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Description  |
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BACKGROUND OF THE INVENTION
1. Field of the Invention.
This invention relates to determination of blood electrolytes, and more
particularly relates to a permeable membrane prepared from a crosslinked
polyetherurethane composition and a blood electrolyte sensing device
including the membrane.
2. Background of the Invention.
Thermoplastic polyurethanes to be used as elastomers and the like have been
known for a long time. Products prepared from organic compounds having two
or more isocyanate groups, high molecular weight polyetherglycols, and low
molecular weight diols and diamines as chain extenders are conventionally
referred to as polyetherurethanes, and this term, abbreviated PEU, will be
used in this disclosure for polyurethanes having a polyether backbone.
PEU compositions develop microdomains conventionally termed hard segments
and soft segments, and as a result are often referred to as segmented
PEUs. The hard segments form by localization of the portions of the
polymer molecules which include the isocyanate and extender components and
are generally of high crystallinity. The soft segments form from the
polyether glycol portions of the polymer chains and generally are either
noncrystalline or of low crystallinity.
PEU formulations having properties such as water absorption and mechanical
strength which make them useful for specific applications have been
developed. It is also known that these properties are greatly influenced
by the choice or ratio of the components of the formulations. For example,
Szycher, in U.S. Pat. No. 4,131,604 discloses a PEU molded into a bladder
capable of continuous flexing making it useful in heart assist systems. In
order to achieve the desired properties, the polyetherglycol component of
the composition is limited to polytetramethylene glycol. Alberino et al.,
in U.S. Pat. No. 4,321,333, discloses that, by using blends of
diisocyanates, formulations having significantly improved green strength
are obtained. Quiring et al., in U.S. Pat. No. 4,371,684, reports that
thermoplastic polyurethanes of improved extrudability are obtained by use
of two low molecular weight diol chain extenders instead of the
theretofore conventional butanediol.
Lyman et al. (Journal of Biomedical Materials Research 1 17 (1967)
discloses dialysis membranes prepared from uncrosslinked PEU by solution
casting onto a glass plate.
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 hydrogels 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 Kronenberg 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 polypropylene.
Blood gases are measured by Lubbers et al. in U.S. Pat. No. Re. 31,879 by a
fluorescence-based sensor using selective gas 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.
Potter, in U.S. Pat. No. 4,534,355, shows an electrochemical device for
sensing blood oxygen and carbon dioxide having a linear PEU membrane
coated onto the mounting of the device. The Potter membrane is disclosed
to absorb up to 50% water. On the other hand, Korlatski, in U.S. Pat. No.
4,123,589, describes a PEU membrane which exhibits impermeability to water
making it useful as a food casing.
Ionic permeability across a hydrophilic PEU membrane occurs by partitioning
ions in a fluid between absorbed water in the membrane and the fluid.
Thus, the rate at which an ionic solute crosses a membrane depends on the
water content of the membrane i.e., faster transmembrane passage and
shorter analysis time may be achieved with membranes of high water
absorptivity. The present invention is directed to membranes of
exceptionally high water retention which, in addition, retain the
mechanical strength necessary for use in blood electrolyte sensing
devices.
SUMMARY OF THE INVENTION
One aspect of the present invention is a sensor for a component of a fluid.
The sensor includes a sensing element and a membrane. 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.
Another aspect of the present invention is a semipermeable partition
membrane prepared from a crosslinked PEU composition. The composition
comprises a diisocyanate, a polyetherglycol, a low molecular weight chain
extender and a low molecular weight trifunctional crosslinker. Preferred
PEU compositions have from 20-50% hard segment content and are prepared
from diphenylmethane-4,4'-diisocyanate (MDI), polyethylene oxide (PEO) or
polyetherglycol mixtures containing at least 50% PEO, a chain extending
diol of up to 10 carbon atoms, water as an additional chain extender and a
crosslinking triol of up to 10 carbon atoms. In the most preferred
composition for membrane fabrication, the polyether glycol and crosslinker
are PEO having a molecular weight of about 1450 and trimethylolpropane
(TMP) respectively, water and 1,4 butane diol (BDO) are chain extenders
and the hard segment content is from 30 to 40% of the total weight of the
composition.
The membranes of the invention absorb from 50-120% of their dry weight in
water, and when saturated with water, exhibit a hydrogen ion diffusion
constant of up to 1.times.10.sup.6 cm.sup.2 /sec.
Because of their high degree of adhesiveness to various surfaces, the
membranes of the invention may be solution cast onto components of blood
sensors whereby blood is precluded from contacting the components. In
addition to exhibiting excellent transmembrane diffusion characteristics
due to their high water content, the membranes also have excellent
mechanical strength making them particularly useful in blood analysis
devices wherein the membrane covers a void volume. The membranes do not
contain any additives, in particular no polymerization catalysts, whereby
they have excellent blood compatibility.
BRIEF DESCRIPTION OF THE DRAWING
The Figure shows the relationship of the hard segment content of the
composition of the invention to its water absorbing capacity.
DETAILED 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 embodiments illustrated and
described. The scope of the invention will be measured by the appended
claims and their equivalents.
The present invention provides a membrane fabricated from a chemically
crosslinked PEU formulation which absorbs 50% or more by weight, of water.
The invention embraces, but is not limited to, blood electrolyte sensing
devices, preferably pH sensors, which include such membranes.
Known blood electrolyte sensors are of three basic types, electrochemical,
fiber optic and solid state, and the invention contemplates inclusion of
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 sehsors 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 herin 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 membranes of the present invention are 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.
PEU compositions suitable for fabrication of the membranes of the present
invention include four essential components, a diisocyanate, a polyether
glycol, a chain extender, and a low molecular weight triol crosslinker.
Preferred compositions include water as an additional extender.
Suitable diisocyanates are aromatic diisocyanates such as
diphenylmethane-4,4'-diisocyanate, (MDI),
diphenylmethane-3,3'-diisocyanate, alicyclic diisocyanates such as
isophorone diisocyanate and dicyclohexylmethane-4,4'-diisocyanate, and
aliphatic diisocyanates, as, for example, hexamethylene diisocyanate. The
most preferred diisocyanate is MDI.
The polyether glycol component may be polyethylene oxide (PEO), alone or
mixed with polypropylene oxide or polybutylene oxide. The preferred polyol
is polyethylene oxide having a molecular weight of from about 600 to 3300,
or a mixture containing 50% or more by weight thereof. The most preferred
polyetherglycols are polyethylene oxides having average molecular weights
of 1000 and 1450.
The chain extender may be water and/or a low molecular weight branched or
unbranched diol, diamine or aminoalcohol of up to 10 carbon atoms or
mixtures thereof. Representative nonlimiting examples of chain extenders
are BDO; ethylene glycol; diethylene glycol; triethylene glycol;
1,2-propanediol; 1,3-propanediol; 1,6-hexanediol; 1,4-bis-hydroxymethyl
cyclohexane, hydroquinone dihydroxyethyl ether, ethanolamine,
ethylenediamine and hexamethylenediamine. Preferred chain extenders are
1,6-hexanediol, ethylenediamine, hexamethylenediamine and, most
preferably, water and BDO.
The crosslinker may be a low molecular weight multifunctional compound
having three or more hydroxyl and amine groups and 10 or less carbon
atoms. Representative suitable crosslinkers are TMP, glycerol,
pentaerythritol, trimethylolethane, mannitol and the like. Preferred
crosslinkers are triols, most preferably TMP.
The percentages of the components may be such that the hard and soft
segments of the composition may be from about 20 to 50% and from about
50-80%, preferably from about 30 to 40% and 60 to 70% respectively of the
total weight of the formulation. The molar ratio of crosslinking extender
to linear extender may be from about 100 to 0.01, preferably from about 20
to 0.05, and the molar ratio of polyetherglycol to the combined chain
extender and crosslinker may be from about 0.1 to 10.
From these percentages and ratios, suitable proportions of the components
may readily be calculated. Derived formulas (1) and (2) below may also be
used to determine suitable proportions of the components.
The PEU compositions of the invention may be prepared by the conventional
two step or prepolymer method. As an example of this procedure, the
hydroxyl containing components, i.e., the extender, crosslinker and
polyether glycol may be reacted in a suitable solvent as, for example,
dimethylformamide or preferably dimethylacetamide (DMAC) with
approximately two equivalents of diisocyanate so that each hydroxyl group
is reacted with a diisocyanate molecule giving a prepolymer having
isocyanate terminal groups (a process conventionally referred to as
capping). An example of a typical prepolymer procedure is given in Example
I, however, various modifications of this conventional procedure are
well-known to those skilled in the art.
The prepolymer molecules may then be further chain extended by reaction
between their terminal isocyanate groups and water and/or the low
molecular weight diol and, if desired, further crosslinked, preferably
concurrently with chain extension, by reacting the prepolymer isocyanate
groups with the low molecular weight triol.
A feature of the method for preparing the PEU formulations of the invention
is that the polymers are prepared from the components without adding a
polymerization catalyst. Conventional catalysts in the art, for example,
organometallic compounds such as dibutyl tin dilaurate, are leachable and
may cause deleterious effects in blood-contacting elements fabricated from
prior art catalyst-containing PEU. By avoiding use of a catalyst, PEUs of
the invention are purer and less toxic than those of the prior art.
The membranes of the invention may be from 0.001 to 0.5, preferably from
0.01 to 0.1 mm thick, and representative procedures for their preparation
are given in Examples II and III. Preparation of membranes from polymeric
compositions is conventional in the art, and the methods of preparation of
the membranes of the invention do not constitute a part of this invention.
Membranes prepared from representative nonlimiting PEU formulations of the
invention are given in Table I wherein the components are given in weight
percent of the final prepolymer.
TABLE I
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% water
PEO absorp-
D
MDI (ave MW) TMP BDO water tion* (cm.sup.2 sec)**
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37.4 60 (1000)
1.3 -- 1.3 59.7 4.6 .times. 10.sup.-9
37.4 59.9 (1000)
0.7 0.7 1.3 60.0 6.9 .times. 10.sup.-9
36.6 61.1 (1000)
0.3 0.8 1.3 61.0 7.6 .times. 10.sup.-9
32.1 65 (1450)
0.1 1.6 1.2 97.6 3.6 .times. 10.sup.-6
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*as determined in Example IV
**diffusion constant, as determined in Example V
In accordance with the present invention, it has been found that the
membranes prepared from the compositions of the invention absorb from
50-120% of their dry weight of water. Several compositional factors acting
together are believed to account for this property. The FIGURE shows that
for any given hard segment content, increasing polyether glycol molecular
weight from 600 to 1450 increases water pickup by about 15%. The FIGURE
also shows that, at constant polyether glycol molecular weight, decreasing
hard segment content from 50% to 20% increases water pickup from 50% to
120%. It is believed, although as yet unsubstantiated, that the increase
in water pickup consequent to decreasing hard segment content is due to
reduced crystallinity in the polymer composition.
The membranes of the invention have excellent transmembrane ion diffusion
properties. It has been found that the hydrogen ion diffusion content
increases linearly with decreasing hard segment content. The diffusion
constants of representative membranes of the invention are given in Table
I.
The approximate water absorption and diffusion constant for any crosslinked
PEU membrane of the invention may be predicted from formulas (1) and (2)
below, derived as given in Example VI. Conversely, the formulas may be
used to approximate the quantities of one or more of the components needed
to prepare a membrane of the invention having a desired water absorption
or diffusion constant.
W=152.03+1.65.times.10.sup.-2 M.sub.n -2.54 HS-8.60.times.10.sup.-4 M.sub.x
(1)
D=1.54.times.10.sup.-8 -1.46.times.10.sup.-13 M.sub.n
-2.49.times.10.sup.-10 HS-1.37.times.10.sup.-13 M.sub.x (2)
In formulas (1) and (2), W is percent water pick-up, D is diffusion
constant, HS is percent hard segment, M.sub.n is PEO molecular weight and
M.sub.x is molecular weight between crosslinks. The term M.sub.x in the
formulas is obtained from formula (3):
##EQU1##
EXAMPLE I
General Procedure for Prepolymer Synthesis
Polyethylene oxides were obtained from Union Carbide Corporation and used
as received after determining the hydroxyl number and water content by the
phthalic anhydride-pyridine method and Karl Fisher titration respectively
and adjusting stoichiometry accordingly.
BDO (obtained from GAF) and TMP (obtained from Celanese) were used as is.
MDI was filtered at about 52.degree. C. and vacuum stripped until cessation
of bubbling before use.
PEO, BDO and TMP were combined in a resin bottle at 60.degree. C., vacuum
stripped for 30 minutes at 4-5 mm Hg and diluted with an equal part by
weight DMAC previously stored over 4A molecular sieves. The mixture was
cooled to ambient temperature and two equivalents of MDI, based on the
total hydroxyl content, was added dropwise, followed by addition of a
quantity of DMAC equal to 1/2 part by weight of the MDI. The mixture was
stirred for about four hours at 50.degree. C. to complete prepolymer
formation.
EXAMPLE II
Preparation of Membranes
Membranes of 5 mil thickness were prepared by casting the PEO-polyurethane
prepolymer in DMAC from Example I onto clean, untreated glass plates using
an adjustable clearance Gardner knife (Gardner Labs) set at 10 mil wet
film clearance. The membranes were then stored on the glass plates at
ambient conditions, usually 1-3 days, during which time chain extension
with atmospheric moisture took place and the membranes formed non-tacky
surfaces. Residual solvent was flashd off (one hour, 70.degree. C., vacuum
oven). The membranes were then soaked in deionized distilled water (24
hours), removed from the glass plate and dried to constant weight in a
vacuum oven at 60.degree. C. Membranes prepared in this way were used for
water pickup and permeability determinations.
EXAMPLE III
Membrane Application to a Sensor
An ion sensitive field effect transistor pH electrode is mounted in
conventional fashion on a catheter through a side hole. The catheter is
coated by dipping into the prepolymer solution of Example I until the
coating is of the desired thickness. The catheter is maintained at ambient
conditions for chain extension by atmospheric water for 24 hours, then
dried in a vacuum oven at 60.degree.-70.degree. C. for 24 hours to remove
solvent.
EXAMPLE IV
Determination of Water Pickup
Five 2.times.2 inch samples from each membrane were immersed in distilled
water for 24 hours at 30.0.degree..+-.0.1.degree. C. At these conditions,
an equilibrium water take-up was achieved. The membranes were then removed
from containers, and the surface water was carefully blotted with filter
paper without applying pressure. Each membrane sample was placed into a
tared, air-tight glass vial and weighed. The samples in the vials were
then vacuum dried at 60.degree..+-.2.degree. C. (4-5 mm Hg) for 24 hours
and reweighed. The percent water pick-up and the degree of swelling were
calculated from weight difference data using the following equation:
W=(W.sub.s -W.sub.p /W.sub.p).times.100
where W is percent water pick-up, W.sub.s is weight of the swollen membrane
and W.sub.p is weight of the dry membrane.
EXAMPLE V
Determination of Membrane Diffusion Constant
Apparent membrane thickness was first calculated from the weight of dry
7.times.7 cm membrane sheets assuming average density of 1.15g/cm.sup.3.
The membrane sheets were then equilibrated in distilled water for 24 hours
at ambient temperature prior to testing. For the measurements, a two
compartment permeability cell was placed in a constant temperature bath
(25.0.degree..+-.1.degree. C.). Compartment A of the cell was filled with
a known volume of 5.0.times.10.sup.-3 M NaCl solution and blanketed with
nitrogen gas. A known volume of 5.0.times.10.sup.-3 M HCl solution was
placed in compartment B and the pH change in both compartments was
measured for 60 minutes using an ORION EA 940 Ionalayzer. The diffusion
constant was calculated from the obtained data using Fick's first law of
diffusion:
J=-D dC/dx
where J is total flux, D is diffusion constant and dC/dx is concentration
gradient across the membrane.
EXAMPLE VI
Formulas (1) and (2) were derived by a statistical analysis, using a
3.times.3 Greaco-Latin Square experimental design, of experimentally
determined values for W and D of the membranes (prepared by the method of
Examples I and II) of Table II having preselected values for HS, Mn and
the molar ratio (R) of TMP to BDO.
TABLE II
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HS Mn R W D (cm.sup.2 /sec)
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50 1000 1 35.4 2.9 .times. 10.sup.-9
55 1450 3 34.8 6.4 .times. 10.sup.-10
60 600 6 8.9 1.0 .times. 10.sup.-16
60 1450 1 19.8 2.2 .times. 10.sup.-12
50 600 3 19.0 9.7 .times. 10.sup.-12
55 1000 6 21.0 3.0 .times. 10.sup.-11
55 600 1 13.3 1.5 .times. 10.sup.-12
60 1000 3 12.9 1.0 .times. 10.sup.-16
50 1450 6 48.0 2.2 .times. 10.sup.-9
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Thus, the invention discloses crosslinked PEU membranes of exceptionally
high water absorptivity and ion diffusion constants. The membranes retain
excellent mechanical strength and are useful in electrolyte sensing
devices.
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