JPS61263448A - Blood vessel prosthesis - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed Description of the Invention] [Field of Industrial Application] The present invention relates to a vascular prosthesis, and more specifically, χ is a new vascular prosthesis that has excellent long-term patency and is particularly applicable as a medium-diameter or small-diameter artificial blood vessel. relating to things.

[Conventional technology]

Generally, defects in the vascular system are corrected by suturing or anastomosing an artificial vascular prosthesis material obtained by removing the pathological portion.

One of the conditions for the successful acceptance of prostheses, such as artificial blood vessels, in living organisms is that the walls constituting the prosthesis are designed to allow living tissue to grow into the implanted artificial blood vessel prosthesis. It has porosity. Therefore, transplants such as artificial blood vessels,
It is generally a porous structure made of interwoven fibrous material that is permeable to water and consists of a flexible tube.

Because conventional artificial blood vessels have such a structure, when they are sutured or anastomosed to a blood vessel in a living body, an extremely thin intima is formed on the inner surface due to blood coagulation, and furthermore, due to the invasion of new blood vessels into the intima, , nutrition is permanently reinforced to the intima, and the organization of the intima progresses. That is, the wall of the artificial blood vessel needs to have appropriate porosity for the adhesion of thrombi and the infiltration of new blood vessels for organizing the intima formed on the inner surface of the artificial blood vessel.

This network structure is a macroscopic network (for example, a woven network of fibers) and is between 100μ and 1μ.

As artificial blood vessels with such porosity, artificial blood vessels made of woven or knitted polyester fibers and porous tetrafluoroethylene artificial blood vessels whose inner surfaces are fibrillated (fine fiber structure) by stretching are currently in practical use. It is provided.

[Problem that the invention seeks to solve]

These artificial blood vessels currently in practical use have a fairly high success rate when the inner diameter is relatively large.

Particularly in the case of vascular prostheses for arteries, when the inner diameter is approximately 7 cranes or more,
He is achieving good results.

Nevertheless, small internal diameter vascular prostheses are not clinically acceptable. In particular, the success rate when applied to veins is even worse than when applied to arteries. The blood velocity in veins is lower than that in arteries, and in artificial veins, it is particularly important to suppress the adhesion and aggregation ability of platelets in order to obtain antithrombotic properties, but this has not been fully satisfied.

When a suitably porous blood vessel is transplanted into an artery, significant blood leakage occurs in the early stages of transplantation due to the porosity. For this reason, it is necessary to pre-process so-called preclotting, in which the pores are filled with the patient's blood and clotted with blood. The inner surface of the transplanted artificial blood vessel is initially covered with a coagulated layer. This coagulated layer is made of fibrin, and its thickness varies depending on the material and surface structure of the blood vessel. Fibrin thickness when using polyester or tetrafluoroethylene artificial blood vessels is 0.5~
Arterial grafts with a diameter of 1011 or larger can actually be used with confidence, as there are concerns about long-term patency with artificial vessels with a smaller diameter, and the thickening of the fibrin layer may cause occlusion. It can only be used in arteries with a diameter of 5 to 6 mm or more, that is, an inner diameter of 5 to 6 mm.
Currently, the long-term patency results are not good.

It is also known that the patency success rate of venous vascular prostheses is far lower than that of arterial vascular prostheses, and there is currently no venous vascular prosthesis that can be used. Arterial artificial blood vessels with a diameter of 6 cm or less that can be put to practical use have not yet appeared. Requirements for artificial blood vessels are (1)-1: No toxicity, (2) No foreign body reaction, (3) Durability and no deterioration, (4)
) It has elasticity and extensibility, (5) It has antithrombotic properties, (6) It is suitable for organizing treatment, (7) It is easy to suture, (8) It can be made into various shapes, ( Although there are many performance requirements such as 9) low blood leakage and (10) sterilization, the most important requirement is that it should function as a blood vessel over a long period of time, that is, long-term patency.

[Means for solving problems].

The present inventors have conducted extensive research on methods for making vascular prostheses (including artificial blood vessels and vascular prosthesis patches) easier to handle and have excellent long-term patency through special processing, and have developed large-diameter vascular prostheses that are currently in the practical stage. This work succeeded in significantly improving the long-term patency of artificial blood vessels and paving the way for practical use in medium- and small-diameter artificial blood vessels, as well as in venous blood vessels.゛The present invention is characterized in that a crosslinked network of polysiloxane molecules is entangled with a water-soluble polymer or a water-swellable polymer to form an interpenetrating network structure on at least a part of the blood vessel contacting surface of the vascular prosthesis. In addition, a water-activated crosslinkable silicon-containing compound is mixed with a solution prepared by dissolving a water-soluble polymer and/or a water-swellable polymer in an organic solvent, and the resulting solution is used to form a vascular prosthesis. The present invention relates to a vascular prosthesis with good biocompatibility, characterized in that polysiloxane is formed by evaporating an organic solvent and causing a condensation reaction accompanied by crosslinking of a silicon-containing compound with moisture in the atmosphere.

The water-soluble or water-swellable polymers mentioned here include heparin, polyethylene glycol, polypropylene glycol, polyethylene glycol-polypropylene glycol copolymers, or block copolymers (A-B type, A-B-A type, etc.). ), polyvinylpyrrolidone, soluble collagen (atelocollagen), gelatin, polyacrylic acid, polymethacrylic acid, polyhydroxyethyl methacrylate,
Hydrophilic acrylic acid or its derivatives such as polyacrylamide and polymethacrylamide, as well as polyvinyl alcohol, 2-acrylamido-2-methylpropanesulfonic acid, diacetone acrylamide, alginic acid, water-soluble starch, methylcellulose, chondroitin sulfate (or its salt) , oxidized starch (dialdehyde starch), natural polysaccharide (
These include natural water-soluble polymers such as polysaccharides.

When using heparin in the present invention, it is necessary to modify the heparin so that it is soluble in an organic solvent. Heparin is usually commercially available as the sodium salt, which is insoluble in common organic solvents, so it is converted to a form that is soluble in organic solvents. Heparin easily forms salts with various quaternary ammonium compounds, and can be solubilized in a variety of solvents by selecting the ammonium compound to be used. Examples of quaternary ammonium compounds suitable for this purpose include tridodecylmethylammonium chloride, tricaprylmethylammonium chloride, cetylpyridinium chloride, cetyldimethylbenzylammonium chloride, benzalkonium chloride, alkylpicolinium chloride, etc. be able to. The present invention relates to a special processing treatment and vascular prosthesis in which a heparin derivative is used alone or in combination with a water-soluble polymer to entangle the crosslinked network molecules of polysiloxane to fully exhibit the antithrombotic function of heparin. Also included.

The biggest problem facing the practical application of small-diameter artificial blood vessels in vascular prostheses is occlusion due to the thrombus layer (~1 Tsuru) that occurs before the formation of the endothelial membrane and the thickening of the endothelial membrane. In order to prevent this, methods such as pre-treating the artificial blood vessel with physiological saline containing heparin or impregnating it as a complex (quaternary ammonium salt) with tertiary ammonium salt and heparin have been attempted, but the heparin molecule is easily leached out, and the effect of heparin only lasts for a very short period of time.On the other hand, if heparin molecules are chemically bonded to the blood contact surface by some chemical method to prevent heparin leaching,
It is known that chemical denaturation dramatically reduces the effectiveness of heparin. Therefore, it can be said that there is no excellent method for effectively immobilizing heparin molecules in the lumen of an artificial blood vessel.

The present inventor has conducted extensive research into methods for suppressing blood coagulation in artificial blood vessels, making the blood clot layer that forms on the surface as thin as possible, and minimizing the thickening of the endothelial membrane. Molecules are entangled in a network of polysiloxane molecules to create an interpene network structure (abbreviated as IPN).
trating PolymerNetworks
L,H,Sperling Encyclopeded
ia PolymerScience and
Technology, Supplement
Vo1, 1+288+ 1976 1ntersci
ence Publishers+ NewYor
The present invention was achieved by discovering that this objective can be achieved by producing k). The important thing here is to produce polysiloxane IPN, and for this purpose, the crosslinkable polysiloxane precursor must be a polysiloxane monomer or oligomer with 10 or less silicon atoms in the molecule. You have to be careful when shouting. Nagata, Iyoda et al.
In the method of No. 89), an interpenetrating network structure is not formed because an organosilicon polymer intermediate (high molecular weight) is used. In order to form an alternating intrusion network structure, it is essential to carry out a crosslinking reaction in a state in which the polymers are completely mixed, and when two or more types of polymers are mixed, they do not mix completely and macroscopically Even though they appear to be mixed at first glance, microscopic phase separation occurs microscopically.In other words, two or more types of polymers are not molecularly immiscible, but polymers with the same composition are microscopically aggregated. These micro-assemblies are mixed together to form an aggregate.

In order to ideally form an alternating infiltration network structure, molecules with crosslinkable functional groups, i.e., crosslinkable monomers or oligomers, are used, and these monomers or oligomers are crosslinked and condensed, and during condensation, coexisting polymer molecules are removed. The present inventors have discovered that it is better to grow a polymer while being entangled, and have made improvements thereto to arrive at the present invention. The inventor also has water-soluble animal bones.

He discovered that when entangled in an alternating penetrating network structure, it swells in water but becomes insoluble. Moreover, even if it becomes insoluble in water, it is entangled and insoluble, indicating that water-soluble polymers have undergone chemical denaturation. Since there is no such thing, its function has essentially not changed at all. Heparin exhibits conventional anticoagulant properties, and chondroitin sulfate and polysaccharides exhibit original antithrombotic properties. We have also discovered that propylene glycol and polyethylene glycol have the property of selectively adsorbing albumin in blood.

The present invention will be explained in detail below.

In the present invention, at least the blood-contacting surface of a vascular prosthesis is treated with an interleaving network structure in which a water-soluble polymer is entangled with a network of polysiloxane molecules.

As water-soluble polymers, water-soluble synthetic polymers and natural polymers are widely used, including the polymers already mentioned, but particularly preferred are polyethylene glycol, polypropylene glycol, and polyethylene glycol-polypropylene glycol copolymers. , polyvinylpyrrolidone, polyvinyl alcohol, gelatin, heparin, atelocollagen, chondroitin sulfate, polysaccharide (polysaccharide), and alginic acid-soluble heparin derivative. The present invention is characterized in that these water-soluble and/or water-swellable polymers are dissolved in an organic solvent, and the silicon compound used in the present invention is not a polymer but a monomer or oligomer (in the molecule). 10 or less, preferably 3 or less silicon atoms), and in order to form a polysiloxane having a network structure, 3 crosslinkable functional groups (hydroxyl groups) are removed by activation treatment.
A low-molecular silicon-containing cross-linking agent that produces more than 100% is used as an essential component.

Refers to a compound having at least 1 but not more than 10, preferably not more than 3 silicon-containing crosslinking agents in its molecule, and having a functional group that can generate crosslinking ability by an appropriate activation method,
Specifically, room temperature crosslinking agents for silicone rubber and silicone resin,
Known compounds known as silane coupling agents are widely used.

As these silicon-containing crosslinking agents, those having a functional group activated by water are preferably used. Typical examples of these are 9SiOCOR+9St 0R (R:~=
Hydrocarbons such as CH+, CzHs, CJt, C4Hq),
U5i-OX.

-) SiX (X: halogen such as Cl + Br), 5t-NR.

(R2 same as above) etc. A crosslinked silicon-containing polymer produced when such a silicon-containing crosslinking agent is used has a polysiloxane structure.

An example of a silicon-containing crosslinking agent having one silicon atom in the molecule that is activated by water to exhibit crosslinking ability and forms a polysiloxane crosslinked product is the general formula Rn5iR''4□ (wherein R is an alkyl group or an aryl group). A hydrocarbon residue such as a group, R
' represents an alkoxy group, an acyloxy group, a halogen or an amine residue, and n represents 0°1).

Specific examples include tetraacetoxysilane, methyltriacetoxysilane, ethyltriacetoxysilane, propyltriacetoxysilane, butyltriacetoxysilane, phenyltriacetoxysilane, methyltriethoxysilane, ethyltriethoxysilane, and tetraethoxysilane. , phenyltriethoxysilane, propyltriethoxysilane, butyltriethoxysilane, methyltrimethoxysilane, tetramethoxysilane,
Ethyltrimethoxysilane, propyltrimethoxysilane, butyltrimethoxysilane, or tetrachlorosilane, methyltrichlorosilane, ethyltrichlorosilane, butyltrichlorosilane, vinyltriacetoxysilane, bis-(N-methylbenzylamide)ethoxymethylsilane, tris -(dimethylamino)methylsilane, vinyltrichlorosilane, tris-(cyclohexylamino)methylsilane, vinyltriethoxysilane,
Typical examples include T-glycidoxypropyltrimethoxysilane, tetrapropoxysilane, and divinyljethoxysilane.

In addition, typical examples of silicon-containing crosslinking agents containing two silicon atoms in their molecules include, for example, tetraacetoxydisiloxane, 1
．． 3-dimethyltetraacetoxydisiloxane, 1.3
- general formula RnR3-n ”Si OSiRm R' such as -divinyltetraethoxydisiloxane
3-11 (in the formula nSm=0.1.2.3, n+m=
0.1.2゜3, R is a hydrocarbon residue without crosslinking ability, and R' and R'' are groups that exhibit crosslinking ability by appropriate activation means). .

Examples of silicon-containing crosslinking agents containing three silicon atoms in their molecules include 1.3.5-) liftoxy-1,1,3,5,5-pentamethyltrisiloxane, 1.1,3.3.5. Examples include 5-hexaacetoxy-1,5-methyltrisiloxane.

As these silicon-containing crosslinking agents, known room temperature crosslinking type silane coupling agents are widely used, such as Petrar.
Catalog Silic published by ch System Inc.
onCompounds, Register & Re
view (91979 and the company's 5 ilicones)
All silicon-containing crosslinking agents described in 01981 can be used.

In addition to the crosslinking (i.e., trifunctional) silicon-containing compounds mentioned above, a low-molecular silicon-containing compound that sequentially forms St-0-Si bonds through bifunctional condensation to produce polysiloxane is used in combination. Of course you can do that. Such bifunctional silicon-containing compounds have two hydrocarbon groups on the silicon atom and two functional groups in the molecule that are activated by water to generate crosslinking ability, such as compounds with the general formula ( r)
R+ R3 Y −Si +O−Si+−, Y′ −−−−−−
---------・------(I)Rz Ra (wherein R1 to R4 are the same or different hydrocarbon groups, n is 0
, 1.2.3, etc.; Y and Y' represent the same or different water-activated crosslinkable functional groups, respectively). Examples of these compounds that contain two non-crosslinking hydrocarbon groups on the silicon atom and two crosslinking functional groups in the molecule include dimethyldiacetoxysilane, diethyldiacetoxysilane, and dimethyljetoxysilane. , diethyljethoxysilane, methylethyldimethoxysilane, diethyldimethoxysilane, dimethyheldichlorosilane, methylphenyldiacetoxysilane, diphenylacetoxysilane, dibenzylacetoxysilane, divinyljethoxysilane, 1.1.3.3-tetramethyl- 1,3-diacetoxysilane, 1.1.3.3-tetramethyl-1,3-dimethoxysilane, 1.1.3.3-tetraethyl-1,
3-Jethoxysilane, 1.1.3,3.5.5-hexamethyl-1,5-diacetoxysilane, 1.1,3.
3,5.5-hexaethyl-1,5-jethoxysilane, 1.1.3.3,5.5-hexamethyl-1,5-dimethoxysilane, 1.1.1.5.5.5-hexamethyl -3,3-diacetoxysilane, 1.1.1,3.5
．． Examples include 5-hexamethyl-3,5-diacetoxysilane.

In any case, it is necessary for the silicon-containing compound used in the present invention to be uniformly dissolved in the system; - 10 silicon atoms in the molecule;
It is desirable that the number of silicon atoms be less than 1, preferably 3 or less. If there are many silicon atoms (if the molecular weight is high), uniform dissolution becomes difficult. This is an important matter for forming a preferable interpenetrating network structure.

In the present invention, the term crosslinkable silicon-containing compound includes a mixture of a silicon-containing crosslinking agent having a trifunctional or higher converting group and a silicon-containing compound having a bifunctional condensation ability.

In order to form at least the inner surface of the vascular prosthesis of the present invention into a network structure in which the hydrophilic polymer of the present invention is alternately impregnated, a processing solution for processing is first prepared. The swelling polymer is dissolved in an organic solvent to form a uniform solution, and the above-mentioned crosslinkable silicon-containing compound is added to this solution to form a uniform solution. Add an appropriate amount of water to this solution to partially activate the silicon compound to a certain extent and allow the crosslinking reaction solution to cross between the coexisting water-soluble or water-swellable polymers to the extent that gelation does not occur. good.

Silicon-containing compounds generate silanol when they react with water, but because they are low molecules and the resulting hydrophilicity -〇H, they mix freely with water-soluble polymers in an aqueous medium, and in that state, there is no interaction between silicon-containing compounds. The condensation reaction proceeds, forming a solution while entangling the water-soluble polymer. When a vascular prosthesis is treated in advance with a solution in which the initial alternating penetration network precursor is prepared, a condensation reaction accompanied by further crosslinking proceeds in the treated vascular prosthesis, resulting in a more complete alternating penetration network. It can be structured.

An important feature of this treatment solution is that the polysiloxane produced by condensation and the water-soluble or water-swellable polymer do not, in principle, chemically react with each other, but are entangled in molecules. Up to now, attempts have been made to coat water-soluble polymers such as gelatin and cross-link them with formaldehyde or glutaraldehyde to make them insoluble in water. It crosslinks by reacting with gelatin, a water-soluble polymer, and the crosslinking incorporates the gelatin molecules themselves.

When the solution of the present invention is applied, the solvent evaporates, the concentration increases, and moderate microphase separation occurs, but the water-soluble or water-swellable polymer and condensed polysiloxane are entangled, and they absorb moisture from the air. The silicon-containing compound is gradually activated, and over time, bonding and crosslinking progress, resulting in a crosslinked structure in which the polysiloxane is also insoluble, and the water-soluble polymer and water-swellable polymer are entangled in this network. What is interesting is that a water-soluble polymer or a water-swellable polymer is used, but since no water is used, the polymer is applied without being swollen at all. That is, a water-soluble or water-swellable polymer is surrounded by hydrophobic polysiloxane and exists in a non-swollen state within the tissue of an artificial blood vessel, the fibrils of a PTEF artificial blood vessel, or the porous pores of a polyurethane blood vessel. This is very important. That is, when physiological saline or blood comes into contact with these blood vessels, both water-soluble polymers and water-swellable polymers absorb water and swell, blocking the pores and preventing blood leakage. The present invention has an important significance in that the water-soluble polymer generated only in the crosslinked polysiloxane molecules is insolubilized by physical entanglement. In this method, the water-soluble polymer is not chemically denatured, so if the water-soluble polymer is heparin or gelatin, for example, it will be immobilized and insoluble, but its original performance and biocompatibility will be completely lost. Moreover, these compounds are not encapsulated in the polysiloxane network but are intertwined, so that when they come into contact with blood, these molecular chains become hydrated and can move freely. It is. In other words, the water-soluble or water-swellable polymers entangled in such interpenetrating network molecules do not flow out into the blood stream, but are present in high concentration on the surface of the vascular prosthesis. What is important here is that the polysiloxane produced by condensation becomes hydrophobic and forms a hydrophobic-hydrophilic micro-heterogeneous structure with the entangled water-soluble polymer, and this structure is similar to the structure of the blood vessel walls of living organisms. It is very similar to the microstructure,
The present inventor believes that it greatly contributes to biocompatibility and antithrombotic properties.

Moreover, water-soluble polymers also swell in water but do not dissolve, so they prevent blood leakage to an appropriate extent and eliminate the need for pre-clotting. These polymers will eventually be absorbed into the body and blood vessels will be covered with endothelial cells.

In the present invention, entangling soluble heparin in the chain molecular structure network of polysiloxane molecules prevents the formation of blood clots on the blood-contacting surface of the vascular prosthesis, or significantly retards the speed of formation of a blood clot film, or It is highly effective in significantly reducing the thickness of blood clot membranes, and the entangled polymer compounds have a high affinity with living organisms and promote the growth of endothelial cells.

Vascular prostheses whose blood-contact surfaces are treated with water-soluble polymers or water-swellable polymers (both hydrophilic) entangled with polysiloxane network molecules (hydrophobic) are unlikely to cause thrombi. , even if a thrombus membrane is formed, it takes a very long time;
Moreover, the thrombus membrane is thin, and although it takes time to generate the endothelial membrane, there is no growth of the thrombus during that time, and there is no thickening of the endothelial membrane.Therefore, the practical use of small-diameter artificial blood vessels, which has long been the subject of much debate, has been improved. It paved the way. In addition, the water-soluble polymer that helps prevent blood leakage is absorbed by the living body over time and is finally completely biotransformed. Water-soluble polymers with good bioabsorption include polyvinyl alcohol, polyethylene glycol, polysaccharide, chondroitin sulfate, atelocollagen, gelatin, and alginic acid.

Atelocollagen used in the present invention is originally insoluble collagen treated with pepsin to make it soluble, and like gelatin, it originally exists in living organisms.
Moreover, there is no antigen-antibody reaction.

These natural compounds are believed to have a beneficial effect on the production of endothelial membranes.

Polyethylene glycol or its copolymer, polyvinylpyrrolidone, used in the present invention has the special property of selectively adsorbing albumin from blood, and the adsorbed albumin plays an important role in providing antithrombotic effects. It has the property of imparting flexibility, and the vascular prosthesis after treatment is extremely flexible, easy to handle, and easy to suture to living tissues such as blood vessels. To provide flexibility, polyethylene glycol must be in liquid form (molecular weight 60
0 or less) is most effective, but spiral-shaped ones (molecule i 1800-1500) and flake-shaped ones (
(molecular weight 1,600 to 3,000) can also be used. Polyvinyl alcohol has a molecular weight of 300-5000
It is preferable that the saponification degree is 95% or more.

Polyvinyl alcohol is preferably used because it does not cause any abnormal reactions in living organisms and has good biocompatibility. Polyvinylpyrrolidone is also used as a plasma substitute, and preferably has a molecular weight of 300 to 10,000. Further, highly water-swellable polymers such as diacetone acrylamide polymer, poly-2-acrylamide-2-methylpropanesulfonic acid (or its salt) polyhydroxyethyl methacrylate, and polyhydroxyacrylate are also preferably used. These water-soluble polymers or water-swellable polymers exist intertwined with polysiloxane networks in the pores of the vascular graft tissue, and when they come into contact with water, they swell and spread into the pores of the vascular graft tissue, forming a gel-like structure. Therefore, it effectively prevents blood leakage, and exhibits the surprising characteristic that it does not cause thrombi because it selectively adsorbs albumin in the blood and converts it into a protobiotic.

Artificial blood vessels that can be applied to the present invention are not particularly limited, but include vascular prostheses made of polyester fiber knitted fabrics, fluororesin systems treated with stretch fibrillation, and so-called E P
T F E (Expanded Pobytet
rafluorEhylene) and polyurethane vascular prostheses are used. The present invention can also be applied to other types of artificial blood vessels, such as woven vascular prostheses made of collagen fibers, artificial blood vessels using parts of animal living bodies such as pig urethral tissue, artificial blood vessels using animal arteries, and human blood vessels. It can also be applied to those using sea bream vein vessels. Vascular prostheses include artificial blood vessels, heart patches, cardiovascular patches,
This includes peripheral vasculature patches.

The treatment method is to fully immerse the vascular prosthesis in the treatment solution of the method, bring the surface of the vascular prosthesis into sufficient contact, and then edit the vascular prosthesis.
It is sufficient to sufficiently wet the IA mesh or the fibrillated thin fiber portion and dry it. The organic solvent evaporates during drying, while the silicon compound absorbs moisture from the air and undergoes condensation polymerization, including a crosslinking reaction, to form a crosslinked product of insoluble polysiloxane molecules, entangling water-soluble or water-swellable polymers. The processing of the present invention is completed. Furthermore, before this immersion, glow discharge or high-frequency unipolar spark discharge may be performed in advance to increase the affinity between the treatment liquid and the inner surface of the vascular prosthesis. As the solvent evaporates, the polymer and siloxane components used are concentrated, and the condensation and crosslinking reaction proceeds to gradually complete the molecular network, completing the processing of the present invention. Processed vascular prosthesis is fluororesin-based PT
In the case of FE or polyurethane, the treated surface is treated in advance with a water-soluble organic solvent such as tetrahydrofuran, acetone, alcohol, etc. in order to reduce its hydrophobicity, and the treated surface is wetted with these solvents before the treatment of the present invention is performed. Processing is preferable because it can be applied evenly to the surface of the vascular prosthesis.

[For production]

As already described in detail, the features of the present invention are, firstly, that the formation of a thrombus membrane in the vascular prosthetic fabric is delayed and the formed membrane is thin, and secondly, that the endogenous membrane is thin and does not thicken. Therefore, the third feature is that the small-diameter artificial blood vessel maintains its patency over a long period of time, and the fourth feature is that with this processing, there is almost no blood leakage during formation (conventional so-called pre-clotting is not required). Fifthly, because the fibers of the knitted fabric adhere to each other through this processing, it has characteristics such as no fraying of the fibers. In the present invention, conventional polyester fibers require porosity in order to promote endothelial membrane formation, and on the other hand, this porosity causes blood leakage, and to prevent this, it is treated with patient's blood before treatment. Pre-clotting, which involves clotting the hole with the patient's own blood, was considered essential. In the present invention, water-soluble polymers are insolubilized by molecular entanglement, so these water-soluble molecules do not elute, but absorb water and swell, thereby preventing blood leakage and eliminating the need for pre-clotting. This point alone has great significance.

Hereinafter, the present invention will be explained in more detail using specific examples, but these examples do not limit the scope of the claims in any way.

Example 1 Preparation of alternately infiltrated network polymer solution 1-(1) Polyethylene glycol (molecular weight 6000) was dissolved in tetrahydrofuran, and a 35% solution was prepared with vigorous stirring at room temperature.
A 30% solution of triacetoxysilane was carefully added dropwise. The weight ratio of polyethylene glycol to triacetoxysilane is 3/2. After the dropwise addition was completed, stirring was continued for another hour, and the resulting solution was designated as the prepared solution (1-(1)).

Preparation of Alternately Penetrated Network Polymer Solution 1-(2) Polyvinyl alcohol (degree of polymerization 1800, degree of saponification 99.8%) was made into an 18% dimethyl sulfoxide solution. A mixture of tetraacetoxysilane and diacetoxydimethylsilane (40% by weight based on the polyvinyl alcohol used) was maintained at 35°C.
8: A dimethyl sulfoxide solution of 2) was carefully added dropwise.

The solution is a clear clear liquid. Add this to the prepared solution (1-(2
)).

Preparation of alternately infiltrated network polymer solution 1-(3) Preparation solution (1
-(1)) was added with water equivalent to 2%, stirred occasionally, and aged for one week. The appearance of the solution was a transparent solution with almost no change in appearance. This was used as a prepared solution (1-(3)).

, - Preparation of alternating infiltration network polymer solution 1-(4) to (7)
A tetrahydrofuran solution of polyvinylpyrrolidone, atelocollagen, and polyethylene glycol-polypropylene glycol block copolymer was prepared, and a tetraethoxysilane-jethoxydimethylsilane mixture (1: 2
) was added dropwise and stirred at 35°C for 3 hours. The solutions prepared in this way were prepared as solutions 1-(4) and 1-(5), respectively.
, 1-(6), 1-(7).

Example 2 Preparation of alternating infiltration network polymer solution 2- (1) Into a 10% aqueous solution of 3.6 g of commercially available heparin sodium salt (164 units/■), 5% of 7.4 g of cetylpyridinium chloride was added.
The aqueous solution was added with stirring, and the resulting white precipitate was isolated and purified by centrifugation, repeated washing with water, freeze-drying, and drying over phosphorus pentoxide under vacuum for 2 days to give 9.3 g of heparin cetylpyridinium salt. I got it.

10 parts by weight of heparin cetylpyridinium salt in dichloromethane? Maybe 4%? Add a mixture of methyltriacetoxysilane and dimethyldiacetoxysilane (
1:12 parts by weight of 2) were added to obtain a homogeneous solution. This solution was designated as a prepared solution (2-(1)').

Reference Example 1 Preparation of heparin-containing solution - Reference solution (R 10 parts by weight of the heparin cetylpyridinium salt obtained in Example 2 was dissolved in dichloromethane to make a 4% solution, and Shin-Etsu Chemical's liquid room temperature curing silicone rubber KE42RTV6 was added to this solution.
Parts by weight were added and stirred vigorously. The silicone rubber liquid used did not dissolve in dichloromethane and was dispersed as fine particles. If left undisturbed, the silicone rubber liquid will separate into two layers without melting. A reference solution (R-1) was prepared by stirring vigorously before use.

Alternate infiltration network polymer solution 2- (2) Dissolve an 80:20 mixture of polyethylene glycol (flake form) with a degree of polymerization of 20,000 and polyethylene glycol (liquid form) with a degree of polymerization of 500 in dichloromethane to give 8%
It was made into a solution. Heparincetylpyridinium salt corresponding to 30 times more polyethylene glycol was added to this and mixed well to form a homogeneous solution. Tetraacetoxysilane was added in an amount of 80% by weight based on the polyethylene glycol used, and the mixture was stirred. Prepare this solution (2-(2))
shall be.

Preparation of alternate infiltration network polymer solution 2-(3) Gelatin was dissolved in dimethylformamide to a concentration of 1.0%. The procedure was the same as the above example, except that methyltriacetoxysilane-dimethyldiacetoxysilane (3:7) was added in the same amount as gelatin to make a homogeneous solution, which was then prepared as a prepared solution (2-(3)). The obtained solution is referred to as a prepared solution (2-(3)).

Preparation of alternately infiltrated network polymer 2-(4) Same as 2-(1) except that dimethylformamide mixture was used as the solvent. The prepared solution in this example is referred to as 2-(4).

Example 3 Preparation of alternate infiltration polymer solution 3-(1)(1)
Polyvinyl alcohol pyrrolidone (molecular weight 40,000
) 5%, polyethylene glycol (degree of polymerization 1300)
Tetraethoxysilane was added in an amount 3 times the weight of the polymer to a dioxane solution containing 5%, and the mixture was vigorously stirred at 40°C to obtain a homogeneous solution (prepared solution 3-(1)). This solution remained quite stable even after two months.

(2) 1% polyethylene glycol with a molecular weight of 60,000
, an ethyl acetate-tetrahydrofuran (1:2) solution containing 5% polyvinylpyrrolidone with a molecular cap of 3600 QO was prepared, and a triacetoxysilane-diacetoxydimethylsilane mixture (7
: Add the tetrahydrofuran solution of 3) dropwise while stirring,
A homogeneous solution was obtained, and 0.5% water of the system was added thereto and thoroughly stirred.

The solution remained transparent even after 2 weeks with no change in appearance (prepared solution 3-(2)'').

(3) Polysaccharide 7% with degree of polymerization 800, molecular weight 6
A dioxane solution of a tetraacetoxysilane-diacetoxydimethylsilane (1:1), -4 mixture was added to a dimethylacetamide solution containing 5% of polyethylene glycol 0,000 and stirred to obtain a homogeneous solution (prepared solution 3). - (3)”).

(4) A dimethylformamide solution containing 1.5% of a mixture of ceratin and atelocollagen (1:1) and 5% of polyethylene glycol was kept at 60°C to make a homogeneous solution, and a mixture of tetramethoxysilane-trimethoxysilane (6%) was added to this solution. : 4) was added and stirred at 50°C to obtain a homogeneous solution (prepared solution 3-(4)).

Example 4 Processing - Polyester artificial blood vessel inner diameter 1
On, 4 m, 3 m, and 2 m of polyester fiber (tetron [phase] plain weave artificial blood vessels with bellows processing were prepared.

The fabric of this artificial blood vessel is woven from 0.3 d polyethylene terephthalate long fibers, and the porosity is 120 (ml/ml).
crl/120 n+j? Hg).

These artificial blood vessels were immersed in each treatment solution prepared in Example 1.2.3 for 5 to 10 minutes, and the lumen of the artificial blood vessels was evenly crushed so that the solution moved from the inside to the outside. I forced it. The treated artificial blood vessels were air-dried.

Example 5 Processing - Polyurethane artificial blood vessel Medical grade polyether polyurethane was dissolved in tetrahydrofuran to make a 24% solution and a tube was made by a wet method. This tube has a membrane wall with a sponge-like structure. The inner diameters of the polyurethane artificial blood vessels prepared in this manner were 3 + u and 10 mm. Using these, the inner surface of the blood vessel is immersed in the treatment solution prepared in Example 1.2.3, and the polyurethane artificial blood vessel is pulled moderately or gently so that the treatment solution spreads into the sponge voids of this polyurethane artificial blood vessel. Make sure that the treatment liquid comes into sufficient contact with each fine fibril by pressing down. The treated artificial blood vessels were air-dried.

Example 6 Using the artificial blood vessel processed in Example 4, transplantation of the artificial blood vessel was carried out in 10 cases in each mongrel adult human by connecting one end to the iliac artery, and the results are summarized below. Ta.

Experiment Artificial blood Transplant location Processing place 3 pieces 6 pieces 1st grade Pipe diameter Slow wave ′ After After (1)
4fi iliac artery 1- (1) ◎ ◎
◎(2) 4 fl Same as above 1-(2)
◎ ◎ 0(3) 4 tm Same as above 1-(3) ◎ ◎ ◎(4)
4 ini Same as above 1-(4) ◎ ◎
◎(5) 4th seal Same as above 1-(5) ◎
◎ 0 (6) 4 wheels Same as above 1-(6) ◎
◎ ◎(7) 4m weight Same as above 1-(7
) ◎ ◎ ◎ (8) 3 m east femoral artery 2- (1) ◎ ◎ 0 (9)
3chem Same as above 2- (2) ◎ ◎
◎(IO”) 3 dragons Same as above 2- (3)
◎ ◎ ◎(11) 2 dragons Same as above
2- (1) ◎ ◎ ○(12) '
2m Same as above 2- (1) ◎ ◎ 0
(13) 2mm Same as above 2- (1)
◎ ◎ ○(14) ' 2 vm Same as above 3- (1) ◎ ◎ ◎(15)
2 points Same as above 3- (2) ◎ ◎ ◎
(16) 2 mm Same as above 3- (3)
◎ ◎ ◎(17) 211 Same as above
R-I X X X (18) 3
n+ Same as above R-1-OXX(19) 3 cranes Same as above (-) (-) (-)<
20) 2n+ Same as above, + (-)(
-)(-)080% or more patency, 060% or more patency,
× Closed patency 60% or less, (-) Totally closed Example 7 The results of transplanting the three dragon vessels prepared in Example 5 into the femoral artery of a mongrel adult are shown below. Ten cases each were performed.

Treatment liquid Number of patent cases: 3 out of 10 cases 1
11 R-(1) 4 2l-(
1) 9 9
l-(2) 8
8l-(3) 10
10l-(4) 9
8l-(5)
9 9l-(6)
1 0 10l-(7)
9 8\\, - 2~(4) 9
8100 * Untreated Example 8 Commercially available punches made of Dacron fabric and Teflon felt were treated with treatment liquids 2-(1), 2-(2), and 3-(1), respectively.
) and prosthesized into the descending aorta of an adult mongrel. Try taking it out after 3 months. There was almost no thrombus and the endothelial cells were immature.

On the other hand, those that were not treated were completely covered with thrombus, and endothelial cells were growing, but the thickness reached about 1 m.

In addition, for short-term comparison, we conducted an experiment under exactly the same conditions and compared the specimens taken out after one week, and found that the untreated specimens had clots all over them, but the specimens treated as described above had no thrombi at all. I couldn't see it.

Comparative Example 2 Using an artificial blood vessel (4 mm manufactured by Dacron) treated with the 2-(1) solution of Example 2 and the Reference Example R-1 solution, the amount of heparin shed was examined at a flow width of 37°C. The data collected over time is summarized as follows.

2-(1) 12% 26% 26% 29% 29
% 31% 34%R-(1) 39% 42% 5
3% 60% 74% 93% 97%R-(1) is I
Since the pH is not reached, 90% of heparin will flow out after one month, but it has been shown that 2-(1) forms IPN, so heparin is retained for a long time.

Claims (1)

[Scope of Claims] 1. A solution obtained by dissolving a water-soluble and/or water-swellable polymer compound in an organic solvent is activated with water to form a polysiloxane by a condensation reaction. A crosslinkable silicon-containing compound having the following silicon atoms is added, and a vascular prosthesis is treated with the resulting solution to produce a crosslinked polysiloxane and an aqueous solution and/or water-swellable polymer made insolubilized by the crosslinked polysiloxane. A vascular prosthesis, characterized in that the composition is formed on the vascular prosthesis. 2. A patent claim characterized in that the vascular prosthesis is treated after adding a predetermined amount of water to an organic solution containing a water-soluble and/or water-swellable polymer compound and the crosslinkable silicon-containing compound. The vascular prosthesis according to item 1.