JPH04146763A - Gelatinous material sticking method to medical substrate - Google Patents

Abstract

PURPOSE:To stick a gelatinous material on the surface of a medical substrate to a uniform thickness without requiring a high-concentration or large-quantity reaction solution by reacting multiple Liquids on the surface of the medical substrate to form the gelatinous material, and pressing and sticking the obtained gelatinous material on the surface of the medical substrate. CONSTITUTION:A substrate is dipped in a gel-active material solution and lifted, it is then dipped in a gel precursor solution, and a gel-active material and a gel precursor are reacted to form a gelatinous material on the surface of a substrate. The order of the solutions to be dipped is not restricted in particular. The gelatinous material is formed to sandwich the substrate, if the substrate is tubular, the solutions may be injected and reacted into the tubular substrate, thus the gelatinous material can be formed only on the inner face. The obtained gelatinous material may be pressed and stuck to the surface of a medical substrate with a member inactive to the solutions to be reacted and the substrate and matching the shape of the medical substrate.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a method for attaching a gel-like substance to a medical substrate. More specifically, the present invention relates to a method for attaching a gel-like substance such as fibrin or collagen to the lumen surface of a tubular body for an artificial blood vessel.

(Prior Art) In recent years, with the remarkable progress of medical care, various medical devices such as artificial blood vessels, vascular catheters, extracorporeal blood circulation circuits, and artificial organs have become widespread (and increasingly used) in areas that come into direct contact with blood. It's here.

These medical devices are required not only to have good physical properties such as durability, but also to have excellent antithrombotic properties, tissue compatibility, and the like.

There are two methods for imparting antithrombotic properties to medical devices: one is to change the structure and physical properties of the materials that make up the medical device to exhibit antithrombotic properties, and the other is to add antithrombotic substances such as anticoagulants to the material. It can be broadly divided into methods to exert antithrombotic properties by applying it to the parts of medical instruments that come into contact with blood.

Particularly, as substances used in the latter method, biological tissue-derived proteins such as collagen and fibrin, and thrombin activity inhibitors such as heparin are known.

In particular, fibrin is known to activate tissue plasminogen activator, an enzyme that acts on the blood fibrinolytic system [Co11en, D.: Thrombos, Tl.
amostas, 43 Near 7, 1980] The present inventors first applied fibrin to the lumen surface of a tubular body for an artificial blood vessel, by sequentially injecting a thrombin solution and a fibrinogen solution into the lumen of the tubular body, or By sequentially immersing the tubular body in a thrombin solution and a fibrinogen solution, thrombin and fibrinogen are allowed to react, and the lumen surface (or outer surface when immersed) of the tubular body is substantially free of blood cells. A method for providing fibrin gel that exhibits excellent antithrombotic properties has been disclosed. [Patent Application No. 63-270788] Also, the present inventors previously
When applying fibrin containing soluble elastin to the lumen surface of a tubular body for an artificial blood vessel, a thrombin solution and an elastin-containing fibrinogen solution are sequentially injected into the lumen of the tubular body, or a thrombin solution and an elastin-containing fibrinogen solution are applied to the tubular body. Disclosed is a method of applying elastin-containing fibrin to the lumen surface of the tubular body by reacting thrombin and fibrinogen by sequentially immersing the tubular body in water. [Japanese Patent Application No. 53410/1989] Although these methods can also provide a fibrin layer that exhibits excellent antithrombotic properties to the lumen surface of a tubular body for an artificial blood vessel, it is difficult to uniformly control the thickness of the fibrin layer. Because it is difficult to do so, when the obtained artificial blood vessel was transplanted, thrombus adhesion was sometimes observed, albeit partially. In addition, in order to improve biocompatibility (cell conductivity) during transplantation, the tubular body for artificial blood vessels is generally made of a porous material. When a fibrin layer is formed, there is a problem that the fibrin does not sufficiently penetrate into the pores, increasing the risk of blood leakage, or that the fibrin has insufficient adhesion to the base material, making it easy to peel off. Furthermore, in the method of forming a gel-like substance by immersion, the gel-like substance is formed by sandwiching the base materials, but air remains in the pores of the base material, resulting in blood leakage during transplantation. There was a risk that the risk would increase and the physical properties of the base material would also deteriorate.

It is possible to form a thick fibrin layer to prevent blood leakage, but this requires a high concentration and large amount of fibrinogen solution, which is not economical.
Another problem was that it was difficult to apply to small-diameter artificial blood vessels.

(Problems to be Solved by the Invention) Therefore, the present invention enables a gel-like substance to be deposited to a uniform thickness on the surface of a medical substrate without requiring a high concentration or large amount of reaction solution. Moreover, even when a porous material is used as a medical base material, the gel-like substance can sufficiently penetrate into the pores, so there is no risk of blood leaking (in addition, there is no risk of the gel-like substance peeling off). An object of the present invention is to provide a method for attaching a gel-like substance to a substrate for use.

(Means for solving the problem) The above object is to form a gel-like substance by reacting a plurality of liquids on the surface of a medical base material, and apply the obtained gel-like substance to the surface of the medical base material. This is achieved by a method of attaching a gel-like substance to a medical substrate, which is characterized by adhesion by pressure bonding.

The medical base material is preferably formed of a porous material.

The present invention also provides a method for adhering a gel-like substance, wherein the medical substrate is a tubular body for an artificial blood vessel.

The present invention also provides a method for attaching a gel-like substance, wherein the gel-like substance is fibrin formed by a reaction between a fibrinogen solution and a solution containing an enzyme having a thrombin-like action.

The present invention also provides a method for attaching a gel-like substance, wherein the gel-like substance is fibrin containing soluble elastin formed by a reaction between a fibrinogen solution containing soluble elastin and a solution containing an enzyme having a thrombin-like action. It shows.

The present invention also provides a method for attaching a gel-like substance, wherein the gel-like substance is a collagen gel formed by a reaction between an acidic collagen solution and an alkaline neutralizing agent or an alkaline buffer.

Further, the present invention provides a medical device characterized in that a region to be brought into contact with blood by any of the above-mentioned attachment methods is coated with a gel-like substance.

The present invention will be explained in detail below.

Various materials can be used as the medical base material in the present invention. For example, materials used for artificial organs, especially artificial blood vessels, include polyurethane polymers, urethane-urea copolymers, or combinations of these and silicone polymers. Blends, polymeric materials such as polyester, polytetrafluoroethylene, and other known materials for artificial blood vessels may be used. In this case, the polyurethane-based polymer or urethane-urea copolymer is preferably a polyether type polymer from the viewpoint of durability in vivo, and polyether segmented polyurethane or polyether segmented polyurethane urea is particularly preferred.

In addition, these polymer materials may contain stabilizers and
A plasticizer, lubricant, etc. may be blended.

Depending on the purpose and type of medical equipment, we also use polyvinyl chloride, polyethylene, polypropylene, nylon, ethylene-vinyl acetate copolymer, polyvinyl chloride-polyurethane copolymer, polyvinyl chloride (ethylene-acetic acid) as base materials. Vinyl copolymers) copolymers, silicone rubber, polypropylene, polycarbonate, high density polyethylene, acrylic resins, etc. can be used.

From the viewpoint of biocompatibility (cell penetration), it is desirable that such a base material be formed from a porous material. Examples of such porous materials include fibrous structures such as knitted fabrics and woven fabrics, and resin foams.

A plurality of liquids are reacted on the surface of such a base material to form a gel-like substance.

As a combination of multiple liquids, fibrinogen solution (gel precursor) and an enzyme with thrombin-like action (gel action substance) are used to form fibrin.
A combination of a fibrinogen solution containing soluble elastin (gel precursor) and a solution containing an enzyme with thrombin-like action (gel acting substance) to form a collagen gel. Examples include combinations of acidic solutions (gel precursors) and alkaline neutralizers or alkaline buffers (gel-acting substances), but are limited to those that react to form gel-like substances. isn't it. Further, the addition ratio of these solutions may be appropriately determined depending on the thickness of the gel-like substance to be attached to the surface of the base material.

Furthermore, if necessary, these solutions may contain a pH adjuster,
To form a gel-like substance on the surface of a substrate to which a humectant or a stabilizer such as a sugar can be added, the substrate is immersed in a solution of a gel-acting substance as described above and pulled up, and then This can be carried out by immersing the gel precursor in a solution and causing the gel acting substance and the gel precursor to react. Note that the order of the solutions to be immersed is not particularly limited.

In addition, by such dipping operation, a gel-like substance is formed by sandwiching the base material, but if the base material has a tubular shape, by injecting the solution into the tubular body and causing a reaction, It is also possible to form a gel-like substance only on the lumen surface.

Furthermore, in order to improve the adhesion of the gel-like substance layer to the surface of the substrate, it is preferable to make the surface of the substrate hydrophilic by treatment with acid, plasma, ozone, or the like.

In order to attach the obtained gel-like substance to the surface of the medical base material, pressure bonding is performed using a member that is inert to the solution to be reacted and the base material and that matches the shape of the medical base material. do it. For example, when the medical base material has a tubular shape, a solution is reacted on the inner surface of the tubular body to form a gel-like substance, and then a mandrel made of Teflon or the like is inserted into the tubular body, and the mandrel surface is The gel-like substance can be attached to the lumen surface by pressing the gel material against the lumen surface of the tubular body. At this time, it is preferable to press the mandrel so that a uniform load is applied to the entire mandrel. By doing so, the thickness of the gel-like material layer attached to the inner surface of the tubular body can be made uniform. Alternatively, the tubular body into which the mandrel is inserted in advance is immersed in a solution or the solution is injected into the lumen to cause a reaction to form a gel-like substance, and then the gel-like substance is applied to the lumen surface by pressing the mandrel. It may also be attached.

At this time, it is possible to adjust the thickness of the gel-like substance adhered to the inner surface of the tubular body by changing the diameter of the inserted mandrel or adjusting the pressing force of the mandrel.

When the medical base material is made of a porous material, by applying a vacuum operation such as degassing when reacting a liquid to form a gel-like substance, the gel-like substance can be easily inserted into the pores. can be invaded.

By doing this, the adhesion of the gel to the base material is increased, and no air bubbles remain in the pores.
Therefore, it is possible to manufacture a medical device with excellent safety and antithrombotic properties without the risk of blood leakage.

Specific examples of the medical device according to the present invention include various artificial organs such as artificial blood vessels, artificial hearts, artificial kidneys, artificial lungs, etc., and furthermore, the main bodies of these devices or parts of these devices. It can be applied individually to gas exchange membranes, dialysis membranes, etc.

In particular, excellent antithrombotic properties can be obtained not only for artificial blood vessels with a relatively large inner diameter, but also for those with a small inner diameter, that is, those with an inner diameter of 5 mm or less.

In addition, the medical device of the present invention includes various tubes constituting the extracorporeal blood circulation circuit, connectors for connecting the tubes, and static and
It can also be applied to arterial insertion catheters, bubble traps, blood bags, chambers, centrifugal pumps, etc.

The medical device of the present invention can also be applied to blood transfusion or blood collection devices such as intravascular indwelling catheters, syringes, blood collection tubes, blood bags, and their accessories.

The present inventors conducted the following experiments in order to confirm the effects of the present invention.

(Example 1) 30 mg/ml human fibrinogen solution (Kabi
Put Vitrum, graded) into a test tube,
In the test tube, prepare an inner diameter of 3. Inner diameter 3. into which the button m1 and 38 mm stainless steel mandrel have been inserted. The polyester knitted tubular body of button m is put in and immersed. Next, the test tube was placed in a glass vacuum chamber, and 4IIIInF
Degassing operation was performed until the weight became 1 g. Next, the tubular body that had been degassed was placed in a test tube containing 50 units/1 Ill of thrombin solution (manufactured by Mochida Pharmaceutical Co., Ltd.), and a dipping operation was performed with the mandrel inserted.

After confirming that fibrin gel was completely formed on the surface of the tubular body, the tubular body was taken out, and then the mandrel was pulled out to create tubular bodies 1 and 2.

(Example 2) 39 mg/m/human fibrinogen solution (Kabi
A polyester knitted tubular body having an inner diameter of 3.3 mm is placed in a test tube and immersed in the test tube. Next, the test tube was placed in a glass vacuum chamber and degassed until it became 4 wings. Next, the tubular body that had been degassed was placed in a test tube containing 50 units/il of thrombin (manufactured by Mochida Pharmaceutical Co., Ltd.) in advance, and an immersion operation was performed. After confirming that fibrin gel has been completely formed on the surface of the tubular body, take out the tubular body and fill the inner lumen with an inner diameter of 3. Buttons m1 and 3. Pass through the stainless steel mandrel of button m, and insert the tubular body 3
and 4 (comparative example) A connector was fixed to one end of a polyester knitted tubular body with an inner diameter of 3.8111 mm, and from the connector, 50 uni
t// thrombin solution (manufactured by Mochida Pharmaceutical Co., Ltd.) was injected using a syringe, and then 30IIg// was injected from the same connector.
Ill's fibrinogen solution (Kabi Vit
rum, graded) using a syringe. Next, close the opening on the opposite side of the connector with forceps,
Furthermore, the same fibrinogen solution is injected under pressure. When fibrin gel is formed on the surface of the tubular body, remove the forceps, and then use a syringe to inject physiological saline into the lumen of the tubular body to wash away the fibrin gel that is not attached to the blood vessel surface. I got it.

The obtained tubular bodies 1 to 5 were cut from the long sleeve direction, and the cross-section was observed under an optical microscope, and it was found that in the tubular bodies 1 to 4 according to Examples, the thickness of the fibrin gel formed was approximately It was uniform, and there were almost no air bubbles remaining in the pores. In particular, in the cases where the mandrel was press-fitted (tubular bodies 2 and 4), the fibrin gel completely penetrated into the pores, and no air bubbles were present. On the other hand, in the tubular body 5 of the comparative example, although there are some parts where fibrin gel has penetrated into the pores, there are also parts where there is almost no fibrin gel and air bubbles remain. Moreover, the thickness was also non-uniform.

(Antithrombotic evaluation in vitro circulation experiment) Bendoparbital was injected into the ear vein of a healthy Japanese white rabbit with no clinical abnormalities, and general anesthesia was administered.

Next, the arteriovenous artery and vein were exposed using a technique similar to general surgery. An A-V shunt circuit was constructed using a vinyl chloride tube with an inner diameter of 4.0 mm in which tubular bodies 1 to 5 were inserted, and after priming with physiological saline, an indwelling needle was inserted into the exposed arterial artery and vein. I connected it and started the circulation experiment.

After circulating for 24 hours, tubular bodies 1 to 5 were removed from the circuit and their surface conditions were visually observed.
No leakage of blood was observed in any of the tube-shaped bodies 4, whereas blood leakage was observed on the outer surface of the tubular body 5.

(Effects of the Invention) As detailed above, the method for attaching a gel-like substance to a medical base material according to the present invention involves forming a gel-like substance by causing a plurality of liquids to react on the surface of a medical base material. The method is characterized in that the obtained gel-like substance is adhered to the surface of the medical base material by pressure bonding, so that the gel-like substance is attached to the surface of the medical base material without requiring a high concentration or large amount of reaction solution. Furthermore, even when a porous material is used as a medical base material, the gel-like substance can sufficiently penetrate into the pores, so there is no risk of blood leakage, and the gel-like substance can be adhered evenly. The effect is achieved without the risk of the substance peeling off.

Claims (1)

[Claims] (1) A plurality of liquids are reacted on the surface of a medical base material to form a gel-like substance, and the resulting gel-like substance is pressed and attached to the surface of the medical base material. A method for attaching a gel-like substance to a medical base material, the method comprising: (2) The method for adhering a gel-like substance according to claim 1, wherein the medical substrate is formed of a porous material. (3) The method for adhering a gel-like substance according to claim 2, wherein the medical base material is a tubular body for an artificial blood vessel. (4) The gel-like substance attachment method according to any one of claims 1 to 3, wherein the gel-like substance is fibrin formed by a reaction between a fibrinogen solution and a solution containing an enzyme having a thrombin-like action. (5) The gel-like substance is fibrin containing soluble elastin formed by a reaction between a fibrinogen solution containing soluble elastin and a solution containing an enzyme having a thrombin-like action. The described gel-like substance adhesion method. (6) The gel-like substance includes an acidic collagen solution;
Claims 1 to 3 are collagen gels formed by reaction with alkaline neutralizers or alkaline buffers.
The method for adhering a gel-like substance according to any one of the above. (7) A medical device characterized in that a region to be contacted with blood is coated with a gel-like substance using the attachment method according to any one of claims 1 to 6.