JPH10324641A - Absorbable barrier - Google Patents

Abstract

(57) [Problem] The problem to be solved by the present invention is to improve the heat stability, processability, reproducibility, storage stability, bioabsorbability and tissue regeneration of animal tissues including humans. Absorbable blocking membrane for tissue regeneration useful for reconstruction, and jaw bone, periodontal tissue, long bone defect using the absorbent blocking film, particularly long bone defect in which bone on both sides of the defect is disconnected It is to provide a reconstruction method. SOLUTION: An absorptive shut-off film used in a tissue regeneration inducing method comprising a lactic acid-based polyester obtained by inactivating a polymerization catalyst as an essential component.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an absorptive barrier for use in a method of inducing tissue regeneration useful for reconstructing tissues of animals including humans, and a jawbone, a periodontal tissue, and a long tube using the absorptive barrier. The present invention relates to a method for reconstructing a bone defect, particularly a long bone defect in which bones on both sides of the defect are disconnected.

[0002]

2. Description of the Related Art As a method for reconstructing a bone tissue, there is known a method other than a tissue regeneration induction method, in which a defective portion is filled with a sintered body of calcium phosphate, which is an absorbable cement or an absorbable ceramic, and embedded therein. There are many patent publications and documents.

[0003] Japanese Patent Publication No. 1-501289 discloses a biocomposite material comprising a polymer and ceramic and having continuous pores. Examples of the polymer and ceramic include polylactic acid and calcium phosphate. It also describes the increase of the ridge, but there is no clear description of the method of inducing tissue regeneration, and there is no description about the deactivation of the polymer polymerization catalyst.

There are many literatures on the method of inducing tissue regeneration in the field of dentistry, and they are described in detail in Nakamura and Uraguchi, Quintessence Publishing, “GTR Science and Clinical Practice”.
Especially when the periodontal tissue is reconstructed for the treatment of periodontal disease, it is performed by preventing the gingiva from entering the space where the periodontal tissue is to be reconstructed with a blocking film, which is mainly non-absorbable Polytetrafluoroethylene is used. But,
Non-absorbable membranes such as polytetrafluoroethylene have the drawback that the burden on the patient is large because surgery is required to remove the membrane after the tissue is reconstructed.

On the other hand, as an absorbent material, polylactic acid, a copolymer of lactic acid and glycolic acid, and the like have been reported. For example, JP-A-2-63465 discloses a lactic acid-based polyester such as a copolymer of lactic acid and ε-caprolactone as a material for periodontal tissue regeneration, but since the polymerization catalyst is not deactivated, In particular, it has a disadvantage that it is easily deteriorated during melt molding. Japanese Patent Application Laid-Open No. 7-498 discloses a mixture of a piezoelectric polymer material and inorganic fine particles, but there is no calcium phosphate as an example of the inorganic fine particles, and the deactivation of a polymerization catalyst for a lactic acid-based polymer. Was not described at all.

[0006] Ossification phenomena include membranous ossification and cartilage ossification. Skulls, jawbones, clavicles and the like are membranous ossifications, and humerus, femur, tibia, fibula, radius, ulna, etc. Is known to be cartilage ossification. Reconstruction of bone by the tissue regeneration induction method has been mainly studied in the jaw bone,
The application of tissue regeneration induction to long bones formed by cartilage ossification has been rarely performed. Japanese Patent Application Laid-Open No. Hei 7-236688 describes the application of the tissue regeneration induction method to long bones, but the application of the method to a defect at the epiphyseal portion is not isolated.

[0007] Examples of the use of dissected long bones include:
A study by Farso-Nielsen et al. (Journal
of Dental Research (speci
alishe, Vol. 70, p. 577, 1991) and a study by Lu Shibi et al. (Chinese Medi).
cal Journal 109, No. 7, 551-5
54), and in the case of Farso-Nielsen et al., An experiment using a resorbable polyurethane membrane was performed, but the membrane alone could not be used to adequately reconstruct the bone. Also, Lu Sh
In the case of ibi et al., since a non-absorbable silicone membrane was used, it was necessary to remove the membrane after bone reconstruction.

[0008] In addition, a tube of polyglycolic acid is known as a tissue regeneration induction method performed by regeneration and connection of a cut peripheral nerve. Japanese Patent Application Laid-Open No. 1-503204 discloses a method mainly for nerve regeneration. Although a device is disclosed, there is a disadvantage that the polymerization catalyst is not deactivated and thus easily deteriorates during molding.

That is, a bioabsorbable membrane such as a conventional polylactic acid or a copolymer of lactic acid and glycolic acid has a high thermal stability and processability because the polymerization catalyst during polymer production is not deactivated. The reproducibility was poor, and furthermore, the monomers produced during melt processing acted as a catalyst for decomposition of the polymer, so that the storage stability was poor. Further, when an inorganic powder was melt-kneaded with a conventional lactic acid-based polyester in which a polymerization catalyst was not deactivated, a decrease in molecular weight and generation of a monomer were remarkable.

[0010]

The problems to be solved by the present invention are heat stability, processability, reproducibility, storage stability,
Bioabsorbable, excellent in tissue regeneration, absorbable blocking membrane for tissue regeneration useful for reconstruction of tissues of animals including humans, and jaw bone, periodontal tissue, long bone defect using the absorbable blocking membrane, In particular, it is an object of the present invention to provide a method for reconstructing a long bone defect in which bones on both sides of the defect are disconnected.

[0011]

Means for Solving the Problems The inventors of the present invention have a moderate elasticity by using a complex of a lactic acid-based polyester in which a polymerization catalyst has been deactivated and calcium phosphate having osteoinductive ability. The inventors have found that a tissue can be quickly induced and a barrier film having excellent workability, reproducibility, and storage stability can be obtained, and the present invention has been completed. That is, the present invention

(1) Absorbent barrier film used in a tissue regeneration inducing method comprising a lactic acid-based polyester in which a polymerization catalyst has been deactivated as an essential component, (2) a lactic acid-based polyester in which a polymerization catalyst has been deactivated and calcium phosphate And (3) deactivating the polymerization catalyst of the lactic acid-based polyester by using a chelating agent and / or an acidic phosphoric acid ester (1). Or the absorbent blocking film according to (2),

(4) The lactic acid-based polyester contains a structural unit derived from lactic acid and a polyester structural unit derived from dicarboxylic acid and diol, and the content of the polyester structural unit derived from dicarboxylic acid and diol is the same as that of the lactic acid-based polyester. The absorbent barrier film according to any one of (1) to (3), which is 2% by weight to 60% by weight based on the total weight of the polyester.

(5) The absorbent blocking membrane according to any one of (2) to (4), wherein the calcium phosphate is tricalcium phosphate.

(6) Absorbent barrier film according to any one of (1) to (5), characterized by having pores having a diameter of 0.1 to 200 μm, (7) Non-woven fabric of lactic acid-based polyester And calcium phosphate (2)
(8) the absorbent blocking membrane according to any one of (1) to (7),
A method for reconstructing a jaw bone, comprising using the absorbable barrier film according to any one of the above (1) to (7),

(9) A method for reconstructing periodontal tissue, characterized by using the absorptive barrier film according to any one of the above (1) to (7), (10) The above (1) to (7) (7) a method for reconstructing a long bone defect using the resorbable blocking membrane according to any one of (7), and (11) a long bone defect in which bone on both sides of the defect is dissected. The method includes the method for reconstructing a long bone defect described in (10), wherein the defect is a long bone defect.

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION The components constituting the absorptive barrier film of the present invention are described below. The lactic acid-based polyester used in the present invention is not particularly limited, and specific examples include polylactic acid and a copolymer thereof. Examples of the copolymer include those having a structure derived from a dicarboxylic acid and a diol, and those obtained by copolymerizing glycolic acid or ε-caprolactone. These copolymer components may be used alone or in combination.

In general, when these copolymer components are increased, flexibility tends to increase, and strength and stability during kneading tend to decrease. However, lactic acid-based polyester having a structure derived from dicarboxylic acid and diol is used. It is particularly excellent in strength, kneading properties and stability as compared with those having other copolymer components.

The molecular weight of the lactic acid-based polyester is not particularly limited. However, when the molecular weight is reduced to some extent, the strength tends to decrease, and when the molecular weight is increased to a certain extent, the moldability deteriorates. Specifically, the weight average molecular weight is usually 20,000 to 400,000, more preferably 30,000 to 30.
It is ten thousand. The weight average molecular weight referred to in the present invention is measured by gel permeation chromatography,
It is a value converted to standard polystyrene.

The method for producing the lactic acid-based polyester used in the present invention is not particularly limited. Specifically, for polylactic acid, lactide which is a cyclic dimer of lactic acid is opened in the presence of a ring-opening polymerization catalyst. There is a method obtained by ring copolymerization, and for a lactic acid-based polyester having a structure derived from dicarboxylic acid and diol, lactide which is a cyclic dimer of lactic acid is added to a polyester having a structure derived from dicarboxylic acid and diol. In the presence of a ring-opening polymerization catalyst, there are a method obtained by a ring-opening copolymerization and a transesterification reaction, and a method obtained by a transesterification reaction between a polyester having a structure derived from a dicarboxylic acid and a diol and polylactic acid.

The polyester used as a raw material of the lactic acid-based polyester having a polyester structural unit derived from a dicarboxylic acid and a diol is not particularly limited, but may be any polyester containing a structural unit derived from a dicarboxylic acid and a diol. It can be obtained by a known and commonly used production method by dehydration / deglycol condensation or transesterification.

The diol component as a component of the lactic acid-based polyester having a polyester structural unit derived from a dicarboxylic acid and a diol is not particularly limited, but specific examples thereof include ethylene glycol, propylene glycol,
2-butylene glycol, 1,3-butylene glycol, 1,4-butylene glycol, 2,3-butylene glycol, 1,4-pentanediol, 1,5-pentanediol, 2,4-pentanediol, 1,6 -Hexanediol, octanediol,

[0023] Neopentyl glycol, cyclohexanedimethanol, xylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol, dipropylene glycol, tripropylene glycol, polypropylene glycol, dibutanediol, polytetramethylene glycol and the like can be mentioned.

The dicarboxylic acid component as a component of the lactic acid-based polyester having a polyester structural unit derived from a dicarboxylic acid and a diol is not particularly limited, but specific examples thereof include succinic acid, methylsuccinic acid, 2-methyladipate, Examples include methylglutaric acid, adipic acid, azelaic acid, sebacic acid, brassic acid, dodecanedicarboxylic acid, cyclohexanedicarboxylic acid, maleic anhydride, and fumaric acid.

The amount of the copolymer component of the lactic acid-based polyester used in the present invention is from 0% by weight to 60% by weight. If it is more than 60% by weight, sufficient strength cannot be obtained, and more preferably 50% by weight. It is as follows. The lactic acid-based polyester contains a structural unit derived from lactic acid and a polyester structural unit derived from dicarboxylic acid and diol, and the content of the polyester structural unit derived from dicarboxylic acid and diol is 2
When the content is from 60% by weight to 60% by weight, a film having a necessary softness can be obtained depending on a portion to be applied.

The deactivation treatment of the polymerization catalyst referred to in the present invention is
This includes not only deactivating the polymerization catalyst with a chelating agent or an acid phosphate, but also removing the polymerization catalyst in the resin after deactivating it. In particular, the polymerization catalyst used in the production of the lactic acid-based polyester can be deactivated by adding the chelating agent and / or the acidic phosphoric acid ester after or after the production of the lactic acid-based polyester.

If the polymerization catalyst used in the production of the lactic acid-based polyester remains in the lactic acid-based polyester, thermal stability is poor,
The lactic acid structural units in the lactic acid-based polyester are regenerated in the form of lactide at the time of heating and molding in the production of the membrane and the composite of the raw material, and the strength and storage stability of the produced membrane are reduced. By adding a catalyst deactivator or removing the polymerization catalyst, these points are remarkably improved. The catalyst deactivator usually adheres to the polymerization catalyst in the lactic acid-based polyester in a chelate-like form and is contained in the lactic acid-based polyester,
It may be further removed.

Examples of the polymerization catalyst used in the production of the lactic acid-based polyester include, for example, metals such as tin, zinc, lead, titanium, bismuth, zirconium, germanium, and cobalt, and compounds thereof, which are known as transesterification catalysts. Metal organic compounds, carbonates, halides, among which tin octoate, zinc chloride, alkoxytitanium and the like are preferably used.

The amount of the chelating agent and / or acidic phosphate ester used in the present invention varies depending on the type of the catalyst used in the production of the lactic acid-based polyester and the reaction conditions, but the polymerization catalyst used is deactivated. Any amount is acceptable.
Before the polymer is removed from the lactic acid-based polyester polymerization reaction or at the time of kneading, it is usually 0.0
01 to 5 parts by weight, preferably 0.1 to 5 parts by weight are added. These chelating agents and / or acidic phosphates may be added and kneaded to the produced lactic acid-based polyester.

The chelating agent component used in the present invention is not particularly limited, but specific examples thereof include ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetate, oxalic acid, phosphoric acid, pyrophosphoric acid, alizarin, acetylacetone, and diethylenetriaminepentaacetic acid. Triethylenetetramine hexaacetic acid, catechol, 4-t-butylcatechol, L (+)-tartaric acid, DL-tartaric acid, glycine, chromotropic acid, benzoylacetone, citric acid, gallic acid, dimercaptopropanol, triethanolamine, Examples include cyclohexanediaminetetraacetic acid, ditoluoyltartaric acid, and dibenzoyltartaric acid. These are particularly preferable as the quenching agent used in the present invention.

The acidic phosphoric esters used in the present invention form a complex with the metal ion of the catalyst contained in the hydroxycarboxylic acid-based polyester, lose the catalytic activity, and have the effect of suppressing the cleavage of the polymer chain. Is shown. The acidic phosphoric acid esters refer to acidic phosphoric acid esters, phosphonic acid esters, alkylphosphonic acids, and the like, and mixtures thereof.

[0032]

Embedded image

(In the formula, R1 represents an alkyl group or an alkoxyl group, and R2 represents an alkyl group, an alkoxyl group, or a hydroxyl group.)

The acidic phosphoric esters used in the present invention include acidic phosphoric esters, phosphonic esters, alkylphosphonic acids and the like, and mixtures thereof.
Specifically, examples of acidic phosphate esters include monomethyl phosphate, dimethyl phosphate, monoethyl phosphate, diethyl phosphate, monopropyl phosphate, dipropyl phosphate, monoisopropyl phosphate, diisopropyl phosphate, monobutyl phosphate, Dibutyl phosphate, monopentyl phosphate, dipentyl phosphate, monohexyl phosphate, dihexyl phosphate, monooctyl phosphate, dioctyl phosphate, mono-2-ethylhexyl phosphate, di-2-ethylhexyl phosphate,
Monodecyl phosphate,

Didecyl phosphate, monoisodecyl phosphate,
Diisodecyl phosphate, monoundecyl phosphate, diundecyl phosphate, monododecyl phosphate, didodecyl phosphate,
Monotetradecyl phosphate, ditetradecyl phosphate, monohexadecyl phosphate, dihexadecyl phosphate, monooctadecyl phosphate, dioctadecyl phosphate, monophenyl phosphate, diphenyl phosphate, monobenzyl phosphate, dibenzyl phosphate, etc.

Examples of the phosphonate include monomethyl phosphonate, monoethyl phosphonate, monopropyl phosphonate, monoisopropyl phosphonate, monobutyl phosphonate, monopentyl phosphonate, monohexyl phosphonate, monooctyl phosphonate, monoethylhexyl phosphonate, Monodecyl phosphonate, monoisodecyl phosphonate, monoundecyl phosphonate, monododecyl phosphonate, monotetradecyl phosphonate, monohexadecyl phosphonate, monooctadecyl phosphonate, monophenyl phosphonate, monobenzyl phosphonate, etc.

Examples of the alkylphosphonic acid include monomethylphosphonic acid, dimethylphosphonic acid, monoethylphosphonic acid, diethylphosphonic acid, monopropylphosphonic acid, dipropylphosphonic acid, monoisopropylphosphonic acid, diisopropylphosphonic acid, monobutylphosphonic acid, Dibutylphosphonic acid, monopentylphosphonic acid, dipentylphosphonic acid, monohexylphosphonic acid, dihexylphosphonic acid, isooctylphosphonic acid, dioctylphosphonic acid, monoethylhexylphosphonic acid, diethylhexylphosphonic acid, monodecylphosphonic acid, didecylphosphonic acid ,

Monoisodecylphosphonic acid, diisodecylphosphonic acid, monoundecylphosphonic acid, diundecylphosphonic acid, monododecylphosphonic acid, didodecylphosphonic acid, monotetradecylphosphonic acid, ditetradecylphosphonic acid, monohexadecylphosphonic Acid, dihexadecylphosphonic acid, monooctadecylphosphonic acid, dioctadecylphosphonic acid, etc., monophenylphosphonic acid,
Mention may be made of diphenylphosphonic acid, monobenzylphosphonic acid, dibenzylphosphonic acid and the like, and mixtures thereof. The acidic phosphoric acid ester component has good workability due to good solubility in an organic solvent, has excellent reactivity with a lactic acid-based polyester, and has an excellent effect of deactivating a polymerization catalyst.

The calcium phosphate of the present invention refers to one containing a total of 50% by weight or more of a portion derived from phosphoric acid and calcium atoms.
Examples include hydroxyapatite, carbonate apatite, magnesium-containing apatite, and fluorapatite. Further, the crystal structure may be any, and may be amorphous. In particular, by using tricalcium phosphate as calcium phosphate, bone tissue is induced and bone is reconstructed more quickly.

The shape of the calcium phosphate particles is not particularly limited, but may be spherical, porous, or amorphous. The method for producing hydroxyapatite used in the present invention is not particularly limited, but specific examples include a dry method, a hydrothermal method, a wet method, and an alkoxide method, and heat treatment may be performed. The method for producing tricalcium phosphate is not particularly specified, but specific examples include a dry method, a hydrothermal method, and a wet method, and heat treatment may be performed.

The presence of calcium phosphate in the film increases the stability of the film and improves the ability to maintain the form required as a protective film. In addition, lactic acid-based polyester
The addition of a chelating agent and / or an acidic phosphate ester easily deactivates the polymerization catalyst, and suppresses the production of lactide when forming a complex with calcium phosphate by melt-kneading, thereby reducing heat stability. -Storage stability is improved.

Although the thickness of the absorptive barrier film of the present invention is not particularly limited, it is specifically 0.01 to 2 mm, and an appropriate thickness can be used depending on the application and conditions. In particular, when used for regeneration of periodontal tissue, the influence on the gingiva can be reduced by reducing the thickness of the film. When high strength is required, it can be dealt with by increasing the thickness.

The diameter of the pores of the absorbent barrier membrane of the present invention is 0.1
~ 200μm, which means that there is a space in which a sphere with a diameter of 0.1μm enters the complex and a sphere with a diameter of more than 200μm does not enter. It may be replaced by a material easily replaced by a bodily fluid such as a thread. The holes may be formed in any manner, such as a method using laser drilling or stretching.

The shape of the holes may be any shape, such as a thread or a band, and may be such as a cloth or a non-woven fabric in which the holes are finally formed. In addition, the holes do not necessarily have to be connected to each other or to the outside, but depending on the application, it is preferable to form a communication hole so that body fluid can permeate. Also,
Holes with a diameter smaller than 0.1 μm may be present,
Holes with a diameter larger than μm may be present. Further, there may be a portion where no hole exists.

In addition, by using a membrane made of a non-woven fabric of lactic acid-based polyester and calcium phosphate, invasion of cells that are not desirable for tissue reconstruction is prevented, body fluids can flow in, and tissue reconstruction proceeds promptly. The membrane of the present invention may contain a drug such as an antibiotic or a substance that induces a tissue, in which case the drug is sustainedly released, the effects of these drugs are maintained for a long time, and the reconstruction and healing of the tissue is delayed. Proceed without.

By using the absorbable barrier film of the present invention for the treatment of marginal periodontitis by the tissue regeneration induction method, it is possible to provide excellent workability and, if necessary, an appropriate elasticity. It is not necessary to take out the tissue, and the periodontal tissue is quickly regenerated. That is, in the "implantation immediately implanting method" in which an artificial tooth root is implanted immediately after tooth extraction, by using the film as a film covering a bone defect, bone is easily regenerated around the artificial tooth root, and after bone formation. There is no need to remove the film.

Further, after the tooth extraction, the extraction socket is covered with the membrane to prevent the epithelium and connective tissue from growing downward in the extraction socket, to form a desired shape of alveolar bone in the extraction socket, and to maintain a stable condition. The artificial root can be planted with the. In addition, the membrane is used to cover bone defects caused by advanced jaw bone resorption and fracture, excision of tumors, skull perforation and traffic accidents, etc., to create a scaffold for regenerating bone tissue, and to induce bones. The bone tissue can be reconstructed to the required shape for each part. In addition, a bone fragment generated by a crushed fracture can be placed in a state covered with the membrane, and bone tissue can be quickly reconstructed.
Further, the membrane can be used for the purpose of correcting the jaw bone, or a peripheral nerve cut by trauma or the like can be joined and reconstructed by using the tubular membrane.

When the method is applied to a transected bone, the portion where the membrane comes into contact with the bone on both sides of the defect may be wound with an absorbent thread and fastened to fix the membrane to the bone. It is preferable that the bones on both sides of the defect are fixed to each other until the bones are reconstructed and sufficient strength is obtained. Therefore, it can be fixed by various currently known splints and external bone fixation devices.However, when using the inner splint, to reduce the burden on the patient due to removal, for the inner splint and fixation It is preferable to use a screw having the same bioabsorbability as the absorptive barrier film of the present invention. By using the resorbable barrier membrane of the present invention, the long bone can be reconstructed by the tissue regeneration induction method without using decalcified bone and without requiring surgery for removing the membrane, and the amputation was performed. The long bone can also be reconstructed.

[0049]

The present invention will be described more specifically with reference to the following examples and comparative examples. All parts in the examples are on a weight basis unless otherwise specified.

(Storage stability test) A film of a sample having a size of 5 cm × 5 cm was placed in a thermo-hygrostat at 35 ° C. and a relative humidity of 80%, left for 4 weeks, and the weight average molecular weight of the resin component before and after the storage was measured. Then, the retention was calculated.

(Thermal Stability Test) The sample was allowed to stand in a vacuum dryer at 200 ° C. for 30 minutes, and the retention of the weight average molecular weight before and after the standing was calculated.

(Workability test) Using a model of the lower jaw, a required shape was cut out from a square sample having a side of 10 cm.
Bending to the required shape, processing operations during the treatment of marginal periodontitis until application were performed, and the processing properties were compared. From ◎ in the case of the best processability to △△ in the order of the best processability, the processability was evaluated as a poor and X was evaluated on a five-point scale.

(Shape maintenance test) A membrane processed into a U-shape was
Easiness of deformation when deformed with a finger at room temperature was evaluated in the order of x when extremely deformable, and was evaluated in the order of △ □ ○, which is difficult to deform, and ◎, which is most difficult to deform.

(Bone Tissue Reconstruction Test) Using a mongrel dog, a 1 cm ³ defect was formed in the mandible, and the defect was covered with a sample film. 4 weeks, 8 weeks,
After 12 weeks, the specimen was taken out, a non-decalcified specimen (toluidine blue staining) was prepared, and observed with an optical microscope (40 ×).

(Periodontal tissue reconstruction test) Using a breed dog, the periodontal tissue of the second premolar of the mandible was 3 m thick using a bar.
m, depth of 5 mm, width of 3 mm, cut the alveolar bone, periodontal ligament and cementum parts to make holes, create artificial periodontal disease, cover the opening of the defect with the sample membrane, 12
Remove after week, non-decalcified specimen (toluidine blue staining)
Was prepared and observed with an optical microscope (× 40).

Reference Example 1 5 parts of an aliphatic polyester (50 mol% of a succinic acid component, 50 mol% of a 1,4-butanediol component, a weight average molecular weight of 40,000), 95 parts of L-lactide and toluene as a solvent Add 15 parts,
Melt both at 170 ° C for 1 hour in an inert gas atmosphere.
After mixing and adding 0.03 parts of tin octoate as a catalyst and reacting for 4 hours, 0.1 parts of 2-ethylhexyl acid phosphate was added and stirred for 30 minutes. At the time of removal, volatile components were removed via a devolatilizer. The mixture was cooled and pelletized. The weight average molecular weight was 179,000. The molecular weight retention of the storage stability test was 100%, and the molecular weight retention of the thermal stability test was 100%. (Lactic acid-based polyester A)

Reference Example 2 30 parts of an aliphatic polyester (50 mol% of sebacic acid component, 25 mol% of ethylene glycol component, 25 mol% of 1,6-hexanediol component, weight average molecular weight of 41,000) was mixed with 30 parts of L- Lactide 70
Parts and 15 parts of toluene as a solvent were added and melted and mixed at 170 ° C. for 1 hour under an inert gas atmosphere.
After adding 0.03 parts of tin octoate as a catalyst and reacting for 4 hours, 0.1 parts of 2-ethylhexyl acid phosphate was added and stirred for 30 minutes. At the time of removal, volatile components were removed via a devolatilizer, and cooling was performed. And pelletized. The weight average molecular weight was 158,000. The molecular weight retention of the storage stability test was 100%, and the molecular weight retention of the thermal stability test was 100%. (Lactic acid-based polyester B)

Reference Example 3 30 parts of an aliphatic polyester (50 mol% of sebacic acid component, 25 mol% of ethylene glycol component, 25 mol% of 1,6-hexanediol component, weight average molecular weight of 41,000) was mixed with 30 parts of L- Lactide 70
Parts and 15 parts of toluene as a solvent were added and melted and mixed at 170 ° C. for 1 hour under an inert gas atmosphere.
After adding 0.03 parts of tin octoate as a catalyst and reacting for 4 hours, 1 part of ethylenediaminetetraacetic acid was added and the mixture was stirred for 30 minutes. At the time of removal, volatile components were removed via a devolatilizer, cooled, and pelletized. . The weight average molecular weight is 161,
000. The molecular weight retention of the storage stability test was 10
0%, and the molecular weight retention in the thermal stability test was 100%. (Lactic polyester C)

Reference Example 4 30 parts of an aliphatic polyester (50 mol% of sebacic acid component, 25 mol% of ethylene glycol component, 25 mol% of 1,6-hexanediol component, weight average molecular weight of 41,000) was mixed with 30 parts of L- Lactide 70
Parts and 15 parts of toluene as a solvent were added and melted and mixed at 170 ° C. for 1 hour under an inert gas atmosphere.
After adding 0.03 part of tin octoate as a catalyst and reacting for 4 hours, 0.04 part of tartaric acid was added and stirred for 30 minutes. At the time of removal, volatile components were removed via a devolatilizer, and the mixture was cooled and pelletized. . The weight average molecular weight was 160,000. The molecular weight retention of the storage stability test was 100%, and the molecular weight retention of the thermal stability test was 100%. (Lactic polyester D)

Reference Example 5 Five parts of an aliphatic polyester (50 mol% of a succinic acid component, 50 mol% of a 1,4-butanediol component, a weight average molecular weight of 40,000) were mixed with 95 parts of L-lactide and toluene as a solvent. Add 15 parts,
Melt both at 170 ° C for 1 hour in an inert gas atmosphere.
After mixing, 0.03 parts of tin octoate was added as a catalyst and reacted for 4 hours, taken out, cooled and pelletized. The weight average molecular weight was 157,000. The retention of molecular weight in the storage stability test was 42%, and the retention of molecular weight in the thermal stability test was 74%. (Lactic polyester C)

Reference Example 6 30 parts of an aliphatic polyester (50 mol% of a succinic acid component, 50 mol% of a 1,4-butanediol component, and a weight average molecular weight of 40,000) were mixed with 70 parts of L-lactide and toluene as a solvent. 15 parts were added, and both were melted and mixed at 170 ° C. for 1 hour under an inert gas atmosphere. After adding 0.03 parts of tin octoate as a catalyst, the mixture was reacted for 4 hours, taken out, cooled and pelletized.
The weight average molecular weight was 133,000. The molecular weight retention in the storage stability test was 39%, and the molecular weight retention in the thermal stability test was 68%. (Lactic polyester D)

(Reference Example 7) 100 parts of L-polylactic acid (manufactured by Purac) was melted with a laboratory plastomill mixer manufactured by Toyo Seiki Seisakusho set at 200 ° C., and 0.1 part of 2-ethylhexyl acid phosphate was added thereto for 5 minutes. It was kneaded and removed. (Lactic polyester E)

Reference Example 8 A phosphoric acid aqueous solution was gradually added dropwise to a vigorously stirred calcium hydroxide suspension until the pH reached 7, and the resulting precipitate was calcined at 800 ° C. for 3 hours to obtain a phosphoric acid triphosphate. The calcium was further ground in a mortar and passed through a sieve.
(Average particle size 45 μm) (Calcium phosphate A)

REFERENCE EXAMPLE 9 A phosphoric acid aqueous solution was gradually added dropwise to a vigorously stirred calcium hydroxide suspension until the pH reached 9, and the resulting precipitate was calcined at 800 ° C. for 3 hours to obtain hydroxyapatite. The mixture was further crushed in a mortar and passed through a sieve. (Average particle size 39 μm) (Calcium phosphate B)

(Example 1) 40 parts of lactic acid-based polyester A and 60 parts of calcium phosphate A were kneaded for 10 minutes with a lab plast mill mixer manufactured by Toyo Seiki Seisakusho set at 180 ° C, and the mixture was heated with a hot press set at 180 ° C.
A film having a thickness of 50 μm was formed, and a processing test and a shape maintaining test were performed. Table 1 shows the results.

(Example 2) 25 parts of lactic acid-based polyester B and 75 parts of calcium phosphate B were kneaded for 10 minutes with a lab plast mill mixer manufactured by Toyo Seiki Seisakusho set at 180 ° C, and the mixture was heated with a hot press set at 180 ° C.
A film having a thickness of 50 μm was formed, and a processing test and a shape maintaining test were performed. Table 1 shows the results.

Example 3 25 parts of a lactic acid-based polyester C and 75 parts of calcium phosphate A were kneaded for 10 minutes with a Labo Plast Mill mixer manufactured by Toyo Seiki Seisakusho set at 180 ° C., and the mixture was heated with a hot press set at 180 ° C.
A film having a thickness of 50 μm was formed, and a processing test and a shape maintaining test were performed. Table 1 shows the results.

(Example 4) 25 parts of lactic acid-based polyester D and 75 parts of calcium phosphate A were kneaded for 10 minutes with a Labo Plast Mill mixer manufactured by Toyo Seiki Seisakusho set at 180 ° C, and the mixture was heated with a hot press set at 180 ° C.
A film having a thickness of 50 μm was formed, and a processing test and a shape maintaining test were performed. Table 1 shows the results.

(Example 5) 50 parts of lactic acid-based polyester E and 60 parts of calcium phosphate A were kneaded for 10 minutes with a lab plast mill mixer manufactured by Toyo Seiki Seisakusho set at 180 ° C, and the mixture was heated with a hot press set at 180 ° C.
A film having a thickness of 50 μm was formed, and a processing test and a shape maintaining test were performed. Table 1 shows the results.

(Comparative Example 1) The same operation and test as in Example 1 were performed using lactic acid-based polyester C. as a result,
It was very brittle and could not be processed.

(Comparative Example 2) The same operation and test as in Example 1 were performed using lactic acid-based polyester D. as a result,
It was very brittle and could not be processed.

Comparative Example 3 Lactic polyester A
A film having a thickness of 250 μm was formed by a hot press set at 0 ° C., and the same test as in Example 1 was performed. Table 1 shows the test results.

[0073]

[Table 1]

(Example 6) A bone tissue reconstruction test was performed using the absorbable barrier film prepared in Example 1. As a result, 4
Soft tissue was formed at week, ossification was observed at week 8, and almost normal recovered at week 12. FIG. 1 shows a micrograph of a non-decalcified sample taken out at 12 weeks. The young bone tissue was regenerated, and the regeneration and induction of the bone tissue could be confirmed. No abnormalities such as inflammation were observed around the tissue, and it was found that the used absorptive blocking film was completely absorbed and disappeared.

(Example 7) A bone tissue reconstruction test was performed using the absorbable barrier film prepared in Example 3. As a result, 4
Soft tissue was formed at week, bone was observed at week 8, and almost normal recovered at week 12. No abnormality such as inflammation was observed in the periphery, and the used absorptive blocking film was completely absorbed and disappeared.

(Example 8) A periodontal tissue reconstruction test was performed using the absorptive barrier film prepared in Example 2. as a result,
He recovered almost normally at 12 weeks. FIG. 2 shows a micrograph of the undecalcified specimen taken out. In the center of FIG. 2, a vertical streak appears in the periodontal ligament, and the portion above the arrow is where the defect is created. The tissue is almost completely removed compared to the untreated tissue below the arrow. You can see that it is recovering. It turns out that the used absorptive barrier film was completely absorbed and disappeared. Also,
No abnormalities such as inflammation were observed around the tissue.

Example 9 A periodontal tissue reconstruction test was performed using the absorptive barrier film prepared in Example 4. as a result,
He recovered almost normally at 12 weeks. No abnormality such as inflammation was observed in the periphery, and the used absorptive blocking film was completely absorbed and disappeared.

(Example 10) A periodontal tissue reconstruction test was performed by attaching 30 parts of calcium phosphate A to 70 parts of a nonwoven fabric having a yarn diameter of 20 µm using lactic acid-based polyester B. As a result, almost normal recovery was achieved in 12 weeks as in Example 5.

(Example 11) After being externally fixed to a tibia of a beagle dog, a 10-mm-long defect was cut off to form a periosteum without leaving a periosteum, and a 200-μm-thick plate was prepared by hot pressing in advance. The lactic acid-based polyester C film is put into a stainless steel ball containing saline in hot water whose temperature is controlled by a hot plate.
After warming to ~ 45 [deg.] C, the membrane was bent into a tube in saline to conform to the shape of the bone and applied to the defect. A schematic diagram is shown in FIG.

In FIG. 3, A represents the tibia, B represents the fibula, C represents the external bone fixator, and D represents the blocking membrane wound around the bone defect. After the operation, the muscles, surrounding tissues, and the like were sutured to the original state, and the progress after the operation was observed by X-ray photography. As a result, in 4 weeks, the calcification of the defect started in a form in which the bones on both sides that had already been cut off were connected, and in 8 weeks, the calcification further progressed.
The x-ray image confirmed that the calcification was almost the same as the surroundings in two weeks, and the bone could be reconstructed.

(Example 12) Lactic acid-based polyester C50
And 50 parts of calcium phosphate A were kneaded for 10 minutes with a laboratory plastomill mixer manufactured by Toyo Seiki Seisakusho set at 180 ° C., and a 200 μm-thick film was formed with a hot press set at 180 ° C. to conduct an animal experiment. . After external fixation to the tibia of a beagle dog, a 10 mm long defect was cut off to create a periosteum without leaving it, and the composite membrane was placed in hot water temperature-controlled with a hot plate. A stainless steel ball filled with water was put in, and after the physiological saline was warmed to about 40 to 45 ° C., the membrane was bent into a tubular shape in accordance with the shape of the bone in the physiological saline, and the same as in Example 11. And applied to the defect.

The muscles, surrounding tissues, etc. were sutured in the original state. The postoperative course was observed by radiography. As a result, the calcification of the defect began in 4 weeks, with the connected bones on both sides already connected, and the calcification progressed further in 8 weeks, and in 12 weeks, the calcification became almost the same as the surrounding area. The X-ray image confirmed that was reconstructed.

(Comparative Example 4) Example 1 except that a 10 mm long defect was cut off from the tibia of a beagle dog after the external fixation, and the periosteum was not left.
In the same manner as in Example 1, the muscles, surrounding tissues, and the like were restored to the original state and sutured. The postoperative course was observed by radiography. As a result, the bones on both sides of the defect were not connected even at 12 weeks.

[0084]

According to the present invention, thermal stability, processability, reproducibility,
Storage stability, bioabsorbability, excellent in tissue regeneration, absorptive barrier for tissue regeneration useful for reconstructing tissue of animals including humans, and jawbone, periodontal tissue, length using the absorptive barrier It is possible to provide a method for reconstructing a canal defect, particularly a long canal defect in which the bones on both sides of the defect are disconnected.

[Brief description of the drawings]

FIG. 1 is a photomicrograph of a non-decalcified specimen taken out at 12 weeks of a bone tissue reconstruction test (Example 6) using the resorbable blocking membrane prepared in Example 1.

FIG. 2 is a photomicrograph of a non-decalcified sample taken out at 12 weeks of a periodontal tissue reconstruction test (Example 8) using the absorbable barrier film prepared in Example 2.

FIG. 3 is a schematic diagram of a reconstruction test of a long bone defect in which bones on both sides of the defect are detached, performed in Examples 11 and 12 and Comparative Example 4.

[Explanation of symbols]

 A Tibia B Fibula C External bone fixer D Blocking membrane

 ────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Ning Suetsugu 1-11-4 204-805 Kasuga, Tsukuba City, Ibaraki Prefecture (72) Inventor Masaki Kikuchi 963-6 Miwanoyama, Nagareyama City, Chiba Prefecture

Claims (11)

[Claims] 1. An absorptive shutoff film for a tissue regeneration inducing method comprising a lactic acid-based polyester obtained by inactivating a polymerization catalyst as an essential component. 2. The absorbent barrier film according to claim 1, comprising a lactic acid-based polyester in which a polymerization catalyst has been deactivated and calcium phosphate. 3. The absorptive barrier film according to claim 1, wherein the deactivating treatment of the polymerization catalyst of the lactic acid-based polyester is performed by using a chelating agent and / or an acidic phosphate. 4. The lactic acid-based polyester includes a structural unit derived from lactic acid and a polyester structural unit derived from dicarboxylic acid and diol, and the content of the polyester structural unit derived from dicarboxylic acid and diol is the lactic acid-based polyester. The absorptive barrier film according to any one of claims 1 to 3, wherein the amount is 2% by weight to 60% by weight of the total weight. 5. The absorptive barrier membrane according to claim 2, wherein the calcium phosphate is tricalcium phosphate. 6. The absorbent barrier film according to claim 1, wherein pores having a diameter of 0.1 to 200 μm are present. 7. The absorptive barrier film according to claim 2, comprising a non-woven fabric of lactic acid-based polyester and calcium phosphate. 8. A method for reconstructing a jaw bone, comprising using the absorbable barrier film according to claim 1. 9. A method for reconstructing periodontal tissue, comprising using the absorptive barrier film according to any one of claims 1 to 7. 10. A method for reconstructing a long bone defect using the absorbable barrier film according to any one of claims 1 to 7. 11. The long bone defect wherein the bone defect on the both sides of the defect is disconnected.
The method for reconstructing a long bone defect according to the above.