JPS6397158A - Artificial blood vessel - Google Patents

Abstract

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

Description

[Detailed Description of the Invention] [Objective of the Invention] (Industrial Application Field) The present invention relates to a new artificial blood vessel, and more specifically, to a new artificial blood vessel that has excellent durability, easy suturing properties, and exhibits reversal patency. Regarding the great blood vessels.

(Prior art) Conventionally, artificial blood vessels have been made from polyethylene terephthalate, which is spun to create a tube-like shape by knitting and weaving polyester polymer fibers. Polytetrafluoroethylene is molded into a tube shape and stretched to form fibrils (fine fibrous structure).
(hereinafter referred to as fluororesin-based artificial blood vessels) have been used. When these are used as blood vessel substitutes, since the structure of the tube wall is porous, there is an advantage that cells can infiltrate and grow in the gaps and become living organisms.

(Problems to be Solved by the Invention) When both conventional artificial blood vessels made of polyester fibers and artificial blood vessels made of stretched polytetrafluoroethylene are transplanted into a living body, a blood clot layer first forms on the inner surface that comes into contact with surface fluid. occurs, and cells proliferate in this -I- to form an endothelial membrane, which becomes an antithrombotic intima. In this way, an artificial blood vessel can only serve as a biological substitute when the inner wall of the blood vessel becomes a living body, but the thickness of the blood clot layer that initially forms reaches 1 mm to 1.5 mm, and the endothelial membrane forms. Thickening of this endothelial membrane can be seen over time even after treatment.

For this reason, after transplantation as a blood vessel, stenosis of the inner diameter usually occurs, and those with an inner diameter of 6 mm or less cannot be practically used. Artificial blood vessels that can actually be safely used have current performance values of less than r+7 yen 1011 IInH.

For those with an inner diameter of 10 mm to 61I1 m, the inner diameter gradually becomes narrower over time, and the patency rate after 3 years is 60 to 70%.

Currently, human T-plane tubes with an inner diameter of 6 mm or less do not have long-term patency, and in particular, there are no tubes with a diameter of 4 mm or less that can be put to practical use.

Coronary artery bypass surgery, which is performed to save patients suffering from heart failure due to coronary artery stenosis, involves removing the own saphenous vein and using it exclusively, but some people use an appropriate saphenous vein. Veins may not be available.

Fortunately, even if the patient's own saphenous vein is extracted and utilized and the coronary artery bypass surgery is successful, the patency rate is said to be 60-70% after 5 years, based on the cumulative results so far, and the patency rate is 30-30%. 4
0% of people will have to undergo another surgery after 5 years.

In this case, it is difficult to save the patient's life because there is no longer a saphenous vein available.

In order to save these people, the inner diameter must be 4+l1f.
There is a need for an artificial blood vessel with excellent patency of fl to 3+ m, but despite over 10 years of strenuous development efforts by researchers around the world, there has been no successful development of a small-diameter artificial blood vessel that can be put to practical use. .

The cause of this failure is the occlusion of the transplanted artificial blood vessel, and this occlusion includes occlusion due to blood clots, panus (growth mass) occurring at the anastomosis, and stenosis (stenosis) occurring near the anastomosis (=j). Many things are caused by this.

The basic performance required for artificial blood vessels is wide-ranging, but the most strongly desired ones at present are: - Mechanical properties that are sufficient for practical use and do not deteriorate in vivo, - Good biocompatibility, and - Resistance. Excellent thrombogenicity, no stenosis or occlusion, ■Easy to handle, especially good sutureability, ■Easy frk property, ■Abnormal morphological changes such as 11 diameter increase due to arterial pressure during use. For example, there is no such thing.

Considering small-diameter artificial blood vessels, in order for them to be put to practical use, it is important to suppress the formation of initial thrombus that forms on the inner wall of the vessel after transplantation, and to suppress the thickening of the endothelial membrane.
The following artificial blood vessels will be difficult to put into practical use unless this is achieved.

On the other hand, renal failure patients receiving dialysis therapy puncture their own blood vessels with catheters to lead or introduce blood outside the body each time they receive treatment, but this catheter insertion needle has an outer diameter of 1.5 mm.
Since the diameter is approximately 5 mm, the damage to the autologous blood vessels caused by puncturing an average of three times a week is severe, and long-term dialysis patients require the creation of a shunt using an artificial blood vessel. In this case, the inner diameter is 5111111
Artificial blood vessels of ~6 mm are used, but as mentioned above, more than 30% of these diameters become unusable within several months after transplantation due to problems such as thrombus formation, clot layer hypertrophy, stenosis, or occlusion. In addition, the thrombus layer formed on the inner wall of the transplanted artificial blood vessel and the grown endothelial cells are peeled off and scattered into the blood every time the graft is punctured, causing various troubles. In order to overcome this situation, it is necessary to reduce the thrombus layer that forms on the inner tube, and it goes without saying that an artificial blood vessel that does not produce any thrombus layer is ideal.

The present inventors have conducted various studies with the aim of developing small-caliber artificial blood vessels and venous artificial blood vessels by preventing the formation of this initial thrombus and promoting biologicalization by some method, and as a result of the present invention. Reached.

The inventors investigated various methods of using heparin to impart antithrombotic properties under severe conditions, but found that the activity of heparin was drastically reduced when chemical changes were made. The present inventors investigated a method of making heparin present on the blood contact surface of an artificial blood vessel without relying on chemical methods, and arrived at the present invention. The present inventors developed an antithrombotic substance using an interleaved network structure (I PN :In
Terpenetrating Polymer Ne
I thought about using tworks). However, it is extremely difficult to form an infiltrated network (IPN) in the heparin intersections 7. The reason is that the interleaved network structure (IP
In order to form N), it is necessary to carry out a crosslinking reaction of the uniformly existing crosslinkable heptamer in the presence of the polymer to be entangled, and a substance that is only soluble in water, such as heparin, is subjected to such conditions. It cannot be set below. This is because heparin is only soluble in an aqueous system, and on the other hand, it is stable and uniformly mixed with heparin in an aqueous system, and there is no monomer that polymerizes while forming crosslinks through activation treatment.

[Structure of the Invention (Means and Effects for Solving the Problems) The artificial blood vessel of the present invention has heparin built into the wall of the artificial blood vessel, and a large number of holes in the lumen surface area communicating with the heparin built-in part. or a water-swellable polymer layer sealing the voids or voids, wherein the water-swellable polymer layer is a water-soluble or water-swellable polymer or a water-soluble or water-swellable polymer layer that seals the voids or voids.
1. It has an alternating interpenetration network structure in which a polymer containing a 1.1 lubricant chain as a segment is intertwined with a crosslinked silicon compound.

The artificial blood vessel used in carrying out the present invention may have a porous inner wall.

The porous material mentioned here may be spongy or a continuum of vacuole groups, or may be made by knitting and weaving conventional polyester polymer fibers, or by stretching polytetrafluoroethylene into fibrils. It may also be an aggregate of fibrous substances.

Particularly preferred is an artificial blood vessel made of polyurethane or polyurethane urea whose tube cross section is spongy or has a group of continuous vacuoles. When the inner surface of the artificial blood vessel of the present invention is coated with the polymer composition of the present invention, in the case of a polyurethane artificial blood vessel, in order to prevent the coated film from peeling off,
It is desirable that there be no skin layer on the inner surface, since in this case the coated polymer composition can be stably maintained.

In carrying out the present invention, it is necessary for the heparin molecules within the inner wall of the artificial blood vessel to migrate to the surface because the heparin present inside the wall of the artificial blood vessel is diluted through the barrier of the water-swellable polymer layer having an IPN structure. Needless to say, the wall of the porous cross-section of the tube must have enough channel pores for heparin molecules to migrate together with water at least to the inner surface of the artificial blood vessel forming the lumen. Polyester with an aggregate or fibrillated structure of fibers m! Of course, dt and expanded polytetrafluoroethylene tubes satisfy this condition, but the present inventors have developed an artificial blood vessel made of polyurethane, which has a porous inner wall and has excellent compliance as a material. I got it.

In general, when an artificial blood vessel is transplanted, stenosis (stenosis) occurs in the host blood vessel at the suture site.The artificial blood vessel is more rigid than the host blood vessel, and lacks compliance to adapt to the pulsatile flow. The present inventors believe that the jet of blood flow abnormally stimulates the host blood vessel wall near the suture site A1, and in response, the host blood vessel wall thickens as a biological reaction. Polyurethane artificial blood vessels are
It has suitable compliance and is therefore particularly suitable for carrying out the present invention.

Examples of water-soluble or water-swellable polymers used in the present invention include polyethylene glycol, polypropylene glycol or copolymers thereof, hyaluronic acid, polysaccharide, chitosan, polyvinylpyrrolidone, atelocollagen, gelatin, polyacrylic acid, Examples include polymethacrylic acid, polyacrylamide, polydiacetone acrylamide, poly-2-acrylamido-2-methylpropanesulfonic acid, polyvinyl alcohol, or copolymers containing bipedal polymers.

Examples of polymers containing water-soluble or water-swellable buttons as segments in the molecule include polyurethanes and polyurethane ureas having polyethylene glycol chains, polypropylene glycol chains, or ethylene oxide-propylene oxide copolymer buttons in the soft segment; Examples include copolymers of polydimethylsiloxane and polyolefin glycol as shown in .

CH3CH3 CH3CH3 CH2CH20+CH2CH20 These hydrophilic polymers may be used alone,
Also, two or more types may be used. Further, the above-mentioned hydrophilic polymer may be used in combination with a relatively hydrophobic polymer to form a composition.

For example, a composition in which a polyurethane urea whose soft segment is composed of relatively hydrophobic polytetramethylene oxide, a combination of polyurethane and polyethylene glycol, polypropylene glycol, polyvinylpyrrolidone, or a polyurethane whose soft segment has a polyethylene oxide chain is used. You can.

The crosslinkable silicon compound used in the present invention is activated by water to form a crosslinked network. The above crosslinkable silicon compound is not a polymer but a monomer or oligomer, and in order to form a polysiloxane having a network structure, 3T of crosslinkable functional groups (hydroxyl groups) are removed by activation treatment. A low-molecular silicon-containing crosslinking agent such as that produced above is used as an essential component.

The term "silicon-containing crosslinking agent" as used herein refers to a compound that has one or more silicon atoms in its molecule and has a functional group that can generate crosslinking ability by an appropriate activation method.

Specifically, room temperature crosslinking agent 1 for silicone rubber and silicone resin.
Known compounds known as silane coupling agents are widely used.

Representative examples of the functional groups of these silicon-containing crosslinking agents include S
i 0COR, S i OR (R: CH3.

Hydrocarbons such as C2H5+ C3H7+ Ca Hs)
.

Examples include S 1-OX, SiX (X: halogen such as C1 and Br1t), and 5t-NR2 (R: same as above). A crosslinked silicon-containing polymer produced when such a silicon-containing crosslinking agent is used has a polysiloxane structure.

Examples of silicon-containing crosslinking agents that exhibit crosslinking ability when activated by water and have one silicon atom in the molecule to form a crosslinked polysiloxane include the general formula % (where R is an alkyl group, aryl There are compounds represented by a hydrocarbon residue such as a group, R' is an alkoxy group, an acyloxy group, a halogen or an amine residue, and n is 0°1.

Specific examples include tetraacetoxysilane, methyltriacetoxysilane, ethyltriacetoxysilane, propyltriacetoxysilane, butyltriacetoxysilane, phenyltriacetoxysilane, methyltriethoxysilane, ethyltriethoxysilane, and tetraethoxysilane. , phenyltriethoxysilane, propyltriethoxysilane, butyltriethoxysilane, methyltrimethoxysilane, tetramethoxysilanerimethoxysilane, butyltrimethoxysilane or tetrachlorosilane, methyltrichlorosilane, ethyltrichlorosilane, butyltrichlorosilane, vinyl ]・
Liace I xysilane, bis-(N-methylbenzylamide)ethoxymethylsilane, tris-(dimethylamino)methylsilane, vinyltrichlorosilane, tris-
Representative examples include (cyclohexylamino)methylsilane, vinyltriethoxysilane, γ-glycidoxypropyltrimethoxysilane, tetrapropoxysilane, and vinyltriethoxysilane.

Further, typical examples of silicon-containing crosslinking agents containing two silicon atoms in the molecule include hexaacetoxydisiloxane, 1
, 3-dimethyltetraacetoxydisiloxane, 1.3
- general formula % such as divinyltetraethoxydisiloxane, where n, m = o, 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.

An example of a silicon-containing crosslinking agent containing three silicon atoms in its molecule is 1, 3, 5-1-rimethoxy-1.1.

3.5.5 Pentamethyltrisiloxane, 1°1,3,
Examples include 3,5.5-hexaacetoxy-1,5-dimethyltrisiloxane.

As these silicon-containing crosslinking agents, known room temperature crosslinking type silane coupling agents are widely used, such as Petrar.
Catalog Silicon published by ch System Inc.
Compounds, Register & Rev
iew■1979 and the company's Si l1 cones @
All the silicon-containing crosslinking agents described in 1981 can be used.

In addition to the crosslinkable (i.e., trifunctional) silicon-containing compounds mentioned above, a low-molecular silicon-containing compound that sequentially generates 5i-0-3i bonds through bifunctional condensation to produce polysiloxane is used in combination. Of course, it is a good thing. 2 like this
As a functional silicon-containing compound, the silicon atom has two hydrocarbon groups, and the molecule has two functional groups that are activated by water to generate crosslinking ability. For example, the general formula % formula % (where R, -R4 are the same or different hydrocarbon groups, n is a positive integer such as 0, 1, 2.3, etc., and Y and Y' are activated by the same or different types of water. There are silicon-containing compounds represented by the following formulas, each representing a crosslinkable functional group. Examples of these compounds are dimethyldiacetoxysilane, diethyldiacetoxysilane, dimethyljethoxysilane, diethyljethoxysilane, methylethyldimethoxysilane, diethyldimethoxysilane, dimethyldichlorosilane, methylphecoldiacetoxysilane, diphenyldiacetoxysilane. , dibenzyldiacetoxysilane, divinyl ethoxysilane, etc. Also, 1,1,3.3-tetramethyl-1,3-diacetoxydisiloxane, 1,1,3
．． 3-tetramethyl-1,3-dimethoxydisiloxane, 1,1,3.3-tetramethyl-1,3-jethoxydisiloxane, 1.1.3,3,5.5-hexamethyl-1, 5-Diacetoxytrisiloxane, 1,1,3゜3.5.5-hexaethyl-1,5-jethoxytrisiloxane, 1,1,3,3,5.5-hexamethyl-1
,5-dimethoxytrisiloxane, 1.1,1,5,5
．． 5-hexamethyl-3゜3-diacetoxytrisiloxane, 1,1,1゜3.5.5-hexamethyl-3,5
Examples include -diacetoxytrisiloxane.

In carrying out the present invention, the following method is used.

First, as a first step, a tube with a porous cross section used in the present invention is treated with an aqueous heparin-containing solution so that the heparin-containing aqueous solution is sufficiently filled in the pores or voids in the cross section of the tube. Although the concentration of heparin in the heparin aqueous solution is arbitrary, a saturated solution may be used. By drying the tube in this state, heparin can be introduced into the void within the tube wall.

As a second step, a monomer and a water-soluble or water-swellable polymer are activated in the presence of water and polymerized through crosslinking.
Alternatively, the inner surface of the heparin-treated tube may be treated with a solution obtained by dissolving a polymer containing a water-soluble or water-swellable segment in its molecule (hereinafter collectively referred to as a hydrophilic polymer) in an organic solvent. Cover uniformly.

At this time, it is necessary to uniformly dissolve the crosslinkable monomer having a crosslinkable functional group and the wood-philic polymer in the organic solvent. This organic solvent desirably does not contain any substance that promotes activation of the crosslinking monomer, such as water. However, it goes without saying that a certain amount of moisture is allowed to achieve the present invention.

In the third step, the monomer to be polymerized with crosslinking is activated, but it is usually sufficient to leave it in an atmosphere with appropriate humidity. The homogeneously existing crosslinking monomers activated by moisture in the air undergo a crosslinking reaction one after another to form an interleaved network structure. The wood-philic polymer is entangled with the network produced by this cross-linked polymerization, resulting in a state in which it swells in water but does not dissolve out.

In order to promote or complete this cross-linking reaction, water may be introduced into the lumen of the artificial blood vessel after the above-mentioned treatment at an appropriate time, or the pH of this water may be adjusted, for example, by acidification to accelerate the reaction. may be applied.

When an artificial blood vessel treated according to the present invention is used, the hydrophilic polymer on the inner surface of the artificial blood vessel that forms the lumen swells with water in the blood. Accordingly, the heparin present in the wall of the artificial blood vessel is gradually released through the water-swellable polymer layer barrier.

This effectively prevents the formation of initial thrombus. Early thrombi are thus prevented by the sustained release of heparin, and intermediate thrombi are prevented by the action of interlaced hydrophilic polymers in an interpenetrating network. During this time, endothelial cells infiltrate and grow into the water IM\H polymer layer, and biogenicization progresses steadily. In the artificial blood vessel of the present invention, it was found that not only no thrombus occurred, but also, interestingly, the endothelium produced extremely F,u<<, and only slight thickening of the endothelial cells was observed over time. In the present invention, the sustained-release heparin decreases over time, but it takes a considerable amount of time for it to completely disappear, so it is necessary to allow the endothelium to grow and biogenize before it completely disappears. Can be done. It can also be used as an A-V shunt to achieve the same effect, and can also be used as a substitute blood vessel for slow-moving venous systems.

The present invention will be explained in more detail below with reference to Examples.

(Example) Example 1 A plain weave tube made of polyethylene terephthalate fiber with a monofilament degree of 0.7 denyl was subjected to bellows processing, and the inner diameter was 4 mm.
, an artificial blood vessel with a length of 30 cm was created. After thorough washing and drying, this was immersed in an aqueous solution containing 20% heparin to sufficiently wet the entire fiber assembly and dried.

Separately, a prepolymer was made from polytetramethylene glycol with a molecular weight of 1350 and 4,4'-diphenylmethane diisocyanate, and this was chain-extended with 1,4-butanediol. Polyurethane (8 parts) was mixed with tetrahydrofuran (90 parts). Polyethylene glycol (8 parts) having a molecular weight of 2400 and methyltriacetoxysilane (15 parts) were added to the tetrahydrofuran solution and uniformly dissolved in this solution. The solution is somewhat viscous.

The tetrahydrofuran solution was placed in the inner cavity of the heparin-treated plain weave tube prepared earlier, and after sufficiently wetting the inner surface with the solution, it was immediately drained and dried in an atmosphere with a relative humidity of 65%. . This operation coats the inner surface of the polyester fiber plain weave tube with the polymer composition.
Methyltriacetoxysilane is approximately uniformly distributed in the coating composition. Methyltriacetoxysilane is deaceticated by water in the atmosphere and starts a crosslinking reaction, and the crosslinking reaction is repeated one after another to form polysiloxane while entangling the hydrophilic polymer. This state was left for one week to complete crosslinking.

In this way, it was possible to create an IPN coating of a woody polymer with good antithrombotic properties on the inner surface.

Example 2 A tube with an inner diameter of 4 mm was made of knitted polyethylene terephthalate fiber with a monofilament degree of 0.6 denyl, and was subjected to bellows processing. This was treated with heparin in the same manner as in Example 1.

4. polytetramethylene glycol with a molecular weight of 1800;
A prepolymer was prepared from 4'-dicyclohexyl diisocyanate, and a polyurethaneurea was prepared from this prepolymer using ethylenediamine as a chain extender.

5 parts of this polyurethaneurea, 4 parts of polyvinylpyrrolidone having a molecular weight of 120.000, and 10 parts of a methyltriacetoxysilane-dimethyldiacetoxysilane mixture (1:1) were dissolved in 79 parts of dimethylacetamide to obtain a viscous solution.

The inner surface of the heparinized tube was coated with this solution and dried under reduced pressure in air. Then further relative humidity 6
Crosslinking was completed by leaving it for 100 minutes in a 5% atmosphere.

In this way, heparin is incorporated and a crosslinked polymer layer having an IPN structure intertwined with a hydrophilic polymer can be formed on the inner surface of the artificial blood vessel.

Example 3 Polytetramethylene glycol (molecular weight 1200) and 4
,4'-diphenylmethane diisocyanate and 1,4-
Polyurethane synthesized using butanediol as the original material was dissolved in a mixed solvent of dimethylacetamide and tetrahydrofuran to form a 24% solution.

A stainless steel forest (circular cross section) with an outer diameter of 4 mm, which is precisely set concentrically with the orifice, is extruded at a constant speed from a circular orifice with a diameter of 6.2), and the mixture of the stainless steel and the orifice is spread over the entire circumferential surface of the extruded stainless steel forest. While uniformly extruding and casting the previously prepared polyurethane solution through the gap, the rod was extruded into 8'O water and slowly solidified. In this case, coagulation of the polyurethane occurs only from the outside. The polyurethane tube was left in water at 8° C. overnight to complete coagulation, and the resulting polyurethane tube was removed and air-dried.

The cross section of the obtained polyurethane tube consisted of a continuous group of vacuoles, and there was no heterogeneous compact layer on the inner surface of the tube, and the inner surface was the same as the wall of the vacuole group inside the tube wall. The compliance of this tube (Sasashima et al. 9 Artificial organs, E., 17
9 (1983)) was 0.15.

This polyurethane tube was immersed in an aqueous solution containing 30% by weight of heparin so that the aqueous heparin solution was sufficiently filled into the vacuoles of the tube. After that, I idled this.

Separately, 10 parts of polyurethane used in this example, molecular weight 3000
10 parts of polyethylene glycol and 20 parts of tetraacetoxysilane were dissolved in a tetrahydrofuran/dioxane mixed solution (mixing ratio 2:1) to form a homogeneous solution.

The lumen surface of the heparin-treated polyurethane tube was uniformly wetted with this solution and dried. Moisture in the air causes a crosslinking reaction, and in order to accelerate this, water vapor was once blown into the material to promote the crosslinking reaction, and then the material was dried again.

Example 4 Polyurethane urea was synthesized using ethylenediamine instead of 1,4-butanediol used in the synthesis of polyurethane in Example 3, and a polyurethane tube was produced in the same manner as in Example 3 using this.

When looking at the cross section of the tube wall, this polyurethane urea consisted of a group of continuous vacuoles, there was no foreign skin structure on the inner surface of the tube, and the compliance value was 0.18.

Separately, a dioxane solution containing 5 parts of the polyurethaneurea used in this example, 5 parts of hyaluronic acid, 73 parts of polyvinylpyrrolid, and 15 parts of the methyltriacetoxysilane-dimethyldiacetoxysilane (1:2) mixture was prepared.

The lumen surface of a polyurethane urea tube containing heparin in the vacuoles of the tube cross section was coated with this prepared solution and dried in a nitrogen stream. Furthermore, crosslinking was carried out in an atmosphere with a relative humidity of 70%. The silicon compound was activated by the action of water in the atmosphere, the crosslinking reaction progressed, and the wood-philic polymer was entangled to form a network, forming IPN on the inner surface.

(Test Example) Test Example 1 Using a mongrel adult dog, the artificial blood vessel of the present invention prepared in Examples 1 and 3 was selected to match the thickness of the artificial blood vessel obtained from the iliac artery to the femoral artery. It was transplanted by joining one end to the other. The transplant experiment was conducted in 8 cases each.

The results after 3 months are shown in the table below in comparison with those without the Fumomogi invention treatment.

Control Comparison of Example 1 Control Comparison Test Example 2 Using an adult mongrel dog, a bypass experiment of the large artery and large 11a vein was performed using the artificial blood vessels of Examples 2 and 4. The results were compared with those not subjected to the treatment of the present invention. The joining method was end-side joining. The total length of the bypass was 23 cm. The results are shown in the table below.

Control comparison of Example 2 and control comparison of tree flow side 4 [Effects of the invention] The artificial blood vessel of the present invention not only has excellent durability and ease of suturing, but also has excellent antithrombotic properties, so it has a small diameter. Even has long-term patency.

Claims (2)

[Claims] (1) Heparin is built into the wall of the artificial blood vessel, and the lumen surface layer has a large number of holes or voids that communicate with the heparin built-in portion and a water-swellable polymer layer that seals the holes or voids. An artificial blood vessel characterized by: (2) The water-swellable polymer layer has an alternating infiltration network structure in which a water-soluble or water-swellable polymer or a polymer containing a water-soluble or water-swellable chain as a segment is entangled with a crosslinked silicon compound. Artificial blood vessel as described in section.