DE3107542C2 - Polymer mixtures with improved blood tolerance, process for their preparation and their use in the production of biomedical devices - Google Patents

Description

The invention relates to polymer mixtures with reduced free upper surface energy and improved blood tolerance and procedures their manufacture. The invention further relates to the use of these Polymer mixtures for the production of biomedical devices or Parts thereof or for coating the surfaces of biomedizini devices or parts thereof that come into contact with blood.

A widely accepted hypothesis on the compatibility of materials with blood states that it is maximized within a narrow range of free surface energy, thereby causing an advantageous interaction with plasma protein. A common measurement of the free surface energy is carried out by the critical surface energy (γ _c ) according to Zisman. The optimal value was determined empirically and lies in the range of the values for γ _c of about 20 to 30 dynes / cm (cf., for example, BRA Baeir, Ann. NY Acad. Sci. 17, page 283 (1977)).

Common polymers (e.g. polyurethanes), which have the desired physics properties for the surface that comes into contact with blood of biomedical devices are often not included this area of critical surface tension.

It is known that polysiloxanes have a particularly low value for have the critical surface tension and it was therefore before  struck to incorporate them in polyurethane to make the surface inherent to improve such materials. However, be knows that polysiloxanes themselves have a tendency from the polyure than base polymer to be excreted, as described in US Pat 3,243,475.

U.S. Patent 3,562,352 discloses polysiloxane-polyurethane block copolymers proposed for use to measure the surface properties of Blood-touching surfaces of biomedizini components to modify shear devices. The one described for this use Technique involves making everything in contact with blood coming device from such block copolymers or the coating device with the copolymers. The block copolymers have even poor structural features due to the high content Polysiloxane. On the other hand, the coated materials are special expensive to form, since it is not by thermoplastic processes are to be processed, such as by an injection molding process or by extrusion. The manufacture of pipes, catheters and other devices exposed to blood from such devices Materials is particularly expensive due to the need for an order application of the technique of manufacturing from solutions.

There is some experimental work on the mixing problem of block copolymers of polydimethylsiloxane with homopolymers of higher critical surface tension have been published. It's be knows that these materials have films with high siloxane surface areas result in concentrations. It will refer to the following publications referenced: D.G. Legrand and R.L. Gaines, Jr., Polym. Prepr. 11, Page 442 (1970); D.W. Dwight et al., Polym. Prepr. 20, (1), page 702 (1979); J.J. O'Malley, Polym. Prepr. 18, (1977). However describe all these literature references the polymer mixtures under science aspects without any indication that this mate rialien progress in biomedical application bring.  

The invention is concerned with the technical problem, Polymerengemi create with low free surface energy that for the Use as a surface of a medi in contact with blood cinical device are suitable. These new polymer blends are said to be inexpensive and quick to process and excellent technical Have properties. Other objects and features of the invention become from the following description of the preferred embodiment shape clearly.

According to the invention, this profile of properties is found in a mixed polymer which consists of at least 95% by volume of a base polymer and at most 5% by volume of an additional polymer and has a free surface energy γ _c of 10 to 35 dynes / cm, the add-on polymer in is dispersed in the base polymer, has a free surface energy γ _c which is lower than that of the base polymer and comprises a polydialkylsiloxane segment which is chemically bonded to a polyurethane segment.

The additive polymer comprises at least two different homopolymer Segments, preferably in the form of a graft or block copolymer. The Polydialkylsiloxan segment has a low free surface energy, while the other segment is characterized by the ability net, the tendency of this material to separate from the base polymer to reduce. Preferably the base polymer and the second are Component of the additional polymer from the same material, preferably made of polyurethane. The additional polymer serves to reduce the criticality surface tension of the base polymer to make it compatible with blood to design.

Typical base polymers whose surfaces are improved according to the invention can be, are polyurethanes, polysulfones, polycarbonates, poly esters, polyethylene, polypropylene, polystyrene, poly (acrylonitrile buta diene-styrene), polybutadiene, polyisoprene, styrene-butadiene-styrene block copolymers, styrene-isoprene-styrene block copolymers, poly-4-methylpen ten, polyisobutylene, polymethyl methacrylate, polyvinyl acetate, poly acrylonitrile, polyvinyl chloride, polyethylene terephthalate, cellulose and their esters and derivatives, but polyurethanes are preferred.  

The base polymer must be suitable for a self-supporting structure relle body or a self-supporting film shaped or as Be Layering can be applied to a self-supporting body can.

Another property of the base polymer is that its kri diagram surface tension (γ _c) lies above that which is Wanting's value for a blood-contacting land surface and also higher is than the critical surface tension of the Zusatzpoly mers that the γ _c - Base polymer value decreased. Measurements of γ _c are carried out using the direct method using a measuring device for measuring the contact angle according to Kernco or Rame-Hart and a sequence of seven solvents, according to the method according to Zisman (AW Adamson, Physical Chemistry for Surfaces, pages 339 to 357 , 351 (3rd edition)). The measurements are carried out at room temperature using increasing angles of solutions cast into films which have been annealed for 4 hours at 60 ° C. The main contact angles are assembled into a Zisman curve using a linear regression calculation program.

It has been found that the homopolymer component of the additive polymer with the lowest value for γ _{c determines} the γ _c value of the total additive polymer. If, for example, the first component has a γ _c value of 25 and the second component has a γ _c value of 35, the total γ _c value of the additional polymer is approximately 25.

According to the invention, the homopolymer for the first component with a γ _c value in the desired range in order to reduce the value of the base polymer is polydialkylsiloxane, preferably polydimethylsiloxane. Polydimethylsiloxane has a γ _c value of approximately 22 dynes / cm. The techniques for forming siloxane copolymers for use in the invention are known, for example from W. Noll, Chemistry and Technology of Silicones (Academic Press, 1968).

If the polymer mixture according to the invention is formed by mixing a pre-formed additional polymer of the type mentioned above with a base polymer, such an additional polymer is expediently made from block copolymers or alternating first and second components which are linked to one another by chemical bonds, according to the known Techniques formed. For example, such block copolymers can be formed in accordance with the aforementioned Noshay and McGrath publications. A suitable number of repeating units of each homopolymer of the first component is that sufficient to maintain the γ _c value of the homopolymer, as evidenced by maintaining about the same glass transition temperature as that of the pure homopolymer. Typically this number is on the order of 5 to 10 units or more. Similarly, there should be a sufficient number of repeating units of the second component in one segment so that the additive polymer is solid at room temperature.

The production of block copolymers (or multipolymers) can by Different procedures are carried out, which differ from each other differ in the extent to which the structure of the Pro product can be defined.

One method involves coupling two (or more) preformed ones Blocks in two separate reactions before the coupling reaction have been produced. This procedure leads to a very de structure when the linking reaction is the implementation of Excludes blocks with itself and just linking different blocks with each other.

A structure that is only slightly less well defined results if two preformed blocks have the ability (via a link re action) with yourself as well as with different blocks react.

An even worse defined structure results when a single ner (or more) preformed block with a second block, the is created during the linking reaction. In  in this case the initial length of the preformed block is known (due to the separate reaction used to make it ), but the sequence distribution of the copolymer is not accurate known because of both a link and chain growth the second reaction is possible, which generates the second block. Suitable procedures for training one type or another of these Copolymers for use in the invention are known from the above named publication by Noshay and McGrath.

The additional polymer according to the invention consists of a block or Graft copolymer segment of a polydialkylsiloxane, preferably one Polydimethylsiloxane, as the first component and a polyurethane seg ment as a second component. The term "poly urethane "includes polyurethane ureas, polyether urethanes, polyesters urethanes and other known polyurethanes, such as be are described in U.S. Patent 3,562,352 (column 2, lines 66 through Column 3, line 37). This copolymer can be made with any base polymer mixed with the desired physical properties will. According to the invention, it is particularly effective for mixing the to use the same type of base polymer as the second component, which improves compatibility.

If desired, three or more types of polymer chains can be used in a sequence, as long as at least one type has a low value for γ _c . An excellent terpolymer additive includes a block copolymer segment of the first and second components. The second component is connected to a segment, which is specifically made of either polyethylene oxide or polyethylene oxide-co polypropylene oxide and is hereinafter referred to as "hydrophilic component". In this case the second component is a hard block with a crystalline melting point above 37 ° C or a glass transition temperature above 37 ° C. In a terpolymer of this type, the second component combines the first component and the hydrophilic component. In a preferred terpolymer, the first component is a polydialkylsiloxane segment, the second component is a segment made of polyurethane and polyurea urethane.

The hydrophilic segment is either a polyoxyethylene or a poly oxyethylene-polyoxypropylene segment. This terpolymer gives an un expected improvement in blood compatibility for a base polymer with the desired structural properties.

The ratio of the first and second components in the additive polymer can vary to a remarkable extent as long as there is sufficient amount of the first component to reduce the γ _c value and there is a sufficient amount of the second homopolymer to do so To prevent the additional polymer from excreting. It is preferred that the additive polymer comprise at least about 20% by volume of the first component. A suitable ratio is in the range of 20 to 80% by volume of the component of the first type and approximately 20 to 80% by volume of the component of the second type of polymer.

The total amount of the additional polymer, which is required to reduce the γ _c value of the base polymer to the desired value for the polymer mixture, is very small. For example, it was found that less than 5% by volume and preferably less than 1 to 2% by volume of the total additive polymer fulfills this function. A suitable ratio of additive polymer to base polymer is in the size of 0.00002 to 2% by volume of additive polymer based on the total polymer mixture. Experimental results have shown that even when the additive polymer is originally mixed with the mass of the base polymer, it migrates to the surface and forms an extraordinarily thin (monomolecular) film which provides the desired surface properties. A sufficient amount of additive polymer should be present to provide this uniform layer. The presence of an adequate amount of additive polymer is indicated by a dramatic drop in the γ _c value of the polymer mixture to approximately the value of the first component. While the required amount differs from system to system, it is generally less than 1% by volume of the first component, based on the total polymer mixture. It is advantageous to use such small amounts of the additional polymer, since large amounts of the first component can be disadvantageous for the physical properties of the polymer mixture.

It was found that the minimum amount of additional polymer required approximated by knowledge of the film thickness of an additional polymer mono layer and the ratio of the surface area to the bulk toluene men of the manufactured material can be determined. This attached approximate determination is based on the simplifying assumption that before Saturation of the surface essentially on the entire additional polymer the surface drifts. By simple calculation, this can be minimal Amount can be calculated based on this knowledge.

The polymer mixture according to the invention can by means of a number of Techniques can be obtained. According to one technique, both are Base polymer and the additional polymer thermoplastic and at elevated melted temperatures to allow mixing. Successor The polymer is solidified by cooling. If desired, can the polymer mixture according to the invention simultaneously with the desired one final form will be processed. Alternatively, the material for the subsequent formation of the material to the desired shape by thermoplastic processes such as injection molding and extrusion be solidified.

Another technique for mixing the additive polymer and the base polymers sees the dissolution of both in a solvent and that subsequent evaporation of the solvent before, whereby the fiction appropriate solid product is formed. This product can subsequently, if desired, also processed thermoplastic will.

A third technique for forming the polymer mixture according to the invention It is in-situ polymerization with a large excess (e.g. of at least 95 vol .-%) of the base polymer and a smaller amount (for example at most 5% by volume) of an addition of the first compo as previously described. For example, a with Low hydroxylpropyl terminated polydimethylsiloxane Molecular weight instead of a small amount of polyether glycol in the synthesis of a typical polyether urethane. Here can the reaction product contains enough silicone / polyurethane block copolymer  to provide the desired surface properties put. The concentration of the additional polymer is so low that the large excess (for example at least 95% by volume) of the base poly mers is not linked to the additional polymer.

The additive polymer of the invention must be thorough in the base polymer be dispersed. For this purpose it is preferred that the additive polymer thermoplastic, soluble in organic solvents and right is relatively little networked.

For most biomedical applications, the Invention Base polymers are thermoplastic, so that if the ge wishes can be processed quickly. However, there are users areas in which the polymers are processed in liquid form can be and subsequently ver to the shape of the manufactured parts can be consolidated, which does not return to the liquid form can be returned. For example, such a base contain polymer thermosetting systems, which immediately after the dispersion of the additional polymer can be cured or vulcanized. These systems can be 2-component polyurethanes or epoxy resin systems include.

The base polymer has end groups that give it high free surfaces Convey energy and especially for hydrogen bonding or reak tion with protein, it is preferred to add the base polymer next fraction to a lower molecular weight fraction separating important and thereby the ability of the hydrogen bond of to reduce the remaining base polymer. Appropriate techniques for Implementation of this method are from the literature (Manfred J.R. Cantow, Polymer Fractionation, Academic Press (New York - London 1967)). These techniques include the liquid chromatography, especially gel chromatography.

It has been found that changes in the process conditions, which would influence the free surface energy to a significant extent, can be minimized in the polymer mixtures according to the invention by the application of a short heat treatment following the surface formation. For example, in a system with a base polymer made of polyether urethane and an additional polymer made of polyether urethane / polyalkylsiloxane, heating for four hours at 75 ° C leads to a γ _c value which corresponds approximately to that of pure polysiloxane, while it takes a remarkably longer time to do so Carry out task at room temperature.

It has also been found that the polarity of the environment around the formation affects the γ _c value of the surface. For example, a surface that is balanced with air provides a lower γ _c value than a surface that is balanced with water.

The polymer mixtures according to the invention are particularly effective in use as surfaces in contact with blood biomedical device or a part thereof. Such devices around include auxiliary ventricles, intra-aortic recipients and various types of blood pumps.

A further explanation of the nature of the present invention is provided with means of the following special practical examples spelled out. The specified data are only for example Specification and do not limit the invention.

example 1 Typical synthesis of a polydimethylsiloxane-polyurethane block copoly mers

In a 500 ml, with a stirrer, a Dean-Stark sheath funnel, a dropping funnel, a drying tube, a thermometer and an inlet for an inert gas-equipped four-necked flask was turned on Mixture of 50 ml of dimethylformamide and 140 ml of tetrahydrofuran added. The mixture was heated under reflux and about 40 ml of tetrahydro furan were distilled off. The reaction mixture was cooled and 12.513 g (0.05 mol) of methylene bis (4-phenyl) isocyanate (MDI) were added  set. A clear solution was obtained. Over the dropping funnel 15,000 g (0.015 mol) of polydimethylsiloxane with 3-hydroxypropyl End groups (molecular weight ≈ 1000) added dropwise. The reak tion mixture was heated at 105 to 100 ° C for 1 hour, then were dropwise 3.15 g (0.035 mol) of 1,4-butanediol within 45 minutes added. The polymerization was carried out for 15 minutes or more leads, then was cooled and poured into water in one Mixer failed. The slightly yellow polymer was washed with water wash and finally washed with ethanol and in a vacuum Drying cabinet dried at 50 ° C. There were about 30 to 31 g of polymer (98 to 100%). The value [η] in tetrahydrofuran at 25 ° C was 0.19.

Example 2

By replacing part of the polydimethylsiloxane with hydroxypropyl End groups by polyethylene glycol became a polydimethylsiloxane / Po made of ethylene oxide / polyurethane terpolymer.

Example 3

By replacing the DMF solvent with dimethylacetamide and replacement of butanediol by ethylenediamine in Example 2 became a polydime thylsiloxane / polyethylene oxide / polyurea urethane terpolymer poses.

Example 4

This example illustrates the preparation of the solution. It was prepared a solution containing about 10 wt .-% mixture in a Lö solvent system made of 90% tetrahydrofuran (volume / volume) and 10% Contained dimethylformamide. The mixture consisted of 99.9% by weight nended polyester urethane and 0.1 wt .-% silicone / polyurethane block co polymer. The block copolymer consisted of about 50% by weight polydimethyl siloxane and 50 wt .-% polyurethane from diphenylmethane diisocyanate and Butanediol.  

The solution was made on conical mandrels made of corrosion-resistant applied in steel by multiple dips. The solvent evaporated and the film was peeled off the mandrel. The received one "Balloon" was pulled onto a pre-drilled catheter and was ge is suitable as a cardiac arrest device Introduction to the downward leading aorta and was inflated with CO₂ sen and sank again together with counterpulsation to the heart.

The γ _c value of the balloon film was 20 to 22 dynes / cm.

Example 5

Small test tubes were placed on their inner surfaces with two under different polymer solutions (in THF) in a concentration of 10 wt .-% coated. One solution contained polyether urethane in the Solvent. The second solution contained 90% by weight of solvent, 9.9% by weight of polyether urethane and 0.1% by weight of copolymer additive. The copo lymer consisted of about 50% polydimethylsiloxane and 50% polyethylene oxide / copolypropylene oxide, which is available from Petrarch Systems under the trade name PS 072 is distributed.

After evaporation of the solvent and approximately 16 hours of equilibrium fresh pure blood was placed in the distillation water introduced three tubes of each type.

The tubes coated with the unmodified polyether urethane gave an average coagulation of the whole blood within 39 minutes. The with polyether urethane with the addition of poly mers coated tubes resulted in an overall coagulation of the total blood after more than 70 minutes.

The γ _c value of the unmodified polyether urethane is about 28 dynes / cm. The γ _c value of the polyether urethane with the addition of the additional polymer is about 20 dynes / cm.

Example 6 This example illustrates thermoplastic manufacturing

A thermoplastic polyurethane was mixed in a screw extruder at about 204 ° C (400 ° F) with an additional polymer of about 50 wt .-% polydimethylsiloxane and 50 wt .-% polyether urethane so that the total silicone concentration of the mixture was 0.01 % By weight. The mixture was extruded into a tube system suitable for blood transfer. The tube system has a γ _c value of approximately 21 dynes / cm after heating at 60 ° C. for 6 hours.

Example 7 This example illustrates 2-component vulcanization

A prepolymer provided with polyether urethane isocyanate end groups DuPont (Adipren L-167) was developed according to the manufacturer's recommendations lers for polyol curing using a gerin gene stoichiometric deficit on butanediol / trimethylolpropane Ge mix. 0.1% by weight of the additional polymer was still in the liquid state ver according to Example 1 with the reactants and an amine catalyst mixes.

The mixture obtained was applied to a previously primed titanium alloy finally applied and hardened in an oven at 100 ° C.

The coated connector had a γ _c of about 20 dynes / cm and was contacted with blood to connect a lead to an auxiliary device in the left ventricle, which is used to treat the low cardiac output (low cardic output syndrome).

Example 8

A 4 mm tubular prosthesis was formed by coating a mandrel made of corrosion-resistant steel with a polymer mixture 99.9% by weight of polyether urethane and 0.2% by weight of polydimethylsil oxane / polyurethane block copolymer made of 50% polydimethylsiloxane and 50% Polyurethane in a solution made from dimethylacetamide. After evaporating the The tube obtained was removed from the mandrel by solvent, Extracted with distilled water at 60 ° C. for 16 hours, dried and heated at 60 ° C for 4 hours. After sterilization with ethylene the tube was inserted into the large carotid artery of a goat sews.

Using an established technique for using radio actively marked platelets did not accelerate blood platelet conversion measured relative to a simulated experiment. A corresponding experiment easily detected changes in blood platelet conversion in polyvinyl chloride tubes, it being known that Polyvinyl chloride has a low tolerance to blood.

Claims (13)

1. Polymer mixture with reduced free surface energy and improved blood tolerance, characterized in that it consists of at least 95 vol .-% of a base polymer and at most 5 vol .-% of an additional polymer and has a free surface energy γ _c of 10 to 35 dynes / cm , wherein the additional polymer is dispersed in the base polymer, has a free surface energy γ _c which is lower than that of the base polymer and comprises a polydialkylsiloxane segment which is chemically bonded to a polyurethane segment. 2. Polymer mixture according to claim 1, characterized in that the Additive polymer in the polymer blend in an amount of 0.00002 up to 2 vol .-%, based on the polymer mixture, is contained. 3. Polymer mixture according to claim 1 or 2, characterized in that the additional polymer is a graft or block copolymer. 4. Polymer mixture according to one or more of the preceding An sayings, characterized in that the base polymer is a polyure than is. 5. Polymer mixture according to one or more of the preceding An sayings, characterized in that the base polymer is free of is low molecular weight. 6. Polymer mixture according to one or more of the preceding An sayings, characterized in that the polydialkylsiloxane seg ment of the additional polymer is a polydimethylsiloxane segment. 7. Polymer mixture according to one or more of the preceding An sayings, characterized in that the additional polymer 20 to 80 vol.% Of the siloxane segment and 80 to 20 vol.% Of the urethane Segment includes.   8. Polymer mixture according to one or more of the preceding An sayings, characterized in that the additional polymer has a ternary res polymer and in addition a polyoxyethylene or a poly oxyethylene-polyoxypropylene segment. 9. A process for the preparation of a polymer mixture according to one or several of the preceding claims, characterized in that the melt of the additional polymer in the melt of the base poly mers dispersed and the melt mixture obtained solidify leaves. 10. A process for the preparation of a polymer mixture according to one or several of claims 1 to 8, characterized in that one the base polymer and the additive polymer in a common solution dissolves solvent and then distilled off the solvent. 11. A method for producing a polymer mixture according to claim 9 or 10, characterized in that before mixing the Base polymer with the additional polymer of the base polymer, the low separates rigmolecular fractions in a manner known per se. 12. The method according to claim 11, characterized in that one of the low molecular weight components of the base polymer through liquid, especially gel chromatography. 13. Use of polymer mixtures according to Claims 1 to 8 for the preparation provision of biomedical devices or parts thereof or for Coating the surfaces of biomedical devices or Parts of it that come into contact with blood.