JPH0214062B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to polymeric surfaces useful as blood-contacting surfaces in biomedical devices and methods for their manufacture.

A widely accepted hypothesis regarding coexistence with blood (blood compatibility) is that the coexistence compatibility is highest within a narrow range of surface free energies;
This surface free energy is enhanced for favorable interactions with plasma proteins. The usual method for measuring surface free energy is Zisman.
This method uses the critical surface tension (γc) of It has been empirically found that the optimum value for this measurement lies in the range where γc is equal to about 20-30 dynes/cm. Literature [e.g. RABaeir, Ann.NYAcad.
Sci.17283 (1977)].

Although common polymers (eg, polyurethanes) possess desirable physical properties for blood contacting surfaces of biomedical devices, they often do not fall within the optimum range of critical surface tensions described above.

Since polysiloxanes exhibit particularly low values of critical surface tension, it has been suggested that polysiloxanes be added to polyurethanes to improve the surface properties of the polyurethanes. However, it is known that polysiloxane itself has a tendency to leach out of the polymer of the polyurethane matrix, as reported in the patent literature (Reishl et al.
al., USP 3243475).

The use of polysiloxane-polyurethane block copolymers to modify the surface properties of blood-contacting surfaces of biomedical devices has also been reported in the patent literature (Nyilas et al.
USP3562352). Techniques disclosed for this application include fabricating the entire blood contacting device with the block copolymer or coating the device with the copolymer. Block copolymers themselves have poor structural properties due to their high proportion of polysiloxane. On the one hand, block copolymers cannot be processed by thermoplastic methods, such as injection molding and extrusion methods, so forming coatings with these materials is particularly expensive. Pipes made of this material,
The manufacture of catheters and other blood-contacting treatment devices is extremely expensive due to the necessity of using solution polymerization fabrication techniques.

Some experimental work has been published regarding the incorporation of high critical surface tension homopolymers into block copolymers of polydimethylsiloxane. This material has been shown in the literature to be useful for producing siloxane films with high surface concentrations [e.g. D.
G.Legrand and RLGaines, Jr., Polymer
Prepr.11442 (1970); DWDwight et al.
Polym.Prepr.20, (1), 702 (1979); and JJ
O'Malley, Polym. Prepr. 18 (1977)]. However, all these documents only describe polymer mixtures in the context of scientific experiments without giving any suggestion that the materials can be usefully utilized in biomedical applications.

The object of the present invention is to develop a new type of material which is inexpensive, easy to process, characterized by excellent mechanical properties and has a low value of surface free energy for use as a surface of blood-contacting medical devices. Provided by polymers. Other objects and aspects of the invention will become apparent from the following description of preferred embodiments of the invention.

In line with the above objectives, a new technique for forming blood-contacting exposed surfaces of biomedical devices or components thereof has now been provided by the present invention. In one embodiment of the invention, a mixed polymer is created by adding and dispersing a small amount of additive polymer into the base polymer. In this case both polymers are fluids. The additive polymer preferably has at least two different homopolymer chains in a copolymer in the form of a graft or block copolymer. One of the chains is a chain with a low surface free energy (e.g. polysiloxane) and the other chain is characterized by its ability to reduce its tendency to exude from the substrate polymer. It is a chain of materials. Preferably, the base polymer and the second component of the additive polymer are of the same material (eg polyurethane). The additive polymer serves to reduce the critical surface tension of the matrix polymer to provide coexistence compatibility with blood.

One main aspect of the present invention is to provide a technique for converting a material surface unsuitable for blood coexistence into a surface compatible with blood coexistence by reducing the surface free energy of a polymer having a good structure. The term "matrix polymer" as used herein refers to the polymer whose surface properties are to be modified in this way. The substrate polymer whose surface is to be improved according to the technique according to the invention is polyurethane.

The matrix polymer is a type of polymer that can be formed into a self-supporting structure, a self-supporting film, or deposited as a coating on a self-supporting surface. The end use of the final product is as a surface for a biomedical device or component.

Other properties of the matrix polymer include a surface tension higher than the critical surface tension (γc) desired for the blood-contacting surface and a higher γc value than the additive polymer (see below) that lowers the γc value. It is the property of having. Zisman procedure [AW
Adamson, Physical Chemistry for Surfaces
339-357351 (3rd Ed.)] and a series of 7 contact angle meters (Kernco or Rame-Hart type).
The γc value is measured by a direct method using a seed solvent. In this case, a dip-molded film (solvent
The measurements are carried out at room temperature using increasing angles on cast films. linear regression calculation method
Fit the average contact angle to a Zisman plot using a calculator program.

In accordance with the present invention, a substrate polymer of the type described above is mixed with the additive polymers indicated below to reduce the surface free energy of the substrate polymer. An additive polymer having a γc value substantially lower than the γc value of the matrix polymer is dispersed throughout the fluid matrix polymer to form a fluid polymer mixture. This polymer mixture is then solidified to form the blood contacting surface of the biomedical device or component. The surface free energy of the polymer mixture has a wide favorable range of 10 to 35 dynes/cm, and a preferable range of 20 to 35 dynes/cm.
30 dynes/cm, with an optimal range of 20-25 dynes/cm.

The additive polymer has at least two different homopolymer chain components with different functional properties.
One homopolymer chain (abbreviated as “first component”)
is more than the matrix polymer and the other “second component”
(see below), which lowers the γc value of the mixed polymer. This type of curved material has a tendency to exude from the matrix polymer in mixed polymers.

To prevent oozing, a second homopolymer chain (abbreviated as "second component") is chemically bonded to the first component of the polymer to reduce this oozing tendency. The second component is from the literature [A.Noshay and JE
McGrath, Block Copolymers Overview and
Critical Survey (Academic Press (1977)) describes hard block polymer segments useful in the production of thermoplastic block copolymers.
For biomedical applications, the hard block may be selected from the group of "blcok" polymer segments) whose crystalline melting point is greater than about 37°C and/or whose glass transition temperature is also about 37°C. ℃
It is characterized by being larger than. The second component has a higher surface free energy than the first component. For compatibility purposes, it is preferred that the second component is made from the same type of polymer as the substrate copolymer.

The additive homopolymer component with the lowest γc value was found to control the γc value of the total additive polymer. That is, for example, the first component has a γc value of 25,
If the second component has a γc value of 35, the total γc value of the annealed additive homopolymer is approximately 25.
becomes.

Homopolymers suitable as the first component are those having a γc value within a range that reduces the γc value of the matrix polymer to reach that value desired for blood cocompatibility. Therefore, the first component is its γc
Preferably, it is characterized by a value of less than 30 dynes/cm. A particularly useful homopolymer for this purpose is polydimethylsiloxane, which has a γc value on the order of 22 dynes/cm. The manufacturing technology of the siloxane copolymer used in the present invention is described in the literature [e.g. W. Noll.
Silicones (Academic Press, 1968)] as described. Suitable first component homopolymers also include polydialkylsiloxanes.

Mixed polymers according to the invention are produced by adding and mixing a preformed additive polymer of the type described above to a matrix polymer. Suitably, the additive polymer is formed from a block copolymer of first and second components alternately interconnected by chemical bonds in accordance with existing technology. The block copolymers are prepared, for example, according to Noshay and McGrath, supra. The appropriate number of repeating units for each homopolymer of the first component is sufficient to maintain the homopolymer's γc value as evidenced by having a glass transition temperature that is approximately the same as that of the pure homopolymer. be. Typically this number will be on the order of 5 to 10 units or more. Similarly, the number of repeating units of the second component within the segment should be sufficient for the additive polymer to be solid at room temperature.

There are several methods for producing block copolymers (or multipolymers), which differ in the extent to which the structure of the resulting product can be determined.

One method consists of coupling two (or more) preformed blocks that have been previously produced in separate reactions prior to the coupling reaction. If similar blocks based on the reaction of similar blocks in the coupling reaction are eliminated and dissimilar blocks are allowed to couple with each other, this method yields products with very well defined structures.

If the two preformed blocks have the possibility of reacting with similar blocks as well as with dissimilar blocks (by coupling reactions), it will give a product with a structure that is better defined, although slightly inferior to that described above. .

Coupling of a single (or multiple) preformed block with a second block produced during the coupling reaction also gives a product with a better defined structure, although less than that described above. In this case, although the initial length of the preformed block is known (during the separate reaction to produce it), the subsequent distribution in the copolymer is not known exactly. This is because in the second block formation reaction, both the coupling reaction and chain growth occur. Suitable methods for making these and other copolymers used in the present invention are disclosed in the above-mentioned literature (by Noshay and McGrath).

The mixed polymer according to the invention comprises as a first component a block or graft copolymer of a poly(dialkylsiloxane), such as poly(dimethylsiloxane), and as a second component a polyurethane. The term "polyurethane" as used herein refers to polyether urethane, polyester urethane, or other known polyurethane, such as the Nyilas patent document [U.S.
P.3562352 (second column, line 66 to third column, line 37)] includes the disclosure. This copolymer can be mixed with a matrix polymer having the desired physical properties. Using the same type of matrix polymer as the second component is particularly effective for providing improved blood compatibility.

Three or more types of polymer chains can be used sequentially if desired, so long as at least one type of polymer chain has a low γc value. An excellent additive terpolymer will contain block copolymer segments of a first component and a second component. The second component is attached to a segment specifically formed from polyethylene oxide or a segment specifically formed from polyethylene oxide-copolypropylene oxide. This component is referred to herein as the "hydrophilic component." In this case, the second component is a hard block with a crystalline melting point of 37°C or higher or a glass transition temperature of 37°C or higher. In this type of terpolymer the second component is combined with the first component and the hydrophilic component. In one example of an excellent terpolymer, the first component is a poly(dialkylsiloxane), the second component is any one of a wide range of groups including polyurethane or polyurea urethane, and the hydrophilic component is polyethylene oxide or polyethylene oxide
It is a copolypropylene oxide. This terpolymer provides unexpected improvements in blood coexistence compatibility for matrix polymers with desired structural properties. This component is, for example, a hard polymer of the same type as the second component.

Other types of linked first and second homopolymers are of the graft copolymer type. The first copolymer or the second copolymer serves as a substrate onto which pendant chains of other types of homopolymers are grafted. Graft copolymer formation methods are well known to those skilled in the polymer manufacturing arts. For example, the above literature (Noshay and
McGrath, pp. 13-23.
The third mechanism shown in this Table 2-1 illustrates a suitable spine structure for the grafting of polydimethylsiloxanes with hydroxyalkyl end groups (e.g., by urethane linkage using diisocyanates). .

The ratio of the first component to the second component in the additive polymer is such that there is a sufficient amount of the first component to reduce the γc value and a sufficient amount of the second component to prevent exudation of the additive polymer. can vary to a considerable extent. The additive polymer is at least about 20
% by volume of the first component.
A suitable ratio is 20-80% by volume of the first polymer component and about 20-80% by volume of the second polymer component.

The total amount of added polymer required to reduce the γc value of the matrix polymer is significantly lower than the amount desired for the blended polymer. The first component typically contains about half or less of the additive polymer, such as less than 5% by volume, preferably 1 to 2% by volume when using silicone as the first component. It has been found that this effect (γc value reducing effect) can be achieved by using the following additive polymers: For suitable ratios of additive polymer to substrate polymer, the amount of additive polymer is from 0.00002 to 2% by volume based on the total mixed polymer. Even if the additive polymer is initially added in a quantity into the substrate polymer and mixed, it will migrate towards the surface and form a very thin (mono-molecular) film, thus providing the desired surface properties. This is an experimentally proven fact. Therefore, a sufficient amount of additive polymer must be added to form a homogeneous layer. The presence of a sufficient amount of additive polymer is evidenced by a dramatic reduction in the γc value of the mixed polymer to approximately the γc value of the first component. The required amount of the first component varies from system to system, but is generally less than 1% by volume of the first component based on the total mixed polymer. It is advantageous to use a small amount of additive polymer, since the use of large amounts of the first component can be detrimental to the physical properties of the mixed polymer.

It has been found that the required minimum amount of additive polymer can be approximately determined by knowing the film thickness of a single layer of additive polymer and the surface area to volume ratio in the fabrication. This is based on the simple assumption that essentially all of the additive polymer migrates to the surface prior to surface saturation. Based on this knowledge, this minimum required amount can be calculated in advance by simple calculations.

A number of techniques can be used to mix the base polymer and additive polymer according to the invention. In one technique, the substrate polymer and additive polymer are thermoplastic and are melted and mixed at elevated temperatures. The polymer is then cooled and solidified. If desired, the bulk polymer can be simultaneously processed into the desired final shape. Alternatively, it may be solidified into the desired shape in a subsequent step by hot molding methods such as injection molding and extrusion.

Another technique for mixing the base polymer and additive polymer is to dissolve both in a solvent and then evaporate the solvent to form the solid product of the present invention. If desired, this product is processed in the next step by a hot molding method.

A third technique for producing mixed polymers according to the present invention comprises combining a large excess (e.g., at least 95% by volume) of the substrate polymer with a small amount (e.g., 5% by volume or less) of the additive polymer of the first component type described above. This method involves polymerization at the site of use. For example, a low molecular weight polydimethylsiloxane with hydroxypropyl end groups is used in place of a small amount of polyether glycol in a curved polyether urethane synthesis. Then the reaction product is a sufficient amount of silicon/
The polyurethane block copolymer content provides the desired surface properties. Since the concentration of additive polymer is low, most (e.g. at least
(95% by volume) of the substrate polymer may not bond with the additive polymer.

The additive polymer according to the invention must be distributed throughout the matrix polymer. For this purpose, the additive polymer is preferably thermoplastic, organic solvent soluble, and relatively non-crosslinked.

For maximum biomedical application, the matrix polymer according to the invention should be thermoplastic and thus can be easily processed as desired. However, in some applications, polymers are manufactured and constructed while in a fluid state and then solidified into the shape of a fabricated part, but cannot become fluid again.
For example, the matrix polymer may include a thermoset system and be cured or vulcanized immediately after dispersing the additive polymer. This system includes two-component polyurethane or epoxy resin systems.

One advantageous system obtainable with the present invention is an additive polymer formed from poly(dialkylsiloxane) segments chemically bonded to polyurethane segments (e.g. in the form of block or graft copolymers) and a suitable matrix polymer, e.g. It includes mixtures obtained by mixing the copolymer with the same type of polyurethane. Particularly effective systems include polyurethane (specifically, polyester urethane) as a substrate polymer with approximately 50% by weight
A suitable ratio is 0.1% block copolymer to 99.9% polyesterurethane base polymer. .

One effective method of pretreatment of substrate polymers to reduce the surface free energy of the substrate polymer is the use of substrate polymers with high energy end groups, particularly end groups with hydrogen bonding ability or the ability to react with proteins. I believe that. In this case, the substrate polymer is first fractionated to separate the lower molecular weight fractions and thereby reduce the hydrogen bonding capacity of the remaining substrate polymer. A suitable technique for making this happen can be found in Kanto's book [Manfred].
JRCantow, Polymer Fractionation,
Academic Press, New York-London 1967. The technique is liquid chromatography, specifically gel permeation chromatography.

Variations in processing conditions that affect the surface free energy to a significant extent can be minimized as a factor in the system of the present invention by using short heat treatments followed by surface formation. For example, in a system consisting of a polyether urethane substrate polymer and a polyether urethane/polyalkylsiloxane block copolymer, when annealed at 75°C for 4 hours, the γc of pure polysiloxane
However, at room temperature it takes a considerable amount of time to achieve this goal.

However, the environmental reactivity of achieving γc (polarity of
It was further found that the environment) influences the γc value of the surface. That is, an air equilibrium surface gives a lower γc value than the γc value in water equilibrium.

The mixed polymers according to the invention are particularly effective for use as blood contacting surfaces of biomedical devices or components. The device includes an auxiliary ventricle, an intra-aortic balloon, and various types of blood pumps.

The features of the invention are further disclosed by the following examples of carrying out the invention. It should be understood that the data presented herein is for illustrative purposes only and is not intended to limit the scope of the invention.

Example 1 This example is a representative example of the synthesis of a polydimethylsiloxane-polyurethane block copolymer.

A 500 ml four-neck flask equipped with a stirrer, a Dean-Stark trap, an addition funnel, a drying conduit, a thermometer and an inert gas inlet was charged with a mixture of 50 ml dimethylformamide and 140 ml tetrahydrofuran. The mixture was heated to reflux and approximately 40 ml of tetrahydrofuran was distilled off. The reaction mixture was cooled and 12.513 g (0.05 mol) of methylene bis(4-phenyl) isocyanate (MDI) was added resulting in a clear solution.
15.000 g (0.015 mol) of 3-hydroxypropyl end group-containing polydimethylsiloxane (molecular weight approximately 1000) was added dropwise from the dropping funnel. The reaction mixture was heated to a temperature of 105-100 °C for 1 hour, then 3.15 g
(0.035 mol) of 1,4-butanediol was added dropwise over 45 minutes. Polymerization was carried out for over 15 minutes, then cooled and the contents were poured into water in a mixer to form a precipitate. The pale yellow polymer was washed with water and finally with ethanol; dried in a vacuum oven at 50°C to yield about 30-31 g (98-100%) of polymer.
[η] value measured at 25℃ in tetrahydrofuran
0.09.

Example 2 By substituting only a certain part of polydimethylsiloxane containing hydroxypropyl end groups with polyethylene glycol, polydimethylsiloxane/
A polyethylene oxide/polyurethane terpolymer was produced.

Example 3 A polydimethylsiloxane/polyethylene oxide/polyureaurethane terpolymer was prepared by replacing the solvent DMF in Example 2 with dimethylacetamide and using ethylenediamine in place of butanediol.

Example 4 This example illustrates production by solution polymerization. Approximately 10% by weight in a solvent system consisting of 90% tetrahydrofuran and 10% dimethylformamide (vol/vol).
A solution containing mixed polymers was prepared. The mixed polymer thus consists of 99.9% by weight pure polyester urethane and 0.1% by weight silicone/polyurethane block copolymer. The block copolymer consisted of about 50% by weight polydimethylsiloxane and 50% by weight "polyurethane obtained from diphenylmethane diisocyanate and butanediol."

This solution was coated by dipping onto a tapered stainless steel mandrel. The solvent was evaporated and the film was removed from the mandrel. The "balloon"-shaped film thus obtained is placed over a pre-perforated catheter and placed in the descending aorta and inflated and deflated with CO ₂ so as to pulse in the opposite direction to the heart. It is useful as a tool to prevent disease progression.

The γc value of this balloon-shaped film is 20 to 22 dyne/
cm.

Example 5 The inner surface of a small test tube was coated with different polymer solutions (in THF) with a concentration of 10% by weight. One solution contained polyether urethane in solvent, and the other, second solution contained 90% by weight solvent, 9.9% by weight polyetherurethane, and 0.1% by weight additive copolymer. This copolymer consists of approximately 50% polydimethyl-siloxane and 50% polyethylene oxide copolypropylene oxide;
It can be obtained from petrarch systems under the trade name PS072.

After solvent evaporation and equilibration in distilled water for approximately 16 hours, whole blood was loaded into three test tubes of each type.

The tubes coated with unmodified polyether urethane had a mean clotting time for whole blood of 39 minutes.
Tubes coated with polyether urethane containing additive block copolymer had mean clot times for whole blood of greater than 70 minutes.

The unmodified polyether urethane had a γc value of about 28 dynes/cm, and the polyether urethane containing the additive block copolymer had a γc value of 20 dynes/cm.

Example 6 This example is a manufacturing example using a hot plastic method.

Approximately 204℃ (approximately 400℃) in a single screw type extruder
In 〓), the thermoplastic polyurethane and the block copolymer for addition were mixed. The additive block copolymer consists of approximately 50% by weight polydimethylsiloxane and 50% by weight polyether urethane, with a total silicon concentration in the mixed polymer of 0.01%.
It was in weight%. The mixed polymer was extruded into tubular shapes suitable for blood transfer. After annealing at 60°C for 6 hours, the γc value of this tube is approximately
It was 21 dynes/cm.

Example 7 This example is a production example using a two-component vulcanization method.

Trade name AdiPrene manufactured by DuPont
A polyether urethane isocyanate-terminated prepolymer available as L-167 was prepared according to DuPont's recommended method for curing polyols. A slightly less than stoichiometric amount of the butanediol/trimethylolpropane mixture was used in this case. While in liquid form, the additive block copolymer described in Example 1 was mixed into the reactants and amine catalyst in an amount of 0.1% by weight. The obtained mixed polymer was coated onto a titanium link body prepared in advance and cured in an oven at 100°C.

The coated connector has a γc value of approximately 20 dynes/
cm and is used to connect conduits in contact with blood to left ventricular assist devices used in the treatment of low output heart conditions.

Example 8 50% polydimethylsiloxane and 50% polyurethane
By coating a stainless steel mandrel with a mixed polymer (in dimethylacetamide solution) consisting of 0.2% by weight of a polydimethylsiloxane/polyurethane block copolymer consisting of % and 99.9% by weight of poly(etherurethane urea). A 4mm tubular prosthesis was fabricated. After evaporation of the solvent, the resulting tubular body was taken out from the mandrel, extracted with distilled water at 60°C for 16 hours, dried, and arylated at 60°C for 4 hours. After sterilization with ethylene oxide, the tubular body was sutured to the goat's carotid artery.

No increase in platelet turnover was measured in sham experiments using the standard radiolabeled platelet method. In similar experiments using polyvinyl chloride tubular bodies, which are known to have poor coexistence with blood, platelet transformation was easily detected.

Claims (1)

[Claims] 1. A method of forming a blood-contacting surface exposed to blood in a biomedical device or a component thereof, comprising: (a) using a polyurethane matrix polymer and an additive polymer in fluid form; The mixed polymer is formed by thoroughly dispersing no more than about 5% by volume of an additive polymer to 95% by volume of the base polymer, provided that the additive polymer comprises a polyurethane-polydialkylsiloxane copolymer. The additive polymer has a characteristic that the γc value is lower than the γc value of the substrate polymer,
The γc value of the mixed polymer is approximately 10 to 35 dynes/cm
and (b) solidifying the mixed polymer to form a blood contacting surface of a biomedical device or component thereof. 2. A biomedical device or a component thereof comprising a blood-contacting surface formed by a mixed polymer and co-compatible with blood, in which the mixed polymer comprises at least 95% by volume of a polyurethane matrix polymer and more than 5% by volume of a polyurethane matrix polymer. an additive polymer, provided that the additive polymer includes a polyurethane-polydialkylsiloxane copolymer dispersed throughout the matrix polymer and has a γc value lower than that of the matrix polymer. and the γc value of the mixed polymer is about 10 to 35 dynes/cm.