U.S. patent number 3,883,901 [Application Number 05/419,450] was granted by the patent office on 1975-05-20 for method of replacing or repairing the body with bioresorbable surgical articles.
This patent grant is currently assigned to Rhone-Poulenc, S.A.. Invention is credited to Jean Coquard, Michel Ruaud, Pierre Sedivy, Jean Verrier.
United States Patent |
3,883,901 |
Coquard , et al. |
May 20, 1975 |
Method of replacing or repairing the body with bioresorbable
surgical articles
Abstract
Implantable surgical articles are provided which are at least
partially bioresorbable and which consist at least partially of a
polyester of succinic acid possessing a plurality of units of the
general formula: ##SPC1## In which R represents a linear or
branched alkylene radical containing 2 to 6 carbon atoms. They are
particularly suitable as sutures.
Inventors: |
Coquard; Jean (Rhone,
FR), Sedivy; Pierre (Hauts-de-Seine, FR),
Verrier; Jean (Bologne-sur-Seine, FR), Ruaud;
Michel (Rhone, FR) |
Assignee: |
Rhone-Poulenc, S.A. (Paris,
FR)
|
Family
ID: |
9108077 |
Appl.
No.: |
05/419,450 |
Filed: |
November 27, 1973 |
Foreign Application Priority Data
|
|
|
|
|
Dec 1, 1972 [FR] |
|
|
72.42838 |
|
Current U.S.
Class: |
128/898; 528/272;
606/231; 57/243; 528/279; 528/285; 623/1.38 |
Current CPC
Class: |
C08G
63/16 (20130101); A61L 27/18 (20130101); A61L
17/105 (20130101); A61L 17/145 (20130101); A61L
27/18 (20130101); C08L 67/00 (20130101) |
Current International
Class: |
A61L
17/14 (20060101); A61L 17/00 (20060101); A61L
27/18 (20060101); A61L 17/10 (20060101); A61L
27/00 (20060101); C08G 63/00 (20060101); C08G
63/16 (20060101); A61f 001/24 (); A61l
017/00 () |
Field of
Search: |
;3/1,DIG.1
;128/334R,334C,335.5,92C,92CA,92B,92D ;260/75R,75T,78A |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
"Polyesters," by V. V. Korshak, et al., Pergamon Press, Oxford
London, Edinburgh, New York, Paris, Frankfurt, 1965, pp. 31 and
53..
|
Primary Examiner: Frinks; Ronald L.
Attorney, Agent or Firm: Cushman, Darby & Cushman
Claims
We claim:
1. In a method of repairing or replacing a part of the body of a
human of non-human animal by incorporating either temporarily or
permanently, a surgical article, the improvement wherein the
surgical article consists at least partially of a polyester of
succinic acid possessing a plurality of units of the general
formula: ##SPC3##
in which R represents a linear or branched alkylene radical
containing 2 to 6 carbon atoms having a film- or filament-forming
molecular weight.
2. The method according to claim 1 in which the polyester is
polyethylene glycol succinate.
3. The method according to claim 1 in which the surgical article is
in the form of a suture element.
4. The method according to claim 3 in which the surgical article is
in the form of a filament, bristle, single filament, twisted
filament, stranded filament, gathered filament, texturized filament
of lapped filament, tape, tent or spun fibre.
5. The method according to claim 1 in which the surgical article is
in the form of a textile fabric.
6. The method according to claim 1 in which the polyester is
combined with another material which is bioresorbable.
7. The method according to claim 6 in which the other material is
selected from the group consisting of a polylactide or a
polyglycolide.
8. The method according to claim 1 in which the polyester is
combined with another material which is non-bioresorbable.
9. The method according to claim 8 in which the polyester is
present as a coating over a core of non-bioresorbable material.
10. The method according to claim 8 in which the nonbioresorbable
material is selected from the group consisting of polyethylene
glycol terephthalate or adipate, polyamide or polypropylene.
11. The method according to claim 1 in which the surgical article
is in the form of a tube.
12. The method according to claim 1 in which the surgical article
is in the form of a bar.
13. The method according to claim 1 in which the surgical article
is in the form of a plate.
14. The method according to claim 1 in which the surgical article
is in the form of a screw.
15. The method according to claim 1 in which the surgical article
is in the form of a ring.
Description
The present invention relates to surgical articles which are
biologically partially or completely resorbable after implantation
in living human or animal tissues.
It is known that human or animal surgery is making use of more and
more articles produced from natural or synthetic materials, in
order to restore living tissues or to strengthen, repair and even
replace various organs. For this purpose, surgical articles are
placed in position either temporarily or permanently. In the case
of temporary implantation, it has been considered preferable to
make use of bioresorbable materials, that is to say materials which
undergo degradation and which disappear after they have been
implanted after a certain length of time, due to a biochemical
process. It is important that the material used and its degradation
products should not cause any unfavourable reaction of the
surrounding tissues. With a permanent implantation, for example for
replacing or strengthening a failing organ, non-resorbable articles
are obviously used; it has been found, however, that in the
majority of cases, the integration of the prosthesis and its
joining to the adjacent tissues are facilitated if the prosthesis
is made partly of a bioresorbable material which is gradually
replaced by the adjacent tissues so as to form an intimate join
between the latter and the implanted foreign body.
The elements for sutures and for ligatures intended for closing
wounds and for repairing blood vessels, nerves and tendons are
examples of surgical articles which are implanted temporarily.
These elements are generally filaments, but they can also be in
other forms, for example as clips or tapes. The most commonly used
bioresorbable material for making suture or ligature filaments is
catgut prepared from the collegen of mammals; the sub-muccous layer
of the small intestine of sheep is most frequently employed. Catgut
possesses numerous disadvantages, such as difficulty in obtaining
it, the unfavourable reactions which it causes with living tissues
and the lack of uniformity of its mechanical properties.
Consequently, ways have been sought of replacing it by
bioresorbable synthetic materials which can easily be converted
into continuous filaments by extrusion techniques, and which
possess readily reproducible mechanical properties. Various
materials have been proposed for this purpose. Thus Belgian Pats.
Nos. 679,726 and 758,156 describe elements for sutures and
ligatures and other partially or completely bioresorbable surgical
articles, which consist of polyesters of copolyesters derived from
lactic acid and produced by polycondensation of a lactide
(preferably a L-lactide) alone or combined with other derivatives
of acid-alcohols such as glycolide, tetramethylglycolide,
.beta.-propiolactone and .beta.-butyrolactone. Although they
possess advantages relative to catgut, these polyesters are very
sensitive to moisture and this has a detrimental effect on their
mechanical properties so that it is necessary to store the surgical
elements and especially the suture filaments made from them in
hermetically sealed packaging. Hence they are not completely
satisfactory.
In addition, it is known that it is important that the surgeon
should have at his disposal various materials which provide him
with a wide range of bioresorbable properties. In fact, the
duration of the resorption varies with the nature of the wound and
with the nature of the tissues involved in the cicatrization
process; it also varies from one individual to another and with the
type of insertion in the case of prosthesis. The development of new
bioresorabable materials increases the number of possibilities from
which the surgeon can choose and there is, consequently, a demand
for new bioresorbable materials.
According to the present invention there is provided a surgical
article which can be used in human or animal surgery, which is
completely or partially bioresorbable and which consists wholly or
partially of a bioresorbable material consisting of a polyester of
succinic acid possessing a plurality of units of the general
formula: ##SPC2##
in which R represents a linear or branched alkylene radical
containing 2 to 6 carbon atoms. More specifically, R can be an
ethylene, methylethylene, 1,2-dimethylethylene, trimethylene,
2-methyl-trimethylene, 2,2-dimethyl-trimethylene,
1-methyl-trimethylene, tetramethylene, pentamethylene or
hexamethylene radical.
The bioresorbable character shown by the polyesters of formula (I),
denoted hereafter by the general term "polysuccinate," is
unexpected because it is known that polyesters such as polyethylene
glycol terephthalate are not resorbed by human or animal tissues
(see U.S. Pat. No. 3,463,158). It has been found that, in addition
to their bioresorbable character, the polysuccinates are
particularly well tolerated by the tissues in which they are
implanted; thus no inflammatory reaction has been observed after a
long-lasting implantation of polyethylene glycol succinate
filaments in rats. Moreover, the polysuccinates possess excellent
mechanical properties (notably tensile strength, tensile strength
at knots and dimensional stability) and are insensitive to
moisture, which make them particularly suitable for the manufacture
of surgical articles and especially elements for sutures.
Polysuccinate filaments are easy to handle and do not necessitate
the use of special storage devices.
Polyglycol succinates have been known for a very long time (see,
for example, U.S. Pat. No. 2,071,250; and V. V. KORSHAK and S. V.
VINOGRADOVA, "Polyesters," edited by PERGAMON PRESS Ltd., 1965,
pages 31 to 46). They can be prepared by the usual polycondensation
processes such as those described by V. V. KORSHAK and S. V.
VINOGRADOVA, loc. cit., or in HOUBEN WEYL, "Methoden der Organische
Chemie - Makromolekulare Stoffe," volume 14/2, pages 1 to 29. Thus
it is possible, for example, to use bulk polycondensation of
glycols with free succinic acid or dimethyl succinate in the
presence of the usual esterification or transesterification
catalysts such as sulphuric or p-toluenesulphonic acids, or metal
salts or oxides such as calcium oxide, strontium oxide, zinc oxide,
aluminium oxide, bismuth oxide, iron oxide, titanium oxide, lead
oxide, antimony oxide, cobalt oxide, calcium chloride, zinc acetate
and zinc borates.
As glycols which can be used to prepare the polyesters used in the
present invention, there may be mentioned ethylene glycol,
propylene glycol, propane-1,3-diol, 2-methyl-propane-1,3-diol,
2,2-dimethyl-propane-1,3-diol, butane-1,4-diol, butane-1,3-diol,
butane-2,3-diol, pentane-1,5-diol and hexane-1,6-diol. These
various glycols can be used separately or as a mixture with one
another. Use can thus be made of mixtures containing 1 to 99 mol %
of ethylene glycol and 99 to 1 mol % of one or more other glycols
such as 2-methylpropane-1,3-diol and
2,2-dimethyl-propane-1,3-diol.
The molecular weight of the polysuccinates used for the production
of surgical articles according to the present invention can vary
within very wide limits but it should generally be sufficiently
high to render them suitable for the formation of films and fibres.
Generally it should be sufficiently high for the polymer to be
converted into filaments and films which can be orientated. The
upper limit is not critical, subject to the condition that the
product can be processed by the usual moulding or shaping
techniques.
Polysuccinates can be used for the production of extremely diverse
surgical articles, such as those described in "Handbook of
Biomedical Plastics," H. LEE and K. NEVILLE, 1971, Pasadena
Technology Press. They are particularly suitable for the production
of elements for surgical sutures and ligatures, especially in the
form of twisted or non-twisted filaments, tapes, bristles, tents or
spun fibres. They can also be used in the form of single filaments,
twisted filaments, stranded filaments, gathered filaments,
texturized filaments or lapped filaments; these various terms are
used in accordance with the definition which is given of them in
French Standard Specification NF G 00-005. These various elements
for sutures can consist wholly or partially of the bioresorbable
polysuccinates. Thus use can be made of a filament of the
polysuccinate or of a filament comprising a core of a
non-resorbable synthetic material such as polyethylene glycol
terephthalate, polyamide or polypropylene, and an outer coating of
polysuccinates. It is likewise possible to use a composite element
consisting of a yarn of natural material, e.g., linen or silk, or
synthetic material covered with a polysuccinate, or of a yarn of
variable structure comprising bioresorbable filaments and
nonresorbable filaments.
Amongst the other surgical articles for which the polysuccinates of
the formula (I) can be used, there may be mentioned knitted fabrics
comprising resorbable yarns and optionally non-resorbable yarns or
non-resorbable yarns covered with a layer of polysuccinate;
non-woven fabrics prepared from non-bioresorbable fibres and a
resorbable binder; and sheets made from non-resorbable materials
covered on one or both faces by a polysuccinate. The wholly or
partially resorbable knitted and woven fabrics can be used in the
form of sheaths intended to facilitate the implantation of diverse
prostheses such as that described in French Pat. Nos. 2,031,699 and
2,071,172 for correcting valvular illnesses, and especially of the
mitral valve; tubes for the removal of biological liquids (in
particular, artificial ureters) as described in French Pat. No.
2,133,083, and vascular prostheses such as those described in
French Pat. No. 2,112,032.
The polysuccinates of formula (I) are also very suitable for the
production of surgical articles such as tubes of various shapes,
for example Y-shaped tubes and T-shaped tubes, bars, plates, rings
and screws, intended to be implanted temporarily or permanently.
Partially or completely bioresorbable tubular prostheses have been
described in U.S. Pat. Nos. 2,127,903, 3,272,204, 3,304,557,
3,316,557, and 3,479,670 to which reference should be made for
further details.
The shaping of the polysuccinates of formula (I) for the production
of surgical articles can be carried out by the usual methods. Thus
filaments, tapes or sheets can be produced by extrusion of the
polymer in the molten state, followed by stretching at a
sufficiently high ratio to cause the orientation of the chains of
the polymer, and the fixing of the article thus produced.
The polysuccinates of formula (I) can contain various adjuvants
such as fillers, dyestuffs and plasticizers which are chemically
inert and do not bring about any reactions with the living
tissues.
They can be used alone or mixed with non-bioresorbable materials,
as indicated above, or with materials which are more or less
resorbable in themselves, for example, respectively, polyesters of
the polyethylene glycol terephthalate or adipate type, or of the
polylactide or polyglycolide type.
The surgical articles according to the invention can be sterilized
easily by the techniques usually employed in surgery, for example
by radiation treatment.
The following Examples further illustrate the present
invention.
EXAMPLE 1
1. Preparation of polyethylene glycol succinate
174g. (1 mol) of diethyl succinate, 93 g. (1.5 mols) of ethylene
glycol, 0.280 g. of zinc acetate and 0.070 g. of antimony trioxide
are introduced, under a stream of nitrogen, into a 300 cm.sup.3
glass flask equipped with a scraping stirrer, a gas inlet tube, a
gas outlet tube, a thermometer, a thermostatically controlled metal
heating bath and a distillation column provided with a condenser
and a receiving container. The contents of the flask are heated to
180.degree.C., with stirring, and these conditions are maintained
for 1 hour 30 minutes. The temperature of the reaction mixture is
then raised to 240.degree.C., over the course of 50 minutes and the
apparatus is connected to a vacuum pump in order to reduce the
pressure in the apparatus to 0.1 mm.Hg over the course of 30
minutes. The whole is maintained under these conditions for 6 hours
30 minutes. The viscous, light brown reaction mixture is dissolved
in hot dioxane and then reprecipitated with methanol. A product is
obtained which is filtered off and dried at 80.degree.C. in a
vacuum oven. In this way, 112 g. of polymer are obtained.
In all, 2 mols of ethanol, 0.368 mol of ethylene glycol and 0.07
mol of diethyl succinate are collected in the various distillates
from the reaction. Taking account of the fact that a further 5 g.
of polyester are recovered on the walls of the apparatus, the
degree of polycondensation rises to 85.5%
The polyester thus obtained has a viscosity of 69 cm.sup.3 /g.,
measured at 25.degree.C., on a 4 g/l solution in chloroform and a
viscosity of 70 cm/g, measured at 25.degree.C. in a 2 g/l solution
in meta-cresol. It melts at 104.degree.C., and is not decomposed by
heating under nitrogen at 300.degree.C.
A filament of gauge 20 decitex is prepared from this polyester by
melt spinning under 30 bars and stretching the yarn issuing from
the spinneret in a ratio of 7 at 55.degree.C. This filament
possesses the following mechanical properties:
tensile strength in accordance with Standard Specification NF G
07,008, April 1961, 2 g/dicitex,
elongation at break in accordance with Standard Specification NF G
07,008, 50%,
tensile strength at knots, in accordance with Standard
Specification NF G 07,008, 1.66 g/decitex,
shrinkage in water at 40.degree.C. in accordance with Standard
Specification BNMP 14,732/27 of February 1972 4%
2. Determination of the local tolerance of implant in rats
Using the polyethylene glycol succinate obtained as described
above, a stretched filament of diameter 300 to 400 .mu. is produced
and is sterilized by immersion for 1 hour in 70.degree. GL ethyl
alcohol.
Samples of length 1 cm are implanted, with a curved needle, in rats
(Caesarean Originated, Barrier Sustained) weighing 250 to 350 g;
the implantation is carried out, on the one hand, in the
paravertebral muscles, and on the other hand, under the skin of one
of the sides of each animal. Four rats (2 male and 2 female) each
received two implants. Two months after the implantation, the
animals are killed and the muscular implantation region (implant
and paravertebral muscular mass) and the subcutaneous implantation
region (skin, implant and underlying muscular portion) are removed
in each case. The following examinations are carried out on each
specimen removed:
a. Macroscopic examination after transverse section of one of the
ends of the muscular mass (intramuscular implant) or detachment of
the skin at one end (subcutaneous implant) of each specimen.
b. Histological examination after fixing the specimens in BOUIN
liquid, inclusion in paraffin, cutting of 5 .mu. thick sections and
colouration by means of hemalun-phloxine saffron. The following
results were obtained:
a. Macroscopic examination
Two months after the implantation, no macroscopically detectable
tissue reaction was observed either at the muscle level or at the
subcutaneous tissue level.
b. Histological examination
Reaction of the tissues
This reaction is limited to a very inconspicuous fibrous sheath
around the implant and to the presence of a few multinucleate giant
macrophage and histiocyte cells situated in contact with the
implant itself.
No change which could relate to a possible toxic effect of the
material was detected on the sections.
In short, the local tolerance in rats is very good from the
macroscopic point of view and from the histological point of
view.
3. Determination of the bioresorbability "in vitro"
The bioresorbability of the polyethylene glycol succinate produced
above is determined by measuring the variation in the reduced
viscosity of a sample of polymer taken in the form of flakes and
incubated for varying periods of time in an enzyme extract. The
test was carried out in the following manner:
a. Preparation of the enzyme extract
"Fauves de Bourgogne" rabbits, of approximately 2.5 kg, are killed
with chloroform. The muscles from the back and the thighs are
removed and are frozen at -20.degree.C. They are then ground
rapidly in a meat mincing machine. 300 g. of ground material are
dispersed in 500 ml. of 0.2 M citrate buffer of pH 4.1, which have
previously been cooled to +2.degree.. The suspension obtained is
ground again twice for 1 minute (grinder turning at 2,000
revolutions/minute), with external cooling (ice and salt mixture at
about -13.degree.C.) to keep the temperature of the homogenized
material below +10.degree.C. during the operation.
The homogenized material is then subjected to an ultrasonic
treatment (frequency: 20 kHz) for 2 minutes with the same cooling
precautions. It is then centrifuged at 6,500 G, at 0.degree. for 20
minutes. The supernatant liquid, filtered through glass wool, forms
the enzyme extract; its pH is approximately 4.5.
b. Reaction between the product to be investigated and the enzyme
extract
A sample of 100 mg. of the polymer to be investigated is incubated
at 37.degree.C., with agitation (shaking table turning at 80
revolutions/minute), in the following reaction mixture:
Enzyme extract 40 ml. Streptomycin sulphate 2 mg. Sodium salt of
penicillin G 2 mg. Sodium nitride 8 mg.
This reaction mixture is renewed every day; during each renewal,
the samples are carefully washed with distilled water.
In parallel, other samples of 100 mg. of the product to be
investigated are incubated in reaction mixtures in which the enzyme
extract is replaced by an inactivated enzyme extract (heating for
30 minutes at 100.degree.C.) or by 0.2 M citrate buffer of pH
4.5.
The product to be investigated, in the form of flakes, is enclosed
in a guaze bag for the incubation.
c. Examination of the polymer after reaction
After 160 hours of incubation, the samples of the product to be
investigated are recovered, washed several times with distilled
water, drained on filter paper and dried under reduced pressure at
50.degree.C.
The reduced specific viscosity of solutions of the product in
1,2-dichloro-ethane, at 40.degree.C., as well as that of the
product before incubation, is then determined.
The following results were obtained:
Nature of the incubation Reduced medium specific viscosity
______________________________________ None 52 Citrate buffer 54
Inactivated enzyme extract 56 Active enzyme extract 34
______________________________________
It is found, under these conditions, that incubation in the active
enzyme extract results in considerable degradation of the
polyester.
EXAMPLES 2
1. Preparation of polybutane-1,4-diol succinate
174 g. of diethyl succinate, 135 g. of butane-1,4-diol, 0.270 g. of
zinc acetate and 0.1 g. of SbF.sub.3 are introduced into the
apparatus described in Example 1 after it has been purged with
nitrogen, and then the reagents are stirred for 20 minutes at
ambient temperature. The contents of the flask are then heated to
190.degree.-200.degree.C. for 1 hour and then to 240.degree.C. over
the course of 30 minutes, and the pressure is reduced to 0.1 mm.Hg
over the course of 40 minutes. After 4 hours 40 minutes under these
conditions, the reaction is stopped.
In this way, 146.7 g. (degree of polycondensation 85.3%) of greyish
polymer are obtained which are dissolved in 400 cm.sup.3 of hot
dioxane. The polymer is reprecipitated by introducing the solution
into 3 l. of methanol, and is then filtered off and dried at
50.degree.C., in vacuo. 138 g. of white polymer, having a viscosity
of 94-97 cm.sup.3 /g, measured at 25.degree.C., in a 2 g/l solution
in meta-cresol, and having a melting point of 114.degree.C., are
recovered.
Filaments of gauge 21 decitex are prepared from the polymer thus
produced by melt spinning under 61 bars and stretching at
85.degree.C.
The filaments possess the following mechanical properties:
elongation at break (Standard Specification NF G 07,008, April
1961) 50% tensile strength (Standard Specification NF G 07,008)
11.8 g/tex.
Braids of 20 strands are then prepared by twisting followed by
fixing by heating at 50.degree.C., for 10 minutes. The braids are
then sterilized by irradiation under 2.5 Mrads and stored in
heat-sealed polyethylene sachets.
2. Implantation of a braid in rats
The implantation is carried out on four rats of the same origin as
in Example 1 and in a rigorously identical manner. After two months
of implantation, the rats are killed and the same samples are
removed and the same examinations carried out as in Example 1. The
results obtained were as follows:
A. Macroscopic examination
Two months after the implantation, no macroscopically detectable
tissue reaction was observed either at the muscle level or at the
subcutaneous tissue level.
B. Histological examination
Reaction of the tissues
The local tolerance is good; reaction to the implantation is
limited to the immediate periphery of the implant and remains
inconspicuous. No change in the tissue due to a toxic effect of the
products was detected.
Resorption of the implants
After two months of implantation, the number of strands visible in
the sections of the intramuscular implants is 3 out of the 20
originally present.
* * * * *