MXPA96004801A - Article coated biocompati - Google Patents

Abstract

The biocompatibility of polymeric and metallic articles used in contact with blood can be substantially improved by coating the articles as described. The coating materials are triblock copolymers of the polylactone-polysiloxane-polylactone type. Optimal biocompatibility is provided by a coating of optimum surface concentration. The porous membranes can be coated, as described, by providing improved biocompatibility of blood oxygenators, hemodialyzers and the like

Description

BIOCQMPATIBLE COATED ARTICLE Field of the invention The invention relates to improved materials for medical devices, in particular to materials proposed to make contact with blood and living cells, where adverse physiological reactions such as the initiation of clots should be minimized or eliminated. These biocompatible materials are useful in blood oxygenation, extracorporeal devices, hemodialysis devices, and the like.

BACKGROUND OF THE INVENTION A basic problem in the construction of medical devices that have components that must make contact with blood and other physiological fluids, is that materials with good mechanical and structural properties have rather poor biocompatibility, while highly biocompatible materials have poor structural properties . Biocompatibility is in itself a multifaceted problem that has different aspects REF: 23352 depending on the type of device, which tissues or fluids make contact, and the duration of contact time. In the devices designed for hemodialysis or blood oxygenation, the materials are in contact with the blood that flows through the pipe, to the containers, through heat exchangers and on membranes. The blood returns to the patient's body. Therefore, the primary elements of biocompatibility are to prevent initiation processes that may subsequently damage the patient, such as the activation of coagulation mechanisms, the activation of the complement system, and the initiation of inflammatory reactions. Materials should not be soluble in blood or other body fluids to prevent them from being transported permanently in the patient's body. Although it is known that certain types of polymers, such as silicones and siloxanes, possess many attributes of biocompatibility, there are no reliable physical concepts that allow predicting biocompatibility with any degree of certainty. In general, hydrophobic surfaces are more biocompatible than hydrophilic surfaces. The critical surface tension of Zisman [Zisman, W.A. (1964) Adv. Chem. Ser. 43 (as a parameter to help assess potential biocompatibility.) Materials with optimal critical surface tension are often biocompatible, although there are notable exceptions.For example, polyethylene and polypropylene have good critical surface tensions within the range Optimal but not biocompatible in a predictable way Other factors are also important Without a clear understanding of the nature of these factors, permanent biocompatibility is impronosticable Due to the attractive structural properties of polyolefins and polyurethanes, several techniques have been developed US Pat. No. 4,872,867 describes the modification of a polyurethane with a water soluble polymer and the crosslinking thereof in situ with silane coupling agent to form a network of crosslinked polysiloxane and crosslinking. US Patent No. 4,636,552 discloses a polydimethylsiloxane with polylactone side chains that will be useful for imparting biocompatibility when combined with a base polymer, or used to replace the plasticizer. U.S. Patent No. 4,929,510 discloses a diblock copolymer having a more hydrophobic block and a less hydrophobic block. A solution of the diblock copolymer in a solvent that swells the matrix polymer is used to introduce the diblock into an article of the matrix polymer. Subsequently, the article is transferred to water, to force the orientation of the incorporated diblock copolymer such that the more hydrophobic block fits in the matrix and the less hydrophobic block is exposed on the surface of the article. Examples of diblock copolymers include poly (ethylene oxide-propylene oxide), N-vinyl-pyrrolidone-vinyl acetate and N-vinyl-pyrrolidone-styrene. U.S. Patent Nos. 4,663,413 and 4,675,361 describe segmented block copolymers, in particular linear block copolymers, of polysiloxane-polycaprolactone. The latter were incorporated into the base copolymer materials to modify the surface properties thereof. Although initially mixed in volume in the base polymer, the copolymer migrates to the surface to form an exceptionally thin film, possibly a monolayer, imparting the desired surface characteristic, specifically, biocompatibility. Although numerous surface modification compositions have been described in the art, their proposed use has been as bulk formulation additives, as mixtures with the base polymer, crosslinked within the polymer matrix, as substitutes for the plasticizer or incorporated in the matrix of polymer. The technique has avoided coatings, in part due to the increased cost of manufacturing and the difficulty of uniform application. For certain applications such as microporous membranes, the application of a coating could adversely affect the properties of the membrane by plugging the pores of the membrane or degrading performance otherwise. In the case of microporous membranes made by a process of elongating the polymeric film material, the total surface area is extended to the extent that the available surface concentration of the surface modifiers added in conventional formulation processes is reduced to inefficiency. The ratio of a biocompatible surface to a microporous membrane remains a material of critical importance, since the membrane has the largest surface area in contact with a patient's blood, any component of an oxygenator or hemodialysis unit. Another component with a large area of contact with blood is a heat exchanger, commonly made of metal, used to maintain a desired extracorporeal blood temperature. Aluminum, titanium and stainless steel are used for various kinds of devices that come into contact with blood. Aluminum is reactive with blood and is commonly coated with epoxy or polyurethane to prevent adverse reactions. Although less reactive than aluminum, both stainless steel and titanium have a sub-optimal biocompatibility in contact with blood. From what is known of its properties as volumetric additives, triblock copolymers would be unlikely candidates for use as coatings, since the blocks that normally hold the copolymer within the matrix of the base polymer would be exposed on the surface. However, as detailed herein, it has now been found that certain triblock copolymers can be applied as coatings to impart biocompatibility to the polymeric surfaces. It has also unexpectedly been found that the same copolymers can be used to revert surfaces of other polymeric and metallic articles, imparting excellent biocompatibility thereto. The same copolymers also improve the biocompatibility of metal surfaces coated with polymer, for example, aluminum coated with epoxy or polyurethane.

BRIEF DESCRIPTION OF THE INVENTION The invention provides porous membranes and other polymeric articles that are coated to improve the biocompatibility of the membrane or other article compared to the base polymer composition of a membrane or article without coating. The invention also provides flat sheets of metal and metal articles that are coated to improve the biocompatibility of the sheet or article compared to the sheet or article of uncoated metal. The coating material is any of several triblock copolymers having a polysiloxane segment confined by, or end capped with, two polylactone segments. The thickness of the coating should be within an optimum range in order to provide optimum biocompatibility. The base polymer composition or base metal can be any material from which porous membranes or other articles can be made. The invention is especially useful for microporous membranes used in extracorporeal blood oxygenators where 02 and C2 propagate through the pores, but H20 does not, and in hemodialysis membranes. In these devices, the blood contact with the surfaces of the membrane is maximized and the need for biocompatibility is a reward. The invention is also useful for metal surfaces in extracorporeal blood processing devices, for example, heat resistance testers, and heat exchangers. Biocompatibility is measured in the present by the reduced tendency to induce the enzymatic activity of coagulation, to induce activity similar to kallikrein, to activate the complement cascade in the exposure of blood and plasma, the induction of IL-Iß by mononucleocytes, by the deposition of platelets in ex vivo derivation studies, and by in vitro platelet activation tests.

Brief description of the figures Figure 1 is a graph of the thrombin-antithrombin III (TAT) complex in whole human blood exposed to several microporous membranes during the indicated times on the abscissa. Solid points: Celgard membrane (Registered trademark Hoechst Celanese, Charlotte, NC) coated by immersion with 0.5% SMA-423 solution; square: Celgard membrane coated by immersion with a 2.5% SMA-423 solution triangles: uncoated Celgard membrane; triangles (inverted): polystyrene plate.

Figure 2 is a graph of the TAT complex in whole human blood containing varying concentrations of heparin, after a 30-minute exposure to several microporous membranes. The dots, squares, and triangles in Figure 1. Triangles (inverted): Celgard membrane with silicone PS-252 (United Chemical Technology, Bristol, PA); Diamonds: polystyrene plate.

Figure 3 is a graph of the kallikrein-like activity in the platelet-poor diluted plasma after a 3-minute exposure at 4 ° C to various surfaces.

Figure 4 is a bar graph showing the rate of exponential increase of the TAT complex in whole human blood recalcified after exposure to various surfaces.

Figures 5A-5G are graphs of the TAT complex in whole human blood, anticoagulated, recalcified, exposed to various surfaces during the indicated times on the abscissa. Figure 5A: 316L stainless steel without coating: Figure 5B: 316L stainless steel coated by immersion with a 0.1% SMA-423 solution; Figure 5C: 316L stainless steel coated by immersion with a 0.5% SMA-423 solution; Figure 5D: 316L stainless steel coated by immersion with a 1.0% SMA-423 solution; Figure 5E: 316L stainless steel coated by immersion with a 2.0% SMA-423 solution; Figure 5F: polystyrene coated with PDMS (PS-252); Figure 5G: polystyrene (without coating).

Figure 6 is a bar graph of the coagulation time of whole recalcitated human blood exposed to various surfaces.

Figure 7 is a bar graph of the delay periods of TAT generation of whole blood of recalcified human exposed to various surfaces.

Figure 8 is a bar graph showing the rate of exponential increase of the TAT complex in whole human blood, recalcitrated after exposure to various surfaces.

Detailed description of the invention The coating materials of the present invention are triblock copolymers having a polysiloxane block (S) bordered by blocks of polylactone (L). The abbreviation LSL is used herein to designate these polylactone-polysiloxane-polylactone copolymers. Suitable triblock copolymers are commercially available, for example, from Thoratec Laboratories, Berkeley, CA., which provides a series of these polymers designated "SMA" in which the siloxane is dimethylsiloxane and the lactone is caprolactone. The nominal molecular weights (number average) of the polysiloxane blocks suitable for use herein range from about 1000 to about 5000, while the nominal molecular weights of the caprolactone blocks range from about 1000 to about 10,000. An LSL triblock copolymer having polycaprolactone blocks of 1000 and polysiloxane blocks of 1000 (SMA-411) has been shown to be useful, since it has a copolymer having blocks of polycaprolactone of 10,000 and blocks of polysiloxane of 5000 ( SMA-10-5-10). A lower molecular weight limit is conferred by the need to have a melting temperature above room temperature, and an upper limit is affected by practical considerations such as solubility, solution viscosity and toughness to fill in the pores of the membrane. The preferred coating material is provided by SMA-422 or SMA-423, which has polycaprolactone blocks of a nominal molecular weight of 2000 and polysiloxane blocks of a nominal molecular weight of 2,000 or 3000, respectively. The physical properties conferred by the respective blocks and the effect of varying the relative sizes are well understood in the art, see for example, Lovinger et al. (1993) J. Polymer Sci. Part B (Polymer Physi cs) 31: 115-123. The porous membrane can be made from any suitable base polymer composition to make the porous membranes. Porous membranes have a variety of uses in medical devices. The pore size varies with use. These uses include dialysis, ultrafiltration, plasma separation, protein purification, blood oxygenation, hemodialysis, hemoconcentration, blood filters and catheter sheaths. Certain dialysis membranes have pore sizes that have Angstrom dimensions and are permeable only to atoms and molecules of a molecular weight of less than about 500. The "microporous" membranes have generally sized pores in microns and can be used for oxygenation blood Even larger pores of 20 μ-40 μ are used in the blood filter elements, designed to allow the passage of blood cells but to exclude thrombi and other aggregates. Porous membranes are manufactured from various base polymers, by a variety of processes in the art. The choice of the base polymer and the manufacturing process is dictated to some degree by the size and type of the desired pores. The biocompatibility of these porous membranes is greatly improved by the coating processes and materials described herein. Typical base polymers that may be used in accordance with the present invention include polycarbonates, fluorocarbon polymers, polyurethanes, polysulfones, polyesters, polyethylenes, polypropylenes, polystyrenes, poly (acrylonitrile-butadiene-styrene), polybutadiene, polyisoprene, block copolymers of styrene-butadiene-styrene, styrene-isoprene-styrene block copolymers, poly (4-methylpentene), polyisobutylene, polymethylmethacrylate, polyvinylacetate, polyacrylonitrile, polyvinylchloride, polyethylene terephthalate, cellulose and their esters or derivatives, copolymers of the foregoing and the like. The porous membranes are manufactured by a variety of well-known techniques, any of which can be applied, as appropriate to the base polymer composition, selected, for example, microporous membranes formed by a stretching or elongation process of a material of polypropylene sheet, such as the Celgardd membranes (Trademark of Hoechst Celanese, Carlotte, NC), are suitable for the invention. These membranes are generally porous oblong having a diameter of less than about 0.2 microns and a principal diameter of about 0.2 microns, and are permeable to 02 and C02, making them suitable for oxygenation of the blood. In addition to articles and polymer membranes, the present invention contemplates a wide variety of articles and biocompatible metal surfaces. Typical metal materials that may be used in accordance with the present invention include stainless steel, aluminum, titanium, polymer coated metals, and the like. A major deficiency of the base polymer compositions of the porous membranes and the metal surfaces of the extracorporeal blood processing devices lies in the fact that, for varying degrees, the materials are not biocompatible. Surprisingly, it has been found that a substantial improvement in biocompatibility is obtained, without sacrificing the exchange capacity of 02 / C02 or the dialysis capacity, by coating a porous membrane with a triblock copolymer of LSL of the type described in I presented. Thus, several unexpected findings are combined in the present: that stable coatings are formed by the LSL copolymers, that the coatings can be formed not to block the pores of the membrane essential for the exchange 02 / C02 or for the passage of ions and small molecules, and that biocompatibility is enhanced by the presence of the coating. In addition, it has been shown that the optimum biocompatibility results from a coating of optimum surface concentration. It is also unexpected to find that a stable LSL coating can also be applied to a metal surface. The coating process will be distinguished from the processes of mixing, mixing by melting, co-dissolving, copolymerizing or formulating another base. Therefore, a coating is that which is applied by a surface application process after manufacture. An LSL copolymer coating can be applied by any convenient technique for coating thin film, solid articles, melting materials and the like, including but not limited to immersion, spraying, passage through a coating bath and Similar. By varying the process parameters, the surface concentration of the LSL coating polymer can be controlled. For example, in a dip coating process, the surface concentration can be controlled by varying the concentration of LSL in the immersion solution. In a continuous passage process, which is more suitable for coating volumetric membrane amounts, the surface concentration is regulated both by the LSL concentration of the coating bath and by the travel speed of the membrane material through the bath. To coat membranes, it is preferred that the solvent be chosen so as not to dissolve the base polymer of the membrane. Optimal surface concentrations of SMA-422 and SMA-423 have been obtained by immersing the Celgard membrane in a 0.5% (w / v) acetone copolymer solution and air drying. Alternatively, an optimum surface concentration was obtained by the continuous passage of the Celgard sheet through a 2% (w / v) copolymer bath in acetone at a rate of 30.4 meters / min (100 feet / min), followed by the passage through a hot drying chamber. Suitable solvents for coating metal surfaces include, without limitation, methyl ethyl ketone (MEK), mixture of methylene chloride and alcohol (eg, isopropanol and ethanol), toluene, acetone, trichlorethylene, cyclohexanone, and tetrahydrofuran. A suitable solvent must be capable of dissolving the LSL copolymer and being capable of wetting the surface of the metal. In general, solvents having a solubility parameter of about 8 to 10 must dissolve the LSL copolymer. For example see Hoy, K.L. (1970). J. Pain t technol ogy 4_2 (541): 761-818. An additional requirement to coat polymers and polymer coated materials is that the solvent should not corrode or degrade the surface of the polymer that is coated. For example, additional, suitable coating solvents include esters of dibasic acids such as diisobutyl glutarate, glycol ethers, such as dipropylene glycol methyl ether, dipropylene glycol methyl ether, (l-methoxy-2-propanol) and monomethyl ether of tripropylene glycol, N-methylpyrrolidone and the like. When mixtures of methylene chloride in alcohol are used, the concentration of methylene chloride is preferably at least 10% (v / v). The optimum surface concentrations of SMA-423 have been obtained by immersing stainless steel discs (316L stainless steel) in 1.0% and 2.0% (w / v) solutions of MEK copolymer and air drying. The relative surface concentration of the LSL copolymer can be quantitatively assessed by X-ray fluorescence (XRF). Silicon has a characteristic X-ray fluorescence band (K), the intensity of which is a function of the concentration of the silicon atoms of the coated surface. By comparing the X-ray fluorescence of the sample with a standard, one can calculate the intensity ratio, which is a measure of the relative silicon surface concentration, and therefore the surface concentration of LSL.

To carry out the analysis by XRF, the sample of film or membrane to be measured is stretched or stretched on an X-ray sample cup (Chemplex sample cup # 1930) and held in place with a ring of retention. A coated metal disc or a coated polymer article is placed directly in the sample compartment. The sample compartment of a Philips AXS Wavelength Dispersive Spectrometer is flooded with helium. The spectrometer should be equipped with a chromium X-ray tube. Other parameters of the machine are listed below.

PARAMETERS OF THE XRF MACHINE Beam filter outside Adjustment KV 60 Collimator in progress Setting MA 50 Disabled detector Base line 10 PHS scintillator Enable flow counter Window PHS 25 Crystal C Maximum 2 17.7 or Theta Order first Maximum time 120 sec.

When the silicon atoms in the triblock copolymer, for example, SMA 423, are excited by the radiation coming from the chromium X-ray tube, they emit a fluorescent radiation which is characteristic of the silicon (K). The intensity of this fluorescent radiation is directly proportional to the surface concentration of the silicon and therefore to the concentration of SMA 423. The intensity of the radiation is measured in terms of counts per second and is normalized to an internal silicon standard of the machine that explains any possible variation in the parameters of the machine. The internal standard of the machine used in these analyzes provides an account speed of 42,000 accounts / second. This relationship is known as the intensity ratio which, again, is directly proportional to the surface concentration of the silicon. As noted previously, the membrane coated by immersion in a 0.5% copolymer solution has an optimum biocompatibility. The intensity ratios measured in the samples of these membranes are as follows: From these studies and similar studies it has been determined that polymers (including membranes) and metal surfaces having copolymer coatings whose surface concentrations exhibit intensity ratios by XRF in the range of 0.02-0.35 provide operable biocompatibility. A preferred range of intensity ratios by XRF is from 0.05-0.25, while the maximum biocompatibility with the membranes tested in the present was observed with membranes having intensity ratios by XRF in the range of 0.16-0.2. It will be understood that those skilled in the art can optimally measure biocompatible surface concentrations of coatings according to the invention by using the XRF technique described above. The coatings applied to porous membranes do not reduce or modify their porosity. For example, an optimally coated Celgard membrane and an uncoated membrane were tested for air flow resistance according to test method ASTM-D-726 (B). The manufacturer's specification for uncoated Celgard membranes is 50-120 Gurley sec. A test sample, without coating, had an air resistance of 74 Gurley sec., While the coated material had the strength of 67 Gurley sec. As previously noted, the stainless steel disc coated by immersion in a 1.0% solution and 2.0% copolymer had optimal biocompatibility. The intensity ratios measured in the 316L stainless steel disc samples were as follows: Stainless steel surfaces having copolymer coatings whose surface concentrations exhibited intensity ratios by XRF in the range of 0.02 to 0.35 provide operable biocompatibility. A preferred range of intensity ratios by XRF for the stainless steel coatings is from 0.05-0.25, while the maximum biocompatibility with the stainless steel discs tested in the present was observed with discs having intensity ratios by XRF in the range from 0.09-0.18. Excellent results have been obtained using SMA-423 at 2.5% (w / w) for membrane coatings and 1.0% SMA-423 (w / w) for stainless steel heat exchanger coatings.

Biocompatibility comprises several aspects of reactions between biological tissue and synthetic materials. The most common and dangerous for the patient are the activation of the blood coagulation cascade, complement activation, inflammatory cellular responses and platelet activation. The activation of the coagulation reactions was measured either by a commercially available thrombin-antithrombin ELISA test (Behring Diagnostica, Inc. Marburg, Germany) or by the kallikrein-like activity assay (intrinsic coagulation cascade) using a chromogenic substrate reaction available from Kabi Diagnostica, Molndal, Sweden. Complement activation was measured by an ELISA assay for the soluble terminal complementation complex (TCC) [Deppisch, R. et al. (1990) Kidney International 37: 696-706]. The generation of Interleukin-lβ (IL-1β) by mononucleocytes exposed to flat sheets or membranes was measured by an ELISA test available from R &D Minneapolis, Minnesota. In addition, platelet adhesion and activation on test surfaces exposed to an ex vivo derivation was examined by scanning electron microscopy. An in vitro platelet activation test was also carried out. It will be recognized that conventional polymeric material, tubing, formed articles and the like can also be coated by an LSL copolymer in the manner described for microporous membranes. Similarly, various metal surfaces and articles can be coated by an LSL copolymer in the manner described for the stainless steel discs. The surface concentration of LSL by XRF can be assessed in the same way with the optimum surface coating that is within the same ranges of intensity ratios for polymer membranes and metal discs. Biocompatibility tests have also been carried out with sheets and polypropylene and polyvinyl chloride pipes. It has been found that effective coating of LSL copolymer can be achieved on surfaces that are in contact with blood from a heat exchanger of a mounted oxygenator or for sub-assembled components of an oxygenator, thereby eliminating the need to use membranes. pre-coated or pre-coated heat exchangers. By applying the coating in a post-assembly stage, the manufacturing cost is reduced, no coated material is wasted and the risk of damage to the coated surface is minimized. The post-assembly coating process is carried out by pumping a LSL copolymer solution of specific concentration at a predetermined flow rate through the channels which are in contact with the blood of a heat exchanger of a mounted oxygenator, or through the sub-assembled components of an oxygenator, such as through the oxygen exchange and heat exchange components, separately. Described herein are specific methods used to separately coat an oxygen exchanger and a heat exchanger, using a recirculation system for pumping LSL copolymer solutions and for cleaning the residual solvent with a gas flow. In a surprising way, it was found that a SMA solution in MEK does not pass through an oxygenator membrane, from the blood side to the gas side, specifically if the gas side orifices are plugged while the copolymer solution is flowing to the gas. through the blood-coated side of the device. A coating machine is used to coat the oxygen exchangers of the oxygenator with the LSL copolymer before the heat exchange attachment. The equipment covers the blood side of the leak-proof oxygenator with SMA-423 using MEK as the solvent / carrier. During the coating operation, the oxygen side of the oxygenator is completely plugged to help prevent the MEK from flowing through the membrane to the gas side of the device. Cylinders that are pneumatically driven are used to plug the gas side openings. The coating machine contains a coating station of the oxygen exchanger. After an operator places the exchanger in a reference assembly, the machine pumps a SMA / MEK solution (2.5% w / w) from a tank through the blood side of the oxygenator and back into the tank during a sufficient period to ensure contact with all surfaces. A flow switch downstream of the oxygenator detects that specific flow rate has typically been achieved around 3.78 liters / min (1 gal / min). Then compressed air, which has been dried and filtered, is forced through the coated oxygenator for a period of time to clean and dry the solvent, usually about 10-30 minutes depending on the air temperature. The complete removal of the solvent can be determined by drying the device at constant weight. Normally, a filter recirculation circuit is activated through the solvent tank. To coat an oxygenator, the SMA / MEK solution is diverted through a set of valves to the oxygenator. The solution then passes through a trap and a flow switch back to the tank. The coated oxygenator is then dried by directing air through a set of valves to the oxygenator and to a liquid / vapor separator. The liquid recovers and goes back to the tank. The air and steam are vented. The wetted materials will consist of stainless steel, Teflon, polypropylene, ethylene-propylene, and silicone. Three runs of test coatings were run using different concentrations of SMA-423 in MEK, a flow rate of 4 1 / min and a contact time of one minute. The resulting surface concentrations of SMA at the surface of the membrane as measured by X-ray fluorescence (XRF) are shown in the following Table.

A flat sheet heat exchanger coating machine is used to coat heat exchangers with LSL copolymer. The equipment covers the blood side of the leak-proof flat sheet heat exchangers with SMA-423 using MEK as the solvent / 1% carrier (w / w). The machine contains three coating stations of heat exchangers. After an operator places a heat exchanger on the fixing pins of one of the stations, the machine pumps a SMA / MEK solution from a tank through the blood side of the heat exchanger and back into the tank. tank for a specific period of time, sufficient to ensure full surface contact. Typically 15-30 seconds. A flow switch downstream of the heat exchanger detects that the constant flow rate (1 gal / min) has been achieved. Then compressed air, which has been dried and filtered, is forced through the coated heat exchanger for a period of time, typically 2-4 minutes, to clean and dry it of the solvent. Normally, a filter recirculation circuit is activated through the tank. When a heat exchanger station is selected for the coating, the SMA / MEK solution is diverted through a valve distributor to the selected station. Then the solution passes through a trap and a flow switch and back to the tank. The coated heat exchanger is then dried by directing air through a valve manifold to the station and to a liquid / vapor separator. The fluid is recovered and directed back to the tank. The air and steam are drained. The wetted materials consist of stainless steel, Teflon, polypropylene, ethylene-propylene and silicone. Biocompatibility is also affected by the stability of the coating in the presence of blood. In particular, a biocompatible coating must not be leached or dissolved in contact with blood. Tests were run on samples of Celgard membrane coated with a 0.5% dip coating of SMA-423. The XRF intensity ratios of the individual samples and the controls were measured before and after an incubation in 6.5 hours at 37 ° C with whole bovine blood. There is no significant difference in the intensity ratios of the membrane before and after incubation. The coating of SMA and metals demonstrates similar stability. It was discovered, in a completely unexpected manner, that the LSL copolymer coatings can be stabilized on the surface by exposing them to ionizing radiation. For example, if an article is coated with solvent with SMA 423 and then exposed to another solvent for SMA 423, the coating of SMA 423 can dissolve completely from the surface. However, if the coated article is exposed to ionizing radiation, examples of which could be X-rays, rays? or a beam of electrons and then put in contact with a solvent for SMA 423, only a fraction of the SMA 423 is dissolved from the surface. The rest of SMA 423 that does not dissolve from the surface, seems to be tenaciously adhered to the surface. Therefore, the biosecurity of the article coated with LSL is improved by exposing a coated article to ionizing radiation, since the tendency of the coating to be removed is reduced. X-rays in the dose range of 0.25 to 13.0 Mrad will result in stabilization of the coating on surfaces that are in contact with blood. An X-ray dose of 12 Mrad results in the production of at least 50% of SMA 423 resistant to washing with ethanol (Example 7).

Example 1. Inertia of the microporous membrane coated with LSL for the activation of coagulation as measured by the thrombin-antithrombin assay. Thrombin, a serine protease, is the central bioregulatory enzyme in hemostasis [Fenton, J.W. (1986) Ann. N. Y. Acad. Sci. 485: 5-15J. The assessment of thrombin generation is essential in order to evaluate the degree of thrombosis or hemostasis. In blood, the activity of thrombin is regulated mainly by serine protease inhibitor antithrombin III, which forms a catalytically inactive, stable complex with thrombin. Since the level of the thrombin-antithrombin III (TAT) complex in the blood reflects thrombin formation, the concentration of TAT has been suggested as a sensitive parameter of coagulation activity during extracorporeal circulation [Deguchi, K. collaborators (1991) Am. J. He a tology _3_8: 86-89]. Celgard membranes coated by immersion with 0.5% SMA-423 (optimal surface concentration by XRF) were compared with a bare-faced Celgard membrane, with a Celgard membrane coated with 2.5% SMA-423 (surface concentration too high by XRF) and membranes of polystyrene. Whole blood of heparinized human (treated with heparin) was exposed to the test membranes for 45 minutes. Samples were withdrawn at intervals and assessed for TAT by a commercial ELISA test (Behring) according to the manufacturer's instructions. The results are shown in Figure 1. The coated membranes showed a TAT significantly lower than either the polystyrene positive control or the uncoated Celgard membrane. In a separate experiment, blood samples containing varying levels of heparin (3.0, 1.0 or 0.3 U / ml) were tested for TAT activation, after a 30-minute exposure to several test membranes, as before, in addition to the Celgard membrane coated with an unfilled silicone (PS-252). The results are shown in Figure 2. The membrane coated by immersion with 0.5% SMA 423 was markedly superior to the other test membranes including the membrane coated with 2.5% SMA-423.

Example 2. Biocompatibility of a microporous membrane coated with LSL as measured by kallikrein-like activity (intrinsic coagulation cascade), terminal complement complex (TCC) activity (complement activation) and Activation of Interleukin-lß (lL-lß) by ononucleocytes. To measure activation in the contact phase, a chromogenic substrate assay was used to inspect the generation of kallikrein-like activity in the plasma. Unlike the Xlla factor, almost all kallikrein was released from the surface in the fluid phase at activation. The chromogenic substrate is commercially available, and the test protocols are well established [Lottenberg, R. et al. (1981) Meth. Enzymol. 80: 341-361; Gallimore, M.J. and collaborators (1982) Thromb. Res. 2_5: 293-298], To measure the activation of complement, we assessed the CBT, which is considered to be the best index of C5-C9 activation during cardiopulmonary bypass [Videm, V. et al. (1992) Ann. , Thorac. Surg. 5_4: 725-731]. In order to validate the results, other biomaterials with a potential for complement activation, strong or weak, known were included in the tests. It has been shown that mononuclear cells (monocytes, lymphocytes) secrete IL-1β when exposed to biocompatible materials. Therefore, IL-lβ is another good index for biocompatibility [Cardona, M.M. et al. (1992) J. Bi omed. ? fater. Res. 2_6: 851-859]. In this study, the production of IL-lβ was measured in different materials including Cuprophan and AN-69 dialysis membranes (two hydrophilic surfaces), and both membranes of uncoated Celgardd polypropylene and coated with SMA (hydrophobic surfaces). A lipopolysaccharide (LPS), a potent inducer of IL-1β production, was used as a positive control (data not shown). The blood of three donors was used in this trial. It should be noted that mononuclear cells from different donors will react differently to different surfaces, resulting in a greater variation among donors in the results. However, samples of coated and uncoated Celgard membranes showed no difference in the released IL-1β (Table 1). In comparison, both Celgard and Celgard coated with SMA induce significantly less production of IL-lß than do the more hydrophilic Cuprophan and AN-69 materials. As in Example 1, whole human blood was exposed for variable times to the membranes described. Activity similar to kallikrein was measured using the chromogenic substrate S-2302 (Kabi), which produces p-nitroanaline in enzymatic hydrolysis, measurable by a change in absorbance at 405 nm. Soluble TCC was measured by an ELISA assay as described by Deppisch (1990). IL-lβ was measured by a commercially available ELISA assay from R &D Systems. The results are given in Table 1.

The kallikrein-like activity test revealed that the optimally coated Celgard membrane was superior to either the uncoated membrane or the heavily coated membrane. All three were superior to polystyrene. The results of complement activation showed that Celgard membranes are weak complement activators, whether they are coated or not. The degree of complement activation was comparable to a commercial polyacrylonitrile dialysis membrane, AN69, known to be a weak complement activator material. Cuprophane, another commercial dialysis membrane, showed the highest activation of the complement, consistent with the reports of others.

TABLE 1 RESULTS OF THE TEST OF B lOCOMPAT IB I I DA: CELGARD MEMBRANE WITHOUT COATING AND COVERED WITH SMA o "Kallikrein-like activity" in plasma samples is proportional to the rate of change of absorbance at 405 nm, the analytical wavelength used in this assay to measure the release of p-nitroanaline from the chromogenic substrate, S-2302. The values of TCC activity assume 1 Unit = 42 ng TCC Material not tested under this test. example 3. Adhesion and activation of platelets. Ex vivo, canine arteriovenous shunts were used to study the adhesion and activation of platelets. Similar studies have been reported by Lelah, M.D. et al. (1984) J. Bi omed. Ma ter. Res. 3jj¡_: 475-496, and by Zingg, W. et al. (1986) Li fe Support Sys t. 4_: 221-229. The SMA-treated polypropylene pipe was compared to the unlined pipe and the unlined polyvinyl chloride pipe. The animals were systematically treated with heparin at extracorporeal mimetic circulation conditions. The shunts were removed at intervals of 30 minutes and three hours. Samples from the control and coated tubing were fixed with 2% glutaraldehyde in saline and examined by scanning electron microscopy using a JEOL JSM-6400 instrument. The platelet deposit exhibited two different designs. On the control surfaces, after a 30 minute exposure, the platelets were uniformly distributed, spherical or dendritic, attached to the surface in an individual layer. At 3 hours, two layers were seen in the control pipe. The platelets initially deposited progressed to the most activated flake form and were covered by the second plate of fresh platelets with a mainly dendritic form. In contrast, on surfaces coated with SMA, only one layer of platelets was seen and activation was less advanced, showing only dendritic forms. The density of the platelets was always lower in the surfaces coated with SMA than in the control surfaces. The results were even more dramatic in tests with animals not treated with heparin, where the uncoated, control tubes were capped with fibrin clots and trapped red cells.

Example 4. Biocompatibility of 316L stainless steel disks coated with LSL as measured by kallikrein-like activity (intrinsic coagulation cascade) and terminal complement activity (TCC) (complement activation). 316L stainless steel discs coated by immersion with variable concentrates of SMA-423 (solutions at 0.1%, 0.5%, 1.0% and 2.0% (w / w) in MEK were compared with an uncoated 316L stainless steel disc, "Wettable" polystyrene and polystyrene coated with PDMS (PS-252) (United Chemical Technology, Inc., Bristol, PA) The diluted platelet poor plasma was exposed to the test surfaces for 10 minutes. were evaluated for kallikrein-like activity using the chromogenic substrate and the test protocol described in Example 2. Soluble TCC was measured by an ELISA assay as described by Deppisch (1990) .The results are given in the Figures 3 and 4. The activity test similar to kallikrein (Figure 3) shows that the 316L stainless steel discs are not contact activators of the intrinsic coagulation cascade, whether coated or not.The results of complement activation ( Figure 4) show that the coating of SMA reduces the levels of TCC over a wide range of concentrations of coating solutions. Complement activation by 316L stainless steel coated with 0.5% SMA-423 resembles that of a commercial polyacrylonitrile dialysis membrane, AN-69, known to be a weak complement activator material.

Example 5. Biocompatibility of the 316L stainless steel discs coated with LSL as measured by the thrombin-antithrombin (TAT) assay. Whole blood anti-aged, recalcified to the test surfaces was exposed for 20 minutes. Samples were removed at intervals and assessed for TAT by a commercial ELISA test, as previously described. The results are shown in Figure 5-8 and Table 2. As shown in Figure 5, an initial delay period is typically followed by an exponential increase in the generation of TAT in recalcified human blood. The coagulation time (Figure 6), defined as the time in which the last sample is collected before the coagulation decreases with the increase of trogenicity on the surface. The delay periods (Figure 7) vary from approximately 1 minute (for strongly contact activating materials) to as much as 12 minutes for non-contact activating materials). The rate of exponential increase in TAT following a period of delay increases with the increase in surface thrombogenicity (Figure 8). As shown in Figure 6, the addition of SMA-423 coatings to the surface of 316L stainless steel produces a significant increase in the coagulation time of recalcified human blood exposed to this surface. The coagulation time increases with the increase in the concentration of SMA in the coagulation solution. As shown in Figure 7, coated and uncoated stainless steel surfaces do not promote the activation of the contact phase of the intrinsic coagulation cascade, consistent with the results of the kallikrein-like activity assay (Example 4) . By coating the 316L stainless steel with SMA-423, the rate of TAT exponential increase in recalcified human blood is reduced in a dose-dependent manner. SMA coatings improve the thromboresistance of the stainless steel surface in a dose-dependent manner, with coatings of 1% and 2% SMA-423 which provide the highest thromboresistance.

Example 6. Study of the compatibility of platelets and leukocytes: The whole blood (WB) of human volunteers was subjected to surface contact in pipelines of various test materials as described in detail below. After one hour of contact, the blood was removed for platelet count analysis as a measure of the total loss of platelets, and of the release of microparticles and percentages of platelets positive for P-selectin as measured by the activation of platelets. The platelet-leukocyte association analysis, as an indicator of platelet activation induced by contact with the test material, was carried out by measuring the GPIIb antigen of the platelet associated with the leukocytes in an activated cell sorter. by fluorescence. Activation of leukocytes was assessed by measuring any loss of L-Selectin and CDllb expression. The data is shown in Table 2. See Gem ell, C.H. and collaborators (1995) J. Lab. Cl in. Med. 125 (2): 276-287, incorporated herein by reference. Platelet preparation: Complete blood was withdrawn from normal volunteers (4 individuals) in pre-filled syringes with anti-aging agent after the first mL was discharged. For further experiments, the anti-coagulant PPACK, a selective inhibitor of thrombin at a final concentration of 60 μM, was used. The calcium chelator, 5 mM EGTA for the metal ion chelator, 5 mM EDTA, was also used as anti-caking agents. All the syringes were preheated to 37 ° C and the whole blood was used immediately for the experiment that was carried out in a room at 37 ° C.

TABLE 2 IN VITRO STUDY OF THE COMPATIBILITY OF PLATELETS AND LEUKOCYTES Blood Material Contact: As shown in Figure 9, fresh, whole blood was added to the tubes (25 cm L, 1.57 mm ID) whose ends were connected to two arms that extend from the sides of a platform rotating (13 oscillations per minute). Ignoring the abrupt change in the direction of flow, the shear velocity at the wall, maximum of less than 25 sec. "1. Both ends of the test segment terminated in Silastic segments (1.57 mm ID, 5 cm L). and at any given time 92% of the blood was within the test segment For each experiment, a sample of whole blood at rest (0.5 ml) was placed aside in a microcentrifuge tube, sealed for one hour at 37 ° C. At the conclusion of the test, 525 μl of the whole blood within the tube was displaced, avoiding an air interface, with 150 μl of Hepes-Tyrodes buffer (HTB: 137 mM NaCl, 2.7 mM KCl, NaHCO3 16 mM, 5 mM MgCl2, 3.5 mM Hepes, 1 g / L glucose, 2 g / L bovine albumin, pH 7.4) At this time, EDTA was added (final concentration 5 mM) to the samples (including resting blood sample) for the determination of platelet count as well as for the flow cytometric analysis of platelet activation and microparticle formation. For the cytometric analysis of the flow of platelet association with leukocytes, blood samples were analyzed without added EDTA. In certain cases, to identify potential putative platelet receptors, comprised in the activation of platelets induced by the material, an unlabeled antibody was added to GPIb (API, capable of blocking the binding cycle of vWF) or the antibody to GPIIb / IIIa (A2A9, capable of blocking the binding of the fibrinogen) up to 100 μg / ml, to the whole blood before contact with the material. The tetrapeptide, RGDS at 1 mg / ml was also sometimes added to inhibit ligand binding to GPIIb / IIIa. Three materials were tested: polyvinyl alcohol hydrogel, polyethylene (Intramedic PE), Silastic ™ (Dow Corning) for up to one hour at 37 ° C and up to 9 tubes were tested simultaneously. The polyvinyl alcohol hydrogel coating in the oxidized PE was prepared as previously described for the crosslinking of glutaraldehyde (Cholakis, C. H. et al. (1989) J. Bi omed. Ma ter. Res. 23_: 417-441). Flow Cytometry: Samples were analyzed in a Becton Dickinson FACScan flow cytometer (Mountain View, CA). For the platelet analysis, the light scattering and the fluorescence channels were adjusted to the logarithmic gain. The two-color analysis was used to determine the degree of a-granule release (P-selectin; KC4.1) and activation of the GPIIb / IIIa receptor (PAC-1, 9F9). Samples of 5 μl of whole blood were diluted ten times with HTB and saturating concentrations of antibodies were added. After a 20 minute incubation, the samples were fixed with 1% paraformaldehyde. Cases with a minimum of 5,000 platelets were acquired by switching flow cytometric cases within an intact / individual platelet window defined by light scattering characteristics and positive for platelet-specific antibodies labeled with FITC (GPIb or GPIIb / IIIa). The presence of the antibody specific for PE-labeled activation (KC4.1, PAC-1, 9F9) was used to determine the percentage of activated platelets. In addition, the arbitrary fluorescent intensity of the population of the activated platelets as well as the total fluorescent signal was recorded. Specific cases of platelets, including microparticles, were identified when switching in positive cases of GPIIb / IIIa (FITC-P2) or GPIb (FITC-AP1) and the microparticles were distinguished by size analysis with forward (front) scattering . The forward scatter cut was established for the immediate left of the intact, individual platelet population of a whole blood sample, at rest, and very little adjustment is required from day to day due to the variability of the instrument. The concentration of the microparticles was estimated by multiplying the count of intact, individual platelets (determined in a sample of WB containing EDTA, so that all aggregates and platelets / leukocytes could be broken) by the percentage of platelet cases ( platelets and microparticles) that falls in the window of the microparticles as it is valued by the flow cytometry. The gates of the platelets of a Coulter counter are between 2 and 30 fl approximately, indicating in this way that the platelets counted are between 1.5 and 3.8 μm, if a spherical shape is assumed. It is possible that some large microparticles could be counted as individual platelets using the Coulter counter. Using fluorescent beads (3, 2, 1, 0.46, 0.23 and 0.14 μm) Polysciences Inc.) it has been shown that the present microparticles are a heterogeneous population that varies in size from 0.1 to 0.8 μl. The cases of 5,000 positive platelets were analyzed and the microparticles were reported as a percentage of the total cases of platelets. To determine the percentage of leukocytes with attached platelet (s), saturating concentrations of PE-anti-CD45 and FITC-P2 (anti-GPIIb / Illa) were added to diluted whole blood samples (5 μl) (1:10). incubated for 20 minutes. Then the samples were diluted, fixed and analyzed. The acquisition was commuted to include only those cases positive for PE-anti-CD45 MoAb, the leukocyte labeling in deposit. The second color (FITC) was used to determine the linearized fluorescent intensity of the platelet signal (anti-GPIIb / IIIa) associated with leukocytes. The fluorescence of background FITC associated with leukocytes was determined from samples containing 10 mM EDTA, so that all platelets would dissociate from leukocytes and an irrelevant monoclonal antibody, labeled with FITC (HL1212), against a factor IX epitope. Significant differences in the response to the test materials were noted in the measurement of the loss of the tablets (Table 2, column marked "Platelet Count"). The presence of SMA either as a coating or incorporated in the polymer, drastically reduced the loss of platelets after contact with polyvinyl chloride (PVC) or polypropylene surfaces. The loss of platelets from PVC surfaces composed with SMA was similar to that observed for Silastic (Trade Mark, Dow Chemical Co., Midland, MI), the negative control. Polypropylene surfaces caused a dramatic loss (69%) of platelets and the presence of SMA, either compound or coated, substantially improved (decreased) the loss of platelets, to the extent that the performance was better than untreated polyethylene. For all surfaces, there was minimal evidence of platelet release in volume, as assessed by the low percentage of platelets positive for p-selectin (a-granule release). The percentage of microparticles after surface contact was only marginally above the bottom for the PVC composed with SMA and for Silastic ™, suggesting a very low degree of activation of the platelets. PVC, polyethylene and polypropylene caused high microparticle formation, with the polypropylene that caused the greatest activation. The presence of SMA reduced the degree of microparticle formation. Analysis of leukocyte activation revealed a minimal up-regulation of CDllb or L-selectin with any of the surfaces tested. However, the presence of SMA has no harmful effect.

Example 7. A polycarbonate disk was coated in a 1% solution of SMA-423 in Arcosolve PM. The disc was then irradiated on an X-ray fluorescence spectrometer, Philips equipped with a chromium anode and operated at 60 KV and 50 MA. Part of the disc was masked by a copper ring so that it did not receive irradiation. The other part of the disc received a dose of 12 Mrads. The disk was then washed in ethanol at 45 ° C which is known to be a good solvent for SMA-423. The retention of SMA-423 was measured before and after the comparison of intensity ratios by XRF. The results are shown in the following table: Shows% Retention of SMA-423 Non-irradiated coating 0% Irradiated coating 50% In a procedure identical to that described above, a stainless steel disc was coated with SMA-423. The results of washing in ethanol at 45 ° C are shown in the following table Shows% Retention of SMA-423 Non-irradiated coating 0% Irradiated coating 56% The teachings of the present invention provide a new approach for manufacturing biocompatible surfaces using coating materials. In addition to the specifically exemplified LSL base polymers, metals and coatings, other base polymers, metals and LSL coatings are proposed to be within the scope of the invention, based on the teachings herein. Other coating methods may be employed as are known in the art. Other materials may be included in addition to the LSL copolymers, to incorporate other desired properties or to further improve biocompatibility, all as understood in the art. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property:

Claims (63)

1. A metallic article, characterized in that it has a base metal and a biocompatible coating thereon comprising a polylactone-polysiloxane-polylactone triblock copolymer, the coating having a relative relative surface concentration sufficient to provide a ratio of fluorescence intensity by X-ray. in the range of 0.02 to 0.35.

2. A metallic article according to claim 1, characterized in that the ratio of fluorescence intensity by X-rays are in the range of 0.05 to 0.25.

3. A metal article according to claim 1, characterized in that the ratio of fluorescence intensity by X-rays is in the range of 0.09 to 0.18.

4. A metallic article according to claim 1, characterized in that the article is a flat sheet heat exchanger or a membrane compartment.

5. A metallic article according to claim 4, characterized in that the article is stainless steel.

6. A metallic article according to claim 5, characterized in that the stainless steel is 316L.

7. A metal article according to claim 1, characterized in that the triblock copolymer is a copolymer of polycaprolactone-polysiloxane-polycaprolactone.

8. A metal article according to claim 7, characterized in that the triblock copolymer comprises polycaprolactone blocks having a nominal molecular weight in the range of 1000 to 10,000 and a polysiloxane block having a nominal molecular weight in the range of 1000 to 5000

9. A metal article according to claim 8, characterized in that the triblock copolymer comprises polycaprolactone blocks having a nominal molecular weight of 2000 and a polysiloxane block having a nominal molecular weight in the range of 2000 to 3000.

10. A metallic article according to claim 1, characterized in that the biocompatible coating is subjected to ionizing radiation to produce a coating that adheres tenaciously and insoluble.

11. A method for coating a metal article with a triblock copolymer of LSL, characterized in that it comprises the steps of contacting the article with a solution of the copolymer in a solvent capable of wetting the article, the concentration imparted to the article, after drying , a sufficient copolymer surface concentration to provide a relative intensity of X-ray fluorescence in the range of 0.02 to 0.35.

12. A method according to claim 11, characterized in that the metal article is a stainless steel article.

13. A method according to claim 11, characterized in that the relative intensity of X-ray fluorescence is in the range of 0.09 to 0.18.

14. A method according to claim 11, characterized in that the copolymer is SMA-423 and the solvent is methyl ethyl ketone.

15. A method according to claim 11, characterized in that it comprises the additional step of subjecting the article having a copolymer surface coating to the ionizing radiation to produce an insoluble coating and which adheres tenaciously.

16. A method according to claim 15, characterized in that the ionizing radiation is in the form of X-rays, rays? or a beam of electrons.

17. A method according to claim 15, characterized in that the radiation is X-rays in the dose range of 0.35 to 13.0 Mrad.

18. A method of coating a metal article with a triblock copolymer of LSL, characterized in that it comprises contacting the article with a solution of the copolymer in a solvent capable of wetting the article, the solution having a specific concentration of copolymer, the speed and concentration which are such that, after drying, the article has a sufficient copolymer surface concentration to provide a relative intensity of X-ray fluorescence in the range of 0.05 to 0.25.

19. A method according to claim 18, characterized in that the metal article is a stainless steel article.

A method according to claim 18, characterized in that the relative intensity of X-ray fluorescence is in the range of 0.09 to 0.18.

21. A method according to claim 18, characterized in that the copolymer is SMA-423 and the solvent is methyl ethyl ketone.

22. A method according to claim 18, characterized in that it comprises the additional step of subjecting the article having a surface coating of copolymer to the ionizing radiation to produce an insoluble coating and which adheres tenaciously.

23. A method according to claim 22, characterized in that the ionizing radiation is in the form of X-rays, rays? or a beam of electrons.

24. A method according to claim 22, characterized in that the radiation is X-rays in the dose range of 0.25 to 13.0 Mrad.

25. A polymeric article, characterized in that it has a base polymer and a biocompatible coating thereon comprising a polylactone-polysiloxane-polylactone triblock copolymer, the coating having a relative relative surface concentration sufficient to provide a ratio of fluorescence intensity by X-ray. in the range of 0.02 to 0.35.

26. A polymeric article according to claim 25, characterized in that the ratio of fluorescence intensity by X-rays is in the range of 0.05 to 0.25.

27. A polymeric article according to claim 25, characterized in that the ratio of fluorescence intensity by X-rays is in the range of 0.16 to 0.20.

28. A polymeric article according to claim 25, characterized in that ratio of fluorescence intensity by X-rays is in the range of 0.1690 to 0.19.

29. A polymeric article according to claim 25, characterized in that the article is a porous membrane.

30. A polymeric article according to claim 29, characterized in that the porous membrane is a polypropylene membrane.

31. A polymeric article according to claim 29, characterized in that the porous membrane is a microporous membrane.

32. A polymeric article according to claim 29, characterized in that the porous membrane is a polyethylene membrane.

33. A polymeric article according to claim 25, characterized in that the base polymer is a metal surface coated with polymer.

34. A polymeric article according to claim 25, characterized in that the triblock copolymer is a copolymer of polycaprolactone-polysiloxane-polycaprolactone.

35. A polymeric article according to claim 34, characterized in that the triblock copolymer comprises polycaprolactone blocks each having a nominal molecular weight in the range of 1000 to 10,000 and a polysiloxane block having a nominal molecular weight in the range of 1000 to 5000.

36. A polymeric article according to claim 35, characterized in that the triblock copolymer comprises polycaprolactone blocks having a nominal molecular weight of 2000 and a polysiloxane block having a nominal molecular weight in the range of 2000-3000.

37. - A polymeric article according to claim 25, characterized in that the biocompatible coating is subjected to ionizing radiation to produce an insoluble coating and that it adheres tenaciously.

38. A method for coating a porous membrane with a triblock copolymer of LSL, characterized in that it comprises the steps of contacting the membrane with a solution of the copolymer having a specific concentration of the copolymer, the concentration imparted to the membrane, after drying , a sufficient copolymer surface concentration to provide a relative intensity of X-ray fluorescence in the range of 0.02 to 0.35.

39. A method according to claim 38, characterized in that the porous membrane is a microporous polypropylene membrane.

40. The method according to claim 38, characterized in that the relative intensity range of fluorescence by X-rays is 0.05 to 0.25.

41. The method according to claim 38, characterized in that the relative intensity range of fluorescence by X-rays is in the range of 0.16 to 0.20.

42. The method according to claim 38, characterized in that it comprises the additional step of subjecting the article having a surface coating of copolymer to the ionizing radiation to produce an insoluble coating and which adheres tenaciously.

43. A method according to claim 42, characterized in that the ionizing radiation is in the form of X-rays, rays? or a beam of electrons.

44. A method according to claim 42, characterized in that the radiation is X-rays in the dose range of 0.25 to 13.0 Mrad.

45. A method for coating a porous membrane with a triblock copolymer of LSL, characterized in that it comprises passing the membrane through a copolymer solution at a constant speed, the solution having a specific concentration of copolymer, the speed and concentration which are such that, after drying, the membrane has a surface concentration of the copolymer sufficient to provide a relative intensity of X-ray fluorescence in the range of 0.02 to 0.35.

46. A method according to claim 45, characterized in that the porous membrane is a microporous polypropylene membrane.

47. The method according to claim 45, characterized in that the relative intensity range of fluorescence by X-rays is from 0.05 to 0.25.

48. The method according to claim 45, characterized in that the relative intensity range of fluorescence by X-rays is in the range of 0.16 to 0.20.

The method according to claim 45, characterized in that the relative intensity range of X-ray fluorescence is in the range of 0.1690 to 0.19.

50. The method according to claim 45, characterized in that the speed is 30.4 meters / minute (100 feet / minute) and the concentration of copolymer is 2% (w / w).

51. The method according to claim 45, characterized in that the copolymer is SMA-423.

52. A method according to claim 45, characterized in that it comprises the additional step of subjecting the article having a surface coating of copolymer to the ionizing radiation to produce an insoluble coating and which adheres tenaciously.

53. The method according to claim 52, characterized in that the ionizing radiation is in the form of X-ray, rays? or a beam of electrons.

54. A method according to claim 52, characterized in that the radiation is X-rays in the dose range of 0.25 to 13.0 Mrad.

55. A method for coating an article having a surface that is in contact with blood, polymeric or metallic, characterized in that it comprises wetting the surface with a solution of a triblock copolymer of LSL in a solvent for the copolymer and removing the solvent, coating This way the surface with the polymer.

56. The method according to claim 55, characterized in that the concentration of the LSL copolymer is in the range of 1.0% to 2.5% (w / w).

57. The method according to claim 55, characterized in that the solvent is methyl ethyl ketone and the solvent is removed by evaporation.

58. The method according to claim 55, characterized in that the step of wetting the surface comprises flowing the polymer solution over the surfaces that are in contact with blood of the device.

59. A method according to claim 58, characterized in that the device is a blood oxygenator.

60. The method according to claim 58, characterized in that the device is a blood heat exchanger.

61. A method according to claim 55, characterized in that it comprises the additional step of subjecting the article having a surface coating of copolymer to the ionizing radiation to produce an insoluble coating and which adheres tenaciously.

62. A method according to claim 61, characterized in that the ionizing radiation is in the form of X-rays, rays? or a beam of electrons.

63. A method according to claim 61, characterized in that the radiation is X-rays in the dose range of 0.25 to 13.0.