的管网状支架， 或者由一种连 续丝链编织而成的编织支架。 优选的， 所述支架的网孔密度在轴向上 为不对称变化。 根据本发明， 所述支架的材料选自生物相容性金属材料或 /和高分 子材料， 或者上述可降解聚合物。 本发明的植入装置具备如下特点：
1 ) 支架输送前或后， 膜材可被微导管、 导管或专用输送器输送通 过迂曲血管到达靶目标；
2 ) 支架植入后能精确、 快速地在瘤颈口实现封堵；
3 ) 支架植入后具有足够的顺应性， 顺应迂曲的脑血管；
4 ) 瘤颈口处支架覆膜， 而其他位置无覆膜， 同时维持正常分支动 脉的通畅。 附图说明
为了更清楚地描述本发明的技术方案， 下面将结合附图作简要介 绍。 显而易见， 这些附图仅是本申请记载的一些具体实施方式。 本发 明的技术方案包括但不限于这些附图。 图 1 示出不均一网格结构的支架， 其中较高网孔密度 （即， 较大 金属覆盖率） 的部分支架覆盖载瘤动脉的动脉瘤颈口， 其他部分支架 为较低网孔密度 （即， 较小金属覆盖率） 。
图 2示出不均一网格结构的支架， 其中较高网孔密度覆盖部分瘤 颈口， 而较低网孔密度覆盖血管分支。 图 3示出均一网格结构的支架。 具体实施方式
为了进一步理解本发明， 下面将结合实施例对本发明的优选方案 进行描述。 这些描述只是举例说明本发明植入装置及其制备方法的特 征和优点， 而非限制本发明的保护范围。 将输送膜材的微导管置于瘤腔内， 然后通过输送系统植入支架至 动脉瘤病变部位， 释放支架， 注射膜材， 膜材在瘤颈口处固化并粘附 于支架上形成一层致密的膜， 从而实现局部覆膜使得支架精确定位。 或者， 当支架为管网状支架时， 输送膜材的微导管也可在支架释放后 经由支架网孔抵达瘤腔， 再在瘤颈口处成膜。 本发明植入装置由支架和通过微导管输送在手术现场实现涂覆的 膜 （1-0 ) 组成 （参见图 1 ) 。 所述膜 （1-0 ) 由包含氰基丙烯酸正辛酯 和钽粉的膜材聚合固化而成。 所述膜 （1-0 ) 也可由包含氰基丙烯酸正 辛酯和钽粉的膜材与胶原蛋白的混合物聚合固化而成， 具体操作步骤 如下： 先将 0.5 mol的胶原蛋白用沸腾床造粒 （参见赵江等于 2007年 发表在 《食品研究与开发》 上的 《沸腾床喷涂卵磷脂造粒技术生产蛋 白粉工艺的优化研究》 一文） ， 得到粒径 50目左右的胶原蛋白粒子， 然后加入到 3 mol的氰基丙烯酸正辛酯的单体中，超声分散使得胶原粒 子能够均匀的分散在单体中。 在 37~50°C下氩气气氛中加入 30 g纳米 钽粉并搅拌， 得到分散均一的氰基丙烯酸正辛酯的磁流体。 支架可以是不均一网格结构的支架， 即不同部位具有不同的金属 覆盖率。 较高网孔密度 （1-2 ) 的那部分支架覆盖载瘤动脉 （1-1 ) 的动 脉瘤 （1-6 ) 口面， 以最大限度地改变动脉瘤内血流， 支架其他部位为 较低网孔密度 （1-3 ) 结构以支撑支架贴附正常血管壁 （1-4 ) ， 保持通 畅的管腔并尽可能减少对分支 （1-5 ) 的覆盖面积。 对于不均一网格的 支架， 本发明也可以在较高网孔密度覆盖部分瘤颈口、 较低网孔密度 覆盖分支时同样实现动脉瘤的治疗 （参见图 2) ； 也可以是均一网格结 构的支架， 只要能保证分支血流通畅同样完全可以完成动脉瘤的治疗 (参见图 3 ) 。 上述装置能够精确、 快捷地封堵动脉瘤颈口， 阻止血流对动脉瘤 的冲击， 并可保持正常动脉分支的血流， 显著改善占位效应， 从而实 现动脉瘤的真正治愈。 以上实施例的说明只是用于帮助理解本发明的核心思想。 应当指 出， 对于本领域的普通技术人员而言， 在不脱离本发明原理的前提下， 还可以对本发明装置进行若干改进和修饰， 但这些改进和修饰也落入 本发明权利要求请求保护的范围内。

Claims

权 利 要 求
1. 一种血管内植入装置包， 其包括待涂覆的膜材以及网孔支架。
2. 权利要求 1所述的植入装置包， 其中所述膜材的主要成分为氰 基丙烯酸烷基酯， 其结构如下式 (1)示：
0
H2C=C-C-OCnH2n+1
CN ( 1 )
其中 l n 12， 优选 4 n 10， 最优 5 n 8。
3. 权利要求 2所述的植入装置包， 其中所述膜材除氰基丙烯酸垸 基酯之外， 还包括阻聚剂、 增塑剂和 /或显影剂。
4. 前述权利要求任一项所述的植入装置包， 其中所述膜材与可降 解聚合物在成膜时混合使用。
5. 权利要求 4所述的植入装置包， 其中所述可降解聚合物选自聚 乳酸、 聚乙交酯、 聚己内酯、 聚己酸内酯、 聚酐、 聚 1,2-亚丙基富马酸 酯、 聚膦腈、 L-酪氨酸衍生高分子、 聚原酸酯、 氨基酸类聚合物、 甲壳 素及其衍生物、 壳聚糖及其衍生物、 透明质酸及其衍生物、 硫酸软骨 素及其衍生物、 胶原蛋白及其衍生物、 明胶及其衍生物、 琼脂及其衍 生物、 纤维蛋白及其衍生物和丝蛋白及其衍生物中的一种或几种。
6. 前述权利要求任一项所述的植入装置包， 其中所述支架是激光 加工的管网状支架， 或者由一种连续丝链编织而成的编织支架。
7. 前述权利要求任一项所述的植入装置包， 其中所述支架的材料 选自生物相容性金属材料或 /和高分子材料， 或者权利要求 5 中定义的 可降解聚合物。
8. 一种局部覆膜的植入装置的制备方法， 包括下列步骤： 将输送膜材的微导管置于瘤腔内，
然后通过输送系统植入支架至血管病变部位，
释放支架，
注射膜材， 以及
膜材在瘤颈口处的支架表面成膜。
9. 一种局部覆膜的植入装置的制备方法， 包括下列步骤： 将支架输送至血管病变部位，
释放支架，
然后通过微导管经由支架网孔将膜材输送至瘤腔内，
膜材在瘤颈口处的支架表面成膜。
10. 权利要求 8或 9所述的制备方法， 其中所述膜材的主要成分 为氰基丙烯酸烷基酯， 其结构如下式 (1)示：
0
H2C=C-C-OCnH2n+1
CN ( 1 )
其中 l n 12， 优选 4 n 10， 最优 5 n 8。
11. 权利要求 10所述的制备方法， 其中所述膜材除氰基丙烯酸垸 基酯之外， 还包括阻聚剂、 增塑剂和 /或显影剂。
12. 权利要求 8-11任一项所述的制备方法， 其中所述膜材与可降 解聚合物在成膜时混合使用。
13. 权利要求 12所述的制备方法， 其中所述可降解聚合物选自聚 乳酸、 聚乙交酯、 聚己内酯、 聚己酸内酯、 聚酐、 聚 1,2-亚丙基富马酸 酯、 聚膦腈、 L-酪氨酸衍生高分子、 聚原酸酯、 氨基酸类聚合物、 甲壳 素及其衍生物、 壳聚糖及其衍生物、 透明质酸及其衍生物、 硫酸软骨 素及其衍生物、 胶原蛋白及其衍生物、 明胶及其衍生物、 琼脂及其衍 生物、 纤维蛋白及其衍生物和丝蛋白及其衍生物中的一种或几种。
14. 权利要求 8-13任一项所述的制备方法， 其中所述支架是激光 加工的管网状支架， 或者由一种连续丝链编织而成的编织支架。
15. 权利要求 8-14任一项所述的制备方法， 其中所述支架的材料 选自生物相容性金属材料或 /和高分子材料，或者权利要求 13中定义的 可降解聚合物。
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