JP2001346866A - Hybrid resin material and its manufacturing method - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a hybrid material which substantially maintains the solubility of a soluble substance in a biophysical body, and makes a controlled release of the soluble substance after the soluble substance is filled in cavities or gaps of a porous hydrophobic resin. SOLUTION: When the soluble substance is arranged in the cavities or gaps which constitute a porous structure comprising the hydrophobic resin, a two-dimensional or three-dimensional structural change using a polar solvent is imparted to the soluble substance. Thus, this hybrid resin material wherein the soluble substance can be solved by the water-containing polar solvent even under a state wherein the soluble substance is arranged in the porous structure can be obtained.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a hybrid resin material comprising a porous structure made of a hydrophobic resin and a soluble material arranged in pores and / or gaps in the porous structure. In addition, the present invention relates to a hydrophobic resin material capable of obtaining an appropriate dissolution delay of a soluble material by disposing the material in a porous structure.

[0002] The hybrid resin material of the present invention can be suitably used, for example, as a material that is compatible with placement in a living body or on a living body surface. It can maintain a (semi) permanent mechanical strength, and after a certain period of time, can be suitably used as a material that can be implanted in a site of a living body requiring cell affinity.

[0003]

2. Description of the Related Art The hybrid resin material of the present invention can be applied without particular limitation to the field in which a proper dissolution delay of a dissolvable material is required by disposing it in a porous structure. Alternatively, background art relating to a material that is compatible with placement on a biological surface (particularly, a material that can be implanted at a site requiring cell affinity after a certain period of time) will be described.

[0004] While having flexibility in a living body or a living body surface, a (semi) permanent mechanical strength, a temporary mass transfer blocking action, a liquid substance leakage preventing action, and the like are required. Several techniques have already been developed in the areas of artificial bones, artificial blood vessels, patch materials and the like as materials suitable for sites to be implanted in sites that also require cell affinity.

[0005] Typical techniques for such materials include:
Collagen-coated artificial blood vessels. This collagen-coated vascular prosthesis maintains its strength in the living body while maintaining (semi) permanently strong strength that does not burst even by internal pressure in the living body. Immediately after implantation, blood leaks from the lumen and the wall of clogging substances After a long period of implantation, the collagen covering the artificial blood vessel is absorbed in the living body, and the host cells derived from the living body displace the collagen. The blood vessels become biocompatible.

Although several types of collagen-coated artificial blood vessels have already been put into practical use, a typical technique is disclosed in US Pat. No. 5,537,025 to Hoffman, Jr., Harmon et al.
197,977. This collagen-coated artificial blood vessel has a tubular shape made of a flexible synthetic polymer material fiber material and has a diameter of 120 mmHg (1 mmHg = 133.322 kP).
By applying a muddy biodegradable substance made of collagen to a porous structure having a water permeability of 3,000 l / min · cm or less in a) while massaging the structure, the structure is made of collagen. In this technique, the collagen is coated with a chemical crosslinking agent to further insolubilize the coated collagen. With this,
The cross-linked collagen temporarily prevents the movement of substances in the living body through the artificial blood vessel, for example, leakage of blood, and after a certain period of time, the collagen is degraded in the living body (cells derived from the living body Substitution), and as a result, the artificial blood vessel exhibits cell affinity. Ultimately, the tubular synthetic polymer material that is not degraded in vivo maintains (semi) permanent mechanical strength.

In this US Pat. No. 5,197,977,
Polyethylene terephthalate fibers are used as a synthetic polymer base material, and the fibers are knitted or woven to form a tubular structure, and the tubular structure is further coated with collagen. Collagen-coated vascular prostheses using this technology are currently being used clinically worldwide, which has led to several difficulties, such as bleeding through vascular prostheses immediately after implantation. Has been resolved.

Other techniques related to the above include US Patent No. 4,842,575 and National Patent No. 5,108,4.
No. 24, National Patent No. 5,131,907, National Patent No. 5,
No. 609,631, U.S. Pat. No. 5,693,098,
U.S. Pat. No. 4,416,208, U.S. Pat.
5,419, U.S. Pat. No. 4,581,028, U.S. Pat. No. 5,716,660, U.S. Pat.
No. 028, and the like.

[0009] Of these patents, US Pat.
No. 2,575, U.S. Pat. No. 5,108,424, etc.
A combination of biodegradable collagen and a tubular structure of non-biodegradable Dacron fiber (Dupont's trademark; polyester fiber) to prevent blood leakage from the artificial blood vessel wall. is there. Also, U.S. Pat.
No. 6,660 discloses a combination of a biodegradable collagen and a heat-stretched e-PTFE tubular structure. Further, in U.S. Pat. No. 4,581,028, metals are simultaneously mixed and fixed by trapping for the purpose of preventing infection. U.S. Pat. No. 5,131,907
The article also uses a collagen coating for the purpose of creating a favorable situation for seeding vascular endothelial cells.

[0010] Only the artificial blood vessel made of Dacron, that is, a polyester fiber, has a small surface area due to its simple structure, and has a limited absorption and adsorption amount of substances.
It is difficult to adsorb a functional substance such as an antithrombotic drug, a cell growth factor, an anti-infective substance, an antibiotic, etc. to such a synthetic polymer material and gradually release the substance in a living body. However, if the artificial blood vessel is coated with collagen or the like which is a biodegradable substance, the collagen or the like adsorbs functional substances such as these drugs, and after the artificial blood vessel is implanted in the living body, By decomposing in vivo, the functional substance and the like adsorbed therein can be released gradually, so that the artificial blood vessel can have multiple functions. It is well known that such techniques are clinically useful.

Therefore, a hybrid material containing a biodegradable material mainly composed of polyester fiber and a biodegradable material can be provided only with an artificial blood vessel from the viewpoint that the above-mentioned functionality can be imparted. It is used in many areas, and it is expected that the range of use will expand in the future.

As an artificial blood vessel, there is an artificial blood vessel made of e-PTFE (expanded / porous PTFE) other than the above-mentioned product using the polyester fiber, and is used mainly in a peripheral blood vessel region. As a technique for hybridizing the e-PTFE artificial blood vessel and the biodegradable material, K. Oki
No. 4,193,138 to Ta. This is a technique in which a water-soluble substance is impregnated into a fibril gap of an e-PTFE artificial blood vessel to make the water-soluble substance water-insoluble. By this technique, the surface as well as the inside of the e-PTFE artificial blood vessel is covered with a hydrophilic substance. As a bioabsorbable substance for this, K. Okita is polyvinylpyrrolidone, polyvinyl alcohol, polyethylene oxide,
It is recommended to use polyvinylamine, polyethyleneimine, polyacrylic and polymethacrylic acid, hydroxyester or carboxyester of cellulose, polysaccharide or the like alone or in combination. e-
Although the PTFE artificial blood vessel is originally a hydrophobic substance, this treatment makes it possible to impart hydrophilicity to the e-PTFE artificial blood vessel.

K. Okita's recommended polyacrylic acid, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene oxide, polyvinylamine, polyethyleneimine,
Polymers such as polyacrylic and polymethacrylic acid, hydroxyester or carboxyester of cellulose, and polysaccharide are strongly hydrophilic, so they are repelled by a hydrophobic e-PTFE artificial blood vessel, and the narrow gaps of e-PTFE fibrils are Difficult to enter. To compensate for this shortcoming, K. Okita pre-treated by immersing the e-PTFE graft in methanol, ethanol, acetone, or a surfactant, and then placing the e-PTFE graft in water. Immersion to replace the methanol, ethanol, acetone, or surfactant with water, and then e-PTF after the water replacement treatment in a liquid of a hydrophilic biodegradable material.
The three-stage method of immersing the E artificial blood vessel is recommended.

K. Okita has adopted a thermal cross-linking method as a method for insolubilizing these polymers inserted into the fibril space of the e-PTFE vascular prosthesis.
Heating the PTFE graft to 150-160 ° C; K. Okita further recommends that the water-soluble polymer be made macromolecules to be insolubilized by acetylation, esterification and the like.

That is, e-PTF which is originally hydrophobic
In the artificial blood vessel made of E, how to form a hybrid state with a hydrophilic biodegradable material, how to entangle the biodegradable material in the wall of the e-PTFE artificial blood vessel, How to insolubilize the biodegradable material has been the point of each technique.

Thus, a technique was developed in which a hydrophilic material was inserted into the fibril space of an e-PTFE vascular prosthesis. However, when a hydrophilic material was thermally cross-linked as employed by K. Okita, K. Okita itself As also pointed out, the hydrophilic property, which is a characteristic of the hydrophilic biodegradable material, may be reduced and the water content may be reduced. Furthermore, even when the hydrophilic substance is inserted into the fibril gap of the e-PTFE artificial blood vessel in this manner, the surface of the e-PTFE artificial blood vessel becomes hydrophilic, but the inside of the e-PTFE artificial blood vessel wall is kept to the last. Remains hydrophobic. Therefore, even if a hydrophilic substance is inserted into the fibril space of the e-PTFE artificial blood vessel, e-PTFE
In some cases, it is difficult to bring the entire FE artificial blood vessel into a state of imparting hydrogel forming properties by making it hydrated.

Apart from the above-mentioned K. Okita technology, e-P
K Weadock, DJ Lentz, RJ Zdrahala include techniques for hybridizing TFE artificial blood vessels with biodegradable materials.
No. 5,665,114 and U.S. Pat. No. 5,716,660. They are e-PTFE
A technique was developed to fill the space between fibrils of an artificial blood vessel with a biodegradable material of natural origin which is insoluble at around pH 7.4.

They recommend collagen, gelatin, fibronectin, laminin, and mixtures thereof as biodegradable materials of natural origin, as well as polyvinyl alcohol, which K. Okita recommended in US Pat. No. 4,193,138. In addition, polyethylene oxide, polyethylene glycol, methylcellulose, ethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose are also recommended.

Among these, they place particular importance on the inclusion of collagen. Collagen fibers of natural origin and not subjected to any chemical treatment are hardly soluble in water at around pH 7.4. In this regard, K. Weadock, DJ Len
U.S. Pat. No. 5,665,11 by tz, RJ Zdrahala et al.
No. 4 and U.S. Pat. No. 5,716,660 utilize morphological changes due to differences in the hydrogen ion concentration of collagen. In other words, collagen has a low ionic strength in an acidic region, and thus easily swells and dissolves. Therefore,
In this acidic state, collagen is dissolved and e-PT
The space between fibrils of the FE artificial blood vessel is filled, and thereafter, the hydrogen ion concentration is changed to return to the neutral region to insolubilize the collagen, and further, an insolubilization treatment for chemically cross-linking the collagen with formalin vapor is added.

Although this method is effective for collagen having an isoelectric point in an alkaline region, other substances such as fibronectin, laminin, polyvinyl alcohol, etc., which are recommended by them, change the form or water solubility by changing the hydrogen ion concentration. Since there is no significant difference in the degree, there is little effect in terms of dissolution in the acidic region. Therefore, their method is a special means which is effective only for collagen fibers which are of natural origin and have not undergone any chemical treatment.

As described above, e-PTFE artificial blood vessels are hydrophobic, and a special device is required for infiltrating them with an aqueous solution of a hydrophilic substance. Further, even if collagen or the like is filled in the space between fibrils of the e-PTFE artificial blood vessel which is a hydrophobic substance, such a hydrophilic substance always tries to dissociate from the surface of the e-PTFE which is a hydrophobic substance. Is unstable due to the nature of

In other words, even if the water solubility of collagen or the like is increased by changing the hydrogen ion concentration, it does not penetrate into the fibrils of the e-PTFE artificial blood vessel which is a hydrophobic substance. To solve such problems, K
Weadock, DJ Lentz, RJ Zdrahala et al.
No. 716,660 discloses that e-PTFE artificial blood vessels are preliminarily treated with plasma, and the surface thereof is modified to form e-PT artificial blood vessels.
A treatment to increase the hydrophilicity of the FE is recommended. This is K. O
kita US Pat. No. 4,193,138.
Although this is a means different from the stepwise method, there is a possibility that a hydrophilic substance can easily enter the fibril gap of the e-PTFE artificial blood vessel having enhanced hydrophilicity.

Further, they close one end of the e-PTFE artificial blood vessel, and inject a collagen solution or the like under pressure from the other end. The injection time and pressure difference are not strict, but are 1 to 10 minutes, and vary depending on the porosity of the e-PTFE artificial blood vessel, but the injection is performed until the pores of the artificial blood vessel are filled with collagen or the like.

In this method, collagen or the like is laminated in the hole of the e-PTFE artificial blood vessel by pressurization, and the space of the hole is almost occupied by collagen or the like. Therefore, the relationship between the e-PTFE artificial blood vessel and the biodegradable substance such as collagen is mechanically entangled. However, there is no description about the solution concentration of a biodegradable substance such as collagen at this time.

Therefore, it is considered that the volume of the biodegradable substance occupies the hole of the e-PTFE artificial blood vessel. This is a very general idea as a method for coating a porous artificial blood vessel. However, in this method, a certain amount of pressure needs to be applied to inject a hydrophilic collagen solution into a narrow fibril space of a hydrophobic e-PTFE artificial blood vessel.

On the other hand, as a method for insolubilizing a biodegradable material, formaldehyde is generally used as shown in US Pat. No. 5,197,977. On the other hand, glutaraldehyde and dialdehyde starch,
Since chemicals such as polyepoxy compounds and isocyanate compounds also have a crosslinking action, they are generally used for the purpose of insolubilizing such biodegradable materials.

However, in a recent report, it is reported that a chemical cross-linking agent such as formaldehyde has cytotoxicity when implanting an artificial blood vessel coated with collagen and insolubilized with a chemical cross-linking agent such as formaldehyde. DP Speer et al .: J. Biomed. Mater. Res.
14; 753-764, 1980). In general, cytotoxicity due to cross-linking agents has been reported for some time.
It has also been reported that its cytotoxicity occurs over the years.

US Pat. No. 4,193,1 to K. Okita
No. 38 and U.S. Pat. Nos. 5,665,114 and 5,716,660 by K. Weadock, DJ Lentz, RJ Zdrahala et al. It is to insolubilize the substance filled in the surface of the blood vessel and the fibril space in vivo.

US Pat. No. 4,193,1 to K. Okita
In No. 38, 1
Heating is performed at 50 to 160 ° C. to change a water-soluble material into a water-insoluble substance. However, sufficient thermal crosslinking must be performed to make the water-soluble material completely water-insoluble, which has the disadvantage that the hydrophilic material becomes hydrophobic. For this reason, even if the material is a hydrophilic material, the water content is reduced, and there is a defect that the whole material is cured. K. Oki
As pointed out in US Pat. No. 4,193,138 to ta, the soluble material remains partially soluble when the degree of crosslinking is low.

[0030]

SUMMARY OF THE INVENTION An object of the present invention is to provide a hybrid resin material which has solved the above-mentioned disadvantages of the prior art. Another object of the present invention is to substantially maintain the solubility of a soluble substance in a living body while maintaining the solubility of the soluble substance in the pores or spaces of the porous hydrophobic resin. It is an object of the present invention to provide a hybrid material that enables a sustained release of a substance.

[0031]

Means for Solving the Problems As a result of earnest studies, the present inventors have found that individual functional groups (for example, proteins constituting proteins) constituting soluble substances (for example, proteins) by pH change, use of a cross-linking agent, etc. as in the past. It is not essential that water insolubility be imparted one-dimensionally to each amino acid functional group itself, but rather, a soluble substance is introduced into the pores or gaps that constitute the porous structure made of hydrophobic resin. The above-mentioned object is to provide a two-dimensional or three-dimensional structural change using a polar solvent when disposing, and rather to temporarily give a soluble substance a change similar to two-dimensional or three-dimensional denaturation. Was found to be extremely effective in achieving

The hydrophobic resin hybrid material of the present invention is based on the above findings, and more specifically, a porous structure made of a hydrophobic resin, and disposed in pores and / or gaps constituting the porous structure. And at least a soluble substance, the soluble substance is soluble in a polar solvent, and the soluble substance is soluble in the water-containing polar solvent even in a state of being disposed in the porous structure. is there.

Further, according to the present invention, by dissolving or dispersing a soluble substance soluble in a polar solvent in a polar solvent in a pore and / or a gap of a porous structure made of a hydrophobic resin. The present invention also provides a method for producing a hybrid resin material that forms a hybrid material that can be dissolved in the polar solvent even when the soluble substance is disposed in the porous structure.

According to the findings of the present inventor, the reason why a favorable effect is obtained in the hydrophobic resin hybrid material of the present invention having the above constitution is presumed as follows. That is, in the present invention, when a soluble substance (generally having a hydrophilic portion and a hydrophobic portion in its molecule) is arranged in a porous structure made of a hydrophobic resin, the soluble material is a polar solvent ( (For example, a water-containing solvent). At this time, the solubility of the hydrophilic substance and / or the hydrophobic group constituting the soluble substance depends on the polarity of the polar solvent (or the balance between hydrophilicity and hydrophobicity). Is in a completely hydrophilic solvent, 100% water (having the hydrophilic groups almost completely oriented toward the outer solvent) in a different two-dimensional or three-dimensional configuration (conformation), It is presumed that the hydrophilic group is oriented to the inside of the molecule of the soluble substance to some extent, and the hydrophobic group is oriented to the outside of the solvent to some extent.

In the present invention, the soluble substance in the polar solvent has a specific conformation (100
% Of water, which is slightly more hydrophobic than the water-balance of the directionality of hydrophobicity), it is presumed that it can be smoothly arranged in a porous structure made of a hydrophobic resin.
On the other hand, the conformation of the soluble substance arranged in the porous structure in this manner gradually becomes conformational (eg, in water) under a predetermined environment (eg, a hydrophilic environment in a living body). , The hydrophilic group is almost completely returned to the outer solvent direction). However, in this case, since the soluble substance has already been arranged in the porous structure made of the hydrophobic resin, its solubility depends on the influence of the “field” of the porous structure made of the hydrophobic resin. It is presumed that it will be strongly received (for example, the approach of the water molecule to the soluble substance will be suppressed or reduced by the repulsion based on the hydrophobic resin). In the present invention, it is presumed that such a “field” effect provides a suitable “delayed solubility” of the soluble substance.

From another viewpoint, the feature of the present invention is that, even under physiological conditions of mammals (typically, pH 7.4), the dissolution or dispersion of a soluble substance can be achieved by using a water-containing polar solvent. Utilizing the ability to control the hydrophobic resin so that it can be easily filled into the pores or gaps of the hydrophobic resin,
It has been found that a soluble substance can be filled into pores or gaps of a hydrophobic resin mildly and substantially intact. By combining this technique, the pores or gaps of the porous structure made of the hydrophobic resin are filled with the soluble substance, and while maintaining the solubility substantially due to intact, the "field" of the hydrophobic resin is maintained. It is presumed that the material is not rapidly dissolved based on the effect, and that the soluble material can be gradually released into the living body from the pores or gaps of the hydrophobic resin.

[0037]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, the present invention will be described more specifically with reference to the drawings as necessary. In the following description, “parts” and “%” representing the quantitative ratios are based on mass unless otherwise specified. (Hybrid material) The hybrid material of the present invention contains at least a porous structure made of a hydrophobic resin and a soluble substance arranged in pores or gaps constituting the porous structure. This soluble substance can be dissolved in a hydrated polar solvent, and can be dissolved in a hydrated polar solvent even when it is disposed in the porous structure. Here, "soluble in a water-containing polar solvent" means that it can be completely dissolved in a 50% ethanol-distilled aqueous solution. The dissolution time (S) required to completely dissolve the soluble substance alone in the hydrated polar solvent, and the dissolution time required for completely dissolving the soluble substance in the hydrated polar solvent in the state disposed in the hydrophobic resin material The ratio (H / S) to the dissolution time (H) is preferably 1.2 or more, more preferably 1.5 or more (especially 2.0 or more).

In the present invention, the presence or absence of such solubility and the dissolution time can be suitably confirmed, for example, as follows. <Confirmation method of solubility and dissolution time> A predetermined amount (for example, about 1 g) of a substance to be dissolved is placed in a glass beaker, and 50% ethanol of 1000 times the volume of the soluble substance is added.
Distilled aqueous solution was gently added to the beaker and allowed to stand at room temperature (25
(° C.) with a stirrer once a second while stirring and standing still (in this case, distilled water for preparing 50% ethanol is used in a pH range of about 7 to 7.4. The pH of distilled water may be adjusted with a pH adjuster or the like, if necessary.)

In this state, the state of the soluble substance is continuously observed visually, and the time when the soluble substance disappears to a state where it does not retain its original form is defined as the time of "completely dissolving". If the complete dissolution time is within 24 hours, it is defined as "soluble" in the present invention. In the measurement of the dissolution time (H) of the soluble substance disposed in the porous structure of the hydrophobic resin described above, unless otherwise specified, 50% of 1000 times the volume of (hydrophobic resin + soluble substance) unless otherwise specified. An ethanol-distilled aqueous solution is used. (Hydrophobic resin) In the present invention, in view of long-term stability and biocompatibility in a living body, a hydrophobic resin is used as a material constituting a porous structure in which a soluble substance is to be held for a certain period of time.

The hydrophobic resin usable in the present invention is not particularly limited as long as the above-mentioned soluble substance can be retained for a certain period of time. However, a polar group containing an oxygen, nitrogen or sulfur atom (for example, -OH , -COOH, -NH ₂ group,
-SO ₃ H group, etc.) per molecule
n and the weight average molecular weight of the resin is Mw, the ratio (Pn / Mw) can be suitably defined. From the viewpoint that hydrophobic resins are frequently used clinically, resins having a Pn / Mw of 1/100 or less (more preferably 1/200 or less, particularly 1/300 or less) can be suitably used. The form of the polymer such as a homopolymer, a copolymer, a polymer blend, and a composite polymer is not limited as long as it has the above characteristics.

Preferred examples of the hydrophobic resin include a fluorine-containing resin, a silicon-containing resin, a polyolefin resin, and a polyester resin. As such a fluorine-containing resin, for example, polytetrafluoroethylene (PTFE)
Resins. Examples of the silicon-containing resin include a silicone resin. As the polyolefin resin, for example, polypropylene (P
P) Resins and the like.

Among these, fluorine-containing resins and silicon-containing resins are preferable from the viewpoint of stability or toxicity in vivo. (Porous Structure) In the present invention, the above-mentioned hydrophobic resin is used as a porous structure. The porous structure that can be used in the present invention is not particularly limited as long as the porous structure can be filled with a soluble substance in pores and / or gaps and can be maintained for a certain period of time. It preferably has a fibril (ie, fiber-containing) structure. Such a fibril structure is not particularly limited.
Specific examples of the fibril structure include, for example, a woven fabric, a knitted fabric, a net-like structure, a nonwoven fabric, and a felt.

In the case of fabric, ANSI / AAMI (As
sociation for the Advancement of Medical Instrument
ation American National Standard Institute, Inc. (1
Water Permeabilty as defined in 994))
It is preferably in the range of not more than 50 ml, more preferably in the range of 2000 to 50 ml (particularly in the range of 1000 to 100 ml). In the case of a material that does not allow water to permeate, such as e-PTFE, the fibril length is 300 μm to 5 μm.
μm, furthermore 100 to 20 μm (particularly 50 to 25 μm)
It is preferred that (Soluble substance) The above-mentioned soluble substance to be disposed in the pores or gaps of the porous structure of the hydrophobic resin preferably has a hydrophilic portion and a hydrophobic portion in its molecule. Here, the “hydrophilic portion” refers to a polar group containing an oxygen, nitrogen, or sulfur atom (for example, —OH, —COOH, —NH ₂
Groups, moieties having -SO ₃ H group, etc.) (e.g., refer to monomer units), the term "hydrophobic moiety" refers to a portion without such polar groups. When all or part of the soluble substance is a protein, the hydrophilic portion is composed of hydrophilic amino acids, and the hydrophobic portion is composed of hydrophobic amino acids.

The above-mentioned soluble substances are not particularly limited as long as they exhibit different solubilities in a water-containing organic solvent and in water. The solubility can be suitably measured by the following method. <Method of Measuring Solubility> Solvent: 50% ethanol or distilled water pH: 7 to 7.4 (can be confirmed using a commercially available pH meter, for example, model 230A manufactured by Orion, Inc.) Dissolution method: Stir with a stirrer 100 times / minute, and slowly put into the solvent.

The above-mentioned soluble substance has a solubility in 50% ethanol at pH 7.4 of 0.1% or more from the viewpoint of facilitating filling and sustained release into a porous structure that can be placed in a living body. Further, it is preferably at least 0.5%, particularly preferably at least 1.0%. Examples of the soluble substance that can be suitably used in the present invention include, for example, gelatin, succinylated gelatin, and alkylated gelatin described below as proteins. In this solubility measurement, if necessary, heating may be performed once (about 50 ° C.).

(Solubility in Distilled Water) The solubility in “distilled water” in the present invention is determined by adding 100 times the volume of a soluble substance to distilled water having a pH of about 7 to 7.4 with a stirrer at room temperature.
When the substance disappears to a state where the original is not retained within one week under the condition of stirring at 00 times / minute, the soluble substance is defined as soluble in distilled water.

(Solubility Under Physiological Conditions) Under physiological conditions, in particular, when examining the solubility of collagen, gelatin, etc., 0.1% of the collagen to be dissolved is at least 100 times the volume of the substance to be dissolved. In a phosphate buffer solution having a pH of 7.4, the temperature was maintained at 37 ° C., and the mixture was stirred every 12 hours with a stirrer at 100 rpm.
Solubility is defined as the case where the substance to be dissolved within 2 hours has disappeared to a state where it does not retain its original form.

A collagen membrane cross-linked with formaldehyde or glutaraldehyde, such as bovine pericardium,
Under such conditions, no solubility is exhibited. On the other hand, 13
Gelatin sponge films thermally crosslinked at 5 ° C. for 24 hours show solubility.

The kind and form of the soluble substance (for example, a substance that can be dissolved at around pH 7.4) usable in the present invention are not particularly limited. Even with the same substance,
As described above, the dissolution rate can be controlled by changing the conditions. (Specific Examples of Soluble Substance) Specific examples of the soluble substance usable in the present invention include, for example, polyglycolic acid, polylactic acid, polylactic acid-polyglycolic acid copolymer, biodegradable (3-hydroxybutyrate-4-hydroxybutyrate) Polyester polymer, polydioxane, collagen, gelatin, albumin, chitosan, chitin, phospholipid, cellulose, fibroin, fibronectin, vitronectin, laminin, protamine, other than mammals by genetic manipulation Collagen made from organisms, gelatin made from non-mammalian organisms by genetic manipulation, hyaluron sun created from non-mammalian organisms by genetic manipulation, laminin created from non-mammalian organisms by genetic manipulation, mammals by genetic manipulation Chondroitin sulfate produced from other organisms, albumin produced from non-mammalian organisms by genetic manipulation, biodegradable substances produced from genetically engineered organisms, polyvinyl alcohol, polyacrylamide, polyvinylamine , Polyethyleneimine, polyvinylpolypyrrolidone, polyacrylic acid, and derivatives thereof. These may be used after adjusting the degree of solubility as needed. The soluble substance that can be used in the present invention is not limited to a biologically-related substance as long as the above-mentioned “solubility” condition is satisfied.

The soluble substance that can be used in the present invention, whether it is a naturally-derived material or a synthetic polymer-derived material, can be genetically engineered into living organisms as long as the above-mentioned “solubility” condition is satisfied. The material may be a prepared material or a derivative thereof, and if necessary, may be a mixture, a complex, or an aggregate obtained by combining them.

Among the above bio-related substances, there are polymers which are artificially produced by bacteria, such as biodegradable (3-hydroxybutyrate-4-hydroxybutyrate) polyester polymers. Among saccharides, there are those having a large molecular weight such as hyaluronsan and those having a small molecule such as chondroitin sulfate. Some of them have a charge and some do not. For example, hyaluronic acid is negatively charged and protamine is positively charged. Gelatin is also weak but positively charged. When these are mixed and used, a macromolecular aggregate is formed by ionic bonding between the polymers, and thus the dissolution rate is further reduced.

(Modification, Modification, etc.) In the present invention, the above-mentioned soluble substance can be arranged in a porous structure made of a hydrophobic resin substantially intact. However, this soluble substance may not meet the solubility conditions described above (and / or
Or "the compound is soluble at around pH 7.4" or "is treated by the action of dissolving, decomposing, dispersing, absorbing, etc. under physiological conditions in a mammalian organism". Alternatively, the side chains and the like of the substance may be changed by a chemical treatment or the like. At this time, if a part of the substance is subjected to chemical modification such that a hydrophobic group such as an acyl group, an alkyl group or a phenyl group is attached, the substance becomes hydrophobic, and the dissolution rate by water decreases. On the other hand, since it is hydrophobic, it easily enters the pores or gaps of the porous structure made of a hydrophobic resin, and more stable filling is possible.

When a hydrophilic group such as a hydroxy group, a carboxy group, an amino group, a carbonyl group, a sulfo group, etc. is introduced into a part of a substance which undergoes such chemical modification, the degree of hydrophilicity of the substance increases. Thus, the solubility in water is improved.
Further, when such a substance is filled in the pores or gaps of the porous structure made of the hydrophobic resin, water is easily introduced into the pores or gaps of the porous structure made of the hydrophobic resin, and the soluble substance It contributes to increasing the dissolution rate.

Therefore, taking into account the control of the dissolution rate of the dissolvable substance and the stability when the pores or gaps of the porous structure made of a hydrophobic resin are filled, a hydroxy group, a carboxy group, etc. , A hydrophilic group such as an amino group, a carbonyl group and a sulfo group, and a hydrophobic group such as an acyl group, an alkyl group and a phenyl group can be attached or bonded as a side chain.

(Embodiment using a substance which can be dissolved under physiological conditions) In the present invention, the substance can be dissolved even under physiological conditions of mammals having a pH of 7.4, but the dissolution is rapid and extremely slow. An embodiment utilizing the existence of an object will be described. For example, taking simple gelatin as an example, gelatin can be dissolved in water heated at around pH 7.4, and if it is at a concentration of about 1%, it will usually be dissolved in water within 5 minutes. However, at a concentration of 30%, it takes about 3 to allow the gelatin to swell and dissolve completely in water.
It takes 0 minutes or more. This is because in a high molecular substance such as gelatin, water molecules infiltrate into the space between individual gelatin molecules,
The individual gelatin molecules swell and the gaps between each other's gelatin molecules open, resulting in the individual gelatin molecules diffusing into the water and the gelatin molecules becoming progressively lower in water (ie, dissolving uniformly). Requires a certain amount of time.

For example, in a succinylated gelatin in which a carboxyl group is attached to a part of a gelatin molecule, the hydrophilicity of the gelatin molecule is increased, so that water molecules can easily enter between the individual gelatin molecules, and thus the gelatin molecule can be easily removed. Easily swells and the solubility is promoted. On the other hand, in the alkylated gelatin to which myristylic acid is attached, the hydrophobicity of the gelatin molecules becomes strong, and water molecules hardly enter between the individual gelatin molecules. Thus, the swelling of the alkylated gelatin is slowed, resulting in a slower dissolution rate and slower dissolution, requiring about 24 hours to reach a 30% solution.
These are phenomena caused by changing the affinity with water by chemical modification of the side chain of gelatin. Even if such a change occurs, both succinylated gelatin and alkylated gelatin have a pH of 7. In the vicinity of 4, the substance is still soluble.

Furthermore, the dissolution rate varies depending on the form of handling such a soluble substance having solubility at around pH 7.4. For example, 10% gelatin in a wet state (the mass of gelatin used is converted to the concentration with respect to water; hereinafter the same in the description of "gelatin") is put into water having a pH of about 7.4 and left at room temperature. Then, it is completely dissolved in about one hour. On the other hand, 10
Once the% gelatin is lyophilized into a sponge, it takes about 2 hours to dissolve it. Further, in the case of a film prepared by naturally drying 10% gelatin as an aqueous solution, it takes 48 hours or more to completely dissolve it. Therefore, the time required for further dissolution varies depending on the type of gelatin used, such as alkylated gelatin or succinylated gelatin. However, both 10% gelatin in a wet state, gelatin that has been freeze-dried to form a sponge, and gelatin that has been formed into a film by natural drying are both substances that can be dissolved at around pH 7.4. There is no change (that is, any form can be used in the present invention).

These substances are all substances that can be dissolved at around pH 7.4, which is one of the physiological conditions, but the dissolution rate may vary greatly depending on the form, concentration, formation conditions and the like. .

Such a substance having solubility at around pH 7.4 diffuses into a body fluid under physiological conditions when implanted in a living body of a mammal, is treated by a phagocytic cell, or is oxidized by an enzyme. As it decomposes, it disappears over time. Therefore, in the present invention, "a substance having solubility at around pH 7.4" and "a substance having a property of being treated by actions such as dissolution, decomposition, dispersion, and absorption under physiological conditions in a mammalian organism" include: It will have almost the same meaning, but "pH
The expression "around 7.4" merely specifies the hydrogen ion concentration in the solvent (no specification of in vitro, in vivo, or temperature). On the other hand, the expression "physiological conditions in a mammalian organism" defines the temperature in addition to the hydrogen ion concentration, and furthermore, the presence of various enzymes and the presence of phagocytic cells in the organism makes it extremely strict. I can say that.
The present invention relates to these "substances having solubility at around pH 7.4" and "substances having properties which are treated by actions such as dissolution, decomposition, dispersion, and absorption under physiological conditions in mammalian organisms". It is applicable to any of the above.

(Modification) As described above, in the present invention, chemical modification of the soluble substance is not essential. However, for soluble substances, the above-mentioned solubility conditions (and / or "dissolve, decompose, disperse, and absorb under physiological conditions in mammalian organisms" or "maintain solubility near pH 7.4" Or the like), a chemical modification treatment such as a characteristic crosslinking treatment may be appropriately performed.

In the case where the cross-linking treatment or the like is performed as described above, the time required for dissolution is maintained while maintaining the solubility and decomposability by keeping partial cross-linking within the molecule of the soluble substance. It is possible to slow it down. The idea is K We
adock, DJ Lentz, RJ Zdrahala et al.
No. 665,114 and US Pat. No. 5,716,660.
In contrast to the change in pH of a soluble substance and the insolubilization treatment using formaldehyde shown in the above item, the present invention is not limited to such insolubilization treatment,
Maintaining the solubility near 7.4 "is a preferable condition for the crosslinking treatment.

(Degree of cross-linking) As an index indicating the degree of cross-linking, when the cross-linking method uses a chemical cross-linking agent such as formaldehyde or glutaraldehyde, the amino group in the molecule of the absorbent substance is mainly used. Since it is used for the reaction, it is possible to measure the crosslinking ratio by measuring the remaining amount of amino groups. More specifically, for example, TNB
Method S (method using 2,4,6-trinitrobenzenesulfonic acid; literature Kakada, ML, Liener IE, Determination
of available lysine in proteins.Ann Biochem. 27:27
3-280.1969.Trinitrobenzene sulfonic Acid (TNBS) meth
od) can be used to determine the degree of crosslinking. However, in the case of physical crosslinking by ultraviolet rays, gamma rays, or the like (for example, in the case of collagen or gelatin, etc.), collagenase is used to reduce the degradability by the enzyme using collagenase (since amino groups are not used for crosslinking). By studying, the degree of crosslinking can be measured.

According to the experiment of the present inventors, for example, in the case of a sponge made of purified 2% atelocollagen,
Crosslinked with formaldehyde and measured by TNBS method as 9
With 0% amino groups used (highly cross-linked), digestion with 0.1% collagenase requires 48 hours for complete digestion. However, TN
In the case of a crosslinking rate of 40% by the BS method, digestion with 0.1% collagenase required 6 hours for complete digestion.

In the present invention, from the viewpoint of maintaining the solubility of the soluble substance, it is preferable that partial crosslinking is stopped even when crosslinking is performed as necessary. More specifically,
In the case of collagen or gelatin, it is preferable to keep light crosslinking within 12 hours (more preferably within 6 hours) for complete digestion by digestion with 0.1% collagenase. As described above, even if many types of substances that can be dissolved at around pH 7.4 are used alone,
Regardless of whether it is used in a mixed state or used after being subjected to a slight crosslinking treatment, the present invention achieves the purpose by considering various conditions such as the concentration and form of each substance, production conditions, degree of crosslinking, and the like. It is possible.

(Filling Method) In the present invention, a preferred embodiment of filling a soluble substance into pores or gaps of a porous structure made of a hydrophobic resin will be described. In this embodiment, a soluble substance is dissolved in a water-containing polar solvent such as alcohol, and a porous tube or sheet made of expanded polytetrafluoroethylene is placed at 5 mmH from one or both sides thereof.
This is a method in which a pressure difference such as a positive pressure or a negative pressure is applied within a range of not less than g and not more than 300 mmHg, and pressure is injected into the fibril gap.

Although the pressure difference is affected by the type and concentration of the soluble substance dissolved in the water-containing polar solvent, the temperature during the operation, etc., in order not to damage the wall of the porous structure made of the hydrophobic resin, It is desirable to be within the range of 30 to 100 Hg.

Injection into pores or gaps of a porous structure made of a hydrophobic resin which is hydrophobic unless an aqueous polar solvent such as an alcohol is used is accompanied by difficulties when the soluble substance is hydrophilic. K. Wea to solve the problem
dock, DJ Lentz, RJ Zdrahala et al.
No. 665,114 and US Pat. No. 5,716,660.
In the technology of No. 2, in order to suppress the hydrophobicity of the porous structure made of a hydrophobic resin, the surface thereof is made hydrophilic by performing a plasma treatment or a glow discharge treatment in advance, but in the present invention, the soluble substance is hydrophilic. Even if such a pretreatment is not essential, the porous structure made of the hydrophobic resin can be filled with a soluble substance. According to the present invention, this filling can be easily performed on a porous structure made of a normal hydrophobic resin.

A method of filling a hydrophilic substance without previously performing a plasma treatment or a glow discharge treatment on the surface thereof to hydrophilize a porous structure made of a hydrophobic resin is disclosed in US Pat. 4,193,13
There is No. 8 technology. K. Okita first performed a pretreatment in which a porous artificial vascular graft made of a hydrophobic resin was immersed in methanol, ethanol, acetone, or a surfactant. Water, replaces methanol, ethanol, acetone, or a surfactant that is immersed in water and penetrates into the fibril space of a porous artificial blood vessel made of a hydrophobic resin, followed by hydrophilic biodegradable material. A three-stage method of immersing a porous artificial blood vessel made of the hydrophobic resin in a liquid is recommended. It is described that a hydrophilic substance gradually permeates into the fibril space of a porous artificial blood vessel made of a hydrophobic resin by this method.

On the other hand, in the present invention, as described above, the object is achieved by a one-step method in which the material is simply dissolved in a water-containing polar solvent and filled into pores or gaps of a porous structure made of a hydrophobic resin. be able to. For example, in the case of a hydrophilic material such as gelatin, if the material is dissolved in 30 to 70% of ethanol, it can be directly filled into pores or gaps of a porous structure made of a hydrophobic resin. Moreover, even for hydrophobic phospholipids such as lecithin,
It can be dissolved in 70% ethanol to fill pores or gaps of a porous structure made of a hydrophobic resin. After filling, the water-containing polar solvent such as ethanol can be simply removed by natural drying or freeze-drying, and this treatment leaves only the soluble substance in the pores or gaps of the porous structure made of hydrophobic resin. Can be.

(Solvent for Filling) The kind of the hydrated polar solvent used is not particularly limited as long as the hydrated polar solvent can be dissolved or dispersed so that the soluble substance can be filled in the porous structure made of the hydrophobic resin. Not done. More specifically, for example, various water-containing polar solvents such as alcohol, dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, hexamethylsulfamide, and water can be used. Alcohols such as ethanol and methanol (and ethanol from the viewpoint of toxicity to living organisms when they remain) can be suitably used from the viewpoint of easy removal in handling. Further, a mixed solution of various solvents and water is preferable because the water-containing polar solvent used after the injection can be easily removed by evaporation or the like.

The mixing ratio at this time depends on the type and concentration of the soluble substance. For example, in the case of gelatin, a 50% ethanol solution is easily used. Further, 70% ethanol can be suitably used for succinylated gelatin having a carboxyl group attached to a gelatin molecule and acylated gelatin further having myristyl acid attached. As described above, the type and the mixing ratio of the water-containing polar solvent can be appropriately selected depending on the type of the soluble substance and its concentration.

(Sustained Release) As described above, according to the present invention, the elution of the material from the pores or gaps of the porous structure made of the hydrophobic resin is maintained in a sustained release while maintaining the solubility of the material. It is possible to do. This method is preferably achieved by utilizing release from pores or gaps of a porous structure made of a hydrophobic resin.

More specifically, in the present invention, for example, a soluble substance is dissolved in a water-containing polar solvent and filled in pores or gaps of a porous structure made of a hydrophobic resin. When implanted in a living body without performing the insolubilization treatment as it is in this state, even if it is a soluble substance that can be easily dissolved under the condition of pH 7.4, the pores of the porous structure made of a hydrophobic resin are used. Or when the gaps are filled, the "field" of the porous structure
Even if the insolubilization treatment of the soluble substance itself is not performed (based on the effect of (1)), the dissolution rate can be extremely slowed.

According to the present invention, the mechanism by which the slow release in the living body becomes possible in the present invention is as follows. That is, since the porous structure made of the hydrophobic resin is hydrophobic and the pores or gaps (for example, fibril gaps) of the porous structure are narrow, the soluble substance is dissolved in the water-containing polar solvent to fill the pores or gaps. Even if it is performed, the body fluid in the living body cannot easily enter the pores or gaps of the porous structure made of the hydrophobic resin. Even if body fluids can enter, the amount is extremely small and the concentration of soluble substances in the dissolved part is extremely high, so that the concentration can not be rapidly reduced to a low level and dissolution may not proceed easily. ing. Therefore, when implanted in another tissue outside the body, for example, in muscle or subcutaneous tissue, it is a soluble substance that is easily dissolved, dispersed in a living body, and disappears in a short time. However, when filled into pores or gaps of a porous structure made of a hydrophobic resin, they are dissolved and dispersed only very slowly, and as a result, can remain in the pores or gaps for a long time Becomes By utilizing the specialty of pores or gaps of the porous structure made of this hydrophobic resin,
Even with a soluble substance, it is possible to obtain a sustained release state from the porous structure made of the hydrophobic resin without performing the insolubilization treatment.

In the present invention, for example, such a substance which can be dissolved in a living body is dissolved in a hydrated polar solvent. When the soluble substance is strongly hydrophilic such as succinylated gelatin, the substance is Easy to be dissolved by water. However, since water does not easily penetrate into the narrow pores or gaps of the porous structural material made of a hydrophobic resin, the dissolution of even a highly hydrophilic substance is delayed. On the other hand, a soluble substance having a hydrophobic property such as lecithin can also be dissolved in a hydrated polar solvent and filled into narrow pores or gaps of a porous structural material composed of a hydrophobic resin. It can be dissolved in water and fats. However, the amount of fats and oils in body fluids in a living body is small in quantity, and its solubility is generally slow, and it is easy to form a large aggregate of molecules by hydrophobic bonds. Accordingly, in such a state, the solubility of the porous structural material made of the hydrophobic resin in the narrow pores or gaps is further delayed, so that a sustained release state can be obtained as in the case of the hydrophilic substance.

(Amphiphilic substance) Some substances may have both hydrophilicity and hydrophobicity (amphiphilicity). For example, succinylated and acylated gelatins are amphiphilic. In the case of such amphiphiles,
Since it can be easily dissolved or dispersed with a water-containing polar solvent such as ethanol, it can also be dissolved in a water-containing polar solvent and filled into narrow pores or gaps of a porous structural material made of hydrophobic resin. And a sustained release state can be obtained in the same manner as the hydrophilic substance and the hydrophobic substance.

As a method of combining such an amphiphilic material, the soluble substance may include at least one kind of hydrophilic group such as a hydroxy group, a carboxy group, an amino group, a carbonyl group, and a sulfo group as a hydrophilic portion. It is most efficient to use a material that has at least one hydrophobic group such as an acyl group, an alkyl group, or a phenyl group as the hydrophobic portion. Furthermore,
By combining a plurality of different materials having such properties and mixing them, it becomes possible to control the fine-grained sustained release, and therefore a place where cells can easily enter,
It is possible to appropriately induce the invasion of cells into a porous structure material made of a hydrophobic resin to be implanted in a living body, in accordance with a place where the invasion is difficult.

(Solution state, etc.) When dissolving a soluble substance in a water-containing polar solvent, it may be in any of a solution state, a suspension state, and a dispersion state. In such a state, as long as narrow pores or gaps can be filled in the porous structure material made of the hydrophobic resin in any of the solution state, the dispersion state, and the suspension state, the present invention can be applied. It is.

According to the present invention, it is possible to prevent a soluble substance from being rapidly dissolved and eluted from narrow pores or gaps of a porous structural material made of a hydrophobic resin without performing insoluble treatment. . In such a case, as long as the solubility of the soluble substance in the living body is maintained, as described above, it is also allowed to perform a somewhat limited cross-linking treatment. Crosslinking using glutaraldehyde or formaldehyde with a chemical crosslinker is generally strong and tends to provide a complete crosslink situation. However, crosslinking by physical energy such as ultraviolet rays, gamma rays, heat, etc. can easily control the degree of crosslinking and can obtain a state of a low degree of crosslinking. Therefore, in the case of crosslinking using a chemical crosslinking agent, it is preferable to take care to avoid excessive crosslinking.

Obtaining such a state of a low degree of cross-linking can be achieved by carefully changing the reaction conditions such as the reaction time, temperature, pH, concentration, and catalyst, even if a chemical cross-linking agent such as formaldehyde is used. It can be controlled. Thus, crosslinking need not necessarily be based on physical energy, but physical methods are easier to control than chemical crosslinking agents. By such treatment with a low degree of crosslinking, it is possible to substantially maintain the solubility while suppressing the antigenicity of the substance.

In the present invention, when a soluble substance is cross-linked as required, the soluble substance may be formed of a porous resin made of a hydrophobic resin as long as the solubility of the soluble substance in a living body is substantially maintained. Crosslinking may be performed before filling the pores or gaps of the structure, or crosslinking may be performed after filling the porous structure (the timing of the crosslinking treatment is not particularly limited).

(Filling into e-PTFE) In the present invention,
For example, alcohol, dimethylformamide, dimethylacetamide, etc. may be used to dissolve a substance having a solubility around pH 7.4 and / or a substance having a property of being treated by the action of dissolution, decomposition, dispersion, absorption and the like under physiological conditions in a mammalian body. , Dimethyl sulfoxide, N-methylpyrrolidone,
A structure in which a solution, suspension, or dispersion is made using a water-containing polar solvent such as hexamethylsulfamide, water, and the like, and the nodules and thin fibril portions connecting the individual nodules are alternately present. A porous tube or sheet made of expanded polytetrafluoroethylene (e-PTFE) having
A pressure difference such as a positive pressure or a negative pressure can be provided within the range of 00 mmHg or less to perform pressure injection into the holes or gaps.

In this case, the substance having solubility and / or the substance having the property of being treated by the action of dissolution, decomposition, dispersion, absorption or the like under physiological conditions in a mammalian organism may be a solution,
Any of a suspension and a dispersion may be used. pH7.
4 as long as the substance having solubility near 4 and / or the substance having the property of being treated by the action of dissolution, decomposition, dispersion, absorption, etc. under physiological conditions in a mammalian organism is dissolved or decomposed. The state of the liquid at the time of filling the pores or gaps of the porous structure made of the conductive resin does not substantially matter.

(Concentration of soluble substance, etc.) A substance having solubility at around pH 7.4 and / or having the property of being treated by the action of dissolution, decomposition, dispersion, absorption, etc. under physiological conditions in a mammalian organism. The concentration of the substance in the aqueous polar solvent is
It can be adjusted appropriately depending on the properties of the substance here.

For example, succinylated atelocollagen has a high viscosity even in a 2% solution, and its handling is difficult. However, when the succinylated atelocollagen is gelatinized by heating, the concentration of the solution can be increased to about 30%. As described above, the optimal concentration may vary depending on the type of the soluble substance, but the materials of the present invention are prepared by preparing solutions, suspensions, dispersions, and the like having concentrations that are easy to handle. be able to.

However, in the case of the same kind of soluble substance solution, when filling into the wall of the porous structure made of a hydrophobic resin, a low-concentration solution, suspension or dispersion is first used. The stepwise pressure injection of a high concentration solution having a concentration difference of at least two or more steps results in homogeneous and efficient dissolution throughout individual pores or gaps of the porous structure made of a hydrophobic resin. It is preferable from the viewpoint of filling the conductive material.

In this way, a substance having solubility at around pH 7.4 and / or dissolved under physiological conditions in a mammalian organism can be dissolved in the wall of an artificial organ having a porous structure made of a hydrophobic resin.
When filled with a substance having the property of being treated by actions such as decomposition, dispersion, absorption, etc., pH 7.
(4) cross-linking a substance having solubility around 4 and / or a substance having a property of being treated by actions such as dissolution, decomposition, dispersion, and absorption under physiological conditions in a mammalian organism;
It is also possible to carry out a crosslinking treatment after filling the inside of the wall of the porous structure made of a hydrophobic resin. In this case, as described above, it is preferable to limit the crosslinking treatment to such a degree that the solubility and degradability in the living body are substantially maintained. (One Preferred Embodiment of Filling) FIG. 1 is a schematic perspective view showing one preferred embodiment of the filling that can be suitably used in the present invention.

Referring to FIG. 1, an artificial blood vessel 1 (for example, having an outer diameter of 8 m) made of fibril hydrophobic resin such as e-PTFE.
m, a length of about 10 cm, and a wall thickness of about 0.6 mm) is connected to a first terminal 3a of a three-way cock 3 (for example, manufactured by Top Co., Ltd.) (for example, attached using No. 1 silk thread).
Next, the artificial blood vessel 1 is placed in an elongated transparent vinyl chloride bag 2, and one end of the bag 2 is connected to the first terminal 3 a of the three-way cock 3 together with the artificial blood vessel 1. The other end of the bag 2 is connected to a connective tube 4 (for example, manufactured by Top Co.), and the other end of the connective tube 4 is connected to the second terminal 3 b of the three-way cock 3.

Separately, a liquid 6 obtained by dissolving or dispersing a biosoluble material (eg, gelatin) in a water-containing polar solvent (eg, 50% ethanol aqueous solution) such as alcohol is put in a syringe 5, and a three-way cock 3 is placed. To the third terminal 3c. In addition, the end of the artificial blood vessel 1 that is not connected to the three-way cock 3 is clamped from above the vinyl chloride bag 2 using the hemostatic forceps 7 to close the end of the artificial blood vessel 1.

After such a device was made and switching was performed so that the terminals 3c-3a of the three-way cock 3 were electrically connected, the in-vivo soluble material 6 was dissolved or dispersed in the water-containing polar solvent such as alcohol from the syringe 5. The liquid is injected into the artificial blood vessel 1. At this time, the dissolved / dispersed liquid 6 of the in-vivo soluble material that has passed through the wall of the artificial blood vessel 1 accumulates in the vinyl chloride bag 2. The liquid thus collected is supplied to the terminal 3 b of the three-way cock 3.
-3a, the syringe 5
Aspirate through the connecting tube 4 and return to the syringe 5.

Next, after switching between the terminals 3c and 3a of the three-way cock 3 so as to conduct, the liquid thus returned into the syringe 5 is injected into the artificial blood vessel 1 again. By repeating such an operation for about 10 minutes, the biosoluble material is gradually adsorbed and accumulated in the wall of the artificial blood vessel 1. When the concentration of the biosoluble material is high, the hole in the wall of the artificial blood vessel 1 is closed by several injections, and the injection cannot be continued. In this case, the injection is stopped at this point.

Next, the operation of injecting the dissolving / dispersing solution 6 from the syringe 5 into the artificial blood vessel 1 is continued with the hemostatic forceps 7 removed from the artificial blood vessel 1, thereby adhering to the lumen of the artificial blood vessel 1. Wash away excess biosoluble material. After this operation is completely completed, the artificial blood vessel 1 is taken out of the plastic bag 2. By this operation, the biosoluble material can be entangled with the wall of the artificial blood vessel 1 in a clean state without causing contamination.

FIG. 2 is a schematic sectional view (a) and an enlarged schematic sectional view (b) showing one embodiment of an artificial blood vessel used in the filling operation as described above (before filling with a biosoluble material). . FIG. 2 (a) is a sectional view 9 of the artificial blood vessel wall 8 in the major axis direction.
Is shown. FIG. 2B shows an enlarged view 10 of the split section 9. Referring to FIG. 2 (b), in this embodiment, nodule portions 11 and fibril portions 12 of artificial blood vessel 1 are alternately present.

FIG. 3 is a schematic sectional view (a) and an enlarged schematic sectional view (b) showing one embodiment of an artificial blood vessel filled with a biosoluble material, which can be obtained by the filling operation as described above. It is. FIG. 3A shows a section 13 in the major axis direction of the artificial blood vessel wall 8 in which the biosoluble material 6 is entangled, and FIG. 2B shows an enlarged view 14 of the section 13. Referring to FIG. 2B, the artificial blood vessel 1 has a nodule 1
1 and fibril portions 12 alternately exist, and the biosoluble material 6 is entangled in the fibril portions 12.

Hereinafter, the present invention will be described more specifically with reference to examples.

[0096]

EXAMPLE 1 Fibrous collagen collected from bovine skin is decomposed to the molecular level by enzymatic treatment with pepsin and the like, and the telopeptide part, which is a part of the collagen molecule, is removed to significantly reduce antigenicity. Atelocollagen (purchased from Koken Co., Ltd.) which had been treated to be used was used.

Next, about 10 amino groups per molecule of the atelocollagen were added using myristynic anhydride.
% Acylamino acid was obtained by attaching 14 carbon atoms of millistyrene acid to 7 to 8 amino groups corresponding to%. Further, the acylated atelocollagen was added to distilled water at a mass ratio of 5% (mass of acylated atelocollagen / mass of distilled water), and the collagen molecules were swollen for 24 hours. Next, this was gently heated to 40 degrees Celsius, and the three chains of the collagen molecules were gradually unraveled, whereby the collagen molecules were decomposed without cutting, thereby producing a parent gelatin.

The same amount of 100% ethanol was poured into the above-mentioned solution of the parent gelatin prepared from the acylated atelocollagen, and the mixture was thoroughly stirred to obtain a 2.5% gelatin-containing aqueous polar solvent (50% ethanol) solution.

Next, the aqueous polar solvent solution of 2.5% gelatin prepared above was cooled to 4 ° C. to coagulate the gelatin. Next, 1 gram of this gelatin was collected and 100 m
When the solution was poured into 1 L of distilled water having a pH of 7.4 and left at room temperature (about 25 ° C.), the gelatin was dissolved in 4 hours, indicating that the gelatin was soluble.

The distal end of an e-PTFE artificial blood vessel (inner diameter of 6 mm, outer diameter of 7.5 mm, length of about 10 cm) having a fibril length of 30 to 60 μm and about 45 μm on average is closed using a hemostatic cone. From the other end, a 2.5% gelatin-containing aqueous polar solvent solution prepared above (about 40 ml in total) was gradually and repeatedly injected (about 20 times) to fill the e-PTFE fibril gap with the gelatin. e-
The filling amount of gelatin to PTFE was determined by Shimadzu TG5.
It was 1.2% (mass / mass) as measured by a thermogravimetric analyzer.

Thus, an e-PTFE artificial blood vessel (hybridized material of the present invention) in which gelatin was filled in the fibril space of e-PTFE was obtained using a 2.5% gelatin-containing polar solvent solution containing water. Next, a 1 cm length of this artificial blood vessel was cut with a sharp scalpel and cooled to 4 ° C.
100 ml of distilled water having a pH of 7.4.
Stirrer was stirred at room temperature for 4 hours. Next, a section (thickness of about 10 μm) of the e-PTFE artificial blood vessel after standing was prepared using a paraffin embedding method, and the section was taken with an optical microscope (magnification of about 2).
(× 00)), it was found that gelatin remained in the fibril gap of e-PTFE even after 24 hours in distilled water (remaining gelatin was stained with eosin in the visual field of an optical microscope). It was confirmed by red dyeing by the method). From this,
It was found that when soluble gelatin was filled into the fibril interstices of e-PTFE, its elution was extremely delayed. The sustained release of such gelatin is e-PTF
It is extremely effective in introducing cell affinity into an E artificial blood vessel.

Example 2 (Use of naturally-dried gelatin) One gram of a 2.5% gelatin-containing aqueous polar solvent solution was poured on a Teflon plate, and allowed to stand in a room at room temperature for 2 days to allow the gelatin to dry naturally. A gelatin film was obtained. Next, this gelatin film was cut out by 1 cm 2, poured into 100 ml of distilled water having a pH of 7.4, and allowed to stand at room temperature while stirring with a stirrer (100 times / minute). As a result, it was not dissolved 12 hours after the introduction, but was completely dissolved after 24 hours. From this, it became clear that the dissolution rate was reduced when the soluble gelatin was naturally dried, but the solubility was still maintained.

The length of 1 cm of the e-PTFE artificial blood vessel filled with gelatin was cut out with the 2.5% gelatin-containing polar solvent solution obtained in Example 1 and cooled to 4 ° C., and then left indoors at room temperature for 2 days. The gelatin was air-dried.
Next, this e-PTFE artificial blood vessel was placed in a 100 ml pH
Put into 7.4 distilled water and stirrer (100 times / min)
Was left at room temperature for 1 week while stirring. Then, a section (thickness: about 10 μm) of the e-PTFE artificial blood vessel after this standing was prepared using a paraffin embedding method, and observed with an optical microscope (magnification: about 200 times). However, it was found that gelatin remained in the fibril gap of e-PTFE (gelatin remained,
It was confirmed by red staining in the visual field of an optical microscope by the eosin staining method). From this, it was clarified that when soluble gelatin was filled in the fibril space of e-PTFE and air-dried, the elution of the soluble gelatin was extremely delayed despite the solubility.

Example 3 (Use of freeze-dried gelatin) One gram of 2.5% gelatin was poured on a Teflon (registered trademark) (manufactured by Iuchi Seisakusho) plate and cooled to 4 ° C. as it was. After freeze-drying, gelatin film sponge (100 mm in size)
× 100 mm, thickness about 50 mm). Next, this sponge membrane was cut into 1 cubic centimeter (1 cm thick) with a sharp knife, poured into 100 ml of distilled water of pH 7.4, and left at room temperature while stirring with a stirrer (100 revolutions / minute). It was not dissolved in 2 hours, but was completely dissolved after 6 hours. From this, it was clarified that the dissolution rate was reduced when the soluble gelatin was freeze-dried, but the solubility was still maintained.

Length of e-PTFE artificial blood vessel filled with gelatin by 2.5% gelatin-containing polar solvent solution
The cm was cut with a sharp scalpel, cooled to 4 ° C., and lyophilized. Next, this artificial blood vessel was
H7.4 into distilled water, stirrer (100 rotations /
Min), the mixture was left at room temperature with stirring, and even after 3 days, the gelatin remained in the e-PTFE fibril gap and disappeared completely after 1 week. It was made and the result of observation with an optical microscope was found. This indicates that soluble gelatin is e-P
When filled in the fibril space of TFE and subjected to lyophilization, it was revealed that, despite its solubility, its elution was extremely delayed.

Example 4 In the same manner as in Example 1, fibrous collagen collected from bovine skin was decomposed to the molecular level by enzymatic treatment with pepsin or the like, and the telopeptide portion, which is part of the collagen molecule, was further reduced. Atelocollagen was obtained by treatment to remove and significantly reduce antigenicity.

Next, a literature (CL Wang et al., Biochem. Bi
ophis. Acta., 1978, 544, p555-567). Attaching succinic anhydride to 70 amino groups corresponding to about 90% of the amino groups per molecule of the atelocollagen. To attach a carboxyl group to obtain succinylated atelocollagen. Further, this was put in distilled water at a mass ratio of 5% to swell the collagen molecules. The succinylated atelocollagen was then gently heated (without agitation) to 40 degrees Celsius and the collagen molecules were degraded without cutting to form the parent gelatin by breaking the three chains of the collagen molecules slowly.

Experiments of filling gelatin into an e-PTFE artificial blood vessel, drying naturally, and freeze-drying were conducted in the same manner as in Examples 1 to 3, except that the succinylated parent gelatin thus prepared was used. However, the same results as in Examples 1 to 3 were obtained. As a result, it was clarified that the dissolving rate of the soluble succinylated parent gelatin decreased when it was filled in the fibril space of e-PTFE.

Example 5 In the same manner as in Example 1, fibrous collagen collected from bovine skin was decomposed to the molecular level by enzymatic treatment with pepsin or the like, and the telopeptide portion, which is part of the collagen molecule, was further reduced. Atelocollagen was obtained by treatment to remove and significantly reduce antigenicity.

Next, this was put into distilled water at a mass ratio of 5%,
The collagen molecules were swollen. Next, gently heat this to 40 ° C
The collagen molecules were broken down without cutting to form the parent gelatin by gradually unraveling the three chains of the collagen molecules.

The e-P was prepared in the same manner as in Examples 1 to 3, except that the simple parent gelatin thus prepared was used.
Experiments of filling the TFE artificial blood vessel with gelatin, air drying, and freeze drying performed the same results as in Examples 1 to 3. At this time, the gelatin molecules were partially cross-linked by ultraviolet rays as follows. That is, gelatin was coagulated by cooling the aqueous polar solvent solution of 2.5% gelatin prepared in the above experiment to 4 ° C.
Next, 1 gram of this gelatin was collected and irradiated with ultraviolet light for 10 minutes (GL lamp of 15 W, range of ultraviolet wavelength: 25).
UV crosslinking of gelatin was performed at 3.7 nm, lamp-gelatin distance: 20 cm). Next, the thus crosslinked gelatin was put into 100 ml of distilled water having a pH of 7.4 and left at room temperature. The gelatin was dissolved in 6 hours, indicating that the gelatin was soluble. did.

A fibril length of 3 was obtained in the same manner as in Example 1.
Close the distal end of the e-PTFE vascular prosthesis of 0 to 60 microns, on average about 45 microns, and gradually add the 2.5% gelatin aqueous hydrated polar solvent solution prepared in Example 1 from the other end. Repeatedly inject gelatin and e-PT
The FE was filled into the fibril gap.

Thus, an e-PTFE artificial blood vessel filled with gelatin by a 2.5% gelatin-containing polar solvent solution was obtained. Next, a length of 1 cm of the artificial blood vessel was cut out with a sharp knife, cooled to 4 ° C., and then irradiated with ultraviolet rays for 10 minutes (GL lamp of 15 W, ultraviolet wavelength range: 2).
UV crosslinking of gelatin was carried out at 53.7 nm, lamp-gelatin distance: 20 cm).

Next, the e-PTFE artificial blood vessel filled with gelatin crosslinked in this manner was placed in 100 ml of pH.
It was poured into distilled water of 7.4 and left at room temperature for one week. Then, the e-PTF after this standing was used using a paraffin embedding method.
A section (about 10 μm in thickness) of an E artificial blood vessel was prepared and observed with an optical microscope (magnification: about 200 times). Even after being left in distilled water for 1 week, gelatin remained in the fibril space of e-PTFE. Turned out to be. From this, it became clear that the dissolution of gelatin, which had been partially cross-linked by ultraviolet rays which are soluble, was further delayed in the fibril gap of e-PTFE.

Example 6 (Use of naturally dried gelatin) One gram of 2.5% gelatin was poured on a Teflon (manufactured by Inuchi Seisakusho) plate, and allowed to stand at room temperature for 2 days at room temperature to naturally dry the gelatin. Then, a gelatin film was obtained. Next, this film was taken for 1 square centimeter and cross-linked by ultraviolet light for 10 minutes. Next, the crosslinked gelatin film was
When poured into 00 ml of distilled water of pH 7.4 and allowed to stand at room temperature, it was not dissolved after 24 hours.
After 3 days, it was completely dissolved. From this,
It became clear that the dissolving rate was reduced when the soluble gelatin was air-dried and crosslinked with ultraviolet rays, but the solubility was still maintained.

Length of e-PTFE artificial blood vessel filled with gelatin by 2.5% gelatin-containing polar solvent solution
After cooling to 4 ° C, the gelatin was allowed to stand in a room at room temperature for 2 days to allow the gelatin to dry naturally. Then add 10
UV irradiation of the gelatin was performed by UV irradiation for 1 minute. Next, the artificial blood vessel filled with gelatin thus cross-linked is poured into 100 ml of distilled water having a pH of 7.4, and stirred at room temperature for 2 hours while stirring with a stirrer (100 rpm).
Left for a week. Next, a section (thickness: about 10 μm) of the e-PTFE artificial blood vessel after standing was prepared using paraffin, and observed with an optical microscope (magnification: about 200 times). It was found that gelatin remained in the fibril gap of e-PTFE even after standing for 2 weeks while stirring. This indicates that soluble gelatin e-PTFE
It was found that when the fibrils were filled in the fibril gap, subjected to natural drying, and subjected to ultraviolet crosslinking, the elution was extremely delayed despite their solubility.

Example 7 (Use of UV-crosslinked gelatin) One gram of a 2.5% gelatin-containing polar solvent solution was poured on a Teflon plate, cooled to 4 ° C as it was, and freeze-dried in that state. A gelatin film sponge was obtained. Next, one square centimeter of this film was cut out, and 1 cm
The gelatin was cross-linked by ultraviolet irradiation for 0 minutes.

Next, the gelatin sponge (1 square centimeter) cross-linked in this way was put in 100 ml of pH
When poured into 7.4 distilled water and allowed to stand at room temperature, 12
It was not dissolved by time, but was completely dissolved after 24 hours. From this, it was clarified that the dissolving gelatin was freeze-dried and further subjected to ultraviolet crosslinking to lower the dissolution rate, but still maintained the solubility.

Length of e-PTFE artificial blood vessel filled with gelatin with 2.5% gelatin-containing polar solvent solution
After cooling to 4 ° C., freeze-drying was performed. Then, it was cross-linked by ultraviolet irradiation for 10 minutes in the same manner as described above. Next, an artificial blood vessel filled with gelatin crosslinked in this way was filled with 100 ml of pH 7.4.
And left at room temperature for one week. A section was prepared in the same manner as in Example 1 and observed with an optical microscope. As a result, it was found that gelatin remained in the e-PTFE fibril gap even after one week.
Further, it was also found that the gelatin had completely disappeared two weeks after the standing. From this, it is clear that when soluble gelatin is filled in the fibril space of e-PTFE and subjected to lyophilization and UV crosslinking, the elution is extremely delayed despite the solubility. became.

Example 8 Reference (J. Biomater-Sci-Polym-Ed. 1994: 6, 447-461, Iwa
Synthetic phospholipids were obtained in the same manner as described in saki et al.). This is Ishihara et al. (J. Biomedical Marerials Rese
arch, 26; 1543-1552: 1992), and is said to have biocompatibility and antithrombotic properties. This material has both a hydrophilic part and a hydrophobic part in one molecule. 5 g of this synthetic phospholipid was dissolved in 90% ethanol to obtain a phospholipid solution.

One gram of the above-prepared 5% phospholipid-containing water-containing polar solvent solution was collected, poured into 100 ml of distilled water having a pH of 7.4, and allowed to stand at room temperature. As a result, the phospholipid was dissolved in 2 hours. This proved that this phospholipid was soluble.

A fibril length of 3 was obtained in the same manner as in Example 1.
The distal end of the e-PTFE vascular prosthesis of 0 to 60 microns, on average about 45 microns, is closed, and the other end is gradually injected with the above-prepared 5% phospholipid in the aqueous polar solvent solution containing water in a polar solvent. The phospholipid was filled into the fibril space of e-PTFE.

Thus, an e-PTFE artificial blood vessel filled with 5% of phospholipid was obtained. Next, 1 cm of the length of the artificial blood vessel was cut out, poured into 100 ml of distilled water having a pH of 7.4, and allowed to stand at room temperature. A section was prepared in the same manner as in Example 1 and observed with an optical microscope. As a result, it was found that the phospholipid remained in the fibril space of e-PTFE even after 3 days. From this, it became clear that the dissolution of the soluble phospholipid was extremely delayed in the fibril crevice of e-PTFE.

Example 9 In the same manner as in Example 1, fibrous collagen collected from bovine skin was decomposed to the molecular level by enzymatic treatment with pepsin or the like, and the telopeptide portion, which is a part of the collagen molecule, was further reduced. Atelocollagen was obtained by treatment to remove and significantly reduce antigenicity. Next, in the same manner as in Example 1, 14-carbon millistyrene acid was attached to 7 to 8 amino groups corresponding to about 10% of the amino groups per molecule of the atelocollagen. Acylated atelocollagen was obtained.

Next, succinylation was performed in the same manner as in Example 4 by adding a carboxyl group to all amino groups remaining in the collagen molecule using succinic anhydride. Next, the acylated succinylated product thus obtained was added to distilled water at a mass ratio of 5% to swell the collagen molecules. Next, this was gently heated to 40 ° C., and the collagen molecules were degraded without cutting by gradually breaking the three chains of the collagen molecules to prepare an acylated succinylated parent gelatin.

To a solution of the parent gelatin prepared from the acylated atelocollagen obtained above, 100% ethanol of the same amount as that of 3 times was separately poured, and the mixture was stirred well and 1.25 times.
% And 2.5% gelatin in aqueous polar solvent solutions were obtained.

Next, 1.25% prepared above and 2.5%
The gelatin was coagulated by cooling the aqueous polar solvent solution of 5% gelatin to 4 ° C. Next, 1 gram of this gelatin was collected, lyophilized, crosslinked by ultraviolet light for 10 minutes, and then poured into 100 ml of distilled water having a pH of 7.4 and allowed to stand at room temperature. As a result, the gelatin was found to be soluble.

A fibril length of 3 was obtained in the same manner as in Example 1.
The distal end of the e-PTFE vascular prosthesis of 0 to 60 microns, on average about 45 microns, is closed, and the other end is gradually injected with the above prepared 1.25% gelatin aqueous polar solvent solution repeatedly. Then, an additional 2.5% of gelatin was injected to sufficiently fill the fibril space of the e-PTFE vascular prosthesis with gelatin.
After cooling to ℃ and further freeze-drying, crosslinking was carried out by ultraviolet rays for 10 minutes in the same manner as in Example 7 to obtain an e-PTFE artificial blood vessel filled with gelatin.

A 1 cm length of the e-PTFE artificial blood vessel filled with gelatin prepared in this manner was cut out, and
The solution was poured into 00 ml of distilled water having a pH of 7.4 and left at room temperature. A section was prepared in the same manner as in Example 1 and observed with an optical microscope. As a result, even after two weeks had passed, e-PTF
It was found that gelatin remained in the fibril space of E. This revealed that the dissolution of the soluble acylated succinylated parent gelatin was extremely delayed in the fibril crevice of e-PTFE.

Example 10 The artificial blood vessel created in Example 9 was cut out to a length of 6 cm, which was subjected to gas sterilization (10% ethylene oxide (EOG) gas, 56 ° C., 12 hours), and the abdominal aorta of an adult dog Was implanted. At the time of implantation, the artificial blood vessel was dry and hard, but when immersed in physiological saline, the artificial blood vessel exhibited water absorption and became flexible. Immediately after implantation, the artificial blood vessel changed from white to red, but no leakage of blood or plasma was observed.

As a control, e-
The PTFE artificial blood vessel was similarly gas-sterilized and implanted in the abdominal aorta of an adult dog. Upon implantation, the vascular prosthesis was dry but flexible. Immediately after implantation, the artificial blood vessel changed from white to slightly red, but no blood leaked. However, 5 minutes after the implantation, a leakage phenomenon was observed in which plasma gushed out from the surface of the artificial blood vessel as if sweating. This phenomenon persisted for about one hour after implantation, after which the amount of leakage gradually decreased.
As a result, it was found that leakage of plasma was suppressed by the gelatin coating.

The artificial blood vessel thus implanted was collected four weeks after the implantation. Both the artificial blood vessel coated with gelatin and the uncoated artificial blood vessel used as a control were covered with connective tissue around the artificial blood vessel, and scar tissue formation and foreign body reaction were not observed. The inner surface of the artificial blood vessel is covered with a thin fibrin layer, and in both artificial blood vessels,
No difference in internal healing was noted. As a result, it was found that the gelatin coating did not adversely affect the healing process of the artificial blood vessel.

As a result of observing the cross section of the artificial blood vessel collected 4 weeks after the implantation with an optical microscope, in the artificial blood vessel coated with gelatin, countless fibroblasts had invaded the fibril space of the e-PTFE artificial blood vessel. A small number of capillaries were also observed to penetrate between the fibroblasts. On the other hand, in the uncoated artificial blood vessel used as a control, the number of fibroblasts was small, and no capillaries were found. As a result, it was found that the artificial blood vessel coated with gelatin had better affinity for surrounding tissues and cells as compared with the control artificial blood vessel.

Example 11 The artificial blood vessel prepared in Example 9 was taken 3 cm in length, gas-sterilized in the same manner as in Example 10, and opened in the longitudinal direction to form a membrane of about 3 cm × 2 cm. Obtained. Next, it is said to promote the growth and migration of fibroblasts and capillaries.
sic Fibroblast Growth Factor (bFGF; Upstate Bio
(manufactured by Technology Co., Ltd.) was sprinkled on a membrane made of 25 ng, and then the membrane was implanted in the abdomen of a rabbit as an artificial abdominal wall. When implanting, the handleability was good.

As a control, no gelatin was filled.
-PTFE prosthesis was gas-sterilized, also taken 3 centimeters, it was gas-sterilized and it was opened longitudinally to obtain a membrane of about 3 cm x 2 cm. Next, basic fibrob is said to promote the growth and migration of fibroblasts and capillaries.
Last growth factor (bFGF) was sprinkled on a membrane made of 25 ng, and the membrane was implanted in the abdomen of a rabbit as an artificial abdominal wall. When implanting, the handling was good. From the above results, it was found that the effect as an artificial abdominal wall was equally good visually with or without gelatin coating.

The artificial abdominal wall implanted in this manner was collected two weeks after implantation. The artificial abdominal wall around which the artificial abdominal wall was coated with gelatin and to which bFGF was adsorbed was covered with connective tissue together with the uncoated artificial blood vessel used as a control, and scar tissue formation and foreign body reaction were not observed. However, invasion of countless capillaries was observed around the artificial abdominal wall coated with gelatin and adsorbed with bFGF,
The effect of bFGF was remarkable. However, almost no such capillary invasion was seen in the control membrane. As a result, it was found that the artificial peritoneum adsorbed and maintained the bFGF in the gelatin coating, and that it was gradually released after implantation.

In this manner, the cross section of the artificial abdominal wall collected two weeks after implantation was observed under an optical microscope (magnification: 200 times).
As a result, in the artificial abdominal wall coated with gelatin and adsorbed with bGHG, it was observed that countless fibroblasts and capillaries invaded the fibril space of the e-PTFE artificial blood vessel. On the other hand, in the artificial abdominal wall not coated with gelatin used as a control, the number of fibroblasts was small, and no capillaries were found. As a result, it was found that the artificial abdominal wall coated with gelatin was excellent in maintaining the adsorption of bFGF.

[0138]

As described above, according to the present invention, at least a porous structure made of a hydrophobic resin and a soluble substance disposed in pores and / or gaps constituting the porous structure are provided. A hybrid resin material is provided, wherein the soluble substance is soluble in a hydrated polar solvent, and is soluble in the hydrated polar solvent even when the soluble substance is disposed (filled) in the porous structure. You.

In the present invention, it is possible to reduce the dissolving rate of a soluble substance by filling the pores or gaps of a porous structure originally made of a hydrophobic resin with a soluble substance.

The soluble substance filled in the pores or gaps of the porous structure made of the hydrophobic resin is temporarily removed from the pores or gaps of the porous structure made of the hydrophobic resin even when placed in a living body. It is possible to prevent leakage of body fluid and plasma.

By filling the pores or gaps of the porous structure made of a hydrophobic resin with a soluble substance, an effective sealing state in a living body or the like can be obtained even when a small amount of a soluble substance is used. It is possible to get.

Since the porous structure made of a hydrophobic resin is sealed with a soluble substance, it is easy to have flexible physical properties even in a state where water or blood does not pass almost completely in a living body or the like.

Although a soluble substance is originally soluble, it is present in pores or gaps of a porous structure made of a hydrophobic resin, and its dissolution rate is low. Until it enters, it is possible to seal the pores or gaps of the porous structure made of a hydrophobic resin.

Since the chemical cross-linking agent can be omitted, it is easy to minimize the foreign substance reaction even after implantation into a living body, and to facilitate cell invasion. It is advantageous for use.

By adsorbing various drugs as soluble substances to the hybrid resin material of the present invention, it is easy to gradually release it by the action of the hybrid resin material.

When a drug which promotes blood coagulation is adsorbed as a soluble material to the hybrid resin material of the present invention, it can be used as a material for contacting blood or for hemostasis in a peripheral region thereof, and the surface of the material can be used. It is possible to promote the formation of a thrombus in.

When a drug that promotes cell proliferation is adsorbed as a soluble material to the hybrid resin material of the present invention, it can be used as a material that promotes tissue healing and regeneration, and can be used to promote cell proliferation, migration, It is possible to guide tissue construction and the like.

When the hybrid resin material of the present invention is adsorbed with a drug that inhibits cell growth as a soluble material,
It can be used as a material for controlling tissue healing and regeneration, and can prevent tissue hyperproliferation by limiting or preventing cell growth, migration, tissue construction, and the like on the surface of the material.

When the hybrid resin material of the present invention is adsorbed with a drug which inhibits bacterial infection as a soluble material, it can be used as a material to be implanted in a living body or a material to be used outside a living body. It is possible to inhibit the properties and to exert the properties of the material in a place where there is no activity of bacteria without side effects.

[Brief description of the drawings]

FIG. 1 is a schematic perspective view showing an example of a method of impregnating a bio-soluble material into an artificial blood vessel wall having a porous structure made of a hydrophobic resin.

FIG. 2 (a) shows an example of a cross section in the longitudinal direction of the artificial blood vessel used in the method of FIG. FIG. 2B shows an example of an enlarged view of the split section.

FIG. 3 (a) shows an example of a longitudinal cross section of an artificial blood vessel wall filled with a soluble material obtainable by the method of FIG. FIG. 3B shows an example of an enlarged view of the split section.

[Explanation of symbols]

DESCRIPTION OF SYMBOLS 1 ... Artificial blood vessel 2 ... Elongated transparent vinyl chloride bag 2 3 ... Three-way cock 4 ... Connective tube 5 ... Syringe 6 ... Biosoluble material 7 ... Hemostatic forceps 8 ... Artificial blood vessel cut in the longitudinal direction 9 ... Artificial Cross-section in the longitudinal direction of the blood vessel 10—Enlarged view of the cross-section in the long-axis direction of the artificial blood vessel 11—Nodule portion of the artificial blood vessel 12—Fibril portion of the artificial blood vessel 13—of the artificial blood vessel in which the biosoluble material is entangled Cross-section in the long axis direction 14: Enlarged view of the cross section in the long axis direction of the artificial blood vessel in which the biosoluble material is entangled

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (reference) // C08L 27:18 C08L 27:18 F term (reference) 4C081 AB13 BB06 CA021 CA131 CA271 DA03 DB03 DC14 4C097 AA15 BB01 CC01 DD01 EE06 FF05 FF16 MM02 MM04 MM05 4F074 AA04 AA24 AA39 AA90 CB91 DA24 DA59

Claims (25)

[Claims] 1. A porous structure comprising a hydrophobic resin and a soluble substance disposed in pores and / or gaps constituting the porous structure, wherein the soluble substance is soluble in a polar solvent. And a hybrid resin material which is soluble in the water-containing polar solvent even when the soluble substance is disposed in the porous structure. 2. A ratio (H / S) of a dissolution time (S) in which the soluble substance alone completely dissolves in the polar solvent to a dissolution time (H) in the hydrophobic resin material is 1. The hybrid resin material according to claim 1, wherein the number is 2 or more. 3. The hybrid resin material according to claim 1, wherein the soluble substance has a hydrophilic part and a hydrophobic part in its molecule. 4. The hybrid resin material according to claim 1, wherein said soluble substance has solubility at a pH of about 7 to 7.4. 5. The hybrid resin material according to claim 1, wherein said hydrophobic resin is a fluororesin. 6. The hybrid resin material according to claim 1, wherein the porous structure has a fibril structure. 7. The hybrid resin material according to claim 1, wherein at least a part of the soluble substance is a naturally occurring material or a derivative thereof. 8. The method according to claim 1, wherein at least a part of the soluble substance is a synthetic polymer-derived material or a derivative thereof.
The hybrid resin material according to any one of the above. 9. The method according to claim 1, wherein at least a part of the soluble substance is a material derived from a material which is not originally present in nature but is artificially made using an organism or a derivative thereof. A hybrid resin material according to any one of the above. 10. At least a part of the soluble substance,
The hybrid resin material according to any one of claims 1 to 10, which is a material having at least one kind of hydrophobic group selected from an acyl group, an alkyl group, and / or a phenyl group. 11. At least a part of the soluble substance,
The hybrid resin material according to any one of claims 1 to 10, which is a material having at least one kind of hydrophilic group selected from a hydroxy group, a carboxy group, an amino group, a carbonyl group, and / or a sulfo group. 12. At least a part of the soluble substance,
The hybrid resin material according to any one of claims 1 to 11, which is a material having at least one kind of hydrophilic group and having at least one kind of hydrophobic group. 13. At least a part of the soluble substance,
The hybrid resin material according to any one of claims 1 to 11, wherein the hybrid resin material is a mixture of a material having one or more kinds of hydrophilic groups and a material having one or more kinds of hydrophobic groups. 14. At least a part of the soluble substance,
It can be dissolved, dispersed or suspended in a polar solvent.
14. The hybrid resin material according to any one of 13. 15. At least a part of the soluble substance,
Claim 1 which is partially crosslinked by a chemical crosslinking agent.
15. The hybrid resin material according to any one of 14. 16. The hybrid resin material according to claim 1, wherein at least a part of the soluble substance is partially cross-linked by physical energy. 17. The method according to claim 17, wherein at least a part of the soluble substance is
17. The hybrid resin material according to claim 15, which has a solubility at a pH of about 7 to 7.4 even after the crosslinking treatment. 18. At least a part of the soluble substance,
Absorption or adsorption of one or more physiologically active substances selected from the group of cell growth factors, cytokines, antibiotics, anticoagulants, procoagulants, cell growth inhibitors, pharmacological agents, etc. Claims 1 to 1 that can be held
18. The hybrid resin material according to any one of 17. 19. A stretched polytetrafluoroethylene (e-PTFE) having a structure in which the porous structure made of the hydrophobic resin has a structure in which a number of nodules and thin fibril portions connecting the individual nodules are alternately present. The hybrid resin material according to any one of claims 1 to 18, comprising fibril fibers. 20. A method for dissolving or dispersing a soluble substance soluble in a polar solvent in a polar solvent in a pore and / or gap of a porous structure comprising a hydrophobic resin. A method for producing a hybrid resin material that forms a hybrid material that can be dissolved in the polar solvent even in a state where is disposed in the porous structure. 21. Applying a positive or negative pressure difference within a range of 5 mmHg or more and 300 mmHg or less from one side or both sides of the porous structure, thereby dissolving the porous structure in the pores and / or gaps of the porous structure. 21. The method for producing a hybrid resin material according to claim 20, wherein a conductive substance is disposed. 22. The method according to claim 20, wherein the dissolving substance is freeze-dried or air-dried after disposing the dissolving substance in the pores and / or gaps of the porous structure.
A method for producing the hybrid resin material as described above. 23. The method for producing a hybrid resin material according to claim 20, wherein the dissolving substance is cross-linked after disposing the dissolving substance in pores and / or gaps of the porous structure. 24. The method for producing a hybrid resin material according to claim 23, wherein the crosslinking of the soluble substance is partial crosslinking by physical energy. 25. The method for producing a hybrid resin material according to claim 23, wherein the crosslinking of the soluble substance is partial crosslinking by a chemical crosslinking agent.