JP3389316B2 - Absorbable biomaterial and method for producing the same - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a biomaterial composed of a material obtained from a natural tissue such as collagen or chitin and used for surgical treatment such as bone defect, damage and tooth extraction, or orthopedic surgery.

[0002]

2. Description of the Related Art Conventionally, a biomaterial composed of a material obtained from a biological tissue such as collagen or chitin is filled in a block form in a bone defect, a damaged portion, an extraction tooth socket or the like, and the portion is prosthesized to maintain its shape. It has been used for the purpose of preventing the infection or the like by sealing the wound as a film-shaped covering material.

Among such biomaterials, as a block-shaped filler, for example, the porous sponge of the invention of JP-A-62-39506 is a non-absorbable substance in vivo, which is formed by crosslinking chitin with a drug. Excellent shape retention.

Further, the composite material of the invention of JP-A-3-23864 is used as a block-shaped filler, and this composite material is composed of collagen sponge and polylactic acid and is absorbable in vivo.

As the above-mentioned wound dressing material, for example, the laminated material of the invention of JP-A-2-268766 is a wound dressing material in the form of a bilayer membrane of porous and non-porous material obtained by crosslinking chitosan with a drug. In order to prevent infection, the outer side is a non-porous membrane, while the inner side is a porous membrane to adhere to the wound.

[0006]

However, the above-mentioned prior art has the following problems. That is, since the porous sponge is filled in the defect portion and then sutures the soft tissue to seal the affected area, the soft tissue may invade the defect portion, delays bone formation, and is non-absorbable. Since it is not completely replaced by bone itself, there is a risk of infection and the risk of detachment of the material itself; the above-mentioned composite material has some antigenicity to atelocollagen, and also polylactic acid is decomposed and absorbed in living tissue. The above-mentioned laminated material prevents the invasion of bacteria by the non-porous membrane, but does not allow tissue fluid containing nutrients to flow in and out, so that the inside of the living body (in the oral cavity, bone defect part, etc.) Can not be applied to, the problem that the process of dissolution, coagulation, neutralization, etc. is complicated in the manufacturing method, and the chemical treatment causes adverse effects on the living body There is a possibility that there is a potential.

[0007]

In order to solve the above problems, the present invention comprises a thermally crosslinked chitin or carboxymethyl chitin, having a thickness of 20 to 100 μm and an average pore diameter of 2
˜20 μm, one side of the porous thin film has a thickness of 300 to 1
Provided is an absorbable biomaterial, which comprises a porous thick film face-to-face fixed with a pore size of 000 μm and an average pore diameter of 50 to 500 μm.

In order to obtain such a material, a solution of chitin or carboxymethyl chitin is freeze-dried to form the thick film, and then the solution is applied to one surface of the thick film to form the thin film, Provided is a method for producing the above-mentioned absorbable biomaterial, which comprises thermally crosslinking these.

[0009]

EXAMPLES Examples of the present invention will be described below. A solution of chitin or carboxymethyl chitin is put into a container such as a cylindrical container or a chalet and freeze-dried, and if necessary, press molding is performed and air-drying is performed at a temperature of 30 ° C. or lower, preferably at a crosslinking temperature. The absorbable biomaterial is manufactured by a process of heat-crosslinking by heating in a vacuum of 120 ° to 180 ° for about 24 hours.

The biomaterial produced in this manner is safe in vivo because it is produced from chitin or carboxymethylchitin, which has excellent biocompatibility, as a raw material and does not use a crosslinking agent. Due to thermal crosslinking in vacuum, it decomposes in vivo over time, and this decomposed chitin or carboxymethyl chitin promotes the formation of capillaries, which results in a block-like filling of bone defects, tooth extraction sockets, etc. The filling point has the property of being completely restored by natural bone.

The biomaterial can be manufactured relatively easily as described above, and in addition to being a block-shaped biomaterial, for example, it can be thinly spread in a chalet and freeze-dried to form a film. A biomaterial can be obtained, which is used to cover bone defects, tooth extraction sockets, and the like.

This single-layer membrane-shaped biomaterial can be controlled in thickness, average pore size and density by adjusting the concentration of the solution or the like, or by adding compression molding if necessary after freeze-drying, By controlling them, an environment that promotes bone formation is created for a necessary period of time, in which tissue fluid containing nutrients is circulated but soft tissue is not infiltrated, which enables complete bone repair by natural bone.

Further, by adding a work of applying the above solution after freeze-drying, it is formed without undergoing freeze-drying,
A bilayer biomaterial can be obtained by adding a membrane having a larger average pore size to the monolayer biomaterial, and the bilayer biomaterial should be adsorbed by bone marrow cells and various cells. By appropriately controlling the film thickness and average pore diameter of the added film and using this as the coating material, active bone formation occurs at the surface portion of this film, and an environment where bone formation is more likely can be provided.

As a result of further research, a biomaterial having a thermal crosslinking temperature lower than 120 ° C. has a high dissolution rate and may dissolve without waiting for bone formation to become active, and has a high mechanical strength. It has been found that the mechanical strength is small, even though it is small and on the other hand due to the thermal crosslinking temperature higher than 180 ° C.

The biomaterial made of heat-crosslinked chitin or carboxymethyl chitin has high water absorption,
Further, since no cross-linking agent is used at all, substances other than inevitable contaminants other than chitin or carboxymethyl chitin are not detected. On the other hand, a biomaterial of chitin or carboxymethyl chitin cross-linked by a drug has low water absorption and is non-absorbable in vivo,
When analyzed by a chemical method or the like, a cross-linking drug is detected.

Next, an example of using the biomaterial will be described in detail with reference to the drawings. FIG. 1 shows one usage state of a biomaterial, in which a fractured bone B is fixed by a fixing plate P as shown in FIG. 1A, and then chitin or carboxymethyl chitin is thermally crosslinked as shown in FIG. 1B. Tena, thickness 10-1
A porous and single-layered biomaterial 1 having a diameter of 000 μm and an average pore diameter of 5 to 1000 μm was attached to the entire circumference of the fracture site B1 (excluding the site of the plate P) using an extremely small amount of an instant adhesive.

Such a biomaterial 1 had the following actions. That is, the biomaterial 1 allows the tissue fluid containing nutrients to flow to the fracture site B ₁ but does not allow soft tissue to invade the bone fracture site B ₁ due to the above-mentioned film thickness and average pore size, thereby allowing the soft tissue to satisfactorily prevent bone growth and prevent bone growth. Providing an environment that promotes production, early and precise bone formation was achieved. In addition, since the biomaterial 1 is obtained by thermally crosslinking chitin or a derivative thereof without using a drug, it has biocompatibility, is safe, and dissolves slowly in vivo. Is decomposed and absorbed in the body, and it is not necessary to remove it by surgery.

FIG. 2 shows another usage state of the biomaterial 1, in which the gingiva S is cut open, and the defect void D ₁ of the alveolar bone D thereunder is covered with the biomaterial 1 in the form of a film. By doing so, it was possible to provide an environment that favorably promotes bone formation as described above, and to treat the bone defect void D ₁ due to early and dense bone formation.

FIGS. 3 to 4 show other usage states of the biomaterial 1, and in both figures, the bone defect void B _{2 of the} bone B is filled with autogenous bone fragments B ₃ and the bone defect void B ₂ Was covered with biomaterial 1.

As shown in FIG. 4, the bone defect void B ₂
In order to fill the remaining void with autogenous bone fragment B ₃ ,
Thermally cross-linked chitin or its derivatives, with an average pore size of 10
Porous and block-shaped biomaterial 2 of up to 1000 μm may be filled. Such a block-shaped biomaterial 2
Is a scaffold for bone formation and promotes the formation of capillaries when it is decomposed in vivo, and causes bone to grow at an early stage at the decomposed site. As a result, the filling site can be completely repaired by the natural bone, and at the same time, the autogenous bone fragment B ₃ is prevented from oscillating, so that the bone defect void B ₂ is treated by the early and dense bone formation. You can

FIG. 5 shows another mode of use in which the membrane-shaped biomaterial 1 and the block-shaped biomaterial 2 are used in combination as shown in FIG. 4, and the block is formed through the gingiva S that is cut open as shown in FIG. The biomaterial 2 in the shape of a tooth was filled in the entire void D ₂ after tooth extraction, and this void D ₂ was covered with the biomaterial 1 in the form of a film.

Next, FIG. 6 shows a biomaterial 3 in the form of a two-layered film in which two porous membranes formed by thermally cross-linking chitin or carboxymethyl chitin and having different average pore sizes are integrated, and the biomaterial 3. In one use state, this biomaterial 3 is
Properties similar to those of the single-layered film-shaped biomaterial 1, that is, one side of the porous thin film 3a having a thickness of 20 to 100 μm and an average pore diameter of 2 to 20 μm, and a thickness of 300 to 1000 μm, and an average pore diameter of 50 to 500 μm. The thick film 3b is fixed face-to-face.

As an example of the usage state, as shown in FIG. 6, an artificial tooth root fixture F is embedded in the remaining alveolar bone by the incised gingiva S at a part where the alveolar bone D is partially lost. After that, the thin film 3a was faced to the gingiva S and the thick film 3b was faced to the alveolar bone D, respectively, and the defect void D ₁ was covered with the bilayer biomaterial 3 as described above.

The biomaterial 3 in the form of a two-layer film as described above has the following actions. That is, the thin film 3a has the same shape as the single-layered film-shaped biomaterial 1 with respect to the defective void D ₁ .
Tissue fluid containing nutrients is circulated through the thick film 3b, but soft tissue does not invade, thereby providing the soft tissue with an environment that favorably promotes bone formation without inhibiting the bone formation, and the thick film 3b forms the membrane. Depending on thickness and average pore size,
Bone marrow cells and various cells are easily adsorbed in the pores, and thus new bone is easily generated in this portion.

Further, as shown in FIG. 6, the above-mentioned defective void D ₁
The block-shaped biomaterial 2 can be filled inside and used together.

Furthermore, the following has been found. [A] In the thin film 3a of the above-mentioned single-layer biomaterial 1 and double-layer biomaterial 3, the film thickness is larger than 1000 μm or the average pore diameter is 1
When it is smaller than 0 μm, the circulation of the tissue fluid becomes inactive. When the film thickness is smaller than 10 μm, the mechanical strength becomes small, and when the average pore size is larger than 1000 μm, the soft tissue is circulated. ˜1000 μm, average pore size 5 to 1000 μm is desirable.

[B] The film thickness 3 of the above-mentioned bilayer biomaterial 3
In b, -When the average pore diameter is 10 to 1000 µm, bone marrow cells and various cells are easily adsorbed in the pores-When the average pore diameter is smaller than 10 µm, or the film thickness is 50
If it is smaller than μm, the adsorbed amount of bone marrow cells and various cells is small. ・ If the average pore size is larger than 1000 μm or the film thickness is larger than 5000 μm, the mechanical strength becomes small. Therefore, the film thickness is 50 to 5000 μm, the average. Pore diameter 10-1000 μm
Is desirable.

In the present embodiment, an example was shown in which single-layer membrane-shaped, block-shaped, and double-layer membrane-shaped biomaterials 1, 2 and 3 were used alone or in combination, but the present invention shows these characteristics. , Is not limited to the combination, in order to provide an optimal environment for bone formation in accordance with the condition of the affected area, a biomaterial formed by thermally crosslinking chitin or carboxymethyl chitin is formed into optimal properties, and It can be used according to the optimal combination of properties, and it dissolves slowly in vivo regardless of the properties, so after healing of the affected area it is decomposed and absorbed into the body, and it is not necessary to take it out by surgery etc. .

The density of the biomaterial is 0.07-
It is preferably 0.7 g / cm ³ . Density is 0.07g /
If it is smaller than cm ³ , the mechanical strength of the biomaterial is small and the absorption rate is too fast, so it may disappear before healing of the affected area, and the amount of chitin or carboxymethyl chitin may be increased to increase the density to more than 0.7. If the amount is increased, it becomes saturated with water, and there is a problem that a drug must be used to completely dissolve it. As a result of diligent studies, it has been found that if the above-mentioned density is 0.2 to 0.6 g / cm ³ , the mechanical strength becomes stable, which is more preferable.

Example 1 The above-mentioned one-layered film-shaped biomaterial 1 was prepared in the following order: A carboxylmethyl chitin (hereinafter referred to as CM chitin) powder having a carboxylmethylation degree of 60% was dissolved in distilled water, and A 0 wt% aqueous solution was prepared. The above aqueous solution 2 in 6 glass chalets of φ10 cm
0 g each was injected and spread. The glass chalet was flash frozen at -20 ° C and freeze-dried. CM chitin body taken out from the glass chalet at 30 ℃
Air dried at the following temperatures.

120 ° C., 140 ° C., 160 ° C., 180
The CM chitin body was subjected to a thermal crosslinking treatment in a vacuum at a temperature of ° C for 24 hours.

The film thickness and average pore size of each biomaterial 1 are shown in Table 1.

[0033]

[Table 1]

Example 2 CM chitin powder having a carboxymethylation degree of 60% was dissolved in distilled water to prepare 20 g of a 10.0 wt% aqueous solution, and this aqueous solution was 1.0 cm × 1. 0c
Two molds (not shown) each having a cubic internal shape of m × 1.0 cm were poured, and the mixture was rapidly frozen at −20 ° C. and freeze-dried. Only one of these CM chitin bodies was press-molded to have a thickness of about half, and they were taken out of the mold and air-dried at a temperature of 30 ° or less. Then, when the CM chitin body was subjected to thermal crosslinking treatment in vacuum at 140 ° C. for 24 hours, biomaterials having thicknesses of 100 μm and 200 μm, respectively were obtained.

The density of these absorbent materials is 0.0352 g
/0.2cm ³ → about 0.176g / cm ³ and 0.0352g /
It was 0.1 cm ³ → about 0.352 g / cm ³ .

Example 3 1.0 g of 50% deacetylated chitin was dissolved in distilled water to prepare a 1.0 wt% aqueous solution. Material 1 was prepared. As a result, it was observed that the average pore size was slightly larger than that of the biomaterial 1 of Example 1.

Embodiment 4 As shown in FIG. 7, a container 10 comprising a cylinder-shaped main body 11 of φ5 mm having an extruding lid 12 having a handle 12a at its lower end and an upper lid 13 having an air hole 13a at its upper end is provided. In accordance with the method of Example 1, a cylindrical block-shaped biomaterial 2 having a diameter of 1.6 to 1.8 mm was produced. The film thickness and average pore diameter of each biomaterial 2 were as shown in Table 2.

[0038]

[Table 2]

Example 5 After freeze-drying, the biomaterial 3 was prepared in the same manner as in Example 1 except that the CM chitin solution was applied to one side of the CM chitin body.
Was produced. The thin film 3 in each biomaterial 3
The film thickness and average pore diameter of a and the thick film 3b are as shown in Table 3.

[0040]

[Table 3]

Animal Experiment 1 As shown in FIG. 8, N, which had a breeding period of 1 week before the operation, was used.
ZW Rabbit: A cylindrical bone defect B ₄ (φ2.0 mm) was formed in the bone B on the medial side of the tibia at the age of 12 weeks, and this bone defect B ₄
The biomaterial 3 in the form of a two-layered membrane prepared in Example 5, which has a thickness of 5 × 5 m in advance
The bone defect B with the biomaterial 3 trimmed to a size of m
₄ is covered with a very small amount of instant adhesive, and after this, muscle,
The skin was quickly sutured.

Four weeks after the operation, the NZW rabbit was sacrificed, the tibia was collected, and a decalcified specimen was prepared according to a conventional method. In addition, as for the staining, HE staining and PAS staining are performed,
Observation with an optical microscope was performed.

As a result, as shown in the schematic view of the image of the tissue sample in FIG. 10, it was confirmed that the new bones were fused at the center on the outer surface side and the bone defect B ₄ was blocked. In the specimen of the biomaterial 3 at 140 ° C. and 160 ° C., the new bone almost completely filled up the bone defect B ₄ .

Animal Experiment 2 From bone defect B ₄ formed and adjusted in the same manner as in Animal Experiment 1,
The block-shaped biomaterial 2 produced in Example 4 was filled as shown in FIG. 9, and a tissue sample was produced and observed by the same method.

Also in this experiment, the thermal crosslinking temperature of 140 ° C.,
In the specimen of biomaterial 2 at 160 ° C., new bone B ₅ was most densely formed. However, as a whole, the specimen of the animal experiment 1 produced new bone more densely than the specimen of this experiment.

As described above, the absorbable biomaterial according to claim 1 of the present invention is a porous absorbable material which has excellent affinity with the living body and is decomposed in the living body when sufficient bone formation occurs. By controlling the thickness of the two-layer membrane and the average pore size, it is possible to provide an environment in which bone is easily generated. Also, a solution of chitin or carboxymethyl chitin is freeze-dried to form the thick film, the solution is applied to one surface of the thick film to form the thin film, and the thin film is thermally crosslinked. It is possible to manufacture the absorbable biomaterial according to the invention of claim 2.

[Brief description of drawings]

FIG. 1 is a diagram showing one usage state of a single-layer film biomaterial according to an embodiment of the present invention.

FIG. 2 is a diagram showing another usage state of the single-layer film biomaterial according to the embodiment of the present invention.

FIG. 3 is a diagram showing another usage state of the single-layer film biomaterial according to the embodiment of the present invention.

FIG. 4 is a diagram showing one use state in which the single-layer film-shaped and block-shaped biomaterials of the present invention are used together.

FIG. 5 is a diagram showing another usage state in which the single-layer membrane-shaped biomaterial and the block-shaped biomaterial according to the embodiment of the present invention are used together.

FIG. 6 is a diagram showing one usage state of a biomaterial having a two-layered membrane form according to an embodiment of the present invention.

FIG. 7 is a cross-sectional view of a container used for producing a block-shaped biomaterial according to an example of the present invention.

FIG. 8 is a horizontal cross-sectional view of the tibia of an NZW rabbit showing the method of Animal Experiment 1.

FIG. 9 is a horizontal cross-sectional view of the tibia of an NZW rabbit showing the method of Animal Experiment 2.

FIG. 10 is a schematic diagram of a tissue specimen image in Animal Experiment 1.

[Explanation of symbols]

1,2,3 Biomaterial 3a Thin film 3b Thick film 10 Container 11 Main body 12 Extrusion lid 12a Handle 13 Upper lid 13a Air hole B Bone B ₁ Fracture site B ₂ Bone defect void B ₃ Autogenous bone fragment B ₄ Bone defect B ₅ New bone D Alveolar bone D ₁ Defect void F Fixture P Plate S Gingiva

─────────────────────────────────────────────────── ─── Continuation of the front page (56) Reference JP 5-123390 (JP, A) JP 3-41131 (JP, A) JP 7-184987 (JP, A) Actual flat 5- 63615 (JP, U) (58) Fields surveyed (Int.Cl. ⁷ , DB name) A61L 27/00-27/60 A61F 13/00-13/84 A61L 15/00-15/64

Claims (2)

(57) [Claims] 1. Heat-crosslinked chitin or carboxymethyl
Made of chitin, thickness 20 ~ 100μm, average pore size 2 ~
One side of the porous thin film having a thickness of 20 μm has a thickness of 300 to 10
00μm, 50-500μm average pore size, porous thick film
An absorptive biomaterial that adheres face-to-face . 2. A solution of chitin or carboxymethyl chitin is freeze-dried to form a thick film , and the solution is added to the thick film.
Apply it on one side without freeze-drying to form a thin film.
A method for producing an absorbable biomaterial, which comprises thermally crosslinking .