JP3141653B2 - Artificial blood vessel - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel artificial blood vessel. More specifically, it is an artificial blood vessel that is transplanted by connecting it to the blood vessel of a living body for the purpose of replacing a diseased blood vessel, and is a particularly high-risk thoracic large blood vessel that combines high safety during operation and excellent operability. The present invention relates to an artificial blood vessel suitable for surgery.

[0002]

2. Description of the Related Art Since the late 1950's, "artificial blood vessels" which replace the function of diseased blood vessels with tubes of artificial material have been used clinically. In other words, it is possible to secure blood circulation to peripheral tissues at the lesion site by replacing the lesion blood vessel or sewing around the lesion site and suturing the blood to the inside of the patient's own blood vessel. Today, in Japan, about 20,000 patients are receiving and benefiting from treatment such as rupture or obstruction of large blood vessels by transplantation of artificial blood vessels.

[0003] Since this artificial blood vessel is implanted in the body and used in direct contact with blood, it is not only excellent in biocompatibility with blood and surrounding tissues, but also a large blood vessel having an inner diameter exceeding 7 to 8 mm. In the case of 100 to 200 mmHg of blood pressure at all times, it is exposed to the pulse pressure of the heart beat as many as 100,000 times a day. In addition to the strength required to withstand this,
It is an indispensable condition that the material has little deterioration in the body.

Accordingly, as a material satisfying these conditions, a knitted or plain-woven cloth of polyester (polyethylene terephthalate) fiber is used. Usually, a crimped one called a crimp is used to prevent bending in the body. The artificial blood vessel is sutured and connected to a blood vessel of a living body with a needle thread. Reducing intraoperative bleeding is crucial to surgical outcomes.

[0005] Therefore, generally, when an artificial blood vessel made of polyester fiber is used, an anticoagulant such as heparin is used. If used without any pretreatment, blood and plasma leak from the artificial blood vessel wall. Occur. To prevent this,
A pretreatment called pre-clotting has been performed.
In this operation, the operation of collecting own blood, immersing the artificial blood vessel to coagulate the blood, and filling the voids between the fibers of the artificial blood vessel is repeated several times. This method consumes a large amount of the patient's blood, requires time for complicated operations, and furthermore, blood clots between fibers after operation may be broken down by the thrombolytic action of the living body and cause major bleeding. .

Accordingly, in recent years, as a method instead of pre-plotting using autologous blood, a method has been frequently used in which albumin, a plasma protein, is applied, denatured and insolubilized by wet heat treatment in an autoclave, and then dried. However, this method is expensive and has a problem in suturing because the treated artificial blood vessel becomes extremely hard.

In view of the above background, artificial blood vessels that do not cause bleeding without pretreatment have recently been used. This technique is a method of coating gelatin pretreated with a polycarboxylic acid or an aldehyde (Japanese Patent Laid-Open No.
And a method of impregnating with a gelatin crosslinked with a diisocyanate such as hexamethylene diisocyanate (Japanese Patent Application Laid-Open No. 62-258666).

[0008] However, it has become clear that the artificial blood vessel of the disclosed technology has important problems as clinical use progresses. That is, a high rate of fever is caused in the patient after transplantation, and bleeding and leakage of plasma occur in the body relatively early after the operation. These can be extremely burdensome for post-operative patients with reduced physical strength, delayed in time to rehabilitation, and can be a serious, life-threatening problem. In addition, there is a danger that the coated layer will be partially peeled off. Furthermore, it is also known that the body expands gradually without being able to withstand blood pressure.

[0009]

SUMMARY OF THE INVENTION An object of the present invention is to provide superior safety and operability as compared with a conventional artificial blood vessel, and to provide a surgical operation without performing any pretreatment before operation. No blood leakage during and after surgery
Further, the present invention has been made in order to provide an artificial blood vessel which does not generate heat, does not peel off the gel layer, has no risk of causing infarction in peripheral tissues at the transplantation site, and has excellent suture operability.

[0010]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to develop an excellent artificial blood vessel, and as a result, have found that a specific porosity and endotoxin content obtained by coating a woven polyester fiber cloth with a crosslinked gelatin. It has been found that the above object can be achieved, and the present invention has been accomplished. In the present invention, gelatin is added to a woven fabric composed of polyester fibers.
It is an artificial blood vessel which is cross-coated with a hide and has a porosity (porosity means a temperature of 37 ° C. for 1 minute from a subject 1 cm 2).
Denotes the volume (ml) of water leaking under a differential pressure of 120 mmHg, and its unit is hereinafter represented by ml. ) Is less than 10ml,
In addition, the present invention relates to an artificial blood vessel characterized in that the amount of endotoxin is 100 pg / g or less, and further, the amount of gelatin to be cross-linked is 5% by weight of the total weight of the artificial blood vessel (hereinafter, "% by weight" is represented by "%"). ) Or less (excluding 0% by weight )
And / or the woven fabric used as the substrate has a porosity of 2
The present invention relates to an artificial blood vessel characterized by being in a range of 0 to 200 ml.

Hereinafter, the present invention will be described in detail. In the artificial blood vessel of the present invention, a woven fabric woven of polyester fibers is used as a basic material (base material), and its porosity is 20 to 200 ml.
Preferably, 30 to 100 ml is selected. The most typical example is a plain weave of a multifilament yarn obtained by bundling tens to hundreds of polyester fibers of about 1 denier alone, or a physically entangled multifilament yarn. .

If the porosity of the base material exceeds 200 ml, the risk of plasma leakage after gelatin decomposition increases rapidly. On the other hand, if it exceeds 200 ml, the amount of gelatin required to reduce the porosity of the product to the target value increases, and as a result, it may cause an excessive foreign body reaction in the living body or peel off and fall off. , And the operability at the time of suturing is significantly reduced. If the porosity of the base material is less than 20 ml, the density of the fibers of the woven fabric becomes high, so that the penetrability of the suture needle is remarkably reduced, and the operability becomes poor. Also, the texture becomes stiff and stiff, making it unsuitable for complicated surgical techniques for inverting or bending artificial blood vessels.

Further, in terms of physical properties, the strength of holding the suture (the strength at which the fabric of the artificial blood vessel is frayed and the suture comes off when a tensile test is performed through the suture at a position 1 mm from the stump of the artificial blood vessel) is measured in the body. It is important as a measure of durability. Since the holding strength of the suture suddenly increases when the porosity of the woven fabric of the base material is 100 ml or less, and when it is 30 ml or more, it is easy to sew, it is easy to increase the flexibility, and the variation is reduced, It is most preferable to select a substrate having a size of 30 ml or more and 100 ml or less.

Gelatin is used as the material to be coated. As the gelatin, use is made of Japanese Pharmacopoeia gelatin as used in capsules for medical use, or a gelatin of the same or higher quality. The amount of endotoxin in the gelatin is preferably as small as possible, but specifically, 400 ng / g or less, preferably 300 ng / g.
It is necessary to use the following as an aqueous solution in order to ensure the endotoxin content of the artificial blood vessel of the present invention to 100 pg / g or less, preferably 70 pg / g or less.

As a method for measuring the amount of endotoxin, a Limulus test was employed. That is, a method in which 1 g of a sample is extracted with 10 ml of endotoxin-free water at room temperature for 72 hours, and the measurement described in "General Test Method 7. Endotoxin Test of the Japanese Pharmacopoeia 12 Revision" is performed. .

Collagen is known as a material similar to gelatin, and this can be used in place of gelatin. However, the viscosity of the aqueous solution is higher than that of gelatin, making it difficult to form a uniform coating with a small amount. Therefore, the amount of adhesion becomes excessive. In addition, it is difficult to obtain collagen having a low endotoxin content,
Purification is also difficult with a simple method.

In the present invention, a 5%, preferably 3% or less, aqueous solution of pharmaceutical gelatin is prepared with pyrogen-free water, and then used after being filtered through a filter having a pore size of 0.2 μm. In this solution, a tube with a fold of the woven fabric is immersed to fill an aqueous gelatin solution between the fibers. If necessary, the pressure may be reduced. Further, in order to improve the wettability on the fiber surface, ethanol may be added to the aqueous solution as long as gelatin does not precipitate. Next, the tube to which the gelatin solution has been applied is removed, for example, by passing excess gelatin by a method such as passing between two rollers.
Coat the entire surface uniformly.

When the gelatin concentration of the coating solution is 5% or more, the viscosity of the solution is high, the coating is apt to be spotted, and the gelatin content of the finally obtained product is higher than 5%, so that the rigidity is high. The operability is poor, and the gelatin is apt to peel off. Preferably, it is 3% or less. If it is less than 0.5%, the physical properties of the obtained coating film become weak. Therefore, the optimum concentration of the gelatin concentration of the coating solution is 0.5 to 3.0%.

The tube impregnated with the solution is immediately left still in an atmosphere of 5 ° C. or less and 0 ° C. or more. Upon rapid cooling, the solution quickly gels and hardens. If the temperature exceeds 5 ° C., the solution flows to form a non-uniform coating before gelation. If the temperature is lower than 0 ° C., freezing occurs, and pinholes are formed in the formed gel layer, so that the porosity cannot be kept low. The cooling gelation is completed within about one hour by air cooling, but it is preferable to further stand for several hours. This cooling gelation is indispensable to prevent the diluted gelatin aqueous solution from dissolving and diffusing when coming into contact with the reaction solution during the next stage of the cross-linking reaction, thereby preventing the coating from becoming uneven or incomplete. .

Crosslinking is rapidly treated with high concentrations of aldehydes such as glutaraldehyde, formaldehyde. More specifically, for example, when immersed in a 5-15% glutaraldehyde aqueous solution and reacted at room temperature, the time required to obtain an insoluble crosslinked gel is about 30 minutes,
Generally, 30 to 60 minutes is appropriate. Since the cooling gel shrinks at the time of crosslinking, glycerin is preferably contained in the gel in advance. Also, by immersing the cooled gel containing glycerin in acetone prior to the crosslinking reaction,
The water content can be reduced while glycerin remains in the gel. According to this method, a uniform coating layer can be obtained by further suppressing the gel shrinkage at the time of crosslinking, and a single aldehyde treatment is sufficient. Since the decomposition rate of the crosslinked product varies depending on the solid, it is desirable to perform crosslinking until substantially all amino groups are consumed.

After completion of the reaction, the aldehyde as a cross-linking agent, for example, glutaraldehyde, is sufficiently washed off with alcohol and dried. At this time, it is desirable to include glycerin as a humectant in order to prevent drying shrinkage. After drying, perform the sterilization operation promptly.

The artificial blood vessel thus obtained has a porosity of 10 ml or less, does not leak blood or plasma, and a part of the outer surface of the coating is damaged by any cause, for example, an intraoperative operation. There is no problem even if you receive. In addition, despite the absence of blood or plasma leakage, the crosslinked layer of gelatin is thin and highly flexible, and in combination with the proper physical properties of the polyester woven fabric, the suture needle may be passed.
Further, in the course of each of the above treatments, endotoxin is washed away and is inactivated by a high concentration of a cross-linking agent, so that a safe artificial blood vessel that does not cause fever immediately after surgery and in the subacute stage is obtained from the product. can get.

[0023]

The artificial blood vessel of the present invention has superior safety and operability as compared with the conventional one. In other words, it can be used for surgery without any pre-operative pretreatment, there is no leakage of blood or plasma during or after surgery, and no heat is generated. In addition, there is no danger of exfoliation of the gel layer on the surface flowing out, and there is no risk of causing infarction in the peripheral tissue at the transplant site. The suture operability is also excellent, which is useful for completing a complicated operation in a short time.

[0024]

Next, the present invention will be described in more detail with reference to Examples and Comparative Examples.

Example 1 A tube was produced by plain weaving a saturated polyester yarn of 50 denier (72 filaments), and fine folds were heat-processed on the entire surface of the tube to prevent bending. In general, those skilled in the art can easily determine the conditions for obtaining a predetermined porosity by changing the warp density. After filtering a 2% aqueous solution of gelatin in the Japanese Pharmacopoeia through a 0.2 μm filter,
A raw material tube having a porosity of 25 ml was dipped in the filtrate at room temperature and allowed to stand for 1 hour. Gelatin was previously dissolved to prepare a 0.5% aqueous solution (using distilled water for injection), and the amount of endotoxin was measured to be 250 ng / g gelatin. Next, excess gelatin aqueous solution was removed by passing between two rollers fixed so that the gap was 200 μm. Promptly 3 ℃
And allowed to stand for 2 hours. After confirming that the coated gelatin gelled by cooling, it was immersed in a 12.5% aqueous solution of glutaraldehyde and reacted at room temperature for 1 hour. After the completion of the reaction, the resultant was washed with ethyl alcohol. In the washing, the ethyl alcohol was exchanged three times, and finally, it was immersed in ethyl alcohol to which glycerin 10% was added. Immediately after drying, sterilization (using ethylene oxide gas) was performed to obtain an artificial blood vessel.

The porosity of the obtained artificial blood vessel is 1.3 m
1, no endotoxin was detected. The crosslinked gelatin contained in the artificial blood vessel was removed by hydrolysis with 6N hydrochloric acid, and the amount of saturated polyester determined by the same treatment was corrected. As a result, the crosslinked gelatin carrying amount was 3.2%.
When the suture needle was passed through this artificial blood vessel, there was no change from the woven fabric before coating, and the operation was easy. The coating did not peel off even when the operation of bending and clamping with forceps was repeated.

Example 2 In the same manner as in Example 1, an artificial blood vessel having an inner diameter of 10 mm was prepared using a raw material tube of woven fabric having a porosity of 100 ml. The porosity of the obtained artificial blood vessel was 1.8 ml, and no endotoxin was detected. An 8 cm long sample was replaced under a thoracotomy with the aorta of a mongrel dog. At this time,
Heparin was administered to maintain ACT at 300 ± 50 seconds. No bleeding from the wall of the vascular prosthesis was observed. After the suture, forceps were intentionally applied, but no bleeding occurred. One month later, necropsy revealed no hematoma around the transplanted vascular graft.

Example 3 The same operation as in Example 2 was carried out except that a raw material tube having a porosity of 180 ml of woven fabric was used. As a result, the porosity of the obtained artificial blood vessel was 4.5 ml, and endotoxin was not detected. An 8 cm long sample was replaced under a thoracotomy with the aorta of a mongrel dog. At this time, heparin was administered to maintain ACT at 300 ± 50 seconds. No bleeding from the wall of the vascular prosthesis was observed. After the suture, forceps were intentionally applied, but no bleeding occurred. One month later, necropsy revealed no hematoma around the transplanted vascular graft.

Comparative Example A 0.5% aqueous solution was prepared using industrial gelatin and distilled water for injection. The value obtained by measuring the amount of endotoxin in this solution and converting it to 1 g of gelatin was 430 ng / g. Using this solution and a tube of a substrate made of a woven fabric having a porosity of 230 ml, an artificial blood vessel was produced in the same manner as in Example 1. The endotoxin test of the Japanese Pharmacopoeia was performed using 1 g of the sample, and the result was 125 ng / g.
The product was tested for pyrogenicity by the Japanese Pharmacopoeia and found to be positive for pyrogenicity. The porosity of the obtained artificial blood vessel was 7.2 ml. This was cut to a length of 8 cm, and transplanted into the aorta of a mongrel adult dog in the same manner as in Example 2. After autopsy three weeks later, hematoma formation was observed around the transplanted artificial blood vessel.

────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-62-258666 (JP, A) JP-A-61-191364 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61L 27/40-27/48

Claims (5)

(57) [Claims] An artificial blood vessel comprising a woven cloth made of polyester fiber and gelatin coated with aldehyde by crosslinking, and having a porosity of 10 ml / cm ² · min · 120 m.
An artificial blood vessel having a mHg or less and an endotoxin amount of 100 pg / g or less. 2. An artificial blood vessel obtained by subjecting a woven cloth made of polyester fibers to a cross-linking coating of gelatin with aldehyde and washing away the aldehyde with alcohol, having a porosity of 10 ml / cm ² · min · 120 mmHg or less and an endotoxin. An artificial blood vessel having an amount of 100 pg / g or less. 3. The artificial blood vessel according to claim 1, wherein the woven fabric is a plain woven fabric alone, or another fabric is physically entangled with the woven fabric. 4. The amount of gelatin to be cross-linked coated is 5% by weight or less (excluding 0% by weight) of the total weight of the artificial blood vessel, and / or the porosity of the woven fabric used as the base material is 20 to 200%.
The artificial blood vessel according to any one of claims 1 to 3, wherein the pressure is in a range of ml / cm ² · min · 120 mmHg. 5. The artificial blood vessel according to claim 1, wherein the aldehyde is glutaraldehyde or formaldehyde.