A METHOD OF PRODUCING A MONO- OR MULTILAYERED PROSTHESIS MATERIAL AND THE MATERIAL HEREBY OBTAINED

Abstract: A method of producing a mono- or multilayered prosthesis material for use with a living body, said material showing mechanical compliance vis-à-vis soft body tissue and possessing biocompatibility, said method comprising the steps: (a) preparing a polymer solution using a mixed solvent, said solution being near its precipitation point; (b) coating a substrate and precipitating thereon the polymer to form a physically stable porous structure by evaporating at least part of the solvent fraction of the mixed solvent; and the multilayered prosthesis material prepared by the method.

Description: A Method of Producing a Mono- or Multilayered Prosthesis Material and the Material hereby obtained. The present invention relates to the provision of a prosthesis material for use with a living body, the material produced showing mechanical compliance vis-a-vis soft body tissue and, furthermore, possessing biocompatibility The invention includes a method for the manufacture of such ma terial. In using synthetic polymers as replacement material for various types of human tissue it is not only the biocompatibility properties of the polymer which is of critical importance to the performance of the material when used with a living body. In addition to bio- compatibility and blood compatibility the mechanical compliance and porosity features are of basic importance. The available materials are not satisfactory in this respect. In other words, due to mechanical factors the applied material does not possess a mechanical per- formance which is in line with that of the surrounding natural tissue. Accordingly, it is an object of the present inven¬ tion to provide a prosthesis material of a synthetic nature showing mechanical compliance vis-a-vis soft body tissue at the same time possessing biocompatibility or blood compatibility. Another object of the invention is to provide a prosthesis material for such use, which shows the desirable porosity in combination with mechanical resistance and compliance. Yet another object of the invention is to provide a method for producing such prosthesis material, the method comprising a new feature of using a solvent of a special nature and a new precipitation technique in connection here¬ with. Still another object is to provide a porous material of a fibrelike structure. In connection with extensive research and experimentation it has been found that a mono- or multi¬ layered prosthesis material can be prepared starting from a solution of a copolymer in a mixed solvent and coating a sub¬ strate with a uniform thickness of such solution. The polymer is precipitated by evaporation and one or several consecutive layer(s) are applied to form a prosthesis material. The invention is based on an entirely new concept of u- sing a mixed solvent and a specific precipitation technique. The mixed solvent comprises as a first constituent a fluid which is miscible with the solvent but functions as a precipi¬ tating non-solvent with respect to polymer. Furthermore, the mixed solvent comprises a second constituent which is solvent for the polymer. In the polymer solution using a mixed solvent two criteria are of importance which will be further explained below. The first criterion of the polymer mixed solvent solution is the feature that the solvent constituent thereof must have a higher rate of evaporation than the non-solvent constituent. The importance of this feature will be explained in the follo- wing. The second criterion of the polymer mixed solvent solution is the feature that the degree of saturation thereof with re¬ gard to the polymer contents must be such that the polymer so¬ lution is near its precipitation point. By a saturation which is "near the precipitation point", is meant that the polymer solution used for preparing the mono- or multilayered material contains at least about 60% and preferably at least 80% by weig of the amount of polymer corresponding to a saturated solution of the same polymer in the same mixed solvent. It- is preferred that the polymer solution used in the method of the invention contains no less than about 901 of the said amount of polymer. In addition to these features of the polymer solution used for making the multilayered prosthesis material the invention also provides for a new precipitating technique which in principle resides in precipitating the substrate coating of the polymer solution by evaporating at least part of the solvent constituent or solvent fraction of the mixed solvent to precipitate the polymer to form a layer thereof on the substrate before applying another coating of polymer solut¬ ion. Evaporation of the solvent constituent of the mixed solvent is facilitated by the fact that the solvent con- stituent is more volatile than the non-solvent constituent of the mixed solvent. Evaporation of the solvent fraction of the mixed sol¬ vent can be achieved in any suitable manner. Thus, evaporat¬ ion can take place merely by autoevaporation into the sur- rounding air or it can be accelerated by heating, forced circulation, applying vacuum or using other conventional technique. In accordance with the invention it is preferred to carry the evaporation of the solvent constituent to a point where some solvent constituent is left in each preceding layer when the subsequent layer is applied. It has been found, that if evaporation takes place in such manner re¬ peating the procedure to form another layer of coating re¬ sults in the formation of inter-phase fibers which form a mechanically strong linkage between the first layer and the subsequent layer. This will prevent progressive delaminat- ion of for example a. 1 graft wall when implanted in a living body. Such delamination is a disadvantage and generally results in the formation of extensive aneurysms upon im- plantation. Although the invention is not limited to any specific theory or mechanism, there are different factors which might explain how the very strong linkage is achieved. It has thus been observed that there are many fibres in the boundary of two subsequent layers, which seem to be inter¬ locked probably due to the fact that many tiny fibres in the outer surface of the first layer are partly dissolved in the mixed solvent system. As soon as the new fibres are precipitated in the subsequent evaporation step, also the partly dissolved fibres produced in the preceding step are reformed, thus giving an interlocking effect of the two sub- sequent layers. There are also fibres precipitated in the second subsequent layer, which are trapped in the pores of the first layer. At last there may also be a kind of glue¬ ing effect between fibres in the outer surface of the first layer and the inner surface of the second layer. This re- suits from the presence of small amounts of solvent left in the precipitated polymer. There are, of course, alternative procedures for pre¬ paring a polymer solution using a mixed solvent which is near its precipitation point. One such alternative which is a simpl one for use in actual practice is as follows. A solution of po lymer is prepared using a solvent, for example tetraTrydrofura?ι To this clear polymer solution there is added a precipitating agent or non-solvent, for example water, until a slight cloudi ness is obtained. Then tetrahydrofurane is added to the cloud solution until a clear solution is again obtained and this cle solution is useful for coating a substrate and meets the requi rements of this invention in regard to nearness to the precipi tation point. According to the present invention it has been found that by using the technique outlined above a polymer layer when precipitated will be obtained which has a fibre-like str ture the pores of which are interconnected. The precipitated relike material consists of fibres of different thickness fro tiny fibres to relatively thick ones. Each precipitated layer has a thickness of for example about 0.01 to 1 mm and up to ab 100 and even more layers may be applied in subsequent operatio to produce a multilayered prosthesis material of the required mechanical strength. Due to the fiberlike porous structure the prosthesis wall is strong, highly compliant and mechanically compatible with the tissue to be replaced. Although the polymer concentration of the mixed solvent solution is not critical for obtaining useful results it is preferred to use a solution containing less than about 5 . by weight of polymer. Sometimes the concentration can be less than about 3. of polymer and in some cases even concentrati¬ ons as low as about 0.5 . or less may be useful. In connection with or after coating the substrate with the polymer solution the coating applied is precipitated by evaporating at least part of the solvent fraction of the mixed solvent. The procedure is then repeated as desired to form a multilayered product. It has been found that the pore size is very much de¬ pendent on the concentration of the polymer solution. An example of relationship between pore size and polymer concen¬ tration for a specific copolyurethane is given below. Concentration Average pore size % bγ weight micron 0.20 ' 300-500 1.00 100-300 1.25 50-150 1.45 35- 60 2.00 ' 30- 50 4.00 5- 15 By using the multilayer precipitating technique accor¬ ding to the invention and described above, it is possible to produce a multilayer prosthesis wall for tissue replacement with different pore size in the different layers. For example in a vascular prosthesis it is possible to produce the inner layers e.g. the layers of the lumen of the prosthesis with a relatively small pore size (5-10 microns) to enhance endotheli zation but the center and the outer layers with a relatively large pore size (30-100 microns) to ensure a good tissue in¬ growth. In the method of the present invention the polymer use for preparing the solution for coating the substrate can be a polymer useful in the context, but it is preferred to use a copolyurethane, particularly a block or segmented copolyureth The technique of this invention permits easy productio of multilayered products with different average pore sizes of the individual layers. This is done by varying the concentrat¬ ion of polymer in the casting solution, i.e. the solution to be applied onto the substrate. This is useful for example for the preparation of a vascular prosthesis, where it is desired to have the lumen face of prosthesis with a much lower pore size, such as within the range about 5 to 15 μm. This is to facilitate endothelization after implantation. On the other hand it is desired that the remaining part of the prosthesis wall has larger pores to allow faster tissue ingrowth. As - solvent there may be used any solvent having the ability to dissolve the polymer used, but preferred solvents are those selected from the group consisting of tetrahydro- furane, amide solvents and sulfoxide solvents. Among sucli solvents there may be mentioned in addition to tetrahydro- furane (TMF) dimethylacetamide (DMAc) , dimethylformamide (DMF) and dimethylsolfoxide (DMSO) . Particularly preferred is a mixed solvent of THF and DMF. As a non-solvent there may be used any fluid having the capacity to precipitate the polymer. A preferred solvent is water but also lower alkanols, such as ethanol, may be used, optionally in combination with water. a) The polymer used in forming the solution should be biocompatible and elasticity is preferred in some applicat¬ ions, such as use in vascular prosthesis. The polymer can be natural or synthetic. Examples of the former are polyamino- acids (e.g. polyglycin) , polysaccharides (e.g. cellulose de¬ rivatives, alginates). Examples of synthetic polymers are silicones and polyurethanes. Mixtures of various polymers can also be used. As previously indicated segmented aliphatic polyuretha¬ nes or segmented aromatic polyurethanes may be used in apply¬ ing the technique of this invention. In order to obtain materials which are non-toxic, non-mutagenic and.non-carcino¬ genic it is preferred to use segmented aliphatic polyuretha- nes or using another expression aliphatic block copolymers. The polymeric material for use in the invention may be conventionally prepared from aliphatic polyurethanes based on diisocyanates, e.g. 1 ,2-diisocyanatoethane, 1 ,5-diisocyan- ato pentane, hexamethylene diisocyanate, methane diisocyanato pentane, 1 ,9-diisocyanato nonane, 1 ,8-diisocyanato octane, 1 ,4-diisocyanato butane, 4,4'-methylenebiscyclohexyl diiso- cyanate, lysine diisocyanate, 1 ,4-transcyclohexane diisocya¬ nate, dimethyldiisocyanato silane, diethyldiisocyanato silane. In addition to such diisocyanates there may be used polyols having■average molecular weight within the range of 500 to 10000, e.g. poly(ethylene adipate) , poly(tetra-methylene adipate), poly(1 ,4-cyclohexyldimethylene adipate), poly- (hexamethylene oxalate) , poly(hexamethylene glutarate) , poly(E-aprolactone) , poly(tetramethylene oxide), poly(ethylene oxide), poly(1 ,2-propylene oxide). Chain extenders e.g. 1 ,4-butandiol, 2,4,6-tris(dimethylaminomethyl)phenol glycerol, 3,6-dioxaoctane 1 7 8-diol, ethylene diol, diethylene diol, tetramethylene diamine, ethylene diamine, hexamethylene diamine, propylene diamine. The copolyurethanes are conventionally formed by e.g. reacting a prepolymer such as a polyether diol, with a diisocyanate, and the product resulting from such reaction may then be chain extended by reacting with a diol or diami¬ ne. By such polymerization process copolymers may be produc¬ ed having preferred molecular weights and preferred visco¬ sity in solution. By varying the molecular weight and thus the viscosity of the polymer in solution the rate of degrad¬ ation and porosity of the material prepared may be control¬ led. The selected polymer material is dissolved in a suit¬ able solvent of the type indicated above and the proport- ions between polymer and solvent are suitably selected so as to give the desired percentage of solids in the resulting solution. The coating solution is then used to coat a sub¬ strate to form an initial coating of uniform thickness. As a sub strate there may be used any mechanical means of suitable type, such as a metal plate or a metal mandrel, preferably coated with a resistant plastic, such as polytetrajELuoro ethylene. The coating can be provided by spraying, extrusion, immersion or dipping or in some other conventional manner. The multilayered prosthesis material of the present in¬ vention can be used in a multitude of medicinal applications. Thus, it can be used as a vascular graft, as a skin graft or as a wound dressing. Moreover, it can be used as elastic membranes for ear drum replacement, as elements for ortho¬ pedic surgery and as anticoagulant tubing for blood trans¬ fusion. b) For use in a graft or a wound dressing a multilayered composite material can be choosen, where the inner and/or the outer layer consists of a porous degradable polymer, e.g. polyhydroxybutyrate or a polysaccharide to enhance endothelia- tion and epitheliation respectively. The invention will now be further described by specific examples which,however, must not be construed to limit the scope of the invention. EXAMPLE I - General procedure Preparation of casting solution Segmented polyurethane was dissolved in dimethylformamid (DMF) at 23°C (2wt-.) solution and then precipitated with wate to remove the oligomeric fractions thereof. Precipitated polymer was dried to constant weight and then dissolved in tetrahydrofuran (THF) . The concentration of polymer in solution was in the range of 0.1-4 wt-., being de¬ pendant on the purpose of the use of the solution. In general, more concentrated solutions are required for preparation of reinforced vascular prostheses while more dilute solutions are needed for the preparation of e.g. wound dressings or artifi¬ cial skins. The resulting polymer solution was heated to 25°C and water was then added dropwise while the solution was stirred vigorously. The amount of water which can be added to the polymer solution at the given temperature without causing the polymer to precipitate is dependant inter alia on the molecular weight and the molecular weight distribution of the polyure¬ thane used and the concentration of polymer in the solution. In general less water (non-solvent) can be added to a solution prepared from a polmer of high molecular weight and broader molecular weight distribution. The presence of water in the polymer solution affects the porosity of the resulting product. It has been found, that the more water is added to the polymer solution, the larger the pores formed. From the polyurethane solutions described in this ex¬ ample, various medical goods can be produced e.g. vascular prostheses, wound dressings, microporous patches etc. These products can be produced using commonly used techniques, e.g. dip-coating, spraying j painting, brushing, blade-coating, etc. The products can be prepared in one operation or in se¬ veral similar operations, e.g. for the preparation of vascular prostheses composed of several layers of varying porosities. Applying the polymer solution to the substrate results in fast precipitation of polymer which is due to evaporation of solvent from the polymer-solvent-non-solvent ternary system. It has been found to be preferred that after depositing the polymer layer on the substrate, excess of solvent is dried or pressed out from this layer, before the subsequent layer is deposited on the previous one. This measure contributes to the formation of strong mechanical binding between the layers for¬ ming the structure of the product and assists in avoiding se¬ paration of the layers upon implantation. EXAMPLE II Preparation of vascular prostheses Polyetherurethane prepared according to the procedure outlined in Example I above with a molecular weight of 1.0 x 10 was dissolved in tetrahydrofuran to prepare a solution with a concentration of about 2 wt-.. The polymer solution was heated to about 25°C and then about 20 wt-. of water (based on a total volume of solvent) was added to the solution under stirring. Stainless steel bars covered with polytetrafluoroethylen (PTFE) were dip-coated with the polymer solution, and about 5 minutes later excess of solvent-non-solvent residue was re¬ moved from the polymer precipitate by applying to the polymer layer an absorbing paper. The dip-coating procedure was re¬ peated 40 times to produce a composite, mechanically strong and highly elastic vascular prosthesis. The prostheses on the moulds were soaked for 16 hours in deionized water, were then removed from the mould and soaked again for 5 hours. The prostheses were dried at 40°C in a vacuum oven before sterilization with ethylene oxide. Prostheses prepared in this manner when implanted in pigs show satisfactory low thrombogenic activity, fast endo- thelialization and regular tissue ingrowth. EXAMPLE III Preparation of a microporous patch (artificial dermis) A polyesterurethane with an average molecular weight of 3.0x10 based on hexamethylene diisocyanate, poly(ethylene adipate) and 14-butadiol was dissolved in a mixture of tetra- hydrofuran-dimethyl-formamide (9.8/0.2 vol/vol) to produce a polymer solution with a concentration of polymer of 0.7 wt-!. The polymer solution was stirred, heated to 28°C and then 20 vol-_ of water (calculated on the total amount of solvent) was added dropwise to the solution. The polymer solution wa.s sprayed against polished PTFG plates. The resulting macroporous patches were finally soaked for 16 hours in deionized water and subsequently dried. The macroporous patches with a porosity in the range of 100-150 μm were used to cover full thickness skin wounds. It was found that this treatment stimulates the healing process of non-infected wounds. EXAMPLE IV Artificial skin Polyetherurethane based on hydrolytically stable cyclo- aliphatic diisocyanate (Texoflex -80a) was dissolved in a tetrahydrofuran-water-mixture (99/1 vol/vol) at 30°C. The con¬ centration of polymer in the mixture was 0.75 wt-.. The polymer solution was sprayed against the microporous polyurethane' patch described in Example III. As a result of spraying, a bilayer membrane was formed composed of an upper protective layer with a porosity in the range of 0.4-0.9 μm and a sublayer with a porosity in the rang of 100-150 μm. This composite membrane is nontoxic, nonmutagenic and noncarcinogenic. The bilayer membrane was used to cover donor sites and full-thickness skin wounds of guinea-pigs. It is found that th membrane protects satisfactorily against bacterial invasion an assures proper water and gas transport to and from the wound. The use of the membrane facilitates the healing process of non infected wounds of guinea-pigs.

Claims: CLAIMS 1. A method of producing a mono- or multilayered pros¬ thesis material for use with a living body, said material sho¬ wing mechanical compliance vis-a-vis soft body tissue and posses¬ sing biocompatibility, said method comprising the steps: (a) preparing a polymer solution using a mixed solvent, said solution being near its precipitation point; (b) coating a substrate and precipitating thereon the polymer to form a physically stable porous structure by evaporating at least part of the solvent fraction of the mixed solvent. 2. The method of claim 1, wherein the mixed solvent com¬ prises as a first constituent a fluid which is miscible in said solvent but functions as a precipitating non-solvent with re¬ spect to the polymer, and further comprises as a second consti¬ tuent a solvent for the polymer, said second constituent having a higher rate of evaporation than said first constituent. 3. The method according to any preceding claim, charac¬ terized by using a copolyurethane in step (a) . 4. The method according to claim 3, wherein the polymer is a segmented copolyurethane. 5. The method according to any preceding claim, wherein the solvent is selected from the group consisting of tetrahydro- furane, amide solvents and sulfoxide solvents. 6. The method according to any preceding claim, wherein the non-solvent is selected from water and lower alkanols. 7. The method of any preceding claim wherein step (b) is repeated as required to form a multilayered material. 8. The method of any preceding claim, wherein by vary¬ ing the concentration of polymer in the solution of step (a) a multilayered material is produced wherein the different layers have different average pore sizes. 9. The method of any preceding claim, wherein the solu¬ tion prepared in step (a) contains less than about 5 % by weight and especially less than about 3. of polymer. * 10. The method of any preceding claim, wherein the eva¬ poration is carried to a point where some solvent is left in each preceding layer when the subsequent layer is applied. 11. A multilayered prosthesis material prepared by the process of any preceding claim, comprising several porous layers of block copolyurethane interconnected by linking fibres integra with the respective adjacent layers. .12.. The material of claim 11 wherein the different lay ers have different average pore sizes. 13. The material of claim 11 or 12 in the form of a vas cular graft, a skin graft or a wound dressing. 14. The material of claim 11, 12 or 13 wherein the thi ness of each layer is about 0.01 to 1 mm. 1 . The material of any of claims 11-1 containing up t about 100 layers. 16. The material of any of claims 11)-15, wherein the po size is within the range about 1 to 100 ,um. 17 -The material of claim 11 in the form of a wound dre sing composed of a first degradable porous membrane facing the wound and a second non-degradable protective membrane allowing fluid transport and preventing bacterial invasion. 18. Prosthesis material whenever prepared by the method of any of claims 1 to 10.

Inventors: GOGOLEWSKI SYLWESTER, GOGOLEWSKI, SYLWESTER
Applicants: WALLSTEN HANS IVAR, WALLSTEN, HANS, IVAR
Application year: 1985
Main classification: A61L27
IPC codes: A61L15, A61L26, A61L27