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BACKGROUND OF THE INVENTION
1. Field of the Invention.
This invention relates to determination of electrolytes, and more
particularly relates to a composite membrane and to an electrolyte sensing
device including the membrane useful in making the determination.
2. Background of the Invention
Hydrophilic polymeric membranes are of interest to the industry for
numerous applications ranging from extracorporeal blood purification
(hemodialysis) to analysis of blood gases and electrolytes. For a typical
biomedical application, a suitable hydrophilic membrane should have high
ion/solute. permeability, mechanical strength and blood compatibility.
Another desirable property, particularly in an analytical medical device
application, is dimensional stability of the membrane upon absorption of
water.
The ionic permeability of most membranes known in the art depends on their
water absorption, which is generally accompanied by swelling. Any
significant swelling in turn leads to dimensional changes. These changes
represent a significant drawback in applications of the membrane in
biosensing devices contemplated for contact with body fluids.
Polypropylene (PP) is a hydrophobic material, nonwettable by water, and
thus, even when porous, it is not permeable to ions in an aqueous solution
unless a positive pressure gradient is applied. It can be converted to a
hydrophilic membrane with excellent dimensional stability and mechanical
properties by treatment with surfactants (i.e. Celgard.sup.R 3500,
Celanese). The surfactant-treated porous PP, however, is unsuitable for
blood and tissue contact applications because the surfactant leaches out
of the membrane matrix causing cell lysis.
It is known in the art that plasma surface treatment techniques can be
utilized to change the surface energy of polymeric films. A coating of
plasma-polymerized ultra thin film changes permanently the surface energy
of a substrate without altering bulk properties of the material. Composite
membranes based on plasma induced polymerization-deposition of polymer
directly onto porous and nonporous substrates have been disclosed by
Zdrahala et al. (Abstracts, The 1987 International Congress on Membranes
and Membrane Processes, Tokyo, Japan, June 1987. page 477) wherein
dimensionally stable hydrophilic membranes are prepared by plasma
polymerizing gaseous acrylic acid with concomitant deposition of a layer
of polyacrylic acid (PAA) on the PP. These membranes, however, showed only
marginal improvement in hydrogen ion diffusion through the disclosed
membrane.
Lazear, in GB patent application 2,058,802A discloses a polyolefinic
open-celled microporous film rendered hydrophilic by chemically affixing
PAA to the pore surfaces. The porous films are limited to those having
interconnected pores, commonly referred to as depth filters, and are
prepared by coating the pores with acrylic acid and polymerizing with
ionizing radiation.
In U.S. Pat. No. 4,717,479, Itoh et al. discloses a porous hydrophilic
polyolefin membrane consisting of a hydrophobic polyolefin membrane having
surface-grafted thereto a polymerized surface active monomer. The membrane
may be of any type, including hollow fiber, planar and tubular types, and
the monomer includes a polymerizable olefin group, a hydrophobic group and
a hydrophilic group. A method for preparing the membrane includes applying
the monomer to the membrane and polymerizing by application of heat or
radiation in the presence of a polymerization catalyst.
Sensing devices for determination of blood components are well-known. All
such devices utilize a membrane which is permeable to the blood component
being analyzed. U.S. Pat. Nos. 4,534,356 and 4.536.274, to Papadakis
disclose electrochemical sensors in which membranes useful for blood gas
analysis are broadly defined as hydroqels or hydrophilic polymers or
copolymers and membranes useful for blood pH determinations are copolymers
of fluorine-containing monomers.
A portable assembly for analysis of blood oxygen and carbon dioxide which
includes a blood sampler, an electrochemical sensor and blood gas analyzer
is disclosed by Cronenberg et al. in U.S. Pat. No. 4,615,340. The sensor
includes a gas permeable, ion permeable membrane fabricated of
polycarbonate or cellulose and a gas permeable, ion impermeable membrane
of polytetrafluoroethylene or PP.
Boold gases are measured by Lubbers et al. in U.S. Pat. No. 31,879 by a
fluorescence-based sensor using selective qas permeable membranes and
optical fibers to direct incident light to a dye and fluorescence from the
dye.
A fiber optic pH probe for physiological studies using an ion permeable
cellulose membrane is described by Peterson et al. in U.S. Pat. No.
4,200,110.
Baxter, in U.S. Pat. No. 4,505,799, discloses an ion sensitive field effect
transistor (ISFET) for measurement of hydrogen ions which includes a
membrane which may be silicon nitride or aluminum oxide.
There is a need for a membrane which combines the high ion permeability of
hydrogels with the dimensional stability and meschanical strength of
polyolefins. The present invention satisfies this need.
SUMMARY OF THE INVENTION
One aspect of the invention is a composite, hydrophilic, ion permeable
membrane which includes a porous polymeric base membrane having a highly
crosslinked coating of a hydrophilic polymer thereon. The base membrane of
the present invention is of the screen or membrane filter type and
consists of a rigid polymeric film having discrete pores (capillaries)
therethrough. The coating is on the surface of the membrane and on the
walls of the pores. In this disclosure, a coating of hydrophilic polymer
on a surface of the membrane and the walls of the pores is referred to as
a continuous coating. Preferred base membranes are polyolefins. The most
preferred ion permeable membrane of the invention is a porous PP base
membrane having thereon a continuous coating of PAA.
Another aspect of the invention is a method for preparing the membrane of
the invention. The method includes coating the polymeric base membrane
with a monomer of the hydrophilic polymer and plasma-polymerizing the
monomer. A preferred method is forming the coating of monomer by steeping
the base membrane in a bath of the monomer and polymerizing the monomer by
exposing the coating of monomer on the base membrane to a plasma generated
from a noble gas.
A third aspect of the present invention is a sensor for a component of a
fluid. The sensor includes a sensing element and the membrane of the
invention. The preferred sensor is a blood electrolyte sensor in which the
sensing element is an ion sensitive field effect transistor. A
particularly preferred sensor is a blood pH sensor.
Thus, the invention provides a porous hydrophilic composite membrane which
includes a polymeric base membrane, preferably PP, and a continuous
coating of hydrophilic polymer thereon. No toxic components, such as
surfactants or catalysts are present in the membrane. The coating of
hydrophilic polymer does not substantially change the bulk properties and
thus the mechanical strength of the PP. Further, minimal absorption of
water by the coating of hydrophilic polymer takes place so that
substantially no dimensional changes in the composite membrane occur. The
membrane is particularly advantageous for use in medical devices in which
the membrane comes into contact with body fluids wherein dimensional
changes due to swelling and leaching of toxic catalyst molecules are
severe disadvantages associated with prior art membranes.
BRIEF DESCRIPTION OF THE DRAWING
The Figure illustrates diffusion of hydrogen ions through the composite
membrane of the invention compared to a prior art membrane.
DESCRIPTION OF THE INVENTION
While this invention is satisfied by embodiments in many different forms,
there will herein be described in detail preferred embodiments of the
invention, with the understanding that the present disclosure is to be
considered as exemplary of the principles of the invention and is not
intended to limit the invention to the embodiment illustrated and
described. The scope of the invention will be measured by the appended
claims and their equivalents.
Known blood electrolyte sensors are of three basic types, electrochemical,
fiber optic and solid state, and the invention contemplates any known
sensor which may be adapted to include the membrane of the invention.
Exemplary of, but not limited to, such sensors are electrochemical sensors
as described in U.S Pat. Nos. 4,536,274 and 4,615,340; fluorescence
sensors as described in U.S. Pat. Nos. 4,200,110 and Re. 31,879; and ISFET
sensors as described in U.S. Pat. No. 4,505,799. The disclosures in these
patents are herein incorporated by reference.
Sensing assemblies generally include a sensor having a sensing element
capable of generating a detectable signal. Exemplary of sensing elements
are dyes which fluoresce or change color in the presence of an
electrolyte, electrodes which sense changes in potential and solid state
transistors which sense a change in the amperage or voltage of an
electrical current. Also included in most sensing assemblies are a
membrane and apparatus to transmit a signal generated by the element to a
data display or analyzer. The membrane generally is selected to be
permeable to a substance being sensed but substantially impermeable to
substances which may be deleterious to the sensing element or which may
interfere with accurate signal generation.
The composite membrane of the present invention combines the hydrophilicity
and ion permeability of hydrogels with the physical-mechanical properties
of polyolefins, and is particularly suitable for inclusion in sensing
assemblies for detection or measurement of water soluble components of a
fluid which may diffuse across the membrane. Most preferably, the membrane
may be included in a blood analysis assembly. Exemplary of blood
components amenable to sensing with the membranes of the invention are
gases such as oxygen and carbon dioxide, solutes such as glucose, uric
acid, urea and the like, and electrolytes such as ions of hydrogen,
potassium, sodium, lithium and chlorine. Preferred components for analysis
using the membrane of the invention are blood electrolytes, most
preferably, blood hydrogen ions.
Included in the membrane of the invention is a porous polymeric base
membrane. Suitable base membranes may be fabricated from, for example,
polyurethanes, polyurethaneureas, polystyrene and, preferably,
polyolefins, such as PP, polyethylene, and polytetrafluoroethylene. The
base membrane may be about 0.01 to 0.1 mm thick and have an effective pore
size of about 0.005 to 1.0 .mu., preferably about 0.01 to 0.1 .mu.. Porous
polymeric membranes and methods for their production are well-known in the
art, and further description of the base membranes is not needed for a
full understanding of the invention.
The base membrane, while porous, is hydrophobic and retains its dimensional
stability and physical properties in water. Being hydrophobic, it is
substantially nonwettable with water and therefore impermeable to water
and ions. In accordance with the invention it may be rendered hydrophilic
and permeable to ions by applying a continuous coating of a hydrophilic
polymer to both the membrane surface and the surfaces of the pores.
Hydrophilic polymers are well known in the art, and any such polymer,
which, when applied as a continuous coating renders the base membrane ion
permeable, is contemplated to fall within the scope of the invention.
Exemplary of, but not limitative of, suitable hydrophilic polymers are
polyacrylic acids, polyhydroxyalkyl acrylates, and olefinically
substituted lactams. Specific nonlimiting examples of suitable hydrophilic
polymers are PAA, polymethacrylic acid, polyhydroxyethyl acrylate and
N-vinyl pyrrolidone. The preferred hydrophilic polymer is PAA, an the
invention will hereinafter be described in terms of this polymer, although
not limited thereto.
Any method of applying a continuous coating of PAA is suitable in
accordance with the invention. A preferred method is applying a continuous
coating of a monomer of the hydrophilic polymer, i.e., acrylic acid, and
polymerizing the applied monomer. It is evident that the acrylic acid may
be applied by any conventional technique such as brushing, dipping or
spraying. Such methods, while providing some improvement in ion
permeability, are less preferred because of difficulty in obtaining
complete wetting of narrow lumen walls of the pores with the acrylic acid.
The most preferred method for achieving a continuous coating of PAA is
steeping the base membrane in a bath of acrylic acid to form a continuous
coating of the monomer and inducing polymerization thereof. The acrylic
acid may be dissolved in a solvent, though it is preferred to steep the
base membrane neat in the monomer. If it is desired to use a solvent
solution of acrylic acid in the steeping process, an organic solvent, such
as acetone, is preferred. Although acrylic acid is soluble in water,
aqueous solutions of acrylic acid are unsatisfactory because the
hydrophobic nature of the PP renders wetting of the pore walls difficult
and much less acrylic acid coats the walls.
Steeping may be carried out for any time and at any temperature suitable
for achieving a continuous coating. Thus, the temperature of steeping may
be from ambient to the softening point of the polymeric base membrane. A
preferred temperature range for steeping is from about 40.degree. to
80.degree. C. The time required to obtain a continuous coating of acrylic
acid depends on such variables as the temperature of steeping, the pore
size, the viscosity of the monomer and the resistance of the base membrane
polymeric substrate to wetting by the acrylic acid. While the
determination of a suitable time for steeping is well within the purview
of one skilled in the art, in general, a steeping time of about 10 minutes
to 24 hours is suitable.
After removal of the base membrane from the steeping bath, excess acrylic
acid may be removed by any convenient method, such as simply allowing the
excess to drip away. The continuous coating of acrylic acid is then ready
for polymerization.
In accordance with the invention, polymerization may be performed by
inserting the monomer-coated base membrane into a conventional plasma
generator and exposing the acrylic acid to a plasma qenerated therein from
a gas. Any suitable means for supporting the base membrane in the plasma
generator may be used. It is convenient to spread the membrane on a glass
plate and place the glass plate between the electrodes of the generator,
although other arrangements will be evident to one skilled in the art. The
plasma induces polymerization and chain propagation of the acrylic acid so
that both sides of the base membrane and the walls of the pores are
covered with a continuous coating of PAA.
A preferred plasma generator is a capacitively coupled unit which includes
parallel plate electrodes, such as the Plasmatherm.sup.R Model 530 unit,
Plasma-Therm, Inc., Kresson, New Jersey. Preferred gases are inorganic
gases, such as nitroqen and noble gases such as helium, arqon and neon.
Most preferably, the plasma is generated from arqon or helium.
A wide range of power settings, radio frequencies, durations of exposure,
temperatures, gas pressures and gas flow rates may be used for plasma
generation. Ranges for these parameters which provide advantageous results
are power levels of up to 1000 watts, RF frequency of 0.05 to 50
megahertz, 0.01 to 12 hours, 0 to 200.degree. C., 0.1 to 100 torr and 60
to 12,000 cubic centimeters/min. Preferred conditions are power of
I5watts, RF frequency of 13.56 megahertz. 2 minutes, 20.degree. C., 0.2
torr and 100 cubic centimeters/min.
The steeping process of the invention causes acrylic acid molecules to
permeate into the PP matrix so that, upon plasma-induced polymerization,
PAA molecules are firmly embedded in the PP matrix, thereby providing a
substantially permanent bond which prevents leaching and removal of the
PAA. The permanently bonded PAA molecules project through the PP surface
to provide the hydrophilic surface for water wettability and ion passage.
The composite membrane of the invention thus has the form of a modified
interpenetrating network (IPN) polymer and is herein referred to as an IPN
type polymer.
It is well known that plasma polymerization of a monomer gives a very
highly crosslinked polymer, in contrast to thermal polymerization in which
no crosslinking occurs in the absence of a crosslinking agent. Thus,
because of the hydrophobicity of the base membrane and the crosslinked
nature of the coating, the composite membrane of the invention absorbs
substantially no water other than that which fills the pores, does not
swell to any extent, and does not undergo any dimensional changes in
contact with water.
Plasma treatment of a polymeric surface is known to be a surface event.
When the layer of acrylic acid coated onto the base membrane of the
invention is subjected to the plasma, polymerization on the surface is
induced. Although the plasma does not penetrate below the surface of the
base membrane and therefore does not reach acrylic acid molecules which
have diffused into the PP matrix, the polymerization reaction initiated on
the surface propagates and adds these molecules to the growing PAA chain
to give the modified IPN type polymer characteristic of the composite
membrane of the invention. Further, because the plasma treatment occurs
only at the surface, no changes in the bulk properties of the base
membrane, such as tensile, modulus and elongation take place, and no
degradation of the base membrane is induced, as commonly occurs when
polymers are treated with electromagnetic radiation.
The ion permeability of the composite membrane of the invention may be
determined, as described in Example III, in a permeability cell having two
compartments separated by the membrane of the invention. The result of
this experiment is shown in the Figure. It is seen that, after 5 minutes,
the pH in the receiving compartment has decreased from 7.5 to 4.5 and
after one hour to pH 3.9 due to migration of hydrogen ions through the
membrane. In contrast, substantially none of the hydrogen ions passes
through the untreated PP base membrane so that no pH change is detected
over one hour. A slight pH decrease to about 7.35 occurs with the PP
membrane of the prior art (Zdrahala et al. supra.) having a layer of
polyacrylic acid resulting from plasma polymerization and deposition of
gaseous acrylic acid. It is further seen that, when this prior art
membrane is annealed, the pH decreases only to a constant value of 6.6
after one hour.
Diffusion constants (D) for the composite membrane of the invention and the
control and prior art membranes were calculated from the ion permeability
data using Fick's First Law of Diffusion and are set forth in the Table.
TABLE
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Membrane Apparent D(cm.sup.2 /sec)
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1. PP base membrane nonpermeable
2. PP base membrane with
8.1 .times. 10.sup.-11
plasma deposited PAA
3. membrane 2 after annealing
7.8 .times. 10.sup.-10
4. composite membrane of
3.9 .times. 10.sup.-7
Example I
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The composite membranes of the invention are translucent when wet and have
retained their translucence and surface hydrophilicity over 1.5 years in
contact with water thereby supporting the IPN type nature of the membrane
matrix having the PAA firmly embedded in the base membrane.
EXAMPLE I
Celgard.RTM. 2500 microporous PP film 25 .mu. thick with an average
effective pore size of 0.04 p was steeped in a bath of acrylic acid at
60.degree. C. for two hours. The film was removed from the bath, excess
acrylic acid allowed to drip off, and the film was spread on a glass
plate. The plate was placed in the Plasmatherm.RTM. Model 530 plasma
generator, and the chamber was evacuated. Argon was bled into the chamber
over one minute until the qas pressure reached 0.2 torr, and a plasma was
generated and maintained at 20.degree. C. for two minutes at 13.56
megahertz 150 watts with an argon flow rate 100 cc/min. The plasma-treated
membrane was removed from the chamber and tested for ion permeability in
accordance with Example III.
EXAMPLE II
The prior art membrane of drahala et al. (supra) was prepared for
comparison purposes as follows:
Celgard200 2500 microporous PP films were placed on the lower electrode of
the chamber of the Plasmatherm.RTM. Model 530 unit. Acrylic acid vapor was
delivered to the chamber from a monomer vessel held at 45.degree. C. while
the chamber walls were maintained at 50.degree. C. The acrylic acid was
plasma polymerized and deposited on the PP with a plasma generated at a
frequency of 50 kilohertz, a power of 220 watts, a chamber pressure of 200
millitorr and a monomer flow rate of 10 cc/min. PAA coatings of varying
thickness were obtained by varying the plasma from about 2-15 minutes.
Thickness of the PAA coating on these prior art membranes was determined
by ellipsometry. Ion permeability was determined in accordance with
Example III. These membranes, although having surfaces which were
completely water wettable, were only marginally better than the control PP
membrane in ion permeability, as shown in the Table and the Figure,
because the PAA did not reach the pore walls.
EXAMPLE III
Permeability measurements of the membranes of the invention (Example I) and
the prior art (Example II) to hydrogen ions were performed in a two
compartment permeability cell which had a membrane test area of 25
cm.sup.2 The membranes were converted to their potassium salts by brief
immersion into 0.1 KOH solution, then removed from the solution and washed
thoroughly with distilled water. Prior to testing, the membranes were
equilibrated for two hours at ambient temperature in distilled water.
After mounting the membranes into the permeability cell, the cell was
placed into a constant temperature bath of 25.degree. C. The receiving
compartment of the cell was filled with 275 ml of 5 mM HCI solution and
225 ml of 5 mM NaCl solution was placed into the other compartment. Dry
nitrogen gas was used as an inert blanket atmosphere. The pH change in
both compartments was measured for 60 minutes using an Orion EA 940 ion
analyzer. The apparent diffusion constants were calculated from the
obtained data using Fick's First Law of Diffusion.
Thus the invention provides a composite membrane particularly useful as a
component of a sensor to be used in contact with body fluids. The
composite membrane includes a polymeric base membrane, having discrete
pores therethrough, which provides mechanical strength. A coating of a
hydrophilic polymer on the membrane surface and the lumen walls of the
pores provides water and ion transmission through the pores. The composite
membrane is of the modified IPN type so that the coating is firmly adhered
to the base polymer without grafting thereby preventing loss of
hydrophilicity. The coating is applied to the base polymer by
catalyst-free plasma polymerization of the corresponding monomer thereby
eliminating the danger of leaching of toxic catalyst into a body fluid.
Plasma polymerization also crosslinks the hydrophilic polymer, thereby
substantially eliminating uptake of any water into the matrix of the
hydrophilic polymer, which is known to cause dimensional changes and
reduction in pore size.
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