JP2012095731A - Bioabsorbable medical material - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a bioabsorbable medical material having effects of hemostasis, adhesion prevention, etc by close contact to a wound part.SOLUTION: A face to be in contact with biological tissue is made as a bioabsorbable porous layer and the opposite side face is constituted by a bioabsorbable hydrophilic film layer. Thereby the bioabsorbable medical material is produced which can prevent not only hemostasis and air leakage but also adhesion with peripheral tissue, at a wound part of biological tissue. Further, by disposing a reinforcing material between the porous layer and the hydrophilic film layer, the sheet-like bioabsorbable medial material with handleability improved even in a wet state is produced.

Description

The present invention provides a film layer and a porous layer that are in close contact with a tissue in a living body and play a role of hemostasis, covering and closing in a wound part, and have an effect of preventing adhesion between the wound part and surrounding tissue. It relates to a bioabsorbable medical material.

When a living tissue is wounded, bleeding occurs from the living tissue. Even if hemostasis is temporarily stopped, if it is left incomplete, it may cause further bleeding, which is not preferable. Moreover, since body fluid etc. leak from the biological tissue of a wound part, it is necessary to close a wound part by some means. Furthermore, when the wound is large, if the wound is not covered with a sheet-like material, cells and living tissues enter from the surroundings, and adhesion occurs between the wound and the surrounding normal tissue. There is a risk that various complications may occur as well as inhibiting the healing.

For these reasons, various sheet-like medical materials such as a hemostatic material, a covering material, a closing material, and an anti-adhesion material for wounds are used in surgery. A well-known example is a sheet-like hemostatic material (trade name Taco Kombu) in which fibrinogen and thrombin are attached to one side of a collagen fleece. Materials intended to prevent adhesion include film-like materials made of hyaluronic acid and carboxymethyl cellulose (trade name Sepra film), cloth-like materials made of oxidized regenerated cellulose (trade name Interseed), materials made of gelatin film (patent document) 1, 2). Moreover, as a medical material aiming at the covering of a wound part, there exists a polyglycolide nonwoven fabric (brand name Neobale) etc. All of these materials are bioabsorbable and are planar materials.

These materials need to adhere to the wound and do not move easily. For example, a sheet-like material in which fibrinogen and thrombin are attached to one side of a collagen fleece adheres to a living tissue due to the adhesive effect of fibrinogen and thrombin. A film-like material composed of hyaluronic acid and carboxymethylcellulose does not have such an adhesive effect, but physically adheres when brought into contact with living tissue. Since the polyglycolic acid non-woven fabric does not have such an adhesive effect and adhesion, it is necessary to adhere and fix to the living tissue using an adhesive such as fibrin glue.

Although these absorbable medical materials have greatly contributed to the improvement of surgical performance, on the other hand, drawbacks have also been pointed out. For example, the adhesion of a film-like material composed of hyaluronic acid and carboxymethyl cellulose to a living tissue is not sufficient, and the material often moves from the wound part, resulting in adhesion. Furthermore, there is a drawback in that the material is easily broken when wetted with moisture, and therefore movement for correcting the position of the material cannot be performed. A sheet-like material having fibrinogen and thrombin attached to one side of a collagen fleece is difficult to adhere to a living tissue due to the low degree of extension of the material, and thus the hemostatic effect may be insufficient. The non-woven fabric made of polyglycolide has a problem that it cannot be adhered and fixed to the surface of a living tissue unless an adhesive is used (Patent Documents 3 and 4).

JP 2004-209228 A JP 2007-44080 A JP 2009-183649 A WO2009 / 128474

Provided is a bioabsorbable medical material that is capable of adhering to a wound portion of a living tissue, has excellent handleability, has an effect of preventing hemostasis, covering, closing, and adhesion, and can promote healing of the wound portion. It is to be.

The inventors of the present invention have conducted extensive research to solve these problems, and as a result, when the bioabsorbable medical material comes into a hydrogel form when it comes into contact with a small amount of moisture present on the surface of a living tissue, Has been found to produce excellent adhesion. That is, a material was designed in which a porous layer that becomes a hydrogel form by a small amount of water exists on the surface of the bioabsorbable medical material that comes into contact with the living tissue. On the other hand, a film layer having a hydrophilic surface was arranged on the opposite surface, and the material was designed so as to have an effect of preventing adhesion with surrounding tissues. In this way, by using a bioabsorbable medical material having a two-layer structure consisting of a porous layer and a film layer, it exerts the effect of adhering to the wound part to stop, cover, and close, and promote the healing of the wound part Furthermore, the present inventors have found that an excellent effect that is not possible with conventional medical materials can be obtained, that is, adhesion between a wound part and surrounding tissues can be prevented. In addition to having a two-layer structure consisting of a porous layer and a film layer, a thin sheet (two-layer sheet) can give the material flexibility and increase adhesion to the tissue. So, it was found that the strength of the material is improved, so that it becomes a material excellent in handling that is hard to break. In addition, by using a three-layer sheet structure in which reinforcing materials are combined, we have succeeded in making the material more resistant to breakage and excellent in handleability.

The bioabsorbable medical material of the present invention is composed of a bioabsorbable polymer and is decomposed and absorbed in the living body after the wound has healed, so that no foreign matter remains in the living body. In addition, the water-absorbing surface is easy to adhere to living tissue, so that not only can sutures and adhesives be used, but the material can be adhered and fixed to the wound part, as well as the effect of hemostasis and closure of the wound part. However, the effect can be further enhanced by the combined use with an adhesive or the like. Moreover, since the surface on the opposite side to the surface which adheres to a wound part is hydrophilic, the effect which prevents adhesion with a surrounding tissue is acquired. That is, the material according to the present invention can be adhered and fixed simply by pressing against the wound part of the living tissue, and further, an unprecedented effect can be obtained that adhesion to the wound part can be prevented. is there.
In addition, by combining with a reinforcing material, the strength of the material is improved as compared with a conventional film-like material, and it is possible not only to move the material once in close contact with the tissue, but also an endoscope. This makes it possible to obtain a material that is easy to handle at an unprecedented medical site that is difficult to break even when an operation is performed with a narrow visual field, such as surgery.

It is a figure which shows the cross section of the medical material which has a three-layer sheet structure which concerns on this invention. FIG. 2 is a graph showing the tensile strength of the two-layer sheet and the three-layer sheet in a wet state. FIG. 3 is a graph showing a change over time in the water absorption amount of the sheet. FIG. 4 is a graph showing weight residual ratios when materials having different crosslinking times are implanted subcutaneously in rats. FIG. 5 is a graph showing the adhesion evaluation of the bilayer sheet in the rat body. FIG. 6 is an intestinal micrograph after 3 weeks when the bilayer sheet is applied to the intestinal tract of a dog. FIG. 7 is a tissue section image after 3 weeks when the material of the control group was applied to the intestinal tract of a dog.

The polymer constituting the bioabsorbable medical material according to the present invention is not particularly limited as long as it is decomposed and absorbed in vivo, but is preferably a hydrophilic polymer, particularly a natural polymer. . Examples of such natural polymers include collagen, gelatin, hyaluronic acid, alginic acid, chitin, and chitosan. Among these, it is preferable to use gelatin that can be dissolved in water and has excellent processability.

Since these natural polymers are readily dissolved in vivo, some kind of crosslinking treatment needs to be performed. Crosslinking includes physical methods such as heat treatment, ultraviolet irradiation and radiation irradiation, and chemical methods using a crosslinking agent such as glutaraldehyde and carbodiimide. Among these, it is preferable to perform crosslinking by a physical method such as heat treatment or ultraviolet irradiation that does not leave a crosslinking agent in the material.

If the bioabsorbable medical material remains in the living body for a long period of time, it will damage surrounding tissues and cause adhesions. On the other hand, if it is decomposed and absorbed in a too short period of time, the effect of hemostasis, wound healing, and adhesion prevention cannot be obtained sufficiently. The bioabsorbable medical material of the present invention needs to exist for 12 hours after implantation in the living body, while it is desirable that the bioabsorbable medical material be quickly decomposed and absorbed within 90 days after implantation.

In order for the bioabsorbable medical material to adhere to the wound of the living tissue, the surface of the material that adheres to the living tissue needs to have a layer that absorbs a small amount of moisture from the living tissue and becomes a hydrogel. . Examples of such a layer include a porous layer made of a hydrophilic material. That is, any structure may be used as long as the surface of the material has a large number of minute holes that facilitate water absorption. Such a structure may be a fiber structure such as a knitted fabric, a woven fabric or a non-woven fabric, or may be a porous structure such as a sponge. Among these, when using a water-soluble polymer, it is preferable to consist of a sponge-like porous body with easy preparation. Due to the presence of such a porous layer made of a sponge-like porous body, a bioabsorbable medical material can be adhered and fixed to a living tissue for a necessary period without using fibrin glue or sutures. Is.

As a method for producing such a sponge-like porous body, there is a method in which a bioabsorbable polymer is dissolved in a solvent such as water and then this solution is freeze-dried. Or, a method of foaming a bioabsorbable polymer aqueous solution and then lyophilizing, air drying, or adding a non-solvent to the bioabsorbable polymer aqueous solution while maintaining its porous structure is exemplified. be able to.

The pore size of the sponge-like porous body is 1 μm to 1,000 μm, preferably 5 μm to 800 μm.
Range. If the pore diameter is smaller than 1 μm, the water of the living tissue is not sucked into the material, so that the adhesion is deteriorated and the material cannot be adhered to the wound part. On the other hand, if the thickness exceeds 1,000 μm, the pore size is too large, and the strength of the porous body is too low and it is easily broken.

The thickness of the sponge-like porous body is 20 μm to 15,000 μm, preferably 50 μm to 10,000 μm. If the thickness is less than 20 μm, the material is fragile. On the other hand, if the thickness is 15000 μm or more, the material becomes hard and does not adhere to the wound part.

In order for the bioabsorbable medical material to prevent adhesion between the wound and the surrounding tissue, the surface of the material opposite to the surface where the material contacts and adheres to the living tissue is a hydrophilic film, and It is necessary that cells and tissues do not adhere to the material surface. Such a material is not particularly limited as long as it is a film-like material that is hydrophilic and has a smooth surface. Since this film-like material lacks flexibility and operability when it is thick, it needs to be as thin as possible. The thickness of the film-like material is 1 μm to 200 μm, and preferably 2 μm to 100 μm. If the thickness is less than 1 μm, the material is fragile and difficult to handle. On the other hand, if the thickness is 200 μm or more, the material is too hard to adhere to the wound.

The method for producing the film-like material is not particularly limited, but after dissolving the bioabsorbable polymer in a solvent, the solution is poured into a mold to remove the solvent, or the solution is cast on a flat plate. Examples thereof include a casting method in which the solvent is removed.

The bioabsorbable medical material according to the present invention comprises a porous layer that constitutes a layer that adheres to a wound part as described above, and a material that constitutes a film layer for preventing adhesion between the wound part and surrounding tissue. It is a two-layer sheet characterized by having a layer structure. In order to obtain a two-layer structure, each layer may be produced separately and then combined, or one layer may be produced and then another layer may be produced. Furthermore, the method of producing two layers simultaneously may be used.

The bioabsorbable medical material according to the present invention is extremely easy to operate by using a two-layer sheet. When the material swells with moisture, softness is generated, and the material can be kept in close contact with a tissue that constantly changes its shape, such as the lung, while maintaining a sheet shape.

The bioabsorbable medical material according to the present invention is assumed to be used in endoscopic surgery. In endoscopic surgery, surgery is performed with a narrow visual field using a surgical instrument, and when the material is brought into close contact with the wound part, the position may be corrected many times. In such a case, the moisture-absorbing material is soft and fragile, and further reinforcement is required.

Examples of the reinforcing material include thin woven fabrics, knitted fabrics, and nonwoven fabrics made of bioabsorbable fibers. The material of the bioabsorbable fiber is not particularly limited as long as it is an absorptive polymer, but is preferably a synthetic absorptive polymer that does not easily swell upon water absorption. Among these, polyglycolide, glycolide-lactide copolymer, or glycolide-ε-caprolactone copolymer having a high absorption rate is more preferable.

The bioabsorbable medical material according to the present invention needs to be flexible in order to improve the adhesion to the tissue. For this purpose, the reinforcing material needs to be as thin and flexible as possible. The thickness of the reinforcing material is 5 μm to 500 μm, preferably 10 μm to 400 μm. When the thickness is less than 5 μm, it is difficult to handle the reinforcing material itself, and molding becomes difficult. On the other hand, when the thickness is 500 μm or more, the material is hard and does not adhere to the wound part. The medical material according to the present invention may be a three-layer sheet having a three-layer structure of a porous layer, a film layer, and a reinforcing material.

As described above, the bioabsorbable medical material of the present invention can be brought into close contact with the wound by pressing the material, and further necessary for various tissue repairs such as hemostasis, closure, tissue regeneration, and adhesion prevention of the wound. Exerts a positive effect.

EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated, this invention is not limited to these Examples.

(Example 1) Production of two-layer sheet by freeze-drying method 1
Gelatin powder (manufactured by Nippi) was dissolved in water for injection to prepare a 1.4% gelatin aqueous solution, and 4 mL of this 1.4% gelatin aqueous solution was cast on a plastic tray (8.5 × 5.5 cm) at 25 ° C. for 24 hours. Air-dried to produce a 10 μm thick gelatin film. From the gelatin film prepared on the tray, 5 mL of 1.0% gelatin aqueous solution was poured and allowed to stand at 25 ° C. for 10 minutes. Thereafter, the tray was placed in a freezer at −80 ° C. for 30 minutes to freeze the aqueous gelatin solution, and then processed in a freeze dryer for 24 hours to produce a gelatin porous layer-film layer composite (bilayer sheet). . At this time, the thickness of the entire sheet was 2 mm. Thereafter, the two-layer sheet was placed in a vacuum dryer and heat-crosslinked by heat treatment at 140 ° C. for 3 hours under vacuum. The obtained two-layer material was sandwiched between stainless plates and pressed by applying a load from above for 5 minutes. The film layer of the obtained material was smooth, and the sponge layer was an uneven opaque body. The material thickness was 1.3 ± 0.1 mm. The pore diameter of the sponge body was 92 μm.

(Example 2) Preparation of bilayer sheet by freeze-drying method 2
Gelatin powder (manufactured by Nippi) was dissolved in water for injection to prepare a 1.4% gelatin aqueous solution, and 4 mL of this 1.4% gelatin aqueous solution was cast on a plastic tray (8.5 × 5.5 cm) at 25 ° C. for 24 hours. Air-dried to produce a 10 μm thick gelatin film. From the gelatin film prepared on the tray, 10 mL of 1.0% gelatin aqueous solution was poured and allowed to stand at 25 ° C. for 10 minutes. Thereafter, the tray was placed in a freezer at −80 ° C. for 30 minutes to freeze the aqueous gelatin solution, and then processed in a freeze dryer for 24 hours to produce a gelatin porous layer-film layer composite (bilayer sheet). . At this time, the thickness of the entire sheet was 4 mm. Thereafter, the two-layer sheet was placed in a vacuum dryer and heat-crosslinked by heat treatment at 140 ° C. for 3 hours under vacuum. The obtained two-layer material was sandwiched between stainless plates and pressed by applying a load from above for 5 minutes. The film layer of the obtained material was smooth, and the sponge layer was an uneven opaque body. The thickness of the material was 2.5 ± 0.1 mm. The pore diameter of the sponge body was 98 μm.

(Example 3) Production of two-layer sheet by freeze-drying method 3
Gelatin powder (manufactured by Nippi) was dissolved in water for injection to prepare a 1.4% gelatin aqueous solution, and 4 mL of this 1.4% gelatin aqueous solution was cast on a plastic tray (8.5 × 5.5 cm) at 25 ° C. for 24 hours. Air-dried to produce a 10 μm thick gelatin film. From the gelatin film prepared on the tray, 5 mL of a 0.3% collagen aqueous solution collagen IP (manufactured by Nitta Gelatin Co., Ltd.) was poured and allowed to stand at 25 ° C. for 10 minutes. After that, the tray is placed in a freezer at -80 ° C for 30 minutes to freeze the gelatin aqueous solution, and then processed in a freeze dryer for 24 hours to produce a collagen porous layer-gelatin film layer composite (bilayer sheet). did. The thickness of the entire sheet at this time was 1 mm. Thereafter, the two-layer sheet was placed in a vacuum dryer and heat-crosslinked by heat treatment at 140 ° C. for 3 hours under vacuum. The obtained two-layer material was sandwiched between stainless plates and pressed by applying a load from above for 5 minutes. The film layer of the obtained material was smooth, and the sponge layer was an uneven opaque body. The material thickness was 1.3 ± 0.1 mm.

(Example 4) Production of two-layer sheet by foaming method 1
Gelatin powder (manufactured by Nippi) was dissolved in water for injection to prepare a 1.4% gelatin aqueous solution, and 4 mL of this 1.4% gelatin aqueous solution was cast on a plastic tray (8.5 × 5.5 cm) at 25 ° C. for 24 hours. Air-dried to produce a 10 μm thick gelatin film. Subsequently, a 2% gelatin aqueous solution was sufficiently agitated to foam, and 6 g of the foamed gelatin aqueous solution was poured from above the gelatin film prepared on the tray to gelate, and then air dried at 25 ° C. The thickness of the entire sheet obtained at this time was 1 mm.
These two-layer sheets were put in a vacuum dryer, and heat-crosslinked under heat at 140 ° C. for 3 hours under vacuum. The tray side of the sheet obtained at this time was a smooth film, and the air surface was a sponge body with irregularities. The pore diameter of the sponge body was 223 μm.

(Example 5) Production of two-layer sheet by foaming method 2
Gelatin powder (Nippi) is dissolved in water for injection to prepare a 1.4% gelatin aqueous solution. 4 mL of this 1.4% gelatin aqueous solution is cast on a plastic tray (8.5 x 5.5 cm ² ), air-dried at 25 ° C for 24 hours. Thus, a 10 μm thick gelatin film was produced. Subsequently, a 4.5% gelatin aqueous solution was sufficiently stirred to foam, and 3 g of the foamed gelatin aqueous solution was poured onto the gelatin film prepared on the tray, gelled at −20 ° C., and then air-dried at 25 ° C. did. The thickness of the entire sheet obtained at this time was 48 μm.
These two-layer sheets were put in a vacuum dryer, and heat-crosslinked under heat at 140 ° C. for 3 hours under vacuum. The tray side of the sheet obtained at this time was a smooth film, and the air surface was a sponge body with irregularities. The pore diameter of the sponge body was 147 μm.

(Example 6) Production of two-layer sheet by foaming method 3
Gelatin powder (Nippi) was dissolved in water for injection to prepare a 1.4% gelatin aqueous solution, and 4 mL of this 1.4% gelatin aqueous solution was cast on a plastic tray (8.5 × 5.5 cm). Subsequently, a 2% gelatin aqueous solution was sufficiently agitated to foam, and the foamed gelatin aqueous solution was poured onto the gelatin film prepared on the 6 g tray, gelled, and then air-dried at 25 ° C. The thickness of the entire sheet obtained at this time was 1 mm.
These two-layer sheets were put into a vacuum dryer and heat-crosslinked under heat at 140 ° C. for 1, 3, 5, and 8 hours under vacuum. The tray side of the sheet obtained at this time was a smooth film, and the air surface was a sponge body with irregularities. The pore diameter of the sponge body was 223 μm.

(Example 7) Production of two-layer sheet by foaming method 3
Gelatin powder (manufactured by Nippi) was dissolved in water for injection to prepare a 2% gelatin aqueous solution, sufficiently stirred to foam, and 6 g of the foamed gelatin aqueous solution was poured into a glass tray (8.5 × 5.5 cm). After gelation, it was air-dried at 25 ° C. The thickness of the entire sheet obtained at this time was 5 mm. This sheet was put into a vacuum dryer and heat-crosslinked under heat at 140 ° C. for 3 hours under vacuum. The glass plate side of the sheet obtained at this time was a smooth film, and the air surface was an uneven sponge body. The pore diameter of the sponge body was 223 μm.

(Example 4) Preparation of bilayer sheet by phase separation method Gelatin powder (manufactured by Nippi) was dissolved in water for injection to prepare a 1.4% gelatin aqueous solution, and 4 mL of this 1.4% gelatin aqueous solution was added to a plastic tray (8.5). × 5.5 cm) and air-dried at 25 ° C. for 24 hours to produce a 10 μm thick gelatin film. Subsequently, a 2% gelatin aqueous solution was poured onto the gelatin film prepared on the tray, and cooled ethanol (10 ml) was further poured thereon to precipitate the gelatin. After washing with ethanol, it was air-dried at 25 ° C. A cloudy gelatin precipitate was fixed on the surface of the obtained two-layer sheet, and was uneven.

(Example 9) Preparation of three-layer sheet with reinforcing material Gelatin powder (manufactured by Nippi) was dissolved in water for injection to prepare a 1.4% gelatin aqueous solution, and 4 mL of this 1.4% gelatin aqueous solution was added to a plastic tray (8.5 × 5cm), air-dried at 25 ° C for 24 hours, and a warp knitted fabric consisting of polyglycolide fibers (12g) as a reinforcing material on the gelatin film prepared on a tray made of a 10μm thick gelatin film / cm ² ). Subsequently, the 2% gelatin aqueous solution was sufficiently stirred to foam, and 6 g of the foamed gelatin aqueous solution was poured onto the warp knitted fabric made of the gelatin film and polyglycolide fiber prepared on the tray, and gelled. Later it was air dried at 25 ° C. The thickness of the entire sheet obtained at this time was 1 mm. These two-layer sheets were put in a vacuum dryer, and heat-crosslinked under heat at 140 ° C. for 3 hours under vacuum. The tray side of the sheet obtained at this time was a smooth film, and the air surface was a sponge body with irregularities. The pore diameter of the sponge body was 223 μm.
As the reinforcing material, in addition to the warp knitted fabric, a polyglycolide nonwoven fabric (needle punch) and a polyglycolide nonwoven fabric (melt blow) were used.

Comparative Example 1 Preparation of Single Layer Film Gelatin powder (manufactured by Nippi) was dissolved in water for injection to prepare a 1.4% gelatin aqueous solution, and 4 mL of this gelatin aqueous solution was cast on a plastic tray (8.5 × 5.5 cm), 25 A gelatin film having a thickness of 10 μm was prepared by air-drying at 24 ° C. for 24 hours. The obtained gelatin film was heat-crosslinked by heat treatment at 140 ° C. for 3 hours in a vacuum dryer. The obtained film was a smooth transparent body on both sides, and was insoluble in hot water at 60 ° C.

(Comparative Example 2) Preparation of a single-layer sponge sheet Gelatin powder (manufactured by Nippi) was dissolved in water for injection to prepare a 1% gelatin aqueous solution, and 1 mL of this 1% gelatin aqueous solution was placed in a plastic tray (8.5 × 5.5 cm). Poured and frozen in a −80 ° C. freezer. Then, it was put into a freeze dryer for 24 hours to produce a sponge. The thickness of the obtained porous layer was ˜1 mm. Unlike the two-layer sheet obtained in Examples 1 to 7 or the three-layer sheet obtained in Example 8, the obtained sponge sheet is easily torn and brittle by simply pulling it by hand. The object of the invention was not achieved.

(Evaluation of tensile strength)
FIG. 2 shows the tensile strength when the two-layer sheet prepared in Example 4 and the three-layer sheet prepared in Example 8 were measured in a wet state. The strength under wet conditions could not be held by the chuck of the testing machine if the entire sheet was wetted, so only the 1cm length in the center of the sheet was moistened with water. And measured.
As can be seen in FIG. 2, there was a slight difference in wet strength depending on the type of PGA fabric, but all were clearly higher than the wet strength of the unreinforced sheet.

(Evaluation of water absorption)
The water absorption of the two-layer sheet produced in Example 4 and the three-layer sheet produced in Example 8 was evaluated by the following method. As a control, the gelatin film prepared in Comparative Example 1 was used. First, phosphate buffered saline was dropped onto a horizontal table so as to be 30 mg / cm ^2, and 1 cm ² of a dried two-layer sheet or three-layer sheet was allowed to stand thereon. The time change of the water absorption amount of the sheet after placing the sheet on a horizontal table is shown in FIG. For comparison, the gelatin single layer sheet prepared in Comparative Example 1 was also measured. As shown in FIG. 2, the two-layer sheet and the three-layer sheet quickly absorbed moisture, whereas the comparative gelatin layer sheet took time to absorb moisture.

(Degradability evaluation)
The in vivo degradability of the bilayer sheet (1 × 1 cm ² ) produced in Example 4 was evaluated by the following method. Under anesthesia, the sterilized sheet weighed was placed under the skin of the rat, and the sheet was taken out after 1, 3, 5, 7, and 10 days. After washing and drying, the remaining amount after decomposition and absorption was measured. The results are shown in FIG.

(Evaluation of adhesion to living tissue)
The bilayer sheet (thickness 1.3 mm) produced in Example 1, the bilayer sheet (thickness 2.5 mm) produced in Example 2, the gelatin single layer film produced in Comparative Example 1, and a commercially available hyaluronic acid and carboxymethylcellulose. The adhesion of the film (trade name Sepra film) to the living tissue was evaluated by the following method. Tape was applied to one side of the double-layer sheet or Sepra film (1 cm × 1 cm) produced in Example 1, and a thread was passed through the middle. A bilayer sheet or Sepra film was applied to the cecum of the sacrificed rat, and it was brought into close contact with a finger for 30 seconds. A strength measuring device was attached to the yarn, and it was slowly pulled vertically to measure the strength when it was peeled off. The tensile strength when the test was performed twice was 117.5 ± 10.6 gf / cm ² for the double-layer sheet prepared in Example 1, whereas that for Sepra film was 70.0 ± 42.4 gf / cm ² . The two-layer sheet was superior in adhesion to the surface.
In addition, for the evaluation of adhesion to the pig liver, the bilayer sheet (thickness 1.3 mm) produced in Example 1, the bilayer sheet (thickness 2.5 mm) produced in Example 2, and the comparative example 1 were produced. The adhesion of the gelatin film to the living tissue was evaluated by the following method. First, a tape was applied to one side of a two-layer sheet or a gelatin film (2 × 4 cm 2), and a thread was passed through the middle. A film or sheet was affixed to the liver of a sacrificed pig and brought into close contact with a finger for 30 seconds. A strength measuring device was attached to the yarn, and it was slowly pulled vertically to measure the strength when it was peeled off. Tensile strength when the test is conducted 5 times is 14.0 ± 3.7 gf / cm2 (double layer sheet, thickness 1.3 mm), 29.0 ± 11.3 gf / cm2 (double layer sheet, thickness 2.5 mm) of the double layer sheet of Example 1. In contrast, the gelatin film of Comparative Example 1 was 9.9 ± 3.7 gf / cm 2 (film), and the double-layer sheet was superior in adhesion to the tissue.

(Evaluation of hemostasis)
The hemostatic effect of the bilayer sheet produced in Examples 1 and 2 was evaluated by the following method. Under anesthesia, the abdomen of the rat was incised to expose the stomach, and a 0.5 × 0.5 cm ² epithelial exfoliation was created on the anterior wall and allowed to bleed from the tissue. After confirming that gauze was pressed against the wound for 30 seconds and hemostasis could not be achieved, a 1 × 2 cm ² double-layer sheet was placed on the wound and pressed with tweezers for 30 seconds. As a result, any two-layer sheet adhered to the wound, and a hemostatic effect was observed even after 5 minutes.

(Evaluation of hemostasis by compression)
The hemostatic effect by compression of the two-layer sheet produced in Example 4 and the three-layer sheet produced in Example 8 was evaluated by the following method. Under anesthesia, the abdomen of the dog was incised to expose the spleen, and a 1.0 × 1.0 cm ² epithelial exfoliation wound was created on the anterior wall, and bleeding was performed to create a model with a large amount of bleeding. After confirming that hemostasis could not be stopped by pressing with gauze for 30 seconds, a 2 × 2 cm ² bilayer sheet or a trilayer sheet was placed on the wound, and gauze was further placed on the sheet. The gauze was pressed firmly for 5 minutes. As a result, when the amount of bleeding was large, the two-layer sheet was deformed and adhered to the gauze and peeled off from the tissue. However, the three-layer sheet adhered to the affected area, and a hemostatic effect was observed.

(Evaluation of adhesion prevention effect)
About the double-layer sheet produced in Example 4, the adhesion prevention effect was evaluated by the following method. Under anesthesia, the abdomen of the rat was incised at the wound site, and the serosa with a diameter of 15 mm was loosely injured so as to cause adhesion between the anterior cecum wall and peritoneum. A 2 × 2 cm ² size double layer sheet was placed thereon and pressed for 30 seconds. After the gelatin medical adhesive was applied, a two-layer sheet was placed and the same operation was performed. As a control example, a commercially available film (trade name Sepra film) composed of hyaluronic acid and carboxymethylcellulose was used. In addition, an example was prepared in which the abdomen was sutured without placing anything on the wound site (Sham Ope). Two weeks later, the abdomen was observed and the presence or absence of adhesion was observed. Using adhesion scores (0 = no adhesion, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe) The rat model was evaluated. The evaluation results are shown in FIG. When no tissue was used and the tissue surface was left injured, strong adhesion occurred in all six mice, and when Sepra film was adhered to the tissue surface, two of the six mice adhered. On the other hand, when the two-layer sheet was brought into close contact with the tissue surface, only 1 out of 6 animals showed adhesion. In addition, when the two-layer sheet was used in combination with an adhesive, no adhesion was observed in all three animals.

(Air leak prevention effect)
The air leak prevention effect of the bilayer sheet produced in Examples 1, 4 and 5 was evaluated by the following method. Air was introduced into the lung of a sacrificed dog, and a hole was created by puncturing with an 18G needle while maintaining the pressure at 5 cm / H ₂ O. After confirming air leakage, place the two-layer sheet of 1.5 × 1.5 cm ² obtained in Example 1 so that the hole is in the middle, press for 30 seconds, and then slowly increase the pressure. It was. Even when any two-layer sheet was used, the pressure at which air leaked was 56 cm / H ₂ O.
When a gelatin medical adhesive was further applied to the periphery of the two-layer sheet, the pressure at which air leaked was 80 cm / H ₂ O. When a similar experiment was performed using fibrin glue (trade name Veriplast), the result was 38 cm / H ₂ O, which was higher in the double-layer sheet or the combination material of the sheet and the adhesive. Since the pressure resistance required when a human coughs is 50 cm / H ₂ O, the air leakage prevention effect of these materials was sufficiently recognized.

(Organizational regeneration ability)
The tissue regeneration effect of the wound part in the case where no bilayer sheet prepared in Example 1, a commercially available hyaluronic acid and carboxymethylcellulose film (trade name Sepra film), and any material was used was as follows. evaluated. First, an incision was made in the abdomen of the dog under anesthesia, and a 10 cm serosa from the ileocecal region was gently scraped by 4 × 3 cm ^{2 with a} sandpaper to create a wound. After hemostasis, a double-layer sheet of 5 × 4.5 cm ² or a hyaluronic acid film was placed on the wound and pressed for 30 seconds. In contrast, the abdomen was sutured without any material. After 3 weeks, the abdomen was opened and the presence or absence of adhesion was observed. The affected area was excised, fixed in formalin, and then a tissue section was prepared. The peritoneal mesothelial was stained with HBME1 antibody by the enzyme antibody method. FIG. 6 shows a tissue slice image when a bilayer sheet is used, and FIG. 7 shows a tissue slice image when a film made of hyaluronic acid and carboxymethylcellulose is used. As a result, regeneration of the mesothelum was confirmed in any two-layer sheet, but regeneration of the hyaluronic acid film mesentery was not confirmed.

(Evaluation of water leakage prevention effect)
About the two-layer sheet produced in Example 4 and the three-layer sheet produced in Example 7, the water leakage prevention effect was evaluated by the following method. A hole was made in the chicken breast and a tube with an inner diameter of 1 mm was inserted, and the end of the tube was fixed to the opening on the surface of the chicken breast. A pump was arranged so that a certain amount of water would flow in the tube, and a water leakage evaluation model was prepared in which water flows from the opening on the surface of the chicken breast. In a water leak evaluation model with a flow rate of 0.5 mL / min, a 2 × 2 cm ² size two-layer sheet or three-layer sheet was pasted on the opening, and gelatin medical adhesive was applied around the sheet. As a comparison, only the gelatin medical adhesive was applied to the opening without using a two-layer sheet or a three-layer sheet. As a result, when a two-layer sheet or a three-layer sheet was used, the sheet could absorb water without coming off the chicken breast and prevent water leakage from the opening, but the two-layer sheet or three-layer sheet was not used. In this case, the gelatinous medical adhesive was removed from the chicken breast, and water leakage from the opening could not be prevented.

The bioabsorbable medical material of the present invention exhibits hemostasis, air leakage prevention, tissue regeneration ability, and adhesion prevention effects in surgical wounds in wounds of biological tissues.

Claims (8)

A bioabsorbable medical material having a two-layer sheet structure in which one surface is composed of a bioabsorbable film layer and the other surface is composed of a bioabsorbable porous layer. A bioabsorbable medical material comprising a three-layer sheet structure having one side composed of a bioabsorbable film layer, the other side composed of a bioabsorbable porous layer, and a bioabsorbable reinforcing material therebetween. The bioabsorbable medical material according to claim 1 or 2, wherein the bioabsorbable film layer and the bioabsorbable porous layer are natural polymers. The bioabsorbable medical material according to claim 3, wherein the natural polymer is collagen or gelatin. The bioabsorbable medical material according to claim 4, wherein collagen or gelatin is crosslinked. The bioabsorbable medical material according to claim 5, wherein the crosslinking is thermal crosslinking. The bioabsorbable medical material according to claim 2, wherein the reinforcing material is a synthetic polymer. The bioabsorbable medical material according to claim 7, wherein the synthetic polymer is glycolide, lactide, caprolactone, trimethylene carbonate, a homopolymer of dioxanone, or a copolymer thereof.