WO2017101022A1 - 一种改良的医用支架材料 - Google Patents

一种改良的医用支架材料 Download PDF

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Publication number
WO2017101022A1
WO2017101022A1 PCT/CN2015/097452 CN2015097452W WO2017101022A1 WO 2017101022 A1 WO2017101022 A1 WO 2017101022A1 CN 2015097452 W CN2015097452 W CN 2015097452W WO 2017101022 A1 WO2017101022 A1 WO 2017101022A1
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Prior art keywords
stent
scaffold
mussel mucin
improved
mussel
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PCT/CN2015/097452
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English (en)
French (fr)
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高敏
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江阴市本特塞缪森生命科学研究院有限公司
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Priority to PCT/CN2015/097452 priority Critical patent/WO2017101022A1/zh
Publication of WO2017101022A1 publication Critical patent/WO2017101022A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances

Definitions

  • the present invention relates to an improved medical stent material and, more particularly, to a product for curing mussel mucin on a medical stent material.
  • the stent refers to an object placed in the lesion segment to support the vessel of the stenosis and occlusion segment, reduce the elastic retraction of the blood vessel and reshape the shape, and maintain the blood flow of the lumen.
  • vascular stents such as coronary stents, cerebrovascular stents, renal artery stents, and aortic stents; cardiac stents and nerve stents.
  • the bracket can be divided into a mesh bracket, a tubular bracket, a wound bracket, and a ring bracket.
  • it can be divided into 316L stainless steel bracket, nickel bracket and tantalum bracket.
  • the stent is implanted into the body, the contact between the stent and the body is prone to rejection. Since the body treats the stent as a foreign object and treats the contact site as a wound area, the repairing effect will occur automatically, and the inflammatory reaction is likely to occur at the stent.
  • Mussel adhesive protein also known as Mytilusedulis foot protein (Mefp)
  • Mefp Mytilusedulis foot protein
  • Mussels are usually attached in groups to the reefs on the coast or to the bottom of the ship, and have the ability to withstand wave impacts in the offshore.
  • mussels can be attached extremely strongly to the substrate of any material, such as metal, wood, glass, and the like. The main reason for the above characteristics of mussels is that they can form and store this special mucin in the girth of the foot. The mussels release the mucin through the foot silk to a solid surface such as rock to form a water-resistant combination. Fix yourself.
  • Mussel mucin has two structural features: (1) containing lysine, which has a high loading of positive charge; (2) containing 3,4 dihydroxyphenylalanine (DOPA, dopa). The cells and tissues of the human body are negatively charged.
  • Mussel mucin binds to cells and tissues through the electrostatic interaction between its own positive charge and the negative charge of cells and tissues of the human body, promoting cell growth and exerting protective and therapeutic effects.
  • dopa oxidation produces ortho-dioxins, which can be cross-linked with unoxidized dopa to form a membrane or a network scaffold, which promotes the protein to adhere more closely and firmly to the surface of the human body, thereby protecting.
  • Mussel mucin is a macromolecular protein that is completely degraded in the human body for about 3-10 days. Its ability to attach to cell tissues is excellent, so that mussel mucin can be stabilized locally and continue to function.
  • mussel mucin products are very limited.
  • the commercial mussel mucin products are Cell-Tak of BD Biosciences, MAP Trix of Kollodis of Korea and Hydrogel of Biopolymer of Sweden. These products are either used directly in the mussel mucin solution state, or are stored as lyophilized powder formulations and dissolved prior to use. Their primary application is limited to microscopic cell adhesion and tissue adhesives. Mussel mucin has also been reported for use in membrane repair, as a coating against seawater corrosion.
  • Mussel mucin can be used for wound healing process because it has the function of promoting cell adhesion and crawling, but its application in medical stents has not been reported.
  • the present invention provides an improved medical stent product comprising: a matrix material usable for a medical stent, and mussel mucin which is curable on the matrix material.
  • mussel mucin refers to marine mites such as Mytilusedulis Linnaeus, Mytilus coruscus, or Pernaviridis from the Mytilidae bivalve mollusc. 11 subclasses of mussel mucin, currently known in the shell, purified: mefp1, mefp-2, mefp-3, mefp-4, mefp-5, mefp-6, collagen pre-COL-P, pre a mixture of one or more of -COL-D, pre-COL-NG, foot silk matrix protein PTMP and DTMP.
  • the mussel viscosity of the mussel mucin used herein may have a pH of 1.0 to 7.0 in an aqueous solution, and particularly may be in the range of pH 3.0 to 6.5 to make the effect better.
  • the mussel mucin used herein may also be obtained by a method of biosynthesis, comprising a mixture of one or more of the known 11 mussel mucin subclasses.
  • the artificially biosynthesized mussel mucin used herein may have a pH of 1.0 to 7.0 in aqueous solution, and particularly may be in the range of pH 3.0 to 6.5 to make it more effective.
  • the mussel mucin used herein may also be a hydrolyzed peptide obtained by hydrolysis of mussel mucin from natural or artificial biosynthesis, or a synthetic peptide containing a functional group thereof obtained by artificial synthesis.
  • the mussel mucin hydrolyzed peptide or synthetic peptide used herein may have a pH of 1.0 to 7.0 in an aqueous solution, and particularly may be in the range of pH 3.0 to 6.5 to make the effect better.
  • the mussel mucin used herein can be obtained by the following preparation method, for example, a method for separating and purifying mussel mucin using mixed adsorption chromatography in Chinese Patent No. ZL200710179491.0, a kind of carboxy using Chinese Patent No. ZL200710179492.5 A method for purifying mussel mucin by methyl ion exchange chromatography, a method for separating and purifying mussel mucin using salting out and dialysis, Chinese Patent No. ZL200910087567.6.
  • the mussel mucin used herein may be in solution or in the form of a jelly.
  • the medical stent may be a dermal stent, a nerve stent, a blood vessel stent, a cardiac occluder and an embolization device, a cardiac drug delivery stent, a digestive system stent, a urinary system stent, a respiratory stent, and an intracranial stent.
  • Spring coil system a dermal stent, a nerve stent, a blood vessel stent, a cardiac occluder and an embolization device, a cardiac drug delivery stent, a digestive system stent, a urinary system stent, a respiratory stent, and an intracranial stent.
  • the definition of the stent described in the present invention is derived from the Catalogue of Medical Devices (2013 edition) promulgated by the State Food and Drug Administration.
  • the invention provides a method for preparing an improved medical stent material, comprising the steps of:
  • curing refers to the adsorption of mussel mucin to a medical scaffold material by physical means.
  • the mussel mucin solution can be added to the scaffold matrix material to cure the mussel mucin to the matrix material after a period of time.
  • the mussel mucin solution can be sprayed onto the surface of the stent matrix material, and the mussel mucin is cured to the stent matrix material after a period of time.
  • the matrix material can be infiltrated into the mussel mucin solution for a period of time.
  • the mussel mucin is then cured to the scaffold matrix material.
  • the mussel mucin solution may be formulated from an acidic, neutral or weakly alkaline solution and is most preferably an acidic solution.
  • the mussel mucin solution may be formulated from citric acid, acetic acid, sodium citrate, oxalic acid, carbonic acid, phosphoric acid, benzoic acid, sodium carbonate, or the like, but is not limited to the above solvent.
  • the concentration of mussel mucin may be from 0.01 to 150 mg/ml, in particular the concentration of mussel mucin in the product may be from 0.1 to 15 mg/ml.
  • the mussel mucin solution is used in an amount sufficient to uniformly cover or infiltrate the scaffold material.
  • the temperature for curing may be any, preferably 10-40 °C.
  • the period of time for curing may be any, preferably from 10 to 60 minutes.
  • the invention provides an improved medical scaffold material which is formed by coating mussel mucin on a matrix material, which can inhibit the inflammatory reaction of the stent portion while avoiding the stent portion while playing the role of the stent. Tissue hyperplasia and scar formation.
  • the present invention also provides an improved medical dermal stent in which mussel mucin is cured onto an existing dermal stent.
  • Medical dermal stents can include: collagen scaffolds, collagen and silica gel hybrid scaffolds.
  • the present invention also provides an improved nerve stent in which mussel mucin is cured onto an existing nerve stent.
  • the nerve scaffold may include: a natural material nerve scaffold such as collagen, and a synthetic material nerve scaffold such as polyacetic acid.
  • the present invention also provides an improved vascular stent in which mussel mucin is cured onto an existing vascular stent.
  • the vascular stent may include an arterial stent, a peripheral vascular stent, a venous filter, and the like.
  • the present invention also provides an improved cardiac occluder and embolization device in which mussel mucin is cured onto existing cardiac occlusion devices and embolization devices.
  • the cardiac occluder may include: an patent ductus arteriosus occluder, an atrial septal defect occluder, a ventricular septal defect occluder, a porous atrial septal defect occluder, etc.;
  • the embolization device may include: alginate microsphere blood vessel Embolization agent, polyvinyl alcohol particle embolization agent, gelatin sponge particle embolization agent, vascular plug, patent ductus arteriosus embolization coil and delivery system.
  • the present invention also provides an improved cardiac drug delivery stent in which mussel mucin is cured onto an existing cardiac drug delivery stent.
  • the cardiac drug-loading stent may include a metal drug-coated stent, a biodegradable drug-coated stent system, and the like.
  • the present invention also provides an improved digestive system scaffold in which mussel mucin is cured onto an existing digestive system scaffold.
  • Digestive system stents can include: biliary stents, esophageal stent systems, pancreatic duct stents, intestinal stents, and the like.
  • the present invention also provides an improved urinary system stent in which mussel mucin is cured onto an existing urinary system stent.
  • the urinary system stent can include: a prostate stent, a urethral stent, a subcutaneous urinary diversion stent, a ureter stent, and the like.
  • the present invention also provides an improved respiratory stent in which mussel mucin is cured onto an existing respiratory stent.
  • Respiratory stents can include: tracheal and bronchial stents, respiratory stents, soft palate implants, and the like.
  • the present invention also provides an improved intracranial stent and coil system in which mussel mucin is cured onto existing intracranial stents and coil systems.
  • the intracranial stent and coil system may include: an internal artery stent system, an intracranial stent graft system, an intracranial stent system, a neurovascular remodeling device, and the like.
  • All of the products of the present invention can be prepared by the above process for preparing improved medical scaffold materials.
  • the present inventors have surprisingly found that curing mussel mucin onto a medical scaffold material can exert mussel mucin activity on the scaffold material, imparting a biological structure to the scaffold material, and is more conducive to reconstructing or rehabilitating damaged human tissue or organ.
  • mussel mucin is cured onto the scaffold material, the physical and chemical stability of the protein is enhanced, the degradation cycle of the protein is prolonged, and the bioactivity of mussel mucin is more favorable.
  • the scaffold material product of the present invention having mussel mucin cured can be prepared by the above method, and the effects have been tested and verified within the scope of the present invention.
  • the effects have been tested and verified within the scope of the present invention.
  • only for the purpose of explanation only implementation A few of them are described in the examples, however, they should not be construed as limiting the invention.
  • the nature and advantages of the products of the present invention are further illustrated in the following non-limiting examples.
  • Example 1 Mussel mucin solidified to a heart occluder to promote endothelial cell growth
  • Preparation of mussel mucin solidified cardiac sealing stent Take 20ml of 0.3mg/ml mussel mucin solution, soak the heart-sealing stent (Germany Laisheng) in mussel mucin solution, and keep it at room temperature for 30 minutes. Dry at 45 ° C, take it out and set aside.
  • Two patients with congenital heart disease were enrolled in the occlusion stent.
  • the patients were enrolled by the cardiac surgeon and were treated with untreated cardiac occlusion stent and mussel mucin-cured cardiac occlusion stent.
  • the operation is performed by a femoral vein puncture intervention method. After the catheter is inserted, the occlusion stent is delivered to the site where treatment is needed.
  • the surface of the occluder was covered by the body's own endothelial cells 1 month after operation, and the occluder was completely buried by the endothelial cells until 3 months.
  • endothelial cells did not completely cover the surface of the occluder 1 month after surgery, and the occluder was completely embedded by endothelial cells 4 months after surgery. It can be seen that the occluder for curing mussel mucin is more conducive to the coverage of endothelial cells and reduces the risk of occluder detachment.
  • Example 2 Curing mussel mucin to renal artery stent promotes smooth blood flow, improved blood pressure and endothelial cell growth
  • Preparation of mussel mucin solidified renal artery stent Take 20ml of 0.3mg/ml mussel mucin solution, soak the renal artery stent (Palmaz) in mussel mucin solution, keep it at 45°C for 20 minutes, then dry it and remove it. After the backup.
  • Example 3 Mussel viscose coated polytetrafluoroethylene artificial blood vessel stent anticoagulant function
  • Preparation of mussel mucin coated polytetrafluoroethylene artificial blood vessel scaffold take 10ml of mussel mucin solution of 0.5mg/ml, soak the polytetrafluoroethylene artificial blood vessel scaffold 0.5g (American Gore) in mussels In the white solution, it was taken out after 10 minutes, and dried at 45 ° C for use.
  • the mussel mucin coated polytetrafluoroethylene artificial blood vessel stent has good anticoagulant properties and blood compatibility.
  • Example 4 Mussel mucin solidified to cerebral vascular stent to promote endothelial cell growth
  • Preparation of mussel mucin solidified cerebrovascular stent Take 20ml of 0.3mg/ml mussel mucin solution, soak the cerebral vascular scaffold (American Gore) in mussel mucin solution, take it out after 20 minutes, and bake at 45 °C. Dry, take it out and set aside.
  • Two patients with cerebral artery stenosis were enrolled and confirmed by a brain surgeon. They were treated with untreated cerebral artery stent and mussel mucin solidified cerebral artery stent. Surgical puncture of the femoral artery under local anesthesia, then insert a 7F sheath catheter from the puncture site, perform angiography, measure the length of the diseased vessel and the diameter of the vessel, select the stent suitable for the lesion, and deliver the fine stent to the stenosis through the catheter. The stent was used to open the blood vessel, and finally the angiography was performed to check the blood flow of the stenosis and distal segments of the vessel after placement of the stent.
  • Example 5 Curing of mussel mucin to an esophageal stent reduces pain and response after chemotherapy
  • Preparation of mussel mucin solidified esophageal stent Take 500ml of mussel mucin solution of 0.5mg/ml, soak the esophageal stent (Ultraflex) in mussel mucin solution, take it out after 10 minutes, dry at 45 °C, take out the reserve. use.
  • Two patients with advanced esophageal stenosis of esophageal and cardiac cancer were enrolled and confirmed by brain digestive physicians. They were treated with untreated esophageal stent and mussel mucin-cured esophageal stent. The operation is in the patient's supine or semi-recumbent position, and the throat is sprayed with anesthesia. Electron esophagoscopy was performed to observe the cause, shape and length of the lesion. After the guide wire is passed through the esophagus of the lesion segment by esophagoscopy, the esophagoscopy is withdrawn.
  • the esophageal stent has been previously compressed in the inner tube of the conveyor, inserted into the esophagus under the guidance of the guide wire, and inserted into the esophagus mirror again. After passing the inner tube through the stenosis under direct vision, adjust the stent to the appropriate position and quickly withdraw from the outer sheath. Released in the esophagus. Oral antibiotics were given 3 to 5 days after surgery.

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Abstract

一种改良的支架材料，其是贻贝粘蛋白固化到基质支架材料上的支架，采用该材料获得支架的同时，还能减轻支架与机体接触部位的排异反应，避免疤痕的形成，并且贻贝粘蛋白固化支架材料后，提高了蛋白的物理、化学稳定性，延长蛋白的降解周期。

Description

一种改良的医用支架材料 技术领域
本发明涉及一种改良的医用支架材料，更具体地，涉及在医用支架材料上固化贻贝粘蛋白的产品。
背景技术
支架是指置入在病变段内以达到支撑狭窄闭塞段血管，减少血管弹性回缩及再塑形，保持管腔血流通畅的物体。支架根据植入部位不同，可以分为血管支架如冠脉支架、脑血管支架、肾动脉支架、大动脉支架等；心脏支架、神经支架等。支架根据设计不同，可以分为网状支架、管状支架、缠绕型支架、环状支架。根据支架材料的不同，可以分为316L不锈钢支架、镍支架、钽支架。根据输送方式的不同，分为球囊膨胀性支架和自膨胀性支架。当支架植入机体后，支架与机体接触部位易产生排异反应。由于机体将支架当成异物，将接触部位当作创伤区，会自动发生修复作用，进而支架处易出现炎症反应。许多病人，尤其是糖尿病人，在支架周围出现严重的疤痕组织增生。这种疤痕组织增生，严重的时候可以造成畅通了的动脉重新狭窄，甚至堵塞。因此，需要对支架表面进行修饰，消除支架作为异物对局部组织的刺激、抑制疤痕组织在支架周围的生长。
贻贝粘蛋白(Mussel adhesive protein，MAP)，也称作贻贝足丝蛋白(Mytilusedulis foot protein，Mefp)，是海洋贝类紫贻贝(Mytilusedulis Linnaeus)、厚壳贻贝(Mytiluscoruscus)、翡翠贻贝(Pernaviridis)等分泌的一种特殊的蛋白质。贻贝通常成群地附着在海岸边的礁石上或者轮船的底部，有在近海耐受波浪冲击的能力。实际上贻贝几乎可以极其牢固地附着在任何材料的基底上，如金属、木材、玻璃等。贻贝具有上述特性的主要原因是其足丝腺内可生成并储存这种特殊的粘蛋白，贻贝通过足丝释放粘蛋白到岩石一类的固体表面上，形成抗水的结合，从而将自己固定。
目前从贻贝中鉴定得到11种粘蛋白亚类，包括mefp1、mefp-2、mefp-3、mefp-4、mefp-5、mefp-6、胶原蛋白pre-COL-P、pre-COL-D、pre-COL-NG、足丝基质蛋白PTMP和DTMP(朱曜曜等，海洋科学进展，2014，32(4)： 560-568)。贻贝粘蛋白具有2个结构特点：(1)含有赖氨酸，使蛋白带有高载量正电荷；(2)含3，4二羟基苯丙氨酸(DOPA，多巴)。人体的细胞和组织带有负电荷。贻贝粘蛋白通过自身正电荷与人体的细胞和组织负电荷之间的静电相互作用与细胞和组织紧密结合，促进细胞的生长，发挥防护和治疗的作用。此外，多巴氧化生成邻位二醌，可以和未被氧化的多巴相互交联形成膜或是网状支架，促使蛋白质更加紧密、稳固地附着在人体表面，起到保护作用。贻贝粘蛋白是大分子蛋白质，在人体内完全降解的时间约为3-10天，其附着于细胞组织的能力优异，使贻贝粘蛋白可以稳固于局部，持续发挥作用。
目前贻贝粘蛋白产品的应用领域非常有限，商品化的贻贝粘蛋白产品有美国BD Biosciences公司的Cell-Tak，韩国Kollodis公司的MAP Trix和瑞典Biopolymer公司的Hydrogel。这些产品或者是以贻贝粘蛋白溶液状态直接使用，或者是以冻干粉制剂保存而在使用前溶解，它们的主要应用限于微观的细胞粘附和组织粘合剂。也有报道贻贝粘蛋白用于胎膜修复、作为抗海水腐蚀涂层等应用。
贻贝粘蛋白由于具有促进细胞贴壁、爬行功能，可用于创面的愈合过程，但在医用支架中的应用尚未见报道。
发明内容
本发明的目的是提供一种改良的医用支架产品，其不但能满足常规医用支架的要求，同时还具有治疗作用。
为了实现上述目的，本发明提供一种改良的医用支架产品，包括：可用于医用支架的基质材料，以及可固化于基质材料上的贻贝粘蛋白。
在本文中使用的贻贝粘蛋白是指从贻贝科(Mytilidae)双壳类软体动物中的紫贻贝(Mytilusedulis Linnaeus)、厚壳贻贝(Mytiluscoruscus)或翡翠贻贝(Pernaviridis)等海洋贻贝中纯化获得的、目前已知的贻贝粘蛋白11个亚类：mefp1、mefp-2、mefp-3、mefp-4、mefp-5、mefp-6、胶原蛋白pre-COL-P、pre-COL-D、pre-COL-NG、足丝基质蛋白PTMP和DTMP中的一种或几种的混合物。在本文中使用的贻贝粘蛋白在水溶液中的酸碱度可以是pH 1.0-7.0，特别是可以在pH 3.0-6.5的范围内以使其效果更佳。
在本文中使用的贻贝粘蛋白也可以是采用生物合成的方法获得的，包含已知的11个贻贝粘蛋白亚类中的一种或几种的混合物。在本文中使用的人工生物合成的贻贝粘蛋白在水溶液中的酸碱度可以是pH 1.0-7.0，特别是可以在pH 3.0-6.5的范围内以使其效果更佳。
在本文中使用的贻贝粘蛋白也可以是天然来源或人工生物合成的贻贝粘蛋白经水解后获得的水解肽，或通过人工合成方式获得的含有其功能基团的合成肽。在本文中使用的贻贝粘蛋白水解肽或合成肽在水溶液中的酸碱度可以是pH 1.0-7.0，特别是可以在pH 3.0-6.5的范围内以使其效果更佳。
在本文中使用的贻贝粘蛋白可以采用以下制备方法获得，例如中国专利号ZL200710179491.0的一种使用混合吸附色谱分离纯化贻贝粘蛋白的方法，中国专利号ZL200710179492.5的一种使用羧甲基离子交换色谱纯化贻贝粘蛋白的方法，中国专利号ZL200910087567.6的一种使用盐析和透析分离纯化贻贝粘蛋白的方法等。
在本文中使用的贻贝粘蛋白可以是溶液或冻于粉形式。
在本发明的实施方式中，医用支架可以是真皮支架，神经支架，血管支架，心脏封堵器及栓塞器械，心脏载药支架，消化系统支架，泌尿系统支架，呼吸系统支架，颅内支架及弹簧圈系统。
本发明所述及的支架定义源于国家食品药品监督管理局颁布的《医疗器械分类目录》(2013版)。
本发明提供的一种制备改良的医用支架材料的方法，包括以下步骤：
(1)配制贻贝粘蛋白溶液，
(2)将贻贝粘蛋白溶液固化至医用支架基质材料，得到改良的医用支架材料。
在本发明中使用的术语“固化”是指通过物理手段将贻贝粘蛋白吸附到医用支架材料上。
在一个实施方式中，可以将贻贝粘蛋白溶液加入到支架基质材料中，一段时间后使贻贝粘蛋白固化至基质材料。
在一个实施方式中，可以将贻贝粘蛋白溶液喷涂到支架基质材料表面，一段时间后使贻贝粘蛋白固化至支架基质材料。
在一个实施方式中，可以将基质材料浸润于贻贝粘蛋白溶液中，一段时 间后使贻贝粘蛋白固化至支架基质材料。
在本发明的实施方式中，贻贝粘蛋白溶液可以是由酸性、中性或弱碱性溶液配制，并以酸性溶液最佳。
在本发明的实施方式中，贻贝粘蛋白溶液可以由柠檬酸、乙酸、柠檬酸钠、草酸、碳酸、磷酸、苯甲酸、碳酸钠等配制，但不限于上述溶剂。
在本发明的实施方式中，贻贝粘蛋白的浓度可以是0.01-150mg/ml，特别是贻贝粘蛋白在产品中的浓度可以是0.1-15mg/ml。
在本发明的实施方式中，贻贝粘蛋白溶液的用量应能均匀覆盖或浸润支架材料。
在本发明的实施方式中，用于固化的温度可以是任意的，优选10-40℃。
在本发明的实施方式中，用于固化的一段时间可以是任意的，优选10-60分钟。
本发明提供了一种改良的医用支架材料，该医用支架材料是在基质材料上包被贻贝粘蛋白后形成的，其能在发挥支架作用的同时，抑制支架部位的炎症反应，避免支架部位组织增生和疤痕的形成。
本发明还提供一种改良的医用真皮支架，其中将贻贝粘蛋白固化到现有的真皮支架上。医用真皮支架可以包括：胶原支架、胶原和硅胶混合支架。
本发明还提供一种改良的神经支架，其中将贻贝粘蛋白固化到现有的神经支架上。神经支架可以包括：胶原等天然材料神经支架，聚乙酸等人工合成材料神经支架。
本发明还提供一种改良的血管支架，其中将贻贝粘蛋白固化到现有的血管支架上。血管支架可以包括：动脉支架、外周血管支架、静脉滤器等。
本发明还提供一种改良的心脏封堵器及栓塞器械，其中将贻贝粘蛋白固化到现有的心脏封堵器及栓塞器械上。心脏封堵器可以包括：动脉导管未闭封堵器、房间隔缺损封堵器、室间隔缺损封堵器、多孔型房间隔缺损封堵器等；栓塞器械可以包括：海藻酸钠微球血管栓塞剂、聚乙烯醇颗粒栓塞剂、明胶海绵颗粒栓塞剂、血管塞、动脉导管未闭栓塞弹簧圈及放送系统等。
本发明还提供一种改良的心脏载药支架，其中将贻贝粘蛋白固化到现有的心脏载药支架上。心脏载药支架可以包括：金属药物涂层支架、生物降解药物涂层支架系统等。
本发明还提供一种改良的消化系统支架，其中将贻贝粘蛋白固化到现有的消化系统支架上。消化系统支架可以包括：胆道支架、食道支架系统、胰管支架、肠道支架等。
本发明还提供一种改良的泌尿系统支架，其中将贻贝粘蛋白固化到现有的泌尿系统支架上。泌尿系统支架可以包括：前列腺支架、尿道支架、皮下尿路改道支架、输尿管支架等。
本发明还提供一种改良的呼吸系统支架，其中将贻贝粘蛋白固化到现有的呼吸系统支架上。呼吸系统支架可以包括：气管及支气管支架、呼吸道支架、软腭植入支架等。
本发明还提供一种改良的颅内支架及弹簧圈系统，其中将贻贝粘蛋白固化到现有的颅内支架及弹簧圈系统上。颅内支架及弹簧圈系统可以包括：内动脉支架系统、颅内覆膜支架系统、颅内支架系统、神经血管重塑装置等。
本发明的所有产品均可由上述制备改良的医用支架材料的方法制备。
本发明人出人意料地发现，将贻贝粘蛋白固化到医用支架材料上，可以在支架材料上发挥贻贝粘蛋白的活性，赋予支架材料生物结构，更有利于重建或康复受损的人体组织或器官。并且特别是，贻贝粘蛋白固化到支架材料上后，提高了蛋白的物理、化学稳定性，延长了蛋白的降解周期，更有利于贻贝粘蛋白生物活性的发挥。
具体实施方式
下面将结合具体实施例对本发明作进一步说明。需要指出的是，本发明的固化有贻贝粘蛋白的支架材料产品，均可由上述方法制备，并且在本发明范围内均已测试并验证了效果，下文中，仅仅是为说明，只在实施例中描述了其中一少部分，然而不应将其理解为对本发明的限制。以下非限制性的实施例中进一步说明了本发明产品的性质和优点。
实施例1：贻贝粘蛋白固化到心脏封堵器上促进内皮细胞生长
贻贝粘蛋白固化心脏封堵支架的制备：取0.3mg/ml的贻贝粘蛋白溶液20ml，将心脏封堵支架(德国莱生)浸泡在贻贝粘蛋白溶液中，室温保持30分钟后，45℃烘干，取出后备用。
收集2例先天性心脏病需植入封堵性支架患者，经心外科医生确认后入组，分别采用未经处理的心脏封堵支架和贻贝粘蛋白固化的心脏封堵支架治疗。手术采用股静脉穿刺介入治疗方法，插入导管后将封堵支架送入达到需要治疗的部位。
采用贻贝粘蛋白固化的封堵器患者，术后1个月封堵器表面已被人体自身的内皮细胞覆盖，至3个月封堵器已完全被内皮细胞包埋。使用未经贻贝粘蛋白处理的封堵器患者，术后1个月，内皮细胞未完全覆盖封堵器表面，至术后4个月，封堵器完全被内皮细胞包埋。可以看出，固化贻贝粘蛋白的封堵器更有利于内皮细胞的覆盖，降低封堵器脱落等风险。
实施例2：贻贝粘蛋白固化到肾动脉支架上促进血流畅通、血压改善及内皮细胞生长
贻贝粘蛋白固化肾动脉支架的制备：取0.3mg/ml的贻贝粘蛋白溶液20ml，将肾动脉支架(Palmaz)浸泡在贻贝粘蛋白溶液中，45℃保持20分钟后烘干，取出后备用。
将8例大动脉炎所致肾动脉狭窄患者，分成两组先行经皮腔内肾动脉成形术，然后分别采用未经处理的Palmaz支架和贻贝粘蛋白固化Palmaz支架治疗。
采用贻贝粘蛋白固化的Palmaz支架的患者，术后1周时血压由术前的(22.9±3.2/14.1±2.0)kPa降为(18.4±1.6/9.3±2.1)kPa，其中3例血压恢复正常，1例血压改善，术后随访肾动脉血流畅通，血压控制满意，至2个月支架已完全被内皮细胞包埋。使用未经贻贝粘蛋白处理支架的患者，术后1周时血压由术前的(22.9±3.2/14.1±2.0)kPa降为(19.4±1.7/10.4±2.0)kPa，其中1例血压恢复正常，3例血压改善，术后随访肾动脉血流畅通，血压控制基本满意，至2个月支架未完全被内皮细胞包埋。至术后3个月，支架完全被内皮细胞包埋。可以看出，固化贻贝粘蛋白的支架更有利于术后血压恢复和内皮细胞的覆盖，降低手术失败的风险。
实施例3：贻贝粘蛋白涂层聚四氟乙烯人工血管支架抗凝血功能
贻贝粘蛋白涂层聚四氟乙烯人工血管支架制备：取0.5mg/ml的贻贝粘蛋白溶液10ml，将聚四氟乙烯人工血管支架0.5g(美国戈尔)浸泡在贻贝粘蛋 白溶液中，10min后取出，45℃烘干，备用。
制备2％红细胞悬液，用普通聚四氟乙烯人工血管片样品0.5g作为参照物，按0.5g/10ml的比例将普通聚四氟乙烯人工血管片样品和贻贝粘蛋白涂层聚四氟乙烯人工血管片在2％红细胞悬液中37℃浸提60min，以0.1％碳酸钠为阳性对照，生理盐水为阴性对照，采用分光光度计法在545nm测吸光度。
结果如下表1所示：
表1
Figure PCTCN2015097452-appb-000001
由上表可以看出，贻贝粘蛋白涂层聚四氟乙烯人工血管支架有良好的抗凝血性能及血液相容性。
实施例4：贻贝粘蛋白固化到脑血管支架上促进内皮细胞生长
贻贝粘蛋白固化脑血管支架的制备：取0.3mg/ml的贻贝粘蛋白溶液20ml，将脑血管支架(美国戈尔)浸泡在贻贝粘蛋白溶液中，20分钟后取出，45℃烘干，取出后备用。
收集2例脑动脉狭窄患者，经脑外科医生确认后入组，分别采用未经处理的脑动脉支架和贻贝粘蛋白固化的脑动脉支架治疗。手术在局麻下行股动脉穿刺，然后从穿刺处插入7F鞘导管，行血管造影，测量病变血管的长度及血管的直径，选取适合于病变的支架，通过导管将精细的支架输送到狭窄处释放支架撑开血管，最后行血管造影，检查放置支架后血管狭窄段和远侧段的血流情况。
采用贻贝粘蛋白固化的脑动脉支架患者，术后4周支架表面已被人体自身的内皮细胞覆盖，术后6周支架内壁被新生的血管内膜覆盖，支架与血管真正融为一体，血流正常。使用未经贻贝粘蛋白处理的脑动脉支架患者，术后4周，内皮细胞未完全覆盖封堵器表面，有轻微血栓形成，至术后10周，脑动脉支架才完全被内皮细胞包埋。可以看出，固化贻贝粘蛋白的脑动脉支架 更有利于内皮细胞的覆盖，降低支架内壁血栓形成。
实施例5：贻贝粘蛋白固化到食管支架上能减轻疼痛和化疗后的反应
贻贝粘蛋白固化食管支架的制备：取0.5mg/ml的贻贝粘蛋白溶液500ml，将食管支架(Ultraflex)浸泡在贻贝粘蛋白溶液中，10分钟后取出，45℃烘干，取出后备用。
收集2例食管贲门癌晚期食管狭窄的患者，经脑消化内科医生确认后入组，分别采用未经处理的食管支架和贻贝粘蛋白固化的食管支架治疗。手术在病人卧位或半卧位，喉部喷雾麻醉。行电子食管镜镜检查，观察病变的原因、形状、长度等。通过食管镜将导丝通过病变段食管后，退出食管镜。食管支架已事先压缩在输送器内管中，在导丝引导下插入食管内，再次插入食管镜在直视下将内管通过狭窄部位后，调整支架于合适位置，迅速退出外鞘，支架即释放于食管内。术后给予口服抗生素3～5天。
采用贻贝粘蛋白固化的食管支架患者，术后有轻微疼痛感，进食明显好转，生活质量提高，进一步行放化疗的反应轻微。使用未经贻贝粘蛋白处理的食管支架患者，术后出现明显疼痛感，需服用止疼药，进一步化疗后反应强烈。可以看出，固化贻贝粘蛋白的食管支架更有利于降低患者疼痛感和化疗的不良反应。

Claims (19)

  1. 一种改良的医用支架材料，由贻贝粘蛋白与医用支架基质材料组成，其中贻贝粘蛋白是以均匀覆盖的方式固化在支架基质材料上。
  2. 根据权利要求1的改良的支架材料，其中所述贻贝粘蛋白是来自亚类：mefp1、mefp-2、mefp-3、mefp-4、mefp-5、mefp-6、胶原蛋白pre-COL-P、pre-COL-D、pre-COL-NG、足丝基质蛋白PTMP和DTMP中的一种或几种的混合物。
  3. 根据权利要求1的改良支架材料，医用支架材料是医用真皮支架，包括胶原支架、胶原和硅胶混合支架；神经支架，包括胶原等天然材料神经支架，聚乙酸等人工合成材料神经支架；血管支架，包括动脉支架、外周血管支架、静脉滤器，心脏封堵器包括动脉导管未闭封堵器、房间隔缺损封堵器、室间隔缺损封堵器、多孔型房间隔缺损封堵器；及栓塞器械包括海藻酸钠微球血管栓塞剂、聚乙烯醇颗粒栓塞剂、明胶海绵颗粒栓塞剂、血管塞、动脉导管未闭栓塞弹簧圈及放送系统；心脏载药支架，包括金属药物涂层支架、生物降解药物涂层支架系统；消化系统支架，包括胆道支架、食道支架系统、胰管支架、肠道支架；泌尿系统支架，包括前列腺支架、尿道支架、皮下尿路改道支架、输尿管支架；呼吸系统支架，包括气管及支气管支架、呼吸道支架、软腭植入支架；颅内支架及弹簧圈系统，包括内动脉支架系统、颅内覆膜支架系统、颅内支架系统、神经血管重塑装置。
  4. 一种制备改良的医用支架材料的方法，包括：
    (1)配制贻贝粘蛋白溶液，
    (2)将贻贝粘蛋白溶液固化至支架基质材料，得到改良的支架材料。
  5. 根据权利要求4的方法，其中所述固化是将贻贝粘蛋白溶液加入到支架基质材料中，或喷涂到支架基质材料表面，或将支架基质材料浸润于贻贝粘蛋白溶液中，一段时间后使贻贝粘蛋白固化至支架基质材料。
  6. 根据权利要求4的方法，其中贻贝为粘蛋白溶液由酸性、中性或弱碱性溶液配制，尤其是由酸性溶液配制。
  7. 根据权利要求6的方法，其中贻贝粘蛋白溶液是由柠檬酸、乙酸、 柠檬酸钠、草酸、碳酸、磷酸、苯甲酸、碳酸钠配制。
  8. 根据权利要求4-7中任一项的方法，其中贻贝粘蛋白浓度是0.01-150mg/ml，特别是0.1-15mg/ml。
  9. 根据权利要求4-7中任一项的方法，其中固化温度为10-40℃。
  10. 根据权利要求4-7中任一项的方法，其中固化时间为10-60分钟。
  11. 一种改良的真皮支架，其中真皮支架以均匀覆盖的方式固化有贻贝粘蛋白。
  12. 一种改良的神经支架，其中神经支架以均匀覆盖的方式固化有贻贝粘蛋白。
  13. 一种改良的血管支架，其中血管支架以均匀覆盖的方式固化有贻贝粘蛋白。
  14. 一种改良的心脏封堵器及栓塞器械，其中心脏封堵器及栓塞器械以均匀覆盖的方式固化有贻贝粘蛋白。
  15. 一种改良的心脏载药支架，其中心脏载药支架以均匀覆盖的方式固化有贻贝粘蛋白。
  16. 一种改良的消化系统支架，其中消化系统支架以均匀覆盖的方式固化有贻贝粘蛋白。
  17. 一种改良的泌尿系统支架，其中泌尿系统支架以均匀覆盖的方式固化有贻贝粘蛋白。
  18. 一种改良的呼吸系统支架，其中呼吸系统支架以均匀覆盖的方式固化有贻贝粘蛋白。
  19. 一种改良的颅内支架及弹簧圈系统，其中颅内支架及弹簧圈系统以均匀覆盖的方式固化有贻贝粘蛋白。
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CN106729998A (zh) * 2017-04-14 2017-05-31 苏州医甸园医疗科技发展有限公司 贻贝粘蛋白修饰的人工血管内壁涂层及其制备方法与应用
CN107308507A (zh) * 2017-07-06 2017-11-03 苏州医甸园医疗科技发展有限公司 一种基于贻贝粘蛋白涂层的血管支架及其制备方法
CN109833509A (zh) * 2019-01-18 2019-06-04 太阳雨林（厦门）生物医药有限公司 一种多重缓释血管栓塞载药组合物
CN112972753A (zh) * 2019-12-02 2021-06-18 太阳雨林（厦门）生物医药有限公司 一种用于治疗慢性炎症引起的支气管扩张性咯血的缓释栓塞微球

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130052712A1 (en) * 2011-08-24 2013-02-28 Postech Academy-Industry Foundation Surface immobilization of various functional biomolecules using mussel adhesive protein
CN103087976A (zh) * 2013-01-05 2013-05-08 高敏 一种促进细胞贴壁生长的材料及其制备方法
CN103638554A (zh) * 2013-11-13 2014-03-19 浙江大学 一种丝素蛋白与海洋贻贝粘附蛋白复合材料的制备方法
CN104069547A (zh) * 2014-07-24 2014-10-01 吉林大学 一种复合血管支架

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130052712A1 (en) * 2011-08-24 2013-02-28 Postech Academy-Industry Foundation Surface immobilization of various functional biomolecules using mussel adhesive protein
CN103087976A (zh) * 2013-01-05 2013-05-08 高敏 一种促进细胞贴壁生长的材料及其制备方法
CN103638554A (zh) * 2013-11-13 2014-03-19 浙江大学 一种丝素蛋白与海洋贻贝粘附蛋白复合材料的制备方法
CN104069547A (zh) * 2014-07-24 2014-10-01 吉林大学 一种复合血管支架

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GAO MIN ET AL.: "Overview of Mussel Adhesive Protein", JOURNAL OF ANHUI AGRICULTURAL SCIENCES, vol. 39, no. 32, 20 October 2015 (2015-10-20), pages 19860 - 19861 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106729998A (zh) * 2017-04-14 2017-05-31 苏州医甸园医疗科技发展有限公司 贻贝粘蛋白修饰的人工血管内壁涂层及其制备方法与应用
CN107308507A (zh) * 2017-07-06 2017-11-03 苏州医甸园医疗科技发展有限公司 一种基于贻贝粘蛋白涂层的血管支架及其制备方法
CN109833509A (zh) * 2019-01-18 2019-06-04 太阳雨林（厦门）生物医药有限公司 一种多重缓释血管栓塞载药组合物
CN109833509B (zh) * 2019-01-18 2021-10-15 太阳雨林（厦门）生物医药有限公司 一种多重缓释血管栓塞载药组合物
CN112972753A (zh) * 2019-12-02 2021-06-18 太阳雨林（厦门）生物医药有限公司 一种用于治疗慢性炎症引起的支气管扩张性咯血的缓释栓塞微球

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