NO135968B - - Google Patents

Description

The present invention relates to surgical products which are partially or completely biologically resorbable after implantation in living tissue in humans or animals. The products are made from chain-shaped polyesters with sufficient molecular weight to be converted into fibers and films.

In human and animal surgery, more and more are used

and more products made from natural or synthetic material to achieve the restoration of living tissue or to reinforce, repair or even replace different organs. For this purpose, the surgical products are placed either temporarily or permanently. In the case of temporary implantation, it is considered to be beneficial

to use biologically resorbable material, i.e. material that breaks down and disappears through a biochemical process after a certain time after implantation. It is important that the material used and its breakdown products do not cause any adverse reaction in the surrounding tissue. At final implantation, e.g. for replacing or strengthening a weakened organ, resorbable products are of course not used. However, it has been established that incorporation of the prosthesis and its binding to the adjacent tissue is in most cases facilitated when the prosthesis partly consists of a biologically resorbable material, which is progressively replaced with the adjacent tissue in such a way that an intimate connection is created between this tissue and the implanted foreign prosthesis.

As examples of surgical specimens that are temporarily implanted, mention should be made of elements for sutures and for ligatures intended for closing wounds and for repairing blood vessels, nerves, tendons, etc. These elements are usually threads, but they can also occur in other forms (e.g. e.g. staples, ribbons). The biologically resorbable material that is most often used for the production of suture threads or ligature threads is catgut made from collagen from mammals. Most often, the layer under the mucosa of the small intestine from sheep is used. Cat gut has several shortcomings, it is difficult to obtain, it provokes unfavorable reactions in living tissue, and the mechanical properties are not homogeneous. As a result, Mån has tried to replace catgut with biologically resorbable synthetic material which is easier to strand spray into continuous fibers and which has reproducible mechanical properties. Various substances have been proposed. In the Belgian patents no. 679,726 and 758,156, elements for sutures and ligatures as well as other surgical products are described, which are partially or completely biologically resorbable, consisting of polyesters or copolymers derived from lactic acid and obtained by polycondensation of a lactide (preferably L-lactide ) either alone or in conjunction with other acid-alcohol derivatives such as glycolide, tetramethylglycolide, |3-propiolactone, g-butyrolactone. Despite the advantages that these polyesters have compared to catgut, however, they exhibit a very high sensitivity to moisture which probably affects their mechanical properties and which means that surgical elements and especially suture threads must be stored in hermetically sealed packages. Because of this, these polyesters are not particularly satisfactory.

It is also known that it is important that surgeons have different materials at their disposal, which materials cover a wide range of properties in terms of biological resorption. The resorption time varies with the nature of the wound and with the nature of the tissues that participate in the scarring process. The resorption time also varies from one individual to another and with the nature of the intervention in the case of prostheses. By producing new biologically resorbable substances, the options for surgeons are thus increased.

The present invention thus relates to surgical products which are applicable in human surgery or animal surgery and which are completely or partially biologically resorbable. These products are characterized by the fact that they consist wholly or partly of a biologically resorbable material which consists of a polyester of succinic acid, showing a number of more with the general formula

where R means a straight or branched alkylene group containing 2-6 carbon atoms. R can be an ethylene group, a methylethylene group, a 1,2-dimethylethylene group, a trimethylene group, a 2-methyltrimethylene group, a 2,2-dimethyltrimethylene group, a 1-methyltrimethylene group,

a tetramethylene group, a pentamethylene group or a hexamethylene group.

The biologically resorbable nature of the polyesters of formula I (hereinafter called polysuccinates) is unexpected as it is known that such polyesters as polyethylene glycol terephthalate are not resorbed by tissues in humans or animals (see US patent no. 3,463,158). It has been established that the polysuccinates, in addition to being biologically resorbable, are very well accepted by the tissues in which they are implanted. Thus, no inflammatory reaction has been observed when threads of polyethylene glycol succinate have been implanted in tissues of rats for a long time. The polysuccinates also exhibit excellent mechanical properties (tensile strength, fixed knots, dimensional stability) and are insensitive to moisture, which makes them particularly well suited for the production of surgical products, especially suture elements. Threads made of polysuccinates are easy to process, and they also do not need to be stored in any special way.

Polysuccinates of glycol are products that have been known for a long time (see US Patent No. 2,071,250 and article by V.V. Korshak and S.V. Vinogradova, "Polyesters", Pergamon Press Ltd., 1965, pages 31-46) and they are prepared according to common polycondensation methods, e.g. as described by V.V. Korshak and S.V. Vinogradova (see above) or in Houben Weil, "Methoden der Organische Chemie - Makro-molekulare Stoffe", volume 14/2, pages 1-29. For the production of polysuccinates, one can e.g. condense a mixture of glycols and free succinic acid or dimethylsuccinate in the presence of common esterification or transesterification catalysts (e.g. sulfuric acid, p-toluenesulfonic acid; metal salts or metal oxides such as oxides of calcium, strontium, zinc, aluminium, bismuth, iron, titanium, lead, antimony and cobalt, calcium chloride, zinc acetate, zinc borate). The polysuccinates used according to the present invention should have a sufficiently high molecular weight to be able to be formed into fibers and films.

Examples of glycols that can be used for the production of polyesters with the formula I should be mentioned ethylene glycol, propylene glycol, propane-1,3-diol, 2-methylpropane-1,3-diol, 2,2-dimethylpropane-1,3-diol, butane-1,4-diol, butane-1,3-diol, butane-2,3-diol, pentane-1,5-diol, hexane-1,6-diol. These different glycols can be used separately or mixed with each other. One can thus use mixtures containing 1-99 mol-% ethylene glycol and 99-1 mol-% of one or more other glycols such as 2-methylpropane-1,3-diol and 2,2-dimethylpropane-1,3-diol .

The molecular weight of the polysuccinates used for the production of surgical products according to the invention can vary within very wide limits. However, the molecular weight should be sufficiently high so that the polymer can be converted into orientable threads and films. The upper limit is not critical on the condition that the product can be formed according to normal forming methods.

The polysuccinates can be used for the manufacture of a wide variety of surgical products of the type described by H. Lee and K. Neville, "Handbook of Biomedical Plastics", Pasadena Technology Press, 1971. They are particularly suitable for the manufacture of elements for surgical sutures and ligatures, in particular in the form of twisted or untwisted filaments, ribbons, coarse fibres, cords or spun yarn. You can use simple, multiple twisted, twisted compound, textured or wrapped threads. (Regarding the definition of the various expressions, reference is made to "Norme Francaise NF G 00-005"). These different suture elements may consist wholly or partly of biologically resorbable polysuccinates. One can thus use a filament of polysuccinate or a filament with a core of a synthetic non-resorbable material (e.g. polyethylene glycol terephthalate, polyamide, polypropylene) and an outer coating of polysuccinate. One can also use a composite element consisting of a thread of natural material (linen, silk) or synthetic material coated with polysuccinate, or of a thread with a variable structure comprising resorbable filaments and non-resorbable filaments.

As examples of other surgical specimens comprising polysuccinates of the formula I, one can mention sewn products comprising resorbable threads and optionally non-resorbable threads or non-resorbable threads coated with a layer of polysuccinate; non-woven fabrics made from non-resorbable fibers and a resorbable binder; sheet of non-resorbable material coated on one side or on side surfaces with a layer of polysuccinate. The fully or partially resorbable leotards and cloth are used in the form of sheaths intended to facilitate the implantation of various prostheses, e.g. the prosthesis described in French Patent No. 2,031,699 and its supplement 2,071-172 for the correction of heart valve defects, particularly as regards the mitral valve; conduits for draining biological fluids (in particular artificial urinary tracts), such as those described in French Patent No. 2,133,083; vascular prostheses such as those described in French Patent No. 2,122,032.

The polysuccinates of formula I are very suitable for the manufacture of such surgical products as tubes of various shapes (Y-tubes, T-tubes), rods, plates, rings and screws, which products are intended to be implanted temporarily or permanently. Partially or fully bioresorbable tubular prostheses are described in US Patent Nos. 2,127-903, 3-272,204, 3-304,557, 3-316. 557 and 3-479-670.

The manufacture of surgical products using poly-. , succinates of the formula I occur by means of conventional methods. Fibers, ribbons or sheets can thus be obtained by string spraying the polymer in a molten state and subsequent stretching with a sufficient degree of stretching to achieve orientation of the polymer chains and fixation of the obtained product.

Polysuccinate with the formula I can contain various additives such as fillers, dyes and plasticizers, which are chemically inert and do not cause reactions in the living tissues.

The polysuccinates can be used alone or in conjunction with materials which are not resorbable or which are more or less resorbable than themselves, e.g. polyesters of the type polyterephthalate or polyacipate of ethylene glycol or of the type polylactides or polyglycolides.

The surgical products according to the invention can be easily sterilized by applying methods known within surgery, such as e.g. radiation treatment.

The invention shall be illustrated by the following examples.

Example 1.

1) Production of polyethylene glycol succinate.

A 300 crti^ glass flask is used which is equipped with a stirrer, a gas inlet pipe, a gas outlet pipe, a thermometer, a thermo-stat regulated metal bath and a distillation column equipped with a cooler and receiver. A stream of nitrogen is passed through the flask and 174 g or one mol of diethyl succinate, 93 g or 1.5 mol of ethylene glycol, 0.280 g of zinc acetate and 0.070 g of antimony trioxide are introduced. The contents of the flask are heated to 180°C with stirring and these conditions are maintained

■ li hour. The reaction mixture is then heated to a temperature of 240°C within 50 minutes and the apparatus is connected to a vacuum pump to lower the pressure in the apparatus to 0.1 mm Hg within 30 minutes. The whole thing is kept under the same conditions for 6 hours. The light brown and viscous reaction mixture is dissolved in dioxane in heat, after which it is precipitated with methanol. This results in a product that is filtered off and dried at 80°C in an oven under vacuum. In this way, 112 g of polymer are obtained.

The various reaction distillates are collected together

2 mol ethanol, 0.368 mol ethylene glycol and 0.07 mol diethyl succinate.

Taking into account that an additional 5 g of polyester is recovered from the walls of the apparatus, the degree of polycondensation amounts to 85.5%.

The polyester thus obtained exhibits a viscosity of 69 cm^ per g, measured at 25°C in a chloroform solution containing 2 g of polyester per litres, and a viscosity of 7j0 cm^ per g, measured at 25°C in a meta-cresol solution containing 2 g of polyester per litres. The polyester melts at 104°C and it does not decompose when heated in nitrogen gas to 300°C.

From this polyester, a thread with a titer of 20 dtex is produced by spinning the polyester in a molten state under a pressure of 30 bar and then stretching the thread coming from the nozzle at 55°C to a degree of stretch of 7. The obtained thread has the following mechanical properties : Breaking strength (according to NF G 07 008, April 1961) 2 p/dtex Breaking stretch (according to NF G 07 008) 50$

Breaking strength in knots (according to NF G 07 008) 1.66 p/dtex Shrinkage in water at 40°C (according to BNMP 14732/27,

February 1972) H%.

2) Determination of the local tolerance during implantation in rats. With the aid of the polyethylene glycol succinate produced above, a wire is produced which is stretched to a wire diameter of 300-400 µm. This thread is sterilized by immersion in ethyl alcohol (70 volume-$) for 1 hour. Using a bent needle, 1 cm long test pieces of said thread are implanted in rats (Caesarean Originated, Barrier Sustain-ed) weighing 250-350 g. The implantation takes place partly in muscles located near the spine and partly under the skin of one side of each animal. 4 rats. (2 males and 2 females) each receive 2 implanted wire pieces. Two months after implantation, the animals are killed,

and from each animal a sample is taken from the muscular implantation zone (implanted wire and muscle mass near the spine) and from the subcutaneous implantation zone (skin, implanted wire and underlying muscle mass). Each sample is subjected to the following examination.

a) Macroscopic examination after a transverse cut through one of the ends of the muscle mass (intramuscularly implanted wire) or after

removal of the skin at one end (subcutaneously implanted wire).

No macroscopically visible tissue reaction could be detected - neither in the intramuscular nor in the subcutaneous samples.

b) Histological examination or fixation of the samples in Bouin's fluid, embedding in paraffin, cutting 5 µm thick sections and

staining with hemalun-phloxin-saffron.

The observed tissue reactions are limited to a clearly defined fibrous sheath around the implanted wire and the presence of some very large multinuclear histiocyte cells and macrophage cells in contact with the implanted wire itself.

In the sections studied, it has not been possible to demonstrate any change that could be connected with a possible toxic effect of the implanted material.

Both the macroscopic and the histological examination thus show that the local tolerance in rats is very good.

3) Determination of the biological resorbability in vitro.

The bioresorbability of the produced polyethylene glycol succinate was determined by measuring the change in the reduced viscosity of a polymer sample, which was incorporated in the form of flakes for different times in an enzymatic extract. The provision was carried out in the following way.

a) Preparation of enzymatic extract.

Rabbits (Fauves de Bourgogne) with a weight of approx. 2.5 kg was

euthanized with chloroform. The back muscles and thigh muscles were taken out and frozen at -20°C. These muscles are then quickly ground in a meat grinder. 300 g of the ground material is dispersed in 500 ml of 0.2 M citrate buffer (pH 4.1) which had previously been cooled to +2°C. The obtained suspension is subjected to a new grinding for 2 x 1 minute (the grinding device rotated at 2000 revolutions per minute) and under external cooling (using a mixture of ice and salt with a temperature of about -13°C) as that during grinding the temperature of the homogenate was kept below +10°C.

The homogenate was then subjected to a treatment with ultra-sound (frequency 20 kHz) for 2 minutes whereby the cooling conditions are the same as above. The homogenate is then centrifuged at 6500 g for 20 minutes at 0°C. The supernatant liquid is filtered through glass wool and then used as an enzymatic extract. The pH value is approx. 4.5. b) Reaction between the polyethylene glycol succinate and the enzymatic extract. 100 mg of the polymer incubate at 37°C with stirring (shaker table rotating at 80 revolutions per minute) in the following reaction medium: Enzymatic extract 40 ml Streptomycin sulfate 2 mg

Sodium salt of penicillin G 2 mg Sodium nitride - , 8 mg

This reaction medium is renewed every day. At each renewal, the sample is carefully washed with distilled water.

At the same time, other samples of 100 mg of polymer are incubated in the reaction medium in which the enzymatic extract has been replaced with an inactivated enzymatic extract (inactivated by heating to 100°C for 30 minutes) or with a 0.2 M citrate buffer, pH 4.5.

During the incubation, the polymer sample in the form of fluff is kept enclosed in a sack of gauze.

c) Examination of the polymer after the reaction.

After 160 hours of incubation, the polymer sample is taken out, several are washed

times with distilled water, distilled off on a paper filter and dried under reduced pressure at 50°C.

The reduced specific viscosity of solutions of the polymer in 1,2-dichloroethane at 40°C is then determined. The same determination is made with a non-incubated polymer sample. The results obtained are indicated in the table below.

Incubation medium Reduced specific

viscosity

Nothing 52

Citrate buffer 54

Inactivated enzymatic extract 56

Activated enzymatic extract 34

From the test results, it appears that the incubation in the active enzymatic extract has led to a significant breakdown of the polyester.

Example 2.

1) Preparation of polysuccinate from butane-1,4-diol.

To the apparatus described in example 1, which is flushed with nitrogen gas, 174 g of diethyl succinate, 135 g of butane-1,4-diol, 0.270 g of zinc acetate and 0.1 g of SbF^ are added, after which the reaction components are stirred for 20 minutes at room temperature. The contents of the flask are then heated to 190-200°C over 1 hour, then to 240°C over 30 minutes, and the pressure reduced to 0.1 mm Hg over 40 minutes. After 4 hours and 40 minutes under these conditions, the reaction is stopped.

In this way, 146.7 g of greyish polymer (degree of polycondensation 85.3%) is obtained, which is dissolved in heat in 400 cm-1 of dioxane. The polymer is precipitated again by adding the solution to 3 liters of methanol, where

after the polymer is filtered off and dried at 50°C under vacuum. One up-

138 g of white polymer with a melting point of 114°C and a visco-

site of 94-97 cm"5 per g, measured at 25°C in a metacresol solution,

containing 2 g of polymer per litres.

By spinning the thus obtained polymer in a molten state

using a pressure of 61 bar and subsequent stretching at 85°C

filaments with a titer of 21 dtex are produced.

The obtained filaments exhibit the following mechanical properties:

Fracture extension (according to NP G 07 008, April 1961) 50%

Breaking strength (according to NF G 07 008) 11.8 p/dtex.

Braids are then produced by twisting together 20 filaments

ments and subsequent fixation by heating to 50°C for 10 minutes. The braids are then sterilized by irradiation (2.5 Mrad) and stored in heat-sealed polyethylene bags.

2) Implantation experiments with rats.

In 4 rats of the same type as example 1, samples of

the manufactured braids in exactly the same way as in example 1. After 2 months of implantation, the rats are euthanized, and the same samples are taken and the same examinations are carried out as in example 1. This results in the following

end results.

a) Macroscopic examination.

No macroscopically visible tissue reaction can be noted, either

in the intramuscular or in the subcutaneous samples.

b) Histological examination.

The local tolerance is good. The tissue reaction to the implant

material is limited to the material's immediate surroundings and does not spread. No tissue change related to a toxic effect of the implanted material can be demonstrated.

The resorption of the implanted material is good. On average

of the intramuscularly implanted material, the number of visible fila-

ments only 3 compared to the original 20. filaments present

Claims (2)

1. Implantable surgical products, which are applicable in human or animal surgery and which are completely or partially biologically resorbable, characterized in that they consist wholly or partly of a polyester of succinic acid, containing a number of more with the general formula: where R means a straight or branched alkylene group, containing 2-6 carbon atoms, where the polyester has such a molecular weight that it can be formed into threads or films. % 2. Products according to claim 1, characterized in that the polyester is polyethylene glycol succinate.