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CN103520777A - Highly-tough hole-adjustable gel artificial blood vessel and making method thereof - Google Patents

Highly-tough hole-adjustable gel artificial blood vessel and making method thereof Download PDF

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CN103520777A
CN103520777A CN201310464616.XA CN201310464616A CN103520777A CN 103520777 A CN103520777 A CN 103520777A CN 201310464616 A CN201310464616 A CN 201310464616A CN 103520777 A CN103520777 A CN 103520777A
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blood vessel
artificial blood
gel
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CN103520777B (en
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张青松
张念一
薛蕊
梁聪聪
穆齐峰
陈莉
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Tiangong University
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Tianjin Polytechnic University
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Abstract

本发明涉及一种高韧性和孔洞可调的凝胶人造血管及其制备方法。所述的凝胶人造血管含有烯烃类单体M1、生物高分子M2、化学交联剂M3、离子交联剂M4,四者用量的质量百分数比别为:9~15%、1~3%、0-0.2‰、4~10%。本制备方法是在水溶液中以M1和M2为功能单体,M3作为化学交联剂,得到凝胶人造血管坯体后再利用M4作为例子交联剂进行强化处理,制成高强高韧、孔洞可调的凝胶人造血管。该方法制得的凝胶人造血管具有较高的强度、韧性和回复性,在拉压弯扭等外力作用下不易破损,且可快速恢复原形;具有多重交联的网络结构,孔洞尺寸可由交联度调节。本发明适用于生物、医疗、组织工程、吸附等领域。The invention relates to a gel artificial blood vessel with high toughness and adjustable holes and a preparation method thereof. The gel artificial blood vessel contains olefinic monomer M1, biopolymer M2, chemical cross-linking agent M3, and ion cross-linking agent M4, and the mass percentages of the amounts of the four are: 9-15%, 1-3% , 0-0.2‰, 4-10%. In this preparation method, M1 and M2 are used as functional monomers in an aqueous solution, and M3 is used as a chemical cross-linking agent to obtain a gel artificial blood vessel body, and then M4 is used as an example cross-linking agent for strengthening treatment to make a high-strength, high-toughness, porous Adjustable gel vascular graft. The gel artificial blood vessel prepared by this method has high strength, toughness and resilience, is not easy to be damaged under the action of external force such as tension, compression, bending, torsion, etc., and can quickly restore the original shape; joint adjustment. The invention is applicable to the fields of biology, medical treatment, tissue engineering, adsorption and the like.

Description

一种高韧性和孔洞可调的凝胶人造血管及其制备方法A gel artificial blood vessel with high toughness and adjustable pores and its preparation method

技术领域technical field

本发明涉及高分子材料、生物医药和组织工程领域,具体涉及一种高韧性和孔洞可调的凝胶人造血管及其制备方法。The invention relates to the fields of polymer materials, biomedicine and tissue engineering, in particular to a gel artificial blood vessel with high toughness and adjustable pores and a preparation method thereof.

背景技术Background technique

血管是生物体内输送血液的管道,人体内除角膜、毛发、指(趾)甲、牙质及上皮等处外,血管遍布全身。血管可以分为动脉、静脉和毛细血管三种。主动脉和大动脉的管壁较厚,含有丰富的弹性纤维,有可扩张性和弹性。毛细血管的口径最小,数量最多,总的横截面积最大,血流速度最慢,管壁最薄,仅由单层内皮细胞和基膜组成,通透性很好,有利于血液与组织进行物质交换。随着医学技术的发展,需要研究以及移植血管,所以人们发明了人工血管,即一种在功能和特点上与生物血管相近,能够代替生物血管的人工血管。Blood vessels are the pipelines that transport blood in the living body. In the human body, except for the cornea, hair, nails, dentin, and epithelium, blood vessels spread all over the body. Blood vessels can be divided into three types: arteries, veins and capillaries. The walls of the aorta and aorta are thick and rich in elastic fibers, which are expandable and elastic. Capillaries have the smallest caliber, the largest number, the largest total cross-sectional area, the slowest blood flow, and the thinnest wall. They are only composed of a single layer of endothelial cells and a basement membrane. material exchange. With the development of medical technology, it is necessary to study and transplant blood vessels, so people have invented artificial blood vessels, that is, artificial blood vessels that are similar in function and characteristics to biological blood vessels and can replace biological blood vessels.

制备人工血管需满足以下要求:1.物理和化学性能稳定;2.网孔度适宜;3.具有一定的强度和柔韧度;4.作搭桥手术时易缝性好;5.血管接通放血时不渗血或渗血少且能即刻停止;6.移入人体后组织反应轻微;7.人体组织能迅速形成新生的内外膜;8.不易形成血栓;9.令人满意的远期通畅率。Preparation of artificial blood vessels must meet the following requirements: 1. Stable physical and chemical properties; 2. Appropriate mesh size; 3. Have certain strength and flexibility; 4. Good sutureability in bypass surgery; No bleeding or less bleeding and can stop immediately; 6. The tissue reaction is slight after being transplanted into the human body; 7. The human tissue can quickly form a new inner and outer membrane; 8. It is not easy to form thrombus; 9. Satisfactory long-term patency rate .

人工血管血管的制造,国内外的研究,绝大多数是采取医用高分子材料进行编织。织造的方法有针织、编织和机织。织成管状织物后,经后处理加工成为螺旋状的人造血管,可随意弯曲而不致吸瘪。我国在50年代末,60年代初,才开始进行研究,起初是用尼龙(Nylon)织成,后因尼龙降解,在生体内植入后发生破裂而被淘汰。现在多采用涤纶(Dacron)纤维编织人工血管,己大量应用于临床,如治疗主动脉瘤,主动脉狭窄,上下腔静脉切除更换术等,最长可达37cm。目前用高分子材料由机器编织的人工血管,平织者内径最小为8mm,针织者内径为3mm,但针织人工血管目前在国内尚未能正式生产。In the manufacture of artificial blood vessels, the vast majority of research at home and abroad is to use medical polymer materials for weaving. Weaving methods include knitting, weaving and weaving. After being woven into a tubular fabric, it is post-processed into a spiral artificial blood vessel, which can be bent at will without being sucked. At the end of the 1950s and the beginning of the 1960s, my country began to conduct research. At first, it was woven with nylon (Nylon), but it was eliminated because of the degradation of nylon and the rupture after implantation in the living body. Dacron fiber braided artificial blood vessels are now mostly used in clinics, such as the treatment of aortic aneurysm, aortic stenosis, resection and replacement of superior and inferior vena cava, etc., the longest can reach 37cm. At present, the artificial blood vessels woven by machines using polymer materials have a minimum inner diameter of 8mm for plain weavers and 3mm for knitted ones. However, knitted artificial blood vessels have not yet been formally produced in China.

涤纶人造血管是最早使用的血管材料,且由于通畅率较高,长期以来被成功地用于大血管置换,但无法完全满足小口径人造血管的制造要求。此后,用于制造人造血管的原料发展为聚四氟乙烯、聚氨酯和天然桑蚕丝。60年代出现以高分子聚四氟乙烯为原料经注塑而成的直型人造血管,商品名称为考尔坦克斯(Core-Tex),已广泛应用于临床。国内外应用最广泛的人造血管材料是膨化聚四氟乙烯,它具有很好的生物相容性与抗凝性,但顺应性较差,移植物的通畅率仅为30%,尤其是直径小于6mm的聚四氟乙烯(ePTFE)人造血管上述缺点更加明显,远期通畅率极差。Polyester artificial blood vessel is the earliest vascular material used, and has been successfully used for large blood vessel replacement for a long time due to its high patency rate, but it cannot fully meet the manufacturing requirements of small-caliber artificial blood vessels. Since then, the raw materials used to make artificial blood vessels have developed into polytetrafluoroethylene, polyurethane and natural mulberry silk. In the 1960s, a straight artificial blood vessel made of high-molecular polytetrafluoroethylene appeared through injection molding. The trade name was Core-Tex, and it has been widely used in clinical practice. The most widely used artificial vascular material at home and abroad is expanded polytetrafluoroethylene, which has good biocompatibility and anticoagulation, but poor compliance, and the patency rate of grafts is only 30%, especially when the diameter is smaller than The above-mentioned shortcomings of 6mm polytetrafluoroethylene (ePTFE) artificial blood vessels are more obvious, and the long-term patency rate is extremely poor.

现用于临床的主要由聚对苯二甲酸乙二酯(PET)、膨体聚四氟乙烯(ePTFE)和聚氨酯(PU)等原料合成高聚物制成的人工血管,聚对苯二甲酸乙二酯主要是以涤纶纤维的形式编织成管状,内皮细胞可以在纤维间的空隙生长;膨体聚四氟乙烯制备的血管壁有多孔网状结构,有利于内皮细胞生长。但涤纶和膨体聚四氟乙烯没有生物活性和抗凝活性,移植后易发生血栓。聚氨酯有良好的生物相容性和血液相容性,可以有效的抗血栓。因此将其合成高聚物可以在一定程度上满足制备人工血管的条件,应用于临床。The artificial blood vessels currently used in clinical practice are mainly made of synthetic polymers such as polyethylene terephthalate (PET), expanded polytetrafluoroethylene (ePTFE) and polyurethane (PU). Ethylene glycol is mainly woven into a tubular shape in the form of polyester fibers, and endothelial cells can grow in the gaps between fibers; the vessel wall made of expanded polytetrafluoroethylene has a porous network structure, which is conducive to the growth of endothelial cells. However, polyester and expanded polytetrafluoroethylene have no biological activity and anticoagulant activity, and thrombosis is prone to occur after transplantation. Polyurethane has good biocompatibility and hemocompatibility, and can effectively resist thrombosis. Therefore, the synthesis of high polymers can meet the conditions for the preparation of artificial blood vessels to a certain extent, and can be used clinically.

由上分析,上述人工血管普遍存在血液在其内部流通性不好,生物相容性以及力学性能差等缺点,有必要寻找一种具有良好的生物血管性能的人工血管,在综合性能上要充分满足移植的要求。From the above analysis, the above-mentioned artificial blood vessels generally have the disadvantages of poor blood circulation inside, poor biocompatibility and poor mechanical properties. Meet the requirements for transplantation.

中国专利CN101284148A公开了一种制备人工血管的方法,配方由聚偏氟乙烯(PVDF)、聚醚砜(PES)和聚砜(PS)中的一种或几种组成,制备成高聚物,将其经过溶胀和溶解配置成膜液,然后过滤脱泡经过干喷湿纺发制备中空纤维膜,再经过后期处理制成血管。然而这种制备方法涉及到有毒溶剂,对生物体有一定毒性,并且制作步骤繁琐,需要一系列的操作,不易制备。Chinese patent CN101284148A discloses a method for preparing artificial blood vessels. The formula is composed of one or more of polyvinylidene fluoride (PVDF), polyethersulfone (PES) and polysulfone (PS), and is prepared into a high polymer. It is swollen and dissolved to form a membrane liquid, then filtered and degassed, and then dry-jet wet-spun to prepare a hollow fiber membrane, and then processed to form a blood vessel. However, this preparation method involves toxic solvents, which have certain toxicity to organisms, and the production steps are cumbersome, requiring a series of operations, and are not easy to prepare.

中国专利CN1313741A公开了一种利用异种生物体血管并且用表面活性剂洗涤血管后完全除去该血管的细胞成分而成的人工血管。这种方法原料不易得到,而且处理起来不方便,不能大批量生产。Chinese patent CN1313741A discloses an artificial blood vessel which utilizes a blood vessel of a heterogeneous organism and washes the blood vessel with a surfactant to completely remove the cellular components of the blood vessel. The raw material of this method is not easy to obtain, and it is inconvenient to handle, so it cannot be mass-produced.

高分子水凝胶是一类具有三维网络结构的高聚物。因其具有独特的保水、力学性能和良好的生物相容性而被广泛应用于生物工程、医药保健等领域。Polymer hydrogel is a kind of polymer with three-dimensional network structure. Because of its unique water retention, mechanical properties and good biocompatibility, it is widely used in bioengineering, medicine and health care and other fields.

凝胶作为一种新型的人造血管材料,其本身为与人体软组织相似的软湿材料,适宜在人体环境中应用。凝胶具有化学结构明确、性能稳定且易于调控、无异物感染、廉价和易于灭菌等优势;通过改变交联机理和配比的调控,能够实现高强度高韧性的力学性能以及优良的可见光透过性能,为凝胶在血管材料的应用提供了力学保障和光学支持,此外,凝胶高分子材料的耐降解性和耐候性使得材料在应用于人体的过程中不易发生降解和排异,材料使用周期较长。As a new type of artificial vascular material, gel itself is a soft and wet material similar to human soft tissue, and is suitable for application in the human environment. The gel has the advantages of clear chemical structure, stable performance and easy regulation, no foreign body infection, cheap and easy to sterilize; by changing the cross-linking mechanism and adjusting the ratio, it can achieve high-strength and high-toughness mechanical properties and excellent visible light transmission. It provides mechanical guarantee and optical support for the application of the gel in vascular materials. In addition, the degradation resistance and weather resistance of the gel polymer material make the material difficult to degrade and reject in the process of being applied to the human body. The material Long service life.

本发明考虑了人造血管的制备需要满足无毒性,生物相容性,选择透过性和力学性能良好,以及制造简单及成本低等特点,运用高分子复合水凝胶的特点进行制备凝胶人工血管,可替代临床上使用的PET、ePTFE和PU人工血管,在医学领域拥有广泛的应用前景。The present invention considers that the preparation of artificial blood vessels needs to meet the characteristics of non-toxicity, biocompatibility, selective permeability and good mechanical properties, as well as the characteristics of simple manufacture and low cost, and uses the characteristics of polymer composite hydrogel to prepare artificial gel. Blood vessels can replace PET, ePTFE and PU artificial blood vessels used clinically, and have broad application prospects in the medical field.

发明内容Contents of the invention

本发明的目的在于克服现有技术的不足,提供一种具有好的生物相容性,同时兼具高强高韧及光学透过性的人造血管材料。本发明得到的血管材料的强度高、韧性好,在生物生存温度下能够满足生物日常活动所需的各种拉压弯扭等动作,利于血管内皮细胞的增殖,且可见光光学透过性能和回复性能良好,能够满足输液、抽血等日常医疗要求。本材料对生物体无毒害作用,生物相容性好,且具有耐降解等优点,利于在人体中长期使用。The purpose of the present invention is to overcome the deficiencies of the prior art and provide an artificial blood vessel material with good biocompatibility, high strength, high toughness and optical transparency. The blood vessel material obtained by the present invention has high strength and good toughness, and can meet various tension, compression, bending, twisting and other actions required by the daily activities of the organism at the living temperature of the organism, which is beneficial to the proliferation of vascular endothelial cells, and the visible light optical transmission performance and recovery It has good performance and can meet the daily medical requirements such as infusion and blood drawing. The material has no toxic effect on organisms, has good biocompatibility, and has the advantages of resistance to degradation, etc., which is beneficial to long-term use in the human body.

本发明是通过以下技术方案实现的:The present invention is achieved through the following technical solutions:

一种高韧性和孔洞可调的凝胶人造血管是由烯烃类单体M1、生物高分子M2、化学交联剂M3、离子交联剂M4溶于水聚合而成。A gel artificial blood vessel with high toughness and adjustable pores is formed by dissolving olefin monomer M1, biopolymer M2, chemical cross-linking agent M3, and ion cross-linking agent M4 into water.

所述的烯烃类单体M1为丙烯酰胺、甲基丙烯酰胺、N-异丙基丙烯酰胺、N-羟甲基丙烯酰胺、2-(二甲氨基)乙基-甲基丙烯酰胺、甲基丙烯酸2-羟基乙酯、丙烯酸、甲基丙烯酸、丙烯酸叔丁酯、丙烯酸钠、2-丙烯酰胺-2-甲基-1-丙磺酸、多缩乙二醇单甲基丙烯酸酯,其无机盐,以及其混合物。The olefinic monomer M1 is acrylamide, methacrylamide, N-isopropylacrylamide, N-methylolacrylamide, 2-(dimethylamino)ethyl-methacrylamide, methyl 2-Hydroxyethyl acrylate, acrylic acid, methacrylic acid, tert-butyl acrylate, sodium acrylate, 2-acrylamide-2-methyl-1-propanesulfonic acid, polyethylene glycol monomethacrylate, its inorganic Salt, and mixtures thereof.

所述的生物高分子M2为海藻酸钠、壳聚糖、黄原胶、腐殖酸、纤维素、聚乳酸、聚赖氨酸、聚谷氨酸、聚乙烯醇、聚羟基脂肪酸酯、胶原蛋白、丝胶状球蛋白中的一种或任意两种组成的混合物。The biopolymer M2 is sodium alginate, chitosan, xanthan gum, humic acid, cellulose, polylactic acid, polylysine, polyglutamic acid, polyvinyl alcohol, polyhydroxyalkanoate, One of collagen, sericin, or a mixture of any two.

所述的化学交联剂M3为N,N’-亚甲基双丙烯酰胺、二(甲基)丙烯酸乙二醇酯、二缩水甘油基乙醚中的任意一种。The chemical crosslinking agent M3 is any one of N,N'-methylenebisacrylamide, ethylene glycol di(meth)acrylate, and diglycidyl ether.

所述的离子交联剂M4为氯化钙、氯化铜、氯化锌、硫酸氢钙、硫酸铜、硫酸锌中的任意一种。The ionic cross-linking agent M4 is any one of calcium chloride, copper chloride, zinc chloride, calcium bisulfate, copper sulfate and zinc sulfate.

本发明一种高韧性和孔洞可调的凝胶人造血管的制备方法,包括如下步骤:A preparation method of a gel artificial blood vessel with high toughness and adjustable pores of the present invention comprises the following steps:

1)A液的配制:25℃下将烯烃类单体M1、生物高分子M2依次加入到去离子水中,配制成质量浓度为10-18%的溶液,搅拌5-30min,静止脱泡15-30min;1) Preparation of liquid A: add olefin monomer M1 and biopolymer M2 into deionized water in sequence at 25°C to prepare a solution with a mass concentration of 10-18%, stir for 5-30min, and statically degas for 15- 30min;

2)B液的配制:25℃下将化学交联剂M3和引发剂过硫酸铵或过硫酸钾依次加入到去离子水中,磁力搅拌5-10min,直至形成均一透明的分散体系;2) Preparation of liquid B: add chemical crosslinking agent M3 and initiator ammonium persulfate or potassium persulfate into deionized water in sequence at 25°C, and stir magnetically for 5-10 minutes until a uniform and transparent dispersion system is formed;

3)预聚液的混配:将步骤2)配制的B液倒入步骤1)制好的A液中,磁力搅拌10-20min,待呈现均一的粘稠状时,立即加入催化剂四甲基乙二胺或亚硫酸钠,磁力搅拌5-10min,制得预聚液;3) Mixing of pre-polymerization solution: Pour the B solution prepared in step 2) into the A solution prepared in step 1), and stir it magnetically for 10-20 minutes. When it becomes uniform and viscous, immediately add the catalyst tetramethyl Ethylenediamine or sodium sulfite, magnetically stirred for 5-10min, to prepare the prepolymer solution;

4)凝胶人造血管坯的制备:将步骤3)制得的预聚液注入中空管状模具中,将端口处密封后在温度为40-70℃下进行聚合反应3-8h,得到凝胶人造血管坯;4) Preparation of the gel artificial vascular blank: inject the pre-polymerization solution prepared in step 3) into the hollow tubular mold, seal the port and carry out the polymerization reaction at a temperature of 40-70°C for 3-8 hours to obtain the artificial gel Blood vessel blank;

5)凝胶人工血管坯的强化处理:将步骤4)制得的凝胶人造血管坯取出,浸泡在质量浓度为4-10%的离子交联剂M4的水溶液中,反应时间为15-60min,取出后用去离子水浸泡冲洗1-5min,制得高韧性和孔洞可调的凝胶人造血管;5) Intensive treatment of the gel artificial blood vessel blank: take out the gel artificial blood vessel blank prepared in step 4), soak it in an aqueous solution of ion cross-linking agent M4 with a mass concentration of 4-10%, and the reaction time is 15-60min , after taking it out, soak and rinse it with deionized water for 1-5 minutes to prepare a gel artificial blood vessel with high toughness and adjustable pores;

6)凝胶人造血管的包装:将步骤5)制得的凝胶人造血管进行无菌真空热封包装。6) Packaging of the gel artificial blood vessel: the gel artificial blood vessel prepared in step 5) is aseptically vacuum heat-sealed and packaged.

本发明步骤1)中A液各组分质量百分比为:烯烃类单体M1:9-15%、生物高分子M2:1-3%、去离子水:82-90%。The mass percentages of the components of liquid A in step 1) of the present invention are: olefin monomer M1: 9-15%, biopolymer M2: 1-3%, deionized water: 82-90%.

本发明步骤2)中B液各组分质量比为:化学交联剂M3:0-0.2‰、引发剂是烯烃类单体M1的1%,去离子水:98-99%。The mass ratio of the components of liquid B in step 2) of the present invention is: chemical crosslinking agent M3: 0-0.2‰, initiator: 1% of olefin monomer M1, deionized water: 98-99%.

本发明步骤3)中的催化剂是烯烃类单体M1的3‰。The catalyst in step 3) of the present invention is 3‰ of the olefinic monomer M1.

本发明步骤5)中各组分质量比为:离子交联剂M4:4-10%、去离子水:90-96%。The mass ratio of each component in step 5) of the present invention is: ion crosslinking agent M4: 4-10%, deionized water: 90-96%.

所述的中空管状模具的内径为0.1-15mm、外径为0.1-17mm。The inner diameter of the hollow tubular mold is 0.1-15 mm, and the outer diameter is 0.1-17 mm.

所述的步骤5)不是制备凝胶人造血管的必要条件,但可增加凝胶人造血管的断裂应力和拉伸强度。The step 5) is not a necessary condition for preparing the gel artificial blood vessel, but it can increase the breaking stress and tensile strength of the gel artificial blood vessel.

所述的凝胶人造血管的孔洞大小为10nm-500μm。The hole size of the gel artificial blood vessel is 10nm-500μm.

所述的凝胶人造血管的韧性、孔洞尺寸、内皮细胞相容性和通畅率通过调节单体浓度、投料比、交联度、反应温度、模具大小和加料顺序调节。The toughness, hole size, endothelial cell compatibility and patency rate of the gel artificial blood vessel are regulated by adjusting monomer concentration, feeding ratio, cross-linking degree, reaction temperature, mold size and feeding sequence.

与现有人造血管材料和制备方法相比,本发明有以下优点:Compared with existing artificial vascular materials and preparation methods, the present invention has the following advantages:

1、具有较高的强度、韧性和回复性,拉压弯扭等外力作用下不易破损,且可快速恢复原形。1. It has high strength, toughness and resilience. It is not easy to be damaged under external forces such as tension, compression, bending and torsion, and can quickly restore its original shape.

2、具有优良的生物相容性,所得材料无毒无害,适用于人体内部组织材料的代替。2. It has excellent biocompatibility, and the obtained material is non-toxic and harmless, and is suitable for replacing internal tissue materials of the human body.

3、具有多重交联的网络结构,孔洞尺寸可由交联度调节,且具有高的使用周期和寿命。3. It has a multi-crosslinked network structure, the pore size can be adjusted by the degree of crosslinking, and it has a high service cycle and life.

4、本发明制备方法简单、原料易得、操作简便、成本低、反应周期短、反应条件温和,易于工业化和批量生产应用。4. The preparation method of the present invention is simple, the raw materials are readily available, the operation is simple, the cost is low, the reaction cycle is short, the reaction conditions are mild, and it is easy for industrialization and mass production.

5、所制备的凝胶血管的内径尺寸及壁厚能根据模具尺寸调节,以满足弹性动脉、肌肉动脉、小动脉等不同类别血管的性能要求。5. The inner diameter and wall thickness of the prepared gel blood vessels can be adjusted according to the size of the mold to meet the performance requirements of different types of blood vessels such as elastic arteries, muscular arteries, and small arteries.

具体实施方案specific implementation plan

本发明可用其他的不违背本发明的精神和主要特征的具体形式来概述。因此,下述具体实施方案仅用于说明本发明而不用于限制本发明的范围,其他的任何未违背本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。此外应理解,在阅读了本发明讲授的内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。The present invention may be embodied in other specific forms without departing from the spirit and main characteristics of the invention. Therefore, the following specific embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention, and any other changes, modifications, substitutions, combinations, and simplifications that do not violate the spirit and principles of the present invention should be Equivalent replacement methods are all included in the protection scope of the present invention. In addition, it should be understood that after reading the teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

实施例1Example 1

1)A液的配制:25℃下将1g丙烯酰胺、0.1g海藻酸钠,依次加入到去离子水中,配制成质量浓度为10%的溶液,搅拌15min,静止脱泡15min;1) Preparation of liquid A: Add 1 g of acrylamide and 0.1 g of sodium alginate to deionized water in sequence at 25°C to prepare a solution with a mass concentration of 10%, stir for 15 min, and stand still for 15 min for defoaming;

2)B液的配制:25℃下将0.001gN,N’-亚甲基双丙烯酰胺和0.1g过硫酸铵依次加入到去离子水中,磁力搅拌5min,直至形成均一透明的分散体系;2) Preparation of liquid B: add 0.001g of N,N'-methylenebisacrylamide and 0.1g of ammonium persulfate to deionized water in sequence at 25°C, and stir magnetically for 5 minutes until a uniform and transparent dispersion system is formed;

3)预聚液的混配:将步骤2)配制的B液倒入步骤1)制好的A液中,磁力搅拌10min,待呈现均一的粘稠状时,立即加入0.002g四甲基乙二胺,磁力搅拌7min,制得预聚液;3) Mixing of pre-polymerization solution: Pour the B solution prepared in step 2) into the A solution prepared in step 1), and stir magnetically for 10 minutes. When it becomes uniform and viscous, immediately add 0.002g of tetramethyl ethyl Diamine, magnetically stirred for 7min to obtain a prepolymer solution;

4)凝胶人造血管坯的制备:将步骤3)制得的预聚液注入内径为0.2mm外径为0.3mm的中空管状模具中,将端口处密封后在温度为40℃下进行聚合反应6h,得到凝胶人造血管坯;4) Preparation of gel artificial blood vessel base: inject the pre-polymerization solution prepared in step 3) into a hollow tubular mold with an inner diameter of 0.2mm and an outer diameter of 0.3mm, seal the port and carry out polymerization reaction at a temperature of 40°C 6h, to obtain the gel artificial blood vessel base;

5)凝胶人造血管坯的强化处理:将步骤4)制得的中空血管坯取出,浸泡在质量浓度为4%的氯化锌的水溶液中,反应时间为30min,取出后用去离子水浸泡冲洗3min,制得高韧性和孔洞可调的凝胶人造血管;5) Strengthening treatment of the gel artificial blood vessel blank: take out the hollow blood vessel blank prepared in step 4), soak it in an aqueous solution of zinc chloride with a mass concentration of 4%, the reaction time is 30min, soak it in deionized water after taking it out Rinse for 3 minutes to prepare a gel artificial blood vessel with high toughness and adjustable pores;

6)凝胶人造血管的包装:将步骤5)制得的凝胶人造血管进行无菌真空热封包装。6) Packaging of the gel artificial blood vessel: the gel artificial blood vessel prepared in step 5) is aseptically vacuum heat-sealed and packaged.

实施例2Example 2

1)A液的配制:25℃下将1.2g N-羟甲基丙烯酰胺、0.15g海藻酸钠依次加入到去离子水中,配制成质量浓度为12%的溶液,搅拌20min,静止脱泡30min;1) Preparation of liquid A: Add 1.2g of N-methylolacrylamide and 0.15g of sodium alginate to deionized water in sequence at 25°C to prepare a solution with a mass concentration of 12%, stir for 20 minutes, and stand still for 30 minutes to defoam ;

2)B液的配制:25℃下将0.0015gN,N’-亚甲基双丙烯酰胺和0.012g过硫酸钾依次加入到去离子水中,磁力搅拌10min,直至形成均一透明的分散体系;2) Preparation of liquid B: Add 0.0015g of N,N'-methylenebisacrylamide and 0.012g of potassium persulfate to deionized water in sequence at 25°C, and stir magnetically for 10 minutes until a uniform and transparent dispersion system is formed;

3)预聚液的混配:将步骤2)配制的B液倒入步骤1)制好的A液中,磁力搅拌15min,待呈现均一的粘稠状时,立即加入0.0036g四甲基乙二胺,磁力搅拌8min,制得预聚液;3) Mixing of pre-polymerization liquid: Pour the B liquid prepared in step 2) into the prepared A liquid in step 1), and stir magnetically for 15 minutes. Diamine, magnetically stirred for 8min to obtain a prepolymer solution;

4)凝胶人造血管坯的制备:将步骤3)制得的预聚液注入内径为0.5mm外径为0.65mm的中空管状模具中,将端口处密封后在温度为50℃下进行聚合反应5h,得到凝胶人造血管坯;4) Preparation of gel artificial blood vessel base: inject the pre-polymerization solution prepared in step 3) into a hollow tubular mold with an inner diameter of 0.5 mm and an outer diameter of 0.65 mm, seal the port and carry out polymerization reaction at a temperature of 50°C 5h, to obtain the gel artificial blood vessel base;

5)凝胶人造血管坯的强化处理:将步骤4)制得的中空血管坯取出,浸泡在质量浓度为7%的硫酸铜的水溶液中,反应时间为20min,取出后用去离子水浸泡冲洗5min,制得高韧性和孔洞可调的凝胶人造血管;5) Strengthening treatment of the gel artificial blood vessel blank: take out the hollow blood vessel blank prepared in step 4), soak it in an aqueous solution of copper sulfate with a mass concentration of 7%, the reaction time is 20min, soak and rinse it with deionized water after taking it out 5min, the gel artificial blood vessel with high toughness and adjustable pores was prepared;

6)凝胶人造血管的包装:将步骤5)制得的凝胶人造血管进行无菌真空热封包装。6) Packaging of the gel artificial blood vessel: the gel artificial blood vessel prepared in step 5) is aseptically vacuum heat-sealed and packaged.

实施例3Example 3

1)A液的配制:25℃下将1.5g甲基丙烯酰胺、0.1g海藻酸钠依次加入到去离子水中,配制成质量浓度为14%的溶液,搅拌30min,静止脱泡30min;1) Preparation of liquid A: Add 1.5 g of methacrylamide and 0.1 g of sodium alginate to deionized water in sequence at 25°C to prepare a solution with a mass concentration of 14%, stir for 30 minutes, and stand still for 30 minutes to defoam;

2)B液的配制:25℃下将0.0015g二(甲基)丙烯酸乙二醇酯和0.015g过硫酸钾依次加入到去离子水中,磁力搅拌5min,直至形成均一透明的分散体系;2) Preparation of liquid B: Add 0.0015g of ethylene glycol di(meth)acrylate and 0.015g of potassium persulfate into deionized water in turn at 25°C, and stir magnetically for 5 minutes until a uniform and transparent dispersion system is formed;

3)预聚液的混配:将步骤2)配制的B液倒入步骤1)制好的A液中,磁力搅拌10min,待呈现均一的粘稠状时,立即加入0.0045g甲基乙二胺,磁力搅拌5min,制得预聚液;3) Mixing of pre-polymerization solution: Pour the B solution prepared in step 2) into the A solution prepared in step 1), and stir it magnetically for 10 minutes. Amine, magnetically stirred for 5 minutes to obtain a prepolymer solution;

4)凝胶人造血管坯的制备:将步骤3)制得的预聚液注入内径为1mm外径为1.2mm的中空管状模具中,将端口处密封后在温度为50℃下进行聚合反应5h,得到凝胶人造血管坯;4) Preparation of gel artificial blood vessel base: inject the pre-polymerization solution prepared in step 3) into a hollow tubular mold with an inner diameter of 1 mm and an outer diameter of 1.2 mm, seal the port and carry out polymerization at a temperature of 50°C for 5 hours , to obtain the gel artificial blood vessel base;

5)凝胶人造血管坯的强化处理:将步骤4)制得的中空血管坯取出,浸泡在质量浓度为7%的硫酸氢钙的水溶液中,反应时间为30min,取出后用去离子水浸泡冲洗4min,制得高韧性和孔洞可调的凝胶人造血管;5) Strengthening treatment of the gel artificial blood vessel blank: take out the hollow blood vessel blank prepared in step 4), soak it in an aqueous solution of calcium bisulfate with a mass concentration of 7%, the reaction time is 30min, soak it in deionized water after taking it out After washing for 4 minutes, a gel artificial blood vessel with high toughness and adjustable pores was prepared;

6)凝胶人造血管的包装:将步骤5)制得的凝胶人造血管进行无菌真空热封包装。6) Packaging of the gel artificial blood vessel: the gel artificial blood vessel prepared in step 5) is aseptically vacuum heat-sealed and packaged.

实施例4Example 4

1)A液的配制:25℃下将1.4g丙烯酰胺、0.2g丝胶状球蛋白依次加入到去离子水中,配制成质量浓度为14%的溶液,搅拌25min,静止脱泡15min;1) Preparation of liquid A: Add 1.4 g of acrylamide and 0.2 g of sericin globulin to deionized water in sequence at 25°C to prepare a solution with a mass concentration of 14%, stir for 25 min, and stand still for 15 min for defoaming;

2)B液的配制:25℃下将0.0020gN,N’-亚甲基双丙烯酰胺和0.014g过硫酸铵依次加入到去离子水中,磁力搅拌10min,直至形成均一透明的分散体系;2) Preparation of liquid B: Add 0.0020g of N,N'-methylenebisacrylamide and 0.014g of ammonium persulfate to deionized water in sequence at 25°C, and stir magnetically for 10 minutes until a uniform and transparent dispersion system is formed;

3)预聚液的混配:将步骤2)配制的B液倒入步骤1)制好的A液中,磁力搅拌20min,待呈现均一的粘稠状时,立即加入催化剂0.0042g四甲基乙二胺,磁力搅拌7min,制得预聚液;3) Mixing of pre-polymerization solution: Pour the B solution prepared in step 2) into the A solution prepared in step 1), and stir it magnetically for 20 minutes. When it becomes uniform and viscous, immediately add catalyst 0.0042g Ethylenediamine, magnetically stirred for 7min to obtain a prepolymer solution;

4)凝胶人造血管坯的制备:将步骤3)制得的预聚液注入内径为6mm外径为7mm的中空管状模具中,将端口处密封后在温度为60℃下进行聚合反应4h,得到凝胶人造血管坯;4) Preparation of gel artificial blood vessel base: inject the pre-polymerization solution prepared in step 3) into a hollow tubular mold with an inner diameter of 6 mm and an outer diameter of 7 mm, seal the port and carry out polymerization reaction at a temperature of 60° C. for 4 hours. Obtain the gel artificial blood vessel blank;

5)凝胶人造血管坯的强化处理:将步骤4)制得的中空血管坯取出,浸泡在质量浓度为5%的氯化钙水溶液中,反应时间为20min,取出后用去离子水浸泡冲洗3min,制得高韧性和孔洞可调的凝胶人造血管;5) Strengthening treatment of the gel artificial blood vessel blank: take out the hollow blood vessel blank prepared in step 4), soak it in a calcium chloride aqueous solution with a mass concentration of 5%, and the reaction time is 20 minutes, soak and rinse it with deionized water after taking it out 3min, a gel artificial blood vessel with high toughness and adjustable pores was prepared;

6)凝胶人造血管的包装:将步骤5)制得的凝胶人造血管进行无菌真空热封包装。6) Packaging of the gel artificial blood vessel: the gel artificial blood vessel prepared in step 5) is aseptically vacuum heat-sealed and packaged.

实施例5Example 5

1)A液的配制:25℃下将1.6g N-异丙基丙烯酰胺、0.2g纤维素依次加入到去离子水中,配制成质量浓度为16%的溶液,搅拌25min,静止脱泡30min;1) Preparation of liquid A: add 1.6g of N-isopropylacrylamide and 0.2g of cellulose to deionized water in sequence at 25°C to prepare a solution with a mass concentration of 16%, stir for 25 minutes, and stand still for 30 minutes to defoam;

2)B液的配制:25℃下将0.0015gN,N’-亚甲基双丙烯酰胺和0.016g过硫酸钾依次加入到去离子水中,磁力搅拌8min,直至形成均一透明的分散体系;2) Preparation of liquid B: Add 0.0015g of N,N'-methylenebisacrylamide and 0.016g of potassium persulfate to deionized water in sequence at 25°C, and stir magnetically for 8 minutes until a uniform and transparent dispersion system is formed;

3)预聚液的混配:将步骤2)配制的B液倒入步骤1)制好的A液中,磁力搅拌20min,待呈现均一的粘稠状时,立即加入0.0048g亚硫酸钠,磁力搅拌10min,制得预聚液;3) Mixing of pre-polymerization liquid: Pour the B liquid prepared in step 2) into the prepared A liquid in step 1), and stir magnetically for 20 minutes. 10min, make the pre-polymerization solution;

4)凝胶人造血管坯的制备:将步骤3)制得的预聚液注入内径为3mm外径为3.5mm的中空管状模具中,将端口处密封后在温度为55℃下进行聚合反应6h,得到凝胶人造血管坯;4) Preparation of gel artificial blood vessel blank: inject the pre-polymerization solution prepared in step 3) into a hollow tubular mold with an inner diameter of 3mm and an outer diameter of 3.5mm, seal the port and carry out polymerization at a temperature of 55°C for 6 hours , to obtain the gel artificial blood vessel base;

5)凝胶人造血管坯的强化处理:将步骤4)制得的中空血管坯取出,浸泡在质量浓度为9%的氯化钙的水溶液中,反应时间为40min,取出后用去离子水浸泡冲洗2min,制得高韧性和孔洞可调的凝胶人造血管;5) Strengthening treatment of the gel artificial blood vessel blank: take out the hollow blood vessel blank prepared in step 4), soak it in an aqueous solution of calcium chloride with a mass concentration of 9%, the reaction time is 40min, soak it with deionized water after taking it out Rinse for 2 minutes to prepare a gel artificial blood vessel with high toughness and adjustable pores;

6)凝胶人造血管的包装:将步骤5)制得的凝胶人造血管进行无菌真空热封包装。6) Packaging of the gel artificial blood vessel: the gel artificial blood vessel prepared in step 5) is aseptically vacuum heat-sealed and packaged.

Claims (8)

1.一种高韧性和孔洞可调的凝胶人造血管是由烯烃类单体M1、生物高分子M2、化学交联剂M3、离子交联剂M4溶于水聚合而成;所述的烯烃类单体M1为丙烯酰胺、甲基丙烯酰胺、N-异丙基丙烯酰胺、N-羟甲基丙烯酰胺、2-(二甲氨基)乙基-甲基丙烯酰胺、甲基丙烯酸2-羟基乙酯、丙烯酸、甲基丙烯酸、丙烯酸叔丁酯、丙烯酸钠、2-丙烯酰胺-2-甲基-1-丙磺酸、多缩乙二醇单甲基丙烯酸酯,其无机盐,以及其混合物;所述的生物高分子M2为海藻酸钠、壳聚糖、黄原胶、腐殖酸、纤维素、聚乳酸、聚赖氨酸、聚谷氨酸、聚乙烯醇、聚羟基脂肪酸酯、胶原蛋白、丝胶状球蛋白中的一种或任意两种组成的混合物;所述的化学交联剂M3为N,N'-亚甲基双丙烯酰胺、二(甲基)丙烯酸乙二醇酯、二缩水甘油基乙醚中的任意一种;所述的离子交联剂M4为氯化钙、氯化铜、氯化锌、硫酸氢钙、硫酸铜、硫酸锌中的任意一种。1. A gel artificial blood vessel with high toughness and adjustable pores is formed by dissolving olefin monomer M1, biopolymer M2, chemical cross-linking agent M3, and ion cross-linking agent M4 into water; the olefin The class monomer M1 is acrylamide, methacrylamide, N-isopropylacrylamide, N-methylolacrylamide, 2-(dimethylamino)ethyl-methacrylamide, methacrylic acid 2-hydroxy Ethyl ester, acrylic acid, methacrylic acid, tert-butyl acrylate, sodium acrylate, 2-acrylamide-2-methyl-1-propanesulfonic acid, polyethylene glycol monomethacrylate, their inorganic salts, and their Mixture; the biopolymer M2 is sodium alginate, chitosan, xanthan gum, humic acid, cellulose, polylactic acid, polylysine, polyglutamic acid, polyvinyl alcohol, polyhydroxy fatty acid One or a mixture of any two of esters, collagen, sericin; the chemical cross-linking agent M3 is N, N'-methylenebisacrylamide, di(meth)acrylic acid ethyl Any one of glycol esters and diglycidyl ethers; the ionic crosslinking agent M4 is any one of calcium chloride, copper chloride, zinc chloride, calcium bisulfate, copper sulfate, zinc sulfate . 2.一种高韧性和孔洞可调的凝胶人造血管的制备方法,包括如下步骤:2. A preparation method of a gel artificial blood vessel with high toughness and adjustable pores, comprising the steps of: 1)A液的配制:25℃下将烯烃类单体M1、生物高分子M2依次加入到去离子水中,配制成质量浓度为10-18%的溶液,搅拌5-30min,静止脱泡15-30min。1) Preparation of liquid A: add olefin monomer M1 and biopolymer M2 into deionized water in sequence at 25°C to prepare a solution with a mass concentration of 10-18%, stir for 5-30min, and statically degas for 15- 30min. 2)B液的配制:25℃下将化学交联剂M3和引发剂过硫酸铵或过硫酸钾依次加入到去离子水中,磁力搅拌5-10min,直至形成均一透明的分散体系;2) Preparation of liquid B: add chemical crosslinking agent M3 and initiator ammonium persulfate or potassium persulfate into deionized water in sequence at 25°C, and stir magnetically for 5-10 minutes until a uniform and transparent dispersion system is formed; 3)预聚液的混配:将步骤2)配制的B液倒入步骤1)制好的A液中,磁力搅拌10-20min,待呈现均一的粘稠状时,立即加入催化剂四甲基乙二胺或亚硫酸钠,磁力搅拌5-10min,制得预聚液;3) Mixing of pre-polymerization solution: Pour the B solution prepared in step 2) into the A solution prepared in step 1), and stir it magnetically for 10-20 minutes. When it becomes uniform and viscous, immediately add the catalyst tetramethyl Ethylenediamine or sodium sulfite, magnetically stirred for 5-10min, to prepare the prepolymer solution; 4)凝胶人造血管坯的制备:将步骤3)制得的预聚液注入中空管状模具中,将端口处密封后在温度为40-70℃下进行聚合反应3-8h,得到凝胶人造血管坯;4) Preparation of the gel artificial vascular blank: inject the pre-polymerization solution prepared in step 3) into the hollow tubular mold, seal the port and carry out the polymerization reaction at a temperature of 40-70°C for 3-8 hours to obtain the artificial gel Blood vessel blank; 5)凝胶人造血管坯的强化处理:将步骤4)制得的凝胶人造血管坯取出,浸泡在质量浓度为4-10%的离子交联剂M4的水溶液中,反应时间为15-60min,取出后用去离子水浸泡冲洗1-5min,制得高韧性和孔洞可调的凝胶人造血管;5) Strengthening treatment of the gel artificial blood vessel base: take out the gel artificial blood vessel base prepared in step 4), soak it in the aqueous solution of the ion cross-linking agent M4 with a mass concentration of 4-10%, and the reaction time is 15-60min , after taking it out, soak and rinse it with deionized water for 1-5 minutes to prepare a gel artificial blood vessel with high toughness and adjustable pores; 6)凝胶人造血管的包装:将步骤5)制得的凝胶人造血管进行无菌真空热封包装。6) Packaging of the gel artificial blood vessel: the gel artificial blood vessel prepared in step 5) is aseptically vacuum heat-sealed and packaged. 3.根据权利要求2所述的一种高韧性和孔洞可调的凝胶人造血管的制备方法,其特征在于:步骤1)中A液各组分质量百分比为:烯烃类单体M1:9-15%、生物高分子M2:1-3%、离子交联剂M4:0-10‰、去离子水:82-90%;步骤2)中B液各组分质量比为:化学交联剂M3:0-0.2‰、引发剂是烯烃类单体M1的1%,去离子水:98-99%;步骤3)中的催化剂是烯烃类单体M1的3‰;步骤5)中各组分质量比配比为:离子交联剂M4:4-10%、去离子水:90-96%。3. The preparation method of a gel artificial blood vessel with high toughness and adjustable pores according to claim 2, characterized in that: in step 1), the mass percentage of each component of liquid A is: olefin monomer M1:9 -15%, biopolymer M2: 1-3%, ionic cross-linking agent M4: 0-10‰, deionized water: 82-90%; the mass ratio of the components of B liquid in step 2) is: chemical cross-linking Agent M3: 0-0.2‰, initiator is 1% of olefinic monomer M1, deionized water: 98-99%; the catalyst in step 3) is 3‰ of olefinic monomer M1; step 5) each The mass ratio of components is as follows: ion cross-linking agent M4: 4-10%, deionized water: 90-96%. 4.根据权利要求2所述的一种高韧性和孔洞可调的凝胶人造血管的制备方法,其特征在于:所述的中空管状模具的内径为0.1-15mm、外径为0.1-17mm。4. The method for preparing a gel artificial blood vessel with high toughness and adjustable pores according to claim 2, characterized in that: the inner diameter of the hollow tubular mold is 0.1-15 mm, and the outer diameter is 0.1-17 mm. 5.根据权利要求2所述的一种高韧性和孔洞可调的凝胶人造血管的制备方法,其特征在于:所述的步骤5)不是制备凝胶人造血管的必要条件,但可增加凝胶人造血管的断裂应力和拉伸强度。5. A method for preparing a gel artificial blood vessel with high toughness and adjustable pores according to claim 2, characterized in that: the step 5) is not a necessary condition for preparing the gel artificial blood vessel, but it can increase the gel artificial blood vessel. Fracture stress and tensile strength of glued vascular prostheses. 6.根据权利要求2所述的一种高韧性和孔洞可调的凝胶人造血管的制备方法,其特征在于:所述的凝胶人造血管的韧性、孔洞尺寸、内皮细胞相容性和通畅率通过调节单体浓度、投料比、交联度、反应温度、模具大小和加料顺序调节。6. The preparation method of a gel artificial blood vessel with high toughness and adjustable pores according to claim 2, characterized in that: the toughness, hole size, endothelial cell compatibility and smoothness of the gel artificial blood vessel The rate can be adjusted by adjusting monomer concentration, feeding ratio, degree of crosslinking, reaction temperature, mold size and feeding sequence. 7.根据权利要求2所述的一种高韧性和孔洞可调的凝胶人造血管的制备方法,其特征在于:所述的凝胶人造血管的孔洞大小为10nm-500μm。7. The method for preparing a gel artificial blood vessel with high toughness and adjustable pores according to claim 2, characterized in that: the hole size of the gel artificial blood vessel is 10 nm-500 μm. 8.根据权利要求1所述的一种高韧性和孔洞可调的凝胶人造血管的制备方法,其特征在于:所制备的凝胶血管的内径尺寸及壁厚能改变模具尺寸调节,以满足弹性动脉、肌肉动脉、小动脉等不同类别血管的性能要求。8. The preparation method of a gel artificial blood vessel with high toughness and adjustable holes according to claim 1, characterized in that: the inner diameter size and wall thickness of the prepared gel blood vessel can be adjusted by changing the mold size to meet Performance requirements of different types of blood vessels such as elastic arteries, muscular arteries, and arterioles.
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CN109675092B (en) * 2018-12-17 2021-09-10 西北工业大学 Multifunctional hydrogel adhesive suitable for high-strength bonding of dynamic tissue surface and preparation method thereof
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