Note: Descriptions are shown in the official language in which they were submitted.
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COMPOSITE CONTAINING POLYMER AND ADDITIVE AS WELL AS ITS USE
Background of the Invention
Field of the Invention
The present invention concerns biocompatible and bioabsorbable composite
materials
containing multimonomer-polymers and/or their blends together with one or more
additive,
as well as a method for manufacturing said composites. These composite
materials have
the required properties tailored to be suitable for use in implantable
surgical devices.
Description of Related Art
In orthopaedic surgery, either biostable or biodegradable devices, such as
pins, fixation
screws, plates, tacks, bolts, intramedullary nails, interference screws,
suture anchors, or
staples, are used in various applications.
Most biostable devices are made of metallic alloys. However, there are several
disadvantages in the use of metallic implants, such as the bone resorption
caused by the
bone plates and screws (Wolff s law), which carry most of the external loads,
as well as
debris formation and the possibility of corrosion. Therefore, surgeons are
recommended to
remove metallic implants in a second operation to be carried out once the
fracture has
healed.
Therefore, bioabsorbable (i.e. biodegradable and resorbable) surgical devices,
generally
made from polymers, are commonly used in surgical fixation. The advantages of
these
devices include that the materials are absorbed in the body and the
degradation products
exerted via metabolic routes. Hence, a further implant removal operation is
not required.
Additionally, the strength of the bioabsorbable polymeric devices decreases
gradually as
the device is degraded, whereby the bone is progressively loaded. This, in
turn, promotes
bone regeneration.
Synthetic biodegradable polymers have many advantages in the medical
applications. They
can be tailored to fulfill specific needs of a particular application. The
hydrophobicity,
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crystallinity, degradability, solubility and thermal properties (glass
transition and melting
temperature) of polymer can be easily modified by copolymerization or by
changing
polymerization conditions. Another feasible route to modify polymer properties
is physical
blending.
Biodegradable polymers are typically synthetic aliphatic polyesters. Most
commonly used
aliphatic polyesters are poly-a-hydroxy acids such as polyglycolides (PGA),
polylactides
(PLA) and their copolymers produced by polycondensation or ring-opening
polymerization. Biocompatible and bioabsorbable surgical devices are normally
made of
these polymers. Glycolide/L-lactide copolymers (PLGA) and glycolide
trimethylene
carbonate copolymers (PGA/TMC) are examples of glycolide based copolymers.
Lactide
based copolymers may comprise lactones (acid dimers) such as L-lactide (L), D-
lactide
(D), D,L-lactide (DL), glycolide (G), c-caprolactone (CL), trimethylene
carbonates (TMC),
p-dioxanone (PD), 2-methyl glycolide (MG), 2,2-dimethyl glycolide (DMG), 1,5-
dioxapane-2-one (DOX-5), para-dioxapane-2-one (DOX-4), 3,3-
dimethyltrimethylene
carbonate (DMTMC), glycosalicylate (GS), and morpholine-2,5-dione (MD) as co-
monomer. In these aliphatic polyesters described, n-alkylene, alkylene oxide
or alkylene
carbonate linking groups may consist more than 5 carbon atoms in backbone (-
CH2-). n-
Alkylene may also be substituted (side-chain polymers) or branched (star
polymers).
Copolymers of L-lactide and D-lactide are also able to form stereocomplexes
(stereopolymers), which behavior is resulting from the enantiomer character of
a single
lactic acid. Polyhydroxyalkanoates (PHA), polyhydroxybutyrates (PHB),
polyhydroxyvalerate (PHV) and poly(hydroxybutyrate-co hydroxyvalerate) (PHBV)
are
belonging to polyhydroxyalkanoates (bacterial polyesters) produced by
bacterial
biosynthesis. Other possible biodegradable polymers are poly(ortho esters),
polyanhydrides, polyamides, polydioxanones, polyoxylates, polyoxamates,
polyacetals,
"pseudo"-poly(amino acids) such as tyrosine-derived polycarbonate,
poly(propylene
fumarates), poly(butylenes adipate-co-terephthalate), polyesteramides,
pocarboantes,
polyiminocarbonates, polyurethanes, poly(alkyl cyanoacrylates),
polyphosphazenes,
polyphosphoesters.
Copolymers of lactides have been chemically prepared to modify the properties
of
homopolymer. For instance co-monomers such as L-lactide (L), D-lactide (D) or
racemic
D,L-lactide (DL) disrupt the crystallinity of L-lactide block, which is
resulting to reduced
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crystallinity and also sometimes to accelerated degradation process. The semi-
crystalline
homopolymer poly(L-lactide) has a modulus about 25% higher than copolymer
poly(D,L-
lactide). The amorphous copolymer poly(L-lactide-co-D,L-lactide) may have
higher
elasticity due to lack of crystallinity.
Biodegradable polyesters decompose mostly by hydrolysis after having been
exposed to
moisture. Normally, there exists a sequence of phenomena; a decrease in
molecular weight,
strength, and mass during the hydrolysis of biodegradable polymers.
Crystalline blocks of
semi-crystalline polylactide are more resistant to hydrolytic degradation than
the
amorphous phase. Time required for certain polylactide implants to be totally
absorbed is
relatively long and depends on polymer quality, processing conditions, implant
site, and
physical dimensions of the implant. For instance PLA degrades in vivo to form
lactic acid
which is normally present in the body. This acid enters tricarboxylic acid
cycle and is
exerted as water and carbon dioxide.
Bioceramics are attractive as biological implants because of their
biocompatibility. During
the last three decades ceramic materials have become widely used in many
medical
applications such as hip prosthesis, cardiac valves and dental implants. Among
the
biomaterials available, medical ceramics or bioceramics, exhibit some of the
most
interesting properties. Calcium phosphates have been used in the form of
artificial bone.
Calcium phosphate ceramics (CPC) have been synthesized and manufactured to
various
forms of implants and coatings. Calcium phosphate ceramics exhibit non-
toxicity to tissues
(biocompatibility), bioreseption and osteoinductive property. Calcium
hydroxyapatite
(HA) and tricalcium phosphates (TCP) are the most typical bioceramics used in
medical
devices. Tricalcium phosphate exits in two different whitlockite
crystallographic
configurations, namely as a-TCP and as the more stable I3-TCP. The
biodegradation rate of
TCP is greater than that of HA, because the differences in the crystalline
structures. Glass-
ceramics (A/W glasses) were developed in the early 1960s. The basic components
in most
bioactive glasses are Si02, Na20, CaO and P205. Bioglass and glass-ceramics
are non-
toxic and are able chemically bond to bone. The primary advantage of bioactive
glasses is
their quick rate of surface reaction resulting in fast bonding.
In its most basic form a composite material is one, which is composed of at
least two
elements working together to produce material properties that are different to
the properties
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of those elements on their own. The mechanical properties of polymers can be
improved
by the addition of the particulate or fiber reinforcement.
A wide variety of bioabsorbable homo- and copolymers containing implantable
prior art
materials and devices have been made and described for instance in the
following
publications:
Eur.Pat.No. 0011528 and U.S. Pat.No. 4,279,249 describe osteosynthesis parts
made of
absorbable polymer composition consisting of a matrix of lactic acid
homopolymer, or
copolymer very high in lactic acid units, having discrete reinforcement
element embedded
therein. The reinforcement elements are made of glycolic acid homopolymers or
copolymers predominant in glycolic acid units. Osteosynthesis part made of
said polymer
compositions containing a charge constituted by a material containing at least
one ion
selected from: calcium, magnesium, sodium, potassium, phosphate, borate,
carbonate and
silicate. Such a composition may be shaped with minimum of polymer degradation
into
osteosynthesis parts exhibiting good resilience, shock resistance, and tensile
strength. One
mentioned example is a composite part prepared by compression-molding
employing as
the polymer the PLA charged with tricalcium phosphate.
Eur.Pat. No. 0204931 and U.S. Pat. No. 4,743,257 describe surgical
osteosynthesis
composite material, which is self-reinforced. This material is formed about
the absorbable
polymer or copolymer matrix which is reinforced with absorbable reinforcements
units
which have the same chemical element percentage composition as the matrix has.
Osteosynthesis material is characterized in that the absorbable matrix and
reinforcement
units are manufactured of polylactide or a lactide copolymer. Other main
material
combination is the one, where the absorbable matrix and reinforcement units
are
manufactured of polyglycolide or a glycolide copolymer. The absorbable matrix
and
reinforcement units can be also manufactured of glycolide/lactide copolymer.
Self-
reinforcement in these patents means that the polymeric matrix with the
reinforcement
element or materials (such as fibers) which the same chemical element
composition as
does the matrix, and then preferred processing method is compression-molding.
U.S. Pat. No. 4,968,317 and Eur.Pat. No.0854734 describes surgical material of
resorbable
polymer, copolymer, or polymer mixture containing at least partially
fibrillated structural
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units, and use thereof Homopolymer and copolymer materials are typically
composed of
the absorbable matrix and reinforcement units are manufactured of polylactide
or a lactide
copolymer. Self-reinforcing in these patents means orientation of the
molecular structure of
absorbable polymeric materials in such a way that they are at least partially
fibrillated.
5
U.S. Pat. No. 6,406,498, and Eur.Pat. No. 1109585 describe a bioactive,
biocompatible,
bioabsorbable surgical composite that is fabricated bioabsorbable polymers,
copolymers or
polymer alloys that are self-reinforced and contain ceramic particles or
reinforcement
fibers, and also can be porous. Polymers matrix is typically composed of poly-
a-hydroxy
acid based absorbable polymers or copolymers such as polylactide or a lactide
copolymer.
Typical ceramic additive is belonging to calcium phosphate ceramic family, and
then the
most typical additive is beta-tricalcium phosphate (I3-TCP). The composite of
the invention
can be formed into devices with the suitable property profile depending on the
indication.
Eur.Pat. No. 1009448 and U.S.Pat.No. 7,541,049 describe surgical
osteosynthesis
composite materials which has three components, namely biodegradable polymer
reinforcement, bioceramic or bioglass filler reinforcement and biodegradable
polymer
matrix. The invention introduces the composites that have two different
reinforcing phases
and one matrix phase. One reinforcing element is referred as the polymeric
reinforcing
element and the other as the ceramic reinforcing element. Typical matrix
polymers are
poly-a-hydroxy acid based absorbable polymers or copolymers such as
polylactide or a
lactide copolymer.
U.S.Pat. No. 6,206,883 and U.S.Pat.No. 6,716,957 describe a bioabsorbable
material such
as a terpolymer of poly-(L-lactide/D-lactide/glycolide). The claims of the
former patent is
relating to an implantable medical device and the ones of the latter to a
material
comprising terpolymer. The material may consist of 85 molar percent L-lactide,
5 molar
percent D-lactide, and 10 molar percent glycolide. The material may hay
tensile strength
retention at 26 weeks of incubation at least 50%, and tensile strength
retention at 52 weeks
of incubation of at most about 25%. The material may be used in implantable
devices such
as bone fixation devices.
U.S.Pat.No. 6,747,121 describes implantable, resorbable copolymers containing
L-lactide
and glycolide repeat units, and in particular to terpolymers containing L-
lactide, glycolide,
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and one other type of repeat unit selected from the group consisting of D-
lactide, D,L-
lactide, and c-caprolactone. Medical devices for in vivo implantation
applications
containing such implantable, resorbable copolymers have also been described,
as well as
methods for making such co- and terpolymers and devices.
Surgeons prefer using devices that eventually are resorbed and disappear from
the body
after they have served their purpose. However, in many cases sufficient
strength properties
are difficult to achieve using bioabsorbable polymeric devices, particularly
since the
strength must be maintained for a sufficient period of time, even after the
absorption of the
material has started. A common way to overcome this challenge is to
manufacture
bioabsorbable medical implants with as high initial molecular weight as
possible. Another
commonly used route is to choose materials having long degradation time. The
result in
both cases is unfortunately prolonged total bioabsorption time, which can be
in certain
cases 5-10 years. Therefore the optimized biodegradation kinetics is needed.
The
optimized kinetics means here long enough strength retention time to guarantee
tissue
healing while biodegradation occurs in reasonable time scale to guarantee the
lack of
negative tissue responses caused by degradation products of polymeric or
composite
device.
For some surgical applications there are challenges to achieve sufficient
strength properties
by using non-reinforced bioabsorbable polymers and composites. For those cases
the use
of various reinforcing techniques is a feasible way to guarantee required
initial strength
properties. Self-reinforced polymeric composites have been developed that show
enhanced
strength compared to conventional polymeric surgical materials (see e.g. EP
1109585).
However, even these do not provide the preferred advantageous properties
bioabsorption
kinetics of the materials of the present invention.
Several publications describe the use of composite materials in surgical
devices, such as
EP 0011528, EP 1009448and EP 1109585. However, none of these solutions
describe the
use of preferred terpolymers of this invention in these materials and devices.
Copolymers have been described extensively as polymer materials examples (e.g.
in EP
0423155). U.S.Pat. No. 6,206,883, U.S.Pat.No. 6,716,957 and U.S.Pat.No.
6,747,121 are
depicting bioabsorbable polymers such as terpolymer of poly-(L-lactide/D-
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lactide/glycolide), which is used in implantable devices such as bone fixation
devices.
These three patents are not claiming any absorbable composite materials or
medical
devices made of said composite materials.
It has been attempted to mix various additives into the bioabsorbable polymers
to modify
their properties and to yield devices having useful properties. The initial
mechanical
strength of surgical materials has been improved by applying reinforcement
units having
the same chemical composition as matrix such as absorbable fibers by mixing
mechanically together and then compression-molded (see e.g. Example 5 in EP
0204931).
The reinforcement fibers typically have a fiber length of l[tm to 10mm.
However, if the
chemical structure or the element composition of the reinforcement units
differ from that
of the matrix material (e.g., EP 0011528), the resulted structures cannot
generally form
strong bonds between each other, which, in turn, leads to poor adhesion.
Adhesion
promoters, such as silanes or titanates, cannot be applied in surgical
materials due to their
toxicity. The poor interface adhesion has been solved by orientation of the
molecular
structure of absorbable polymeric material in such a way that it is at least
partially
fibrillated because of molecular orientation of polymer by means of self-
reinforcing
process (EP 0854734 and EP 1109585).
The self-reinforced materials described in EP 0204931 and EP 0854734 are
composed of
plain polymer/polymers, and therefore they lack direct bone-bonding
properties. To
overcome this challenge the composite properties have been modified by
additives
including bioceramics, which optionally can be bioactive (such as in EP
1009448). These
additives can be in various forms including particle fillers, fibers, etc.,
and these additives
can promote osteoconductivity, i.e. such bioabsorbable bone fracture fixation
devices can
create direct contact with the bone tissue.
A general problem with addition of said ceramic particles has been the
brittleness of the
formed composites, since the addition of ceramic fillers into the polymeric
matrix changes
most thermoplastic polymers from tough and ductile to brittle in nature. This
is a
consequence of lack of adhesion between said ceramic particles and polymer
matrix. This
is evidenced by a significant reduction in both the elongation at break and
the impact
strength. Moreover, even non-filled bioabsorbable thermoplastic polymer
devices can be
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brittle in their mechanical behavior. The brittleness can be a severe
limitation on
bioabsorbable devices, leading to premature breaking or other adverse
behavior.
Thus, there remains a need for non-toxic bioabsorbable composite materials
having
sufficient strength retention properties during the degradation, reasonable
estimated total
bioabsorption time and osteoconductive potential. The osteoconductive
potential means
here a good adhesion particularly to solid contact with bone tissue.
Summary of the Invention
It is an object of the present invention to provide a biocompatible,
bioabsorbable polymer
composite material suitable for use in surgical devices.
Particularly, it is an object of the present invention to provide such
bioabsorbable polymer
composites for surgical devices, which provide these devices with an improved
bioabsorption kinetics at the same time maintaining equivalent strength
compared to the
prior art. The improved bioabsorption kinetics means here long enough strength
retention
time to ensure mechanical support during the required healing period and short
enough
degradation in terms of decline of molecular weight (or inherent viscosity) to
guarantee
faster total bioabsorption than plain PLLA polymer.
Further, it is an object of the invention to provide said surgical devices,
the strength of
which can be maintained on a sufficiently high level for a required healing
time compared
to the prior art.
Likewise, it is a particular object of the invention to provide said improved
and prolonged
strength retention without significantly impairing the adhesion of the
surgical devices to
bone and without prolonged total mass loss time.
These and other objects, together with the advantages thereof over known
polymer
composites (as well as compositions, devices and manufacturing processes), are
achieved
by the present invention, as hereinafter described and claimed.
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Thus, the present invention concerns a biodegradable composite material for
use in
surgical devices, which composite contains a biocompatible polymer matrix
composition
and one or more biocompatible additives, preferably in the form of
bioceramics. Further,
the invention concerns a surgical device containing said composite, and a
process for its
manufacture.
More specifically, the composite material of the present invention is
characterized by what
is stated in the characterizing part of Claim 1.
Further, the process for manufacturing said composite is characterized by what
is stated in
Claim 8, the surgical device containing said composite is characterized by
what is stated in
Claim 12, and the process for manufacturing the device is characterized by
what is stated
in Claim 14.
The preferred embodiments of the invention relating to bioabsorbable composite
materials
and medical devices made of them, as well as methods for manufacturing said
devices,
comprise:
(a) compositions of multimonomer-polymer and/or their blends as matrix,
wherein one
or more additives are dispersed;
(b) multimonomer-polymer matrix encompasses repeat units, which are derived
from
lactone-based monomers as a primary matrix component;
(c) multimonomer-polymer matrix consists the lactone-based repeat unit
compositions, which are composed of more than two co-monomers (biopolymers),
namely the ones of three monomers (terpolymers), or the ones of four monomers
(quaterpolymers), or the ones of five monomers (quinterpolymers), etc. as a
secondary matrix components;
(d) multimonomer-polymer matrix consists of the blends of polymers, which are
composed of more than two co-monomers (biopolymers), namely the ones of three
monomers (terpolymers), or the ones of four monomers (quaterpolymers), or the
ones of five monomers quinterpolymers, etc. as a tertiary matrix components;
(e) additive component encompasses bioceramics, which are selected from
calcium
phosphate ceramics and/or bioactive glasses and glass-ceramics as one or more
primary additives;
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(f) additive component encompasses one or more assistive additives in addition
to one
or more primary additive;
(g) said composite materials are manufactured by mixing (molten or solution)
selected
one or more bioabsorbable matrix and selected one or more additive components
5 with
each other in molten or solution phase, the preferred manufacturing process is
molten;
(h) bioabsorbable medical devices are manufactured from said preferred one or
more
composite compositions by means of one or more continuous or non-continuous
processes depending on the product application;
10 (i)
medical devices made of said composite materials are used in selected
indications.
Considerable advantages are obtained by means of the invention. Among others,
the
present invention provides an optimized bioabsorption profile, i.e. the
material exhibits a
fast enough rate of absorption (i.e. reduced total mass loss time) while
maintaining its
strength for a sufficiently long time. Particularly the shear strength
provides the advantages
that are significant in manufacturing surgical devices.
The composite materials of this invention can be further processed by means of
various
orientation techniques such as self-reinforcing. By orientating preferred
polymer matrix
components of this invention, high ceramic contents can be added to matrix
polymer
matrix without resulting to brittle composite material. Such high ceramic
contents as 50wt-
% can lead to composite structures which are hand malleable at room
temperature.
Next, the invention will be described more closely with reference to the
attached drawings
and a detailed description.
Brief Description of the Drawings
Figure 1 shows the bending of self-reinforced 50-wt-% beta-TCP containing
terpolymer
composite without breakage.
Figure 2 shows the bending of injection molded terpolymer composites without
breakage.
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Figure 3 shows the eyelet strength of self-reinforced terpolymer (85L/5D/10G
PLDGA)
and terpolymer composite (85L/5D/10G PLDGA + TCP) suture anchors
Figure 4 shows the torsion strength of self-reinforced terpolymer (85L/5D/10G
PLDGA)
and terpolymer composite (85L/5D/10G PLDGA + TCP) suture anchors.
Figure 5 shows the eyelet strength of various injection molded terpolymer and
terpolymer
composite suture anchors
Figure 6 shows the torsion strength of various injection molded terpolymer and
terpolymer
composite suture anchors
Figure 7 shows the estimated total biodegradation time for composites of this
invention.
Detailed Description of the Preferred Embodiments of the Invention
The present invention concerns a biocompatible, bioabsorbable composite
material for use
in surgical devices, containing one and more multimonomer-polymers and/or
their blends
together with one or more additives, as well as a method for manufacturing
said
composites. Particularly, the composite material comprises a bioabsorbable
polymer
composed of three or more lactone-based repeat units as a matrix, wherein one
or more
biocompatible ceramics are dispersed as said one or more additive components.
These bioabsorbable composite materials include a bioabsorbable matrix
polymer, which
preferably is composed of three chemically differing repeat units, i.e. it is
a terpolymer,
and where the ceramic is bioabsorbable and bone adhesion promoting as well as,
preferably, bone growth promoting, bioceramic additive.
Tailor-made medical devices, such as interference screws and suture anchors,
may be
manufactured of said bioabsorbable composite materials.
The bioabsorbable polymeric matrix of the invention may be selected from a
diversity of
synthetic bioabsorbable polymers. Such synthetic biocompatible, bioabsorbable
polymers
are preferably aliphatic polyesters such as poly-a-hydroxy acids. These
multimonomer
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based polymers as a matrix contain preferably one or more repeat units
selected from
lactones (cyclic acid dimers) such as L-lactide (L), D-lactide (D), D,L-
lactide, glycolide
(G), c-caprolactone (CL), trimethylene carbonates (TMC), p-dioxanone (PD), 2-
methyl
glycolide (MG), 2,2-dimethyl glycolide (DMG), 1,5-dioxapane-2-one (DOX-5),
para-
dioxapane-2-one (DOX-4), 3,3-dimethyltrimethylene carbonate (DMTMC),
glycosalicylate (GS), and morpholine-2,5-dione (MD). However, in the primary
embodiment of the invention terpolymer matrix consists of lactide and
glycolide repeat
units, most preferable terpolymers of a L-lactide repeat unit (L), a D-lactide
repeat unit
(D), and/or a racemic D,L-lactide repeat unit (D,L) and glycolide (G). The
bioabsorbable
composite contains preferably only one terpolymer as a matrix component.
The additive component of the invention can be selected from bioceramic and
glass groups
such as hydroxyapatite (HA) and tricalcium phosphates (a- and I3-TCPs), but
also from
other calcium phosphates such as monocalcium phosphate monohydrate (MCPM),
monocalcium phosphate anhydrate (MCPA), dicalcium phosphate dehydrate (DCPD,
i.e.,
brushite), dicalcium phosphate anhydrate (DCPA, i.e., monenite), octacalcium
phosphate
(OCP), amorphous calcium phosphate (ACP), calcium-deficient hydroxyapatite
(CDHA)
and tetracalcium phosphate (TTCP), Bioglass, Cerevital bioactive glass-
ceramics, alumina,
zirconia, bioactive gel-glass, bioactive glasses and glass ceramics. However,
the
bioceramic additive material component of the composite is preferably beta-
tricalcium
phosphate (beta-TCP) or a mixture of hydroxyapatite and beta-tricalcium
phosphate
(HA/TCP) in the primary embodiment of the invention. Particularly, at least a
portion of
the additives are always selected from biominerals, providing a composite
structure at least
partially to resemble the bone matrix.
The optimized biodegradation kinetics of the composite materials of this
invention
comprises long enough strength retention time typically 6-26 weeks to
guarantee tissue
healing depending on the application and reasonable total bioabsorption time
1.5 - 4 years.
Too quick bioabsorption may cause negative tissue responses because of high
concentration of degradation products. Therefore, in this invention preferable
composite
compositions are introduced to avoid too quick degradation and not compromise
mechanical performance.
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According to a preferred primary embodiment of the invention, the composite
material is
composed of polymer matrix, preferably a terpolymer PLDGA of L-lactide, D-
lactide and
glycolide (G), particularly of the type 70-90 mol% L / 1-20 mol% D / 1-20 mol%
G
PLDGA, or a blend thereof, mixed with 1-90 wt% biocompatible ceramic additive.
More
preferably, the composite material is formed from 80mol% L /5-15 mol% D / 5-10
mol%
G PLDGA, or a blend thereof, and 10-60 wt% biocompatible additives.
According to a preferred primary embodiment of the invention, the additive is
a bioceramic
material, which may be selected from any biocompatible ceramic material such
as a
calcium phosphate and bioactive glass. Most suitably, the ceramic material is
beta-
tricalcium phosphate (beta-TCP) or a mixture of HA/TCP. Ceramic additive is
mainly
inducing osteoconductivity to composite.
In another embodiment of the invention, the polymer matrix consists of more
than three
lactone-based repeat units in addition to L-lactide, D-lactide and glycolide
(PLDGA) such
as trimethylene carbonate (TMC), c-caprolactone (CL) and/or p-dioxanone (PD)
or a blend
thereof, mixed with 1-90 wt% biocompatible ceramic additive.
In still another embodiment of the invention, the composite material is
composed of
colorant containing polymer matrix, preferably a terpolymer PLDGA of L-
lactide, D-
lactide and glycolide (G), particularly of the type 70-90 mol% L / 1-20 mol% D
/ 1-20
mol% G PLDGA, or a blend thereof, mixed with 1-90 wt% biocompatible ceramic
additive and with 0.01-0.3 wt-% colorant such as 1-hydroxy-44(4-
methylfenyl)amino]-
9,10-antrasenedione (D&C Violet #2) or 9,10-anthracenedione, 1,4-bis[(4-
methylphenyl)amino] (D&C Green 6). More preferably, the composite material is
formed
from 80 mol% L /5-15 mol% D / 5-10 mol% G PLDGA, or a blend thereof, and 10-60
wt% biocompatible additive with 0.01-0.3 wt-% colorant such asl-hydroxy-4-[(4-
methylfenyl)amino]-9,10-antrasenedione (D&C Violet #2) or 9,10-
anthracenedione, 1,4-
bis[(4-methylphenyl)amino] (D&C Green 6).
In further another embodiment of the invention the composite matrix may
contain a
physical blend of two or more terpolymers, or a physical blend of one or more
terpolymer
with one or more copolymer or homopolymer or both. Most suitable, the
terpolymer
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14
composition consists of a single terpolymer mixed with said one or more
biocompatible
preferred ceramic additives.
In a further embodiment of the invention the bioactive glasses optionally
employed as
primary ceramic additives are based on a network former and at least one
additional
additive component. The network former can, for example, be P205. The
additional
components typically provide the resulting composite with a further
advantageous
function, such as change its rate of solubility, whereby these are also called
functional
additives.
One group of additional additives include alkali and alkaline earth metal
oxides, such as
sodium oxide, potassium oxide, calcium oxide and magnesium oxide, and their
respective
carbonates and phosphates.
Particularly, the bioactive glasses of this embodiment include both alkali
metal oxides (or
their respective carbonates or phosphates, or a mixture thereof) and alkaline
earth metal
oxides (or their respective carbonates or phosphates, or a mixture thereof).
As a general
rule, the rate of solubility is increased by increasing the proportion of
alkali metal oxides,
and is decreased by increasing the proportion of alkaline earth metal oxides.
The second group of the additional additives, i.e., functional additives can
be selected from
organic or inorganic bioactive substances such as osteoconductive agents,
antibiotics,
chemotherapeutic agents, agents activating the healing of wounds, growth
factors, bone
morphogenic proteins and anticoagulants. Such agents provide the additional
advantage of
promoting tissue healing.
The third group of additional additives can be, for example, additives for
facilitating
processing of the material or for altering its properties, such as adhesion
promoters,
stabilizers, antioxidants and plasticizers, or for facilitating its handling,
such as colorants.
Some preferred exemplary composite compositions include:
¨ 78 wt-% or 50 wt-%(85 mol%L / 5 mol%D / 10 mol%G) PLDGA+ 22 wt-
%TCP or 50 wt-%TCP,
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¨ 78 wt-% or 50 wt-%(85 mol%L / 10 mol%D / 5 mol%G)PLDGA + 22 wt-
%TCP or 50 wt-%TCP, and
¨ 78 wt-% or 50 wt-%(90mol%L / 5 mol%D / 5 mol%G)PLDGA + 22 wt-t%TCP
or 50 wt-%TCP).
5
The composite is manufactured by mixing the ceramic additive with the
composite matrix
component. The additive can be used in any form, preferably as a powder,
flakes, granules,
cut-off fibers or continuous fibers. However, the addition of additive to the
composite
matrix component is preferably carried out with the components heated to a
molten state
10 (melt processing) or dissolved in a suitable solvent, such as an aqueous
solution, more
preferably with the polymeric matrix components in molten state.
After the addition of the additive to the composite polymer matrix component,
the
composite material is subjected to mechanical treatment step to form the final
composite
15 structure. This treatment step preferably includes injection molding,
extrusion followed by
machining and/or the use of some orientation technique, such as self-
reinforcing.
The addition of the primary and/ or secondary additive components to the
polymer matrix
component can be carried out gradually, in several steps. However, the final
content of
additive in the composite, after addition of the final portion of additive, is
1 to 90 wt-%.
Additional additives may be added in a selected step suitable for process
methods used.
The mechanical treatment can be divided into two parts, whereby, in the first
part, the
polymer raw material, with additives, is melted with a continuous process,
such as
extrusion, or with a noncontinuous process, such as injection or compression
molding, or
maintained in a molten state after mixing its components. The melted material
is cooled so
that it solidifies to an amorphous or partially crystalline (crystallinity
typically 0-60%)
perform. The cooling is carried out, for example, inside a mold, on a cooling
belt or in a
cooling solution.
A feasible way of carrying out the second part of the mechanical deformational
treatment
is by orientation. This optional orientation can be carried out using a
temperature (T) that is
above the glass transition temperature (Tg) of the polymer matrix material,
but below its
melting temperature, particularly if it is partially crystalline (semi-
crystalline), and by
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drawing the above melt-processed, non-oriented billet or preform (such as a
rod, a plate or
a film) to a typical drawing ratio of 1.1 to 7 in the direction of the
longitudinal axis of the
preform, such as billet.
The drawing can be done freely by fixing the ends of the preform into fixing
clamps of a
drawing machine, tempering the system to the desired drawing temperature, and
increasing
the distance between the fixing clamps so that the preform is stretched and
oriented
structurally. This type of orientation is mainly uniaxial.
The drawing can also be done through a conical die, which can have, e.g., a
circular, an
ellipsoidal, a square, a star-like, a rectangular or other suitably shaped
cross-section. When
the cross-sectional area is circular like in the polymer billet, which is to
be drawn through
the die, is bigger than the cross-sectional area of the die outlet, the billet
is deformed and
oriented uni- or biaxially (or both) during drawing, depending on the
geometries of the die
and the billet. The ratio of the cross-sectional areas of the undrawn and
drawn billet defines
the draw ratio (DR or X).
Also pushing deformation can be carried out, e.g. using a piston as an
effective force.
Further, it is possible to create orientation by shearing the flat billet
between two flat
plates, which glide in relation to each other, or by rolling a rod-like or
plate-like preform
between rollers, which flatten the preform to a desired thickness,
simultaneously orienting
the material biaxially. Heating can be used in all these methods.
As a result of the drawing, the molecular chains or parts thereof are directed
increasingly to
the draw direction, wherein the strength and toughness of the material are
growing in the
draw direction. After the drawing, the drawn billet is cooled under stress to
room
temperature, and can be further shaped into various surgical implants or other
structures.
Suitable processes for further shaping include machining, stamping, turning,
milling,
shearing, compression molding and thermoforming.
Toughening of composite materials described in the invention can be also
attained, when
the final products of this invention are manufactured by injection molding
after which they
may also contain flow induced orientation of polymer chains. This will result
in more
ductile mechanical behavior as described in Example 3 and Figure 2 of the
invention.
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The composites of the invention can be treated also by using so called solvent
methods,
wherein at least a part of the polymer matrix material is dissolved or
dispersed into a
suitable solvent and/or mixed with additives, or softened by the solvent
and/or mixed with
additives, whereafter the formed dispersion or paste is compressed into a
suitably shaped
object using pressure and, optionally, heat. The dispersed or softened
composite and/or
polymer matrix material then functions as a glue to maintain the given shape
of the object,
from which the solvent can be removed, e.g., by evaporating.
After finishing, cleaning and drying, the surgical devices of the present
invention are ready
for transportation and use. Thus, they can be packed, and the packages sealed.
Since these
products are to be used in surgery, they are also required to be sterilized
before use.
The following non-limiting examples are intended to merely illustrate the
properties of
certain preferred embodiments of the invention.
Examples
Example 1
Various samples were prepared using the terpolymer 85 mol%L/5 mol%D/10 mol%G
and
from composites of said terpolymer and beta TCP. Mechanical properties of such
composites are shown in the following Table 1.
Table 1
Composition Sample Measured Strength
85L/5D/10G Diameter Draw Shear Strength
PLDGA beta-TCP (mm) ratio (Mpa) StDev
100 0 2.38 1 55.6 1.2
100 0 1.45 2.5 99.5 0.9
100 0 1.18 4.4 128.7 2.6
100 0 3.95 4.4 96.8 2.1
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18
78 22% 3.95 4.5 84.5 1.8
78 22 % 5.4 2.5 61.7 0.8
50 50 % 5.4 2.2 48.9 0.2
Example 2
A self-reinforced rod containing the terpolymer 85L/5D/10G PLDGA of Example 1
and 50
wt-% beta-TCP was subjected to manual bending in room temperature. This
composite
material of the invention could be shaped in room temperature without any
additional
equipment such a way without showing any signs of breaking or tearing (as
shown in
Figure 1).
Example 3
Injection molded composite samples composed of three different terpolymers
(85L/10D,L/5G PLDGA, 75L/20D,L/5G PLDGA and 85L/5D/10G PLDGA) and 22-50
wt-% TCP was subjected to manual bending. The material could be shaped in such
a way
without showing any signs of breaking or tearing (as shown in Figure 2). 22 wt-
% beta-
TCP containing specimens could be bent to sharp angle and 50 wt-% beta-TCP
containing
specimens could be bent to mellow angle without any signs of breakage. After
heating
above glass transition temperature the test samples shrank, which indicate
molecular
orientation relaxation.
Example 4
Various composites were prepared by means of self-reinforcement and they were
further
shaped into suture anchors. The terpolymer used was 85L/5D/10G PLDGA and it
was
mixed with 0 wt-%, 22 wt-% and 50 wt-% TCP. The eyelet strength and the
torsion yield
strength of the resulting composites are shown in Figures 3 and 4.
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Example 5
Various composites were prepared by means of injection molding into suture
anchors. The
terpolymers used were PLDGA, 75L/20D,L/5G PLDGA and 85L/5D/10G PLDGA and
was mixed with 22 wt-% and 50 wt-% beta-TCP. The eyelet strength and the
torsion yield
strength of the resulting composites are shown in Figures 5 and 6.
Example 6
A terpolymer of the invention (85L/5D/10G PLDGA) was self-reinforced (DR=4.5).
The
biodegradation (particularly the rate of biodegradation) of the formed
terpolymer structures
was monitored. The degradation study was made in 37 C in phosphate buffer
saline (PBS).
During the degradation the shear strength and inherent viscosity of the
structures was
measured at different points of time. These formed structures of the invention
showed
strength retention over 18 weeks without remarkable strength loss. Results of
shear
strength and inherent viscosity during the degradation are presented in Tables
2 and 3.
Example 7
A terpolymer of the invention (85L/5D/10G PLDGA) was mixed with 22% ceramic
(TCP)
and self-reinforced (DR=4.5) into composite structures.
The same tests were carried out as in Example 6. These composite structures of
the
invention showed strength retention over 16 weeks without grammatical strength
loss.
These composite structures of the invention showed strength retention over 16
weeks
without remarkable strength loss. Results of shear strength and inherent
viscosity during
the degradation are presented in Tables 2 and 3.
Example 8
A terpolymer of the invention (85L/5D/10G PLDGA) was mixed with 22 wt-%
ceramic
(TCP) and self-reinforced (DR=4.4) into composite structures.
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The same tests were carried out as in Examples 6 and 7. These composite
structures of the
invention showed strength retention over 20 weeks without grammatical strength
loss.
These composite structures of the invention showed strength retention over 20
weeks
5 without remarkable strength loss. Results of shear strength and inherent
viscosity during
the degradation are presented in Tables 2 and 3.
Example 9
10 A terpolymer of the invention (85L/5D/10G PLDGA) was mixed with 22 wt-%
ceramic
(TCP) and the resulting composite was self-reinforced (DR=2.5) into surgical
structures.
The same tests were carried out as in Examples 6-8.These composite structures
of the
invention showed strength retention over 18 weeks without remarkable strength
loss.
Example 10
A terpolymer of the invention (85L/5D/10G PLDGA) was mixed with 22% ceramic
(TCP)
and the resulting composite was self-reinforced (DR=2.5) into surgical
structures.
The same tests were carried out as in examples 6-9. These composite structures
of the
invention showed strength retention over 22 weeks without remarkable strength
loss.
Example 11
A terpolymer of the invention (85L/5D/10G PLDGA) was mixed with 50 wt-%
ceramic
(TCP) and the resulting composite was self-reinforced (DR=2.2) into surgical
structures.
The same tests were carried out as in examples 6-10. These composite
structures of the
invention showed strength retention over 20 weeks without remarkable strength
loss.
Example 12
A terpolymer of the invention (85L/10D,L/5G PLDGA) was mixed with 22 wt-%
ceramic
(TCP) and the resulting composite was injection molded into surgical
structures.
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21
The same tests were carried out as in examples 6-11. These composite
structures of the
invention showed strength retention over 6 weeks without remarkable strength
loss.
Example 13
A terpolymer of the invention (85L/10D,L/5G PLDGA) was mixed with 22 wt-%
ceramic
(TCP) and the resulting composite was injection molded into surgical
structures.
The same tests were carried out as in examples 6-12 .These composite
structures of the
invention showed strength retention over 6 weeks without remarkable strength
loss.
Example 14
A terpolymer of the invention (75L/20D,L/5G PLDGA) was mixed with 22 wt-%
ceramic
(TCP) and the resulting composite was injection molded into surgical
structures.
The same tests were carried out as in examples 6-13 .These composite
structures of the
invention showed strength retention over 6 weeks without remarkable strength
loss.
Example 15
A terpolymer of the invention (75L/20D,L/5G PLDGA) was mixed with 22 wt-%
ceramic
(TCP) and the resulting composite was injection molded into surgical
structures.
The same tests were carried out as in examples 6-14 .These composite
structures of the
invention showed strength retention over 6 weeks without remarkable strength
loss.
Example 16
A terpolymer composite of this invention will demonstrate total biodegradation
(i.e. total
mass loss) within 1.5-4 years biodegradation in physiological conditions
(Figure 7). The
total biodegradation time depends on terpolymers chemical structure, amount of
additive
material, type of additive, temperature, moisture, patient related factors,
etc.
Table 2. Shear strength of terpolymer composites during the degradation
process
r Material Processing 0 week 6 week 12 week 14 week 16
week 18 week 20 week 22 week
method Shear Shear Shear Shear
Shear Shear Shear Shear 0
Strength Strength Strength Strength
Strength Strength Strength Strength =
1--,
-a 5
INTPa % MP a % M:Pa % M.Pa ' % MPa % MPa % MPa % MPa %
vo
oo
.6.
oo
1--,
85115D/10G Self-reinforced, 94.7 1 100 95.8 .101.2 98.3
103,8 - - - - 74,3 78.5 - - - -
PLDGA Draw mtio 4.5
85115D/10G Self-reinforced. 84.4 100 -
- 70.4 83.4 - - 64.3 76.2 - - - - - -
PLDGA + 22% Draw ratio 4,5
beta-TCP
85Li5Dfl0G Self-reinforced. 88.5 100 - - 81.6 92.2 - - - - - - 74.6 84.2 - -
PLDGA + 22% Draw ratio 4.4
ln
beta-TCP
0
851.15D/10G Self reinforced 70.'7 100 - - 48.0 67.9 -
- - - 44.2 62.4 - - .. - iv
co
PLDGA + 22% Draw ratio 2.5
co
co
beta-TCP
co
85115D/10G Self-reinforced, 60.5 100 -
- 56.6 93.5 - - - - - - 52.6 87.0 51.1 84,4 n.) H
PLDGA +22% Draw ratio 2.5
iv
0
beta-TCP
H
FP
85115DilOG Self-reinforced. 52.2 100 - - 47.1 90.2 - - - - 45.4 87,0 43,1 82.6
0
PLDGA + SO% Draw ratio 2.2
0,
1
0
beta-TCP
0,
beta-TCP
851110D,L/5G Injection
42.4 100 40.9 96.5 - - - - - - - - - - - -
PLDGA + 22% molded
beta-TCP
_______________________________________________________________________________
_________________ __, IV
75L/20D,LI5G Injection 43.2 100 43.1 99.8 - - - .
- , - .. - - - - n
PLDGA +22% molded
1-3
beta-TCPF--t
_________________________________________________________________ -
_________________________________________________
75L/20D,U _ 5G Injection 44.2 100 44 99.5 - -
- - .. - . . - - . =
1--,
PLDGA + 22% molded
iµ.)
beta-TCP
u ,
w
oo
oo
o
t..)
Table 3. Inherent viscosity of terpolymer composites during the degradation
process .
materiai PrOCeSSing .0 Week 6 week 12 week 16
week 18 week
method Inherent Inherent Inherent
Inherent Inherent oe
.6.
oe
Viscosity Viscosity Viscosity
Viscosity Viscosity 1--,
dlig % tilfg % (Dig % Wig % (Dig %
851.15D/10G PLDG A Self-reinforced, 1,26 100
1,03 81.7 0,52 41,3
Draw ratio 4.5
8.51.150/10G PLDGA + Self-reinforced. 1.36 100 - -
0.87 64.0 0,81 59.6 - -
22% beta-1'CP Draw ratio 4.5
õ
8Lì5 /10G PLDGA Self-reinforced, 2.66 100 ¨ 1.87
70.3 - - - r)
22% beta-TCP Draw Julio 4.4
0
I.)
co
851.15D/110G PLDGA + Self-reinforced, 1,35 100 - -
0.88 65.2
co
22% beta-TCP Draw ratio 2,5
Ui
k,j
0
W H
85Lí /10G PLDGA + Self-reinforced. 2.72 100 __ - L- 1:76
64.7 - -
22% beta-TCP Draw ratio 2.5
i 0
H
FP
-------------------------------------------------------------------- -,----
.. ---.4,. _______________________ 1
85115D/10G PLDGA 4- Self-reinforced, 2.65 100 - - 1.64
61.9 -
50% beta-TCP Draw ratio 2.2
1 (5)
1
0
(5)
851110D,U5G PLDGA Injection molded 1,84 100 1.51 82,0 _ -
- -
22% beta-TCP
_______________________________________________________________________________
_________________ -I-- --4
_
851-,/10D.L/5G PLDGA Injection molded 3.88 100 3.99
102,8 _ . _ _ -
+ 22% beta-TCP ,
75L/20D,115G PLDGA Injection molded -4 1 83 100 1,63
89.1 - _ -
22% beta-TCP
n
7.5L/20D,115G PLDGA Injection molded 3.69 100 [3-.36 91,1
___________ _ __________ i
F¨t
+ 22% beta-TCP
=
=
_______________________________________________________________________________
____________________________
t.,
-a
u,
t..,
oe
oe
