CN105294971A - Material for artificial blood vessels and preparation method and application thereof - Google Patents
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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Abstract
The invention provides a material for artificial blood vessels and a preparation method and an application thereof; the material for the artificial blood vessels is a random copolymer formed by chemically connecting polycaprolactone, polyurethane and an anticoagulant; the random copolymer has the general formula represented by the formula I, wherein in the formula I, PU represents a polyurethane block, PCL represents a polycaprolactone block, B represents a block with the anticoagulant, PCL and PU are connected by an urethane bond, PU and B are connected by an urethane bond, n and m are integers greater than zero, moreover, n+m=100-20000, and n/m=1/3-3/1. The material for the artificial blood vessels has the advantages of excellent mechanical properties and good biocompatibility, is safe and reliable, has an anticoagulation effect, and has great potential in clinical application when used as a novel vascular implant material.
Description
Technical field
The invention belongs to artificial blood vessel material's technical field, relate to a kind of material for artificial blood vessel and its preparation method and application.
Background technology
Cardiovascular disorder is one of common disease of harm humans health, more serious patient, what it was main is vascular transplantation with auxiliary treatment means, autologous vein limited source, therefore, artificial blood vessel is the substitute of many Serious Stenosis or artery occlusive clinically, desirable artificial blood vessel should have following characteristics: process based prediction model is stablized, mesh degree is suitable for, there is certain intensity and suppleness, when making bypass surgery, easily seam property is good, when blood vessel connects bloodletting not oozing of blood or oozing of blood few and can at once stop, after moving into human body, tissue reaction is slight, tissue can form rapidly newborn interior adventitia, not easily form thrombus, and gratifying long-term patency rate.
Raw material at present for the manufacture of artificial blood vessel has terylene, tetrafluoroethylene, urethane and natural mulberry silk.Woven method have knitting, braiding and woven.After being made into tubing, be processed into spiral helicine artificial blood vessel through aftertreatment, can arbitrarily bending and unlikely suction be flat.It is the straight type artificial blood vessel that raw material is formed by injection molding that the sixties occurs with high molecular weight ptfe, and trade name is Cauer tank this (Core-Tex), has been widely used in clinical.With terylene or tower teflon for the artificial blood vessel that system knitted by raw material has the tube wall of fine hair shape.Commercial multiple macromolecular material heavy caliber artificial blood vessel reaches realistic scale all at present, includes (1) dacron-made artificial blood vessel; (2) Applications of Pure Silk Vascular Prosthesis; (3) expanded PTFE (ePTFE) artificial blood vessel.
Dacron-made artificial blood vessel is the vascular grafts used the earliest, and due to patency rate higher, be successfully used to great vessels displacement for a long time, but the manufacture requirements of small-caliber artificial blood vessel cannot be met completely.Thereafter the Applications of Pure Silk Vascular Prosthesis developed is stable not because its spiral type crimps, and easily cause blood vessel to inhale flat, and conformality is poor, brute force is lower, and limits clinical application.Domestic and international application the most widely artificial blood vessel material is expanded polytetrafluoroethylsealing, it has good biocompatibility and anticoagulant, but conformability is poor, and the patency rate of graft is only 30%, especially diameter is less than the above-mentioned shortcoming of ePTFE artificial blood vessel of 6mm more obviously, long-term patency rate extreme difference.The essential defect of their threes is all non-constant of conformability, does not possess snappiness and the elasticity of human body artery completely, and this defect is just show clearly with during small-bore arterial anastomosis, and this is also that thrombus is easily in the major cause of stoma site formation.
The manufacture and exploit of small-caliber artificial blood vessel is focus nearly ten years in the world always, but up to the present all do not have formal product to be born, reason is that the biocompatibility of small-caliber artificial blood vessel and anticoagulant requirement are far away higher than common heavy caliber artificial blood vessel.And the whole world has the cardiac of nearly 1,000,000 to need to accept bypass surgery every year at present, grafting vessel now used is still the human vas taking from patient oneself, and the blood vessel of human body self is very limited, and wound is also very large, now urgently to be resolved hurrilyly can produce the small-caliber artificial blood vessel meeting and put up a bridge and require exactly, its market outlook are by considerable.
Urethane (PU) material receives much attention in recent years, this material has more excellent biocompatibility compared with ePTFE, someone think with PU material make artificial blood vessel can solve the problem, therefore it is the direction that external many scholars study at present.For PU type small-caliber artificial blood vessel, also there are many research reports in China.The micro phase separation structure of polyurethane material makes it have biocompatibility (comprise blood compatibility and histocompatibility) more better than other macromolecular material, the very similar organism blood vessel of this structure: be macroscopically very smooth surface, but from microcosmic, but be the fluid matrix layer of a lipid bilayer, centre is embedded with all kinds of glycoprotein and glycolipid matter.This macroscopic view is smooth, the structure of microcosmic multi-phase separation makes its vessel wall have excellent anticoagulation function.PU has again excellent resistance to fatigue, wear resistance, snappiness and high strength simultaneously, is therefore widely used in field of biomedical materials, for manufacturing artificial heart, artificial liver, interposing catheter and polymer control slow releasing pharmaceutical, etc.
PU is used for existing history for many years in organism, and the research that PU the is used for artificial blood vessel only history of 10 years.Gupta by PU together with polyester shuffling, making a kind of internal diameter very similar to people's arteria carotis communis conformability is the artificial blood vessel of 4 ~ 6mm, show that implantation is after 6 months in dog in vivo test, this vascular patency is good, and blood vessel surface defines the stable new intima of skim.Jeschke then develops internal diameter 1.5mm, the PU blood vessel of long 10mm, and the PU blood vessel it obtained through carbonizing treatment and ePTFE blood vessel carry out experimentation on animals contrast, finds that PU blood vessel possesses more excellent performance than ePTFE blood vessel.Although existing 30 years of the history in PU implant into body, up to now, existing PU material can't meet the high standard of artificial blood vessel clinical application.As found in life-time service process, PU there will be degradation with aging and calcification phenomenon in vivo, and crackle appears in material, even all destroys.The mechanism of degradation of many investigators to PU is studied, and thinks that PU mechanism of degradation is mainly the oxidative degradation of immunoreactive cell caused by scavenger cell, foreign-body giant cell.From the experimentation on animals that we do early stage, we find to be implanted to the carotid small-bore PU composite vascular prosthesis of dog, 2 Ge Yuehouhang tissue pathology checkings, what have the more inflammatory cell be dispersed in the tube wall of discovery artificial blood vessel invades profit, further demonstrate that conclusion above.Thus Inflammatory response is the basic factor bringing out degraded, and so improving materials microstructure consistency is exactly material is not brought out or brings out the Inflammatory response of body less.For solve the artificial blood vessel of synthetic materials braiding with the more adaptability of living organism, be coated with last layer biomaterial on synthesized polymer material surface, Here it is biological mixed type artificial blood vessel.The general artificial coating be coated with comprises following several: albumin, can improve the anti-freezing performance of artificial blood vessel; Fibronectin, can promote that inner membrance is formed, and then the generation of anticoagulant; Collagen protein, can promote that inner membrance is formed, and anti-hemostasis-coagulation occurs, and can also improve the conformability of artificial blood vessel; Gelatin, has the function promoting cell adhesion and growth, thus inner membrance can be induced after the implantation to be formed, anti-hemostasis-coagulation.But general mode carries out modification to material, when improving its histocompatibility, often again can give material mechanical property even blood compatibility bring negative impact.
Summary of the invention
For the deficiencies in the prior art, the object of the present invention is to provide a kind of material for artificial blood vessel and its preparation method and application.
For reaching this object, the present invention by the following technical solutions:
First aspect, the invention provides a kind of material for artificial blood vessel, and described material is the random copolymers being connected through chemistry by polycaprolactone, urethane and anti-coagulant and formed, and described random copolymers has with general formula shown in following formula I:
-(PU-PCL)
n-(PU-B)
m-
Formula I
In formula I, PU represents polyurethane blocks, and PCL represents polycaprolactone block, and B represents the block with anti-coagulant, is connected between described PCL and PU and PU and B by ammonia ester bond, n, m be greater than 0 integer, and n+m=100-20000, n/m=1/3-3/1.
The invention provides a kind of is that the tunica fibrosa sleeve pipe of main base material is as the synthetic method of the material of artificial blood vessel and preparation means using PU, PU is polymerized with the anti-freezing inhibitor of two hydroxy-end capped PCL and double ion, obtain the described material for artificial blood vessel, it has excellent mechanical property, and there is good biocompatibility, safe and reliable, there is anticoagulation, in clinical application, have great potential as novel Vascular implantation material.
Of the present invention in the material of artificial blood vessel, the relative molecular weight of described random copolymers is 60,000-200 ten thousand, such as 6.3 ten thousand, 70,000,80,000,100,000,150,000,200,000,300,000,400,000,500,000,600,000,700,000,800,000,900,000,1,000,000,1,200,000,1,400,000,1,600,000,1,800,000,1,900,000 or 1,950,000.
Preferably, in described random copolymers, the relative molecular weight of polycaprolactone block is 500-20000, such as 500,550,580,600,700,800,900,1000,1300,1600,2000,2500,3000,4000,6000,8000,10000,12000,14000,16000,18000 or 20000.
Preferably, described urethane is for being that monomer is formed through polymerization by vulcabond and polyamine.
Preferably, described anti-coagulant is the combination of any one or at least two kinds in sulphobetaine, ethylenediamine tetraacetic acid (EDTA), Sodium Citrate or heparin, is preferably sulphobetaine.
Of the present invention in the material of artificial blood vessel, described material is for having the random copolymers such as formula structure shown in II:
In formula II, PCL is polycaprolactone block, its relative molecular weight is 500-20000, such as 500,550,580,600,700,800,900,1000,1300,1600,2000,2500,3000,4000,6000,8000,10000,12000,14000,16000,18000 or 20000; N, m be greater than 0 integer, n+m=100-20000 (such as n+m=110,120,150,200,300,400,500,600,800,1000,1200,1500,1800,2000,4000,6000,8000,10000,12000,14000,16000,18000 or 19000), n/m=1/3-3/1 (such as n/m=1/3,1/2.8,1/2.5,1/2.3,1/2,1/1.8,1/1.5,1/1.3,1/1,1.3/1,1.5/1,1.8/1,2/1,2.2/1,2.4/1,2.8/1 or 3/1).
Preferably, the relative molecular weight of described random copolymers is 60,000-200 ten thousand, such as 6.3 ten thousand, 70,000,80,000,100,000,150,000,200,000,300,000,400,000,500,000,600,000,700,000,800,000,900,000,1,000,000,1,200,000,1,400,000,1,600,000,1,800,000,1,900,000 or 1,950,000.
Preferably, the viscosity of described random copolymers is 0.3dl/L-30dl/L, such as 0.5dl/L, 1dl/L, 2dl/L, 3dl/L, 5dl/L, 7dl/L, 9dl/L, 12dl/L, 15dl/L, 18dl/L, 20dl/L, 22dl/L, 25dl/L, 27dl/L, 29dl/L or 30dl/L.
Of the present invention in the material of artificial blood vessel, said method comprising the steps of:
A, anti-coagulant is carried out binary alcoholization, obtain the anti-coagulant of binary alcoholization;
The anti-coagulant that b, the binary obtained by step a are refined is connected by ammonia ester bond with vulcabond with the polycaprolactone that binary is refined, and then obtains the described material for artificial blood vessel again with polyamine and vulcabond polymerization reaction take place.
Preferably, the preparation method of the material for artificial blood vessel shown in formula II comprises the following steps:
(1) under protective gas protection, anti-coagulant sulphobetaine and butyl diethanolamine are obtained by reacting the anti-coagulant that the binary shown in formula III is refined;
(2) under protective gas protection; the anti-coagulant of binary alcoholization step (1) obtained and the polycaprolactone of binary alcoholization are respectively with 1; 4-bis-butyl isocyanate reacts under initiator effect, obtains compound shown in compound and formula V shown in formula IV respectively
(3) under protective gas protection, formula IV compound and formula V compound and Putriscine are reacted, obtain Compound II per,
In the present invention, described protective gas is any one in helium, neon, argon gas or nitrogen;
Preferably, the mol ratio of the described anti-coagulant sulphobetaine of step (1) and butyl diethanolamine is 1:(1-1.3), such as 1:1,1:1.03,1:1.05,1:1.07,1:1.1,1:1.13,1:1.15,1:1.18,1:1.2,1:1.22,1:1.25,1:1.28 or 1:1.3.
Preferably, the medium of step (1) described reaction is methylene dichloride and/or trichloromethane.
Preferably, the temperature of step (1) described reaction is 40-60 DEG C, such as 41 DEG C, 42 DEG C, 43 DEG C, 44 DEG C, 45 DEG C, 46 DEG C, 47 DEG C, 48 DEG C, 49 DEG C, 50 DEG C, 51 DEG C, 52 DEG C, 53 DEG C, 54 DEG C, 55 DEG C, 56 DEG C, 57 DEG C, 58 DEG C or 59 DEG C.
Preferably, the time of step (1) described reaction is 8-24h, such as 9h, 10h, 11h, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, 21h, 22h or 23h.
In preparation method of the present invention, the molar ratio of the polycaprolactone that the anti-coagulant of the described binary alcoholization of step (2) and binary are refined is 1:3-3:1, such as 1:3,1:2.8,1:2.5,1:2.2,1:1,1.3:1,1.5:1,1.7:1,2:1,2.2:1,2.5:1,2.8:1 or 3:1, preferred 1:2-2:1.
Preferably, the molar weight of step (2) described Isosorbide-5-Nitrae-two butyl isocyanate is more than or equal to the molar weight sum of institute's hydroxyl in the anti-coagulant of binary alcoholization and the polycaprolactone of binary alcoholization.
Claims (10)
1. for a material for artificial blood vessel, it is characterized in that, described material is the random copolymers being connected through chemistry by polycaprolactone, urethane and anti-coagulant and formed, and described random copolymers has with general formula shown in following formula I:
-(PU-PCL)
n-(PU-B)
m-
Formula I
In formula I, PU represents polyurethane blocks, and PCL represents polycaprolactone block, and B represents the block with anti-coagulant, is connected between described PCL and PU and PU and B by ammonia ester bond, n, m be greater than 0 integer, and n+m=100-20000, n/m=1/3-3/1.
2. the material for artificial blood vessel according to claim 1, is characterized in that, the relative molecular weight of described unregulated polymer is 60,000-200 ten thousand;
Preferably, in described random copolymers, the relative molecular weight of polycaprolactone block is 500-20000;
Preferably, described urethane is for being that monomer is formed through polymerization by vulcabond and polyamine;
Preferably, described anti-coagulant is the combination of any one or at least two kinds in sulphobetaine, ethylenediamine tetraacetic acid (EDTA), Sodium Citrate or heparin, is preferably sulphobetaine.
3. the material for artificial blood vessel according to claim 1 and 2, is characterized in that, described material is for having the random copolymers such as formula structure shown in II:
In formula II, PCL is polycaprolactone block, and its relative molecular weight is 500-20000; N, m be greater than 0 integer, n+m=100-20000, n/m=1/3-3/1;
Preferably, the relative molecular weight of described random copolymers is 60,000-200 ten thousand;
Preferably, the viscosity of described random copolymers is 0.3dl/L-30dl/L.
4. the preparation method of the material for artificial blood vessel according to any one of claim 1-3, is characterized in that, said method comprising the steps of:
A, anti-coagulant is carried out binary alcoholization, obtain the anti-coagulant of binary alcoholization;
The anti-coagulant that b, the binary obtained by step a are refined is connected by ammonia ester bond with vulcabond with the polycaprolactone that binary is refined, and then obtains the described material for artificial blood vessel again with polyamine and vulcabond polymerization reaction take place.
5. the preparation method of the material for artificial blood vessel according to claim 3, is characterized in that, said method comprising the steps of:
(1) under protective gas protection, anti-coagulant sulphobetaine and butyl diethanolamine are obtained by reacting the anti-coagulant that the binary shown in formula III is refined;
(2) under protective gas protection; the anti-coagulant of the binary alcoholization that step (1) is obtained and the polycaprolactone and 1 of binary alcoholization; 4-bis-butyl isocyanate reacts under initiator effect, obtains compound shown in compound and formula V shown in formula IV respectively
(3) under protective gas protection, in the reaction solution of step (2), add Putriscine react, obtain Compound II per,
6. preparation method according to claim 5, is characterized in that, described protective gas is any one in helium, neon, argon gas or nitrogen;
Preferably, the mol ratio of the described anti-coagulant sulphobetaine of step (1) and butyl diethanolamine is 1:(1-1.3);
Preferably, the medium of step (1) described reaction is methylene dichloride and/or trichloromethane;
Preferably, the temperature of step (1) described reaction is 40-60 DEG C;
Preferably, the time of step (1) described reaction is 8-24h.
7. the preparation method according to claim 5 or 6, is characterized in that, the molar ratio of the polycaprolactone that the anti-coagulant of the described binary alcoholization of step (2) and binary are refined is 1:3-3:1, preferred 1:2-2:1;
Preferably, the molar weight of step (2) described Isosorbide-5-Nitrae-two butyl isocyanate is more than or equal to the molar weight sum of institute's hydroxyl in the anti-coagulant of binary alcoholization and the polycaprolactone of binary alcoholization;
Preferably, step (2) described initiator is stannous octoate;
Preferably, the consumption of step (2) described initiator is the 0.05-1% of Isosorbide-5-Nitrae-two butyl isocyanate quality;
Preferably, the temperature of step (2) described reaction is 60-80 DEG C;
Preferably, the time of step (2) described reaction is 2-5h;
Preferably, the medium of step (2) described reaction is the mixture of any one or at least two kinds in dimethyl sulfoxide (DMSO), DMF or Isosorbide-5-Nitrae-dioxane.
8. the preparation method according to any one of claim 5-7, is characterized in that, the mol ratio of step (3) described Putriscine and step (2) described Isosorbide-5-Nitrae-two butyl isocyanate is 1:(1-2).
9. the preparation method according to any one of claim 5-8, is characterized in that, the temperature of step (3) described reaction is 20-30 DEG C;
Preferably, the time of step (3) described reaction is 6-18h;
Preferably, the medium of step (3) described reaction is the mixture of any one or at least two kinds in dimethyl sulfoxide (DMSO), DMF or Isosorbide-5-Nitrae-dioxane.
10. the application in Vascular substitutes prepared by the material for artificial blood vessel according to any one of claim 1-3.
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| US20140248232A1 (en) * | 2013-03-01 | 2014-09-04 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Biodegradable, non-thrombogenic elastomeric polyurethanes |
| CN104548198A (en) * | 2014-12-31 | 2015-04-29 | 胡作军 | Dipyridamole-loaded polyurethane anticoagulative material and preparation process thereof |
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