Note: Descriptions are shown in the official language in which they were submitted.
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BACKGROUND OF THE INV_NTION
Field of the Invention
This inventl.on relates to synthetic absorbable
sutures, and more particularly, to synthetic absorbable
sutures comprising extruded and oriented filaments of
copolymers of polyoxalates having isomorphic sequences.
Description of Prior Art
Absorbable suture materials have traditionally
been natural collagenous materials obtained from sheep or
beef intestine, commonly known as catgut. More recently,
it has been proposed to manufacture synthetic absorbable
sutures from polyesters of hydroxycarboxylic acids, notably
polylactide, polyglycolide, and copolymers of lactide and
glycolide. Such synthetic absorbable sutures are described
in USP 3,636,956 3,297,033 and elsewhere in the literature.
Polyesters of succinic acid have also been suggested for
at least partially bioresorbable surgical articles as
disclosed for example in USP 3,883,901.
Among the requirements of an ideal absorbable
suture are that it should have good handling properties,
should approximate and hold tissue for proper healing with
minimal tearing and tissue damage, should have adequate
straight tensile and knot strength, should be controllably
uniform in properties including dimensional stability within
the body, should be sterilizable, should be absorbable by
living tissue, preferably at a constant rate regardless of
the place in the body or the condition of the patient and
without causing such unfavorable tissue reactions as walling
off, granuloma formation or excessive edema, and finally
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should be capable of being properly and easily tied into
surgical knots.
While multifilament sutures manufactured from
polymers of lactide and glycolide fulfill the above require-
ments to a large degree, monofilament sutures of these
materials are considerably less flexible than catgut and
these synthetic sutures are accordingly generally limited
to a multifilament, braided construction. Sutures of gly-
colide polymers are also not suitable for sterilization by
radiation without suffering severe- degradation of physical
properties.
We have discovered that copolyoxalate copolymers
having isomorphic sequences can be melt extruded into pliable,
monofilament fibers which have good in vivo strength reten-
tion and are absorbed in animal tissue without significant
adverse tissue reaction. The fibers have good tensile and
knot strength, and can be sterilized by gamma radiation
without serious loss of these properties. In addition,
monofilament sutures of the polymers of the present invention
have a high degree of softness and flexibility not fou~d in
many synthetic absorbable sutures of the prior art.
The preparation of polyoxalate polymers is de-
scribed in the art. Carothers et al, J. Amer. Chem. Soc.
52, 3292 (1930) for example, describes the ester interchange
reaction of diols such as ethylene glycol, 1,3-propanediol,
or 1,4-butanediol with diethyl oxalate to yield a mixture
of monomer, soluble polymer and insoluble polymer. The
reaction of oxalic acid and an alkylene glycol to form
polyester resins is described in U.S. 2,111,762, while the
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preparation of polyesters of fiber-forming quality from
dicarboxylic acids and diols is described in U.S. 2,071,250-1
and 2,952,652. Isomorphic polymers including polyester
copolymers have been discussed in the literature(l). The
particular isomorphic copolyoxalates of the present inven-
tion however, have not previously been known, nor has their
preparation or use as synthetic absorbable sutures been
suggested heretofore.
It is accordingly an object of the present inven-
tion to provide new and useful polyme~sof isomorphic co-
polyoxalates and articles made therefrom. A further object
of this invention is to provide synthetic absorbable sutures
of isomorphic copolyoxalates. It is a yet further object
of this invention to provide surgical aids and prostheses
fabricated of fibers or cast or machined from blocks of
isomorphic copolyoxalate polymers.
SUMMARY
Highly crystalline isomorphic polyoxalate polymers are
prepared by reacting mixtures of cyclic and linear diols with
dialkyl oxaiate, preferably in the presence of an inorganic or
organometallic catalyst. The diols comprising the reaction mixture
have the ~ame carbon chain length separation between terminal
OH groups of 6 or 8 carbon atoms. The cyclic diol may be trans
1,4-cyclohexane dialkanol or p-phenylene dialkanol and comprises
(1) Isomorphism in Synthetic Macromolecular Systems,
. Allegra and I. W. Bassi, Adv. Polymer Sci.
6, 549 (1969)
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from about 5 to 95 mol percent, and preferably from 40
to 75 mol percent of the total diol reactant.
Copolymers prepared by the transesterification
reaction of the two diols and diethyl oxalate are melt
extruded into highly crystalline filaments suitable for use as
synthetic absorbable sutures. Drawn and oriented filaments
are characteri~ed by high tensile and knot strength, a Young's
modulus in most cases of less than about 600,000 psi
providing a high order of filament softness and flexibility,
and good strength retention and minimal tissue reaction in vivo.
DESCRIPTION OF DRAWINGS
FIGURE 1 is a perspective view of a needle-
suture combination;
FIGURE 2 is a perspective view of a needle-
suture combination within a hermetically sealed container;
FIGURE 3 illustrates a screw machined from the
polymer of the present invention;
FIGURE 4 is a cross-sectional view of a composite
yarn containing filaments of different composition and;
FIGURE 5 is a plan view of a surgical fabric
knitted from fibers of the present invention.
DESCRIPTIO~ OF PREFERRED EMBODIMENTS
Polymers of the present invention are comprised
of isomorphic units of cyclic and linear oxalates and have
the general formula
r O O- I
t - R - O - C - C- ~x
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wherein ea^h R is
(CH2)n - A ~ (CH2)n
or
- (CH2) -
4+2n II
with from about 5 to 95 mol percent, and preferably from
about 40 to 75 mol percent of R groups being I; A is trans
1,4-cyclohexylene or p-phenylene, n is 1 or 2 and is the
same for I and II, and x is the degree of polymerization
resulting in a fiber forming polymer having a molecular
LO weight greater than about 10,000.
Polymers of the present invention are conveni-
ently prepared by an ester interchan~e reaction between
the afore-described mixture of diols and a lower ester of
oxalic acid, preferably in the presence of an ester interchange
L5 catalyst. The preferred ester of oxalic acid is diethyl oxalate.
The ester interchange is most preferably conducted in two stages
wherein the reactants are first heated with stirring under
a nitrogen atmosphere to form a prepolymer with the removal
of ethanol, followed by postpolymerization under heat and
reduced pressure to obtain a final polymer of the desired
molecular weight and fiber forming quality. Polymers with
low or moderate degrees of polymerization are postpolymerized
in the li~uid state or as finely-divided solid particles,
depending on their melting temperature range.
~5 The polymer is melt extruded through a spinner-
ette in a conventional manner to form one or more filaments
which are subsequently drawn about 4X to 6X in order to
achieve molecular orientation and improve tensile properties
The resultin~ oriented filaments have good tensile and dry
knot strength and good in vivo strength retention.
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It is well documented that the crystallinity
and hence suitability for fiber-formation in both
the AB and AA-BB type polyesters decreases significantly
when the mol fraction of the major comonomer sequence
decreases below about 80%. In some instances, if the
comonomer sequences are isomorphic, chains composed of
slightly less than 80% of the major sequences can pack into
a crystalline form. However, randomly constructed copolyester
chains based on almost equal amounts of the isomorphic
comonomer sequences are generally found to be non-crystalline
and poor fiber formers. Contrary to this general rule,
the isomorphic copolyesters of the present invention
display an unexpectedly high level of crystallinity of about
45% in a 50/50 copolyester. The polymers of the present
invention are also unusual in that all copolymers through the
entire composition range of from 5 to 95% of each isomorphic
comonomer demonstrate levels of crystallinity comparable to
those encountered in the parent homopolymers; namely between
30 and 50% depending on the thermal history. A similarly
striking observation characteristic of these copolyesters is
their display of melting endotherms, as shown by DSC,
for the crystalline regions of all copolymers within the
composition range of from about 5 and 95 mol % of each
isomorphic comonomer. Constructed curves of the melting
temperature versus composition did not reveal any positive
eutectic composition in these systems. The X-ray and DSC
data suggest strongly the uncommon presence of almost complete
isomorphism in the copolyesters of the present invention.
Dimensional stability and tensile strength retention
of the oriented filaments may be enhanced by subjecting the
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filaments to an annealing treatment. This optional
treatment consists of heating the drawn filaments to a
temperature of from about 40 to 130~C, most preferably from
about 60 to 110C while restraining the filaments to prevent
any substantial shrinkage. The filaments are held at the
annealing temperature for a few seconds to several days or
longer depending on the temperature and processing conditions.
In general, annealing at 60 to 110C for up to about 24 hours
is satisfactory for the polymers of the present invention.
Optimum annealing time and temperature for maximum fiber
in vivo strength retention and dimensional stability is
readily determined by simple experimentation for each fiber
compositi.on.
Filaments of the present invention may be used
as sutures in either 2 monofilament or a multifilament
construction. Multifilament sutures are preferably
braided but may also be twisted or covered in accordance
with common practice. For use as sutures, it is
necessary that the fibers be sterile, and sterilization
may be accomplished by exposing the fibers to Cobalt 60
gamma radiation or to ethylene oxide. Such sterilization
techniques are well known and commonly practiced in
suture manufacture.
Since the function of a suture is to join and
hold severed tissue until healing is well along, and to
prevent wound separation as a result of movement or exercise,
a suture must meet certain minimum standards of strength. It
is particularly important that strength be maintained when
knots are tied and during the actual procedure of drawing
tight a suitable knot. Sutures prepared from oriented
filaments of the present invention are characterized by a
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straight tensile strength of at least about 30,000 psi and
a knot strength of at least about 20,000 psi, altho~gh
significantly higher strengths may be obtained
The prepara~ion of high molecular weight
oriented filaments of isomorphic polyoxalates is further
illustrated by the following examples where all percentages
are on a molar basis unless otherwise noted. The following
analytical methods were used to obtain the data reported
in the examples. Inherent viscosity (~inh) was obtained on
polymer solutions (1 gram/liter) in chloroform or hexa-
fluoro-2-propanol (HFIP). The infrared spectra of polymer
films (cast from CHC13 or HFIP) were recorded on a Beckman
Acculab 1 spectrophotometer. The NMR spectra of the
polymer solutions in CHC13 were recorded on an MX-100 or
CFT-20 spectrophotometer. A DuPont 990 DSC apparatus was used
to record the glass transition (Tg), crystallization (Tc)
and melting (Tm~ temperatures of the polymers under nitrogen,
using about 5 mg samples and a heating rate of 10C/min. or as
otherwise specified. The thermogravimetric analysis (TGA)
data of the polymers were recorded under nitrogen using a
DuPont 950 TGA apparatus and a heating rate of 10 or 20C/min.
B with about 10 mg samples. A Philips vertical goniometer with
graphite crystal monochromatized copper K~ radiation was
used to obtain the X-ray powder and fiber diffraction
patterns of the polymers. Crystallinity was determined by
the method of Hermans and Weidinger and the diffractometer
patterns were resolved with a DuPont 310 curve analyzer.
In vitro hydrolysis of polymer discs (about
1.2 g, 2.2 cm diameter) and monofilaments (7-25 mil) was
conducted at 37C in phosphate buffer comprising a solution
of 27.6 g sodium dihydrogenphosphate monohydrate in 1000 ml
~ T~e~ k
g
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water adjusted to pH 7.25 with sodium hydroxide.
In vivo absorption (muscle) was determined by
implanting two 2 cm segments of monofilament fiber into the
left gluteal muscles of female Long Evans rats. The im-
plant sites were recovered after periods of 60, 90,
120 and 180 days and examined microscopically to determine
the extent of absorption. In vivo absorption (subcutaneous)
is a non-histological technique in which continuous ob-
servation of the biological degradation of segments of
suture is made by implanting two segments of suture, 2 cm
long, into the abdominal subcutis of young female rats.
The implants are readily visible when the skin is wetted
with propylene glycol and extent of absorption can be
determined by subjective visual examination.
In vivo strength retention was determined by
implanting segments of sutures in the posterior dorsal sub-
cutis of female Long Evans rats for period of 5 to 30 days.
The sutures were recovered at the designated periods and
pull-tested for straight tensile strength.
In vitro strength retention was determined by placing
segments of sutures in the afore-defined buffer at 50C for
periods of 2 to 4 days. The sutures were recovered at the
designated periods and pull-tested for straight tensil~ strength.
EXAMPLES
General Polymerization Procedure
Diethyl oxalate was heated with selected diols
in a mechanically-stirred reactor using a stannous alkanoate
or organic titanate catalyst. The reaction was conducted
under a nitrogen atmosphere at suitable temperatures until
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a substantial portion of the calculated amount of ethanol
was obtained. Postpolymerization of the resulting prepolymer
was then continued under reduced pressure using a suitable
heating scheme. At the end of the postpolymerization period,
the molten polymer was allowed to cool slowly at room
temperature, isolated, ground and dried at 25C to 80C
(depending on the ~mer Tm) in vacuo for at least one day.
Alternatively, the prepolymer can be postpolymerized
partially in the liquid state, cooled, and then post-
polymerized further in the solid state as finely divided
particles. Detailed experimental conditions for the
preparation of representative samples of isomorphic poly-
oxalates and important properties of the resulting polymers
are presented below.
EXAMPLE I
95/5 Poly (trans 1 4-CyclohexYlenedicarbiny~
co-hexamethylene Oxalate): Distilled diethyl oxalate
(19.0 g, 0.130 mol), recrystallized trans 1,4-cyclohexanedi-
methanol (19.8 g, 0.137 mol), 1,6-hexadiol (0.856 g,
0,00724 moli and stannous octoate (0.33 M in toluene;
0.080 ml, 0.026 mmol) were added under dry and oxygen-
free conditions to a glass reactor equipped for magnetic
stirring. The prepolymer was formed by heating the mixture
at 120C for 3 hours under nitrogen at 1 atmosphere while
allowing the formed ethanol to distill, followed by heating
at 160C for 2 hours. The prepolymer was then heated in vacuo
(0.05 mm Hg) at 220C for 1 hour, and the postpolymerization
completed by heating at 215C for an additional 6 hours. The
polymer was thenallowed to cool to room temperature, isolated
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and ground, and finally dried in vacuo at room temperature.
Polymer Characteriæation:
inh in CHC13 = 0.50
DSC (20C/min.): Tm = 210C
Polymer Melt-Spinning: Th~ polymer was spun using an In-
stron Rheometer with a 30 mil die at 207C.
In Vitro Evaluation: The undrawn fibers lost 21 and 66
percent of their initial mass after immersion in phosphate
buffer at 37C for 42 and 127 days, respectively.
EX~PLE II
85/15 Poly (1,4-CyclohexylenedicarbinYl-co-
hexamethylene Oxalate): Distilled diethyl oxalate (58.4 g,
0.400 mols), recrystallized trans 1,4-cyclohexanedimethanol (less
than 1% cis isomer; 53.9 g, 0.374 mols), 1,6-hexanediol
(7.8 g, 0.066 mol), and stannous octoate (0.33M in toluene;
0.40 ml, 0.13 mmol) were added under dry and oxygen-free
conditions to a glass reactor equipped for mechanical stir-
ring. The mixture was heated at 120 and 150C for 2 and 3
hours, respectively, under nitrogen at one atmosphere while
the formed ethanol distilled. The prepolymer was allowed
to cool, then reheated to 200C under reduced pressure
(0.1 mm Hg). Temperatures of 200, 220 and 230C were
maintained for 2, 3 and 4 hours while the collection of
distillates continued. The resulting polymer ~ inh in
CHC13 = O.49) was cooled, isolated, ground (2 mm screen
size), and then dried in vacuo at room temperature. Portions
(30 g) of this ground polymer were postpolymerized in the
solid state in glass reactors equipped for magnetic stir-
ring by heating in vacuo (0.1 mm Hg) at 185C for 22 hours.
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Polymer-Characteri7ation:
~inh in CHC13 = 1.14
DSC (20C/min.): Tm = 187C
Polymer Melt-Spinning: The polymer was spun at 230C using
an Instron Rheometer with a 40 mil die. The fiber was
quenched in ice water, wound, dried and subsequently drawn.
Fiber Properties: Fibers drawn 5X in two stages, 4X at 62C
followed by 1.25X at 119C exhibited the following properties:
diameter = 8.5 mils, straight tensile strength = 8.39 x 104
psi; knot tensile strength = 5.06 x 104 psi; modulus = 6.61 x
10 psi; elongation = 15%.
In Vivo Evaluation: Sterilized (via ~-radiation, 2.5 Mrads),
drawn monofilament (8.5 mils) retained 89, 75, 10 and zero
percent of its initial breaking strength (4.8 lbs.) after
subcutaneous implantation in rat muscle for 3, 7, 14 and 21
days respectively. Drawn filaments implanted into the gluteal
muscles of rats elicited median tissue responses in the slight
range throughout a 180 day post-implantation period. Filaments
drawn 4X at 60C followed by 1.25X at 110C and having a straight
tensile of 6.76 x 104 psi showed indications of initial degradation
20 to 26 weeks after implantation.
In Vitro Evaluation: Fibers drawn 4X at 60C (exhibiting
a straight tensile of 4.33 x 104 psi) lost 40 percent of their
initial mass after immersion in phosphate buffer at 37C
for 84 days.
EXAMPLE III
80/20 Poly (1,4-Cyclohexylenedicarbinyl-co-
hexamethylene Oxalate): Distilled diethyl oxalate ~43.8 g,
0.300 mol), recrystallized trans 1,4-cyclohexanedimethanol (cis
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1~2~6~0
isomer content = 1.0%, 36.3 g, 0.252 mol), 1.6-hexanediol
(7.4 g, 0.063 mol), and stannous oxalate (12.4 mg., 0.060
mmol) were added under dry and oxygen-free conditions to a
glass reactor equipped for mechanical stirring. The pre-
polymer was formed by heating the mixture at 120C for 2
hours under nitrogen at 1 atmosphere while allowing the
formed ethanol to distill, followed by 160C for 2.5 hours.
The mixture was allowed to cool, then reheated in vacuo
(0.1 mm Hg) to 140C and maintained until the prepolymer
melted. The temperature was then increased to 190C, main-
tained for 30 minutes, then raised to 200C for 1.5 hours.
The melt post-polymerization of the stirred polymer was
completed by heating at 220C for 4.5 hours. The polymer
was cooled, isolated, ground (screen size = 2 mm) and dried
in vacuo at room temperature. To obtain the final product,
the ground polymer was post-polymerized in the solid state
in a glass reactor equipped for magnetic stirring by heating
at 180C in vacuo (0.05 mm Hg) for 24 hours while allowing
the formed diols to distill.
Polymer Characterization:
inh in CHC13 = 1.33
DSC (20C/min.): Tm = 205C
Polymer Melt-Spinning: The polymer was spun at 240C using
an Instron Rheometer equipped with a 40 mil die. The extruded
filaments were quenched in ice water, wound, then dried
at room temperature in vacuo, and subsequently drawn 4X.
Fiber Properties: Diameter = 9.0 mils; straight tensile
strength = 7.31 x 104 psi; knot tensile strength = 3.46 x-104
psi; modulus = 7.7 x 105 psi; elongation = 15%.
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In Vivo Evaluation: Sterilized (by ~-radiation, 2.5 Mrads),
fibers (9.0 mil) retained 85, 20 and zero percent of their
initial breaking strength (4.2 lbs.) after subcutaneous
implantation in rat muscles for 3, 7 and 14 days, respectively.
These fibers were also implanted into the gluteal muscles of
rats to determine tissue response and absorption characteristics.
The median tissue response elicited by the samples was in the
slight range after 5 days post implantation and in the minimal
range after 42 days; absorption of the samples was first noted
at 120 days and by 180 days approximately fifty percent of
the material had been absorbed.
EX~'IPLE IV
80/20 Poly (1,4-Cyclohexylenedicarbinyl-co-
.
hexameth~lene Oxalate): Distilled diethyl oxalate (23.4 g,
0.160 mol), recrystallized trans 1,4-cyclohèxanedimethanol
(cis isomer content = 6.3%; 20.0 g, 0.139 mol), 1,6-
hexanediol (4.1 g, 0.035 mol) and Tyzor OG* (0.117M in
toluene, 0.28 ml, 0.033 mmols) were added under dry and
oxygen-free conditions to a glass reactor equipped for
magnetic stirring. A prepolymer was formed by heating the
mixture at 120C for 19 hours under nitrogen at 1 atmosphere
while allowing the formed ethanol to distill. The pressure
was then reduced (0.05 mm Hg) and heating at 120C continued
for 30 minutes longer. The temperature was then increased
and maintained at 180C, 190C and 200C for 2, 5 and 2
hours, respectively, while removing excess and formed diols
The polymer was allowed to cool, isolated, ground, and dried
in vacuo at room temperature.
3 r ~r~c~e wla~k ~`o~--
B *Tyzor OG,~a titanium glycolate catalyst manufactured by
E. I. DuPont de Nemours and Co., Wilmington, Delaware, 19898
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Polymer Characterization:
inh in CHC13 - 0.46
DSC (10C/min.): Tm = 171C
TGA (10C/min. under N2): 0.25% weight lost at 275C
Polymer Melt-Spinning: The polymer was spun using an Instron
Rheometer with a 30 mil die at 172C. The extruded filaments
were quenched in ice water, dried in vacuo at room temperature,
and finally drawn 5X at 43C.
Fiber Properties:
~inh in CHC13 = 0.42
X-ray: Major reflections correspond to 8.9 (W), 4.84 (M),
4.41 (S) and 3.42A (W) d-spacings; 26% crystallinity.
(Undrawn filaments were found to be 22% crystalline
which increased to 31% by annealing at 70C for one hour).
Physical Properties: Diameter = 11.1 mils; straight tensile
strength = 2.07 x 104 psi; elongation = 35%.
In Vivo Evaluation: The rate of absorption and tissue response
of drawn filaments was determined by implantation into the
ventral abdominal subcutis of Long-Evans rats. Some evidence
of filament degradation was noted 11 to 14 weeks after implant-
ation, with the bulk of the fiber being absorbed by 20 to
23 weeks. No tissue reaction to the implants was noted at any
period.
In Vitro Evaluation: The drawn fibers exhibited a 43% decrease
in mass after immersion in the phosphate buffer at 37C for
28 days.
EXAMPLE V
67/33 Poly(trans 1,4-cyclohexylenedicarbinyl-co-
hexamethylene Oxalate): Distilled diethyl oxalate (40.0 g,
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0.274 mol). recrystallized trans 1,4-cyclohexanedimethanol
(25.9 g, 0.180 mol), 1,6-hexanediol (10.6 g, 0.0897 mol),
and stannous octoate (0.33 M in toluene; 0.16 ml. 0.053
mmol) was added to a glass reactor equipped for mechanical
stirring. The prepolymer was formed by heating the mixture under
nitrogen at 120C for 9 hours, followed by 125C for 9 hours
while collecting the distillates. The prepolymer was cooled,
then reheated in vacuo (O.Oq mm Hg) and maintained at
80, 120, 150, 170 and 180C for 1, 2, 2, 3 and 1.5 hours,
respectively. The postpolymerization of the polymer
melt was completed by heating at 195C for 6 hours while
continuing to stir and remove distillates. The polymer was
cooled, isolated, ground, and then dried at room temperature.
Polymer Characterization:
~ inh in CHC13 = 0.49
DSC (20C/min.): Tm = 179C
Polymer Melt Spinning: The polymer was spun at 175C using
an Instron Rheometer with a 30 mil die. The resulting fibers
were subsequently drawn 4X at 50C.
Fiber Properties: Diameter = 9.3 mils, straight tensile
stength = 2.65 x 104 psi, knot tensile strength = 2.21 x 104
psi, modulus = 3.7 x 10 psi.
In Vivo Evaluation, Tissue Reaction: Two centimeter long
samples of sterilized (by y-radiation, 2.5 Mrads) drawn
fiber were implanted subcutaneously in the abdominal wall
of young female Long Evans strain rats. At intervals of 3,
14, 28, 56 and 90 days, two rats were sacrificed for examination
of implants. The skin containing the fibers was excised
and affixed to plastic sheets for preservation in formalin.
Two tissue blocks were cut transversely from each site
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and embedded in paraffin for histologic preparation.
Eight stained samples were examined at each interval for
tissue reaction to the fibers. Only mild foreign body re-
actions were detected.
In Vivo Evaluation, Absorption: Fiber segments sterilized by
~-radiation (2.5 Mrads) approximately 2 cm in length were
inserted into the ventral abdominal subcutis of Long Evans
rats (100 g, female) to determine the ra~e of absorption of
the drawn fibers. One to two rats were sacrificed after various
periods after implantation. The skin containing the implant
sites was removed and dried. These preparations were examined
and evaluated using both dissecting and transmission microscopes.
Estimates of the amount of implant remaining were based on the
length of the segment or fragments remaining and the de-
crease in the surface area made by palpating the implant in
the dried hide and comparing it with a one week old prepara-
tion. Implants were fragmented at one week; migration and
clumping of fragments was noted at subsequent kill periods.
Evidence of degradation was first seen 16 weeks after im-
plantation. Palpable fragments, in diminishing amounts,
were present until 30 weeks. Quantitatively, about 100, 75, 45,
40, 20, 15 and 5 or less percent of the suture remained after
14, 16, 20, 23, 26, 30 and 36 weeks.
EX~PLE VI
50/50 Poly (trans 1,4-cyclohexyldicarbinyl-co-
hexameth~lene Oxalate): Distilled diethyl oxalate (38.0 g,
0.260 mol), recrystallized trans 1,4-cyclohexanedimethanol
(20.2 g, 0.140 mol), 1,6-hexanediol (16.5 g, 0.140 mol),
and stannous octoate (0.33 M in toluene, 0.16 ml, 0.053
mmol) were added under dry and oxygen-free conditions to a
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mechanically stirred glass reactor. Under nitrogen at one
atmosphere, the mixture was heated to and maintained at 120C
for 20 hours, while allowing the formed ethanol to distill.
The prepolymer was cooled and then reheated in vacuo
(0.05 mm Hg~ to and maintained at 80, 120, 140, 165, 175, 185,
and 195C for 1, 1, 3, 3.5, 2, 1 and 1 hour respectively.
The removal of the diols was continued by heating at 200C
for 8 hours to complete the postpolymerization. The polymer
was cooled, isolated, ground, and then dried in vacuo at
room temperature.
Polymer Characterization:
inh in CHC13 = 0.36
DSC (20C/min.): Tm = 138C
Polymer Melt Spinning: The polymer was spun at 136C using
an Instron Rheometer (40 mil die) and was immediately drawn
5X at 53C.
Fiber Properties:
X-ray Data: Major reflections correspond to 8.9 (W),
4.84 (M), 4.41 (S), and 5.40 A (W) d-spacings;
36% crystallinity.
Physical Properties: Diameter = 10.6 mils, straight
tensile strength = 1.36 x 104 psi, knot tensile strength -
1.13 x 104 psi, modulus = 1.33 x 105 psi, elongation =
- 27%.
In Vivo Evaluation: Sterilized (by ~-radiation) drawn fiber
segments (2 centimeters in length) were implanted into the
ventral abdominal subcutis for study of the rate of absorption
and tissue reaction.
At one week the implants were fragmented, clumping, and
migrating, with the bulk of the suture being absorbed between
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6 to 11 weeks. Thereafter, fragments with scattered
birefringent particles or birefringent particles in a shell-
like outline were observed. The birefringent particles de-
creased in amount until at 36 wee~s only a few widely
scattered particles were noted.
Only mild foreign body reactions were observed to be
elicited by the sterilized drawn fiber segments during the
test intervals of 3, 14, 28, 48, ~0 and 180 day post im-
plantation.
In Vitro Evaluation: Undrawn fibers exhibited a 57 percent
decrease in their initial mass after immersion in phosphate
buffer at 37C for 28 days.
EXAM~LE VII
50/50 Poly Strans 1,4-cyclohexyldicarbinyl-co-
hexamethylene Oxalate): Distilled diethyl oxalate (58.5 g,
0.400 mol), recrystallized trans 1,4-cyclohexanedimethanol
(cis isomer conten~ = 0.7%; 29.7 g, 0.206 mol), 1,6-hexanediol
(24.3 g, 0.206 mol), and stannous oxalate (16.5 mg, 0.080 mmols),
were added under dry and oxygen-free conditions to a
mechanically stirred glass reactor. The mixture was heated
under nitrogen at one atmosphere to and maintained at
120 and 160C for 3 and 2 hours respectively while allowing
the formed ethanol to distill. The prepolymer was cooled
and then reheated in vacuo (0.05 mm Xg) and maintained
at 170, 190 and 205C for 3, 2.5 and 3 hours respectively
while continuing to remove excess and formed diol to
complete the postpolymerization. The polymer was cooled,
isolated, ground, and then dried in vacuo at room temperature.
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ETH-423
112~)1640
Polymer Characterization:
~inh in HFlP = 1.07
DSC (20C/min.) Tm = 132C
Polymer Melt Spinning: The polymer was spun at 150C
j using an Instron Rheometer (40 mil die) and was drawn
4X at 50C followed by 1.5X at 72C.
Fiber Properties:
X-raY Data: Major reflections correspond to 9.11 (MS),
4.82 (S), 4.60 (W), 4.37 (S) and 3.45 A (W) d-spacings;
0 46% crystallinity.
Physical Properties: Diameter = 7.6
straight tensile strength = 51,300 psi, knot
tensile strength = 36.400 psi, elongation = 31%.
EXAMPLE VIII
30/70 Poly (trans 1,4-c~clohexylenedicarbinyl-co-
hexamethylene Oxalate):Distilled diethyl oxalate (36.5 g,
0.250 mol), recrystallized trans 1,4-cyclohexanedimethanol
(11.5 g, 0.0797 mol), 1,6 hexanediol (22.4 g, 0.190 mol),
0 and stannous octoate (0.33 M in toluene; 0.16 ml, 0.053
mmol) were added under dry and oxygen-free conditions to a
mechanically stirred reactor. The mixture was heated to
and maintained at 125, 140 and 160C for 2, 2 and 1 hour,
respectively, under nitrogen at one atmosphere while
allowing the formed ethanol to distill. The prepolymer was
cooled and then reheated in vacuo (0.1 mm Hg) and
maintained at 150 and 185C for 16 and 3 hours, respectively.
The postpolymerization was completed by maintaining the polymer
at 200C for 5.5 hours while continuing to remove the diols under
,0 vacuum. The polymer was then cooled, isolated, ground and
dried in vacuo at room temperature.
- 21 -
~ 640 ETH-423
Polymer Characterization:
inh in CHC13 = 0.82
DSC (20C/min): Tm = 85C
Polymer Melt Spinning: The polymer was spun at 125C using
B an Instron Rheometer with a 40 mil die. The fiber was
ql1enched in ice water, wound, dried in vacuo at room tempera-
ture, and subsequently drawn 5.6~ at room temperature, fol-
lowed by annealing at 55C.
Fiber Properties: Diameter 8.3 mils, straight tensile
strength 5.18 x 104 psi, knot tensile strength 3.51 x 104 psi,
modulus 2.11 x 105 and elongation 50%.
In Vivo Evaluation: Sterilized (by ~-radiation, 2.5 Mrads),
drawn fibers (9.8 mil diameter; 3.64 x 104 psi straight
tensile strength; 2.34 x 104 psi knot tensile strength;
1.47 x 105 psi modulus; and an elongation of 45%) were im-
planted into the gluteal muscles of rats to determine their
absorption and tissue response characteristics at 5, 21, 42
and 150 days post implantation.
At the 42 day period, there was no evidence of
any morphologic changes o the implant sites indicating ab-
sorption. At the 150 day period, the fibers had a median
value of 2 percent suture cross sectional area remaining (with
a range of 0 to 20 percent).
Foreign body tissue responses to the samples were
in the slight range at 5, 21 and 42 day periods and in the
minimal range at the 150 day period.
In Vitro Evaluation: Drawn fibers possessing physical pro-
perties similar to those of fibers used in the in vivo
testing exhibited a 100% decrease in their initial mass
after 141 days of immersion in phosphate buffer at 37C.
~ r~ L~k
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ETH-423
EXAMPLE IX
5/95 Poly (trans 1,4-cyclohexylenedicarbinyl-co-
hexamethylene Oxalate): Distilled dlethyl oxalate (19.0 g,
0.130 mol), recrystallized trans 1,4-cyclohexanedimethanol
(1.0 g, 0.0069 mol), 1,6-hexanediol (16.3 g, 0.138 mol),
and stannous octoate (0.33 M in toluene; 0.08 ml, 0.026 mmol)
were added under dry and oxygen-free conditions to a glass
reactor equipped for magnetic stirring. The prepolymer was
formed by heating the mixture at 120C for 3 hours under
nitrogen at one atmosphere while allowing the formed ethanol
to distill, followed by 160C for 2 hours. The prepolymer
was heated and maintained at 205C for 8 hours in vacuo
(0.05 mm Hg). The polymer was then cooled, isolated, ground,
and dried at room temperature.
Polymer Characterization:
~linh in CHC13 = O.88
DSC (20C/min): Tm = 69C
TGA (20C/min. under N2): Less than 0.5% weight loss at
275C was recorded.
Polymer Melt Spinning: The polymer was spun in an Instron
Rheometer using 30 mil die at 85C. The fibers were quenched
in ice water and subsequently drawn 5X at room temperature.
Fiber Properties: Diameter = 14.7 mils, straight tensile
strength = 1.36 x 104 psi, knot tensile strength = 1.41 x
104 psi, modulus = 4.8 x 104 psi, elongation = 90%.
In Vitro Evaluation: The drawn fibers exhibited a 93 percent
decrease in their initial mass after immersion in phosphate
buffer at 37C for 42 days.
ETH-423
6~(~
EXAMPLE X
58/42 Poly (1,4-phenylenedicarbinyl-co-hexamethylene
Oxalate): Diethyl oxalate (14.6 g, 0.100 mols), recrystal-
lized 1,4-benæenedimethanol (6.9 g, 0.050 mols), 1,6-
hexanediol (8.3 g, 0.070 mols), and Tyzor TOT* catalyst
(0.4 ml of a 1% solution) were added under dry and oxygen-free
conditions to a glass reactor equipped for stirring. The
prepolymer was formed by heating under nitrogen at one
atmosphere at 140C for 4 hours while allowing the formed
ethanol to distill. The mixture was then heated in vacuo
(0.1 mm Hg) at 165C for 22 hours while continuing to remove
distillates. A postpolymerization was conducted at 180, 190,
and 200C for 2, 1 and 4 hours respectively. The polymer
was cooled, ground and dried.
Polymer Characterization:
~inh in HFlP = 0.48
DSC (10C/min): Tm = 170C
TGA (10C/min in N2): Less than 1% cummulative weight loss
experienced at 250C.
Polymer Melt Spinning: The polymer was spun at 166C using
an Instron Rheometer equipped with a 30 mil die.
In Vitro Evaluation: Immersion of a molded disc, 2.2 cm in
diameter, for 8 and 78 days in phosphate buffer at 37C
resulted in a loss of 3 and 99 percent of the
initial mass, respectively.
*Tyzor TOT, a tetraalkyl titanate catalyst manufactured
by E. I. DuPont de Nemours and Co., Wilmington, Delaware, 19898.
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ETH-423
6~0
EXAMPLE XI
56/44 Poly (1,4-phenYlenedicarbinyl-co-hexamethylene
Oxalate): Dibutyl oxalate (20.2 g, 0.100 mols), 1,4-benzene-
dimethanol ~8.3 g, 0.060 mols), 1,6-hexanediol (5.6 g,
0.047 mols), and tetraisopropylorthotitanate catalyst (0.3 ml,
of a 0.01M solution) were added under dry and oxygen-free
conditions to a glass reactor equipped for magnetic stirring.
The prepolymer was formed by heating at 140, and 160C for 1,
and 17 hours respectively under nitrogen at one atmosphere
while allowing the formed butanol to distill. The pressure
was reduced (0.2 mm Hg) while continuing to heat at 160C
for an additional hour. The postpolymerization of the
polymer melt was completed by heating at 180C and 200C
for 2, and 3.5 hours, respectively, while continuing to
remove distillates. The polymer was cooled, and isolated,
PolYmer Characterization:
~inh in HFtP = O.42
DSC (10C/min): Tm = 165C
TGA (10C/min in N2): Less than 1% cummulative weight loss
experienced at 250C.
In Vitro Evaluation: Immersion of a molded disc, 2.2 cm in
diameter, for 7 and 77 days, in phosphate buffer at 37C
resulted in a loss of 3 and 56 percent of the initial mass,
respectively.
EXAMPLE XII
50/50 Poly (1,4-phenylenedicarbinyl-co-hexamethylene
Oxalate): In a manner similar to that employed in Examples
X and XI, the above identified copolymer having the following
characteristics was produced:
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ETH-423
0
DSC (lO~C/min): Tm = 175C
TGA (13C/n~n, in N2): Less than 1% cummulative
weight loss experienced at 250C.
In Vi_ro Evaluation: Immersion of a molded disc, 2.2 cm
in diameter, for 8 and 78 days in phosphate buffer at 37C
resulted in a loss of 6 and 54 percent of the initial mass,
respectively.
While the preceding examples have been directed to
the preparation of specific copolymers of polyoxalates,
these examples are for purposes of illustration only and
are not limiting of the invention. Mixtures of these polymers
and combinations of these polymers with up to about 50
percent by weight of poly (alkylene oxalates) and other
compatible polymers which produce non-toxic and absorbable
polymers are likewise included within the present invention.
It is to be u~derstood that inert additives such
as coloring materials and plasticizers can be incorporated
in the sutures. As used herein, the term "inert" means
materials that are chemically inert to the polymer and
biologically inert to living tissue, i.e., do not cause any
of the adverse effects previously discussed. Any of a
variety of plasticizers such as, for instance, glyceryl
triacetate, ethyl benzoate, diethyl phthalate, dibutyl
phthalate and bis-2-methoxyehtyl phthalate can be used if
desired. The amount of plasticizer may vary from 1 to
about 20 percent or more based on the weight of the polymer.
Not only does the plasticizer render the filaments of the
present invention even more pliable, it also serves as a
processing aid in extrusion and thread preparation.
- 26 -
ETH-423
4~
Filaments of the present invention are adversely
affected by moisture and are accordingly preferably stored
in hermetically sealed and substantially moisture-free
packages, a preferred form of which is shown in FIGURE 2.
In FIGURE 2, there is shown a suture package 14 having
disposed therein a coil of suture 12, one end of which is
attached to needle 13. The needle and suture are positioned
within a cavity 16 that is evacuated or filled with a dry
atmosphere of air or nitrogen. The illustrated package is
fabricated of two sheets of aluminum foil or an aluminum
foil-plastic laminate and heat sealed or bonded with
adhesive at the skirt 16 to hermetically seal the cavity
and isolate the contents of the package from the external
atmosphere.
Filaments of the present invention may be used
as monofilament or multifilament sutures, or may be woven,
braided, or knitted either alone or in combination with
other absorbable fibers such as poly (alkylene oxalate),
polyglycolide or poly (lactide-co-glycolide), or with non-
absorbable fibers such as nylon, polypropylene, poly-
ethylene-terephthalate, or polytetrafluoroethylene to form
multifilament sutures and tubular structures having use in
the surgical repair of arteries, veins, ducts, esophagi and
the like.
Multifilament yarns that contain isomorphic co-
polyoxalate filaments of the present invention together with
nonabsorbable filaments are illustrated in FIGURE 4 wherein
the nonabsorbable fiber is represented by the hatched fiber
cross-section 19. In FIGURE 4, the fibers 20 are extruded
from polymer compositions of the present invention as
described above. The relative proportions of absorbable
. - 27 -
6~0
filaments 20 and nonabsorbable filaments 19 may be varied
to obtain the absorption characteristic desired in the
woven fabric or tubular implants.
Composite fabrics of absorbable and nonabsorbable
materials fashioned by textile processes including weaving,
knitting and nonwoven felting are described in U.S.P.
3,108,357 and U.S.P. 3,463,158. Methods of weaving and
crimping tubular vascular prostheses are described in
U.S.P. 3,096,560. Similar techniques may be used in the
manufacture of surgical aids wherein nonabsorbable fibers
are combined with absorbable fibers composed of the polymers
of this invention. The surgical utility of "bi-component
filaments" containing absorbable and nonabsorbable compo-
nents is described in U.S.P. 3,463,158. Monofilaments
of the polymers of the present invention may be woven or
knitted to form an absorbable fabric having the structure
illustrated in FIGURE 5, useful surgically in hernia repair
and in supporting damaged liver, kidney and other internal
organs.
The polymers of the present invention are also
useful in the manufacture of cast films and other solid
surgical aids such as scleral buckling prostheses. Thus,
cylindrical pins, screws as illustrated in FIGURE 3, re-
inf~rcing plates, etc.., may be machined from solid polymer
25 having in vivo absorption characteristics depending upon the
polymer composition and molecular weight.
Many different embodiments of this invention will
be apparent to those skilled in the art and may be made
without departing from the spirit and scope thereof. It is
--28--
1~2~640 ETH-423
accordingly understood that this invention is not limited
to the specific embodiments thereof except as defined in
the appended claims.
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