JPH07136242A - Artificial blood vessel - Google Patents

Abstract

PURPOSE:To provide the artificial blood vessel which has excellent safety and operability and is usable for operation without making any pretreatment at all by forming the artificial vessel obtd. by coating a woven fabric of polyester films with crosslinked gelatin to specific porosity and endotoxin quantity. CONSTITUTION:The porosity of the artificial blood vessel obtd. by crosslinking coating the woven fabric consisting of the polyester fibers with the gelatin is specified to <=10ml/cm<2>.min.120mmHg and the endotoxin quantity thereof to <=100pg/g. Further, the amt. of the gelatin to be used for crosslinking coating is confined to <=5wt.% of the total weight of the artificial blood vessel and/or the porosity of the woven fabric used as the base material is specified to a range from 20 to 200ml/cm<2>.min.120mmHg. The artificial blood vessel is usable for operation without making any pretreatment before an operation at all, does not leak the blood and plasma during and after the operation and does not generate heat either. Further, the outflow of the peeled mater of the gel layer of the surface does not arise and there is no danger of inducing sclerosis and embolism in the peripheral tissues of the implanted section.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a new artificial blood vessel. More specifically, it is an artificial blood vessel that is transplanted by connecting it to a blood vessel of a living body for the purpose of substituting a lesioned blood vessel, and has a particularly high risk of a large thoracic blood vessel that has both high safety during surgery and excellent operability. The present invention relates to an artificial blood vessel suitable for surgery.

[0002]

2. Description of the Related Art Since the latter half of the 1950s, "artificial blood vessels" in which the function of diseased blood vessels is replaced by a tube made of an artificial material have been clinically used. That is, it becomes possible to secure blood circulation to the peripheral tissues of the lesion site by replacing the lesion blood vessel or by sewn with the human blood vessel by bypassing the lesion site and sewn to the inside thereof. Today, in Japan, about 20,000 patients are treated with vascular grafts, such as ruptures and blockages of large blood vessels, and benefit from them.

Since this artificial blood vessel is embedded in the body and is used in direct contact with blood, it is of course good in biocompatibility with blood and surrounding tissues, and also a large blood vessel having an inner diameter of 7 to 8 mm or more. Then, under constant blood pressure of 100-200 mmHg, it is exposed to pulse pressure due to the pulsation of the heart 100,000 times a day, so in addition to the strength required to withstand this,
It is an essential condition that the material has little deterioration in the body.

Therefore, a knitted or plain-woven cloth of polyester (polyethylene terephthalate) fiber is used as a material satisfying these conditions. Usually, a crimp with a fold is used to prevent bending in the body. The artificial blood vessel is sutured to the blood vessel of the living body by a thread with a needle. Reducing the amount of bleeding during surgery is extremely important for surgical outcome.

Therefore, when using an artificial blood vessel made of polyester fiber, an anticoagulant such as heparin is generally used. Therefore, if it is used without any pretreatment, blood or plasma leaks from the artificial blood vessel wall. Occur. To prevent this
A pretreatment called pre-clotting has been performed.
In this operation, the operation of taking self blood, soaking 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 a complicated operation and takes time, and further, the blood clot between the fibers after the operation may be decomposed by the thrombolytic action of the living body to cause major bleeding. .

Therefore, in recent years, a method of applying albumin, which is a plasma protein, and subjecting it to wet heat treatment in an autoclave to denature and insolubilize it, followed by drying, has been widely used as an alternative method to pre-plotting with autologous blood. However, this method has a high cost and has a problem in suturability because the treated artificial blood vessel becomes extremely hard.

Based on 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 previously treated with polycarboxylic acids or aldehydes (Japanese Patent Laid-Open No. Sho 6-62).
1-135651) and a method of impregnating gelatin cross-linked with a diisocyanate such as hexamethylene diisocyanate (JP-A-62-258666).

However, it has become clear that the artificial blood vessels of the disclosed techniques have important problems as their clinical use progresses. That is, a high rate of fever is caused in the patient after transplantation, and bleeding and plasma leakage occur in the body relatively early after the operation. These can be extremely burdensome for post-operative patients with decreased physical strength, delay in the time to return to society, and can be a serious life-threatening problem. In addition, there is a risk that the coated layer will be partially peeled off. Further, it is known that the body cannot bear blood pressure and gradually expands.

[0009]

DISCLOSURE OF THE INVENTION The present invention aims to provide superior safety and operability as compared with conventional artificial blood vessels, and to be subjected to surgery without any pretreatment before surgery. And there is no blood or plasma leakage during or after surgery,
Further, the present invention was made in order to provide an artificial blood vessel which does not cause fever, does not peel off the gel layer, has no risk of causing infarction in the peripheral tissue at the transplant site, and has excellent suture operability.

[0010]

[Means for Solving the Problems] As a result of intensive studies to develop an excellent artificial blood vessel, the present inventors have found that a specific porosity and an amount of endotoxin obtained by coating a woven cloth of polyester fibers with cross-linked gelatin. It was found that the above-mentioned object can be achieved by the above-mentioned, and the present invention has been completed. The present invention is an artificial blood vessel in which a woven fabric made of polyester fiber is cross-linked with gelatin, and has a porosity (porosity is 1 cm ² for 1 minute of a subject, 120 mm at 37 ° C.).
It refers to the volume (ml) of water that leaks under a differential pressure of Hg, and the unit is hereinafter referred to as ml. ) Is 10 ml or less and the amount of endotoxin is 100 pg / g or less, and the amount of gelatin to be cross-linked is 5% by weight of the total weight of the artificial blood vessel (hereinafter referred to as “% by weight”).
Is represented by "%". ) The following, and / or the woven fabric used as a substrate has a porosity of 20 to 200 ml.

The present invention will be described in detail below. 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 the porosity thereof is 20 to 200 ml,
Preferably, 30 to 100 ml is selected. The most typical examples include, for example, a plain woven multifilament yarn in which several tens to several hundreds of polyester fibers of about 1 denier are bundled, or one in which another fiber is physically entangled. .

When the porosity of the base material exceeds 200 ml, the risk of plasma leakage suddenly increases after gelatin decomposition. If it exceeds 200 ml, the amount of gelatin required to reduce the porosity of the product to the target value increases, resulting in excessive foreign body reaction in the body or exfoliation and detachment. And the operability at the time of suturing is significantly reduced. When the porosity of the base material is less than 20 ml, the density of the fibers of the woven fabric is high, so that the penetrability of the suture needle is remarkably reduced and the operability is deteriorated. Also, the texture becomes stiff and stiff, making it unsuitable for complex surgical techniques such as inverting or bending an artificial blood vessel.

Further, in terms of physical properties, the holding strength of the suture thread (the strength with which the cloth of the artificial blood vessel is frayed and the suture thread comes off when a tensile test is performed by passing the suture thread at a position 1 mm from the stump of the artificial blood vessel) It is important as a measure of durability. When the porosity of the woven fabric of the base material is 100 ml or less, the holding strength of the suture is suddenly increased, and when it is 30 ml or more, the sewability and flexibility are easily increased, and variations are reduced. Most preferably, a base material of 30 ml or more and 100 ml or less is selected.

Gelatin is used as the material to be coated. As this gelatin, gelatin of the Japanese Pharmacopoeia, which is used in medical capsules, or a gelatin equivalent in quality or better is used. The amount of endotoxin in this gelatin is preferably as low as possible, specifically 400 ng / g or less, preferably 300 ng / g.
It is necessary to use the following as an aqueous solution in order to guarantee the endotoxin amount of the artificial blood vessel of the present invention to 100 pg / g or less, preferably 70 pg / g or less.

The limulus test method was adopted as the method for measuring the amount of endotoxin. That is, it is a method of performing the measurement described in "General test method of Japanese Pharmacopoeia 12 amendment 7. Endotoxin test" using a liquid extracted from 1 g of sample with 10 ml of endotoxin-free water at room temperature for 72 hours. .

Collagen is known as a material similar to gelatin, and it is possible to use this instead of gelatin, but the viscosity of the aqueous solution is higher than that of gelatin, and it is difficult to make a uniform coating with a small amount. Therefore, the adhesion amount is inevitably too large. In addition, it is difficult to obtain collagen with a low endotoxin content,
Purification is also difficult with a simple method.

In the present invention, an aqueous solution of 5%, preferably 3% or less of medicinal gelatin is prepared with pyrogen-free water and then filtered with a filter having a pore size of 0.2 μm for use. A tube having folds on the woven cloth is dipped in this solution 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 within the range in which gelatin does not precipitate. Next, while removing the excess gelatin by, for example, passing the tube provided with the gelatin solution between two rollers,
The entire surface is coated uniformly.

When the gelatin concentration of the coating solution is 5% or more, the viscosity of the solution is high, the coating is likely to have spots, and the final product has a gelatin content of more than 5%, which is rigid. The operability is poor, and peeling off of gelatin easily occurs. It is preferably 3% or less. If it is less than 0.5%, the resulting coating film will have poor physical properties. Therefore, the optimum concentration of gelatin in the coating solution is 0.5 to 3.0%.

The tube impregnated with the solution is immediately left to stand in an atmosphere of 5 ° C. or lower and 0 ° C. or higher. By cooling rapidly, the solution rapidly gels and sets. If the temperature exceeds 5 ° C, the solution will flow and a non-uniform coating will occur before gelling. Since freezing occurs at 0 ° C or lower, pinholes are generated in the formed gel layer, so that the porosity cannot be maintained low. The cooling gelation is completed within about 1 hour by air cooling, but it is desirable to extend the cooling gelation for several hours and let it stand still. This cooling gelation is indispensable for preventing the coating from becoming uneven or incomplete when the dilute aqueous gelatin solution is dissolved and diffused when coming into contact with the reaction solution in the next step of the crosslinking reaction. .

The crosslinks are treated rapidly with high concentrations of aldehydes such as glutaraldehyde, formaldehyde. More specifically, for example, when immersed in a 5 to 15% glutaraldehyde aqueous solution and reacted at room temperature, the time required to obtain an insoluble gel crosslinked product is about 30 minutes,
Generally, 30 to 60 minutes is suitable. Since shrinkage of the cooling gel occurs during crosslinking, it is advisable to include glycerin 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 leaving the glycerin in the gel. By this method, it is possible to further suppress the shrinkage of the gel at the time of crosslinking to obtain a uniform coating layer, and the aldehyde treatment is sufficient once. Since there is a difference in the decomposition rate of the crosslinked product, it is desirable to crosslink until substantially all the amino groups are consumed.

After completion of the reaction, the aldehyde as a crosslinking agent, such as glutaraldehyde, is thoroughly washed with alcohol and dried. At this time, it is desirable to include glycerin as a moisturizing agent in order to prevent drying shrinkage. After drying, carry out sterilization operation immediately.

The artificial blood vessel thus obtained has a porosity of 10 ml or less, does not leak blood or plasma, and is damaged by some reason, for example, during operation due to an operation during operation. There is no problem even if you receive the. In addition, although the leakage of blood and plasma does not occur, the layer of gelatin crosslinked material is thin and highly flexible, and the suture needle may be passed along with the physical properties of a suitable polyester woven fabric.
Furthermore, in the course of passing through each of the above treatments, endotoxin is washed away and inactivated by a high-concentration cross-linking agent, so that a safe artificial blood vessel that does not cause fever immediately after surgery and in the subacute phase is obtained from the product. can get.

[0023]

The artificial blood vessel of the present invention has excellent safety and operability as compared with the conventional ones. That is, it can be used for surgery without any pretreatment before surgery, and there is no leakage of blood or plasma during or after surgery, and no fever occurs. In addition, the exfoliated product of the gel layer on the surface does not flow out, and there is no risk of causing infarction in peripheral tissues at the transplant site. It has excellent operability for suturing and is useful for completing complicated surgery in a short time.

[0024]

EXAMPLES The present invention will be described in more detail with reference to Examples and Comparative Examples.

Example 1 A tube was prepared by weaving a saturated polyester yarn of 50 denier (72 filaments) with a plain weave, and fine folds for the purpose of preventing bending were heat-processed on the entire surface of the tube. Generally, a person skilled in the art can easily determine the conditions for empirically obtaining the predetermined porosity by changing the warp density. After filtering a 2% aqueous solution of gelatin in the Japanese Pharmacopoeia with a 0.2 μm filter,
A raw material tube having a porosity of 25 ml was dipped in the filtrate at room temperature and left standing for 1 hour. When gelatin was dissolved in advance to prepare a 0.5% aqueous solution (using distilled water for injection), and the amount of endotoxin was measured, it was 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 ℃
It was cooled in the air atmosphere and left 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 completion of the reaction, it was washed with ethyl alcohol. In the washing, the ethyl alcohol was exchanged 3 times, and finally, it was immersed in ethyl alcohol containing 10% glycerin. 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, endotoxin was not detected. The crosslinked gelatin contained in the artificial blood vessel was hydrolyzed and removed with 6N hydrochloric acid, and the weight loss of the saturated polyester obtained by the same treatment was corrected. As a result, the crosslinked gelatin supported amount was 3.2%.
When a suture needle was passed through this artificial blood vessel, there was no change from the unwoven cloth before coating, and the operation was easy. The coating did not peel off even after repeated bending and pinching with forceps.

Example 2 By the same method as in Example 1, an artificial blood vessel having an inner diameter of 10 mm was produced using a raw material tube having a porosity of 100 ml of woven cloth. The obtained artificial blood vessel had a porosity of 1.8 ml and no endotoxin was detected. An 8 cm long sample was placed under the thoracotomy in the aorta of a mongrel dog. This time,
Heparin was administered to maintain ACT at 300 ± 50 seconds. No bleeding from the wall of the artificial blood vessel was observed. After the suture, a forceps operation was intentionally applied, but no bleeding occurred. Autopsy was performed one month later, but there was no hematoma around the transplanted artificial blood vessel.

Example 3 The same operation as in Example 2 was carried out except that a raw material tube having a woven fabric having a porosity of 180 ml was used. As a result, the resulting artificial blood vessel had a porosity of 4.5 ml, and endotoxin was not detected. An 8 cm long sample was placed under the thoracotomy in 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 artificial blood vessel was observed. After the suture, a forceps operation was intentionally applied, but no bleeding occurred. Autopsy was performed one month later, but there was no hematoma around the transplanted artificial blood vessel.

Comparative Example A 0.5% aqueous solution was prepared using industrial gelatin and distilled water for injection. The amount of endotoxin in this solution was measured and converted to 1 g of gelatin, which was 430 ng / g. An artificial blood vessel was produced in the same manner as in Example 1, using this solution and a tube of a base material made of a woven cloth having a porosity of 230 ml. The endotoxin test of the Japanese Pharmacopoeia was carried out using 1 g of the sample, and the result was 125 ng / g.
As a result of conducting a pyrogenic substance test according to the Japanese Pharmacopoeia using this product, it was positive for pyrogenicity. The resulting artificial blood vessel had a porosity of 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, and autopsy was performed 3 weeks later. Hematoma formation was observed around the transplanted artificial blood vessel.

Front Page Continuation (72) Inventor Hideki Uno 8-1 Goi Minamikaigan, Ichihara City, Chiba Ube Industries Ltd. Chiba Research Institute

Claims (2)

[Claims] 1. An artificial blood vessel obtained by cross-linking gelatin on a woven fabric made of polyester fiber, the porosity of which is 10 ml / cm ² · min · 120 mmHg or less,
An artificial blood vessel having an endotoxin content of 100 pg / g or less. 2. The amount of gelatin for cross-linking coating is 5% by weight or less of the total weight of the artificial blood vessel, and / or the porosity of the woven fabric used as a substrate is 20 to 200 ml / cm ² · m.
The artificial blood vessel according to claim 1, which is in the range of 120 mmHg.