JPH07275344A - Medical material for soft tissue - Google Patents

Abstract

PURPOSE:To provide a material with high bio-compatibility and prevent problems on the safety such as cytotoxic effect, etc., by composing the material with fiber aggregate and polyester copolymer with a 3-hydroxybutylate unit and a 4-hydroxybutylate unit shown by the specific formulae. CONSTITUTION:A medical material for soft tissue consists of fiber aggregate and polyester copolymer with 3-hydroxybutylate shown by the formula I and 4-hydroxybutylate shown by the formula II. This medical material for soft tissue has good decomposition and absorption to biomedical tissue, and holds the designated shape even after decomposition and absorption. The copolymer is covered by the tissue as it penetrates into the biomedical tissue and the decomposition and absorption of this material gradually progresses by the action of the tissue. Even in a case fiber aggregate consisting of a material with a strong foreign matter reaction such as polyglycol acid, etc., the decomposition and absorption of the copolymer into biomedical tissue is good and it suppresses the foreign matter reaction with biomedical tissue.

Description

Detailed Description of the Invention

[0001]

The present invention relates to an artificial blood vessel, artificial skin,
The present invention relates to a medical material for soft tissue, which is suitable as a surgical suture, an adhesion preventing material, a blood vessel repairing material and the like.

[0002]

2. Description of the Related Art Medical materials for soft tissues used for artificial blood vessels, artificial skin, surgical sutures, anti-adhesion materials and blood vessel repair materials have no mechanical compatibility such as flexibility and strength, and no toxicity. In addition to safety, etc., it is required to be biodegradable, that is, to be decomposed and absorbed by a biological tissue depending on the invasion of the tissue.

Since aliphatic polyesters such as polyglycolic acid and polylactic acid used for surgical sutures and the like lack flexibility, they are poorly compatible with a flexible living body. Therefore, a mechanical stimulus occurs on the boundary surface with the living body as the living body moves. Further, since it is hydrolyzable and decomposes irrespective of invasion of living tissue, it cannot follow the repairability of living tissue, causing incongruity with living tissue and causing an inflammatory reaction in the living body.

Animal-derived materials such as collagen, gelatin, chitin, etc. used for artificial skin and the like are caused by other animal materials such as heterologous proteins in order to control the degradation and absorption into living tissues in response to the invasion of the tissues. In order to reduce the activity of antigen-antibody reaction (antigenicity) or to control excessive decomposition, it is necessary to carry out cross-linking, and in addition, there is a problem of cytotoxicity due to the remaining cross-linking agent. was there.

As an example of a soft tissue medical material in which a knitted fabric or a woven fabric is combined with an animal-derived material, an artificial blood vessel in which a polyester fiber knitted fabric or a woven fabric is clogged with a cross-linked product of gelatin or collagen is known. However, since the gelatin or the crosslinked material of collagen has no elasticity, the whole artificial blood vessel becomes hard and the flexibility is impaired. Therefore, if it is excessively stretched, the inflexible collagen or gelatin may be separated from the knitted fabric or the like. Further, there is a problem that there is a problem of cytotoxicity due to the remaining crosslinking agent.

Further, as an example of a soft tissue medical material in which a knitted fabric or a woven fabric is combined with an aliphatic polyester, a non-absorbable water-permeable layer such as a porous structure made of a knitted fabric or a woven fabric such as polyester, and polyglycol. A prosthetic material for living organs has been proposed in which a water-impermeable layer including at least an absorbent material layer made of acid, polylactic acid, or the like is laminated, and the water-impermeable layer is placed on the side that comes into contact with blood (Japanese Patent Laid-Open No. HEI 2- 206457
Issue). However, since this prosthetic material is impermeable to water, when blood coagulation deposits on the surface, the discharge of body fluid from the inside of the blood coagulation becomes insufficient and the blood coagulation accumulates. In addition, since this material is water impermeable, there is a problem that it lacks adhesiveness to living tissue. Further, even if the composition of the absorptive material layer is optimized to optimize the absorption period into the biological tissue, there is a problem that the absorptive material layer is decomposed and absorbed regardless of invasion of the biological tissue. Therefore, satisfactory results have not always been obtained with artificial skin and artificial blood vessels made of these prosthetic materials.

On the other hand, various properties such as biocompatibility, sutureability with living tissue, stretchability, and flexibility are required for a blood vessel repair material used for artificial blood vessels, hearts, patches for blood vessels and the like.

[0008] Polyester fiber knitted fabrics or woven fabrics are excellent in sutureability with living tissues, but are difficult to apply to heart and vascular patches unless the distance between the fibers is made small in order to prevent blood leakage. It was Therefore, a polyester fiber knitted or woven fabric that has elasticity and flexibility is
It was rarely used in vascular patches. If the fiber gap is wide, a method of contacting blood immediately before use to form a thrombus in the mesh of the fiber gap and thereby clogging, or a method of clogging with a bioabsorbable substance such as collagen or gelatin However, if the extensibility of the base material is 10% or more, the clogging is removed and there is a risk of bleeding.

A medical composite structure comprising a polyvinyl alcohol or vinyl alcohol-based copolymer having a cross-linking bond and a stretchable fiber knitted fabric or a woven fabric is excellent in biocompatibility, stretchability and flexibility in a wet state, and an artificial blood vessel or the like. (Japanese Patent Publication No. 4-1631, column 1, columns 2 to 1)
3 lines, column 3, lines 18-24). However, since this medical composite structure is basically formed of a water-swellable material, it is difficult to handle because it does not exhibit elasticity and flexibility in a normally used dry state, and the process of introducing a crosslinkage is complicated. There is a possibility that it may cause cytotoxicity due to the remaining cross-linking agent, and that polyvinyl alcohol and vinyl alcohol-based copolymers remain without being decomposed in the living body, resulting in poor organizing due to invasion of living tissue. was there.

[0010]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a novel soft tissue which has good biocompatibility, stretchability and flexibility, does not cause safety problems such as cytotoxicity and solves the above problems. The point is to provide medical materials for medical use.

[0011]

The first aspect of the present invention is to provide an aggregate of fibers and a 3-hydroxybutyrate unit represented by the following formula (1) and a 4-hydroxybutyrate unit represented by the following formula (2). A medical material for soft tissue, comprising a polyester copolymer having

A second aspect of the present invention relates to an artificial blood vessel or a blood vessel repair material, which is formed of the above-mentioned medical material for soft tissue.

(Regarding Fiber Aggregate) The fiber aggregate of the present invention may be a knitted fabric, a woven fabric, a non-woven fabric, a net, or a laminate of any combination thereof.

The structure of the fiber assembly constituting the medical material for soft tissue of the present invention and the material and properties of the fibers constituting the assembly are not particularly limited. Examples of such materials include bioabsorbable materials such as polyglycolic acid, polylactic acid-polyglycolic acid copolymers and polydioxanone; polyesters represented by polyethylene terephthalate,
Polyetherester, polyurethane, nylon, rayon, polypropylene, polytetrafluoroethylene,
Non-bioabsorbable materials such as cotton and silk.
Among them, polyester is preferable from the viewpoint of compatibility with living tissue, and polyethylene terephthalate is particularly preferable among the polyesters.

The fiber aggregate is preferably stretchable, but especially the fiber aggregate used for artificial blood vessels and vascular repair materials has an elastic elongation of 10% or more, preferably 20% or more, in at least one direction. Those having properties are suitable for forming an artificial blood vessel or a blood vessel repair material. When used in an artificial blood vessel or a vascular repair material, the distance between the fibers of the fiber assembly is usually about 1 to 5000 μm, preferably 20.
A material having a distance of ˜2000 μm is preferable from the viewpoint of organizing by invasion of living tissue. The property of the fiber is not particularly limited, but a fiber having a thickness of about 0.01 to 50 denier is preferable for producing a knitted fabric or a woven fabric.

The biodegradable polyester copolymer constituting the soft tissue medical material of the present invention has the following formula (1):

[Chemical 3] 3-hydroxybutyrate (hereinafter referred to as 3HB) unit represented by the following formula (2)

[Chemical 4] Is a copolymer having a 4-hydroxybutyrate (hereinafter referred to as 4HB) unit (hereinafter, this copolymer is referred to as a 3HB / 4HB polyester copolymer). 3H
The B4HB polyester copolymer is enzymatically decomposed by lipase / esterase and the like existing in the living tissue and does not remain in the living body.

Constituting the medical material for soft tissue of the present invention 3
The HB / 4HB polyester copolymer may be produced by a conventionally known method and is not particularly limited. Typical 3H
The production method of the B.4HB polyester copolymer is described, for example, in JP-A-64-48821, page 2, lower right column, line 1 to page 4, upper right column, line 18, JP-A-1-222788. Lower left column, line 2 to page 4 Upper left column, line 4
-304891, page 2, lower left column, line 11 to page 4, upper left column, line 17; JP-A-2-27992, page 2, lower left column, line 2 to page 4, upper left column, line 3; -32509
No. 4, column 2, line 19 to column 3, line 39, JP-A-4-
No. 326932, column 2, line 7 to column 4, line 2.

In these known representative methods, cells capable of producing a hydroxybutyrate polymer are treated with nitrogen and / or nitrogen of a culture medium in the presence of a carbon source serving as a substrate for hydroxybutyrate and citric acid. Alternatively, phosphorus is restricted and cultured to accumulate the copolymer in the microbial cells. In addition,
A pre-stage culture for growing the bacterial cells may be performed prior to the culture for producing the polyester.

As an example of the bacterial cells, Alcaligenes
Fekaris (ATCC 8750), Alcaligenes Rulandi (ATCC15749), Alcaligenes
Rattus (ATCC29712), Alcaligenes Aquamarinus (ATCC14400), Alcaligenes
Examples include the genera Alcaligenes such as Yutrophus (ATCC17699). The medium is not particularly limited as long as it is a substance that can be assimilated by the cells. Examples include yeast extract,
Natural products such as polypeptone and meat extract; sugars such as glucose; inorganic nitrogen compounds such as ammonium sulfate; inorganic salts such as sodium hydrogen phosphate, potassium hydrogen phosphate and magnesium sulfate.

Examples of the compound used as a carbon source serving as a substrate of hydroxybutyrate include butyric acid derivatives such as 4-hydroxybutyric acid and 4-chlorobutyric acid; inorganic salts of the butyric acid derivative such as sodium 4-hydroxybutyrate; - butyrolactone; following general formula _{HO (CH 2) nOH (n} = 2,4,6,8,10,
12) Aliphatic diols represented by The amount used is not particularly limited, but is preferably 3 to 100 g / 1, and particularly preferably 3 to 50 g / 1. 4HB of 3HB / 4HB polyester copolymer by changing the amount used
The unit content can be changed. Generally, as the amount used increases, the 4HB unit content tends to increase.

It is preferable to add citric acid and / or citrate to the culture system, in particular to obtain a polyester copolymer containing about 60 mol% or more of 4HB units.
Specific examples of the citrate salt include sodium salt, potassium salt and ammonium salt. The amount of citric acid or citrate varies depending on the strain of the microorganism used, the desired copolymer composition, etc.
It is usually about 0.3 to 40 g, preferably about 1 to 30 g per liter. If the amount used is too large, the amount of the copolymer obtained will decrease.

When the pre-stage culture for growing the microbial cells is carried out prior to the culturing for producing the polyester, the microbial cells are removed from the culture solution obtained by the pre-culture.
Separation and collection by an ordinary solid-liquid separation means such as filtration and centrifugation, and subjecting the collected bacterial cells to subsequent culture, or
Alternatively, nitrogen and / or phosphorus can be substantially depleted in the first-stage culture, and this culture solution can be transferred to the second-stage culture without separating and recovering the bacterial cells.

From the culture broth obtained by culturing for polyester production, for example, cells are separated and recovered by a usual solid-liquid separation means such as filtration and centrifugation, and the cells are washed, dried and dried. Get the body. From the dried cells, a 3HB / 4HB polyester copolymer is extracted by an ordinary method with an organic solvent such as chloroform or acetone, and a poor solvent such as hexane is added to the extract to precipitate the copolymer. Thereby, a 3HB / 4HB polyester copolymer is obtained.

In the culture for producing polyester and optionally the pre-culture, the pH is usually 6 to
10, preferably 6.5 to 9.5, and cultivated aerobically. The dissolved oxygen concentration is usually 0.5 to 40 ppm, preferably 5 to 20 ppm. The culture temperature is usually 20
-40 degreeC, Preferably it is 25-35 degreeC. When the culture is performed under these conditions, the amount of polyester produced and accumulated in the dried cells is extremely low, which is not advantageous for industrial production.

Constituting the medical material for soft tissue of the present invention 3
The 4HB unit content of the HB-4HB polyester copolymer is usually 30 to 99 mol%, preferably 40 to 98 mol%, and particularly preferably 60 to 95 mol%. If the content of the 4HB unit is too low, the flexibility and elasticity are lowered, and the decomposition and absorption into the tissue due to the invasion of living tissue become too slow, so that the effect of the present invention cannot be sufficiently obtained. If it is too high, flexibility and elasticity tend to decrease. The content of the 3HB unit is usually 1 to 70 mol%, preferably 2 to 60 mol%, more preferably 5 to 40 mol%. Also, 3
HB-4HB polyester copolymer is 4HB and 3HB
It may have a monomer unit other than the unit. The content of monomer units other than 4HB and 3HB units is usually 3
It is 0 mol%, preferably 20 mol% or less, more preferably 10 mol% or less.

The melting point of the 3HB / 4HB polyester copolymer is generally 37 to 185 ° C., preferably 40 to 185 ° C.
180 ° C, more preferably 45 to 170 ° C, the molecular weight is
Usually, about 20,000 to 5,000,000, preferably 50,000 to 2,000,000, more preferably 100,000 to 1,000,000 (converted to polystyrene standard sample by gel permeation chromatography) ). If the molecular weight is too small, the elasticity decreases, and if it is too large, it becomes difficult to produce a medical material for soft tissues. If the melting point is too low, the structural stability of the artificial blood vessel or the like made of the soft tissue medical material will be poor, and if it is too high, the production of the soft tissue medical material will be difficult.

The medical material for soft tissue of the present invention comprises a fiber assembly such as a knitted fabric or a woven fabric and a 3HB / 4HB polyester copolymer. In the medical material for soft tissues of the present invention, at least a part of the fiber assembly is usually 3H.
Although it is covered with the B.4HB polyester copolymer, it may be only the 3HB.4HB polyester copolymer interposed between the fibers. In the medical material for soft tissues of the present invention, the weight ratio of the fiber aggregate to the 3HB / 4HB polyester copolymer is 3HB / 4HB with respect to 100 parts by weight of the fiber aggregate.
The amount of the polyester copolymer is usually 0.1 to 1000 parts by weight, preferably 0.5 to 500 parts by weight, more preferably 1 to 300 parts by weight. As a method for obtaining the medical material for soft tissues of the present invention, a solution-state 3HB / 4HB polyester copolymer is used to soak / dry a fiber assembly, soak / poor solvent treatment, and freeze-dry using a mold. Examples include a method of processing. In this case, other components may be included in the solution, if necessary, within a range that does not impair the object of the present invention. As an example of the treatment method using the melted 3HB / 4HB polyester copolymer, a film or powder of the 3HB / 4HB polyester copolymer is heated to a temperature equal to or higher than the melting point of the copolymer in contact with a knitted fabric or a woven fabric. And a method of adhering the film or powder of the copolymer with an organic solvent or an adhesive in a state where the film or powder of the copolymer is brought into contact with the knitted fabric or the woven fabric.

The above-mentioned dipping / drying treatment is a very general method, and the copolymer concentration of the dipping liquid in the case of the present invention is
0.01-30 (w / v)%, preferably 0.1-10
(W / v)%, particularly preferably 0.2 to 5 (w / v)%
Is. The unit (w / v)% represents the number of solutes dissolved in 100 ml of solvent.

The dipping / poor solvent treatment is a method in which, after the dipping / drying treatment, the treatment with a poor solvent is continued. The treatment temperature with the poor solvent is not particularly limited, and may be low temperature, room temperature, or high temperature. As a poor solvent, hydrocarbons such as hexane and cyclohexane, alcohols such as methanol, ethanol and isopropanol,
Or water etc. can be mentioned.

The freeze-drying treatment using a mold is a method in which the fiber assembly is immersed in the immersion liquid of the copolymer and then freeze-dried. Lyophilization is not particularly limited as long as it can be dried while maintaining a frozen state, and a solvent having a melting point of usually -50 ° C to 50 ° C, preferably -20 ° C to room temperature and capable of dissolving a copolymer is used, Examples of such a solvent include dioxane, benzene and the like. The freezing temperature is usually liquid nitrogen temperature to about 50 ° C., and dry ice is put into ethanol, and the temperature of ethanol when a mass of dry ice remains in ethanol is about 10 ° C. As a general tendency, the porous structure obtained by freeze-drying rapidly followed by freeze-drying is often dense, and the porous structure obtained by freezing slowly and freeze-drying is often coarse. Further, in order to control the structure, it is possible to bring a specific surface into contact with the cooling body so that only the specific surface has a different structure. Drying does not have a great influence on the obtained porous structure under the temperature condition in which the frozen substance does not thaw, but in order to perform the drying quickly, the degree of reduced pressure is set to 5 Torr or less, preferably 2 Torr or less, and more preferably 1 Torr or less, In the case of a tray-type dryer, drying is often performed with the temperature of the tray near or above the melting point of the solvent.

As a method for forming a porous structure, fine particles soluble in a specific solvent are dispersed in a solution of a polyester copolymer in a dipping / poor solvent treatment or freeze-drying treatment to prepare a copolymer-treated product. There is also a method of dissolving the fine particles and treating with a solvent which does not dissolve the copolymer to dissolve and remove only the fine particles, a method of incorporating a foaming agent or a method of using these methods in combination. Particularly, the freeze-drying treatment is suitable because a porous material having high flexibility and elasticity can be obtained.

The thickness of the medical material for soft tissue of the present invention is not particularly limited, but it is preferably 1000 μm or less from the viewpoint of rapid removal of foreign substances in the living body by achieving decomposition and absorption in a short time and suppression of side effects. It is preferably 50 μm or less, and particularly preferably 50 μm or less. However, even if the thickness is large, if part or all of the structure of the material is made porous, decomposition and absorption can be performed in a short time.

The medical material for soft tissue of the present invention is well decomposed and absorbed into living tissue, and maintains a predetermined shape even after the decomposition and absorption. It is presumed that the mechanism is that the 3HB / 4HB polyester copolymer is covered by the tissue as the biological tissue invades, and the action of this tissue causes the degradation and absorption of the 3HB / 4HB polyester copolymer to proceed gently. Also,
Even when a fiber assembly made of a material having a strong foreign body reaction such as polyglycolic acid is used, the 3HB / 4HB polyester copolymer is well decomposed and absorbed into the living tissue, so that the foreign body reaction with the living body does not occur. Suppressed.

When the soft tissue medical material of the present invention is sutured to the serosa defect in the abdominal cavity, the soft tissue medical material is covered with living tissue and the serosa is regenerated on the tissue. And, the medical material for soft tissue of the present invention is gradually decomposed from the surface with the healing of serosa defect by the action of the biological tissue covering the material, and finally absorbed into the biological tissue, and an aggregate of fibers. Are covered with living tissue.

The medical material for soft tissue of the present invention is suitably used for artificial blood vessels, artificial skin, surgical sutures, adhesion preventing materials, blood vessel repairing materials and the like.

(About artificial blood vessel or blood vessel repair material) The artificial blood vessel or blood vessel repair material of the present invention is formed of the above-mentioned medical material for soft tissue. The artificial blood vessel or vascular repair material of the present invention comprises at least one medical material for soft tissue.
In the tensile test in the direction, the strain does not usually have a yield point within 10% of strain, preferably within 20% of strain. The tensile test in at least one direction referred to here does not have a yield point within 10% of strain, and when a tensile test in various directions is performed, there is no yield point within 10% of strain and the fracture It means that there is at least one direction in which there are no points.

The method for obtaining the artificial blood vessel and the blood vessel repair material of the present invention is the same as the method for obtaining a medical material for soft tissue after forming a fiber aggregate into a desired shape such as a tubular shape or a sheet shape. Examples of the method include a method of treating with a 3HB / 4HB polyester copolymer or a method of forming after obtaining a medical material for soft tissue. The former method is preferable from the viewpoint of ease of formation.

The artificial blood vessel and the blood vessel repair material of the present invention are usually
Has water permeability that does not cause blood leakage. The water permeability referred to here means a wall surface of 1 cm ² when a water pressure of 120 mmHg is applied.
This is the amount of water that can pass in one minute. The arterial system and the left heart system with high blood pressure have a water permeability of 100 ml to prevent blood leakage.
/ Cm ² / min / 120 mmHg or less is preferably used, and 50 ml / cm ² / min / 120
It is particularly preferable to use one having a diameter of mmHg or less. On the other hand, the venous system / right heart system has a water permeability of 100 ml / cm ² / min from the viewpoint of the formation of the intima by the extension of the biological tissue.
/ 120 mmHg or more is preferably used, and particularly preferably 200 ml / cm ² / min / 120 mmHg or more is used.

The artificial blood vessel and the blood vessel repairing material of the present invention may have a roughened surface or may be made porous so as to enhance water permeability. As a result, the vascular repair material of the present invention has excellent adhesion of blood coagulation on the inner surface of the blood vessel. To make the surface rough, it is usually 3HB-4 according to the above method.
The HB polyester copolymer is made into a porous shape, or the spacing and thickness of the fibers of the knitted or woven fabric are adjusted.

The artificial blood vessel or vascular repair material of the present invention may be subjected to surface treatment by a known method using a surface-active substance in order to improve the handleability when sutured to a living tissue. Examples of the surfactant used include phospholipids such as lecithin. Examples of the surface treatment method include dipping treatment with an aqueous phospholipid solution and dipping treatment with a mixed liquid of an aliphatic polyester and a phospholipid.

The artificial blood vessel and the blood vessel repair material of the present invention are blood,
It can be applied to a living body with or without pre-clotting treatment with fibrin glue or the like.

The artificial blood vessel and the blood vessel repair material of the present invention are well organized by the invasion of biological tissue. The reason is 3HB
-The 4HB polyester copolymer itself has no foreign substance and has high cell affinity, and in addition, due to its enzymatic degradability or hydrolyzability, the 3HB / 4HB polyester copolymer part is gradually contacted with the body fluid. It is thought that this is because the biological tissue is invaded and the living tissue invades into the resulting void, and because it has appropriate elasticity and flexibility, it has good physical compatibility with the biological tissue and blood flow.

The artificial blood vessel and the blood vessel repair material of the present invention have good biocompatibility, stretchability and flexibility. Moreover, it is excellent in handleability when suturing to a biological tissue. Even if stretched by 10% or more, dissociation does not occur between the aliphatic polyester portion and the base material, so that the handleability is good and the risk of bleeding is low and it is safe. The artificial blood vessel and blood vessel repair material of the present invention,
It may be in any shape such as a sheet shape, a straight tubular shape, a curved tubular shape, a crimped tubular shape, or the like, depending on the use site and purpose.

When the vascular repair material of the present invention prepared by using a crimped tubular knit or woven fabric is used, it is possible to widen the blood vessel diameter after the aliphatic polyester is decomposed and absorbed in the living body. it can. The expansion of the diameter may be naturally performed according to the need of the living body (for example, according to the growth of the living body), but can also be performed using a balloon-equipped intravascular catheter or the like at the discretion of the doctor. Conventionally,
When an artificial blood vessel is used for a pulmonary artery tube or the like due to a child's heart disease or the like, it is necessary to perform re-operation according to the growth of the child, but the artificial blood vessel or the vascular repair material of the present invention should be used. Thereby, the number of operations for replacing the artificial blood vessel can be minimized.

The vascular repair material of the present invention plays a role of absorbing a shock caused by pulsation when it is used as a heart / blood vessel patch on a blood vessel wall. As a result, it is possible to suppress disturbance of blood flow in the heart and blood vessels and thickening of the new blood vessel wall and the attached thrombus layer.

Aspects of the present invention are shown below. (1) A medical material for soft tissue, which comprises a fiber aggregate and a polyester copolymer having 3-hydroxybutyrate units and 4-hydroxybutyrate units. (2) 4H of the 3HB / 4HB polyester copolymer
The soft tissue medical material according to (1) above, wherein the B unit content is 30 to 99 mol%. (3) The medical material for soft tissues according to (2), wherein the 4HB unit content is 40 to 98 mol%. (4) The medical material for soft tissue according to (2), wherein the 4HB unit content is 60 to 95 mol%. (5) The medical material for soft tissue according to (2), (3) or (4), wherein the 3HB / 4HB polyester copolymer has a number average molecular weight of 20,000 to 5,000,000. (6) The above (1), which has a thickness of 1000 μm or less,
The medical material for soft tissue according to (2), (3), (4) or (5). (7) The above (1), (2), (3) having a porous structure,
The medical material for soft tissue according to (4), (5) or (6). (8) The melting point of the 3HB / 4HB polyester copolymer is 3
7 to 185 ° C. (1), (2), (3),
An artificial blood vessel or a blood vessel repairing material comprising the soft tissue medical material of (4), (5), (6) or (7). (9) The artificial blood vessel or vascular repair material according to (8), wherein the elastic elongation of the fiber assembly in at least one direction is 10% or more. (10) Each of the fibers constituting the fiber assembly is about 5 to 50
The artificial blood vessel or vascular repair material according to the above (8) or (9), which has an interval of 00 μm. (11) The thickness of the fibers forming the fiber assembly is 5 to 5
The artificial blood vessel or vascular repair material according to the above (9) or (10), which has 0 denier. (12) The above-mentioned (9), (1) which is a patch for heart and blood vessels.
The artificial blood vessel or the blood vessel repair material according to 0) or (11). (13) An artificial blood vessel or a vascular repair material, characterized in that the medical material for soft tissue does not have a yield point within a strain of 10% in a tensile test in at least one direction.

[0047]

EXAMPLES The present invention will be specifically described below based on Reference Examples, Examples, Comparative Examples and Test Examples.

Reference Example 1 (Production of 3HB / 4HB Polyester Copolymer) Medium A (10 g of yeast extract, 10 g of polypeptone, 5 g of meat extract, 5 g of (NH ₄ ) ₂ SO ₄ was dissolved in deionized water to 1 liter. , Adjusted to pH 7.0) 200
Add ml to a 2 liter flask, and add the bacterial cells [Alkaligenes eutrophus (ATCC17699)] to 28
After culturing at 24 ° C. for 24 hours, bacterial cells B0 were separated by centrifugation.

Medium B (4.4 g of Na ₂ HPO ₄ , KH ₂ P
O ₄ 1.2 g, MgSO ₄ 0.2 g, sodium 4-hydroxybutyrate 15.0 g, sodium citrate 5.0 g
Was dissolved in deionized water to 1 liter and adjusted to pH 7.0) 4 g of the bacterium B0 was suspended per 1 liter. 100 ml of this suspension was put into a 500 ml Sakaguchi flask, cultured at 28 ° C. for 48 hours, and bacterial cells B1 were separated by centrifugation.

The obtained bacterial cell B1 was washed with distilled water and dried under reduced pressure to obtain dried bacterial cell Bd1. A polyester copolymer was extracted from the dried bacterial cells Bd1 thus obtained with hot chloroform, and the extract was concentrated and then dropped into a large amount of hexane to precipitate the polyester copolymer, and the precipitate was collected by filtration, Dry to separate the polyester copolymer and
A B.4HB polyester copolymer was obtained.

The 3HB / 4HB polyester copolymer is
Yield 1.0g / 1, composition 4HB80%, 3HB20
%, Tg was −43 ° C., melting point was 53 ° C., and number average molecular weight was about 600,000. The composition is ₁ H-NMR.
(Solvent (1) CDCl ₃ ) was used for analysis, and the number average molecular weight was shown as a polystyrene standard sample conversion value by gel permeation chromatography.

Reference Example 2 Same as Reference Example 1 except that medium C (prepared in the same manner as medium B except that sodium citrate was not contained) was used instead of medium B, and the amount of suspension was 50 ml. And then mycelium B
0 was cultured to obtain a 3HB / 4HB polyester copolymer. The copolymer had a yield of 1.1 g / 1 and a composition of 4HB.
50%, 3HB50%, Tg-11 ° C, melting point 51
The temperature and the number average molecular weight were about 610,000. The composition and the number average molecular weight were determined in the same manner as in Reference Example 1.

Reference Example 3 Instead of the medium B, the medium C (prepared in the same manner as the medium B except that sodium citrate was not contained) was used, the amount of the suspension was 500 ml, and a 2000 ml Sakaguchi flask was used. Others were cultured in the same manner as in Reference Example 1 and 3
An HB / 4HB polyester copolymer was obtained. The copolymer has a yield of 1.2 g / 1, a composition of 4HB 20%, 3HB
80%, Tg was -9 ° C, melting point was 163 ° C, and number average molecular weight was about 500,000. The composition and the number average molecular weight were determined in the same manner as in Reference Example 1.

Each of the copolymers obtained in Reference Examples 1 to 3 was treated with Rhizopus delemar-derived lipase (manufactured by Seikagaku Corporation) and Rhizopus in a phosphate buffer.
When treated with lipase derived from arrhizus (manufactured by Boehringer Mannheim), it was confirmed that all of them decomposed.

Comparative Example 1 200 ml of a 2 (w / v)% chloroform solution obtained by dissolving 4 g of the 3HB / 4HB polyester copolymer obtained in Reference Example 1 in 200 ml of chloroform was prepared. Cast on a 15 cm glass petri dish, gradually evaporate chloroform to a thickness of about 200 μm.
m film was made. This film was cut into a 4 cm square to obtain a sample 1.

Comparative Example 2 Sample 2 was obtained in the same manner as Comparative Example 1 except that the 3HB / 4HB polyester copolymer obtained in Reference Example 2 was used.

Comparative Example 3 Sample 3 was obtained in the same manner as Comparative Example 1 except that the 3HB / 4HB polyester copolymer obtained in Reference Example 3 was used.

Example 1 10 ml of a 2 (w / v)% chloroform solution of the 3HB / 4HB polyester copolymer obtained in Reference Example 1 was prepared, and this was cast on a glass petri dish having a diameter of 15 cm and gradually added. Chloroform is volatilized to the thickness of about 10 μm
I made a film. Polyglycolic acid mesh ("Dexon mesh", model number # 2, Da on the film
vis + Geck, Inc. (Manufactured by Seisakusho Co., Ltd.), lightly pressed from above, and treated in an oven at 90 ° C. for 30 minutes, a film and a polyglycolic acid mesh were stuck together, and this was cut into 4 cm squares to obtain sample 4.

Comparative Example 4 Sample 5 was obtained by cutting the polyglycolic acid mesh used in Example 1 as it was into a 4 cm square.

Comparative Example 5 2 (w / v)% of polycaprolactone (manufactured by Aldrich) in place of the 3HB / 4HB polyester copolymer solution
Sample 6 was obtained in the same manner as in Example 1 except that the chloroform solution was used.

Comparative Example 6 2 (w / w) of poly (L-lactic acid) (manufactured by Polyscience) was used instead of the 3HB / 4HB polyester copolymer solution.
v) Sample 7 was obtained in the same manner as in Comparative Example 1 except that the% chloroform solution was used.

Example 2 Commercially available polyester fiber artificial blood vessel a1 (length 7 cm,
Inner diameter 8 mm, water permeability: 1200 ml / cm ² / min /
120 mmHg) was impregnated with a 1 (w / v)% chloroform solution of the 3HB / 4HB polyester copolymer obtained in Reference Example 1 from the inside using a Pasteur pipette, and then immersed in a hexane solvent to form chloroform. The 3HB / 4HB polyester copolymer in the solution was precipitated, chloroform was removed, and the mixture was dried in a nitrogen stream. The above operations of impregnation with chloroform and drying were repeated three times to obtain an artificial blood vessel a2 treated with a 3HB / 4HB polyester copolymer. Next, the artificial blood vessel a2 was fitted onto a Teflon rod (outer diameter 8 mm), and a polyester mesh was wrapped around the outer circumference of the artificial blood vessel a2, and 3 (w / w) of the 3HB / 4HB polyester copolymer obtained in Reference Example 1 was used.
v) It was dipped in a 1,4-dioxane solution and freeze-dried, and then the polyester mesh on the outer periphery was peeled off and removed from the Teflon rod to obtain a porous sample a3. The water permeability of the sample a3 is 10 ml / cm ² / min / 120.
It was mmHg. The water permeability was measured by applying a water pressure corresponding to 120 mmHg to the sample and determining the outflow amount of water per 1 cm ^{2 of} the sample wall surface for 1 minute. When the sample a3 was observed with a scanning electron microscope, it was found that the polyester fiber was 3HB with a thickness of 10 to 30 μm and a pore diameter of 1 to 20 μm.
The 4HB polyester copolymer porous layer was integrated.

Test Example 1 Using a rabbit having a body weight of about 3 kg, under general anesthesia of pentobarbital sodium, the abdomen was shaved and disinfected, and then the skin and abdominal wall were midline incised, and a serosa defect of 3 cm square was formed on the inside of the abdominal wall. Created 8 places. Samples 1 to 6 were sutured to the serosa defect, and the abdominal wall incision and the skin incision were sutured in this order. At this time, Samples 4 and 6 were sutured by applying the polyglycolic acid mesh side to the serosal defect. Sample 7 was too stiff to be sutured.
After breeding for 10 weeks, the animals were exsanguinated to death under anesthesia, and laparotomy was performed for evaluation.

When each experimental site was visually evaluated, adhesion was observed between the abdominal wall and the intestinal tract at the site where Sample 5 was sutured. No adhesion was observed at the site where the other samples were sutured.

The cross section of each experimental site was observed histologically by hematoxylin-eosin staining. As a result, in Samples 1, 2 and 3, macrophages and fibroblasts were adhered to the surface of each sample, but the 3HB / 4HB polyester copolymer was completely decomposed only on the surface part. Not disassembled.

It was observed that the polyglycolic acid mesh of Sample 4 (Example 1) was covered with living tissue on the periphery and the 3HB / 4HB polyester copolymer was completely decomposed entirely. In addition, the serosa regenerated at the site where the sample was sutured, and the foreign body reaction was also weak.

Sample 5 had a strong foreign body reaction and partial regeneration of the serosa.

The periphery of the polyglycolic acid mesh of Sample 6 was covered with living tissue, but the polycaprolactone portion was hardly decomposed. Although the serosa was regenerated at the site where the sample was sutured, a foreign body reaction was observed.

Test Example 2 Sample a3 was cut into 5.5 cm and transplanted into the thoracic aorta of a mixed breed dog. The transplant could be done without pre-clotting treatment. No bleeding from the wall of the artificial blood vessel was observed. The sample a3 was soft and well adapted to the shape and shape of the soft arterial wall, and had good sutureability. After 10 weeks, the blood was killed by exsanguination under anesthesia, and the chest was opened for evaluation. Sample a3 was well patent and maintained the function as an aorta. As a result of histological observation performed in the same manner as in Test Example 1, it was found that the penetration of the tissue into the sample a3 was good and that the 3HB / 4HB polyester copolymer was almost completely decomposed. Further, the foreign body reaction was weak, and endothelization was partially observed on the inner surface of the sample a3.

Example 3 A polyester knitted fabric having an elastic elongation of about 100% (horizontal knitted plain knit, 3 denier, fiber interval: 250 μm in width, 50 in length)
(0 μm) is cut into 7 × 9 cm and immersed in a 2 (w / v)% chloroform solution of 3HB / 4HB polyester copolymer, and then chloroform is volatilized on a glass petri dish having a diameter of 15 cm to give 3HB / 4HB polyester. A knitted fabric coated with a copolymer was prepared. Similarly, 3HB / 4
40 ml of a 2 (w / v)% chloroform solution of HB polyester copolymer was cast on a glass petri dish, and chloroform was gradually vaporized to form a film having a thickness of about 40 μm. A knitted fabric coated with a 3HB / 4HB polyester copolymer was placed on this film, which was lightly pressed from the top and treated in a 90 ° C. oven for 30 minutes to obtain a vascular repair material sample 11. When the sample 11 was observed with a scanning electron microscope (hereinafter referred to as SEM), it had a two-layer structure of a knit and a film, and the film side surface was smooth.

Example 4 Sample 11 was placed on a 15 × 13 cm stainless steel tray with the 3HB / 4HB polyester copolymer film side down, treated in a 90 ° C. oven for 30 minutes, allowed to cool, and placed in a tray. I made them stick. 19 ml of a 2 (w / v)% 1,4-dioxane solution of the 3HB / 4HB polyester copolymer was poured on it, and this was freeze-dried to obtain a vascular repair material sample 12. When the sample 12 was observed by SEM, it had a three-layer structure in which a knit was sandwiched between a film layer and a porous layer having a pore size of about 100 μm. The surface of the porous layer was rough and the surface of the film layer was The surface was almost smooth.

Example 5 5% by weight of egg lecithin (manufactured by Wako Pure Chemical Industries, Ltd.) was used in place of the 2 (w / v)% 1,4-dioxane solution used in Example 4.
Containing 3HB / 4HB polyester copolymer 2 (w /
v) A vascular repair material sample 13 was obtained in the same manner as in Example 4 except that the 1,4-dioxane solution was used. When the sample 13 was observed by SEM, it had the same structure as the sample 12.

Example 6 A 7 × 9 cm mold was prepared using an aluminum material having a thickness of 1 mm, and the sample 11 was set in the mold so that the 3HB / 4HB polyester copolymer film surface faced down. ,
1m between the bottom of a 15 x 13 cm stainless steel tray
It was placed on the tray with an interval of m. On top of that, 2 (w / 3HB / 4HB polyester copolymer)
v) 38 ml of a 1,4-dioxane solution was poured, and this was freeze-dried to obtain a vascular repair material sample 14. Sample 1
4 was observed by SEM, a knit was present in the middle of the porous layer. The porous layer on the bottom side of the stainless steel tray had a pore diameter of about 10 μm, and the porous layer on the other surface side had a pore diameter of about 10 μm. It was 100 μm, and the surface was rough.

Example 7 The same polyester knitted fabric as used in Example 3 was fused and formed into a tube having an inner diameter of 12 mm and a length of 3 cm by a heat sealer, and fitted into a glass U-shaped tube having an outer diameter of 10 mm to give 150.
Heat treatment was performed at 0 ° C. to obtain a crimped polyester knitted tube a11 having an inner diameter of 10 mm. This curved tube a11 is 3HB
・ Immersed in a 2 (w / v)% chloroform solution of 4HB polyester copolymer, fitted in a glass U-shaped tube with an outer diameter of 10 mm, and dried in a nitrogen stream, and then coated with 3HB / 4HB polyester copolymer. A crimped polyester knitted curved tube a22 was prepared. The outer circumference of the curved pipe a22 is wrapped with a polyester mesh, and then immersed in a 3 (w / v)% 1,4-dioxane solution of a 3HB / 4HB polyester copolymer, which is freeze-dried, and then the outer polyester mesh is peeled off. Then, the blood vessel was removed from the glass U-shaped tube to obtain a vascular repair material sample 15. When the sample 15 was observed by SEM, it was 3H with a polyester knitted fabric and a pore size of 1 to 20 μm.
The B / 4HB polyester copolymer porous layer was integrated.

Test Example 3 The blood vessel restoration material samples 11 to 15 and the polyester knitted fabrics constituting each sample were cut into strips having a width of 20 mm, and a tensile tester (TENSILON UTM-250, manufactured by Orientec Co., Ltd.) was used. The tensile speed was 200 mm / min and the measurement was performed at room temperature. The tensile directions were all lateral, and the tensile stress was determined as the load per unit width of the test piece. The tensile strength and strain at break were determined as the tensile strength and strain when the sample broke. The results are shown in Table 1.

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[Table 1] Note *) Sample 11 had no yield point.

Test Example 4 A part of the right ventricle of a dog was incised, and appropriately cut vascular repair material samples 11 to 14 were sutured and the chest was closed. Two weeks later, the blood was killed by exsanguination under anesthesia, and the chest was opened for evaluation. The suturing was carried out with the smooth copolymer film side in Sample 11, the porous layer side in Samples 12 and 13, and the porous layer side with a pore size of about 100 μm in Sample 14 as the blood surface side. Each sample is flexible and adapts well to the flexible muscle wall properties and shape of the right heart,
The sutureability was also good. Sample 13 was excellent in water wettability, but other samples did not cause any inconvenience in use.

When the thoracotomy was visually evaluated, all the samples were flexible. No abnormal reaction was observed in any of the samples.

A cross section of the sample was stained with hematoxylin-eosin and observed histologically by an optical microscope. As a result, in Sample 11, a large blood clot was formed on the smooth copolymer film on the blood surface side. The state of invasion of the tissue into the polyester knitted fabric from the outside was good.

In Samples 12 and 13, a thin and stable blood coagulum layer was formed on the porous layer, and part of the porous layer was beginning to become organized due to invasion of tissue, but the film layer had tissue. Was not invading.

In Sample 14, a thin and stable blood coagulation layer was formed on the porous layer having a pore size of about 100 μm, and the tissue was formed by the invasion of fibroblasts, smooth valve cells, capillaries, etc. into the porous layer. The formation was good, and endothelialization was progressing in which the inner surface was covered with endothelial cells. Moreover, the decomposition of the copolymer has also started.

Test Example 5 A dog pulmonary artery was partially excised and replaced with a vascular repair material sample 15. The sample was flexible, and was well adapted to the shape and properties of the pulmonary artery wall, which was extremely flexible and highly expandable, and had good sutureability. Two weeks later, the blood was killed by exsanguination under anesthesia, and the chest was opened for evaluation. Sample 15 retained its function as a pulmonary artery tube. As a result of histological observation in the same manner as in Test Example 4, a thin and stable blood coagulation layer was formed inside the pulmonary artery duct, and a part of the porous layer began to be organized due to invasion of tissue. I was there. Moreover, the decomposition of the copolymer has also started.

Test Example 6 From the right ventricle of a dog to the pulmonary artery, a bypass was created with an artificial blood vessel made into a tubular shape with the vascular repair material sample 15, then the origin of the original pulmonary artery was ligated, and all pulmonary arterial blood was passed through the bypass. I let it flow. When the shape of the bypass portion was examined by an X-ray test three months after the implantation, the morphology at the time of implantation was kept good. Next, when the inner diameter of the bypass was doubled with a balloon attached to the tip of the catheter, it could be reasonably expanded, and no change in hemodynamics was observed. Three months later, when the shape of the bypass portion was examined again by X-ray examination, the shape remained in the expanded state. That is, the present material creates a “growth-prone vascular repair material, a growth-promoting artificial blood vessel” that can be expanded at any time, in any size, and by utilizing its flexibility and biodegradability. I was able to.

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EFFECTS OF THE INVENTION According to the present invention, there is obtained a medical material for soft tissue, which is decomposed and absorbed by a living tissue according to the invasion of the living tissue and satisfies mechanical compatibility and safety. The medical material for soft tissues of the present invention is suitably used for artificial blood vessels, artificial skin, surgical sutures, adhesion preventive materials and the like. As a result of examination by cell culture, the medical material for soft tissue of the present invention showed better cell engraftment, migration and proliferation than the collagen membrane. In particular, those modified with phospholipids such as lecithin were even better. The artificial blood vessel or the blood vessel repair material of the present invention has good biocompatibility, stretchability, and flexibility, and is excellent in handleability when sutured to a biological tissue.

Claims (2)

[Claims] 1. A fiber assembly and the following formula (1): 3-hydroxybutyrate unit represented by the following formula (2) A medical material for soft tissue comprising a polyester copolymer having a 4-hydroxybutyrate unit represented by 2. An artificial blood vessel or a vascular repair material, which is formed of the medical material for soft tissue according to claim 1.