CA1340354C - Periodontium-regenerative materials - Google Patents
Periodontium-regenerative materialsInfo
- Publication number
- CA1340354C CA1340354C CA000608766A CA608766A CA1340354C CA 1340354 C CA1340354 C CA 1340354C CA 000608766 A CA000608766 A CA 000608766A CA 608766 A CA608766 A CA 608766A CA 1340354 C CA1340354 C CA 1340354C
- Authority
- CA
- Canada
- Prior art keywords
- lactide
- degradable
- bio
- periodontium
- caprolactone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/58—Materials at least partially resorbable by the body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/765—Polymers containing oxygen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K6/00—Preparations for dentistry
- A61K6/50—Preparations specially adapted for dental root treatment
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0063—Periodont
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
Abstract
A periodontium-regenerating material for the regenerative treatment of the periodontium consists of bio-degradable/absorable copolymers of lactide/ .epsilon. -caprolactone or lactide/glycolide having a weight-average molecular weight of 40,000 to 500,000 as well as a dynamic modulus of 5 x 10 7 to 5 x 10 9 dynes/cm2 and a elongation rate of 100 to 2,000 %, both measured at room temperature (25 °C).
Those copolymers may be used in the form of a sheet or film which may or may not be porous.
Those copolymers may be used in the form of a sheet or film which may or may not be porous.
Description
13~n~5~
PERIODONTIUM-REGENERATIVE MATERIALS
The present invention relates to a bio-degradable/absorbable dental material required for the regeneration of the tissues of a living body attacked by periodontosis.
In current periodontal treatments of healthy cementum and periodontal ligament attacked by periodontal diseases, hydroxyapatite and calcium phosphate are used as the alveolar bone fillers to be filled in lost periodontal tissues.
However, such treatments are considered to be only effective to prevent periodontal diseases from re~chin~ an advanced stage or recurring to some degrees. In recent years, the Guided Tissue Regeneration Technic developed by Professor S. Nyman et al (University of Gothenburg) from a biological standpoint of view has attracted attention in dental fields. For such epoch-making Guided Tissue Regeneration Technic, it has been reported that certain results are achievable with what is called Goretex membrane which is neither degradable nor absorbable in a living body. See S. Nyman et al, "The regenerative potential of the periodontal ligament - An expcrimental study in the monkey", J. Clin. Periodontol, g:257, lg82.
Since Goretex membrane is neither degradable nor absorbable in a living body, it constitutes an alien substance to the living body and is reactive to the tissues. Therefore we must take off Goretex membrane after first treatment and second operation is thus again needed. From such a standpoint of view, a report of the studies of using bio-degradable/absorbable membranes for the Guided Tissue ~ Trademark 13~0~ 1 Regeneration Technic has been presented. See I. ~gn11~son et al, "New Attachment Formation Following Controlled Tissue Regeneration Using Biodegradable Membranes", J. Periodontol, 5~ 6, January, 1988.
However, since a homopolymer consisting of 10~ ~ polylactic acid is used as the bio-degradable/absorbable membrane, it is impossible to control both dynamic (or mechanical) properties and a rate of hydrolysis simultaneously.
Due to its glass transition temperature higher than a temperature of a body, the homopolymer consisting of 100 ~ polylactic acid gives a physical stimulus to the soft tissues of a living body with the resulting inducement of inflammation. With the homopolymer, it is difficult to freely vary the rate of hydrolysis.
The present inventors have made intensive and extensive studies to eliminate the weak points of the above homopolymer of polylactic acid, i.e., to improve especially its dynamic (or mechanical) properties, thermal properties and the rate of hydrolysis. As a consequence, it has been found that a film or sheet of a lactide/~ -caprolactone or a glycolide copolymer is best-suited for the Guided Tissue Regeneration Technic. Thus, the present invention has been accomplished.
An aspect of the present invention ~esides in using a lactide/~ -caprolactone or a glycolide cqpolymer as the bio-degradable/absorbable high-molecular materials applied to the Guided Tissue Regeneration Technic to be effective to prevent periodontal diseases. Such bio-degradable/absorbable materials may be formed into films or sheets by dissolving the lactide/~ -caprolactone or lactide/glycolide copolymers in a solvent such as an organic solvent, e.g., methylene chloride, chloroform, dioxane, toluene, benzene, di~ethylformamide or acetone and subjecting the resulting solutions to - 13403~4 casting or hot pressing. In order to allow such films or sheets to transmit body fluids such as nourishment therethrough or give flexibility thereto, they may be made porous by stretching or freeze-drying treatment in benzene or dioxane solution.
The bio-degradable/absorbable high-molecular materials according to the present invention excel in not only flexibility but also biocompatibility. Thus, they tend to disappear immediately after a cure of injured sites with no fear of interfering with the bony ankylosis of the connective tissue separated from a surface of a root by discission or lesion. The reason why such excellent biocompatibility is obtained is that it is possible to use materials whose dynamic and thermal properties as uell as the rate of hydrolysis can be varied by the copolymerization of lactide that is an aliphatic polyester with ~ -caprolactone or glycolide used in suitable ratios and that the materials can be selected in application depending upon how much the injured sites are to be cured.
The present invention uill now be explained in more detail with reference to the accompanying drawings, which are given for the purpose of illustration alone and in which: -Figure 1 is a graphical view showing the relation between themolar fraction of ~ -caprolactone in the copolymer of L-lactide/~ -caprolactone and the glass transition temperature of that copolymer, Figure 2 is a graphical view illustrating the relation between the molar fraction of ~ -caprolactone in the copolymer of L-lactide/~
caprolactone and the dynamic modulus of elasticity thereof at room temperature, Figure 3 is a graphical view showing the relation between the time of hydrolysis and the weight and rate of residual molecular weight of the copolymer of L-lactide/~ -caprolactone, and 134035~-~
Figure 4 is a graphical view showing the relation between the time of hydrolysis and the tensile strength of the copolymer of L-lactide/~-caprolactone.
The bio-degradable/absorbable high-molecular materials used in the present invention are widely distributed in the natural world and are a copolymer of lactide/~-caprolactone or lactide/glycolide found in the bodies of animals. The composition and molecular weight of such a copolymer may be selected depending upon the mechanical properties and bio-degrading/absorbing rate of material suitable for thecondition of a periodontal disease. However, a weight-average molecular weight in the range of 40,000 to 500,000, preferably 170,000 to 260,000, has been found to be suitable. The lactide/~-caprolactone copolymers used in the present invention are synthesized according to the following scheme.
L - lactide monomer Im.~&
D~L - lactide, L-lactide D,L - lactide m~cmerTm.128&
CH3 CH3 3HC\ /O\
OH-C-COOH ~ - O-C-C - ~ HC C=O
H H ~ n ~ = C\ /C\H
~ - caprolact~e 2H IC--(CHz)~
O - C=O ~ - caprolactone monomer Tm. -5&
1340~54 o=oo=v o ~ 0=0 ~ o o o X N
O=~) ~ ~1 V-V ~, I X
0=0 -~ O=V
O > :~C
~ 1 V--V
~_)--V ~ V=O
o 1) 0 ~ '' V-V
O
,_ ~ 11 C 'O
V-V ~ ~
o + o 3 o ~ ~ +
o O
~~ V/~ I ~ ~ 0/ \
V ~ 1l 13~035~
The bio-degradable/absorbable high-molecular materials used in the present invention come in touch with the soft tissues of a living body, and is thus required to have some fle~ibility, since inflammatory reactions are induced by physical stimuli at the time when there is a large difference between dynamic properties of such materials and those of the soft tissues of a living body, especially, when their hardness is in excess. In order to accomplish this aim, it is preferred that their glass transition temperature is in the vicinity of a temperature of a body. To meet such a requirement, it is required to select the composition of the lactide/~ -caprolactone or the lactidelglycolide copolymers according to suitable compositional ratios. Figure 1 illustrates a change in the glass transition temperature on the molar fraction of ~ -caprolactone in the copolymer of lactidel~ -caprolactone. It is understood that the measurement of glass transition temperature was carried out with a differential sc~nning calorimeter (~SC) - marked by ~ and a dynamic modulus meter - marked by ~).
The bio-degradable/absorbable high-molecular materials used in the present invention are required to have a certain dynamic strength.
In other words, when there is a need of fixing the bio-degradablelabsorbable films or sheets to a given region with a suture, a grave problem will arise if the fixed part tears up. ~n ~he absence of a certain strength or modulus of elasticity, on the other hand, it poses a problem in connection with the retainment of shape tending to change due to hydrolysis, so that the desired object cannot be attained. Therefore, the materials used i~ the present invention should preferably have a dynamic modulus in a ran~e of S x 107 to 5 x 10~ dynes/cm2 that is attainable by the selection of the composition of the copolymers. Figure 2 illustrates a change at room temperature in the dynamic modulus of elasticity on the molar fraction ~ ~ .. . . ... .
13403~
of ~ -caprolactone in the copolymer of L-lactide/~ -caprolactone. It is understood that the dynamic modulus of elasticity was measured with Rheo-Vibron available from Toyo Balldwin, On the one hand, the bio-degradable~absorbable high-molecular materials used in the present invention should be retained in the form of a film or a sheet within a period during which the regeneration of the alveolar bone and the recombination of the surface of a root with the connective tissue are achieved. On the other hand, it is not desirable that they remain as an alien substance in a living body after curing. Thus, they are required to be rapidly degraded, absorbed and disappeared. The degradable/absorbable rate can also be controlled by vsrying a composition and a molecular weight of the copolymers.
Changes in the in-vitro hydrolysis on the ~olar fraction of E-caprolactone in the copolymer of L-lactide/~ -caprolactone therein are illustrated in Figures 3 and 4, wherein O stands for 100 Z L-lactide molecular weight, O 88 % L-lactide molecular weight, A 65 % L-lactide molecular weight, (~ 15 % L-lactide molecular weight, x 100 Z
~ -caprolactone molecular weight, ~ 100 Z L-lactide mass, 1~ 88 Z
L-lactide mass, and ~ 65 % L-lactide mass. The rate of hydrolysis of samples in the in-vitro were estimated in a solution having a certain volume (3 mm long x 5 mm wide x 1 mm thick) in a phosphate buffer solution of 37 ~C ~pH: 7.4) with an elution tester according to T~IE
PHARMACOPOEIA OF JAPAN. The weight, molecular mass and the rate of reductions of tensile strength of the hydrolysated products were measured before and after hydrolysis and expressed in terms of percentage.
Then, the bio-degradable/absorbable rates and reactivity to a tissue were investigated by in-vivo tests. The dorsal muscles of house rabbits, each weighing about 3 kg, were incised along the * Trademark 1~403~4 fibrous direction, the samples were filled, and the fasciae were then sutured. Prior to the filling, the samples were sterilized with an ethylene oxide gas. After the filling, the rabbits were slaughtered with the lapse of time to examine changes in the physical properties of the samples and the reactivity of the peripheral tissues. As a consequence, the homopolymer consisting of 100 % polylactic acid remained substantially in its entirety even after the lapse of six months and the soft tissue in touch with the periphery of the material suffered from some inflammation. However, the copolymers of lactide/~ -caprolactone (at a molar ratio of 70:30 mol %) and lactide/glycolide (at a molar ratio of 75:25 mol %) were completely degraded and absorbed with no sign of any tissular reaction.
From the above results, it is appreciated that the copolymers of lactide/~ -caprolactone and lactide/glycolide are superior to the homopolymer consisting of 100 % polylactic acid in the dynamic properties and the rate of hydrolysis as well as the biocompatibility.
The copolymers of lactide/~ -caprolactone and lactide/glycolide are interesting materials since, as is the case with the homopolymer consisting of 1~0 % polylactic acid7 they cause non-enzymatical hydrolysis in a living body to give hydrolyzates which are degraded and absorbed and finally discharged from the living body in the form of water and carbon dioxide. Thus, the bio-degradable/absorbable high-molecular materials according to the present invention are not only useful materials for the Guided Tissue Regeneration Technic, but are also clinically useful materials in other dental fields.
The bio-degradable/absorbable high-molecular materials of the present invention will now be explained specifically but not exclusively with reference to the following examples.
Example 1 A fully developed ~ongrel was forcedly made to suffer from a 1340.3~4 periodontal disease, thereby inducing gingival retraction. The bio-degradable/absorbable porous ~ilm was used in the form of an about 200~m thick sheet consistin~ of a L-lactide/~ -caprolactone copolymer (at a molar ratio of 70:30 mol %) having a weight-average molecular weight of about 220,000 as well as a dynamic modulus of elasticity of 9.5 x 10~ dynes/cm2 and a elongation rate of 150 %, both at room temperature (25 ~C). After the surface of the root had been covered with such the sheet in a form of a patched tent, a flap of the gingival tissue was back-sutured to prevent the connective tissue from coming in contact with the surface of the root and taking part in the process of healing. After the lapse of three months, the process of healing was observed. As a result, the L-lactide/~ -caprolactone copolymer was found to lose a substantial part of its dynamic strength and cause considerable hydrolysis, although its shape was remained.
However, new attachment including a formation of the new alveolar bone indicated that the periodontal disease was cured.
Example 2 As the bio-degradable/absorbable film, use was made of an about 180~m thick film-like material consisting of a D,L-lactide/glycolide copolymer (at a molar ratio of 80:20 mol %) having a weight-average molecular weight of 170,000 as well as a dynamic modulus of elasticity 9.8 x 10~ dynes/cm2 and a elongation rate of 200 ~, both at room temperature (25 ~C). According to the procedures of Example 1, the process of healing was estimated after the lapse of three months. As a consequence, it was found that the film consisting of the D,L-lactide/glycolide copolymer was substantially degraded and absorbed, and that the periodontal ligament fibers were formed simultaneously with the formation of a new ~one, a sign of healing of the periodontal disease.
139~.3~4 Example 3 A 10 % dioxane solution of a L-lactidejglycolide copolymer (at a molar ratio of 90:10 mol %) having a weight-average molecular weight of about 260,000 as well as a dynamic modulus of elasticity of 1.8 x 108 dynes/cm2 and a elongation rate of 1000 %, both at room temperature (2~ ~C) was freeze-dried to prepare a bio-degradable/absorbable porous film in the form of an about 220~m sheet.
With this film, an animal experiment was performed in a similar manner as described in Example 1. After the lapse of three months, it was found that the porous sheet-like film consisting of the L-lactide/glycolide copolymer was completely degraded and absorbed with a healing of periodontal disease.
Example 4 A 10 % dioxane solution of a D,L-lactide/glycolide copolymer (at a molar ratio of 75:25 mol %) having a weight-average molecular weight of about 190,000 as well as a dvnamic modulus of elasticity of 3.2 x lG8 dynes/cm2 and a elongation rate of 1500 %, both at room temperature ~25 ~(~) was freeze-dried to prepare a bio-degradable/absorbable porous film in the form of an about 160~m sheet.
With this film, an animal experiment was performed in a similar manner as described in Example 1. After the lapse of three months, it was found that the porous sheet-like film consisting of the D,L--lactide/glycolide copolymer was completely degraded and absorbed with a healing of periodontal disease.
Comparative Example 1 An experiment was performed according to Example 1, provided that an about 200~m thick material consisting of polylactic acid having a molecular weight of about 220,000 ~as used as the bio-degradable/absorbable film, to observe the degree of healing after the lapse of three months. As a result, it was found that the polylactic I O -13403~
acid film was not substantially degraded with the inducement of partial inflammation in the gingival tissue in touch with the edges of the film consisting of 100 % polylactic acid.
The bio-degradable/absorbable high-molecular materials of the present invention have the following advantages in comparison with the high-molecular materials which are neither degradable nor absorbable in a living body.
According to the Guided Tissue Regeneration Technic proposed by Professor S. Nyman et al (University of Gothenburg), it is essentially required to remove the material inplanted in the periodontium immediately after the periodontium are found to be healed by such inptant. For such removal, it is again necessary to perform an operation. With the bio-degradable/absorbable high-molecular materials of the present invention, however, it is unnecessary to perform a re-operation, thus easing a patient of pain and relieving an economical burden to considerable degrees.
The material inplanted in the periodontium is required to have strength at the beginning, but is rather needed to lose that strength after the healing of the periodontal disease. No change in strengh tends to induce inflammation. However, the bio-dagradable/absorbable high-molecular materials of the present invention have strength at the start, which can be decreased gradually or sharply with the lapse of time, and so there is no possibility of inducing inflammation in the periodontium.
Moreover~ the bio-degradable/absorable high-molecular materials of the present invention have the following advantages in comparison with those consisting of homopolymers of 10~ % polylactic acid.
The dynamic/mechanical properties suitable for the conditions of the periodontium can be given to the bio-degradable/absorbable high-molecular materials of the present invention because the materials 13403~4 consist of the copolymers of ~actide/~--caprolactone or lactide/glycolide. It is required to vary the rates of bio-degradation and -absorption of the material inplanted in the periodontium depending upon the degree of periodontal disease.
Especially when it is intended to decrease sharply the dynamic/mechanical properties of the bio-degradable/absorbable high-molecular materials at the time when a certain period of time elapses after its inplant in the periodontium, difficulty is involved in freely varying the rate of hydrolysis of the bio-degradable/absorbable high-molecular material consisting of the homopolymer of 100 %
polylactic acid. With the bio-degradable/absorbable high-molecular materials of the present invention, however, it is possible to freely control their rates of degradation and absorption.
Further, the bio-degradable/absorbable high-molecular materials of the present invention give little or no physical stimuli to the soft tissues of a living body because their glass transition temperature is in the vicinity of body heat in comparison with the bio-degradable/absorbable materials consisting of the homopolymer of 100 %
polylactic acid.
PERIODONTIUM-REGENERATIVE MATERIALS
The present invention relates to a bio-degradable/absorbable dental material required for the regeneration of the tissues of a living body attacked by periodontosis.
In current periodontal treatments of healthy cementum and periodontal ligament attacked by periodontal diseases, hydroxyapatite and calcium phosphate are used as the alveolar bone fillers to be filled in lost periodontal tissues.
However, such treatments are considered to be only effective to prevent periodontal diseases from re~chin~ an advanced stage or recurring to some degrees. In recent years, the Guided Tissue Regeneration Technic developed by Professor S. Nyman et al (University of Gothenburg) from a biological standpoint of view has attracted attention in dental fields. For such epoch-making Guided Tissue Regeneration Technic, it has been reported that certain results are achievable with what is called Goretex membrane which is neither degradable nor absorbable in a living body. See S. Nyman et al, "The regenerative potential of the periodontal ligament - An expcrimental study in the monkey", J. Clin. Periodontol, g:257, lg82.
Since Goretex membrane is neither degradable nor absorbable in a living body, it constitutes an alien substance to the living body and is reactive to the tissues. Therefore we must take off Goretex membrane after first treatment and second operation is thus again needed. From such a standpoint of view, a report of the studies of using bio-degradable/absorbable membranes for the Guided Tissue ~ Trademark 13~0~ 1 Regeneration Technic has been presented. See I. ~gn11~son et al, "New Attachment Formation Following Controlled Tissue Regeneration Using Biodegradable Membranes", J. Periodontol, 5~ 6, January, 1988.
However, since a homopolymer consisting of 10~ ~ polylactic acid is used as the bio-degradable/absorbable membrane, it is impossible to control both dynamic (or mechanical) properties and a rate of hydrolysis simultaneously.
Due to its glass transition temperature higher than a temperature of a body, the homopolymer consisting of 100 ~ polylactic acid gives a physical stimulus to the soft tissues of a living body with the resulting inducement of inflammation. With the homopolymer, it is difficult to freely vary the rate of hydrolysis.
The present inventors have made intensive and extensive studies to eliminate the weak points of the above homopolymer of polylactic acid, i.e., to improve especially its dynamic (or mechanical) properties, thermal properties and the rate of hydrolysis. As a consequence, it has been found that a film or sheet of a lactide/~ -caprolactone or a glycolide copolymer is best-suited for the Guided Tissue Regeneration Technic. Thus, the present invention has been accomplished.
An aspect of the present invention ~esides in using a lactide/~ -caprolactone or a glycolide cqpolymer as the bio-degradable/absorbable high-molecular materials applied to the Guided Tissue Regeneration Technic to be effective to prevent periodontal diseases. Such bio-degradable/absorbable materials may be formed into films or sheets by dissolving the lactide/~ -caprolactone or lactide/glycolide copolymers in a solvent such as an organic solvent, e.g., methylene chloride, chloroform, dioxane, toluene, benzene, di~ethylformamide or acetone and subjecting the resulting solutions to - 13403~4 casting or hot pressing. In order to allow such films or sheets to transmit body fluids such as nourishment therethrough or give flexibility thereto, they may be made porous by stretching or freeze-drying treatment in benzene or dioxane solution.
The bio-degradable/absorbable high-molecular materials according to the present invention excel in not only flexibility but also biocompatibility. Thus, they tend to disappear immediately after a cure of injured sites with no fear of interfering with the bony ankylosis of the connective tissue separated from a surface of a root by discission or lesion. The reason why such excellent biocompatibility is obtained is that it is possible to use materials whose dynamic and thermal properties as uell as the rate of hydrolysis can be varied by the copolymerization of lactide that is an aliphatic polyester with ~ -caprolactone or glycolide used in suitable ratios and that the materials can be selected in application depending upon how much the injured sites are to be cured.
The present invention uill now be explained in more detail with reference to the accompanying drawings, which are given for the purpose of illustration alone and in which: -Figure 1 is a graphical view showing the relation between themolar fraction of ~ -caprolactone in the copolymer of L-lactide/~ -caprolactone and the glass transition temperature of that copolymer, Figure 2 is a graphical view illustrating the relation between the molar fraction of ~ -caprolactone in the copolymer of L-lactide/~
caprolactone and the dynamic modulus of elasticity thereof at room temperature, Figure 3 is a graphical view showing the relation between the time of hydrolysis and the weight and rate of residual molecular weight of the copolymer of L-lactide/~ -caprolactone, and 134035~-~
Figure 4 is a graphical view showing the relation between the time of hydrolysis and the tensile strength of the copolymer of L-lactide/~-caprolactone.
The bio-degradable/absorbable high-molecular materials used in the present invention are widely distributed in the natural world and are a copolymer of lactide/~-caprolactone or lactide/glycolide found in the bodies of animals. The composition and molecular weight of such a copolymer may be selected depending upon the mechanical properties and bio-degrading/absorbing rate of material suitable for thecondition of a periodontal disease. However, a weight-average molecular weight in the range of 40,000 to 500,000, preferably 170,000 to 260,000, has been found to be suitable. The lactide/~-caprolactone copolymers used in the present invention are synthesized according to the following scheme.
L - lactide monomer Im.~&
D~L - lactide, L-lactide D,L - lactide m~cmerTm.128&
CH3 CH3 3HC\ /O\
OH-C-COOH ~ - O-C-C - ~ HC C=O
H H ~ n ~ = C\ /C\H
~ - caprolact~e 2H IC--(CHz)~
O - C=O ~ - caprolactone monomer Tm. -5&
1340~54 o=oo=v o ~ 0=0 ~ o o o X N
O=~) ~ ~1 V-V ~, I X
0=0 -~ O=V
O > :~C
~ 1 V--V
~_)--V ~ V=O
o 1) 0 ~ '' V-V
O
,_ ~ 11 C 'O
V-V ~ ~
o + o 3 o ~ ~ +
o O
~~ V/~ I ~ ~ 0/ \
V ~ 1l 13~035~
The bio-degradable/absorbable high-molecular materials used in the present invention come in touch with the soft tissues of a living body, and is thus required to have some fle~ibility, since inflammatory reactions are induced by physical stimuli at the time when there is a large difference between dynamic properties of such materials and those of the soft tissues of a living body, especially, when their hardness is in excess. In order to accomplish this aim, it is preferred that their glass transition temperature is in the vicinity of a temperature of a body. To meet such a requirement, it is required to select the composition of the lactide/~ -caprolactone or the lactidelglycolide copolymers according to suitable compositional ratios. Figure 1 illustrates a change in the glass transition temperature on the molar fraction of ~ -caprolactone in the copolymer of lactidel~ -caprolactone. It is understood that the measurement of glass transition temperature was carried out with a differential sc~nning calorimeter (~SC) - marked by ~ and a dynamic modulus meter - marked by ~).
The bio-degradable/absorbable high-molecular materials used in the present invention are required to have a certain dynamic strength.
In other words, when there is a need of fixing the bio-degradablelabsorbable films or sheets to a given region with a suture, a grave problem will arise if the fixed part tears up. ~n ~he absence of a certain strength or modulus of elasticity, on the other hand, it poses a problem in connection with the retainment of shape tending to change due to hydrolysis, so that the desired object cannot be attained. Therefore, the materials used i~ the present invention should preferably have a dynamic modulus in a ran~e of S x 107 to 5 x 10~ dynes/cm2 that is attainable by the selection of the composition of the copolymers. Figure 2 illustrates a change at room temperature in the dynamic modulus of elasticity on the molar fraction ~ ~ .. . . ... .
13403~
of ~ -caprolactone in the copolymer of L-lactide/~ -caprolactone. It is understood that the dynamic modulus of elasticity was measured with Rheo-Vibron available from Toyo Balldwin, On the one hand, the bio-degradable~absorbable high-molecular materials used in the present invention should be retained in the form of a film or a sheet within a period during which the regeneration of the alveolar bone and the recombination of the surface of a root with the connective tissue are achieved. On the other hand, it is not desirable that they remain as an alien substance in a living body after curing. Thus, they are required to be rapidly degraded, absorbed and disappeared. The degradable/absorbable rate can also be controlled by vsrying a composition and a molecular weight of the copolymers.
Changes in the in-vitro hydrolysis on the ~olar fraction of E-caprolactone in the copolymer of L-lactide/~ -caprolactone therein are illustrated in Figures 3 and 4, wherein O stands for 100 Z L-lactide molecular weight, O 88 % L-lactide molecular weight, A 65 % L-lactide molecular weight, (~ 15 % L-lactide molecular weight, x 100 Z
~ -caprolactone molecular weight, ~ 100 Z L-lactide mass, 1~ 88 Z
L-lactide mass, and ~ 65 % L-lactide mass. The rate of hydrolysis of samples in the in-vitro were estimated in a solution having a certain volume (3 mm long x 5 mm wide x 1 mm thick) in a phosphate buffer solution of 37 ~C ~pH: 7.4) with an elution tester according to T~IE
PHARMACOPOEIA OF JAPAN. The weight, molecular mass and the rate of reductions of tensile strength of the hydrolysated products were measured before and after hydrolysis and expressed in terms of percentage.
Then, the bio-degradable/absorbable rates and reactivity to a tissue were investigated by in-vivo tests. The dorsal muscles of house rabbits, each weighing about 3 kg, were incised along the * Trademark 1~403~4 fibrous direction, the samples were filled, and the fasciae were then sutured. Prior to the filling, the samples were sterilized with an ethylene oxide gas. After the filling, the rabbits were slaughtered with the lapse of time to examine changes in the physical properties of the samples and the reactivity of the peripheral tissues. As a consequence, the homopolymer consisting of 100 % polylactic acid remained substantially in its entirety even after the lapse of six months and the soft tissue in touch with the periphery of the material suffered from some inflammation. However, the copolymers of lactide/~ -caprolactone (at a molar ratio of 70:30 mol %) and lactide/glycolide (at a molar ratio of 75:25 mol %) were completely degraded and absorbed with no sign of any tissular reaction.
From the above results, it is appreciated that the copolymers of lactide/~ -caprolactone and lactide/glycolide are superior to the homopolymer consisting of 100 % polylactic acid in the dynamic properties and the rate of hydrolysis as well as the biocompatibility.
The copolymers of lactide/~ -caprolactone and lactide/glycolide are interesting materials since, as is the case with the homopolymer consisting of 1~0 % polylactic acid7 they cause non-enzymatical hydrolysis in a living body to give hydrolyzates which are degraded and absorbed and finally discharged from the living body in the form of water and carbon dioxide. Thus, the bio-degradable/absorbable high-molecular materials according to the present invention are not only useful materials for the Guided Tissue Regeneration Technic, but are also clinically useful materials in other dental fields.
The bio-degradable/absorbable high-molecular materials of the present invention will now be explained specifically but not exclusively with reference to the following examples.
Example 1 A fully developed ~ongrel was forcedly made to suffer from a 1340.3~4 periodontal disease, thereby inducing gingival retraction. The bio-degradable/absorbable porous ~ilm was used in the form of an about 200~m thick sheet consistin~ of a L-lactide/~ -caprolactone copolymer (at a molar ratio of 70:30 mol %) having a weight-average molecular weight of about 220,000 as well as a dynamic modulus of elasticity of 9.5 x 10~ dynes/cm2 and a elongation rate of 150 %, both at room temperature (25 ~C). After the surface of the root had been covered with such the sheet in a form of a patched tent, a flap of the gingival tissue was back-sutured to prevent the connective tissue from coming in contact with the surface of the root and taking part in the process of healing. After the lapse of three months, the process of healing was observed. As a result, the L-lactide/~ -caprolactone copolymer was found to lose a substantial part of its dynamic strength and cause considerable hydrolysis, although its shape was remained.
However, new attachment including a formation of the new alveolar bone indicated that the periodontal disease was cured.
Example 2 As the bio-degradable/absorbable film, use was made of an about 180~m thick film-like material consisting of a D,L-lactide/glycolide copolymer (at a molar ratio of 80:20 mol %) having a weight-average molecular weight of 170,000 as well as a dynamic modulus of elasticity 9.8 x 10~ dynes/cm2 and a elongation rate of 200 ~, both at room temperature (25 ~C). According to the procedures of Example 1, the process of healing was estimated after the lapse of three months. As a consequence, it was found that the film consisting of the D,L-lactide/glycolide copolymer was substantially degraded and absorbed, and that the periodontal ligament fibers were formed simultaneously with the formation of a new ~one, a sign of healing of the periodontal disease.
139~.3~4 Example 3 A 10 % dioxane solution of a L-lactidejglycolide copolymer (at a molar ratio of 90:10 mol %) having a weight-average molecular weight of about 260,000 as well as a dynamic modulus of elasticity of 1.8 x 108 dynes/cm2 and a elongation rate of 1000 %, both at room temperature (2~ ~C) was freeze-dried to prepare a bio-degradable/absorbable porous film in the form of an about 220~m sheet.
With this film, an animal experiment was performed in a similar manner as described in Example 1. After the lapse of three months, it was found that the porous sheet-like film consisting of the L-lactide/glycolide copolymer was completely degraded and absorbed with a healing of periodontal disease.
Example 4 A 10 % dioxane solution of a D,L-lactide/glycolide copolymer (at a molar ratio of 75:25 mol %) having a weight-average molecular weight of about 190,000 as well as a dvnamic modulus of elasticity of 3.2 x lG8 dynes/cm2 and a elongation rate of 1500 %, both at room temperature ~25 ~(~) was freeze-dried to prepare a bio-degradable/absorbable porous film in the form of an about 160~m sheet.
With this film, an animal experiment was performed in a similar manner as described in Example 1. After the lapse of three months, it was found that the porous sheet-like film consisting of the D,L--lactide/glycolide copolymer was completely degraded and absorbed with a healing of periodontal disease.
Comparative Example 1 An experiment was performed according to Example 1, provided that an about 200~m thick material consisting of polylactic acid having a molecular weight of about 220,000 ~as used as the bio-degradable/absorbable film, to observe the degree of healing after the lapse of three months. As a result, it was found that the polylactic I O -13403~
acid film was not substantially degraded with the inducement of partial inflammation in the gingival tissue in touch with the edges of the film consisting of 100 % polylactic acid.
The bio-degradable/absorbable high-molecular materials of the present invention have the following advantages in comparison with the high-molecular materials which are neither degradable nor absorbable in a living body.
According to the Guided Tissue Regeneration Technic proposed by Professor S. Nyman et al (University of Gothenburg), it is essentially required to remove the material inplanted in the periodontium immediately after the periodontium are found to be healed by such inptant. For such removal, it is again necessary to perform an operation. With the bio-degradable/absorbable high-molecular materials of the present invention, however, it is unnecessary to perform a re-operation, thus easing a patient of pain and relieving an economical burden to considerable degrees.
The material inplanted in the periodontium is required to have strength at the beginning, but is rather needed to lose that strength after the healing of the periodontal disease. No change in strengh tends to induce inflammation. However, the bio-dagradable/absorbable high-molecular materials of the present invention have strength at the start, which can be decreased gradually or sharply with the lapse of time, and so there is no possibility of inducing inflammation in the periodontium.
Moreover~ the bio-degradable/absorable high-molecular materials of the present invention have the following advantages in comparison with those consisting of homopolymers of 10~ % polylactic acid.
The dynamic/mechanical properties suitable for the conditions of the periodontium can be given to the bio-degradable/absorbable high-molecular materials of the present invention because the materials 13403~4 consist of the copolymers of ~actide/~--caprolactone or lactide/glycolide. It is required to vary the rates of bio-degradation and -absorption of the material inplanted in the periodontium depending upon the degree of periodontal disease.
Especially when it is intended to decrease sharply the dynamic/mechanical properties of the bio-degradable/absorbable high-molecular materials at the time when a certain period of time elapses after its inplant in the periodontium, difficulty is involved in freely varying the rate of hydrolysis of the bio-degradable/absorbable high-molecular material consisting of the homopolymer of 100 %
polylactic acid. With the bio-degradable/absorbable high-molecular materials of the present invention, however, it is possible to freely control their rates of degradation and absorption.
Further, the bio-degradable/absorbable high-molecular materials of the present invention give little or no physical stimuli to the soft tissues of a living body because their glass transition temperature is in the vicinity of body heat in comparison with the bio-degradable/absorbable materials consisting of the homopolymer of 100 %
polylactic acid.
Claims (2)
1. A periodontium-regenerating material consisting essentially of bio-degradable/absorbable high-molecular weight material of lactide/~-caprolactone copolymer or a lactide/glycolide copolymer which is used for the regenerative treatment of the periodontium, said copolymer being in a form of a porous film or a sheet and having a weight-average molecular weight in the range of 40,000 to 500,000, a molar ratio in the range of 90:10 to 5:9 mol %, a thickness in the range of 10 to 500 µm, a dynamic modulus of elasticity in the range of 5X10 7 to 5X10 9 dynes/cm2, a tensile strength of 3.1 N/mm2 or greater, an elongation rate of 100 to 2,000% each measured at room temperature (25° C.), retention rate of tensile strength reduced to zero after a lapse of one to six months due to hydrolysis action in vitro measured in a phosphate buffer solution of 37° C. and pH
7.4; and the transition temperature is below body temperature.
7.4; and the transition temperature is below body temperature.
2. The periodontium-regenerating material of Claim 1, wherein the molecular weight is in the range of 170,000 to 260,000.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP214835/1988 | 1988-08-31 | ||
| JP63214835A JP2709349B2 (en) | 1988-08-31 | 1988-08-31 | Materials for periodontal tissue regeneration |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1340354C true CA1340354C (en) | 1999-01-26 |
Family
ID=16662325
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000608766A Expired - Fee Related CA1340354C (en) | 1988-08-31 | 1989-08-18 | Periodontium-regenerative materials |
Country Status (10)
| Country | Link |
|---|---|
| JP (1) | JP2709349B2 (en) |
| AU (1) | AU624847B2 (en) |
| BE (1) | BE1002656A5 (en) |
| CA (1) | CA1340354C (en) |
| CH (1) | CH679836A5 (en) |
| DE (1) | DE3928933C2 (en) |
| DK (1) | DK426989A (en) |
| FR (1) | FR2635685B1 (en) |
| GB (1) | GB2223027B (en) |
| SE (1) | SE503230C2 (en) |
Families Citing this family (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5502158A (en) * | 1988-08-08 | 1996-03-26 | Ecopol, Llc | Degradable polymer composition |
| US5444113A (en) * | 1988-08-08 | 1995-08-22 | Ecopol, Llc | End use applications of biodegradable polymers |
| US6323307B1 (en) | 1988-08-08 | 2001-11-27 | Cargill Dow Polymers, Llc | Degradation control of environmentally degradable disposable materials |
| JPH02152461A (en) * | 1988-12-01 | 1990-06-12 | Nippon Sogo Igaku Kenkyusho:Kk | Tissue absorbable film |
| US5171148A (en) * | 1989-06-30 | 1992-12-15 | Ethicon, Inc. | Dental inserts for treatment of periodontal disease |
| US5077049A (en) * | 1989-07-24 | 1991-12-31 | Vipont Pharmaceutical, Inc. | Biodegradable system for regenerating the periodontium |
| US5487897A (en) | 1989-07-24 | 1996-01-30 | Atrix Laboratories, Inc. | Biodegradable implant precursor |
| US5324519A (en) * | 1989-07-24 | 1994-06-28 | Atrix Laboratories, Inc. | Biodegradable polymer composition |
| DE4229924C2 (en) * | 1991-04-17 | 1995-12-07 | Juergens Christian Dr Med | Use of absorbable lactide copolymers |
| DE4112489C2 (en) * | 1991-04-17 | 1994-06-09 | Christian Dr Med Juergens | Use of resorbable, physiologically harmless copolymers for the topical treatment of human or animal skin |
| DE4226465C2 (en) * | 1991-08-10 | 2003-12-04 | Gunze Kk | Jaw bone reproductive material |
| FR2691901B1 (en) * | 1992-06-04 | 1995-05-19 | Centre Nat Rech Scient | Use of mixtures of polymers derived from lactic acids in the preparation of bioresorbable membranes for guided tissue regeneration, in particular in periodontology. |
| US5576418A (en) * | 1992-06-29 | 1996-11-19 | Jurgens; Christian | Resorbable biocompatible copolymers and their use |
| JP3257750B2 (en) * | 1993-07-20 | 2002-02-18 | エチコン・インコーポレーテツド | Liquid copolymer of ε-caprolactone and lactide |
| US5681873A (en) * | 1993-10-14 | 1997-10-28 | Atrix Laboratories, Inc. | Biodegradable polymeric composition |
| DE4343988A1 (en) * | 1993-12-22 | 1995-06-29 | Peter Prof Dr Dr Diedrich | Dental implant anchoring |
| NL9401703A (en) * | 1994-10-14 | 1996-05-01 | Rijksuniversiteit | Chewing gum. |
| US5962006A (en) * | 1997-06-17 | 1999-10-05 | Atrix Laboratories, Inc. | Polymer formulation for prevention of surgical adhesions |
| US6165217A (en) * | 1997-10-02 | 2000-12-26 | Gore Enterprise Holdings, Inc. | Self-cohering, continuous filament non-woven webs |
| US6245345B1 (en) * | 1998-07-07 | 2001-06-12 | Atrix Laboratories, Inc. | Filamentous porous films and methods for producing the same |
| DE19830992C2 (en) * | 1998-07-10 | 2000-06-08 | Eckhard Binder | Molded parts, especially foils, to promote the new formation of bone material in the jaw |
| DE19940977A1 (en) * | 1999-08-28 | 2001-03-01 | Lutz Claes | Film of resorbable polymer material and process for producing such a film |
| US8226598B2 (en) | 1999-09-24 | 2012-07-24 | Tolmar Therapeutics, Inc. | Coupling syringe system and methods for obtaining a mixed composition |
| JP2005046538A (en) * | 2003-07-31 | 2005-02-24 | Jms Co Ltd | Porous body for medical treatment and method for manufacturing it |
| JP4279233B2 (en) | 2004-10-25 | 2009-06-17 | 国立大学法人広島大学 | Sheet for inducing mesenchymal tissue regeneration and method for producing the same |
| JP2011062356A (en) * | 2009-09-17 | 2011-03-31 | Gc Corp | Bioabsorbable membrane for guided tissue regeneration and manufacturing method of the same |
| JP2017052725A (en) * | 2015-09-10 | 2017-03-16 | 田畑 雅士 | Blocking membranes for open wounds in dental region, and formation methods thereof |
| CZ308980B6 (en) * | 2020-01-24 | 2021-11-03 | Contipro A.S. | Dental preparation made of hyaluronic acid fibres with adjustable biodegradability |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1332505A (en) * | 1970-10-16 | 1973-10-03 | Ethicon Inc | Sutures and other surgical aids |
| US3839297A (en) * | 1971-11-22 | 1974-10-01 | Ethicon Inc | Use of stannous octoate catalyst in the manufacture of l(-)lactide-glycolide copolymer sutures |
| CA1123984A (en) * | 1977-11-16 | 1982-05-18 | Yuzi Okuzumi | Block copolymers of lactide and glycolide and surgical prosthesis therefrom |
| NZ205680A (en) * | 1982-10-01 | 1986-05-09 | Ethicon Inc | Glycolide/epsilon-caprolactone copolymers and sterile surgical articles made therefrom |
| US4523591A (en) * | 1982-10-22 | 1985-06-18 | Kaplan Donald S | Polymers for injection molding of absorbable surgical devices |
| JPS6014861A (en) * | 1983-07-05 | 1985-01-25 | 株式会社日本メデイカル・サプライ | Adhesion preventing material |
| US4578384A (en) * | 1984-02-15 | 1986-03-25 | The United States Of America As Represented By The Secretary Of The Army | Polylactic-polyglycolic acids combined with an acidic phospholipid-lysozyme complex for healing osseous tissue |
| US4595713A (en) * | 1985-01-22 | 1986-06-17 | Hexcel Corporation | Medical putty for tissue augmentation |
| SU1830708A1 (en) * | 1989-04-27 | 1996-02-20 | Театр полифонической драмы | Device for movement of decorative equipment of information and entertainment complexes |
-
1988
- 1988-08-31 JP JP63214835A patent/JP2709349B2/en not_active Expired - Fee Related
-
1989
- 1989-08-10 AU AU39490/89A patent/AU624847B2/en not_active Ceased
- 1989-08-11 GB GB8918343A patent/GB2223027B/en not_active Expired - Fee Related
- 1989-08-11 BE BE8900868A patent/BE1002656A5/en not_active IP Right Cessation
- 1989-08-18 CA CA000608766A patent/CA1340354C/en not_active Expired - Fee Related
- 1989-08-28 CH CH3113/89A patent/CH679836A5/fr not_active IP Right Cessation
- 1989-08-29 SE SE8902867A patent/SE503230C2/en not_active IP Right Cessation
- 1989-08-30 DK DK426989A patent/DK426989A/en not_active Application Discontinuation
- 1989-08-30 FR FR898911387A patent/FR2635685B1/en not_active Expired - Fee Related
- 1989-08-31 DE DE3928933A patent/DE3928933C2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| SE8902867D0 (en) | 1989-08-29 |
| SE8902867L (en) | 1990-03-01 |
| BE1002656A5 (en) | 1991-04-23 |
| AU624847B2 (en) | 1992-06-25 |
| GB8918343D0 (en) | 1989-09-20 |
| SE503230C2 (en) | 1996-04-22 |
| FR2635685A1 (en) | 1990-03-02 |
| JP2709349B2 (en) | 1998-02-04 |
| DK426989A (en) | 1990-06-20 |
| JPH0263465A (en) | 1990-03-02 |
| DK426989D0 (en) | 1989-08-30 |
| GB2223027A (en) | 1990-03-28 |
| AU3949089A (en) | 1990-03-08 |
| GB2223027B (en) | 1993-04-21 |
| DE3928933A1 (en) | 1990-03-01 |
| CH679836A5 (en) | 1992-04-30 |
| FR2635685B1 (en) | 1994-10-14 |
| DE3928933C2 (en) | 1997-08-07 |
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