CA1291956C - Membrane and a sensor and analytical method based upon the improved membrane - Google Patents
Membrane and a sensor and analytical method based upon the improved membraneInfo
- Publication number
- CA1291956C CA1291956C CA000524145A CA524145A CA1291956C CA 1291956 C CA1291956 C CA 1291956C CA 000524145 A CA000524145 A CA 000524145A CA 524145 A CA524145 A CA 524145A CA 1291956 C CA1291956 C CA 1291956C
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- CA
- Canada
- Prior art keywords
- membrane
- sulphonated
- layer
- enzyme
- sensor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/001—Enzyme electrodes
- C12Q1/002—Electrode membranes
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N11/00—Carrier-bound or immobilised enzymes; Carrier-bound or immobilised microbial cells; Preparation thereof
- C12N11/02—Enzymes or microbial cells immobilised on or in an organic carrier
- C12N11/08—Enzymes or microbial cells immobilised on or in an organic carrier the carrier being a synthetic polymer
- C12N11/089—Enzymes or microbial cells immobilised on or in an organic carrier the carrier being a synthetic polymer obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
Abstract
ABSTRACT
"Membrane and a Sensor and Analytical Method based upon the Improved Membrane"
A membrane particularly for use in a sensor of the enzyme-electrode type which comprises one or more layers of material and an enzyme-containing layer ant in which one layer is formed from a sulphonated or unsulphonated polyarylsulphone or a sulphonated or unsulphonated polyarylketone. The specification also relates to a non-enzymic sensor having a membrane including a layer formed from one of these polymers. Methods for determining an analyte using an enzymic or non-enzymic sensors are also included in the scope of the invention.
"Membrane and a Sensor and Analytical Method based upon the Improved Membrane"
A membrane particularly for use in a sensor of the enzyme-electrode type which comprises one or more layers of material and an enzyme-containing layer ant in which one layer is formed from a sulphonated or unsulphonated polyarylsulphone or a sulphonated or unsulphonated polyarylketone. The specification also relates to a non-enzymic sensor having a membrane including a layer formed from one of these polymers. Methods for determining an analyte using an enzymic or non-enzymic sensors are also included in the scope of the invention.
Description
1 129i95~ 33693 "Membrane and a Sensor and Analytical Method based upon the Improved MembraneN
This inventlon relates to a membrane having lmproved propertle~ for a sensor of the enzyme-electrode type, to a sensor whlch ln partlcular is a ~ensor of the enzyme-electrode type comprlslng the lmproved membrane and to an analytlcal method whlch ln partlcular ls a method uslng an enzyme-electrode type sensor comprlslng an improved membrane.
Enzyme elec~rodes are increa~lngly used in medical and other laboratories partlcularly for the determination of materials such as glucose and urea in specimens of blood and other physio-logical fluids. Such electrodes are described in many publications notably an article by Clark and Lyons (Annals of the New York Academy of Science, 102, 29 - 45, 1962) and US Patents 3539455 ant 3979274 to Clark and Newman respectively. Enzyme electrodes are generally used to determine materials which themselves are not electrochemically active but which in the presence of suitable enzymes take part in reactions which produce specie~ which can be readily detected by the electrodes. In enzyme electrodes the enzymes are frequently located on polymerlc membranes in close contact with the underlylng electrode.
A conslderable amount of research has been carrled out ln order to lmprove the propertles of membranes for use ln enzyme electrodes and many membranes for thl~ purpose have been dls-clo~ed. An example of a type of membrane which 18 often used is the lamlnated membrane dlsclosed by Newman in US Patent 3979274.
Thls membrane comprlses an lnner layer of an essentlally homo-geneous material, for e~ample cellulose acetate, whlch can prevent the passage of materlals of even low molecular welght llkely to lnterfere with the enzyme-medlated slgnal, a closely opposed layer of the enzyme itself (with or without such other materials that may be blended with it), and an outer layer of a porous support film which can prevent the passage of cellular and colloidal elements.
The determination of glucose can be taken as an example of the determination of a material by an enzyme electrode. In the ~f~9195~
This inventlon relates to a membrane having lmproved propertle~ for a sensor of the enzyme-electrode type, to a sensor whlch ln partlcular is a ~ensor of the enzyme-electrode type comprlslng the lmproved membrane and to an analytlcal method whlch ln partlcular ls a method uslng an enzyme-electrode type sensor comprlslng an improved membrane.
Enzyme elec~rodes are increa~lngly used in medical and other laboratories partlcularly for the determination of materials such as glucose and urea in specimens of blood and other physio-logical fluids. Such electrodes are described in many publications notably an article by Clark and Lyons (Annals of the New York Academy of Science, 102, 29 - 45, 1962) and US Patents 3539455 ant 3979274 to Clark and Newman respectively. Enzyme electrodes are generally used to determine materials which themselves are not electrochemically active but which in the presence of suitable enzymes take part in reactions which produce specie~ which can be readily detected by the electrodes. In enzyme electrodes the enzymes are frequently located on polymerlc membranes in close contact with the underlylng electrode.
A conslderable amount of research has been carrled out ln order to lmprove the propertles of membranes for use ln enzyme electrodes and many membranes for thl~ purpose have been dls-clo~ed. An example of a type of membrane which 18 often used is the lamlnated membrane dlsclosed by Newman in US Patent 3979274.
Thls membrane comprlses an lnner layer of an essentlally homo-geneous material, for e~ample cellulose acetate, whlch can prevent the passage of materlals of even low molecular welght llkely to lnterfere with the enzyme-medlated slgnal, a closely opposed layer of the enzyme itself (with or without such other materials that may be blended with it), and an outer layer of a porous support film which can prevent the passage of cellular and colloidal elements.
The determination of glucose can be taken as an example of the determination of a material by an enzyme electrode. In the ~f~9195~
presence of the enzyme glucose ox$dase the following reaction occurs:-D-Glucose + 2 + ~2 glucose ~ D-Gluconic Acid + H202 oxidase The hydrogen peroxide produced in this reaction passes through the inner layer of a membrane such as that of US Patent 3979274 and can be determinet using the electrode. Since the hydrogen peroxide produced is dependent upon the glucose present in a specimen, the glucose concentration can be determined using a suitably callbrated sensor.
To date a number of difficulties have limited the utility of enzyme electrodes and restricted the scale of their use in routlne analysis of, e.g. blood samples. An important difficulty i9 the effect of interfering species in the sample under test which can themselves give rise to a signal thereby enhancing the overall signal and causing an electrode to give a reading which is too high. For example when an enzyme-electrode is used to measure glucose in blood the enzyme-mediated signal produced may be appropriate but the observed signal may be elevated by a number of other species in the blood such as ascorbic acit which can give direct electrochemical signals at the hydrogen-peroxlte detectlng electrode.
Accordlng to the present invention we provide a membrane permeable to liquids and solutes which comprises an enzyme-containing layer and one or more layers of material wherein at least one layer of material is formed from a sulphonated or unsulphonated polyarylsulphone or a sulphonated or unsulphonated polyarylketone.
Further according to the present invention we provide a sensor which incorporates a membrane permeable to liquids and solutes and comprising one or more layers of material wherein at least one layer of material is formed from a sulphoDated or unsulphonated polyarylsulphone or a sulphonated or un~ulphonated polyarylketone.
Further according to the present invention we provide a ~91~5~i sensor of the enzyme-electrode type which incorporates a membrane permeable to liquids and solutes and comprising an enzyme-containlng layer and one or more layers of material wherein at least one layer of material is formed from a sulphonated or unsulphonated polyarylsulphone or a sulphonated or unsulphonated polyarylketone.
Further according to the invention we provide a method for determining an analyte in a specimen which comprises bringing the speciment into contact with the outer face of a membrane, permeable to liquids and solutes and comprising one or more layers of material, incorporated into a sensor sensitive to the analyte and measuring the response of the sensor to the analyte whereln at least one layer of materlal ls formed from a sulphonated or unsulphonated polyarylsulphone or a sulphonated or unsulphonated polyarylketone.
Further according to the invention we provide a method for determinlng an analyte ln a specimen which comprlses bringing the speclment lnto contact wlth the outer face of a membrane, permeable to llquids and solutes and comprising an enzyme, in the presence of which the analyte is convertable into a species detectable by a sensor which lncorporates the membrane, and one or more layers of material, and measuring the response of the sensor to the specles, whereln at least one layer of materlal is formed from a sulphonated or unsulphonated polyarylsulphone or a sulphonated or unsulphonated polyarylketone.
Throughout the remainder of this specification the term sulphonated or unsulphonated polyarylsulphone will be abbrev$ated to PAS and the term sulphonated or unsulphonated polyarylketone will be abbreviaged to PAK.
The sensor of the invention ls not restricted to sensors of the enzyme-electrode type and lncludes sensorq lncorporatlng membranes which do not comprlse enzyme layers. The membranes ln such non-enzyme type sensors comprise one or a plurallty of layers of layers of materlal, the lamlnated membranes belng formed from layers of the same or different materials.
To date a number of difficulties have limited the utility of enzyme electrodes and restricted the scale of their use in routlne analysis of, e.g. blood samples. An important difficulty i9 the effect of interfering species in the sample under test which can themselves give rise to a signal thereby enhancing the overall signal and causing an electrode to give a reading which is too high. For example when an enzyme-electrode is used to measure glucose in blood the enzyme-mediated signal produced may be appropriate but the observed signal may be elevated by a number of other species in the blood such as ascorbic acit which can give direct electrochemical signals at the hydrogen-peroxlte detectlng electrode.
Accordlng to the present invention we provide a membrane permeable to liquids and solutes which comprises an enzyme-containing layer and one or more layers of material wherein at least one layer of material is formed from a sulphonated or unsulphonated polyarylsulphone or a sulphonated or unsulphonated polyarylketone.
Further according to the present invention we provide a sensor which incorporates a membrane permeable to liquids and solutes and comprising one or more layers of material wherein at least one layer of material is formed from a sulphoDated or unsulphonated polyarylsulphone or a sulphonated or un~ulphonated polyarylketone.
Further according to the present invention we provide a ~91~5~i sensor of the enzyme-electrode type which incorporates a membrane permeable to liquids and solutes and comprising an enzyme-containlng layer and one or more layers of material wherein at least one layer of material is formed from a sulphonated or unsulphonated polyarylsulphone or a sulphonated or unsulphonated polyarylketone.
Further according to the invention we provide a method for determining an analyte in a specimen which comprises bringing the speciment into contact with the outer face of a membrane, permeable to liquids and solutes and comprising one or more layers of material, incorporated into a sensor sensitive to the analyte and measuring the response of the sensor to the analyte whereln at least one layer of materlal ls formed from a sulphonated or unsulphonated polyarylsulphone or a sulphonated or unsulphonated polyarylketone.
Further according to the invention we provide a method for determinlng an analyte ln a specimen which comprlses bringing the speclment lnto contact wlth the outer face of a membrane, permeable to llquids and solutes and comprising an enzyme, in the presence of which the analyte is convertable into a species detectable by a sensor which lncorporates the membrane, and one or more layers of material, and measuring the response of the sensor to the specles, whereln at least one layer of materlal is formed from a sulphonated or unsulphonated polyarylsulphone or a sulphonated or unsulphonated polyarylketone.
Throughout the remainder of this specification the term sulphonated or unsulphonated polyarylsulphone will be abbrev$ated to PAS and the term sulphonated or unsulphonated polyarylketone will be abbreviaged to PAK.
The sensor of the invention ls not restricted to sensors of the enzyme-electrode type and lncludes sensorq lncorporatlng membranes which do not comprlse enzyme layers. The membranes ln such non-enzyme type sensors comprise one or a plurallty of layers of layers of materlal, the lamlnated membranes belng formed from layers of the same or different materials.
When the sensor of the invention is a sensor of the enzyme-electrode type, the simplest form of the membrane in it and the slmplest form of the membrane of the invention consists of the enzyme-containing layer and the layer formed from a PAS or a PAK with the latter layer preferably positioned between the enzyme-containing layer and the electrode.
It is preferred however that the membrane of the invention and the membrane in enzyme-electrode type sensors of the invention is a laminated membrane of the type of which that disclosed in US Patent 3979274 is an example. Such a membrane comprises a first or inner layer of material positioned between the enzyme-containing layer ant the electrode, the enzyme-containing layer and a second layer of material on the other side of the enzyme-containing layer which second layer may be a layer lS having restricted permeability. It is much preferred that the first layer should be formed from a PAS or a PAK.
Generally the porous material of restricted permeabil$ty used in the second layer will be a polymeric material but other suitable materials may be used. Thus the second layer may be formed from a glass or a metal having pores cut by lasers.
Hereafter in this specification the enzyme-electrode type sensor of the lnventlon whlch ls described will contain a lamlnated membrane of the type of whlch the membrane described ln US Patent 3979274 is an e~ample having flrst and second polymer layers.
It should be unterstood that the membrane of the lnventlon can contain more than two layers of material. For instance the second layer 18 not necessarlly the outermost layer of the membrane. There may be a further layer or layers of material, l.e. thlrd, fourth etc layers, between the second layer and a speclmen. Qften however the second layer will be the outer layer and its outer face will be contacted by the specimen in the method of the invention.
Any suitable PAS or PAK may be used in the membrane of the invention. However many of the polymers used will be 956`
It is preferred however that the membrane of the invention and the membrane in enzyme-electrode type sensors of the invention is a laminated membrane of the type of which that disclosed in US Patent 3979274 is an example. Such a membrane comprises a first or inner layer of material positioned between the enzyme-containing layer ant the electrode, the enzyme-containing layer and a second layer of material on the other side of the enzyme-containing layer which second layer may be a layer lS having restricted permeability. It is much preferred that the first layer should be formed from a PAS or a PAK.
Generally the porous material of restricted permeabil$ty used in the second layer will be a polymeric material but other suitable materials may be used. Thus the second layer may be formed from a glass or a metal having pores cut by lasers.
Hereafter in this specification the enzyme-electrode type sensor of the lnventlon whlch ls described will contain a lamlnated membrane of the type of whlch the membrane described ln US Patent 3979274 is an e~ample having flrst and second polymer layers.
It should be unterstood that the membrane of the lnventlon can contain more than two layers of material. For instance the second layer 18 not necessarlly the outermost layer of the membrane. There may be a further layer or layers of material, l.e. thlrd, fourth etc layers, between the second layer and a speclmen. Qften however the second layer will be the outer layer and its outer face will be contacted by the specimen in the method of the invention.
Any suitable PAS or PAK may be used in the membrane of the invention. However many of the polymers used will be 956`
materials which contain repeating units of the general formula A
-(-Ar - Y-)- A;
whereln Ar is a divalent aromatic radical and optionally, but preferably, at least some of the groups Ar are sulphonated; and Y is - S02 - or - C0 -.
The group Ar is preferably a group containing at least two aromatic rings which may be fused together or linked together by a dlrect bond, or linked together by an aliphatic group, an oxygen or sulphur atom or a sulphone or ketone group.
Preferably the PAS or PAK is a sulphonated polymer and in particular 18 a sulphonated polyarylethersulphone or a sulphonatet polyaryletherketone in which the group Ar contains at least two aromatic groups linked together by an oxygen atom.
Sulphonated polymers of this type include polymers which contain repeating units of the formula B;
_I_(_phl _ -)n-Phl ~ Y-]- B
wherein Y is as defined;
phl represents a phenylene residue, preferably a para-phenylene residue, wherein at least some of the groups Phl are sulphonated; ant n is 1 or 2 and the value of n can differ along the polymer chain.
If the group Y is a - S02 - group in the sulphonated polymer of formula B, the value of n may be only one or only two, but we prefer to use a copolymer in which the value of n is one for some repeatlng unlts and 18 two for other repeating unlts.
Such copolymers, and the preparation thereof, are disclosed in European Patent Speclfication No. 8894. Suitable sulphonated polysulphones have repeating units of the formula C:-_(_ph2 _ o - Ph3 - o - ph2 - S02-)- C
together with the repeating units of the formula D:-_(_ph2 _ 0 _ ph2 - S02-)- D
wherein l~l9S~
-(-Ar - Y-)- A;
whereln Ar is a divalent aromatic radical and optionally, but preferably, at least some of the groups Ar are sulphonated; and Y is - S02 - or - C0 -.
The group Ar is preferably a group containing at least two aromatic rings which may be fused together or linked together by a dlrect bond, or linked together by an aliphatic group, an oxygen or sulphur atom or a sulphone or ketone group.
Preferably the PAS or PAK is a sulphonated polymer and in particular 18 a sulphonated polyarylethersulphone or a sulphonatet polyaryletherketone in which the group Ar contains at least two aromatic groups linked together by an oxygen atom.
Sulphonated polymers of this type include polymers which contain repeating units of the formula B;
_I_(_phl _ -)n-Phl ~ Y-]- B
wherein Y is as defined;
phl represents a phenylene residue, preferably a para-phenylene residue, wherein at least some of the groups Phl are sulphonated; ant n is 1 or 2 and the value of n can differ along the polymer chain.
If the group Y is a - S02 - group in the sulphonated polymer of formula B, the value of n may be only one or only two, but we prefer to use a copolymer in which the value of n is one for some repeatlng unlts and 18 two for other repeating unlts.
Such copolymers, and the preparation thereof, are disclosed in European Patent Speclfication No. 8894. Suitable sulphonated polysulphones have repeating units of the formula C:-_(_ph2 _ o - Ph3 - o - ph2 - S02-)- C
together with the repeating units of the formula D:-_(_ph2 _ 0 _ ph2 - S02-)- D
wherein l~l9S~
ph2 represents a phenylene residue, preferably a para-phenylene residue;
Ph3 represents a phenylene residue, preferably a para-phenylene residue, havlng one or two groups -S03M;
M is a hydrogen atom, a metal atom and/or a group NR4, wherein the groups M may be the same or different and the proportion of the groups M is sufficient to combine with the unsatisfied valencies of the group -S03; and R is a hydrogen atom or an alkyl group.
The sulphonated polysulphone may also include a proportion of unsulphonated copolymer having repeating units of the formula E:-_(_ph2 _ 0 _ ph2 _ 0 _ ph2 _ S02-)_ E
together with the repeating units of the formula D and the formula E, wherein ph2 is as tefined.
In the repeating units of the formula C, when Ph3 is an ortho-or para-phenylene residue, there is typically only one group - S03M whereas, when Ph3 is a meta-phenylene residue, there are typlcally two groups -S03M. When Ph3 is an ortho-phenylene resldue, the -S03M group is located in a position whlch ls para-to one ether group and meta- to the other ether group, any further sulphonation occurrlng to locate the -S04M in positlons meta- to each other. When Ph3 is a para-phenylene residue, the -S03M group 1~ located in a position ortho- to one ether group and meta- to the other ether group. When Ph3 is a meta-phenylene residue, the -S03M groups are located in the postion ortho- to one ether group and para- to the other ether group.
The sulphonated copolymers may be prepared by sulphonating a copolymer conslsting of repeating units D and E.
The sulphonation is readily effected by dissolving the copolymer ln concentrated sulphurlc acid (98% Wlw) at amblent temperature and agltating the mlxture for a sufficlent time for sulphonatlon of essentlally all of the sub-unlts - o - ph2 - 0 - ln the repeat unlts of formula E. The copolymers which are sub~ected to sulphonation suitably have from 1 to 99 mole % of units ~ and 12~95~
Ph3 represents a phenylene residue, preferably a para-phenylene residue, havlng one or two groups -S03M;
M is a hydrogen atom, a metal atom and/or a group NR4, wherein the groups M may be the same or different and the proportion of the groups M is sufficient to combine with the unsatisfied valencies of the group -S03; and R is a hydrogen atom or an alkyl group.
The sulphonated polysulphone may also include a proportion of unsulphonated copolymer having repeating units of the formula E:-_(_ph2 _ 0 _ ph2 _ 0 _ ph2 _ S02-)_ E
together with the repeating units of the formula D and the formula E, wherein ph2 is as tefined.
In the repeating units of the formula C, when Ph3 is an ortho-or para-phenylene residue, there is typically only one group - S03M whereas, when Ph3 is a meta-phenylene residue, there are typlcally two groups -S03M. When Ph3 is an ortho-phenylene resldue, the -S03M group is located in a position whlch ls para-to one ether group and meta- to the other ether group, any further sulphonation occurrlng to locate the -S04M in positlons meta- to each other. When Ph3 is a para-phenylene residue, the -S03M group 1~ located in a position ortho- to one ether group and meta- to the other ether group. When Ph3 is a meta-phenylene residue, the -S03M groups are located in the postion ortho- to one ether group and para- to the other ether group.
The sulphonated copolymers may be prepared by sulphonating a copolymer conslsting of repeating units D and E.
The sulphonation is readily effected by dissolving the copolymer ln concentrated sulphurlc acid (98% Wlw) at amblent temperature and agltating the mlxture for a sufficlent time for sulphonatlon of essentlally all of the sub-unlts - o - ph2 - 0 - ln the repeat unlts of formula E. The copolymers which are sub~ected to sulphonation suitably have from 1 to 99 mole % of units ~ and 12~95~
correspondingly from 99 to 1 mole % of units D, and especially from 5 to 80 mole % of units E and correspondingly from 95 to 20 mole % of units D. Sulphonation is desirably effected to convert at least 90% of the units E to the units C.
The sulphonated polysulphones are polymeric materials of high molecular weight such that the reduced viscosity (RV) of the polymer, (measured as a 1% by weight solution of the polymer in dimethylformamide at 25C) is at least 0.2 and preferably at least 0.4. The polymer may be such as to give an RV of up to 2.5, but it is generally preferred that the RV of the polymer does not exceed 2Ø
The sulphonated polysulphone contains the groups - S03M, where M may be hydrogen, a metal atom or a group NR4. Sulphonated polysulphones in which M is a divalent metal atom, particularly an alkaline earth metal, are the sub~ect of our published European Patent Application No. 145305, which also discloses a method for the production of such divalent metals salts and the use thereof for the production of asymmetric semi-permeable membrane~.
Less preferably the membrane can contain a layer formed from a material of formula B in whlch the group Y is a ketone group. Sulphonated polyketones whlch may be used include polymers whlch contaln repeatlng unit~ of the formula F:-_[_(_phl _ o -)n-Phl - C0-)-]- F
whereln Phl and n are as defined.
The sulphonatet polyketone may be a materlal in which the value of n 18 only one or is only two or ln whlch the value of n tlffers along the polymer chain ant is both one and two at various points along the chain. Thus, the sulphonated polyketone may be a materlal obtalned by sulphonatlng a polyketone havlng only the repeatlng unlts G:-_(_ph2 _ 0 _ ph2 _ 0 _ ph2 _ C0-)- G
or only the repeatlng unlts H:-_(_ph2 _ 0 _ ph2 _ C0-)-, H
whereln ph2 ls as teflnet.
Alternatively, the sulphonatet polyketone may be 1~195~
The sulphonated polysulphones are polymeric materials of high molecular weight such that the reduced viscosity (RV) of the polymer, (measured as a 1% by weight solution of the polymer in dimethylformamide at 25C) is at least 0.2 and preferably at least 0.4. The polymer may be such as to give an RV of up to 2.5, but it is generally preferred that the RV of the polymer does not exceed 2Ø
The sulphonated polysulphone contains the groups - S03M, where M may be hydrogen, a metal atom or a group NR4. Sulphonated polysulphones in which M is a divalent metal atom, particularly an alkaline earth metal, are the sub~ect of our published European Patent Application No. 145305, which also discloses a method for the production of such divalent metals salts and the use thereof for the production of asymmetric semi-permeable membrane~.
Less preferably the membrane can contain a layer formed from a material of formula B in whlch the group Y is a ketone group. Sulphonated polyketones whlch may be used include polymers whlch contaln repeatlng unit~ of the formula F:-_[_(_phl _ o -)n-Phl - C0-)-]- F
whereln Phl and n are as defined.
The sulphonatet polyketone may be a materlal in which the value of n 18 only one or is only two or ln whlch the value of n tlffers along the polymer chain ant is both one and two at various points along the chain. Thus, the sulphonated polyketone may be a materlal obtalned by sulphonatlng a polyketone havlng only the repeatlng unlts G:-_(_ph2 _ 0 _ ph2 _ 0 _ ph2 _ C0-)- G
or only the repeatlng unlts H:-_(_ph2 _ 0 _ ph2 _ C0-)-, H
whereln ph2 ls as teflnet.
Alternatively, the sulphonatet polyketone may be 1~195~
obtained by sulphonating a copolymer having both the repeating units G and the repeating units H. In the polyketone which is to be sulphonated, it is preferred that the groups ph2 are para-phenylene groups.
Sulphonated polyketones which may be used are described in the prior art, for example in European Patent Specifications 8895 and 41780. Thus, it is possible to use the products obtained by sulphonating a polymer having the repeating units of the formula G, optionally together with other repeat units.
Sulphonation may be effected by dissolving the polyketone in concentrated sulphuric acid (98% W/w) and agitating the solution until the polymer has been sulphonated to a deslred extent. The sulphonation in concentrated sulphuric acid may be carried out at ambient temperature or at an elevated temperature, for example at least 50C, depending on the polyketone to be sulphonated.
The polyketone which is sulphonated is preferably one containing the repeating units of the formula G only or a copolymer containing the repeating units of the formula G
together with up to 50 mole X of comonomer units of the formula J:-_ (_ph2 _ O _ ph2 _ y or comonomer units of the formula E (as herein described) where ph2 ant Y are both as tefinet.
Preferret sulphonated polyketones contain the repeating units K:-_(_ph2 _ o - Ph3 - o - ph2 - C0-)- K
together with the repeating units G and optionally also the repeating units H, wherein ph2 and Ph3 are both as defined.
The sulphonatet polyketones are conveniently prepared by sulphonation of polyetherketones using the procedures described herein and in European Patent Specifications 8895 and 41780. The polyetherketones which are sulphonated are suitably crystalline polymers containing the repeating units G alone or together with lZ~lgs~
Sulphonated polyketones which may be used are described in the prior art, for example in European Patent Specifications 8895 and 41780. Thus, it is possible to use the products obtained by sulphonating a polymer having the repeating units of the formula G, optionally together with other repeat units.
Sulphonation may be effected by dissolving the polyketone in concentrated sulphuric acid (98% W/w) and agitating the solution until the polymer has been sulphonated to a deslred extent. The sulphonation in concentrated sulphuric acid may be carried out at ambient temperature or at an elevated temperature, for example at least 50C, depending on the polyketone to be sulphonated.
The polyketone which is sulphonated is preferably one containing the repeating units of the formula G only or a copolymer containing the repeating units of the formula G
together with up to 50 mole X of comonomer units of the formula J:-_ (_ph2 _ O _ ph2 _ y or comonomer units of the formula E (as herein described) where ph2 ant Y are both as tefinet.
Preferret sulphonated polyketones contain the repeating units K:-_(_ph2 _ o - Ph3 - o - ph2 - C0-)- K
together with the repeating units G and optionally also the repeating units H, wherein ph2 and Ph3 are both as defined.
The sulphonatet polyketones are conveniently prepared by sulphonation of polyetherketones using the procedures described herein and in European Patent Specifications 8895 and 41780. The polyetherketones which are sulphonated are suitably crystalline polymers containing the repeating units G alone or together with lZ~lgs~
other repeating units and having an RV (measured at 25C in a 0.1% W/w so]ution of the polymer in concentrated sulphuric acid) of at least 0.7. Such polymers are more fully described in European Patent Speclfication 1879.
The sulphonated polyarylsulphones are preferred to the sulphonated polyarylketones. The polymers are conveniently those having a sulphonation ratio of at least 2, for example at least 4, and not more than 20, preferably not more than 15. By 'sulphonation ratio is meant the ratio of the number of unsulphonated phenylene residues in the sulphonated polymer to the number of sulphonated phenylene residues in the sulphonated polymer. The sulphonation ratio can be determined by titration or by n.m.r. In the sulphonsted polysulphone, the group -S03M may be in the free acid form as -S03H or may be a salt, for example an ammonium salt or a salt of a metal such as sodium, calcium, barium or a metal of Group VIII of the Periodic Table.
In the membrane of the invention it is preferred that the fiFst layer of material, i.e. thst between the enzyme snd the electrode is formed from the PAS or PAK. Suitably the first layer has a thickness in the range 0.2 to 1.0 microns.
The second polymeric layer in the membrane of the lnventlon acts as a permeability barrier and prevents or restricts the pas~age of compounds of high~molecular weight and gives strength to the membrane sufficient to enable it to retain its shape and to maintain suitable contact with the electrode.
Suitsble polymeric materials for the second layer include porous polycarbonates, polyurethanes and modified cellulose, such a8 cellulose scetate. Suitable materials also include materials having a percentage porosity (the product of pore area X pore density X 100) which is not greater than 5% and preferably in the rsnge 0.001% to 0.5%. Often such materials will have pores of mean diameter less thsn 0.03 microns. To ensure rspld electrode response the thickness of the second polymeric layer is preferably less thsn 20 microns, especislly in the rsnge 1 to 10 microns.
Especially suitable polymeric materials for the second layer are 1~195t~
the materials havlng a percentage porosity not greater than 5 whlch are used for a simllar purpose ln the sensors of our Canadian Patent Nb. 1,244,085. In such materials the permeabillty of the ~econd layer is restricted to an exteDt such that the rate of permeation of the analyte across the layer i8 the rate limlting step for its reaction with the sensor.
The enzyme present in the membrane of the invention may be located therein in any suitable manner. Preferably in a laminated membrane it is present between the first and second layers of material and cau~es them to adhere together. In this situation and also generally, the enzyme is preferably immobilised by mixing with a material whlch causes cross llnking to occur. A
very sultable material for this purpose is glutaraldehyde;
proteins such as albumin and other materials may also be included.
In orter to facilitate the obtaining of rapid stable readings from the sensor incorporating the membrane it is preferred that the enzyme-containing layer is thin, i.e. not 8reater than 50 microns thick.
The enzyme to be used in the membrane of the lnventlon will depent upon the analyte whose concentration 18 to be teterminet. If the analyte 18 glucose then the enzyme wlll be for e~ample glucose o~idase. Other enzymes whlch may be present lnclute urlcase ant lactate oxltase for teterminatlon of uric aclt ant lactlc acld respectively.
The outer face of the outermost layer of the membrane, i.e. that face which contacts the specimen, may if deslret be treated wlth an organo-sllane.
A lamlnatet embrane for use ln the sensor of the lnventlon for the tetermlnatlon of glucose may be preparet by a 30 methot including the following steps:-1. 1 mg glucose oxidase ig dissolved in 50 ~1 of (100 mg/ml) albumin:
2. 3 ~l of 12.S% glutaraldehyde solution is mixed with 3 ~l of the enzyme/albumin mixture on a glass microscope slide:
~a~
~g.lss~
3. l ~1 of the mixture produced in the previous step is applied to one face of a 1 cm2 polycarbonate film having pores with a mean diameter below 0.03 microns:
4. The other surface of the enzyme layer is covered immediately with a thin sulphonated polysulphone film and the resulting laminated membrane is clamped for 3 minutes between glass slides. After removal from the glass slides the laminated membrane produced by the above sequence of steps may be applied to a platinum electrode to form the sensor of the invention, the sulphonated polysulphone film being nearest to the electrode and forming the flrst layer.
In addition to the method described above in which the first or inner layer of PAS is formed by pressing out a droplet of polymer solution between 2 glass slides other methods are possible. For instance a spin coater could be used with optimisation of droplet size, polymer concentration, spin speed and time. Any type of spin coater could be used including the flat chuck type. Such a method should be capable of producing films of 1 ~m or less reproducibly. Other methods include a varlety of printlng techniques such as screen or gravure and use of a water or other liquid surface on which to cast the film.
Casting onto water gives the possibility of obtaining extremely thin films and controlling orientation and surface compaction.
2S These methods allow a film to be cast directly onto an electrode assembly or, in the case of the liquid surface ehe film can be picked up onto the electrode avoiding unneces~ary handling.
The sensor of the invention may have a detachable membrane or it may be a disposable sensor with an adherent membrane. Materials used in the formation of suitable electrodes for the sensors include inert metals and/or carbon. The electrode assembly may be formed by vacuum evaporation sputtering or ion-plating OD to a substrate.
Use of the analytical method of the invention has the advantage that it enables the effect of interfering species on the signal to be measured by the sensor to be greatly reduced or in some cases effectively eliminated. This greatly increases the rellability of the enzyme-electrode sensors of the invention.
The invention is illustrated by Figures 1 and 2 of the accompanying drawings wherein:-Figure l shows in cross-section part of an enzyme-electrode type sensor with a membrane of the invention attached thereto; and Figure 2 is an exploded cross-sectional view of part of a sensor of the invention for the determination of hydrogen peroxide.
In Figure l, reference numeral 1 is the second polymer layer of the membrane formed from a polycarbonate film having pores of mean dlameter below 0.03 microns and having a percentage poroslty whlch is not greater than 5%, 2 is a layer of glucose oxldase enzyme dissolved in albumin and mixed with glutaraldehyde, 3 i8 the first polymer layer formed from a sulphonated poly-sulphone, 4 is the platinum working electrode and 5 is the silver reference electrode. l, 2 and 3 together form a laminated membrane. Platinum worklng electrode 4 acts as an anode whllst sllver reference electrode S acts as a cathode. The membrane 18 held ln place on the electrode by a perspex rlng presslng down on outer layer 1 towards lts outer edges at 6.
In Flgure 2, reference numeral 7 is a platinum working electrode polarlsed at +6.50 mV against the reference electrode, 8 is a sllver/silver chlorlde reference electrode, 9 is a sealing '0' ring, 10 is a sulphonated polysulphone membrane, 11 ls a current meter and source of polarlsing voltage and 12 ls a screw-flt top with sample compartment. To place this sensor in a contltlon for use, a few drops of a buffer solutlon containing 50 m mol l 1 sodlum chlorlde ls applied to the surface of the sensor to provide electrolytic contact between the worklng and reference electrodes 7 and 8 respecSlvely. The sulphonated polysulphone membrane 10 is then placed over the working electrode 7 and beld ln place by screw-flt top 12 of the electrode body.
1~919~i The sensor is now ready to measure aqueous solutions of hydrogen peroxide.
Membrane formation The sulphonated polysulphone films for the membranes of the enzyme-electrode type sensor of Figure 1 and the sensor of Figure 2 were cast from a lC% W/v solution of sulphonated poly-sulphone (5, 10 or 20 sulphonation ratios tried; 10 type exemplified herein) in dimethyl sulphoxide. 50 ~1 of solution was spread evenly over a glass plate of surface area 20 cm2. The plate was placed in a vacuum oven and left at 0.1 mm Hg, 50C for 6 hrs.
NB: The polymers hat ~he following RV: 5 - RV - 0.95:
The sulphonated polyarylsulphones are preferred to the sulphonated polyarylketones. The polymers are conveniently those having a sulphonation ratio of at least 2, for example at least 4, and not more than 20, preferably not more than 15. By 'sulphonation ratio is meant the ratio of the number of unsulphonated phenylene residues in the sulphonated polymer to the number of sulphonated phenylene residues in the sulphonated polymer. The sulphonation ratio can be determined by titration or by n.m.r. In the sulphonsted polysulphone, the group -S03M may be in the free acid form as -S03H or may be a salt, for example an ammonium salt or a salt of a metal such as sodium, calcium, barium or a metal of Group VIII of the Periodic Table.
In the membrane of the invention it is preferred that the fiFst layer of material, i.e. thst between the enzyme snd the electrode is formed from the PAS or PAK. Suitably the first layer has a thickness in the range 0.2 to 1.0 microns.
The second polymeric layer in the membrane of the lnventlon acts as a permeability barrier and prevents or restricts the pas~age of compounds of high~molecular weight and gives strength to the membrane sufficient to enable it to retain its shape and to maintain suitable contact with the electrode.
Suitsble polymeric materials for the second layer include porous polycarbonates, polyurethanes and modified cellulose, such a8 cellulose scetate. Suitable materials also include materials having a percentage porosity (the product of pore area X pore density X 100) which is not greater than 5% and preferably in the rsnge 0.001% to 0.5%. Often such materials will have pores of mean diameter less thsn 0.03 microns. To ensure rspld electrode response the thickness of the second polymeric layer is preferably less thsn 20 microns, especislly in the rsnge 1 to 10 microns.
Especially suitable polymeric materials for the second layer are 1~195t~
the materials havlng a percentage porosity not greater than 5 whlch are used for a simllar purpose ln the sensors of our Canadian Patent Nb. 1,244,085. In such materials the permeabillty of the ~econd layer is restricted to an exteDt such that the rate of permeation of the analyte across the layer i8 the rate limlting step for its reaction with the sensor.
The enzyme present in the membrane of the invention may be located therein in any suitable manner. Preferably in a laminated membrane it is present between the first and second layers of material and cau~es them to adhere together. In this situation and also generally, the enzyme is preferably immobilised by mixing with a material whlch causes cross llnking to occur. A
very sultable material for this purpose is glutaraldehyde;
proteins such as albumin and other materials may also be included.
In orter to facilitate the obtaining of rapid stable readings from the sensor incorporating the membrane it is preferred that the enzyme-containing layer is thin, i.e. not 8reater than 50 microns thick.
The enzyme to be used in the membrane of the lnventlon will depent upon the analyte whose concentration 18 to be teterminet. If the analyte 18 glucose then the enzyme wlll be for e~ample glucose o~idase. Other enzymes whlch may be present lnclute urlcase ant lactate oxltase for teterminatlon of uric aclt ant lactlc acld respectively.
The outer face of the outermost layer of the membrane, i.e. that face which contacts the specimen, may if deslret be treated wlth an organo-sllane.
A lamlnatet embrane for use ln the sensor of the lnventlon for the tetermlnatlon of glucose may be preparet by a 30 methot including the following steps:-1. 1 mg glucose oxidase ig dissolved in 50 ~1 of (100 mg/ml) albumin:
2. 3 ~l of 12.S% glutaraldehyde solution is mixed with 3 ~l of the enzyme/albumin mixture on a glass microscope slide:
~a~
~g.lss~
3. l ~1 of the mixture produced in the previous step is applied to one face of a 1 cm2 polycarbonate film having pores with a mean diameter below 0.03 microns:
4. The other surface of the enzyme layer is covered immediately with a thin sulphonated polysulphone film and the resulting laminated membrane is clamped for 3 minutes between glass slides. After removal from the glass slides the laminated membrane produced by the above sequence of steps may be applied to a platinum electrode to form the sensor of the invention, the sulphonated polysulphone film being nearest to the electrode and forming the flrst layer.
In addition to the method described above in which the first or inner layer of PAS is formed by pressing out a droplet of polymer solution between 2 glass slides other methods are possible. For instance a spin coater could be used with optimisation of droplet size, polymer concentration, spin speed and time. Any type of spin coater could be used including the flat chuck type. Such a method should be capable of producing films of 1 ~m or less reproducibly. Other methods include a varlety of printlng techniques such as screen or gravure and use of a water or other liquid surface on which to cast the film.
Casting onto water gives the possibility of obtaining extremely thin films and controlling orientation and surface compaction.
2S These methods allow a film to be cast directly onto an electrode assembly or, in the case of the liquid surface ehe film can be picked up onto the electrode avoiding unneces~ary handling.
The sensor of the invention may have a detachable membrane or it may be a disposable sensor with an adherent membrane. Materials used in the formation of suitable electrodes for the sensors include inert metals and/or carbon. The electrode assembly may be formed by vacuum evaporation sputtering or ion-plating OD to a substrate.
Use of the analytical method of the invention has the advantage that it enables the effect of interfering species on the signal to be measured by the sensor to be greatly reduced or in some cases effectively eliminated. This greatly increases the rellability of the enzyme-electrode sensors of the invention.
The invention is illustrated by Figures 1 and 2 of the accompanying drawings wherein:-Figure l shows in cross-section part of an enzyme-electrode type sensor with a membrane of the invention attached thereto; and Figure 2 is an exploded cross-sectional view of part of a sensor of the invention for the determination of hydrogen peroxide.
In Figure l, reference numeral 1 is the second polymer layer of the membrane formed from a polycarbonate film having pores of mean dlameter below 0.03 microns and having a percentage poroslty whlch is not greater than 5%, 2 is a layer of glucose oxldase enzyme dissolved in albumin and mixed with glutaraldehyde, 3 i8 the first polymer layer formed from a sulphonated poly-sulphone, 4 is the platinum working electrode and 5 is the silver reference electrode. l, 2 and 3 together form a laminated membrane. Platinum worklng electrode 4 acts as an anode whllst sllver reference electrode S acts as a cathode. The membrane 18 held ln place on the electrode by a perspex rlng presslng down on outer layer 1 towards lts outer edges at 6.
In Flgure 2, reference numeral 7 is a platinum working electrode polarlsed at +6.50 mV against the reference electrode, 8 is a sllver/silver chlorlde reference electrode, 9 is a sealing '0' ring, 10 is a sulphonated polysulphone membrane, 11 ls a current meter and source of polarlsing voltage and 12 ls a screw-flt top with sample compartment. To place this sensor in a contltlon for use, a few drops of a buffer solutlon containing 50 m mol l 1 sodlum chlorlde ls applied to the surface of the sensor to provide electrolytic contact between the worklng and reference electrodes 7 and 8 respecSlvely. The sulphonated polysulphone membrane 10 is then placed over the working electrode 7 and beld ln place by screw-flt top 12 of the electrode body.
1~919~i The sensor is now ready to measure aqueous solutions of hydrogen peroxide.
Membrane formation The sulphonated polysulphone films for the membranes of the enzyme-electrode type sensor of Figure 1 and the sensor of Figure 2 were cast from a lC% W/v solution of sulphonated poly-sulphone (5, 10 or 20 sulphonation ratios tried; 10 type exemplified herein) in dimethyl sulphoxide. 50 ~1 of solution was spread evenly over a glass plate of surface area 20 cm2. The plate was placed in a vacuum oven and left at 0.1 mm Hg, 50C for 6 hrs.
NB: The polymers hat ~he following RV: 5 - RV - 0.95:
10 - RV - 0.86 and 20 - RV - 0.70.
The use of the enzyme-electrode type sensor shown in ~5 Figure 1 is illustrated in the following Example:-EXAMPLE
One of the main problems in the use of glucose enzyme electrodes for blood measurements is the effect of interfering specles in bloot such as ascorbic acid, which give a tirect electrochemical signal at an H202-detecting electrode. This example illustrates how the sulphonated polysulphone layer in the membrane of the invention may be uset to screen out these interferlng species ant allow selective measurement of H202, formed from the reactlon of the enzyme glucose oxida~e (EC
1.1.3.4) with its substrates, glucose and oxygen.
A solution (10 ~1) containing 3 mg ml 1 glucose oxidase and 200 mg ml 1 serum albumin was mixed with a 5X aqueous solution of glutaraldehyde (5 ~1), and left to become viscous. 2 ~1 of the mixture was applied to one side of a polycarbonate film (l cm2) having pores of mean diameter 0.015 ~m. Onto the enzyme layer was pressed a 1 cm2 piece of sulphonated polysulphone film and the laminate was left to allow the enzyme to crosslink further. The laminate can then be used as a substitute for the pla~n sulphonated polysulphone membrane in the sensor of Figure 2 or can be uset in the sensor of Figure 1 to provide an enzyme electrode ~919~
responsive to glucose solutlons. In the sensor the laminate was positioned with the first sulphonated polysulphone layer facing toward~ the sensor surface.
The Table gives the results obtained when the laminate membrane was used in the presence of glucose and glucose with various interfering species. In the Table the results are compared with the results obtained with a membrane lacking the sulphonated polysulphone layer. It can be seen that the membrane with the sulphonated polysulphone layer gave a response which was much less affected by interfering species than that of the conventional membrane.
1f~919~
Table l l Response ¦ IConventionall I Enzymic I I enzymic I I membrane I Solutes I membrane I % I with I %
I ¦ (arbitrary lincrease¦sulphonated lincrease units) IIpolysulphone first layer (a) 1 mmol glucose -alone 1 9 l l 4.2 (b) +0.2 m mol I 1 1 ascorbic ~
I acid 1 14.5 160 1 4.3 1 2 (c) +0.1 m mol ~ cysteine 1 9.9 110 1 4.2 1 0 I(d) + 1 m mol 1 1-1 gluta-I thione 1 11.5 128 1 4.2 1 0 Ite) + 0-5 m moll ~ urate 1 26 1190 1 4.2 1 0 I(f) a solutlon I containing all the above¦
I ingretients 133 1270 1 4.4 1 5 I(g) 1 m mol 1-1 81ucose +
1 m mol 1 1 I acetaminophenl 78 1 770 15.0 1 20 PA/JNA/MP
6 November 1986/L123A
The use of the enzyme-electrode type sensor shown in ~5 Figure 1 is illustrated in the following Example:-EXAMPLE
One of the main problems in the use of glucose enzyme electrodes for blood measurements is the effect of interfering specles in bloot such as ascorbic acid, which give a tirect electrochemical signal at an H202-detecting electrode. This example illustrates how the sulphonated polysulphone layer in the membrane of the invention may be uset to screen out these interferlng species ant allow selective measurement of H202, formed from the reactlon of the enzyme glucose oxida~e (EC
1.1.3.4) with its substrates, glucose and oxygen.
A solution (10 ~1) containing 3 mg ml 1 glucose oxidase and 200 mg ml 1 serum albumin was mixed with a 5X aqueous solution of glutaraldehyde (5 ~1), and left to become viscous. 2 ~1 of the mixture was applied to one side of a polycarbonate film (l cm2) having pores of mean diameter 0.015 ~m. Onto the enzyme layer was pressed a 1 cm2 piece of sulphonated polysulphone film and the laminate was left to allow the enzyme to crosslink further. The laminate can then be used as a substitute for the pla~n sulphonated polysulphone membrane in the sensor of Figure 2 or can be uset in the sensor of Figure 1 to provide an enzyme electrode ~919~
responsive to glucose solutlons. In the sensor the laminate was positioned with the first sulphonated polysulphone layer facing toward~ the sensor surface.
The Table gives the results obtained when the laminate membrane was used in the presence of glucose and glucose with various interfering species. In the Table the results are compared with the results obtained with a membrane lacking the sulphonated polysulphone layer. It can be seen that the membrane with the sulphonated polysulphone layer gave a response which was much less affected by interfering species than that of the conventional membrane.
1f~919~
Table l l Response ¦ IConventionall I Enzymic I I enzymic I I membrane I Solutes I membrane I % I with I %
I ¦ (arbitrary lincrease¦sulphonated lincrease units) IIpolysulphone first layer (a) 1 mmol glucose -alone 1 9 l l 4.2 (b) +0.2 m mol I 1 1 ascorbic ~
I acid 1 14.5 160 1 4.3 1 2 (c) +0.1 m mol ~ cysteine 1 9.9 110 1 4.2 1 0 I(d) + 1 m mol 1 1-1 gluta-I thione 1 11.5 128 1 4.2 1 0 Ite) + 0-5 m moll ~ urate 1 26 1190 1 4.2 1 0 I(f) a solutlon I containing all the above¦
I ingretients 133 1270 1 4.4 1 5 I(g) 1 m mol 1-1 81ucose +
1 m mol 1 1 I acetaminophenl 78 1 770 15.0 1 20 PA/JNA/MP
6 November 1986/L123A
Claims (10)
1. A membrane permeable to liquids and solutes which comprises an enzyme-containing layer and one or more layers of material wherein at least one said layer of material is formed from a polymer selected from the group consisting of a sulphonated polyarylsulphone and a sulphonated polyarylketone.
2. A membrane according to claim 1 wherein the layer formed from the polyarylsulphone or polyarylketone is formed from a sulphonated polyarylether sulphone.
3. A membrane according to claim 2 wherein the sulphonated polyarylether sulphone has a sulphonation ratio in the range 2 to 20.
4. A sensor which incorporates a membrane permeable to liquids and solutes, which membrane comprises one or more layers of material wherein at least one said layer of material is formed from a polymer selected from the group consisting of a sulphonated polyarylsulphone and a sulphonated polyarylketone.
5. A sensor of the enzyme-electrode type which incorporates an electrode and a membrane permeable to liquids and solutes, which membrane comprises an enzyme-containing layer and one or more layers of material wherein at least one said layer of material is formed from a polymer selected from the group consisting of a sulphonated polyarylsulphone and a sulphonated polyarylketone.
6. A sensor according to claim 5 in which the membrane comprises a first layer of material positioned between the enzyme-containing layer and the electrode, the enzyme-containing layer and a second layer of material on the other side of the enzyme-containing layer wherein the first layer is formed from a polymer selected from the group consisting of a sulphonated polyarylsulphone and a sulphonated polyarylketone.
7. A sensor according to claim 6 wherein the first layer has a thickness in the range 0.2 to 1.0 microns.
8. A sensor according to claim 6 wherein the second layer is formed from a polymeric material having a percentage porosity in the range 0.001% to 0.5%.
9. A method for determining an analyte in a specimen which comprises bringing the specimen into contact with the outer face of a membrane, permeable to liquids and solutes and comprising one or more layers of material, incorporated into a sensor sensitive to the analyte and measuring the response of the sensor to the analyte wherein at least one layer of material is formed from a polymer selected from the group consisting of a sulphonated polyarylsulphone and a sulphonated polyarylketone.
10. A method for determining an analyte in a specimen which comprises bringing the specimen into contact with the outer face of a membrane, permeable to liquids and solutes and comprising an enzyme, in the presence of which the analyte is convertible into a species detectable by a sensor which incorporates the membrane, and one or more layers of material, and measuring the response of the sensor to the species, wherein at least one layer of material is formed from a polymer selected from the group consisting of a sulphonated polyarylsulphone and a sulphonated polyarylketone.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8529300 | 1985-11-28 | ||
| GB858529300A GB8529300D0 (en) | 1985-11-28 | 1985-11-28 | Membrane |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1291956C true CA1291956C (en) | 1991-11-12 |
Family
ID=10588911
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000524145A Expired - Lifetime CA1291956C (en) | 1985-11-28 | 1986-11-28 | Membrane and a sensor and analytical method based upon the improved membrane |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US4832797A (en) |
| EP (1) | EP0225094B1 (en) |
| JP (1) | JPH0746085B2 (en) |
| AT (1) | ATE68824T1 (en) |
| AU (1) | AU595260B2 (en) |
| CA (1) | CA1291956C (en) |
| DE (1) | DE3682169D1 (en) |
| DK (1) | DK172854B1 (en) |
| ES (1) | ES2026458T3 (en) |
| FI (1) | FI87932C (en) |
| GB (1) | GB8529300D0 (en) |
| GR (1) | GR3003076T3 (en) |
| IE (1) | IE59740B1 (en) |
| IL (1) | IL80753A (en) |
| NO (1) | NO174897C (en) |
| NZ (1) | NZ218427A (en) |
| PT (1) | PT83823B (en) |
| ZA (1) | ZA868715B (en) |
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| US5208154A (en) * | 1991-04-08 | 1993-05-04 | The United States Of America As Represented By The Department Of Energy | Reversibly immobilized biological materials in monolayer films on electrodes |
| DE59307719D1 (en) * | 1992-03-23 | 1998-01-08 | Siemens Ag | Biosensor |
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1985
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1986
- 1986-11-14 AT AT86308918T patent/ATE68824T1/en not_active IP Right Cessation
- 1986-11-14 ES ES198686308918T patent/ES2026458T3/en not_active Expired - Lifetime
- 1986-11-14 EP EP86308918A patent/EP0225094B1/en not_active Expired - Lifetime
- 1986-11-14 DE DE8686308918T patent/DE3682169D1/en not_active Expired - Lifetime
- 1986-11-17 ZA ZA868715A patent/ZA868715B/en unknown
- 1986-11-18 IE IE304786A patent/IE59740B1/en not_active IP Right Cessation
- 1986-11-20 AU AU65532/86A patent/AU595260B2/en not_active Expired
- 1986-11-25 IL IL80753A patent/IL80753A/en unknown
- 1986-11-25 US US06/936,720 patent/US4832797A/en not_active Expired - Lifetime
- 1986-11-27 NO NO864772A patent/NO174897C/en unknown
- 1986-11-27 NZ NZ218427A patent/NZ218427A/en unknown
- 1986-11-27 PT PT83823A patent/PT83823B/en unknown
- 1986-11-28 FI FI864865A patent/FI87932C/en not_active IP Right Cessation
- 1986-11-28 CA CA000524145A patent/CA1291956C/en not_active Expired - Lifetime
- 1986-11-28 JP JP61284073A patent/JPH0746085B2/en not_active Expired - Lifetime
- 1986-11-28 DK DK198605745A patent/DK172854B1/en not_active IP Right Cessation
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1991
- 1991-11-07 GR GR91401685T patent/GR3003076T3/en unknown
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| FI87932C (en) | 1993-03-10 |
| NZ218427A (en) | 1989-09-27 |
| NO864772L (en) | 1987-05-29 |
| PT83823B (en) | 1989-06-30 |
| DE3682169D1 (en) | 1991-11-28 |
| EP0225094B1 (en) | 1991-10-23 |
| PT83823A (en) | 1986-12-01 |
| ZA868715B (en) | 1987-07-29 |
| NO864772D0 (en) | 1986-11-27 |
| ES2026458T3 (en) | 1992-05-01 |
| FI864865A0 (en) | 1986-11-28 |
| IE59740B1 (en) | 1994-03-23 |
| JPS62132164A (en) | 1987-06-15 |
| EP0225094A3 (en) | 1988-12-14 |
| GR3003076T3 (en) | 1993-02-17 |
| DK574586D0 (en) | 1986-11-28 |
| IL80753A (en) | 1990-03-19 |
| NO174897B (en) | 1994-04-18 |
| FI864865A (en) | 1987-05-29 |
| ATE68824T1 (en) | 1991-11-15 |
| FI87932B (en) | 1992-11-30 |
| AU6553286A (en) | 1987-06-04 |
| DK172854B1 (en) | 1999-08-16 |
| NO174897C (en) | 1994-07-27 |
| DK574586A (en) | 1987-05-29 |
| EP0225094A2 (en) | 1987-06-10 |
| GB8529300D0 (en) | 1986-01-02 |
| IE863047L (en) | 1987-05-28 |
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| AU595260B2 (en) | 1990-03-29 |
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