POROUS MEDIUM HAVING A PLASMA POLYMERIZED SURFACE BACKGROUND OF THE INVENTION This invention relates to a porous medium having bulk properties which differ from its surface properties and to a process for preparing the same. The invention relates to the modification of the surface properties of polymeric microporous membranes and other porous structures. In particular, the method includes rendering hydrophobic surfaces permanently hydrophilic, the imparting of desirable charge characteristics to the surfaces of porous media, and the creation of surfaces with specific chemical bonding features.

For many porous media applications, a preferred medium must have both certain specific bulk properties and specific surface properties. In many cases, however, a substrate having desirable bulk properties (such as mechanical strength or solvent resistance) has not had appropriate surface properties (such as water wettability, low protein absorbing tendency, thromboresistivity, controlled ion exchange capacity, controlled surface chemical reactivity, and the like). The modification of the surface properties of such substrates has a long history.

One of the oldest methods for modifying surface properties is to coat a porous medium, e. g. a membrane having desired bulk properties, with an agent having the desired surface properties. This has been done to make an otherwise hydrophobic membrane function as if it is hydrophilic. To deposit a hydrophilic coating, a coating composition including surfactants or other wetting agents is used. This approach to modifying surface properties is generally undesirable because the resulting coatings tend to be temporary and are removed in whole or in part shortly after initial use. Indeed, porous polymeric membranes treated in this fashion usually can be wetted with water only a single time. In addition, the membranes exhibit a high level of extractables due to removal of the coating. This is unacceptable in many filtration applications, particularly those which entail processing biological fluids which are to be sterilized or subsequently analyzed.

U. S. Pat. No. 4,702,840 discloses a variant of the simple coating composition in that a surface active agent is included in a casting dope which is used to form the basic membrane.

This technique usually reduces the rate of extraction of the surfactant. It does not eliminate extraction.

U. S. Pat. No. 4,340,482 discloses a more sophisticated approach in which the surface of a porous membrane formed from hydrophobic fluorine-containing polymers is made hydrophilic by grafting thereto a primary amine, such a glycine. The modified membranes exhibit properties which are undesirable for use with certain materials. For example, the resultant membrane oftentimes has a non-white color and gives off colored extractables during use. Furthermore, the membrane has a tendency to absorb proteins from solution and therefore is unacceptable in applications such as clinical diagnostic assays.

Graft polymerization has been proposed for the modification of the surface characteristics of a polymeric substrate. U. S. Pat. Nos. 3,253,057; 4,151,225; 4,278,777 and 4,311,573 disclose typical examples of such graft polymerizations. However these approaches require high energy ionizing radiation and have not been commercially viable.

Moreover, presently available graft polymerization techniques have not succeeded in modifying the entire surface of a porous membrane, i. e. including the portions of the surface located within the pores, while avoiding substantial pore blockage and thereby substantially retaining the porosity of the original membrane.

It would be beneficial to be able to modify the surfaces of porous media by the polymerization of monomers in situ. In this approach the copolymerization of more than one monomer can yield properties not available from commercially available polymers. Also the use of polyfunctional monomers can produce highly insoluble polymer coatings which will be highly insoluble in process fluids.

U. S. Pat No. 4,618,533 proposes the conversion of a membrane from hydrophobic to hydrophilic by depositing a crosslinked polymer over the surface of a membrane by free radical polymerization of a monomer in a liquid medium. The method requires the use of a free radical initiator in an amount that is at least 1000% more, preferably 5000 to 25,000% more, than the amount of initiator that would be used in a typical free-radical polymerization. The patent asserts that such a high concentration of initiator is required to limit the length of the polymer chains to avoid plugging of the pores of a membrane while uniformly coating the entire exposed pore surface of the substrate polymer. In view of the large amount of initiator required, the resulting membrane must contain a substantial amount of extractable residual initiator. The membrane must require substantial washing before use to reduce this contaminant.

It would be desirable to develop a method for producing a modified membrane surface while avoiding the presence of any free radical initiator.

U. S. Pat No. 5,468,390 discloses surface modification of a polysulfone membrane by polymerizing a vinyl monomer using ultra-violet light without initiators. The polymerization of a monomer under these conditions is slow because the substrate is opaque to UV light. Moreover, the polymerization can proceed only from the surfaces which actually receive exposure to the UV light. As such, complete polymerization is unlikely and extractables will result.

Accordingly, it would be highly desirable to provide a composite porous medium having both desirable bulk physical strength and chemical resistance and having desired surface properties that are different from the bulk properties over the entire internal surfaces. Furthermore, it would be desirable to provide a method for preparing the porous medium which is sufficiently rapid to have commercially viability and which is characterized by very low levels of extractables.

Gas plasmas are attractive since roll processing equipment is commercially available and penetration of the porous structure by the gas plasma should initiate rapid surface modification throughout the structure. The direct application of a plasma has long been used to modify porous surfaces, usually with the goal of improved wettability.

However, the direct treatment of surfaces by plasma is undesirable in the case of membranes where surface ablation and polymer embrittlement occur. Also, the use of plasma of- ten produces a surface layer which is easily removed by washing. Thus as the surface layer is extracted, the temporarily wettable surface returns to its original, unmodified state.

It has also been reported that plasma has been proven to be an inadequate technique for modifying the inner surface of pores. M. Gato et al, Journal of Membrane Science, 96, (1994) 299,307, for instance, reports a failure to modify the inner surface of a hollow fiber membrane with plasma because the "plasma could not penetrate into the hollow fiber membrane." Since hollow fiber membranes commonly have lengths in the range of a few inches to several feet, it is possible that the plasmas used were not sufficient to penetrate the full length of the hollow fiber.

A variety of papers disclose the use of a plasma to induce free radical formation in a porous substrate, usually a polypropylene membrane, followed in a separate step by exposure to a monomer to produce a graft polymerization. This two step process has been found to lead to substrates with completely filled void volume which have had some utility as membranes in pervaporation processes. (Yamaguchi, Nakao, Kimura. Macromolecules 1991,24,5522-5527.) In view of the relative ease of performing plasma processes at low costs, it would be desirable to develop a method in which the inner pore surfaces of a membrane are permanently modified using plasma in a single step process without significant loss of void volume.

SUMMARY OF THE INVENTION This invention is directed to a method of directly coating the entire, i. e. both internal and external, surface of a porous medium such as a polymeric membrane with a polymer or crosslinked polymer comprising the steps of (a) coating the substrate with a solution of a monomer containing at least two plasma-polymerizable vinyl groups and (b) exposing the coated porous substrate to a gas plasma which causes polymerization of the monomer in situ over all of the surfaces of the porous structure, said exposure being under conditions which avoid any substantial reduction of the void volume of the porous medium. The monomer solution may include one or more co-monomers which produce a desirable characteristic after polymerization.

This invention provides a composite porous medium, such as a membrane, which includes a porous substrate having certain characteristic bulk properties and a permanent coating formed thereon atop the entire porous structure, including its inner surfaces, in which the coating has physical and chemical properties that are different from the bulk properties of the porous medium. The composite porous medium exhibits substantially no extractables. Unlike the composite membrane products of the prior art, the present invention polymerizes monomers on a porous medium without utilizing any initiator or any intermediate binding chemical moiety which result in substantial extractables.

The external surface of a porous medium can be modified to exhibit controlled ion exchange capacity, reduced affinity to proteins, low or no thrombogenicity, hydrophilicity, and the like. The porous medium surface is permanently modified and therefore can be used in filtration of any fluids which are compatible with the underlying porous medium. Since the outer surface of the porous medium can be made to have low protein absorbing capacity, the composite structures can be useful in apparatus for analyzing, filtering or treating body fluids, including but not limited to blood and blood plasma.

DESCRIPTION OF THE PREFERRED EMBODIMENTS In accordance with this invention, a porous medium such as a polymeric membrane having desired bulk properties is directly coated about substantially its entire surface with a monomer that is plasma polymerized into a coating having the desired surface properties.

The deposition of the polymer on the porous membrane (including on the inner surface of the pores) can be accomplished without the use of any free-radical initiator and does not require or utilize an intermediate binding chemical moiety such as an amino acid or the like. Such modified surfaces include those with the properties of hydrophilicity, positive charge, negative charge, low protein binding and other desirable attributes.

The term"substrate"is used herein to refer to any porous material capable of being uniformly coated with a plasma-polymerizable monomer or monomers that can modify the surface properties of the substrate without undue reduction in void volume of the substrate.

While both polymeric and non-polymeric porous materials can be utilized, preferably the substrate is a polymeric porous matrix. The polymeric matrix may be in the form of a cast single layer or it may be as fibers deposited as a matt by a wet-laid process. Generally, the polymer membranes have an average pore size in the range of between about 0.1 and 100 or more micrometers, more usually from about 0.1 to about 20 micrometers.

The polymeric matrices may be prepared from polymers such as polysulfone, polyethersulfone, or the like; polyolefins such as polyethylene, polymethylpentene, or the like ; polystyrenes or substituted polystyrenes; fluorinated polymers including polyvinylidene fluoride or the like; polyesters; polyacrylate and polycarbonate or the like, vinyl polymers such a polyvinylchloride and polyacrylonitrile; polyamide polymers such as nylon 66, nylon 46, type 8 nylons, and aromatic polyamides; cellulosic polymers such as cellulose nitrate and cellulose acetate; and the like.

Representative monomers include unsaturated monofunctional or polyfunctional entities such as-vinylic, acrylic and allylic group containing monomers, although plasma polymerization is not limited to unsaturated entities.

The plasma polymerization of the monomer is effected so that substantially the entire surface area of the porous medium (including the interior surfaces) is coated with a cross-linked polymer.

Prior to testing the porous media for enhanced surface properties, extraction is performed to ensure the permanence of the treatment. Thus, for example, after extensive extrac- tion and subsequent drying, a hydrophobic membrane which is treated to be hydrophillic wets out fully in about 5 seconds or less after being floated on the surface of water then it is deemed that substantially the entire surface of the membrane has been covered with a permanently hydrophilic coating.

For purposes of this invention, a membrane is "permanently"hydrophillic if it is hydrophilic after being subjected to at least one of the following test conditions: (a) Dry heat: exposure to 100°C for one hour; (b) Steam: autoclaving at 30 psi for one hour; (c) Water extraction: flowing one liter of water through a 47 mm disk and drying; and (d) Alcohol extraction: flowing one liter of methanol through a 47 mm disk and drying.

Preferably the membrane will withstand each of the conditions.

The present invention also contemplates the use of one or more additional monomers that can copolymerize to impart a desirable second characteristic to the plasma-polymerized crosslinked polymer coating. For example, when it is desired to incorporate a positive charge into the deposited coating, the aqueous solution can contain a positively charged monomer such as a quaternary ammonium salt.

In a first step of the process, a porous matrix is contacted with a monomer or monomers in a suitable medium.

Since plasma induced polymerization of these monomers takes place at reduced pressure, suitable monomers are limited to those with sufficiently low vapor pressure that little is lost by vaporization in the plasma chamber prior to treatment. It is thought that a polyunsaturated monomer, either alone or in combination with other monomers, including monofunctional monomers, may be desirable since this encourages branching and crosslinking of the polymer produced. Generally such monomers are di-, tri-, or higher acrylates or methacrylates. Examples of suitable such polyfunctional monomers include tetra- ethyleneglycol diacrylate (TEGDA), pentaerythritol tri- acrylate, bisphenol A ethoxylate diacrylate, 1,4 butanediol dimethacrylate, and the like.

Tetraethyleneglycol diacrylate (TEGDA) is currently the preferred monomer to render very hydrophobic surfaces (such as PVDF membranes) hydrophilic since it leads to water wettability at lower concentrations than alternatives.

A preferred polyfunctional monomer for rendering surfaces positively charged is diallyldimethyl ammonium chloride (DADMAC). It may be used alone, though preferably it is used in combination with TEGDA or other polyfunctional monomer.

DADMAC also reduces the water contact angle for most substrates.

Example of suitable monofunctional monomers which may be incorporated include acrylamide, vinyl sulfonic acid, acrylic acid, hydroxypropylacrylate, 4-styrene sulfonic acid or the like.

Suitable monofunctional cationic monomers which can render surfaces positively charged include the methosulfate or methylchloride quaternaries of such as dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate, diethylaminoethyl acrylate, and diethylaminoethyl methacrylate, as well as 3-methylacrylamidopropyltrimethylammonium chloride, methacryloyl-oxyethyl-trimethylammonium chloride, 1-trimethylammonium-2-hydroxypropyl methacrylate and the like.

Methacryloyl-oxyethyl-trimethylammonium chloride is currently preferred.

Preferred monomers for rendering surfaces negatively charged include acrylic acid or 4-styrene sulfonic acid in combination with a polyfunctional monomer. Ethacrylic acid, vinyl sulfonic acid and the like can also be employed.

A preferred polyfunctional monomer for rendering surfaces hydrophobic is pentaerythritol triacrylate, however bisphenol A ethoxylate diacrylate can also be employed.

Surfaces can also be rendered rich in amine functionality by utilizing monomers such as triallylamine.

Similarly surfaces can be enriched with primary amide functionality utilizing acrylamide (especially in combination with hydroxypropyl acrylate).

In like manner surfaces can be enriched with hydroxyl functionality by using pentaerythritol triacrylate (in combination with TEGDA to maintain hydrophilicity) or hydroxypropyl acrylate. The utilization of hydroxyl rich moieties reduces any protein binding attribute of the substrate porous medium.

The porous matrix can be coated with the monomer or mono- mers by conventional means. If the porous matrix is hydrophilic, then the monomer can be applied to a-dry substrate either from an organic or an aqueous solution or even from a dispersion of the monomer in a diluent, although true solutions are preferred. If the porous medium is hydrophobic, the monomer (s) can be applied to a dry substrate in an organic solvent. Alternatively, a dry hydrophobic sub- strate can be pre-wetted with alcohol followed by exchange with water. The water-wetted hydrophobic medium can then be treated with an aqueous solution of the monomer (s). Choice of the method used to coat the substrate with the monomer (s) depends upon the compatibility of the substrate to the solvents and the particular solubility characteristics of the monomers.

Often in manufacturing processes the porous substrate is in a water wet state from a washing step. The monomer can be applied to the substrate in this condition by exchange usinq a bath containing the diluted monomer (s). If processing conditions permit only a short contact time between the prewetted porous substrate with the monomer solution, then the monomer concentration can be increased to reach the desirable level in the substrate prior to drying.

The concentration of the applied monomer is sufficiently high to provide a uniform distribution of plasma-polymerized surface with desirable characteristics. In general, the concentration of the monomer is generally about 1 wt % or higher, commonly from about 5 to about 15 wt % or even more, consistent with achieving a desired result without loss of void volume. Higher percentages of monomer, as would be expected, produce surfaces with enhanced surface property.

Thus by increasing the concentration of a cationic monomer, porous structures with differing levels of positive charge can be prepared. Similarly one can increase the wettability of the surface of a hydrophobic substrate using TEGDA so that it becomes ever more wettable to even very concentrated aqueous ionic solutions.

The membrane is preferably dried by any suitable method, e. g. air dried, before being placed in a plasma generator chamber and suspended between the electrodes thereof. Since the plasma generator operates at relatively high vacuums the monomers employed must be sufficiently non-volatile that serious loss by vaporization does not occur prior to polymerization.

Suitable plasma generators are commercially available.

Desirably, the plasma generator has the capacity to process entire rolls of substrate. After placing the monomer-coated membrane into the plasma gerator chamber, the chamber is pumped down to a suitable pressure, e. g. a vacuum of about 0.2 Torr. Pressures greater than about 0.75 Torr are not recom- mended. Suitable plasmas include but are not limited to those selected from the group of oxygen, nitrogen, argon, and air.

Nitrogen and air plasmas are preferred.

Plasma is generated at a voltage that causes the monomer to polymerize into a cross-linked polymer coating over the entire surface of the substrate without serious reduction in the void volume of the substrate, i. e. it does not substantially reduce the flow rate of a liquid through the structure. Preferably, the plasma is generated at the lowest voltage that leads to the successful polymerization of the monomer. Suitable power range for the plasma generally range from about 50 to about 1000 watts. The monomer-coated membrane is subjected to plasma conditions for a period from about 5 to 90 seconds, usually from about 30 to about 60 seconds.

To determine if the surface modification is permanent, the product can either be placed in conditions which simulate actual use, e. g. subjecting the modified product to water or ethanol extraction, or evaluated per the test conditions specified above. Thereafter, the material can be tested for the modifying property.

The method of the invention further includes any variation which will enable a user of the invention to plasma-polymerize monomers over substantially the entire surface of a porous substrate in a way that does not substantially reduce the void volume of that substrate.

Having now generally described the invention, the same will become better understood by reference to specific examples, which are included herein for the purposes of illustration only and are not intended to be limiting of the invention. All parts and percents are by weight unless otherwise specified. Unless otherwise noted all membranes were produced by Osmonics and all dyes and monomers were obtained from Aldrich Chemical.

EXAMPLE 1 In this example, a hydrophilic surface made from polymerizing tetraethyleneglycol diacrylate (TEGDA) monomer is produced over the entire surface of various porous substrates in accordance with the invention. The membranes used are (i) a polysulfone membrane having a nominal pore size of 0.2 micrometers, and (ii) a polyethersulfone membrane having a nominal pore size of 0.2 micrometers, and (iii) a polyvinylidene difluoride (PVDF) membrane having a nominal pore size of 0.45 micrometers. The substrates are coated with an alcoholic TEGDA solution and dried by conventional means.

The coated substrates are then placed In the chamber of the plasma generator. The pressure of the chamber is pumped down to about 0.2 Torr. The membranes are then plasma-treated in nitrogen gas at 1000 watts for 60 seconds.

Afterwards the samples are tested for wettability and those that are wettable are subjected to various tests to evaluate the permanence of the treatment. Samples of each membrane are exposed to the following test conditions: (a) dry heat: exposure to 100°C for one hour; (b) steam: autoclaving at 30 psi for one hour; (c) water extraction: flowing one liter of water through a 47 mm disk and drying; and (d) alcohol extraction: flowing one liter of methanol through a 47 mm disk and drying. The membranes are dried in an oven at a temperature of about 90°C.

To evaluate the wettability characteristics of the mem- branes to water, each was floated onto the surface of water.

Membranes that wet out fully in about 5 seconds or less are considered hydrophilic. The results are shown in Table 1.

TABLE 1 WATER WATER TEGDA WATER WETTABILITY WETTABILITY SUBSTRATE Conc. WETTABILITY (after (after % (as made) water ethanol extraction) extraction) Polysulfone 5 Hydrophilic Hydrophilic Hydrophilic Polyethersulfone 10 Hydrophilic Hydrophilic Hydrophilic PVDF 5 Hydrophobic Hydrophobic Hydrophobic PVDF 10 Hydrophilic Hydrophilic Hydrophilic The results indicate that a permanent plasma-polymerized TEGDA layer is formed over the entire surface of the polysulfone membrane at both concentrations whereas the PVDF membrane requires more than 5% TEGDA to make it permanently hydrophilic.

Under the same conditons without the TEGDA plasma polymerization, all the substrates are hydrophilic immediately after plasma treatment yet all revert to hydrophobic after being subjected to the extraction conditions.

The results confirm the presence of a cross-linked, plasma-polymerized TEGDA coating uniformly deposited over the entire surface of the polysulfone membrane and the 10% TEGDA coated PVDF membrane.

EXAMPLE 2 The procedure of Example 1 is repeated and the hydrophilic PVDF and polysulfone membranes are flow tested.

The flow rates for treated and untreated 47 mm disc samples taken from the same sheet of polymeric membrane are compared.

The flow rates (in cc/cm2-min-psi) are for 100 ml of clean water at 20 inches of mercury vacuum. The results in Table 2 indicate (i) no change in flow time for the PVDF membrane and (ii) a loss in flow time for the polysulfone membrane.

TABLE 2 MEMBRANE UNTREATED FLOW RATE TREATED FLOW RATE cc/cm2-min-psi) cc/cm2-min-psi) PVDF 24.5 sec 23.1 sec POLYSULFONE 12.1 sec EXAMPLE 3 The procedure of Example 1 is repeated using only PVDF membranes but varying the TEGDA concentrations from 2.5% to 15% by weight. After coating with the TEGDA solutions, the membranes are plasma processed in nitrogen at 1 kw for 60 seconds at 20°C.

The wettability of the membranes by water and 80% sodium hydroxide is determined as made and after an alcohol extraction. The results are shown in Table 3. TEGDA WATER WATER 80% NaOH Conc. % WETTABILITY WETTABILITY WETTABILITY (as made) (after C2H5OH extraction) 2.5 Hydrophobic------ 5 Wet in 30 sec Hydrophobic--- 7.5 Wet in 5 sec Wet in 30 sec--- 10 Wet in 1 sec Wet in 10 sec 120-180 sec 12.5 Instantly Instantly--- 15 Instantly Instantly--- 20 Instantly Instantly 7 sec The 2.5% TEGDA-coated sample is hydrophobic after being exposed to plasma. When the TEGDA concentration reached 7.5%, the resulting membrane is permanently hydrophilic. Increasing the TEGDA concentration produces membranes wettable even to an 80% aqueous solution of sodium hydroxide.

The results indicate that the hydrophilic properties of the modified surface increase with increasing concentration of TEGDA.

EXAMPLE 4 The procedure of Example 1 is repeated for several concentrations of a mixture of TEGDA and diallyldimethyl ammonium chloride cationic monomer (DADMAC) using various porous media substrates.

The substrates evaluated are: (i) a hydrophobic aromatic nylon membrane of polyhexamethylene terephthalamide, (ii) a polyethersulfone membrane, (iii) filter paper (Whatman Catalog # 1113150), (iv) non-woven polyester scrim and (v) a nylon 66 membrane. After coating with the monomers, the coated substrates are exposed to plasma in nitrogen for 1 minute at 1 kW.

To measure the degree of positive charge enhancement of the substrates treated in accordance with this procedure, the binding behavior of a negatively charged dye to the substrates is observed. Specifically, an aqueous solution (4 milligrams per liter) of a negatively-charged dye (Metanil Yellow) is filtered through each test membrane. The positive charge on the substrates bound to the dye and the filtrate is observed to be clear until all of the binding sites are saturated.

Thereafter the dye begins to pass through the charged substrate. The dye absorption of the charged substrates is comparable to the dye absorption of commercially available positively charged membranes made by other means, i. e. mem- branes from Pall Corp. or Cuno Inc.

The results indicate a direct correlation between the DADMAC concentration and the amount of dye absorbed.

The aromatic nylon membrane, when positively charged, is also permanently hydrophilic (not readily achieved by 5% TEGDA alone). The membrane has a dye binding capacity comparable to that of the commercially available products.

The polyethersulfone membrane without treatment has a very low background dye binding. Thus, the enhancement due to the positively charged surface is readily apparent. The treated membrane, both before and after exposure to the permanance test conditions has a dye binding comparable to commercially available products.

The filter paper and polyester scrim exhibit a lower total binding capacity than the membranes, probably due to a much lower total surface area.

The treated nylon 66 membrane is compared with an untreated nylon 66 membrane for DNA binding ("plaque lifting"). The treated membrane, both as made and after exposure to dry heat, steam, water extraction, and alcohol extraction conditions, shows an enhanced signal typical of other commercially available positively charged nylon 66 membranes.

The same samples coated with DADMAC/TEGDA and not subjected to plasma polymerization conditions show no binding.

The coating is easily washed off when un-polymerized.

EXAMPLE 5 The procedure of Example 4 is repeated for several concentrations of a mixture of TEGDA and methacryloyl- oxyethyl-trimethylammonium chloride as the cationic monomer in place of the DADMAC.

Substantially similar results are observed.

EXAMPLE 6 A negatively charged surface is prepared by following the general procedure of Example 1 but using (i) an acrylic acid (6%)/TEGDA (6%) monomer mixture and (ii) a vinyl sulfonic acid (10%)/TEGDA (3%) monomer mixture. A polyethersulfone membrane and an AmodelO polyphthalamide membrane are used as porous medium substrates.

To measure the degree of negative charge enhancement of the plasma processed membranes, the binding behavior of the positively-charged dye Alcian Blue 8GX is observed. A pre-filtered, aqueous solution of this dye is filtered through each test membrane. The negative charge on the membrane binds to the dye and the filtrate is observed to be clear until all of the binding sites are saturated after which the filtrate becomes colored. All samples bind the positively charged dye, indicating that a negative charge has been permanently imparted to the membrane.

The dye binding indicates that the acrylic acid derivatives bind approximately twice as much dye as the vinyl sulfonic acid products.

EXAMPLE 7 A highly hydrophilic nylon 66 membrane is coated with a 10% ethanolic solution of pentaerythritol triacrylate. After plasma treatment as in Example 1 and water extraction, the resulting membrane is permanently hydrophobic.