Note: Descriptions are shown in the official language in which they were submitted.
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
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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
0
,_
~ 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
~ ~ .. . . ... .
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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
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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.
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