WO2012115275A1

WO2012115275A1 - Vascular prosthesis

Info

Publication number: WO2012115275A1
Application number: PCT/JP2012/055151
Authority: WO
Inventors: 慎治内田
Original assignee: Uchida Shinji
Priority date: 2011-02-25
Filing date: 2012-02-23
Publication date: 2012-08-30
Also published as: JP2012187398A

Abstract

[Problem] To provide a small-caliber vascular prosthesis having an inner diameter of at most 6 mm when a vascular prosthesis that employs PET fibers, polybutylene terephthalate fibers, or other aromatic polyester fibers made by reacting an aromatic dicarboxylic acid and an aliphatic diol is connected to an in situ blood vessel, that does not produce thrombi or become occluded over the long-term. Also, to provide a very safe vascular prosthesis having an inner diameter of at most 7 mm in which PET fibers, which have been put to practical use in the past, serve as the base material, wherein thickening of a thrombus layer and occlusion are prevented at a branched site, bent site, or anastomosis site. [Solution] With this vascular prosthesis, in which a tubular article having a knitted fabric, woven fabric, or nonwoven fabric made of aromatic polyester fiber as the base material is coated with or impregnated and coated with polyamino acid urethane resin, an endothelial cell film is formed when the vascular prosthesis is connected to an in situ blood vessel and blood flows through; because no thrombus will occur thereon, the foregoing problem can be resolved.

Description

Artificial blood vessel

The present invention relates to an artificial blood vessel, and particularly to an artificial blood vessel having excellent biocompatibility and safety.

Since around 1950, artificial blood vessels have been used clinically for the purpose of blood circulation reconstruction.

Then, as the artificial blood vessel, a polyethylene terephthalate fiber (PET fiber) knitted fabric, a woven fabric tubular material, or a polytetrafluoroethylene stretched porous resin (e-PTFE) tubular material is used. The tube wall tissue of these artificial blood vessels is rich in porosity.

Among these, knitted PET fibers and tubular fabrics (artificial blood vessels) form a thrombus layer when blood flows, and endothelial cells are formed on the thrombus layer. In addition, since PET fibers are biocompatible, living cells invade from the outer wall of the blood vessel and reach new endothelial cells. Furthermore, a fine blood vessel enters from the outer wall of the blood vessel and reaches a neovascular endothelial cell membrane generated in the blood vessel, and the thrombus is absorbed into the body with time. The neointima in the blood vessels is metabolized by the blood flow of the small blood vessels, and is constantly maintained and managed as new.

That is, the artificial intravascular neovascular membrane generated in this way has the same structure and function as a biological blood vessel, and is therefore an artificial blood vessel that is excellent in patency.

On the other hand, since an artificial blood vessel using e-PTFE is PTFE (polytetrafluoroethylene), which is a typical non-biocompatible (biologically inert) substance, when e-PTFE is connected to a biological blood vessel (biological blood vessel) The endothelial cell membrane enters from the living blood vessel toward the anastomosis part, but the invasion power of living cells from the outer wall of the blood vessel is very large even if the hole of e-PTFE is increased. Inferior, since fine blood vessels do not invade, artificial blood vessels having a structure similar to biological blood vessels are not generated in artificial blood vessels like artificial blood vessels based on PET fibers. In addition, the endothelial cell membrane that invades from the blood vessels toward the anastomosis part is difficult to adhere to e-PTFE, and even if it adheres, it peels off to form a hematoma, and this part becomes thickened over a long period of time. This causes stenosis in the part and causes obstruction.

However, in the case of an artificial blood vessel having an inner diameter of 6 mm or less, when blood flows, e-PTFE is a biologically inert substance, so that blood coagulation does not occur as in the case of PET fibers, and the patency state remains for a certain period of time. Retain, but long-term patency cannot be expected.

Currently, most of the artificial blood vessels that have been put into practical use are artificial blood vessels that have been tubularized with a knitted or woven fabric of PET fibers.

However, when blood flows in an artificial blood vessel of PET fiber, a blood clot is formed in the tube wall, and the blood vessel is blocked in an artificial blood vessel having a small diameter (inner diameter of 6 mm or less). In addition, when blood flows in an artificial blood vessel made of PET fiber, it causes a leakage phenomenon of blood cells and plasma.

Therefore, in order to prevent this, 1. 1. a pre-clotting method in which an artificial blood vessel is previously treated with a patient's blood; 2. a method of sealing with fibrin glue; A method of heat-treating albumin has been used. However, in recent years, artificial blood vessels that have been clogged with gelatin, collagen or the like in advance so as to cope with emergency surgery have been frequently used.

Even in an artificial blood vessel clogged by these methods, when blood flows, the blood is coagulated and the blood vessel is blocked in an artificial blood vessel having a small diameter, so that it is practical only for an artificial blood vessel having a medium diameter or larger (inner diameter 7 mm or larger). Has a point.

To date, artificial blood vessels based on PET fibers with an inner diameter of less than 6 mm have not been used. Further, even in a practical artificial blood vessel having an inner diameter of 7 mm or more based on a PET fiber, a thickened thrombus layer is blocked at a branched portion, a bent portion or an anastomosis portion with a biological blood vessel in some cases. There is.

In addition, as an ideal artificial blood vessel, an artificial blood vessel that is finally absorbed in the living body has been studied, but in the process where a biological blood vessel is formed in the artificial blood vessel and the artificial blood vessel is absorbed, It is said that it will gradually swell due to the internal pressure that is constantly applied to form an aneurysm and eventually rupture.

It seems that the application of bioabsorbable fibers to artificial blood vessels has been attempted for more than 20 years, but it has not been put into practical use at all because of the problem of forming and rupturing the aneurysm.

As for PAU, Patent Document 1 shows that PAU made a tube having an inner diameter of 1.0 mm and a length of 10 mm and transplanted into the abdominal aorta of a rat, and was bred for one week. Yes. In Example 4 of Patent Document 2, an anti-thrombotic material that can be used for a cell culture membrane, an inner diameter of 1.5 mm and a 7 mm e-PTFE human T-vessel coated with PAU, is transplanted into a rat abdominal aorta, and e -It has been shown that antithrombogenicity is improved compared to PTFE artificial blood vessels. In Non-Patent Document 1, when an e-PTFE artificial blood vessel having an inner diameter of 1.5 mm is coated with PAU and transplanted to the abdominal aorta of a rat, thrombus does not occur at all, and endothelial cells are well infused on the inner surface of the artificial blood vessel. This is explained by reactions with endothelial cell markers, electron micrographs, and optical micrographs. However, since the e-PTFE artificial blood vessel is inactive in the living body, the invasion property of the living cell from the outer wall of the blood vessel is poor, and it is difficult for the fine blood vessel to reach the blood vessel from the outer wall of the blood vessel. Biological blood vessels that can be metabolized, such as fiber artificial blood vessels, are not generated.

Furthermore, in e-PTFE artificial blood vessels, e-PTFE has poor adhesion to other materials, and therefore, in a relatively long-term test, the PAU coating component and the endothelial cell membrane formed thereon may be detached by blood flow. However, the risk of the blood vessel (artificial blood vessel or biological blood vessel) becoming blocked due to the peeled material cannot be denied, and it cannot be used for a long time.
Patent Document 3 proposes that a polyamino acid urethane resin (PAU) is used as a cell adhesion layer in a tube made of bioabsorbable aliphatic polyester fibers such as polyglycolic acid and polylactic acid. Since an artificial blood vessel using a tube is bioabsorbable, it is difficult to put it to practical use in view of the problems and background of the bioabsorbable artificial blood vessel. Patent Document 4 describes that PAU is bioabsorbable. In Patent Document 5, “at least the inner surface of a porous tubular structure is provided with (1) a polyamino acid urethane resin copolymer, (2) collagen or gelatin, and (3) an endothelial cell proliferation promoter having collagen binding activity. ”, An artificial blood vessel formed by sequentially laminating and fixing”. As the porous tubular structure used here, it is described that polyethylene terephthalate, polybutylene terephthalate and the like can be used in addition to e-PTFE. This artificial blood vessel is made by coating a porous tubular structure with polyamino acid urethane (PAU), coating with collagen or gelatin, and then laminating and coating an endothelial cell growth agent (endothelial cell growth factor). To fix. Examples of the endothelial cell growth factor include other in vivo substances such as HGF (hepatocyte growth factor) and VEGF (vascular endothelial growth factor).
In addition, it is written here that “the use of PAU has been found to be effective in maintaining collagen on the surface of the e-PTFE tube for a long period of time”. In addition, when an endothelial cell proliferating agent is coated on collagen and transplanted and blood flows, an endothelial cell is formed on the inner wall of the blood vessel by the proliferating agent (HGF, VEGF, etc.) to create an antithrombotic artificial blood vessel. To do. On the other hand, the present invention is a method for producing an antithrombotic artificial blood vessel by producing an endothelial cell membrane by the endothelial cell proliferation action of PAU by flowing blood directly in contact with the PAU coating surface. Completely different.
That is, Patent Document 5 uses PAU as an adhesive for immobilizing endothelial cell proliferating agents such as HGF and VEGF on the inner surface of an artificial blood vessel, whereas the present invention uses PAU itself as an endothelium. It is used as a cell proliferating agent.

JP-A-11-239612 JP 2001-136960 A JP 2005-319165 A JP-A-1-124464 JP 2006-68401 A

An object of the present invention is to use an artificial polyester fiber made by a reaction of an aromatic dicarboxylic acid and an aliphatic diol, such as a PET fiber that is not easily decomposed or absorbed in vivo, or a polybutylene terephthalate fiber. A thrombus is not generated when a blood vessel is connected to a living body blood vessel, and an artificial blood vessel that does not occlude for a long time is provided even in a small-diameter artificial blood vessel having an inner diameter of 6 mm or less.
Further, by not causing thrombus, even in an artificial blood vessel having an inner diameter of 7 mm or more based on a conventional PET fiber that has been put to practical use, a thrombus layer at a branched portion, a bent portion, or in some cases, an anastomosis portion is thick. Therefore, it is possible to provide a highly safe artificial blood vessel.

In the present invention, the uppermost layer on the inner surface of a tubular product obtained by coating or impregnating a polyamino acid urethane resin (PAU) on a tubular product based on a knitted fabric, a woven fabric, and a nonwoven fabric of an aromatic polyester fiber. An artificial blood vessel formed of PAU.

The present invention can also be applied to an artificial blood vessel in which an aromatic polyester fiber base material is clogged with gelatin, collagen or the like.

That is, when an artificial blood vessel coated with PAU is connected to a biological blood vessel (or replaced with a biological blood vessel), leakage of blood cells and plasma is prevented by PAU, gelatin, collagen, etc., and at the top of the artificial blood vessel. Since the entire inside of the artificial blood vessel is covered with the endothelial cell membrane before the anti-thrombogenicity and endothelial cell adhesion of the coated PAU function to form a thrombus, the thrombus does not occur.

Anti-thrombogenicity and endothelial cell adhesion even if the amount of PAU coating is small, since blood leakage is prevented for artificial blood vessels whose aromatic polyester fiber base is clogged with gelatin, collagen, etc. A superior artificial blood vessel can be obtained. Also in this case, when blood flows through an artificial blood vessel coated with PAU, an endothelial cell membrane is formed preferentially, so that a thrombus does not occur as in a conventional artificial blood vessel of polyester fiber.

Thereafter, the living cells and the small blood vessels enter the blood vessel from the outer wall of the blood vessel in the same manner as the conventional artificial polyester fiber of aromatic polyester fiber, reach the endothelial cells, and a living blood vessel having a metabolic function is generated in the artificial blood vessel. .
This is illustrated in the following diagram.
Fig. 1 shows the process after transplantation of a conventional aromatic polyester fiber-based artificial blood vessel when an artificial blood vessel is transplanted (biological results are connected to both ends of the artificial blood vessel to cause blood flow). FIG. 2 shows a course after transplantation of an artificial blood vessel in which a blood vessel is coated with PAU (a course after transplantation of a PAU-coated aromatic polyester fiber artificial blood vessel).
FIG. 3 shows a structure diagram of a biological blood vessel generated in an artificial blood vessel of an aromatic polyester fiber-based artificial blood vessel and a PAU-coated aromatic polyester fiber.

In the case of the artificial blood vessel of the conventional aromatic polyester fiber shown in FIG. 1, for example, when blood is passed through an artificial blood vessel having an inner diameter of 7 mm or more and clogged with only gelatin or collagen, the blood condenses on the tube wall. Since the thickness is about 2 mm or less, the blood vessel does not occlude, and the endothelial cell membrane covers the coagulated blood (thrombus layer) to form a surface structure similar to that of a biological blood vessel, and the fiber gap from the outer wall of the artificial blood vessel Incorporation of living cells and microvessels, smooth muscle cell layers under the endothelial cell layer, and formation of fibroblasts under them promotes integration with living tissue, creating artificial blood vessels that can withstand long-term use. It is formed. However, the thrombus layer may become thicker and occluded at the branched portion, the bent portion, and in some cases, at the anastomosis.

Also, in a small-diameter blood vessel having an inner diameter of 4 mm or less, the blood vessel is blocked by the thickness of the thrombus layer generated by the patient's blood.

On the other hand, when PAU is coated on an artificial blood vessel of aromatic polyester fiber as shown in FIG. 2 and PAU is present on the uppermost layer of the inner surface of the artificial blood vessel, it is excellent in antithrombogenicity and endothelial cell membrane formation. When blood flows, the endothelial cell membrane covers the entire inner wall of the blood vessel before blood clots (thrombus) are formed, so that no thrombus is formed. Since thrombus does not occur, it can be used for a small-diameter artificial blood vessel having an inner diameter of 6 mm or less and further having an inner diameter of 4 mm or less, which is not practically used. Eventually, PAU is absorbed into the living body, and a metabolizable living blood vessel is generated in the artificial blood vessel of the aromatic polyester fiber, so that it becomes an artificial blood vessel that does not occlude for a long time.
In addition, since a thrombus does not occur, even in the case of an artificial blood vessel having an inner diameter of 7 mm or more, a thrombus may be generated in a branched portion, a bent portion, and in some cases, an anastomosis portion like a conventional artificial blood vessel of aromatic polyester fiber. It is a highly safe artificial blood vessel.
Furthermore, when PAU is coated on an aromatic polyester fiber product (woven fabric, knitted fabric, non-woven fabric, etc.), a product with good touch and texture can be obtained. Due to the features of touch and texture, synthetic leather and waterproof cloth for clothing have been put into practical use for many years, and this touch and texture are important physical properties even in artificial blood vessels that have been put to practical use. Moreover, since PAU has an amino acid chain, it is a coating agent having excellent fitting properties with living cells.

In particular, it is only coated or impregnated with PAU on knitted fabrics, woven fabrics, and non-woven fabrics of aromatic polyester fibers such as polyethylene terephthalate and polybutylene terephthalate, or those packed with collagen, gelatin, etc. An artificial blood vessel in which PAU is present in the uppermost layer on the inner surface of the manufactured tubular article has never existed in the literature so far.
The artificial blood vessel made by this method has the function that the PAU coating layer in the artificial blood vessel generates the endothelial cell membrane in the same way as the thrombus layer that occurs when blood flows into the artificial blood vessel of normal aromatic polyester fiber have.

The cause of this phenomenon is thought to be due to the eclectic action of the relatively antithrombogenic urethane segment in the PAU component and the peptide segment having an endothelial cell generating action.

The artificial blood vessel of the present invention has an effect that it does not occlude for a long time even if it has a small diameter of 6 mm or less.
For medium and large diameters with an inner diameter of 7 mm or more, a thick thrombosis layer is formed at the bent portion of an artificial blood vessel and, in some cases, the anastomosis portion, of a conventional aromatic polyester (PET) fiber that has been put to practical use. However, in the artificial blood vessel of the present invention, since a thrombus layer is not formed, the blood vessel is not obstructed in this way and becomes a highly safe artificial blood vessel.

Progress after transplantation of conventional artificial polyester fiber grafts Progress after grafting of artificial blood vessel of PAU coated aromatic polyester fiber of the present invention Conventional artificial blood vessel of aromatic polyester fiber and biological blood vessel formed in artificial blood vessel of PAU coated aromatic polyester fiber of the present invention Aromatic polyester fiber artificial blood vessel with branch

Hereinafter, the present invention will be described in detail.
The aromatic polyester fiber of the present invention is a polyethylene terephthalate (PET) fiber or a polybutylene terephthalate fiber obtained by fiberizing a reaction product of an aromatic dicarboxylic acid and an aliphatic diol. Mixtures of fibers or mixtures of these fibers with other fibers can be used.

The starting amino acid used in the PAU in the present invention may be any of an optically active substance, a racemate, or a mixture thereof. A polyamino acid is a structure in which an average of 4 or more amino acid units are continuously bonded, and means a structure in which an average of 4 or more amino acids of the same or different types are continuously bonded. There are roughly two methods for synthesizing such a copolymer of polyamino acid and urethane.

The first method is a method in which polyamino acid and polyurethane are synthesized separately and then copolymerized. This method is a method of reacting urethane with a polyamino acid obtained by polymerizing an active monomer as a polyamino acid synthesized by sequentially combining amino acids or a precursor of polyamino acid. In this method, it is difficult to increase the molecular weight of the polyamino acid or copolymer.

The second method is a method of copolymerizing an active monomer (polymerizable monomer) as a precursor of polyamino acid and urethane. When α-amino acid-N-carboxylic acid anhydride is used as a polyamino acid precursor in this method, it is easy to increase the molecular weight of both the polyamino acid chain in the copolymer to be produced and the copolymer. is there. Therefore, the polyamino acid urethane resin used in the present invention is obtained by this second method, that is, (a) an α-amino acid-N-carboxylic acid anhydride, (b) a urethane prepolymer having an isocyanate group at the terminal, and ( c) It is preferably formed of a polyamino acid urethane resin obtained by reacting at least one selected from water, hydrazine and organic amine.

Specific examples of amino acids used include neutral amino acids having 2 to 12 carbon atoms such as glycine, alanine, leucine, isoleucine, valine, α-aminoheptanoic acid, β-benzylaspartic acid, γ-methyl-L- Monoesterified acidic amino acids such as glutamate, γ-methyl-D-glutamate, and γ-benzyl-L-glutamate, and ω-amino groups such as ε-acyllysine and δ-acylortinin are protected with an appropriate masking group. Examples thereof include ω-diaminocarboxylic acid derivatives and O-acetylleonine. In this case, the racemic or optically active form can be used as the α-amino acid.

When α-amino acid-N-carboxylic acid anhydride (hereinafter, N-carboxylic acid anhydride is abbreviated as NCA) is used as a polyamino acid precursor, all of the above α-amino acids-NCA can be used. It is. Typical examples include glycine-NCA, alanine-NCA, leucine-NCA, and γ-methyl-L-glutamate-NCA.

The urethane prepolymer having an isocyanate group at the terminal is obtained by reacting a polyisocyanate compound and a polyol under the condition of an equivalent ratio NCO / OH> 1. As the polyisocyanate component, aromatic diisocyanate, aliphatic diisocyanate and alicyclic diisocyanate are used alone or as a mixture thereof. For example, toluene-2,4-diisocyanate, 4,4'-diphenylmethane diisocyanate, metaphenylene diisocyanate, 3,3'-dimethyl-4,4'-biphenyl diisocyanate, metaxylene diisocyanate, paraxylene diisocyanate, hexanemethylene diisocyanate, 1, Examples thereof include 10-decamethylene diisocyanate, 1,4-cyclohexane diisocyanate, dicyclohexylmethane-4,4'-diisocyanate, 3-isocyanate methyl-3,5,5-trimethylcyclohexyl isocyanate (isophorone diisocyanate).

Examples of the polyol component include polyether polyol and polyester polyol alone or a mixture thereof. Examples of polyether polyols include polypropylene ether glycol, polyethylene polypropylene ether glycol, polytetramethylene ether glycol, polypentamethylene ether glycol, polyethylene polytetramethylene ether random copolymer, polyethylene polytetramethylene ether block copolymer alone or Examples thereof include a glycol having an aromatic ring obtained by adding propylene oxide or ethylene oxide to bisphenol A and a mixture thereof.

Representative examples of polyester polyols include polycaprolactone polyols or those obtained by reaction of diols such as ethylene glycol and 1,4-butanediol with dibasic acids such as adipic acid and sebacic acid. Also, special polyols such as polyols obtained by adding caprolactone to polytetramethylene ether polyols or polypropylene ether polyols, and polysiloxane polyols can be used. Further, polycarbonate polyol obtained by deethanol reaction by adding excess molar ratio of 1,6-hexanediol or 3-methylpentanediol to diethylene carbonate is used.

These polyether polyols, polyester polyols and special polyols preferably have a number average molecular weight of 200 or more. The water used in the present invention means ordinary water and may be tap water, non-demineralized water, or demineralized water. Hydrazine may be either anhydrous hydrazine or hydrous hydrazine, and hydrous hydrazine is industrially more advantageous in terms of safety.

Representative examples of organic amines include tertiary amines such as trimethylamine, triethylamine and tripropyldiamine, secondary diamines such as piperazine, primary diamines such as ethylenediamine, 1,3-propanediamine and 1,4-butanediamine, Suitable are primary and secondary amines such as 2-propanediamine and 1,3-butanediamine, and dihydrazides having a hydrantoin ring, such as 1,3-bis (hydrazidecarboethyl) -5-isopropylhydantoin. In addition to these organic amines, hydrazine can be used.

The weight ratio of the α-amino acid NCA and the urethane prepolymer in obtaining the polyamino acid urethane resin is 5:95 to 95: 5, preferably 10:90 to 90:10, and more preferably 20:80. It is in the range of ~ 80: 20. This weight ratio is determined according to the desired antithrombogenicity, endothelial cell adhesion and mechanical properties. The amount of hydrazine and the organic amine having primary or secondary active hydrogen is preferably at least 1/2 equivalent, more preferably at least 2/3 equivalent, based on the isocyanate group of the urethane prepolymer as an amino group. The amount of tertiary amine used is preferably 1/1000 mol or more of α-amino acid NCA.

Since water reacts with isocyanate groups to form amino groups, water can be used as an alternative to amines. The polyamino acid urethane resin in the present method is obtained by reacting an α-amino acid-N-carboxylic acid anhydride, a urethane prepolymer having an isocyanate group at the terminal, and water, hydrazine or an organic amine in an organic solvent.

Examples of the organic solvent used herein include chlorinated aliphatic hydrocarbons such as dichloromethane, 1,2-dichloroethane, 1,1,2-trichloroethane, chloroform, 1,1,2,2-tetrachloroethane, and benzene. , Aromatic hydrocarbons such as toluene and xylene, chlorinated aromatic hydrocarbons such as chlorobenzene and dichlorobenzene, acetates such as ethyl acetate and butyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, etc. Water-soluble organic solvents that do not contain active hydrogen such as ketones, dimethylformamide, diethylformamide, dimethylacetamide, N-methylpyrrolidone, ethylene carbonate, dimethylsulfoxide, dioxane, tetrahydrofuran, hexamethylphosphoramide, or the like seed Including mixtures of the above.

The amount of the organic solvent used is such that the resin concentration in the polyamino acid urethane resin liquid of the final product is usually in the range of 3 to 50% by weight, preferably in the range of 10 to 30% by weight in terms of the produced resin solution. It is good to do. If the concentration is too high, the viscosity becomes remarkably high and a gel is formed. When the tube is coated or impregnated and processed, it may be diluted with a solvent, but it is difficult to handle. On the other hand, if the concentration is too low, it is difficult to obtain a product having a high viscosity (10,000 cps or more), and the versatility is poor.

Further, in the case where optical activity and α-amino acid NCA are used in this method, the reaction temperature when producing a polyamino acid urethane resin liquid is preferably a temperature at which a single polymer having a high molecular weight can be synthesized from α-amino acid NCA. A range of 60 ° C. is good. When the temperature is higher than 60 ° C., the amino acid chain hardly takes an α-helix structure at the time of copolymerization, so that the degree of polymerization of the amino acid chain does not increase and a high molecular weight product may not be obtained. In addition, when the reaction is performed at a high temperature, the isocyanate group may undergo a burette reaction with the urea bond generated by the reaction between the isocyanate group and the amino group, thereby causing gelation.

When the dimethylformamide is used as a solvent in the polyamino acid urethane resin liquid obtained as described above, the α-amino acid NCA and the urethane prepolymer have a weight ratio of, for example, 5:95 to 15: In the range of 85, the solution becomes relatively less turbid, and as the ratio of α-amino acid NCA increases, the turbidity increases, and a solution having an arbitrary viscosity within the range of 10 cps to 1 million cps / 25 ° C. is obtained. . Structurally, when optically active α-amino acid NCA is used as the amino acid component, when the amino acid content is low, the α-helix content is low, the β structure content is high, and the amino acid content is high. , The α-helix content tends to increase and the β structure tends to decrease.

As a preferred method for obtaining a polyamino acid urethane resin, (i) a method in which a urethane prepolymer and an α-amino acid NCA are mixed in the organic solvent and then a tertiary amine is added and reacted.
(B) A method in which an α-amino acid NCA and a urethane prepolymer are mixed in the organic solvent, and then an organic amine having water, hydrazine or active hydrogen is added and reacted.
(C) A method in which a urethane prepolymer and an α-amino acid NCA are mixed in the organic solvent, an organic amine having water, hydrazine or active hydrogen is added and reacted, and then a tertiary amine is further added and reacted.
(D) A method in which a urethane prepolymer and water, hydrazine or an organic amine having active hydrogen are reacted in the organic solvent, and then α-amino acid NCA is added and reacted.
(E) A method of mixing an α-amino acid NCA and a urethane prepolymer in the organic solvent, then adding water, hydrazine, or an organic amine having active hydrogen to react, and further adding a urethane prepolymer.
(F) After reacting the urethane prepolymer with water, hydrazine, or an amine having active hydrogen in the organic solvent, α-amino acid-N-carboxylic acid anhydride is added and reacted, and then water is added. And a method of adding and reacting hydrazine or amines having active hydrogen.
In the above method for obtaining a polyamino acid urethane resin (PAU), the type of the organic solvent is adapted to the use of PAU and the type of raw material (α-amino acid NCA, urethane prepolymer).

In the present invention, a polyamino acid urethane resin obtained by the above method can be used by mixing a polyamino acid or a polyurethane resin. The artificial blood vessel of the present invention can be obtained by coating or impregnating a polyamino acid urethane resin obtained by the above-mentioned method with a polyamino acid urethane resin on a knitted, woven or non-woven tubular article of an aromatic polyester fiber.

The concentration of the PAU solution is preferably 5% by weight or more when the tubular product of the aromatic polyester fiber that is not clogged with gelatin or collagen is immersed and impregnated in the PAU solution.

In addition, the concentration of the PAU solution when an artificial blood vessel is obtained by coating or impregnating a polyamino acid urethane resin with the above-mentioned tubular product of aromatic polyester fiber clogged with gelatin or collagen is preferably 1% or more, preferably 3 wt. % Or more.

When an artificial blood vessel made of polyamino acid urethane resin (PAU) is processed into a tube made of aromatic polyester fiber knitted fabric, woven fabric, or nonwoven fabric is impregnated and coated, the amino acid content in the PAU is constant. When the amount exceeds the limit, endothelial cells enter the artificial blood vessel, in addition to the invasion of living blood vessels, the uptake and growth of endothelial cells or endothelial cell-forming factors from blood by PAU resin, and the fine blood vessels from the artificial blood vessel outer wall to the artificial blood vessel The endothelial cell membrane adheres and spreads throughout the artificial blood vessel when it enters the artificial blood vessel and opens in the artificial blood vessel. In this way, the formation of a biological blood vessel starts in the artificial blood vessel. In this case, since the artificial blood vessel is entirely covered with the endothelial cell membrane, there is no vascular occlusion due to the removal of the pannunu from the thrombus or the anastomosis, and there is a smooth muscle cell layer below the endothelial cell membrane, and below that Fibroblasts are created, and biological blood vessels are smoothly generated in the artificial blood vessel.

In this process, the PAU component, gelatin, collagen, etc. in the artificial blood vessel are gradually absorbed into the living body, and finally the living blood vessel is inserted into the gap between the knitted or woven fiber aggregates constituting the aromatic polyester fiber tube. Is formed. It is reported in the said patent document 4 that PAU is bioabsorbable.

In this case, if there are too few amino acid components in the PAU, the formation of the endothelial cell membrane is poor, and thrombosis is likely to occur during long-term use. If the amino acid component is too much, the production of the endothelial cell membrane is improved, but prior to that, the antithrombogenicity is reduced, and a thrombus is generated in an artificial blood vessel having a small inner diameter (6 mm or less).

Therefore, the amino acid content in the PAU is 5 to 95%, preferably 10 to 90%, more preferably 15 to 85%. When amino acids other than α-amino acid NCA are used as amino acids, those according to this range are preferred.

Hereinafter, the method for producing a resin used in carrying out the present invention and the method for producing an artificial blood vessel using the same will be described more specifically with reference to Examples and Comparative Examples. However, the present invention is not limited to these examples.

B) Production of polyamino acid urethane resin 980 g of polytetramethylene ether glycol (OH value 57.25) and tolylene diisocyanate (a mixture of 2,4-tolylene diisocyanate and 2,6-tolylene diisocyanate, 2,4 -Tolylene diisocyanate 80 wt%) 174 g was reacted at 70 ° C. for 5 hours to obtain a urethane prepolymer having an isocyanate group at the terminal (NCO equivalent, 1164). 58.2 g of the urethane prepolymer and 58.2 g of γ-methyl-L-glutamate NCA were dissolved in 394.3 g of dimethylformamide (DMF), and a solution of 1.375 g of hydrazine hydrate in 20 g of DMF was added dropwise to the reaction. Thus, a polyamino acid urethane resin solution (A) (concentration, 20 wt% DMF solution) having a viscosity of 16000 cps / 25 ° C. was obtained.

The average degree of polymerization of amino acid chains in this solution is the reactivity of primary amines and isocyanates and the mechanism of NCA polymerization by primary amines (Murray Goodman and John Hutchison. J. Am. Chem. Soc., 88, 3627 (1966). )) To calculate approximately 62.

In addition, the ratio of the α-helix structure to the β-structure of the copolymer of the present copolymer is as follows: IR-spectrum 1655 cm ⁻¹ (α-helix C═O stretching) and 1625 cm ⁻¹ (β-structure C = O stretch) is 95/5, most of which is an α-helix structure.

B) Manufacture of artificial blood vessel The polyamino acid urethane resin (A) (concentration 20 wt% DMF solution) was diluted with DMF to obtain a concentration 10 wt% DMF solution. Next, a metal rod is passed through a tubular knitted tube (a) made of polyethylene terephthalate fiber having an inner diameter of 3 mm and a length of 70 mm, and this is immersed in the polyamino acid urethane resin 10 wt% DMF solution to obtain the resin solution. Was impregnated. Next, this was taken out from the solution and put into squeezed water with a roll to remove DMF. Subsequently, this was air-dried, the metal rod was taken out, and the artificial blood vessel (sample 1) clogged with the polyamino acid urethane resin was obtained. This artificial blood vessel had a dry touch and good tactile sensation. In addition, an artificial blood vessel was obtained in which PAU was considered to have good fitting properties to a living body from a combination of an amino acid and urethane. This thing was made into the artificial blood vessel for biological experiment.

Comparative Example 1
B) Preparation of urethane resin A solution in which 1.25 g of hydrazine hydrate was dissolved in 80.5 g of DMF, and 52.8 g of the same urethane prepolymer used in Example 1 was dissolved in 58.2 g of DMF under a nitrogen atmosphere. Were dropped and reacted to obtain a urethane resin solution (B) having a viscosity of 14,000 cps / 25 ° C. (concentration, 28 wt% DMF solution).

B) Manufacture of artificial blood vessel The urethane resin solution (B) was diluted with DMF to a concentration of 10 wt% as in Example 1, and immersed in this solution through a metal rod in the same tubular product (a) as in Example 1. After impregnating with the urethane resin solution, it was taken out and put into squeezed water with a roll to remove DMF. Next, this was air-dried, the metal rod was taken out, and an artificial blood vessel (sample 2) clogged with urethane resin was obtained. This artificial blood vessel had a rubber-like and sticky feel. This sample was used as a sample for a biological experiment for a comparative example.

The tubular product (a) used in Example 1 was clogged with collagen to produce a tubular product (b) from which leakage of blood was eliminated, and a metal rod was passed through the tube. Next, the polyamino acid urethane resin solution (A) (concentration 20 wt%) obtained in Example 1 was diluted with dichloroacetic acid to a concentration of 5 wt%, and a tubular material (b) passed through a metal rod was added thereto, and the concentration was 5 wt%. % Solution was impregnated. Subsequently, this was taken out, put into water and desolvated (solvent, DMF and dichloroacetic acid), then air-dried, a metal rod was taken out, and an artificial blood vessel (sample 3) coated with a polyamino acid urethane resin was obtained. This product was an artificial blood vessel with a dry touch and good tactile sensation. Moreover, it is thought that it is an artificial blood vessel with a good fitting property from the combination of an amino acid and urethane. This was used as a sample for biological experiments.

Comparative Example 2
The tubular product (b) obtained by clogging the tubular product (a) used in Example 1 with collagen was used as an artificial blood vessel (sample 4). This was used as a comparative biological experiment sample.

The polyamino acid urethane resin (A) synthesized in Example 1 (concentration 20 wt% DMF solution) was diluted with DMF to obtain a concentration 10 wt% DMF solution. Next, a metal rod is passed through a tube of a tubular product (c) knitted from polyethylene terephthalate fiber having an inner diameter of 1.5 mm and a length of 10 mm, which is immersed in the polyamino acid urethane resin 10 wt% DMF solution, and the resin The solution was impregnated. Next, this was taken out from the solution and put into squeezed water with a roll to remove DMF. Next, this was air-dried, the metal rod was taken out, and an artificial blood vessel (sample 5) clogged with polyamino acid urea resin was obtained. This product had a dry touch and good touch. This was used as a sample for biological experiments.

Comparative Example 3
The urethane resin solution synthesized in Comparative Example 1 was diluted with DMF to a concentration of 10 wt%. Next, a metal rod is passed through a tube of a tubular product (c) formed by knitting polyethylene terephthalate fibers having an inner diameter of 1.5 mm and a length of 10 mm into a tube shape, and this is immersed in the urethane resin 10 wt% solution. The solution was impregnated. Next, this was taken out from the solution and put into squeezed water with a roll to remove DMF. Next, this was air-dried, the metal rod in the tube was taken out, and an artificial blood vessel (sample 6) clogged with urethane resin was obtained. This was a rubber-like texture and a sticky feel. This was used as a comparative biological experiment sample.

The tubular product (c) used in Example 3 (knitting of polyethylene terephthalate fiber having an inner diameter of 1.5 mm and a length of 10 mm) was clogged with gelatin to prepare a tubular product (d) in which leakage of blood was eliminated. Next, the polyamino acid urethane resin solution (A) (concentration 20 wt%) obtained in Example 1 was diluted with dichloroacetic acid to a 5 wt% solution. Next, a metal rod was passed through the tube of the tubular article (d), and this was put into the 5 wt% solution and impregnated with the solution. Subsequently, this was taken out, squeezed with a roll, and then put into water to remove the solvent (solvent, DMF and dichloroacetic acid). It was taken out from the water and air-dried, the metal rod was taken out, and an artificial blood vessel (sample 7) coated with a polyamino acid urethane resin was obtained. This product was an artificial blood vessel with good tactile sensation. This was used as a sample for biological experiments.

Comparative Example 4
A tubular product (sample 8) obtained by clogging the tubular product (c) used in Example 4 with gelatin was obtained. This was used as a comparative artificial blood vessel for biological experiments.

The polyamino acid urethane resin (A) synthesized in Example 1 (20% by weight DMF solution) was diluted with dichloroacetic acid to give a 3% concentration solution. Next, a polyethylene terephthalate fiber is passed through a tube made by clogging a tubular knitted fabric with an inner diameter of 2 mm and a length of 10 mm with collagen, and this is diluted with dichloroacetic acid and immersed in a polyamino acid urethane solution having a concentration of 3%. Then, the resin solution was impregnated. Next, this was taken out from the solution and placed in water to remove the solvent (DMF and dichloroacetic acid), and then air-dried to remove a metal rod to obtain an artificial blood vessel impregnated with a polyamino acid urethane resin (sample) 9). This was used as a sample for biological experiments.
Although only a small amount of polyamino acid urethane resin (PAU) is attached to this artificial blood vessel, it has excellent antithrombogenicity as in the case of non-patent document 1 when e-PTFE is coated with 3% concentration of PAU. It is thought that.
Comparative Example 5
Next, a tubular product (e) obtained by clogging a tubular knitted fabric of polyethylene terephthalate fiber having an inner diameter of 2 mm and a length of 10 mm with collagen was used as a sample for biological experiments (sample 10).

Fig. 4 shows a tubular product in which an artificial blood vessel made of polyethylene terephthalate (PET) fiber branched into a T-shape is plugged with collagen (e) {main tube (thick portion): tubular product having an inner diameter of 12 mm and a length of 140 mm, side A metal rod was inserted into a main pipe and a side pipe of a pipe (branch pipe: tubular product having an inner diameter of 8 mm and a length of 150 mm connected to the central portion of the main pipe), and then the polyamino acid urethane resin solution (A) obtained in Example 1 After diluting (concentration 20 wt%) with dichloroacetic acid to a concentration of 3 wt% and immersing the artificial blood vessel into which the metal rod was inserted, it was lifted and desolvated in water, air-dried to extract the metal rod, and coated with PAU An artificial blood vessel (sample 10) of a woven fabric of PET fiber was obtained, which had good tactile sensation and texture, and was used as a sample for biological experiments.

Comparative Example 6
As a comparative example, a tubular product (f) obtained by clogging an artificial blood vessel of a PET fiber fabric branched into a T shape in FIG. 4 with collagen was used as a sample for biological experiment (sample 11).

The present invention can be used as an artificial blood vessel.

DESCRIPTION OF SYMBOLS 1 Conventional aromatic polyester fiber type artificial blood vessel 2 Thrombus layer 3 generated after transplantation Endothelial cell membrane 4 formed on the thrombus layer Living body blood vessel 5 generated in the fiber assembly of the conventional aromatic polyester fiber artificial blood vessel PAU coated aromatic polyester fiber artificial blood vessel 6 Endothelial cell membrane 7 formed on the inner wall of the artificial blood vessel of the PAU coated aromatic polyester fiber of the present invention 7 PAU coated aromatic polyester fiber artificial blood vessel fiber assembly of the present invention Generated in the body (PAU component is absorbed into the body)
8 Length of main pipe (thick one): 140mm
9 Length of the side pipe connected to the center of the main pipe: 150mm

Claims

The uppermost layer of the inner surface of a tubular product obtained by coating or impregnating a polyamino acid urethane resin on a tubular material based on a knitted, woven or nonwoven fabric of an aromatic polyester fiber is formed of a polyamino acid urethane resin. Artificial blood vessels.
The artificial blood vessel according to claim 1, wherein the aromatic polyester fiber is polyethylene terephthalate fiber, polybutylene terephthalate fiber, or a mixture of the two.
The artificial blood vessel according to claim 1 or 2, which can be used for a small-diameter artificial blood vessel.
The artificial blood vessel according to claim 1 or 2, wherein the inner diameter is 6 mm or less.