JP2709349B2 - Materials for periodontal tissue regeneration - Google Patents

Description

The present invention relates to a material for periodontal tissue regeneration, which is a biodegradable and absorbable dental material necessary for regenerating biological tissue eroded by periodontal disease. It is about.

[Conventional technology]

At present, as a periodontal treatment in which healthy cementum and periodontal ligaments are eroded due to periodontal disease, hydroxyapatite, calcium phosphate, and the like are used as a bone filling material for filling lost periodontal tissue.

However, their treatment simply stops the progression of periodontal disease,
In addition, it is considered that there is no other way than to prevent the recurrence to some extent. In recent years, a method for regenerating an embroidery tissue based on a biological viewpoint has been developed by Professor Neiman of the University of Gothenburg, etc. Have been. In this innovative periodontal tissue regeneration method, non-biodegradable and absorbable GORE-TEX (registered trademark) is used, and a certain result has been reported [Nyman, et al .: The regenerative potential
of the periodontal ligament.An experimental study
in the monkey, J. Clin Periodontol, 9: 257, 1982.].

However, since Gore-Tex is non-biodegradable and absorbable, it is a foreign substance to the living body, and also has tissue reactivity, so that a reoperation for removal is required after treatment. From such a viewpoint, a study using a biodegradable and absorbable membrane for regeneration treatment of periodontal tissue has recently been reported (Magnusson, et al .: N
ew Attachment Formation Following Controlled Tissu
e Regeneration Using Biodegradable Membranes, J. Per
iodontol, 59, 1-6, January, 1988.].

However, here, polylactic acid is used as a biodegradable absorbent membrane.
Since 100% homopolymer is used, mechanical properties and hydrolyzability cannot be controlled simultaneously.

A homopolymer of 100% polylactic acid has a glass transition temperature of 5
Since the temperature is higher than 7 ° C., which is higher than the body temperature, it gives physical irritation to living soft tissue, which is accompanied by inflammation, and it is difficult to arbitrarily change the hydrolysis rate with a homopolymer.

[Problems to be solved by the invention]

The present inventors have conducted intensive studies to improve the drawbacks of the above-mentioned polylactic acid homopolymer, especially the mechanical properties, thermal properties and hydrolyzability, and as a result, have found that lactic acid / ε-caprolactone copolymer or lactic acid / glycolic acid copolymer. The present inventors have found that a polymer film or sheet is most suitable for periodontal tissue regeneration treatment, and have completed the present invention.

[Means for solving the problem]

The present invention relates to the use of a material composed of only a lactic acid / ε-caprolactone copolymer or a lactic acid / glycolic acid copolymer as a biodegradable and absorbable polymer material used for periodontal tissue regeneration treatment in periodontal disease. There is novelty.

Such a biodegradable and absorbable dental material is lactic acid / ε-
The caprolactone copolymer or lactic acid / glycolic acid copolymer is dissolved in a solvent such as methylene chloride, chloroform,
After being dissolved in an organic solvent such as dioxane, toluene, benzene, dimethylformamide, and acetone, it can be formed into a film or sheet with a uniform structure by a casting method or hot pressing, and can pass through body fluids such as nutrients. It is used as a porous film obtained by making it porous by stretching or by freeze-drying from a dioxane or benzene solution to impart flexibility.

[Action]

The properties of the material for periodontal tissue regeneration, which is a biodegradable and absorbable polymer material according to the present invention, are not only excellent in flexibility but also excellent in biocompatibility, so that a bond cut off by incision or damage. After repairing the injured site, it will disappear gracefully without hindering reconnection of the tissue with the root surface. The reason why such excellent biocompatibility is obtained is that the mechanical properties and thermal properties and the hydrolysis are further improved by copolymerizing lactic acid and ε-caprolactone or lactic acid and glycolic acid in an appropriate ratio. Is to use a material that is suitable for the degree of repair of the damaged site by arbitrarily changing.

〔Example〕

The material for periodontal tissue regeneration, which is a biodegradable and absorbable polymer material according to the present invention, is widely distributed in nature and also present in the body of animals with lactic acid and ε-caprolactone, or with lactic acid and glycolic acid. It is a material consisting only of a polymer. The compositional molar ratio and molecular weight of these copolymers can be selected according to the mechanical properties and the rate of biodegradation and absorption of the material suitable for the purpose of treatment. The synthesis scheme of the lactic acid / ε-caprolactone copolymer used in the present invention is shown in the following formula.

The material for periodontal tissue regeneration, which is a biodegradable and absorbable polymer material according to the present invention, is in contact with the soft tissue of a living body. The material must have some flexibility to elicit an inflammatory response. For that purpose, the glass transition temperature of the material is preferably around body temperature.
In order to satisfy such requirements, it is necessary to select an appropriate composition molar ratio of the lactic acid / ε-caprolactone copolymer or the lactic acid / glycolic acid copolymer. FIG. 1 shows the change in the glass transition temperature depending on the mole fraction of ε-caprolactone in the lactic acid / ε-caprolactone copolymer. Here, the glass transition temperature is measured by a differential calorimeter (DSC). And by

The material for periodontal tissue regeneration, which is a biodegradable and absorbable polymer material according to the present invention, requires a certain degree of mechanical strength.
That is, in addition to a certain degree of flexibility, when a biodegradable and absorptive membrane needs to be fixed to a certain site with a suture, tearing of the membrane may cause a problem in use, and a certain strength and elasticity. If the ratio is not sufficient, there is a problem in maintaining the shape due to hydrolysis, and the initial purpose cannot be achieved. Therefore, the material used in the present invention has a dynamic elastic modulus at room temperature (25 ° C.) of 5 × 10 ^{7 to} 5 × 10 ⁹ dyne / cm ² and an elongation of 10 × 10 ⁷ dyne / cm ^2.
A range of 0-2,000% is required. They can be obtained by arbitrarily selecting the composition molar ratio of the copolymer. However, in order to satisfy the above dynamic elastic modulus, in the present invention, lactic acid /
The composition molar ratio of the ε-caprolactone copolymer or the lactic acid / glycolic acid copolymer was limited to 95: 5 to 5:95. FIG. 2 shows the change in elastic modulus at room temperature depending on the molar fraction of ε-caprolactone in the L-lactic acid / ε-caprolactone copolymer. Here, the dynamic elastic modulus was measured by Leo Vibron manufactured by Toyo Baldwin Co., Ltd.

The material for periodontal tissue regeneration, which is a biodegradable and absorbable polymer material according to the present invention, has a membrane shape during the period until regeneration of periodontal support tissue and reconnection of root surface and connective tissue are achieved. On the other hand, since it is not preferable to remain in the living body as a foreign substance after healing, it must be quickly decomposed and absorbed and disappear. For this purpose, the material for periodontal tissue regeneration, which is a biodegradable and absorbable polymer material according to the present invention, needs to be a film or sheet having a uniform structure with a thickness of 10 to 500 μm, and further, such as nutrients. It is necessary to have a porous and uniform structure for the passage of bodily fluids and the provision of flexibility. Further, the decomposition and absorption can be controlled by changing the composition molar ratio and the molecular weight of the copolymer, but in the present invention, the lactic acid / ε-caprolactone copolymer or lactic acid /
The weight average molecular weight of the glycolic acid copolymer is from 150,000 to 50
Limited to 0,000. The copolymer in this range is in vi
In the hydrolysis at tro (37 ° C., PH 7.4, in a phosphate buffer), it is preferable that the retention of the tensile strength becomes 0 in 1 to 6 months.

FIGS. 3 and 4 show changes in in vitro hydrolysis characteristics depending on the molar fraction of ε-caprolactone in the copolymer of L-lactic acid / ε-caprolactone.

In the drawings, ○ indicates L-lactic acid molecular weight 100%, □ indicates L-lactic acid molecular weight 88%, Δ indicates L-lactic acid molecular weight 65%, and ◎ indicates L-lactic acid.
Lactic acid molecular weight 15%, x mark is ε-caprolactone molecular weight 100
%, ● indicates L-lactic acid weight 100%, Δ indicates L-lactic acid weight 88
%, The symbol ▲ indicates L-lactic acid weight of 65%. The in vitro hydrolysis characteristics were measured using a sample of a fixed volume (3 mm long, 5 mm wide, 1 mm thick).
The test was carried out in a phosphate buffer (PH7.4) at 7 ° C using a dissolution tester conforming to the Japanese Pharmacopoeia standards. The degree of reduction in the weight, molecular weight and tensile strength of the hydrolysis was expressed as a percentage of each ratio before and after the hydrolysis.

Next, the biodegradation absorption and tissue reactivity were examined by in vitro test. The rabbit spine muscle weighing about 3 kg was incised in the fiber direction, a sample was embedded, and the fascia was sutured. The samples were sterilized with ethylene oxide gas prior to implantation. After implantation, the animals were sacrificed over time, and the changes in the physical properties of the samples and the reactivity of the surrounding tissues were examined. As a result, the homopoimer of 100% polylactic acid had a low rate of biodegradation and absorption. The soft tissue remaining and in contact with the periphery of the material was slightly inflamed. In contrast, the lactic acid / ε-caprolactone copolymer (composition molar ratio 70/30 mol%) and the lactic acid / glycolic acid copolymer (composition molar ratio 75% 25 mol%) completely decompose after 6 months. It was absorbed and no tissue reaction was observed.

From the above results, the lactic acid / ε-caprolactone copolymer and the lactic acid / glycolic acid copolymer are superior to the homopolymer of 100% polylactic acid in their mechanical properties, hydrolysis properties, and biocompatibility. understood. This lactic acid / ε-
Caprolactone copolymer and lactic acid / glycolic acid copolymer undergo non-oxygenous hydrolysis in vivo as in the case of 100% polylactic acid homopolymer, and are metabolized to the decomposition products, and finally water and carbonic acid. It is an interesting material that is excreted outside as gas. Therefore, the material for periodontal tissue regeneration, which is a biodegradable and absorbable polymer material according to the present invention, is a material that can be widely applied to clinical applications in other dental fields.

Next, a material for periodontal tissue regeneration, which is a biodegradable and absorbable polymer material according to the present invention, will be described with reference to examples, but the present invention is not limited to only these examples.

Example 1 Gingival regression was induced by causing a mongrel dog to suffer from periodontal disease. Weight average molecular weight of about 220,000, room temperature (25
° C) dynamic elastic modulus at 9.5 × 10 dyne / cm ² , elongation at 15
A sheet-like biodegradable and absorbable porous membrane having a uniform structure and a thickness of about 200 μm comprising L-lactic acid / ε-caprolactone copolymer (composition molar ratio 70/30 mol%) of 0%,
After covering the root surface like a tent, the flap was returned and sutured to prevent the connective tissue from contacting the root surface and participating in the healing process, and the healing state after three months was observed.
As a result, the L-lactic acid / ε-caprolactone copolymer is
Although its shape remained, it had little mechanical strength and hydrolysis progressed considerably, but new adhesions including the supporting alveolar bone were formed and periodontal disease was cured.

Example 2 A biodegradable and absorbable membrane having a weight average molecular weight of 170,00
0, dynamic elastic modulus at room temperature (25 ℃) is 9.8 × 10dyne / cm ² ,
A film-like material having a uniform structure and a thickness of about 180 μm, made of a D, L-lactic acid / glycolic acid copolymer (composition molar ratio 80/20 mol%) having an elongation of 200%, was used. Others were the same as Example 1, and the healing state after 3 months was observed. as a result,
The membrane composed of the D, L-lactic acid / glycolic acid copolymer was almost completely decomposed and absorbed, and at the same time as periodontal ligament fibers were formed, new bone was formed in the bone and periodontal disease was cured.

Example 3 L having a weight average molecular weight of about 260,000, a dynamic elastic modulus at room temperature (25 ° C.) of 1.8 × 10 ⁸ dyne / cm ² , and an elongation of 1000%
-Lactic acid / glycolic acid copolymer (composition molar ratio 90/10 mol
%) Of a dioxane 10% solution was freeze-dried to prepare a sheet-like biodegradable and absorbable porous membrane having a thickness of about 220 μm, which was subjected to animal experiments in the same manner as in Example 1. After 3 months, the sheet-like film composed of the L-lactic acid / glycolic acid copolymer was completely decomposed and absorbed, and the periodontal disease was cured.

Example 4 D, L having a weight average molecular weight of about 190,000, a dynamic elastic modulus at room temperature (25 ° C.) of 3.2 × 10 ⁸ dyne / cm ² , and an elongation of 1500%
-Lactic acid / glycolic acid copolymer (composition molar ratio 75/25 mol
%) Of a dioxane 10% solution was freeze-dried to prepare a film-like biodegradable and absorbable film having a thickness of about 160 μm, which was subjected to animal experiments in the same manner as in Example 1. The film-like film composed of the L-lactic acid / glycolic acid copolymer was completely decomposed and absorbed after three months, and the periodontal disease was cured.

Comparative Example 1 The same procedure as in Example 1 was carried out except that a material composed of polylactic acid having a molecular weight of about 220,000 and having a thickness of about 200 μm was used as the biodegradable and absorptive membrane, and a healing state after three months was observed. As a result, the polylactic acid film was hardly degraded, and the gingival tissue in contact with the edge of the polylactic acid film was partially inflamed.

〔The invention's effect〕

The periodontal tissue regeneration material which is the biodegradable and absorbable polymer material according to the present invention as described in detail above has the following advantages as compared with the non-bioabsorbable polymer material in vivo. .

According to the method of regenerating periodontal tissue by Professor Niemann of Gothenburg University, the material inserted into the periodontal tissue needs to be removed promptly if the periodontal tissue is improved after filling. It was necessary to perform surgery again for removal, but the material for periodontal tissue regeneration, which is a biodegradable and absorbable polymer material according to the present invention, has been decomposed and absorbed in the living body. It is possible to considerably reduce the pain and the economic burden on the patient.

In addition, the material inserted into the periodontal tissue requires strength at first, and after the periodontal tissue is improved, it is not necessary to have strength.If the strength does not change, it may cause inflammation. Such a material for periodontal tissue regeneration, which is a biodegradable and absorbable polymer material, has strength at first, and can gradually or rapidly reduce the strength over time, so that gingival tissue becomes inflamed. I will not let you.

The material for periodontal tissue regeneration, which is a biodegradable and absorbable polymer material according to the present invention, has the following advantages as compared with a biodegradable and absorbable polymer material composed of 100% polylactic acid homopolymer. have.

Since the material for periodontal tissue regeneration, which is the biodegradable and absorbable polymer material according to the present invention, is a lactic acid / ε-caprolactone copolymer or a lactic acid / glycolic acid copolymer, dynamics suitable for the state of the periodontal tissue Characteristic can be imparted.

In addition, it is necessary to change the rate of decomposition and absorption in the living body of the material inserted into the periodontal tissue depending on the degree of periodontal disease. It is difficult to arbitrarily change the hydrolysis rate of a biodegradable and absorbable polymer material composed of a homopolymer of 100% polylactic acid when it is desired to rapidly decrease the mechanical properties after the period. The material for periodontal tissue regeneration, which is such a biodegradable and absorbable polymer material, can freely control the rate of decomposition and absorption.

In addition, the material for periodontal tissue regeneration, which is the biodegradable and absorbable polymer material according to the present invention, is composed of a homopolymer of 100% polylactic acid. There is little physical stimulation.

[Brief description of the drawings]

FIG. 1 shows the relationship between the glass transition temperature and the molar fraction of ε-caprolactone in a lactic acid / ε-caprolactone copolymer, and FIG. 2 shows the relationship between the ε-caprolactone copolymer in an L-lactic acid / ε-caprolactone copolymer. FIG. 3 shows the relationship between the molar fraction of caprolactone and the dynamic elastic modulus at room temperature. FIG. 3 shows the hydrolysis time and L-
FIG. 4 is a diagram showing the relationship between the weight of the lactic acid / ε-caprolactone copolymer and the residual molecular weight, and FIG. 4 is a diagram showing the relationship between the hydrolysis time and the tensile strength of the L-lactic acid / ε-caprolactone copolymer. . In FIG. In FIG. 3 and 4, ○: L-lactic acid molecular weight: 100% □: L-lactic acid molecular weight: 88% △: L-lactic acid molecular weight: 65%: L-lactic acid molecular weight: 15% ×: ε- Caprolactone molecular weight 100% ● …… L-lactic acid weight 100% ■ …… L-lactic acid weight 88% ▲ …… L-lactic acid weight 65%

 ──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-61-217170 (JP, A) JP-A-61-149160 (JP, A) JP-A-60-153868 (JP, A) 505535 (JP, A)

Claims (2)

(57) [Claims] (1) Lactic acid / ε- is used for the treatment of periodontal tissue regeneration.
A material consisting solely of a caprolactone copolymer or a lactic acid / glycolic acid copolymer is used as a biodegradable and absorbable polymer material, and the copolymer has a weight average molecular weight of 150,000 to 500,000.
At a composition molar ratio of 95: 5 to 5:95 mol% at room temperature (25
℃) dynamic elastic modulus of 5 × 10 ^{7 to} 5 × 10 ⁹ dyne / cm ² ,
Elongation is in the range of 100-2,000% and thickness is 10-500μm
A material for regenerating periodontal tissue, which is a film or sheet having a porous and uniform structure. 2. The tensile strength of lactic acid / ε-caprolactone copolymer or lactic acid / glycolic acid copolymer in vitro (37 ° C., pH 7.4, in phosphate buffer). The material for periodontal tissue regeneration according to claim 1, wherein the retention rate becomes 0 in 1 to 6 months.