CA1290015C - Sensor with supported liquid membrane - Google Patents
Sensor with supported liquid membraneInfo
- Publication number
- CA1290015C CA1290015C CA000573855A CA573855A CA1290015C CA 1290015 C CA1290015 C CA 1290015C CA 000573855 A CA000573855 A CA 000573855A CA 573855 A CA573855 A CA 573855A CA 1290015 C CA1290015 C CA 1290015C
- Authority
- CA
- Canada
- Prior art keywords
- layer
- membrane
- enzyme
- sensor
- analyte
- 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 - Fee Related
Links
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
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S435/00—Chemistry: molecular biology and microbiology
- Y10S435/817—Enzyme or microbe electrode
Abstract
Abstract: "Sensor"
A sensor of the enzyme-electrode type comprising an electrode and a membrane permeable to liquids and solutes which is positioned between the electrode and a specimen containing the analyte to be determined, is characterised by the fact that a layer of a porous material, positioned in the membrane between the enzyme-containing layer and the specimen, has been treated to at least partially fill the pores with a liquid of limited volatility which is not significantly soluble in water and is to some degree a solvent for the analyte.
A sensor of the enzyme-electrode type comprising an electrode and a membrane permeable to liquids and solutes which is positioned between the electrode and a specimen containing the analyte to be determined, is characterised by the fact that a layer of a porous material, positioned in the membrane between the enzyme-containing layer and the specimen, has been treated to at least partially fill the pores with a liquid of limited volatility which is not significantly soluble in water and is to some degree a solvent for the analyte.
Description
~290~S
SEaSOR
Th1s invention relates to a senRor of the enzyme electrode type comprislng an improved membrane and to an analytical me~hod using the sen60r.
~nzyme electrodes are increasln~ly used in medlcal and other lahora~ories particularly for the de~erminatlon of materials æuch as ; glucose and urea in ~pecimens of blood and other phy~iological fluids.
Such electrodes are descr$bed in many publication~ notably an artlcle by Clark and Lyons (Anals of the New York Acadamy of Sclence, 102, 29-45, 1962) and US Patents 3539455 and 3979274 to Clark and Newman respectively. Enzyme electrodes are generally used to determine materials which themselves are not electrochemically active but ~hich in the presence of suitable en2ymes take part in reactions which produce species which can be readily detected by the electrodes. In enzyme elec~rodes the enæymes are frequently located within polymeric materials in close proximity to the underlylng electrode.
A considerable amount of research ha~ been carried out ln order to improve the propertles of membranes for use in enzyme electrodes and many membranes for this purpose have been disclosed, An ~xample of a type of membrane which is often used is the laminated membrane disclosed by Newman in US Patent 3979274. This membrane comprises a first or inner layer of an essentialJyhomogeneous material, for example cellulose acetate, which can prevent the passage of materials of lo~
molecular weight likely to interfere wlth the enzymic signal, a close adherent layçr of the enzyme itself (wlth or without such other materials that may be blended with lt), and a second layer (ln this instance an outer layer3 of a porous support film whlch can prevent the pa~sage of cellular and colloidal elements.
The determinat~on of glucose can be taXen a~ an example of the dete~mination of a materlal by an enzyme electrode. In the p~es2.~e of the enzy~e gluco~e oxida~e the following reactior. occur~
gluco~e Gluco~e ~2 > Gluconic acid f H22 oxida6e The hydrogen peroxlde produced in this reaction pa~6es through the Pir~t layer of a membrane ~uch as that of US Paten~ 3979274 and can be de~ermined u~ing ~he electrode. Since the hydrogen perox~d~ produced i~ dependent upon the glucose pre~ent in a ~pecimen, the gl~cose concentration can be determined u~lng a suitably calibrated sensor.
To date a number of dlfficulties have llmited the utllity sf enzyme electrodes and restricted the 6cale of thelr use in routine analyRl of, e.g. blood sample6. Signlficant among the6e difficulties i6 the limlted llnearlty of ehe tesponse of electrode6 to analytes such a~ gluco~e or lactate ~hlch a~e substraees for the enæyme catalysed reactions, The response ie llnear only o~er a limited range of low concentrations of the analytes and hence the concentratlons of the materlals to be determined must be low and generally dlluted samples must be used in spec~mens for analy~l6 using enzyme electrode6. It 16 not always practicable Eo make diluted ~amples for routine analy61s out~ide the laboratory and lt would be impos61ble for invasl~e monltoring.
In our published ~uropean Patent Applicatlon No. 216577 we -30 describe and clalm a sensor for the determlnation of an an lyte having a membrane between it~ electrode and a specimen of the analyte to be tested. Prefe~ably the membrane i~ a membrane ~uch a~ that of US
Patent 3979274. However~ in the membrane of the ~ensor of ~uropean appllcation No. 216577 there i8 a testricted permeabillty layer of material between the enzyme-contalnlng layer and the specimen which lZ9~5 restricted peLmeability layer contains an area through ~hich analyte can pass ~ormed from a porous material of restricted permeability having a porosity which is not greater than 5%.
s According to the pre ænt invention we ~rovide a sensor of the enzyme-electrode type for the determination of an analyte, said analyte being oonvertible in the presence of an en~yme into a species ~which can be detected by the sensor, which camprises an electrsde and a membrane permeable to liquids and solutes positioned between the electrode and a specimen containing the analyte, said membrane 03mpris mg a layer containing one or more enzymes and a layer of material positioned between the enzyme-containing layer and the specimen characterised in that said layer of material contains an area thLough which analyte can pass for~ed frYm a porous material which has been treated to fill its pores wholly or partially with a liquid thereby forming a supFDrted liquid membrane.
Further according to the invention we provide a method for determining an analyte in a specimen which comprises contacting the specimen with the outer layer of a membrane, permeable to liquids and solutes and ccmprising one or m~re enzymes, in the presence of which the analyte is convertible into a species detectable by a sensor which incorporates the membrane, and one or mDre layers of material, and measuring the response of the sensor to the species, characterised in that a layer in the membrane between the enzyme and the specimen con~ains an area through which analyte can pass formed from a porous material which has been treated to fill its pores wholly or partially with a liquid thereby forming a supp3rted liquid ~mbrane.
m e liquid is of.limited volatility and is not significantly soluble in water so that loss of the liquid frcm the me~brane via evaporation and/or dissolution.is reduced and hence the stability of - ~Z900~5 the liquld membrane enhanced. Ths llquid ia to s w e degree a ~olvent for the analyte 80 that the analyte may pass through the llquld ln the liquld membrane to reach the enzyme.
The phrase'~lquid of limitet volatllity"lncludes systems in ~hich a volatile llquid is held below another liquid having limi~ced volatility, although such sys~em~ have llmited utllity in the sensora of the l~vention. Preferably the liquid of limited volatility i~
either not a ~olvent for interfering specie~ such as agcorbic acid ~hich wlll give rise to signals interfering with tho~e fro~ the analyte or is a solvent for such interfering species only to a limited extent.
The liquid may be in the form of a solution. The liquid may comprise a lipid or a fatty acid ester. The liquid treated layer can be formed by dipping a membrane in a suitable liquld, particularly lipid solutions, e.g. in n-butanol or n~decane or mi~tures as solvents. Preferred lipid~ for liquid treatments are isopropyl myristate (IPM) and lecithin. These liplds when usad in concentrations of approxima~ely 0.5 mM will allow catechol and glucose to pass through them but are substantially lmpermeable to interfering species such as ascorbic acid, uric acld, hydrogen peroxide and paracet~mol.
A suitable technique for forming the treated laye~ i8 to dip the membrane into the liquid, e.g. a llpid 601ution for a short tlme, e.g.
SEaSOR
Th1s invention relates to a senRor of the enzyme electrode type comprislng an improved membrane and to an analytical me~hod using the sen60r.
~nzyme electrodes are increasln~ly used in medlcal and other lahora~ories particularly for the de~erminatlon of materials æuch as ; glucose and urea in ~pecimens of blood and other phy~iological fluids.
Such electrodes are descr$bed in many publication~ notably an artlcle by Clark and Lyons (Anals of the New York Acadamy of Sclence, 102, 29-45, 1962) and US Patents 3539455 and 3979274 to Clark and Newman respectively. Enzyme electrodes are generally used to determine materials which themselves are not electrochemically active but ~hich in the presence of suitable en2ymes take part in reactions which produce species which can be readily detected by the electrodes. In enzyme elec~rodes the enæymes are frequently located within polymeric materials in close proximity to the underlylng electrode.
A considerable amount of research ha~ been carried out ln order to improve the propertles of membranes for use in enzyme electrodes and many membranes for this purpose have been disclosed, An ~xample of a type of membrane which is often used is the laminated membrane disclosed by Newman in US Patent 3979274. This membrane comprises a first or inner layer of an essentialJyhomogeneous material, for example cellulose acetate, which can prevent the passage of materials of lo~
molecular weight likely to interfere wlth the enzymic signal, a close adherent layçr of the enzyme itself (wlth or without such other materials that may be blended with lt), and a second layer (ln this instance an outer layer3 of a porous support film whlch can prevent the pa~sage of cellular and colloidal elements.
The determinat~on of glucose can be taXen a~ an example of the dete~mination of a materlal by an enzyme electrode. In the p~es2.~e of the enzy~e gluco~e oxida~e the following reactior. occur~
gluco~e Gluco~e ~2 > Gluconic acid f H22 oxida6e The hydrogen peroxlde produced in this reaction pa~6es through the Pir~t layer of a membrane ~uch as that of US Paten~ 3979274 and can be de~ermined u~ing ~he electrode. Since the hydrogen perox~d~ produced i~ dependent upon the glucose pre~ent in a ~pecimen, the gl~cose concentration can be determined u~lng a suitably calibrated sensor.
To date a number of dlfficulties have llmited the utllity sf enzyme electrodes and restricted the 6cale of thelr use in routine analyRl of, e.g. blood sample6. Signlficant among the6e difficulties i6 the limlted llnearlty of ehe tesponse of electrode6 to analytes such a~ gluco~e or lactate ~hlch a~e substraees for the enæyme catalysed reactions, The response ie llnear only o~er a limited range of low concentrations of the analytes and hence the concentratlons of the materlals to be determined must be low and generally dlluted samples must be used in spec~mens for analy~l6 using enzyme electrode6. It 16 not always practicable Eo make diluted ~amples for routine analy61s out~ide the laboratory and lt would be impos61ble for invasl~e monltoring.
In our published ~uropean Patent Applicatlon No. 216577 we -30 describe and clalm a sensor for the determlnation of an an lyte having a membrane between it~ electrode and a specimen of the analyte to be tested. Prefe~ably the membrane i~ a membrane ~uch a~ that of US
Patent 3979274. However~ in the membrane of the ~ensor of ~uropean appllcation No. 216577 there i8 a testricted permeabillty layer of material between the enzyme-contalnlng layer and the specimen which lZ9~5 restricted peLmeability layer contains an area through ~hich analyte can pass ~ormed from a porous material of restricted permeability having a porosity which is not greater than 5%.
s According to the pre ænt invention we ~rovide a sensor of the enzyme-electrode type for the determination of an analyte, said analyte being oonvertible in the presence of an en~yme into a species ~which can be detected by the sensor, which camprises an electrsde and a membrane permeable to liquids and solutes positioned between the electrode and a specimen containing the analyte, said membrane 03mpris mg a layer containing one or more enzymes and a layer of material positioned between the enzyme-containing layer and the specimen characterised in that said layer of material contains an area thLough which analyte can pass for~ed frYm a porous material which has been treated to fill its pores wholly or partially with a liquid thereby forming a supFDrted liquid membrane.
Further according to the invention we provide a method for determining an analyte in a specimen which comprises contacting the specimen with the outer layer of a membrane, permeable to liquids and solutes and ccmprising one or m~re enzymes, in the presence of which the analyte is convertible into a species detectable by a sensor which incorporates the membrane, and one or mDre layers of material, and measuring the response of the sensor to the species, characterised in that a layer in the membrane between the enzyme and the specimen con~ains an area through which analyte can pass formed from a porous material which has been treated to fill its pores wholly or partially with a liquid thereby forming a supp3rted liquid ~mbrane.
m e liquid is of.limited volatility and is not significantly soluble in water so that loss of the liquid frcm the me~brane via evaporation and/or dissolution.is reduced and hence the stability of - ~Z900~5 the liquld membrane enhanced. Ths llquid ia to s w e degree a ~olvent for the analyte 80 that the analyte may pass through the llquld ln the liquld membrane to reach the enzyme.
The phrase'~lquid of limitet volatllity"lncludes systems in ~hich a volatile llquid is held below another liquid having limi~ced volatility, although such sys~em~ have llmited utllity in the sensora of the l~vention. Preferably the liquid of limited volatility i~
either not a ~olvent for interfering specie~ such as agcorbic acid ~hich wlll give rise to signals interfering with tho~e fro~ the analyte or is a solvent for such interfering species only to a limited extent.
The liquid may be in the form of a solution. The liquid may comprise a lipid or a fatty acid ester. The liquid treated layer can be formed by dipping a membrane in a suitable liquld, particularly lipid solutions, e.g. in n-butanol or n~decane or mi~tures as solvents. Preferred lipid~ for liquid treatments are isopropyl myristate (IPM) and lecithin. These liplds when usad in concentrations of approxima~ely 0.5 mM will allow catechol and glucose to pass through them but are substantially lmpermeable to interfering species such as ascorbic acid, uric acld, hydrogen peroxide and paracet~mol.
A suitable technique for forming the treated laye~ i8 to dip the membrane into the liquid, e.g. a llpid 601ution for a short tlme, e.g.
2 to 4 minutes. After this tlme the membrane is removed using a tlssue before the membrane is fitted to the electrode. It bas been found that the liquid tceated membran i8 quite stable with time.
The sensor of the lnvention is selective ~ieh regard to analytes and gives a response which is linear over a range slmilar to that of our published European Patent Application No. 216577. It enables this similar degree of linearity to be achieved using membranes with layers of restricted penmeabllity which have larger pores and~or greater porosities than those of the membranes of Europeàn Application No.
216577.
.. , ~ ._. , _. , . .. -_ - 5 The treated area causes the layer containing lt to have restricted permeability. Preferably all or a ma~or proportlon of the effective area of thl~ layer has been treated.
In lts most simple form the membrane ln the sensor o~ the invention consists of the enzyme-containing layer and the treated layer. The treated layer is the outer layer in this simple form of membrane and is contacted directly by the specimen in the method of the invention for determining an analyte.
However, it 18 possible for the membrane to be a laminated membrane of the type of which that disclosed ln US Patent 3979274 ls an example. Such a membrane comprlses a flrst or innet layer of material positloned between the enzyme-containlng layer and the electrode, the enzyme-containing layer and a second layer of material on the other side of the enzyme-contalning layer which second layer is the treated layer.
~ereafter ln this specification the sensor of the invention which is de6cribed will contain a laminated membrane of the type of ~hich the membrane described in US Patent 3979274 is an example having first and second layers the treated layer being the second layer.
It should be understood that the membranes in the sensor of the inventlon can con~ain more than two layers of material in addition to the enzyme-containing layer. ~or lnstance the second layer, i.e. the treaeed layer is not neces6arlly the outermo6t layer of the membrane.
There may be.a further layer or layers of material, i~e. third, fourth e~c layers, bet~een the second layet or treated layer and the specimen. Often however the second layer will be the outer layer and itæ outet face will be contacted by the speclmen.
Generally the porous material of the treated layer will be a polymeric material but other suitable materlals may be used. Thus the treated layer may be formed from porous glass, a metal, e,g. a sintered metal, having pores cut by laser~ or porous etched and slntered ceramics such a~ aluminas.
Suitably the treated layer of material 1B formed from material having a porosity in the range 0.05 to 20~.
The pore ~ize i8 selected 80 that the liquid of limited 10 volatili~y fills the pore ~holly or partlally to form a ~upported liquid membrane. The mean diameters of the pore~ may be les~ than 5 ~m, and are preferably equal to or less than 3 ~m. For example the mean diameters of the pores may be in the range 3 ~m to 0.05 ~m, particularly for the case where the liqu~d comprises isopropyl 15 myristate and the layer i~ formed from a polycarbonate.
The sensor of the invention may have a detachable membrane or lt may be a di6posable sensor with an adherent membrane. Materials used ln the formation of suitable electrodes for the sensors include inert 20 metals and/or carbon.
~hen the sensor incorporates a laminated membrane of tbe type disclosed in US Patent 3979274 the first layer which is to be located between the enzyme layer and the electrode is suitably formed from 25 polymethyl-meth~crylate, polyurethane, cellulose acetate or another porous material which ~ill restrict or prevent passage of electroactive interfering compounds such as ascorbic acid and tyroRine. S~itably the fir6t layer has a thicknes6 in the range 0.1 microns to 1.0 microns. Preferably the membrane contains a layer 30 formed from a polyarylsulphone or a polyarylketone as described in our published European Patent Application No. 225094.
Suitable porous materials for the second layer include porous A polycarbonates, polyurethanes, and modified cellulose particularly35 cellulose nltrate, cellulose acetate and regenerated cellulose.
The enzyme present in the sensor of the invention may be loca~ed in the membrane in any suitable manner. Preferably in a laminated membrane it i8 present between the first and second layers of material and forms the bond between them. In this situation, and also generally, the enzyme i8 preferably immobilised in a gel. A very sultable material for this purpose is glutaraldehyde proteins such as albumin and other materials may also be lncluded. In order to facilltate the obtalnlng of rapid stable readings from the sensor it i8 preferred that the enzyme-containing layer is thin, i.e. not greater than 5 microns thlck.
The enzyme to be used in the 6ensor of the lnventlon will depend upon the analyte whose concentration is to be determined. If the analyte is glucose then the enzyme ~ill be for example glucose oxidase. Other enzymes which may be present lnclude urlcase and lactate oxidase for de~ermination of urie acld and lactlc acid respectlvely. Enzyme systems comprising two or more enzymes may also be present.
A lamlnated membrane for use ln the sensor of the invention for the determination of glucose may be prepared by a method including the follo~ing steps:-1. A porous polycarbonate fllm havlng a porosity of less than 20%
and pores of diameter less than 10 ~m and preferably less than 5 ~m is dipped in isopropyl myristate in n-butanol for 3 minutes to treat it. When removed from the solution, excess liquid is remo~ed from the film using a tissues 2, 1 mg glucose oxidase is dissolved in 50 ~1 of (100 mg~ml) albumin.
The sensor of the lnvention is selective ~ieh regard to analytes and gives a response which is linear over a range slmilar to that of our published European Patent Application No. 216577. It enables this similar degree of linearity to be achieved using membranes with layers of restricted penmeabllity which have larger pores and~or greater porosities than those of the membranes of Europeàn Application No.
216577.
.. , ~ ._. , _. , . .. -_ - 5 The treated area causes the layer containing lt to have restricted permeability. Preferably all or a ma~or proportlon of the effective area of thl~ layer has been treated.
In lts most simple form the membrane ln the sensor o~ the invention consists of the enzyme-containing layer and the treated layer. The treated layer is the outer layer in this simple form of membrane and is contacted directly by the specimen in the method of the invention for determining an analyte.
However, it 18 possible for the membrane to be a laminated membrane of the type of which that disclosed ln US Patent 3979274 ls an example. Such a membrane comprlses a flrst or innet layer of material positloned between the enzyme-containlng layer and the electrode, the enzyme-containing layer and a second layer of material on the other side of the enzyme-contalning layer which second layer is the treated layer.
~ereafter ln this specification the sensor of the invention which is de6cribed will contain a laminated membrane of the type of ~hich the membrane described in US Patent 3979274 is an example having first and second layers the treated layer being the second layer.
It should be understood that the membranes in the sensor of the inventlon can con~ain more than two layers of material in addition to the enzyme-containing layer. ~or lnstance the second layer, i.e. the treaeed layer is not neces6arlly the outermo6t layer of the membrane.
There may be.a further layer or layers of material, i~e. third, fourth e~c layers, bet~een the second layet or treated layer and the specimen. Often however the second layer will be the outer layer and itæ outet face will be contacted by the speclmen.
Generally the porous material of the treated layer will be a polymeric material but other suitable materlals may be used. Thus the treated layer may be formed from porous glass, a metal, e,g. a sintered metal, having pores cut by laser~ or porous etched and slntered ceramics such a~ aluminas.
Suitably the treated layer of material 1B formed from material having a porosity in the range 0.05 to 20~.
The pore ~ize i8 selected 80 that the liquid of limited 10 volatili~y fills the pore ~holly or partlally to form a ~upported liquid membrane. The mean diameters of the pore~ may be les~ than 5 ~m, and are preferably equal to or less than 3 ~m. For example the mean diameters of the pores may be in the range 3 ~m to 0.05 ~m, particularly for the case where the liqu~d comprises isopropyl 15 myristate and the layer i~ formed from a polycarbonate.
The sensor of the invention may have a detachable membrane or lt may be a di6posable sensor with an adherent membrane. Materials used ln the formation of suitable electrodes for the sensors include inert 20 metals and/or carbon.
~hen the sensor incorporates a laminated membrane of tbe type disclosed in US Patent 3979274 the first layer which is to be located between the enzyme layer and the electrode is suitably formed from 25 polymethyl-meth~crylate, polyurethane, cellulose acetate or another porous material which ~ill restrict or prevent passage of electroactive interfering compounds such as ascorbic acid and tyroRine. S~itably the fir6t layer has a thicknes6 in the range 0.1 microns to 1.0 microns. Preferably the membrane contains a layer 30 formed from a polyarylsulphone or a polyarylketone as described in our published European Patent Application No. 225094.
Suitable porous materials for the second layer include porous A polycarbonates, polyurethanes, and modified cellulose particularly35 cellulose nltrate, cellulose acetate and regenerated cellulose.
The enzyme present in the sensor of the invention may be loca~ed in the membrane in any suitable manner. Preferably in a laminated membrane it i8 present between the first and second layers of material and forms the bond between them. In this situation, and also generally, the enzyme i8 preferably immobilised in a gel. A very sultable material for this purpose is glutaraldehyde proteins such as albumin and other materials may also be lncluded. In order to facilltate the obtalnlng of rapid stable readings from the sensor it i8 preferred that the enzyme-containing layer is thin, i.e. not greater than 5 microns thlck.
The enzyme to be used in the 6ensor of the lnventlon will depend upon the analyte whose concentration is to be determined. If the analyte is glucose then the enzyme ~ill be for example glucose oxidase. Other enzymes which may be present lnclude urlcase and lactate oxidase for de~ermination of urie acld and lactlc acid respectlvely. Enzyme systems comprising two or more enzymes may also be present.
A lamlnated membrane for use ln the sensor of the invention for the determination of glucose may be prepared by a method including the follo~ing steps:-1. A porous polycarbonate fllm havlng a porosity of less than 20%
and pores of diameter less than 10 ~m and preferably less than 5 ~m is dipped in isopropyl myristate in n-butanol for 3 minutes to treat it. When removed from the solution, excess liquid is remo~ed from the film using a tissues 2, 1 mg glucose oxidase is dissolved in 50 ~1 of (100 mg~ml) albumin.
3. 3 ~1 of 12.5% glutaraldehyde solution is mixed with 3 ~1 of enzyme/albumin mixture on a glass microscope slide:
l. 1 ~1 of the mixture produced in the prevlous step is applied to one face of the 1 cm2 polycarbonate produced in step l:
~290~1S
5. The other surface of the enzyme layer 18 covered lmmediately ~ith a thin cellulose acetate fllm and ~he resultlng lamlnated membrane i8 clamped for 3 mlnutes between glass slldes~
6. The membrane is applled to a platlnum electrode to form the sensor of the invention, the cellulose acetate film belng nearest to the electrode and forming the flrst layer. ~~
Use of the method of the invention giveA the advantage of an lncrease in the concentration range over ~hlch a graph of concentration against Bell~Or re8pOn8e i8 linear. Wlth conventlonal methods linearl~y was generally extended only up to approxlmately a concentration of 3 m mol per lltre for glucose. U~ing the method of the invention linearity ls increafied and the range extends to glucose concentrations of 50 m mol lS per litre and even higher. Thls is achieved through restric~ion of substrate entry into the enæyme layer and therefore ~ith some 10BB of sen~ltivity. Thus the range covers the concentrations of glucose which can be antlclpated in blood samples thereby enabling blood glucose levels to be determined more readily. This is a considerable advantage in situations where large numbers of determinations must be made regularly and with minimal sample preparation. Llnearity is also extended by applying to the second layer of ~he membrane a medium comprising an organo-silane having reac~ive groups as described in our published European Patent Application No. 204468. This treatment may be applied to the second layer of the membrane in the sensor of the ptesent invention to produce a combined effect and further improved linearity.
The invention is illustrated by Figure 1 of the accompanying drawings.
In ~lgure 1, reference numeral l i6 the second layer of the membrans formed from a polycarbonate fllm treated with a 30% solution of lsopropyl myristate (IPN), 2 is a layer of glu~ose oxidase enzyme dissolved in albumin and mixed with glutaraldehyde, 3 is the first ~29~(~1S
_ g _ layer formed from cellulose acetate, 4 i8 the platinum vorking electrode and 5 18 the silver reference electrode. 1, 2 and 3 ~ogether form a laminated membrane. Platinum working electrode 4 acts as an anode whilst silver reference electrode 5 acts as a cathode.
The membrane is held in place on the electrode by a perspex ring pressing do~n on outer layer 1 to~ards it~ outer edges at 6.
The use of the sensor shown in ~igure 1 is illustrated in the following examples-103~PLE
Experiments ~ere carried out using sensors having membranes prepared as described above. The 6econd or outer layers of the membranes u6ed were formed from polycarbonate film trea~ed by dipping in llpid solutiona in n-butanol, n-decane a~d mixture of these solvents. Lipids used ~ere lecithin and isopropyl myrl~tate. These treated me~branes were found to be readily permeable to catechol but only permeable with difficulty to species such as hydrogen peroxide, ascorbic acid, paracetamol and phiroglucinol (concentrations of the species used were 0.5 mM). This is illustrated in the following table ~hich shows the reduction in signal 6ize obse~Yed for each of the interferring ~pecies when polycarbonate membranes ~ith pore sizes 0.8 ~m and 0.2 ~m a~e treated with IPM.
I SPECI~S I ~eduction in Slgnal ~ize ~
I , l0.8 ~u pore ize 1 0.2 p~ pore size .
IHydrogen Peroxide 1 86.3 1 98.5 IAscorbic acid 1 94.65 i 100 IUric Acid 1 91.31 IParacetamol I 56 1 82 IPhiroglucinol I 66.6 1 95 ~29~01S
,. . .
The treated membranes ~ere permeable to glucose although the magnitude of the response registered by the sensor wa~ reduc~d.
It was found that the range of linearity of the responses obtained ln a serles of experiments with dlfferent gluco~e concentrations was increased iQ treated membranes.
Thls is lllustrated by the graph~ sho~n in Figure~ 2 to 10 of the drawings in which response magnitude is plotted against glucose concentratlon (mM)~ The treatsd membranes referred to are polycarbonate membranes treated with IPM.
AB shown in Figure 2, the response (in arbitrary units) obtained with membrane~ treated with IPM (plot A) is linear up to at least 50 mM~ m oontrast bo the-response (pLot B) obtained with the untreated memhrane.
Figures 3 to 10 further illustrate the result shown in Figure 2 and also show the effect of pore ~ize on linearity of response. In Figure 3, Plot B ~s the response obtained ~ith an untreated membrane having a pore size of 2 ~m, and Plot A i8 the response obtained with a membrane treated with IPM. Linearity is thus increased for the treated membrane.
Figure 4 shows the response obtalned with membranes having a pore size of 0.2 ~m. The untreated membrane gives a llnear response only up ~o a concentration of ~ust over 2 mM glucose ~see Plot B) ~5 wherea~ the treated membrane (Plot ~) gives a linear response at least up to a concentratlon of 10 mM.
.
As shown ln Plgures 5 and 6 the response obtained wlth an untreated membrane having a pore size of O.OS ~m is llnear up to about a concentratlon of 4 mM glucose (Figure 5); whereas the treated membrane gives a iinear response up to at least 60 mM glucose (Figure 6).
lS
,.~
The response obtalned wlth membranes having a pore ~lze of 0.8 ~' ~m i8 sho~n in ~igure 7 and 8. As shown in ~igure 7, the untreated membrane gives a llnear response only up to a concentration of 2 ~H
glucose ~Plot B). ~owever, a membrane treated with lPM gives a linear re6ponse up to a concentration of about 20 mM glucose tsee Plot A
~igure 7, and Ylgure 8).
. . .
Similarly, an lncrea6e in linearlty of response was observed with a pore ~ize of 0.015 ~m when treated with lPM - see Figure 9 (untreated membrane~ and Pigure 10 (treated membrane).
The experiments referred to above lllustrate that the range of linearity is increased with treated membranes. It was alRo observed that the upper concentration limit of the range may vary wlth concentration of the liquid. For example an untreated polycarbonate membrane (pore size 0.2 ~m) gave a llnear response up to ~ust over Z mM glucose whereas a membrane treated with 100% IPM was linear up to 30 mN glucose and a membrane treated wlth 90% lPM/lOX n-decanol was linear up to at least 60 mM glucose.
~ xperiments also showed that membranes treated with the fatty acid e6*ers methyl oleate and methyl linoleate increased lineaty of response in a similar way to IPM. Membranes treated with lecithin also behaved in a similar fa6hion to these trated ~ith IPM.
l. 1 ~1 of the mixture produced in the prevlous step is applied to one face of the 1 cm2 polycarbonate produced in step l:
~290~1S
5. The other surface of the enzyme layer 18 covered lmmediately ~ith a thin cellulose acetate fllm and ~he resultlng lamlnated membrane i8 clamped for 3 mlnutes between glass slldes~
6. The membrane is applled to a platlnum electrode to form the sensor of the invention, the cellulose acetate film belng nearest to the electrode and forming the flrst layer. ~~
Use of the method of the invention giveA the advantage of an lncrease in the concentration range over ~hlch a graph of concentration against Bell~Or re8pOn8e i8 linear. Wlth conventlonal methods linearl~y was generally extended only up to approxlmately a concentration of 3 m mol per lltre for glucose. U~ing the method of the invention linearity ls increafied and the range extends to glucose concentrations of 50 m mol lS per litre and even higher. Thls is achieved through restric~ion of substrate entry into the enæyme layer and therefore ~ith some 10BB of sen~ltivity. Thus the range covers the concentrations of glucose which can be antlclpated in blood samples thereby enabling blood glucose levels to be determined more readily. This is a considerable advantage in situations where large numbers of determinations must be made regularly and with minimal sample preparation. Llnearity is also extended by applying to the second layer of ~he membrane a medium comprising an organo-silane having reac~ive groups as described in our published European Patent Application No. 204468. This treatment may be applied to the second layer of the membrane in the sensor of the ptesent invention to produce a combined effect and further improved linearity.
The invention is illustrated by Figure 1 of the accompanying drawings.
In ~lgure 1, reference numeral l i6 the second layer of the membrans formed from a polycarbonate fllm treated with a 30% solution of lsopropyl myristate (IPN), 2 is a layer of glu~ose oxidase enzyme dissolved in albumin and mixed with glutaraldehyde, 3 is the first ~29~(~1S
_ g _ layer formed from cellulose acetate, 4 i8 the platinum vorking electrode and 5 18 the silver reference electrode. 1, 2 and 3 ~ogether form a laminated membrane. Platinum working electrode 4 acts as an anode whilst silver reference electrode 5 acts as a cathode.
The membrane is held in place on the electrode by a perspex ring pressing do~n on outer layer 1 to~ards it~ outer edges at 6.
The use of the sensor shown in ~igure 1 is illustrated in the following examples-103~PLE
Experiments ~ere carried out using sensors having membranes prepared as described above. The 6econd or outer layers of the membranes u6ed were formed from polycarbonate film trea~ed by dipping in llpid solutiona in n-butanol, n-decane a~d mixture of these solvents. Lipids used ~ere lecithin and isopropyl myrl~tate. These treated me~branes were found to be readily permeable to catechol but only permeable with difficulty to species such as hydrogen peroxide, ascorbic acid, paracetamol and phiroglucinol (concentrations of the species used were 0.5 mM). This is illustrated in the following table ~hich shows the reduction in signal 6ize obse~Yed for each of the interferring ~pecies when polycarbonate membranes ~ith pore sizes 0.8 ~m and 0.2 ~m a~e treated with IPM.
I SPECI~S I ~eduction in Slgnal ~ize ~
I , l0.8 ~u pore ize 1 0.2 p~ pore size .
IHydrogen Peroxide 1 86.3 1 98.5 IAscorbic acid 1 94.65 i 100 IUric Acid 1 91.31 IParacetamol I 56 1 82 IPhiroglucinol I 66.6 1 95 ~29~01S
,. . .
The treated membranes ~ere permeable to glucose although the magnitude of the response registered by the sensor wa~ reduc~d.
It was found that the range of linearity of the responses obtained ln a serles of experiments with dlfferent gluco~e concentrations was increased iQ treated membranes.
Thls is lllustrated by the graph~ sho~n in Figure~ 2 to 10 of the drawings in which response magnitude is plotted against glucose concentratlon (mM)~ The treatsd membranes referred to are polycarbonate membranes treated with IPM.
AB shown in Figure 2, the response (in arbitrary units) obtained with membrane~ treated with IPM (plot A) is linear up to at least 50 mM~ m oontrast bo the-response (pLot B) obtained with the untreated memhrane.
Figures 3 to 10 further illustrate the result shown in Figure 2 and also show the effect of pore ~ize on linearity of response. In Figure 3, Plot B ~s the response obtained ~ith an untreated membrane having a pore size of 2 ~m, and Plot A i8 the response obtained with a membrane treated with IPM. Linearity is thus increased for the treated membrane.
Figure 4 shows the response obtalned with membranes having a pore size of 0.2 ~m. The untreated membrane gives a llnear response only up ~o a concentration of ~ust over 2 mM glucose ~see Plot B) ~5 wherea~ the treated membrane (Plot ~) gives a linear response at least up to a concentratlon of 10 mM.
.
As shown ln Plgures 5 and 6 the response obtained wlth an untreated membrane having a pore size of O.OS ~m is llnear up to about a concentratlon of 4 mM glucose (Figure 5); whereas the treated membrane gives a iinear response up to at least 60 mM glucose (Figure 6).
lS
,.~
The response obtalned wlth membranes having a pore ~lze of 0.8 ~' ~m i8 sho~n in ~igure 7 and 8. As shown in ~igure 7, the untreated membrane gives a llnear response only up to a concentration of 2 ~H
glucose ~Plot B). ~owever, a membrane treated with lPM gives a linear re6ponse up to a concentration of about 20 mM glucose tsee Plot A
~igure 7, and Ylgure 8).
. . .
Similarly, an lncrea6e in linearlty of response was observed with a pore ~ize of 0.015 ~m when treated with lPM - see Figure 9 (untreated membrane~ and Pigure 10 (treated membrane).
The experiments referred to above lllustrate that the range of linearity is increased with treated membranes. It was alRo observed that the upper concentration limit of the range may vary wlth concentration of the liquid. For example an untreated polycarbonate membrane (pore size 0.2 ~m) gave a llnear response up to ~ust over Z mM glucose whereas a membrane treated with 100% IPM was linear up to 30 mN glucose and a membrane treated wlth 90% lPM/lOX n-decanol was linear up to at least 60 mM glucose.
~ xperiments also showed that membranes treated with the fatty acid e6*ers methyl oleate and methyl linoleate increased lineaty of response in a similar way to IPM. Membranes treated with lecithin also behaved in a similar fa6hion to these trated ~ith IPM.
Claims (13)
1. A sensor of the enzyme-electrode type for the determination of an analyte which is convertible in the presence of an enzyme into a species which is detectable by the sensor, which sensor comprises an electrode and a membrane permeable to liquids and solutes which is positioned between the electrode and a specimen containing the analyte, which membrane comprises a first layer containing at least one enzyme and a second layer positioned between the enzyme-containing layer and the specimen, wherein said second layer contains an area through which analyte can pass formed from a porous material of which the pores have been at least partially filled with a liquid, whereby a supported liquid membrane is formed.
2. A sensor according to claim 1, wherein said membrane further comprises a third layer of material disposed between the enzyme-containing layer and the electrode.
3. A sensor according to claim 2, wherein said third layer is formed from a material selected from the group comprising polymethylmethacrylate, polyurethane and cellulose acetate.
4. A sensor according to Claim 1, 2 or 3, where the porous material is selected from the group comprising polycarbonates, polyurethanes and modified celluloses.
5. A sensor according to Claim 1, 2 or 3, wherein the proous material has a porosity within the range from 0.05 to 20 per cent.
6. A sensor of the enzyme-electrode type for the determination of an analyte in a specimen containing said analyte, said analyte being convertible in the presence of an enzyme into a species detectable by the sensor, which sensor comprises an electrode and a membrane permeable to liquids and solutes which is positioned between the electrode and the specimen, said membrane comprising an enzyme-containing layer, a layer of material disposed between said enzyme-containing layer and said electrode and a layer disposed between said enzyme-containing layer and said specimen and having an area of a porous material of average pore diameter less than 5 µm, said pores being at least partially filled with a liquid.
7. A sensor according to claim 6, wherein the liquid comprises a lipid.
8. A sensor according to claim 7, wherein said lipid is selected from the group comprising isopropyl myristate and lecithin.
9. A sensor according to claim 6, wherein the liquid comprises an ester of a fatty acid.
10. A sensor according to claim 9, wherein the fatty acid ester is selected from the group comprising methyl oleate and methyl linoleate.
11. A sensor according to Claim 6, 7 or 9 wherein the membrane contains a layer formed from a polymeric material selected from the group comprising polyarylsulphones and polyarylketones.
12. An enzyme-electrode sensor for determining an analyte in a specimen, which analyte is convertible in the presence of an enzyme into a species detectable by the sensor, which sensor comprises an electrode, a first layer of a material selected from polymethylmethacrylate, polyurethane and cellulose acetate, disposed between the electrode and the specimen, an enzyme-containing second layer overlying said first layer, and a porous third layer overlying said second layer, which porous layer comprises a material selected-from polycarbonates, polyurethanes and modified celluloses, has an average pore diameter less than 5 µm and has said pores at least partially filled with a liquid comprising a lipid or a fatty acid ester.
13. A method for determining an analyte in a specimen which comprises contacting the specimen with the outer layer of a membrane, permeable to liquids and solutes and comprising one or more enzymes, 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, characterised in that a layer in the membrane between the enzyme and the specimen contains an area through which analyte can pass formed from a porous material which has been treated to fill its pores wholly or partially with a liquid thereby forming a supported liquid membrane.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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GB878718430A GB8718430D0 (en) | 1987-08-04 | 1987-08-04 | Sensor |
GB8718430 | 1987-08-04 |
Publications (1)
Publication Number | Publication Date |
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CA1290015C true CA1290015C (en) | 1991-10-01 |
Family
ID=10621794
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000573855A Expired - Fee Related CA1290015C (en) | 1987-08-04 | 1988-08-04 | Sensor with supported liquid membrane |
Country Status (16)
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US (1) | US4919767A (en) |
EP (1) | EP0302661B1 (en) |
JP (1) | JP2614277B2 (en) |
AT (1) | ATE118543T1 (en) |
AU (1) | AU608875B2 (en) |
CA (1) | CA1290015C (en) |
DE (1) | DE3853029T2 (en) |
DK (1) | DK170656B1 (en) |
ES (1) | ES2070852T3 (en) |
FI (1) | FI91331C (en) |
GB (1) | GB8718430D0 (en) |
IE (1) | IE67374B1 (en) |
IL (1) | IL87263A (en) |
NO (1) | NO302846B1 (en) |
NZ (1) | NZ225672A (en) |
PT (1) | PT88183B (en) |
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- 1987-08-04 GB GB878718430A patent/GB8718430D0/en active Pending
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- 1988-07-27 IE IE230388A patent/IE67374B1/en not_active IP Right Cessation
- 1988-07-28 EP EP88306938A patent/EP0302661B1/en not_active Expired - Lifetime
- 1988-07-28 DE DE3853029T patent/DE3853029T2/en not_active Expired - Fee Related
- 1988-07-28 ES ES88306938T patent/ES2070852T3/en not_active Expired - Lifetime
- 1988-07-28 AT AT88306938T patent/ATE118543T1/en not_active IP Right Cessation
- 1988-07-29 IL IL87263A patent/IL87263A/en unknown
- 1988-08-02 FI FI883622A patent/FI91331C/en not_active IP Right Cessation
- 1988-08-03 NZ NZ225672A patent/NZ225672A/en unknown
- 1988-08-03 NO NO883441A patent/NO302846B1/en unknown
- 1988-08-03 AU AU20355/88A patent/AU608875B2/en not_active Ceased
- 1988-08-03 DK DK433588A patent/DK170656B1/en not_active IP Right Cessation
- 1988-08-03 PT PT88183A patent/PT88183B/en not_active IP Right Cessation
- 1988-08-04 JP JP63195277A patent/JP2614277B2/en not_active Expired - Lifetime
- 1988-08-04 US US07/228,153 patent/US4919767A/en not_active Expired - Fee Related
- 1988-08-04 CA CA000573855A patent/CA1290015C/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
PT88183B (en) | 1994-09-30 |
ES2070852T3 (en) | 1995-06-16 |
NO883441L (en) | 1989-02-06 |
PT88183A (en) | 1989-06-30 |
IE67374B1 (en) | 1996-03-20 |
JP2614277B2 (en) | 1997-05-28 |
GB8718430D0 (en) | 1987-09-09 |
FI91331B (en) | 1994-02-28 |
IL87263A0 (en) | 1988-12-30 |
FI883622A0 (en) | 1988-08-02 |
DE3853029D1 (en) | 1995-03-23 |
DE3853029T2 (en) | 1995-08-24 |
FI883622A (en) | 1989-02-05 |
NO302846B1 (en) | 1998-04-27 |
DK170656B1 (en) | 1995-11-20 |
JPH01131446A (en) | 1989-05-24 |
AU608875B2 (en) | 1991-04-18 |
NO883441D0 (en) | 1988-08-03 |
US4919767A (en) | 1990-04-24 |
FI91331C (en) | 1994-06-10 |
NZ225672A (en) | 1991-01-29 |
AU2035588A (en) | 1989-02-09 |
EP0302661A1 (en) | 1989-02-08 |
DK433588A (en) | 1989-02-05 |
DK433588D0 (en) | 1988-08-03 |
EP0302661B1 (en) | 1995-02-15 |
ATE118543T1 (en) | 1995-03-15 |
IL87263A (en) | 1992-08-18 |
IE882303L (en) | 1989-02-04 |
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