技术领域Technical Field
本发明属于生物材料用于血管组织工程技术领域，特别涉及一种长效功能化双层仿生小口径人工血管及其制备方法和应用。The invention belongs to the technical field of using biomaterials for vascular tissue engineering, and particularly relates to a long-acting functionalized double-layer bionic small-caliber artificial blood vessel and a preparation method and application thereof.
背景技术Background technique
心血管疾病(CVD)一直是全球死亡的主要原因，世界心脏病联盟(WHF)发布的2023年世界心脏报告显示，2021年心血管疾病致死人数约占全球死亡总人数的三分之一。在国内，CVD患病率也处于持续上升阶段，在城乡居民疾病死亡构成比中居于首位。临床上小口径血管损伤和病变十分常见，通过血管移植手术置换病变部位血管是治疗心血管和骨科血管损伤疾病的一种重要手段，但是小口径人工血管(内径≤6mm)因血流慢、易形成血栓、长期通畅率低，在国内乃至全球范围内仍未有成熟产品上市，研发具有长期保持抗凝血、抑制增生的具有远期通畅率的小口径人工血管十分重要且紧迫。Cardiovascular disease (CVD) has always been the leading cause of death worldwide. The 2023 World Heart Report released by the World Heart Federation (WHF) shows that in 2021, the number of deaths caused by cardiovascular disease accounted for about one-third of the total number of deaths worldwide. In China, the prevalence of CVD is also in a stage of continuous increase, ranking first in the proportion of disease deaths among urban and rural residents. Clinically, small-caliber vascular injuries and lesions are very common. Replacing the diseased blood vessels through vascular transplantation surgery is an important means of treating cardiovascular and orthopedic vascular injury diseases. However, small-caliber artificial blood vessels (inner diameter ≤6mm) have slow blood flow, easy thrombosis, and low long-term patency. There are still no mature products on the market in China or even globally. It is very important and urgent to develop small-caliber artificial blood vessels with long-term anticoagulation, inhibition of proliferation and long-term patency.
在血管组织再生过程中，调节损伤或病变血管的生理微环境是促进血管组织再生和功能重塑至关重要的环节。丹参素(DSS)可动态调控氧化应激，联硒类化合物可催化内源性供体亚硝基硫醇(RSNO)持续释放NO，从而抑制血小板黏附/激活促进促进受损内皮组织修复。同时，NO能够促进平滑肌细胞内源性合成H2S，而H2S又可进一步促进RSNO分解释放NO。目前，基于“本体共聚”合成的综合力学性能良好且能够原位动态调控DSS、NO或H2S“全生命周期”释放的可降解聚氨酯小口径人工血管尚未且有报道。In the process of vascular tissue regeneration, regulating the physiological microenvironment of damaged or diseased blood vessels is a crucial link in promoting vascular tissue regeneration and functional remodeling. Danshensu (DSS) can dynamically regulate oxidative stress, and selenium compounds can catalyze the endogenous donor nitrosothiol (RSNO) to continuously release NO, thereby inhibiting platelet adhesion/activation and promoting the repair of damaged endothelial tissue. At the same time, NO can promote the endogenous synthesis of H2 S by smooth muscle cells, and H2 S can further promote the decomposition of RSNO to release NO. At present, there is no report on the biodegradable polyurethane small-caliber artificial blood vessels synthesized based on "bulk copolymerization" with good comprehensive mechanical properties and the ability to dynamically regulate the "full life cycle" release of DSS, NO or H2 S in situ.
基于可降解聚氨酯改性的小口径人工血管具有优良的力学顺应性和力学强度，在工艺、成本、生产条件、保存条件等方面优势显著，可用于体内原位诱导血管组织再生。而现有人工血管的功能仿生改性难以实现控制释放功能因子，往往是早期快速释放导致后期功能性缺失，或因表面接枝位点有限难以负载较多的功能因子，且随着表面材料在早期降解未功能化部分裸露导致早期形成的内皮退化，难以实现长距离血管组织重塑。所以，小口径人工血管材料急需进行长效功能化改性，解决功能化不足导致的病理性重塑问题。Small-caliber artificial blood vessels modified with degradable polyurethane have excellent mechanical compliance and mechanical strength, and have significant advantages in terms of process, cost, production conditions, and storage conditions. They can be used to induce vascular tissue regeneration in situ in vivo. However, it is difficult to achieve controlled release of functional factors in existing artificial blood vessels with bionic functional modification. Early rapid release often leads to functional loss in the later stage, or it is difficult to load more functional factors due to limited surface grafting sites. In addition, as the surface material degrades in the early stage, the unfunctionalized part is exposed, resulting in early endothelial degeneration, making it difficult to achieve long-distance vascular tissue remodeling. Therefore, small-caliber artificial blood vessel materials are in urgent need of long-term functional modification to solve the problem of pathological remodeling caused by insufficient functionalization.
综上所述，制备一种可动态响应修复微环境的长效功能化双层仿生小口径人工血管在医疗器械和生物医药领域具有重要意义，其应用和推广可以填补当前小口径人工血管的市场空白，缓解临床小口径血管移植的紧张局势，带来巨大的经济效益和社会效益。In summary, the preparation of a long-lasting functional double-layer bionic small-caliber artificial blood vessel that can dynamically respond to the repair microenvironment is of great significance in the field of medical devices and biomedicine. Its application and promotion can fill the current market gap in small-caliber artificial blood vessels, alleviate the tension in clinical small-caliber blood vessel transplantation, and bring huge economic and social benefits.
发明内容Summary of the invention
为了解决上述问题，本发明的主要目的是提供一种长效功能化双层仿生小口径人工血管的制备方法，包括基于“本体共聚原理”，通过三步溶液聚合法合成力学匹配的能够长效释放活性组分的可降解聚氨酯人工血管材料，通过近场直写纺制轴向取向纤维血管内层，通过特制模具结合热致相分离技术制备绕轴取向拓扑微结构血管外层。In order to solve the above problems, the main purpose of the present invention is to provide a method for preparing a long-lasting functional double-layer bionic small-caliber artificial blood vessel, including synthesizing a mechanically matched degradable polyurethane artificial blood vessel material capable of long-term release of active components through a three-step solution polymerization method based on the "bulk copolymerization principle", spinning an axially oriented fiber vascular inner layer through near-field direct writing, and preparing an axially oriented topological microstructured vascular outer layer through a special mold combined with thermally induced phase separation technology.
本发明的另一目的是提供一种长效功能化双层仿生小口径人工血管，通过所述长效功能化双层仿生小口径人工血管的制备方法制得，其具有“全生命周期”内持续释放具有交互加强作用效果的DSS、NO和H2S，以及原位动态调控和修复血管组织微环境的功能。Another object of the present invention is to provide a long-acting functionalized double-layer bionic small-caliber artificial blood vessel, which is prepared by the preparation method of the long-acting functionalized double-layer bionic small-caliber artificial blood vessel and has the function of continuously releasing DSS, NO andH2S with interactive reinforcing effects during the "whole life cycle", as well as dynamically regulating and repairing the microenvironment of vascular tissue in situ.
本发明的再一目的是提供所述长效功能化双层仿生小口径人工血管作为或制备可动态调控和修复微环境的医疗产品中的应用。Another object of the present invention is to provide the application of the long-acting functionalized double-layer bionic small-caliber artificial blood vessel as or in the preparation of a medical product that can dynamically regulate and repair the microenvironment.
为实现上述目的，本发明采用如下技术方案：To achieve the above object, the present invention adopts the following technical solution:
本发明提供一种长效功能化双层仿生小口径人工血管的制备方法，包括以下步骤：The present invention provides a method for preparing a long-acting functionalized double-layer bionic small-caliber artificial blood vessel, comprising the following steps:
(1)基于本体共聚，通过三步溶液聚合法分别合成可降解聚氨酯弹性体PCHU-DSeSe、PCHU-DTA，合成单体包括软段二醇和二异氰酸酯，还包括扩链剂，保持PCHU-DSeSe、PCHU-DTA弹性体的重均分子量均在8～10万、粘度系数在1.2～1.8之间；(1) Based on bulk copolymerization, biodegradable polyurethane elastomers PCHU-DSeSe and PCHU-DTA were synthesized by a three-step solution polymerization method. The synthetic monomers included soft segment diol and diisocyanate, and also included a chain extender, so that the weight average molecular weight of PCHU-DSeSe and PCHU-DTA elastomers were kept between 80,000 and 100,000, and the viscosity coefficient was between 1.2 and 1.8;
(2)通过近场直写在模具的具有轴向沟槽的不锈钢轴芯上静电纺丝步骤(1)中PCHU-DSeSe，得到PCHU-DSeSe取向纤维作为轴向取向纤维血管内层，纤维直径控制在0.1～80μm之间，纤维和轴芯整体放入真空干燥箱干燥至少2天；(2) electrospinning the PCHU-DSeSe in step (1) on a stainless steel shaft core having axial grooves of a mold by near-field direct writing to obtain PCHU-DSeSe oriented fibers as the axially oriented fiber vascular inner layer, wherein the fiber diameter is controlled between 0.1 and 80 μm, and the fiber and the shaft core are placed in a vacuum drying oven and dried for at least 2 days;
(3)将步骤(2)中复合的连同轴芯的轴向取向纤维血管内层装配到外壳内壁具有径向取向纹路的聚四氟乙烯模具中；(3) assembling the axially oriented fiber vascular inner layer with the shaft core compounded in step (2) into a polytetrafluoroethylene mold having radially oriented patterns on the inner wall of the shell;
(4)称取PCHU-DTA，在50～60℃条件下溶于二甲基亚砜(DMSO)中，搅拌溶解，获得8～16％(质量体积比，w/v)的澄清均一溶液，该溶液迅速浇铸到步骤(3)中带有取向纤维层的聚四氟乙烯模具内，迅速放置在-80℃条件下使其发生热致相分离，放置时间48h以上，得到绕轴取向拓扑微结构血管外层；(4) Weighing PCHU-DTA, dissolving it in dimethyl sulfoxide (DMSO) at 50-60° C., stirring and dissolving to obtain a clear and uniform solution of 8-16% (mass volume ratio, w/v), and quickly casting the solution into the polytetrafluoroethylene mold with the oriented fiber layer in step (3), and quickly placing it at -80° C. to allow thermally induced phase separation to occur for more than 48 hours, thereby obtaining an outer layer of a blood vessel with an axially oriented topological microstructure;
(5)取出模具，退去模具的外壳后浸泡在0℃超纯冰水混合物中10min，得到人工血管，并将其从模具的轴心上褪下，继续浸泡在0℃超纯冰水混合物中，每隔4h换一次水交换溶剂，共计换水6～10次；从去离子水中取出人工血管后冷冻干燥3天以上，得到长效功能化双层仿生小口径人工血管。(5) taking out the mold, removing the outer shell of the mold and immersing it in a 0°C ultrapure ice-water mixture for 10 minutes to obtain an artificial blood vessel, and then removing it from the axis of the mold and continuing to immerse it in a 0°C ultrapure ice-water mixture. The water is changed every 4 hours to exchange the solvent, and the water is changed 6 to 10 times in total. After taking out the artificial blood vessel from the deionized water, freeze-dry it for more than 3 days to obtain a long-lasting functional double-layer bionic small-caliber artificial blood vessel.
优选地，步骤(1)中，所述可降解聚氨酯弹性体PCHU-DSeSe和PCHU-DTA的合成单体软段二醇、二异氰酸酯和扩链剂的投料摩尔比为1：2：1。Preferably, in step (1), the molar ratio of the soft segment diol, diisocyanate and chain extender of the synthetic monomers of the degradable polyurethane elastomers PCHU-DSeSe and PCHU-DTA is 1:2:1.
优选地，步骤(1)中，所述软段二醇选自聚己内酯二醇(HO-PCL-OH)、聚碳酸酯二醇(HO-PC-OH)、聚乳酸二醇(HO-PLLA-OH)、聚(乳酸-羟基乙酸)二醇(HO-PLGA-OH)、聚(乳酸-己内酯)二醇(HO-PLCL-OH)、聚(羟基乙酸-己内酯)二醇(HO-PGCL-OH)中的一种或几种。Preferably, in step (1), the soft segment diol is selected from one or more of polycaprolactone diol (HO-PCL-OH), polycarbonate diol (HO-PC-OH), polylactic acid diol (HO-PLLA-OH), poly(lactic acid-glycolic acid) diol (HO-PLGA-OH), poly(lactic acid-caprolactone) diol (HO-PLCL-OH), and poly(glycolic acid-caprolactone) diol (HO-PGCL-OH).
优选地，步骤(1)中，所述二异氰酸酯选自甲苯二异氰酸酯(TDI)、异佛尔酮二异氰酸酯(IPDI)、二苯基甲烷二异氰酸酯(MDI)、二环己基甲烷二异氰酸酯(HMDI)、六亚甲基二异氰酸酯(HDI)、赖氨酸二异氰酸酯(LDI)中的一种或几种。Preferably, in step (1), the diisocyanate is selected from one or more of toluene diisocyanate (TDI), isophorone diisocyanate (IPDI), diphenylmethane diisocyanate (MDI), dicyclohexylmethane diisocyanate (HMDI), hexamethylene diisocyanate (HDI), and lysine diisocyanate (LDI).
优选地，步骤(1)中，所述可降解聚氨酯弹性体PCHU-DSeSe和PCHU-DTA的合成单体所用的扩链剂包括扩链剂1和扩链剂2；其中合成PCHU-DSeSe所用扩链剂1为丹参素(DSS)，所用扩链剂2选自2-(2-羟乙基二硒)乙醇(SeDO)、硒代胱胺盐酸盐(SeCA)、3,3'-二(联)硒二丙酸(SeDPA)、4,4'-二硫二基双(4,1-亚苯)二甲醇、双(4-羧苯基)二硒化物、双(4-氨基苯基)二硒化物)中的一种或几种；合成PCHU-DTA所用扩链剂1为丹参素(DSS)，所用扩链剂2为O-羟甲基-2-羟基硫代乙酸酯(TA)；扩链剂的添加顺序是：先添加扩链剂1后再添加扩链剂2。Preferably, in step (1), the chain extender used in the synthesis monomers of the degradable polyurethane elastomers PCHU-DSeSe and PCHU-DTA includes chain extender 1 and chain extender 2; wherein the chain extender 1 used in the synthesis of PCHU-DSeSe is danshensu (DSS), and the chain extender 2 used is selected from one or more of 2-(2-hydroxyethyl diselenol)ethanol (SeDO), selenocystamine hydrochloride (SeCA), 3,3'-di(diselenide)dipropionic acid (SeDPA), 4,4'-dithiodiylbis(4,1-phenylene)dimethanol, bis(4-carboxyphenyl) diselenide, and bis(4-aminophenyl) diselenide); the chain extender 1 used in the synthesis of PCHU-DTA is danshensu (DSS), and the chain extender 2 used is O-hydroxymethyl-2-hydroxythioacetate (TA); the order of adding the chain extenders is: first add chain extender 1 and then add chain extender 2.
更优选地，步骤(1)中，所述PCHU-DSeSe的合成单体所用扩链剂1与扩链剂2的摩尔比为1：99～99：1。More preferably, in step (1), the molar ratio of chain extender 1 to chain extender 2 used in the synthetic monomers of PCHU-DSeSe is 1:99 to 99:1.
更优选地，步骤(1)中，所述PCHU-DTA采用的扩链剂为DSS和TA摩尔比为1：99～99：1。More preferably, in step (1), the chain extender used in the PCHU-DTA is DSS and TA in a molar ratio of 1:99 to 99:1.
优选地，步骤(1)中，所述PCHU-DSeSe、PCHU-DTA的合成反应过程中，软段二醇和二异氰酸酯的反应温度为50～80℃，搅拌速率为80～250rpm，反应时间为2～3h。Preferably, in step (1), during the synthesis reaction of PCHU-DSeSe and PCHU-DTA, the reaction temperature of the soft segment diol and the diisocyanate is 50-80° C., the stirring rate is 80-250 rpm, and the reaction time is 2-3 h.
优选地，步骤(1)中，所述PCHU-DSeSe、PCHU-DTA的合成反应过程中，DSS经DMSO溶解逐滴加入，DSS/DMSO溶液浓度控制在0.02～0.01g/mL，最佳浓度为0.04g/mL；滴入速度为8～12mL/h，最佳速度为10mL/h。Preferably, in step (1), during the synthesis reaction of PCHU-DSeSe and PCHU-DTA, DSS is dissolved in DMSO and added dropwise, and the concentration of DSS/DMSO solution is controlled at 0.02-0.01 g/mL, with an optimal concentration of 0.04 g/mL; the dripping speed is 8-12 mL/h, with an optimal speed of 10 mL/h.
优选地，步骤(1)中，所述PCHU-DSeSe、PCHU-DTA的合成反应过程中，加入扩链剂后的搅拌速率控制在500～800rpm，DSS加入后反应时间控制在3～5h，扩链剂2经DMAc溶解后滴加三乙胺(TEA)作为缚酸剂，然后扩链剂2/DMAc/TEA逐滴加入预聚物中，每毫升扩链剂2/DMAc溶液中滴加0.1mLTEA，且扩链剂2/DMAc溶液浓度为0.02～0.01g/mL，滴入速度为8～12mL/h，在各自反应中反应时间为8～24h。Preferably, in step (1), during the synthesis reaction of PCHU-DSeSe and PCHU-DTA, the stirring rate after adding the chain extender is controlled at 500-800 rpm, the reaction time after adding DSS is controlled at 3-5 h, the chain extender 2 is dissolved in DMAc and triethylamine (TEA) is added dropwise as an acid binding agent, and then the chain extender 2/DMAc/TEA is added dropwise to the prepolymer, 0.1 mL of TEA is added dropwise to each milliliter of the chain extender 2/DMAc solution, and the concentration of the chain extender 2/DMAc solution is 0.02-0.01 g/mL, the dropping rate is 8-12 mL/h, and the reaction time in each reaction is 8-24 h.
优选地，步骤(2)中，所述近场直写静电纺丝制备轴向取向纤维血管内层时，轴芯转速为10～18rpm，针头移动速度为800～1200mm/min。Preferably, in step (2), when preparing the axially oriented fiber vascular inner layer by near-field direct writing electrospinning, the shaft core speed is 10-18 rpm and the needle moving speed is 800-1200 mm/min.
优选地，所述长效功能化双层仿生小口径人工血管的内外层尺寸通过静电纺丝和模具可控调节，控制在：内径(d1)为1.2～6mm，总壁厚(T)为0.1～3mm，内层PCHU-DSeSe取向纤维厚度(t1)为0.05～1.5mm，外层取向拓扑微结构PCHU-DTA多孔材料厚度(t2)为0.05～2mm，人工血管长度(L)控制为0.5～25cm；外层螺纹牙型为三角形或梯形，螺牙高度(h)与人工血管总壁厚(T)的比为1：5～10，线数为1～2，螺距为0.1～2mm，导程为0.1～4mm。Preferably, the inner and outer layer sizes of the long-acting functionalized double-layer bionic small-caliber artificial blood vessel are controllably adjusted through electrospinning and molds, and are controlled to be: the inner diameter (d1 ) is 1.2-6 mm, the total wall thickness (T) is 0.1-3 mm, the inner layer PCHU-DSeSe oriented fiber thickness (t1 ) is 0.05-1.5 mm, the outer layer oriented topological microstructure PCHU-DTA porous material thickness (t2 ) is 0.05-2 mm, and the artificial blood vessel length (L) is controlled to be 0.5-25 cm; the outer layer thread profile is triangular or trapezoidal, the ratio of the thread height (h) to the total wall thickness (T) of the artificial blood vessel is 1:5-10, the number of threads is 1-2, the pitch is 0.1-2 mm, and the lead is 0.1-4 mm.
本发明还提供一种长效功能化双层仿生小口径人工血管，通过所述长效功能化双层仿生小口径人工血管的制备方法制得。The present invention also provides a long-acting functionalized double-layer bionic small-caliber artificial blood vessel, which is prepared by the preparation method of the long-acting functionalized double-layer bionic small-caliber artificial blood vessel.
本发明还提供所述长效功能化双层仿生小口径人工血管作为或制备用于动静脉造瘘、心脏冠脉及外周血管搭桥治疗的医疗产品中的应用。The present invention also provides the use of the long-acting functionalized double-layer bionic small-caliber artificial blood vessel as or in the preparation of a medical product for arteriovenous fistula, coronary artery and peripheral vascular bypass treatment.
作为优选，所述长效功能化双层仿生小口径人工血管具有“全生命周期”内持续释放DSS、NO和H2S以及原位动态调控和修复血管组织微环境的功能。Preferably, the long-acting functionalized double-layer bionic small-caliber artificial blood vessel has the function of continuously releasing DSS, NO and H2 S during the "whole life cycle" and dynamically regulating and repairing the microenvironment of vascular tissue in situ.
与现有技术相比，本发明的有益效果至少在于：Compared with the prior art, the beneficial effects of the present invention are at least:
1、本发明基于本体共聚原理，通过三步溶液聚合法制备两种可降解聚氨酯弹性体PCHU-DSeSe、PCHU-DTA，具有良好的生物相容性、可加工性和力学弹性，且制备成本低、工艺简单且性能可控。1. Based on the principle of bulk copolymerization, the present invention prepares two degradable polyurethane elastomers PCHU-DSeSe and PCHU-DTA by a three-step solution polymerization method. They have good biocompatibility, processability and mechanical elasticity, low preparation cost, simple process and controllable performance.
2、本发明中长效功能化双层仿生小口径人工血管具有内层持续释放DSS、NO，外层持续释放DSS、H2S，且内外层释放的活性分子能够交互加强作用效果，实现二者相互相应联动协同作用，以及原位动态调控和修复血管组织微环境功能，可快速促进血管组织重塑。2. The long-acting functionalized double-layer bionic small-caliber artificial blood vessel of the present invention has the inner layer continuously releasing DSS and NO, and the outer layer continuously releasing DSS andH2S , and the active molecules released from the inner and outer layers can mutually enhance the effect, realize the mutual corresponding linkage synergy between the two, and dynamically regulate and repair the microenvironment of vascular tissue in situ, which can quickly promote vascular tissue remodeling.
3、本发明中长效功能化双层仿生小口径人工血管通过静电纺丝得到纤维轴向取向内表面，有效实现细胞内皮细胞募集，促进内皮细胞迁移和增殖；通过热致相分离得到的取向多孔结构外表面不仅提高血管抗弯折效果，还可动态调控平滑肌细胞的迁移和增殖；人工血管内外层能够持续释放DSS，与炎症、氧化应激微环境响应，有效抑制相关不良反应，保护内皮细胞和平滑肌细胞免受损伤。3. In the present invention, the long-lasting functional double-layer bionic small-caliber artificial blood vessel obtains an axially oriented inner surface of the fiber through electrospinning, which effectively realizes the recruitment of endothelial cells and promotes the migration and proliferation of endothelial cells; the oriented porous structure outer surface obtained by thermally induced phase separation not only improves the anti-bending effect of blood vessels, but also can dynamically regulate the migration and proliferation of smooth muscle cells; the inner and outer layers of the artificial blood vessel can continuously release DSS, respond to the inflammatory and oxidative stress microenvironment, effectively inhibit related adverse reactions, and protect endothelial cells and smooth muscle cells from damage.
4、本发明中长效功能化双层仿生小口径人工血管可用于动静脉造瘘、心脏冠脉及外周血管搭桥治疗，血管内层PCHU-DSeSe取向纤维能够原位催化内源性NO源持续释放NO，外层取向拓扑微结构PCHU-DTA可降解聚氨酯多孔材料可控降解释放H2S、NO和H2S，能够交互促进调控血管功能。4. The long-acting functionalized double-layer bionic small-caliber artificial blood vessels of the present invention can be used for arteriovenous fistula, coronary artery and peripheral vascular bypass treatment. The PCHU-DSeSe oriented fibers in the inner layer of the blood vessels can in situ catalyze the endogenous NO source to continuously release NO, and the outer layer oriented topological microstructure PCHU-DTA degradable polyurethane porous material can controllably degrade and releaseH2S , NO andH2S , which can interactively promote and regulate vascular function.
5、本发明中长效功能化双层仿生小口径人工血管具有可调控的力学顺应性、爆破强度和生物相容性，在移植手术时对人体无超敏反应，同时与人体内的血液及周边组织具有亲和力，移植后可实现降解全周期内调控活性小分子释放，可快速稳定地重塑内皮细胞层实现长效抗凝，动态调控修复微环境，快速实现长距离小口径血管组织的再生和功能化重塑，在心血管外科、血透中心、肾内科、骨科修复手术中具有很好的应用前景。5. The long-acting functionalized double-layer bionic small-caliber artificial blood vessel of the present invention has adjustable mechanical compliance, burst strength and biocompatibility, has no hypersensitivity reaction to the human body during transplantation surgery, and has affinity with the blood and surrounding tissues in the human body. After transplantation, the release of active small molecules can be regulated during the entire degradation cycle, and the endothelial cell layer can be quickly and stably reshaped to achieve long-term anticoagulation, dynamically regulate the repair microenvironment, and quickly achieve the regeneration and functional remodeling of long-distance small-caliber vascular tissues. It has good application prospects in cardiovascular surgery, hemodialysis center, nephrology, and orthopedic repair surgery.
附图说明BRIEF DESCRIPTION OF THE DRAWINGS
图1为实施例1中“三步溶液聚合法”合成用于制备人工血管内层取向纤维的可降解聚氨酯弹性体PCHU-DSeSe的合成反应示意图。FIG. 1 is a schematic diagram of the synthesis reaction of the degradable polyurethane elastomer PCHU-DSeSe for preparing oriented fibers for the inner layer of artificial blood vessels by the “three-step solution polymerization method” in Example 1.
图2为实施例1中“三步溶液聚合法”合成用于制备人工血管外层取向拓扑微结构多孔材料的可降解聚氨酯弹性体PCHU-DTA的合成反应示意图。FIG. 2 is a schematic diagram of the synthesis reaction of the degradable polyurethane elastomer PCHU-DTA synthesized by the “three-step solution polymerization method” in Example 1 for preparing the porous material of the oriented topological microstructure of the outer layer of the artificial blood vessel.
图3为实施例中长效功能化双层仿生小口径人工血管的制备工艺示意图。FIG3 is a schematic diagram of the preparation process of a long-acting functionalized double-layer bionic small-caliber artificial blood vessel in an embodiment.
图4为实施例中长效功能化双层仿生小口径人工血管生物调控机制示意图。FIG4 is a schematic diagram of the biological regulation mechanism of the long-acting functionalized double-layer bionic small-caliber artificial blood vessel in the embodiment.
图5为实施例中制备的长效功能化双层仿生小口径人工血管及其X射线衍射电镜图，其中图5A为制备的长效功能化双层仿生小口径人工血管实物图，图5B为横截面图，图5C为纵切面图，5D为管腔内部剖面图，图5E为外表面扫描图。Figure 5 is a long-acting functional double-layer bionic small-caliber artificial blood vessel prepared in the embodiment and its X-ray diffraction electron microscope image, wherein Figure 5A is a physical image of the prepared long-acting functional double-layer bionic small-caliber artificial blood vessel, Figure 5B is a cross-sectional view, Figure 5C is a longitudinal view, 5D is a cross-sectional view of the interior of the lumen, and Figure 5E is a scanned image of the outer surface.
具体实施方式Detailed ways
为使本发明实施例的目的、技术方案和优点更加清楚，下面将结合本发明实施例的附图，对本发明实施例的技术方案进行清楚、完整地描述。显然，所描述的实施例是本发明的一部分实施例，而不是全部的实施例。基于所描述的本发明的实施例，本领域普通技术人员在无创造性劳动的前提下所获得的所有其它实施例，都属于本发明保护的范围。In order to make the purpose, technical solution and advantages of the embodiment of the present invention clearer, the technical solution of the embodiment of the present invention will be clearly and completely described below in conjunction with the accompanying drawings of the embodiment of the present invention. Obviously, the described embodiment is a part of the embodiment of the present invention, not all of the embodiments. Based on the described embodiment of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work belong to the scope of protection of the present invention.
实施例1Example 1
本实施例制备长效功能化双层仿生小口径人工血管，可降解聚氨酯弹性体PCHU-DSeSe合成单体软段二醇选用HO-PCL-OH，二异氰酸酯选用HDI，扩链剂2选用SeDO，扩链剂1与扩链剂2的摩尔比为1：3；可降解聚氨酯弹性体PCHU-DTA合成单体软段二醇选用HO-PCL-OH，二异氰酸酯选用HDI，DSS与TA的摩尔比为1：3，步骤如下：In this embodiment, a long-acting functional double-layer bionic small-caliber artificial blood vessel is prepared. The soft segment diol of the synthetic monomer of the degradable polyurethane elastomer PCHU-DSeSe is HO-PCL-OH, the diisocyanate is HDI, the chain extender 2 is SeDO, and the molar ratio of the chain extender 1 to the chain extender 2 is 1:3; the soft segment diol of the synthetic monomer of the degradable polyurethane elastomer PCHU-DTA is HO-PCL-OH, the diisocyanate is HDI, and the molar ratio of DSS to TA is 1:3. The steps are as follows:
(1)基于本体共聚原理三步溶液聚合法制备可降解聚氨酯弹性体PCHU-DSeSe和PCHU-DTA的具体操作如下：称取5g聚己内酯二醇(PCL二醇，Mn为2000)于250mL三颈烧瓶中，60℃下180rpm搅拌10min；后升温至120℃真空除水30min，再通氮气保护并降温至60℃；取0.81mL HDI加入三颈烧瓶中反应2.5h；后降温至45℃，转速调整为560rpm，称取0.12g DSS用5mL DMSO完全溶解并逐滴滴入三颈烧瓶中，约30min滴完，继续搅拌反应3h，反应过程中根据溶液粘度变化加入约10mLDMSO；称取0.47g的SeDO用10mL DMSO溶解后逐滴滴入三颈烧瓶中继续反应12h，反应过程中根据粘度变化加入约15mL DMSO；停止反应后，用去离子水析出聚合物并进行溶剂交换48h，每6h更换一次，共更换8次去离子水以彻底洗去DMSO；后取出洗净的材料经-80℃冷冻3h后，通过冷冻干燥得到PCHU-DSeSe。PCHU-DTA的制备过程同PCHU-DSeSe，不同的是0.47g的SeDO更改为0.23g的TA，反应溶剂为DMAc，且需要通过添加TEA调控反应pH值，最终制备得到PCHU-DTA。(1) The specific operation of preparing the degradable polyurethane elastomers PCHU-DSeSe and PCHU-DTA by three-step solution polymerization based on the principle of bulk copolymerization is as follows: weigh 5g of polycaprolactone diol (PCL diol, Mn is 2000) in a 250mL three-necked flask, stir at 180rpm for 10min at 60℃; then heat to 120℃ and remove water in vacuum for 30min, then pass nitrogen protection and cool to 60℃; take 0.81mL HDI and add it to the three-necked flask to react for 2.5h; then cool to 45℃, adjust the speed to 560rpm, weigh 0.12g DSS and dissolve it completely with 5mL DMSO and drip it into the three-necked flask drop by drop, drip it in about 30min, continue to stir and react for 3h, and add about 10mL DMSO during the reaction according to the change of solution viscosity; weigh 0.47g SeDO and dissolve it with 10mL DMSO and drip it into the three-necked flask drop by drop and continue to react for 12h according to the change of viscosity during the reaction. DMSO; after stopping the reaction, the polymer was precipitated with deionized water and the solvent was exchanged for 48 hours, and the deionized water was replaced every 6 hours, and the deionized water was replaced 8 times in total to completely wash away the DMSO; the washed material was then taken out and frozen at -80°C for 3 hours, and then freeze-dried to obtain PCHU-DSeSe. The preparation process of PCHU-DTA is the same as that of PCHU-DSeSe, except that 0.47g of SeDO is changed to 0.23g of TA, the reaction solvent is DMAc, and the reaction pH needs to be adjusted by adding TEA, and finally PCHU-DTA is prepared.
(2)称取0.35g PEO溶于10mL去离子水中，完全溶解，得到脱模层纺丝溶液，通过近场直写在直径为3mm的轴芯上获得均匀的PEO脱模层，放置过夜挥发掉水分；称取0.8gPCHU-DSeSe溶于10mL六氟异丙醇(HFIP)中，完全溶解后在轴芯转速为10rpm，针头移动速度为1000mm/min的条件下，将PCHU-DSeSe/HFIP溶液静电纺丝经过真空干燥后得到厚度为0.4mm的轴向取向的人工血管内层。(2) Weigh 0.35 g of PEO and dissolve it in 10 mL of deionized water until it is completely dissolved to obtain a release layer spinning solution. A uniform PEO release layer is obtained on a shaft core with a diameter of 3 mm by near-field direct writing, and the solution is left overnight to evaporate the water. Weigh 0.8 g of PCHU-DSeSe and dissolve it in 10 mL of hexafluoroisopropanol (HFIP). After it is completely dissolved, the PCHU-DSeSe/HFIP solution is electrospun at a shaft core speed of 10 rpm and a needle moving speed of 1000 mm/min to obtain an axially oriented artificial blood vessel inner layer with a thickness of 0.4 mm after vacuum drying.
(3)将步骤(2)中复合的连同轴芯的轴向取向的纤维管装配到的内径为5mm的模具外壳中，内壁具有径向取向纹路(三角螺纹、线数为1、螺距为1mm、螺牙高0.2mm)的聚四氟乙烯模具中备用；然后在分析天平上称取0.8g的PCHU-DTA，在60℃条件下溶于10mL的DMSO中，搅拌溶解，获得澄清均一溶液。随后，将混合溶液迅速浇铸到装配好的带有取向纤维层的特定型号的聚四氟乙烯模具内，迅速放置在-80℃条件下使其相分离，放置时间48h以上。之后取出模具，退去模具的外壳后浸泡在0℃超纯冰水混合物中，10min后将人工血管从模具的轴芯上褪下，继续浸泡在0℃超纯冰水混合物中，每隔4h换一次水交换溶剂，共计换水6～10次，从去离子水中取出人工血管后，冷冻干燥3天以上，得到内径约为3mm、厚度约为1mm的双层仿生小口径人工血管。(3) The axially oriented fiber tube with the axial core composited in step (2) is assembled into a mold shell with an inner diameter of 5 mm and a polytetrafluoroethylene mold with radially oriented lines (triangular thread, number of threads is 1, pitch is 1 mm, thread height is 0.2 mm) on the inner wall for standby use; then 0.8 g of PCHU-DTA is weighed on an analytical balance, dissolved in 10 mL of DMSO at 60° C., stirred to dissolve, and a clear and uniform solution is obtained. Subsequently, the mixed solution is quickly cast into a polytetrafluoroethylene mold of a specific model with an oriented fiber layer assembled, and quickly placed at -80° C. for phase separation, and the placement time is more than 48 hours. Then take out the mold, remove the outer shell of the mold and immerse it in a 0℃ ultrapure ice water mixture. After 10 minutes, remove the artificial blood vessel from the axis of the mold and continue to immerse it in a 0℃ ultrapure ice water mixture. Change the water and solvent every 4 hours, and change the water 6 to 10 times in total. After taking out the artificial blood vessel from the deionized water, freeze-dry it for more than 3 days to obtain a double-layer bionic small-caliber artificial blood vessel with an inner diameter of about 3 mm and a thickness of about 1 mm.
实施例2Example 2
本实施例制备长效功能化双层仿生小口径人工血管，可降解聚氨酯弹性体PCHU-DSeSe合成单体软段选用HO-PC-OH，二异氰酸酯选用HDI，扩链剂2选用SeDO，扩链剂1与扩链剂2的摩尔比为1：1；PCHU-DTA合成单体软段选用HO-PCL-OH，二异氰酸酯选用HDI，DSS与TA的摩尔比为1：1，操作步骤如下：In this embodiment, a long-acting functional double-layer bionic small-caliber artificial blood vessel is prepared. The soft segment of the synthetic monomer of the degradable polyurethane elastomer PCHU-DSeSe is HO-PC-OH, the diisocyanate is HDI, the chain extender 2 is SeDO, and the molar ratio of the chain extender 1 to the chain extender 2 is 1:1; the soft segment of the synthetic monomer of PCHU-DTA is HO-PCL-OH, the diisocyanate is HDI, and the molar ratio of DSS to TA is 1:1. The operation steps are as follows:
(1)基于本体共聚原理三步溶液聚合法制备PCHU-DSeSe和PCHU-DTA的具体操作如下：称取5g聚碳酸酯二醇(PC二醇，Mn～2000)于250mL三颈烧瓶中，60℃下180rpm搅拌10min；后升温至120℃真空除水30min，再通氮气保护并降温至60℃；取0.81mL HDI加入三颈烧瓶中反应2.5h；后降温至45℃，转速调整为560rpm，称取0.24g DSS用10mL DMSO完全溶解并逐滴滴入三颈烧瓶中，约50min滴完，继续搅拌反应3h，反应过程中根据溶液粘度变化加入约10mL DMSO；后称取0.11g的SeDO用6mL DMSO溶解后逐滴滴入三颈烧瓶中继续反应12h，反应过程中根据粘度变化加入约15mL DMSO；停止反应后，用去离子水析出聚合物并进行溶剂交换48h，每6h更换一次，共更换8次去离子水以彻底洗去DMSO；后取出洗净的材料经-80℃冷冻3h后，通过冷冻干燥得到PCHU-DSeSe。PCHU-DTA的制备过程同PCHU-DSeSe，不同的是0.47g的SeDO更改为0.15g的TA，反应溶剂为DMAc，且需要通过添加TEA调控反应pH值，最终制备得到PCHU-DTA。(1) The specific operation of preparing PCHU-DSeSe and PCHU-DTA by three-step solution polymerization based on the principle of bulk copolymerization is as follows: weigh 5g of polycarbonate diol (PC diol, Mn ~ 2000) in a 250mL three-necked flask, stir at 180rpm for 10min at 60℃; then heat to 120℃ and remove water in vacuum for 30min, then pass nitrogen protection and cool to 60℃; take 0.81mL HDI and add it to the three-necked flask to react for 2.5h; then cool to 45℃, adjust the speed to 560rpm, weigh 0.24g DSS and dissolve it completely with 10mL DMSO and drip it into the three-necked flask drop by drop, and drip it in about 50min, continue to stir and react for 3h, and add about 10mL DMSO during the reaction according to the change of solution viscosity; then weigh 0.11g SeDO and dissolve it with 6mL DMSO and drip it into the three-necked flask drop by drop and continue to react for 12h according to the change of viscosity during the reaction. DMSO; after stopping the reaction, the polymer was precipitated with deionized water and the solvent was exchanged for 48 hours, and the deionized water was replaced every 6 hours, and the deionized water was replaced 8 times in total to completely wash away the DMSO; the washed material was then taken out and frozen at -80°C for 3 hours, and then freeze-dried to obtain PCHU-DSeSe. The preparation process of PCHU-DTA is the same as that of PCHU-DSeSe, except that 0.47g of SeDO is changed to 0.15g of TA, the reaction solvent is DMAc, and the reaction pH needs to be adjusted by adding TEA, and finally PCHU-DTA is prepared.
(2)称取0.35g PEO溶于10mL去离子水中，完全溶解，得到脱模层纺丝溶液，通过近场直写在直径为3mm的轴芯上获得均匀的PEO脱模层，放置过夜挥发掉水分；称取1g的PCHU-DSeSe溶于10mL六氟异丙醇(HFIP)中，完全溶解后在轴芯转速为12rpm，针头移动速度为1200mm/min的条件下，将PCHU-DSeSe/HFIP溶液静电纺丝经过真空干燥后得到厚度为0.4mm的轴向取向的人工血管内层。(2) Weigh 0.35 g of PEO and dissolve it in 10 mL of deionized water until it is completely dissolved to obtain a release layer spinning solution. A uniform PEO release layer is obtained on a shaft core with a diameter of 3 mm by near-field direct writing, and the solution is left overnight to evaporate the water. Weigh 1 g of PCHU-DSeSe and dissolve it in 10 mL of hexafluoroisopropanol (HFIP). After it is completely dissolved, the PCHU-DSeSe/HFIP solution is electrospun at a shaft core speed of 12 rpm and a needle moving speed of 1200 mm/min to obtain an axially oriented artificial vascular inner layer with a thickness of 0.4 mm after vacuum drying.
(3)将步骤(2)中复合的连同轴芯的轴向取向的纤维管装配到的内径为5mm的模具外壳中，内壁具有径向取向纹路(三角螺纹、线数为1、螺距为1mm、螺牙高0.2mm)的聚四氟乙烯模具中备用；然后在分析天平上称取1g的PCHU-DTA，在60℃条件下溶于10mL的DMSO中，搅拌溶解获得澄清均一溶液。随后，将混合溶液迅速浇铸到之前装配好的带有取向纤维层的特定型号的聚四氟乙烯模具内，迅速放置在-80℃条件下使其相分离，放置时间48h以上。之后取出模具，退去模具的外壳后浸泡在0℃超纯冰水混合物中，10min后将人工血管从模具的轴芯上褪下继续浸泡在0℃超纯冰水混合物中，每隔4h换一次水交换溶剂，共计换水6～10次，从去离子水中取出人工血管后冷冻干燥3天以上，得到内径约为3mm、厚度约为1mm的双层仿生小口径人工血管。(3) The axially oriented fiber tube with the axial core composited in step (2) is assembled into a mold shell with an inner diameter of 5 mm and a polytetrafluoroethylene mold with radially oriented lines (triangular thread, number of threads is 1, pitch is 1 mm, thread height is 0.2 mm) on the inner wall for standby; then 1 g of PCHU-DTA is weighed on an analytical balance, dissolved in 10 mL of DMSO at 60° C., and stirred to dissolve to obtain a clear and uniform solution. Subsequently, the mixed solution is quickly cast into a previously assembled polytetrafluoroethylene mold of a specific model with an oriented fiber layer, and quickly placed at -80° C. for phase separation, and the placement time is more than 48 hours. Then take out the mold, remove the outer shell of the mold and immerse it in a 0℃ ultrapure ice water mixture. After 10 minutes, remove the artificial blood vessel from the axis of the mold and continue to immerse it in a 0℃ ultrapure ice water mixture. Change the water and solvent every 4 hours, and change the water 6 to 10 times in total. After taking out the artificial blood vessel from the deionized water, freeze-dry it for more than 3 days to obtain a double-layer bionic small-caliber artificial blood vessel with an inner diameter of about 3 mm and a thickness of about 1 mm.
对比例1Comparative Example 1
本对比例与实施例1的区别在于PCHU-DSeSe合成过程中扩链剂1与扩链剂2的摩尔比为15：85；PCHU-DTA合成过程中DSS与TA的摩尔比为15：85。The difference between this comparative example and Example 1 is that the molar ratio of chain extender 1 to chain extender 2 during the synthesis of PCHU-DSeSe is 15:85; the molar ratio of DSS to TA during the synthesis of PCHU-DTA is 15:85.
对比例2Comparative Example 2
本对比例与实施例1的区别在于PCHU-DSeSe合成过程中扩链剂1与扩链剂2的摩尔比为35：65；PCHU-DTA合成过程中DSS与TA的摩尔比为35：65。The difference between this comparative example and Example 1 is that the molar ratio of chain extender 1 to chain extender 2 during the synthesis of PCHU-DSeSe is 35:65; the molar ratio of DSS to TA during the synthesis of PCHU-DTA is 35:65.
对比例3Comparative Example 3
本对比例与实施例1的区别在于PCHU-DSeSe合成过程中扩链剂1与扩链剂2的摩尔比为1：1；PCHU-DTA合成过程中DSS与TA的摩尔比为1：1。The difference between this comparative example and Example 1 is that the molar ratio of chain extender 1 to chain extender 2 during the synthesis of PCHU-DSeSe is 1:1; and the molar ratio of DSS to TA during the synthesis of PCHU-DTA is 1:1.
对比例4Comparative Example 4
本对比例与实施例1的区别在于PCHU-DSeSe合成过程中扩链剂1与扩链剂2的摩尔比为65：35；PCHU-DTA合成过程中DSS与TA的摩尔比为65：35。The difference between this comparative example and Example 1 is that the molar ratio of chain extender 1 to chain extender 2 during the synthesis of PCHU-DSeSe is 65:35; the molar ratio of DSS to TA during the synthesis of PCHU-DTA is 65:35.
对比例5Comparative Example 5
本对比例与实施例1的区别在于PCHU-DSeSe合成过程中扩链剂1与扩链剂2的摩尔比为75：25；PCHU-DTA合成过程中DSS与TA的摩尔比为75：25。The difference between this comparative example and Example 1 is that the molar ratio of chain extender 1 to chain extender 2 during the synthesis of PCHU-DSeSe is 75:25; the molar ratio of DSS to TA during the synthesis of PCHU-DTA is 75:25.
对比例6Comparative Example 6
本对比例与实施例1的区别在于PCHU-DSeSe合成过程中扩链剂1与扩链剂2的摩尔比为85：15；PCHU-DTA合成过程中DSS与TA的摩尔比为85：15。The difference between this comparative example and Example 1 is that the molar ratio of chain extender 1 to chain extender 2 during the synthesis of PCHU-DSeSe is 85:15; the molar ratio of DSS to TA during the synthesis of PCHU-DTA is 85:15.
性能测试Performance Testing
分别对上述实施例和对比例制备的长效功能化双层仿生小口径人工血管进行径向力学拉伸测试和内皮覆盖率统计，并通过扫描电子显微镜(SEM)观察内层纤维取向。The long-acting functionalized double-layer bionic small-caliber artificial blood vessels prepared in the above-mentioned examples and comparative examples were subjected to radial mechanical tensile testing and endothelial coverage statistics, and the inner layer fiber orientation was observed by scanning electron microscopy (SEM).
径向力学拉伸测试Radial mechanical tensile test
实施例和对比例所有样品被切成相同长度(5mm)进行径向力学拉伸试验。拉伸试验开始前分别将所有样品浸没于0.01M磷酸盐缓冲液(PBS，pH＝6.8)中在37℃下浸泡24h。采用拉伸试验机(HY-940FS)，采用径向单轴张力试验，传感器载荷范围为0-200N，拉伸速度为1mm/min。All samples of the embodiments and comparative examples were cut into the same length (5 mm) for radial mechanical tensile test. Before the tensile test, all samples were immersed in 0.01 M phosphate buffer (PBS, pH = 6.8) at 37 ° C for 24 h. A tensile tester (HY-940FS) was used, and radial uniaxial tension test was performed, with a sensor load range of 0-200 N and a tensile speed of 1 mm/min.
内皮覆盖率测试Endothelial coverage test
测试方法：将实施例和对比例的PCHU-DSeSe制备成24孔大小的取向纤维膜灭菌后铺在24孔板底部，在24孔板的每个孔中用特制的无菌316L不锈钢条与取向方向垂直叠压在纤维膜上，将孔分成两个部分。接着，将HUVECs原代细胞均匀接种到24孔板中(1×105个/孔)的样品膜上。培养12h后取出钢条，继续培养48h。48h后，用4％的多聚甲醛固定细胞2h以上，PBS清洗3～5遍；加入罗丹明标记的鬼笔环肽室温避光孵育1.5h，用PBS清洗3～5遍；用DAPI染液避光染色5min，PBS清洗3～5遍。最后在倒置荧光显微镜下观察细胞迁移形态和染色的细胞核与原始状态相比的迁移距离，并通过Image J软件计算细胞覆盖面百分率，内皮覆盖百分率(％)＝细胞覆盖面积/孔板置留原始面积×100％。Test method: The PCHU-DSeSe of the embodiment and the comparative example was prepared into an oriented fiber membrane of 24 wells and sterilized and laid on the bottom of a 24-well plate. In each well of the 24-well plate, a special sterile 316L stainless steel bar was superimposed on the fiber membrane perpendicular to the orientation direction to divide the well into two parts. Then, HUVECs primary cells were evenly inoculated on the sample membrane in the 24-well plate (1×105 cells/well). After 12 hours of culture, the steel bar was removed and cultured for another 48 hours. After 48 hours, the cells were fixed with 4% paraformaldehyde for more than 2 hours and washed with PBS 3 to 5 times; rhodamine-labeled phalloidin was added and incubated at room temperature in the dark for 1.5 hours, and washed with PBS 3 to 5 times; DAPI staining solution was used to stain for 5 minutes in the dark and washed with PBS 3 to 5 times. Finally, the cell migration morphology and the migration distance of the stained cell nuclei compared with the original state were observed under an inverted fluorescence microscope, and the cell coverage percentage was calculated using Image J software: endothelial coverage percentage (%) = cell coverage area/original well plate area × 100%.
表1：实施例和对比例性能测试结果Table 1: Performance test results of examples and comparative examples
如表1所示，只有控制好DSS和扩链剂2与TA的比例以及加工工艺参数，才能通过三步溶液聚合法、静电纺丝和热致相分离技术制备出力学性能匹配且可以有效发挥NO和H2S协同作用的长效功能化双层仿生小口径人工血管，其能够稳定长效的原位动态调控血管移植微环境，实现快速内皮化效果，缩短血管重塑周期，实现长距离血管组织再生。As shown in Table 1, only by controlling the ratio of DSS and chain extender 2 to TA and the processing parameters can a long-lasting functionalized double-layer bionic small-caliber artificial blood vessel with matching mechanical properties and effective synergistic effects of NO and H2 S be prepared through three-step solution polymerization, electrospinning and thermally induced phase separation technology. It can stably and long-term dynamically regulate the vascular transplantation microenvironment in situ, achieve rapid endothelialization effect, shorten the vascular remodeling cycle, and realize long-distance vascular tissue regeneration.
以上所述为本发明的较佳实施例，但本发明不应该局限于该实施例所公开的内容。所以凡是不脱离本发明所公开的精神下完成的等效或修改，都落入本发明保护的范围。The above is a preferred embodiment of the present invention, but the present invention should not be limited to the contents disclosed in the embodiment. Therefore, any equivalent or modification completed without departing from the spirit disclosed in the present invention shall fall within the scope of protection of the present invention.
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410451145.7ACN118304471B (en) | 2024-04-16 | 2024-04-16 | Long-acting functionalized double-layer bionic small-caliber artificial blood vessel and preparation method and application thereof |
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410451145.7ACN118304471B (en) | 2024-04-16 | 2024-04-16 | Long-acting functionalized double-layer bionic small-caliber artificial blood vessel and preparation method and application thereof |
| Publication Number | Publication Date |
|---|---|
| CN118304471Atrue CN118304471A (en) | 2024-07-09 |
| CN118304471B CN118304471B (en) | 2024-10-29 |
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202410451145.7AActiveCN118304471B (en) | 2024-04-16 | 2024-04-16 | Long-acting functionalized double-layer bionic small-caliber artificial blood vessel and preparation method and application thereof |
| Country | Link |
|---|---|
| CN (1) | CN118304471B (en) |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080268019A1 (en)* | 2006-07-07 | 2008-10-30 | Badylak Stephen F | Biohybrid elastomeric scaffolds and methods of use thereof |
| CN107789666A (en)* | 2016-08-30 | 2018-03-13 | 北京航空航天大学 | A kind of inwall micro-patterning small-caliber artificial blood vessel |
| CN109651586A (en)* | 2018-12-19 | 2019-04-19 | 中国科学院长春应用化学研究所 | The polyurethane containing selenium and the preparation method and application thereof of stable, controllable nitric oxide releasing |
| CN110124108A (en)* | 2018-02-02 | 2019-08-16 | 复旦大学附属中山医院 | A kind of double-layer artificial blood vessel and preparation method thereof |
| CN116899014A (en)* | 2023-07-24 | 2023-10-20 | 上海工程技术大学 | Three-dimensional topological structure multichannel nerve conduit and preparation method thereof |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080268019A1 (en)* | 2006-07-07 | 2008-10-30 | Badylak Stephen F | Biohybrid elastomeric scaffolds and methods of use thereof |
| CN107789666A (en)* | 2016-08-30 | 2018-03-13 | 北京航空航天大学 | A kind of inwall micro-patterning small-caliber artificial blood vessel |
| CN110124108A (en)* | 2018-02-02 | 2019-08-16 | 复旦大学附属中山医院 | A kind of double-layer artificial blood vessel and preparation method thereof |
| CN109651586A (en)* | 2018-12-19 | 2019-04-19 | 中国科学院长春应用化学研究所 | The polyurethane containing selenium and the preparation method and application thereof of stable, controllable nitric oxide releasing |
| CN116899014A (en)* | 2023-07-24 | 2023-10-20 | 上海工程技术大学 | Three-dimensional topological structure multichannel nerve conduit and preparation method thereof |
| Title |
|---|
| YONGHANG LIU等: "Durable Immunomodulatory Nanofiber Niche for the Functional Remodeling of Cardiovascular Tissue", 《ACS NANO》, vol. 18, no. 1, 26 December 2023 (2023-12-26), pages 951* |
| Publication number | Publication date |
|---|---|
| CN118304471B (en) | 2024-10-29 |
| Publication | Publication Date | Title |
|---|---|---|
| Gan et al. | Mussel-inspired dopamine oligomer intercalated tough and resilient gelatin methacryloyl (GelMA) hydrogels for cartilage regeneration | |
| Liu et al. | Additive-lathe 3D bioprinting of bilayered nerve conduits incorporated with supportive cells | |
| Chen et al. | Gas foaming of electrospun poly (L-lactide-co-caprolactone)/silk fibroin nanofiber scaffolds to promote cellular infiltration and tissue regeneration | |
| Tang et al. | Functional biomaterials for tendon/ligament repair and regeneration | |
| Ma et al. | PEGylated poly (glycerol sebacate)-modified calcium phosphate scaffolds with desirable mechanical behavior and enhanced osteogenic capacity | |
| Da et al. | Composite elastomeric polyurethane scaffolds incorporating small intestinal submucosa for soft tissue engineering | |
| Jeffries et al. | Highly elastic and suturable electrospun poly (glycerol sebacate) fibrous scaffolds | |
| Yuan et al. | Collagen and chondroitin sulfate functionalized bioinspired fibers for tendon tissue engineering application | |
| JPH04226119A (en) | Polyurethane stable in vivo and manufacture thereof | |
| JP2020080922A (en) | Meniscus recycled substrate | |
| Yan et al. | An interference screw made using a silk fibroin-based bulk material with high content of hydroxyapatite for anterior cruciate ligament reconstruction in a rabbit model | |
| Yu et al. | A bilayered scaffold with segregated hydrophilicity-hydrophobicity enables reconstruction of goat hierarchical temporomandibular joint condyle cartilage | |
| Mercado-Pagán et al. | Development and evaluation of elastomeric hollow fiber membranes as small diameter vascular graft substitutes | |
| Li et al. | Bladder acellular matrix graft reinforced silk fibroin composite scaffolds loaded VEGF with aligned electrospun fibers in multiple layers | |
| Du et al. | Electrospun poly (p-dioxanone)/poly (ester-urethane) ureas composite nanofibers for potential heart valve tissue reconstruction | |
| Zhu et al. | Evaluation of electrospun PCL diol-based elastomer fibers as a beneficial matrix for vascular tissue engineering | |
| Patel et al. | In vitro degradation and cell attachment studies of a new electrospun polymeric tubular graft | |
| Qin et al. | Chitosan/collagen layer-by-layer deposition for improving the esophageal regeneration ability of nanofibrous mats | |
| Zhu et al. | High mechanical performance and multifunctional degraded fucoidan-derived bioink for 3D bioprinting | |
| Rahimi et al. | Acrylated epoxidized soybean oil/polyvinylidene fluoride nanocomposites: demonstrating the potential role of plant oils in biomedical applications | |
| Meng et al. | Conjugated electrospinning toward a polycaprolactone scaffold simultaneously containing micro-/nano-fibers for potential biomedical application | |
| CN118304471B (en) | Long-acting functionalized double-layer bionic small-caliber artificial blood vessel and preparation method and application thereof | |
| Wang et al. | Fabrication, characterization and potential application of biodegradable polydopamine-modified scaffolds based on natural macromolecules | |
| Hao et al. | Enhanced hemocompatibility and antibacterial activity of biodegradable poly (ester-urethane) modified with quercetin and phosphorylcholine for durable blood-contacting applications | |
| Rui et al. | High-performance silk/polylactic acid composite scaffold material with immunomodulation and osteogenesis function |
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |