WO2001013103A1 - Dispositif et procede analitique - Google Patents

Dispositif et procede analitique Download PDF

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Publication number
WO2001013103A1
WO2001013103A1 PCT/GB2000/003108 GB0003108W WO0113103A1 WO 2001013103 A1 WO2001013103 A1 WO 2001013103A1 GB 0003108 W GB0003108 W GB 0003108W WO 0113103 A1 WO0113103 A1 WO 0113103A1
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WO
WIPO (PCT)
Prior art keywords
electrode
coating
electrodes
active agent
phenolic compound
Prior art date
Application number
PCT/GB2000/003108
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English (en)
Inventor
Pankaj Madganal Vadgama
Andrew Gill
Original Assignee
Iit Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from GBGB9919192.6A external-priority patent/GB9919192D0/en
Priority claimed from GBGB9928633.8A external-priority patent/GB9928633D0/en
Application filed by Iit Limited filed Critical Iit Limited
Priority to AU64599/00A priority Critical patent/AU6459900A/en
Publication of WO2001013103A1 publication Critical patent/WO2001013103A1/fr

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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

Definitions

  • This invention relates to an improved analytical method and apparatus, more particularly those useful for electro-analytical work and especially in amperometric electrodes for use in chemical and biochemical sensing, and to analytical methods using them.
  • Electrodes in analytical procedures to detect and measure a variety of chemical species present in a liquid medium.
  • the procedures may involve the measurement of various properties of the medium so that the presence of particular chemical species or groups of such species may be detected or measured. It is desirable to make these measurements as accurate, quantitative and selective as possible, so that the result of the measurements can be interpreted and used with maximum reliability.
  • Electrodes are used in the analysis of blood or serum, to detect amounts of components which may be very small but also very significant for diagnostic purposes. Especially, it is often important to measure hydrogen peroxide -- which may be generated in situ as a result of the action of cellular enzymes (as present in leukocytes) or an immobilised or soluble oxidase enzyme. Oxidases are used as reagents in various biological media, and so it is often desirable to be able to detect their activity.
  • coated electrodes so described are very effective, but we have found that they can be further improved by incorporating a surface-active agent in the said coating of oxidised phenolic compound.
  • a surface-active agent in the said coating of oxidised phenolic compound.
  • the surface active agent is preferably incorporated in the coating of an oxidised phenolic compound by forming the coating of an oxidised phenolic compound in the presence of the surface active agent, so that it is incorporated into the coating as it forms.
  • This procedure may incorporate the surface-active agent by physical adsorption or trapping or by involvement chemically in the in the electro-oxidised film structure as it is formed, or by a combination of such modes, as we have found that the surface-active agent cannot be incorporated by simply applying the surface-active agent to a pre-formed coating (e.g. by dipping in a solution of the surface- active agent) .
  • a pre-formed coating e.g. by dipping in a solution of the surface- active agent
  • we we also provide an improved method for making an electrode having a coating of selective permeability, which comprises electrolytically oxidising a phenolic compound at the surface of the said electrode in the presence of a surface active agent.
  • the methods used for the formation of the coating of electrolytically oxidised phenolic compound are those more fully described in the specification of our European Patent No. 0672167, and all the details of that specification are imported and incorporated herein by reference, including details of the said methods and coatings.
  • the deposit on the electrode surface may sometimes be referred to as a "polymerised phenol” though this term may not be entirely appropriate. It is referred to herein as an "oxidised phenol.”
  • Formation and deposition of the film of electro- oxidised phenolic compound is conveniently carried out using the phenolic compound and the surface-active agent in solution in an aqueous medium.
  • a wholly aqueous medium and other media may be used - for example organic solvents or mixtures which have the appropriate conductivity to allow the electro-oxidation and film deposition to take place and can dissolve the starting components.
  • mixed media which are partly aqueous may be used, for example using a proportion of water mixed with organic solvents or components.
  • the electrode itself may be any electrode having the properties of an anode at which the current for peroxide, or any other species which may be sought, can be determined. It is preferably platinum metal, but it may be any other conventional form and/or material, for example gold or glassy carbon.
  • the phenolic compound may be substituted (for example with alkyl groups, halogens, a ino groups, carboxylic acid groups, or combinations of these) but should allow ortho- to para- radical polymerisation following generation of a radical phenol electrochemically, and preferably any substituents should be ones not causing major steric hindrance.
  • the term phenolic compound or "phenol” is also used here to include polyhydric phenolic compounds (for example catechol) and polycyclic phenolic compounds (for example naphthols) , which may if desired be substituted, as mentioned above.
  • Especially useful examples of phenolic compounds are phenol itself and dopamine, but other phenolic compounds, often of relatively complex structure but nevertheless still phenolic in nature, may be used if desired.
  • the voltage applied to form the coating or film is in the range + 0.4 to + 0.8 volts (+400 to +800 mV) or higher if so desired, and commonly about + 0.6 volt
  • the surface active agent may be any of those known in the art. These usually contain a hydrophilic group (e.g. a long-chain hydrocarbon group) in conjunction with a hydrophilic group which may be ionic or non-ionic.
  • a hydrophilic group e.g. a long-chain hydrocarbon group
  • the surface-active agent may be of any nature -- i.e. it may be anionic, cationic or non- ionic, or even may have a structure combining more than one of these characteristics. Likewise, mixtures or combinations of more than one surface active agent may be used if desired.
  • Such surface-active agents include many which are commercially available under trade names or otherwise known in the art, for example :- (a) Anionic (usually sulphonated or sulphated compounds, as free acid or salts), for example :- taurocholic acid.
  • Anionic usually sulphonated or sulphated compounds, as free acid or salts
  • taurocholic acid This compound is (2- [3-alpha, 7- alpha, 12-alpha trihydroxy-24-oxo-5-beta-cholan-24-yl] ethane sulphonic acid, (derived from taurine and cholic acid) and is available from Sigma, catalogue number T4009. sodium dodecylsulphonate. dodecylbenzenesulphonic acid.
  • Cationic usually quaternised amino compounds
  • MTAC methyltrialkylammonium chloride
  • Adogen 464 Aldrich catalogue number 85,657-6 (the alkyl being C8 to CIO) . cetyltrimethylammonium bromide .
  • Non- ionic usually hydroxy or amino compounds condensed with various proportions of ethylene oxide and/or propylene oxide to form condensates containing poly-oxyalkylene chains, for example :
  • Pluronic 68 This is a commercially available product derived from a polyethylene oxide/polypropylene oxide condensate (Sigma catalogue, number P7061) .
  • Triton X100 This is a commercially available product which is stated in the supplier's list to be a condensate of 4-octylphenol with approximately 10 molecular proportions of ethylene oxide, in which the octyl substituent is 1, 1, 3, 3-tetramethylbutyl .
  • Mixtures of two or more surfactants may be used if desired, and these may be of the same or different types. Indeed, we find that a combination of anionic and cationic properties is advantageous as this gives superior results .
  • the two properties may be combined together in the same molecule, as in the zwitterion type (mentioned above) , but may be obtained by using a mixture of both cationic and anionic types of surfactant together, for example by using both methyltrialkylammonium chloride and taurocholic acid.
  • the surface active agent is preferably included as a component in the liquid medium (solution) containing the phenolic compound used for the formation of the electro- oxidised coating by deposition. This makes it more easy for the surface active agent to become incorporated in the film as it is formed.
  • the surface active agent may be present at the start, before electrolytic oxidation begins, or may be added after the oxidation has started and some of the coating has commenced to form.
  • the surface-active agent is preferably not left in contact with the bare surface of the electrode material (e.g. platinum) for long before the electro-oxidation is started, to minimise the possibility of it being adsorbed first on to the electrode surface and thereby affecting the desired formation and/or adhesion of the electro-oxidised coating. Any extensive adsorption of the surface-active agent on the surface of the electrode (e.g. platinum) can impede formation of the electro-oxidised phenolic coating, and it is desirable to start with a well-cleaned surface.
  • the electrode material e.g. platinum
  • the surface-active agent it is in general most convenient for the surface-active agent to be included in the solution used for forming the coating at the start provided these possible causes of adverse effects are borne in mind.
  • the proportion of the surface active agent used in forming the coating in this way may vary, depending upon such factors as the particular surface active agent and phenolic compound used, and the optimum in any particular case may be determined by simple trial.
  • the concentration of the surface active agent in the liquid medium (solution) used for the electro-deposition of the coating is kept below the critical micelle concentration
  • CMC surface active agent
  • the CMC can be expected to vary according to the surface active agent used, and possibly also other conditions, but in general we prefer to use the surface active agent in low concentration - below 0.1% (by volume for liquid surface active agents or by weight for solid surface active agents), and especially 0.05% or even less. Higher concentrations may be used if desired, subject to reasonable trial to optimise them to suit the particular components use and properties desired in the final coating, but this is usually not necessary as the smaller amounts indicated give satisfactory results.
  • the amount of surface-active agent used should not lead to appreciable micelle formation.
  • the method of our invention may be used to produce new electrodes which are useful for the analysis in a biological environment, for example in biological fluids and under biological conditions. Especially, it provides electrodes which are useful for the measurement of the components of blood and serum while eliminating inter erents .
  • controlled film deposition it is possible to form an array of cross-reacting sensors which enable the user to "pattern recognise" some analytes .
  • the electrode may be immersed in a sample of the fluid (e.g. blood) and then linked with a suitable cathode in conventional manner. Measurement of the voltage, current and the like may be taken and the measurements taken and recorded as desired, intermittently or continuously.
  • conventional apparatus may be used.
  • the method can be carried out using conventional electrodes, for example as in an oxygen cell, but with the anode as the platinum metal and the cathode as the silver/silver chloride electrode (which also acts as a pseudo-reference electrode) .
  • a three-electrode cell of working/reference/counter electrodes can also be employed if desired for the coating procedure using the phenolic compound .
  • the use of the electrode as anode in a liquid medium as electrolyte displays a high degree of selectivity to hydrogen peroxide and is exceptionally free from interference from the presence of a number of compounds which normally are prone to interfere considerably, especially ascorbate and paracetamol (acetaminophen) .
  • selectivity is superior to that obtainable using the conventional cellulose acetate membranes, as in oxidase-based bio-sensors, and also has the added advantage of giving superior results even when compared with those obtained using electrodes with the electro-oxidised phenol coatings without the surfactant incorporated in them.
  • This membrane may be composed of any permeable polymer layer, for example a dialysis membrane or a polycarbonate with pores, depending upon the application intended.
  • a new composite electrode device comprising as anode an electrode having a coating of an oxidised phenolic compound on its surface (as more fully described above) in conjunction with a second electrode as cathode, with the two electrodes being held together in an assembly which prevents direct electrical contact between them.
  • a cathode surrounds the anode, and is spaced from it by a non-conductive spacer element which also secures a membrane in place around the anode and the cathode in a sealed relationship which provides a means for retaining an appropriate electrolyte between the membrane and the anode and also provides some added physical protection of the anode against surface damage.
  • the electrode can also be associated with an enzyme, so that the electrode can extend its usefulness to the detection and measurement of an analyte compound which does not itself produce a suitable response at the electrode but can be converted, for example by enzymic action, into another compound which can produce a more suitable response at the electrode.
  • an enzyme for example, hydrogen peroxide generated by enzymic action from a substrate compound can be used to provide an indirect measure of that substrate compound.
  • hydrogen peroxide generated by enzymic action from a substrate compound can be used to provide an indirect measure of that substrate compound.
  • An especially useful example of this is the determination of glucose, using glucose oxidase as the enzyme.
  • the enzymic reaction can be at or near the electrode surface, so the enzyme may be incorporated on or near the electrode or the apparatus in which it is used or it may be further away from the electrode.
  • an improved method for the detection and measurement of hydrogen peroxide or any other desired species which comprises adding a sample material under examination to a liquid medium and then detecting by electrolytic analysis (especially amperometric analysis) the amount of hydrogen peroxide (or other desired species, as the case may be) present as such or indirectly formed (e.g. from an enzymic reaction) using an electrode having a coating of selective permeability made by electrolytically oxidising a phenolic compound at the surface of the said electrode according to the present invention.
  • an enzyme allows the substrate on which it acts (e.g. glucose) to become the analyte even though it is not detected directly as such at the electrode .
  • the enzymes used may be any of those known in the art, and they may be located anywhere in the system which is found to be convenient, provided they are not detrimental to the function of the
  • the sample may especially be a biological one, for example a biological fluid and especially blood or serum.
  • the liquid medium which acts as the electrolyte in the cell containing an electrode of the present invention, may be any in which the desired action of the enzyme can take place and in which the components are soluble. Thus, it need not necessarily be aqueous, and organic solvents (as such or as mixtures with each other and/or water) may be used provided that they do not interfere with the desired electrochemical processes and the deposition of the film on the anode.
  • the electrolyte is an aqueous buffer solution (most conveniently a phosphate buffer solution) which maintains the pH of the solution and added sample at a desired level. This pH is not critical in the broad sense, as it depends principally on the pH needs of the enzyme for its activity. An example is thus approximately pH 7.4 (the pH of blood) .
  • the proportion of the hydrogen peroxide or peroxide precursor in it is preferably in the range 10 ⁇ 5 to 10 m/1 of the liquid medium, though larger or smaller proportions may be used if desired.
  • Water-miscible organic solvents may be present if they do not interfere with the essential oxidation or reduction processes involved.
  • the procedure and apparatus to be used for carrying out the amperometric electrolytic analysis, and for displaying and/or recording the resulting measurements, may be any of those which are known or conventional for the purpose .
  • an improved electrode system for use in amperometric analysis which comprises an electrode as defined above, i.e. an electrode having a coating of selective permeability comprising a film of an oxidised phenolic compound on its surface.
  • the sample of the blood or serum for examination may be obtained by standard methods .
  • the quantity of the blood or serum added to the liquid medium should be such as to provide a quantity in the range 10 3 to 10 m/1 of the liquid medium.
  • the procedure can be much improved by surrounding the anode with a membrane which serves to reduce the access of undesired materials to the anode surface.
  • This membrane may act by virtue of its effectiveness as a dialysis membrane (i.e. by impeding passage of larger molecules) or as a perm-selective membrane (which controls the passage of molecules or ions according to their properties other than just physical size) . These function to reduce the fouling of the electrode and increase accuracy.
  • a membrane may be for example composed of conventional materials, especially a polycarbonate, cellulose acetate, nitro- cellulose, or the like.
  • a convenient example is an outer polycarbonate membrane of porosity 0.03 to 0.05 ⁇ m, which allowed the phenolic compound to pass through to the platinum surface. This (a) prevented any damage or scratching of the surface films and (b) allowed slower, more controlled deposition of the phenolic compounds.
  • the physical state of the membrane may be controlled in terms of such features as thickness, pore size, and any other feature which may have an effect on it permeability so as to control diffusion to the electrode surface to prevent excess of solute exposure.
  • the membrane and/or anode may be prepared for use in the analytical process of the invention by soaking it, when it is in place around the anode, in a solution corresponding to the electrolyte medium before the blood/serum sample is added.
  • the polarised electrodes may be immersed in a predetermined volume of the buffer solution to which can be added the sample (for example a sample of blood or serum) under test, so that the amperometric measurements can be made and compared before and after the addition of the sample under test .
  • the procedure may also be calibrated by use of solutions containing known amounts of any components sought or believed to interfere, so that the results can be properly standardised and the apparatus calibrated.
  • Measurements may be made continuously or intermittently, as desired.
  • the advantages of the invention are that measurements can be made with reduced interference from other components of blood and serum, which can be eliminated or at least greatly reduced to a level at which they no longer interfere with the measurement to a degree which renders the measurements unreliable or misleading under clinical conditions .
  • the modification of the surface characteristics of poly (phenols) through surfactant incorporation permits specific tailoring of conditions to match the requirements of the system under investigation. This may for example be due to charge-charge interactions, but also could be due to some other functional group that could be introduced to the sensor surface.
  • variations can be made not only to the phenolic compound which is electro-oxidised and the thickness of the coating formed from it, but also the surface-active agent (or the components and proportions in a combination of such surface-active agents) can be varied to modify the properties of the coated surface.
  • the ionic properties of the modified coating can be varied, an opportunity is available to cope with varying properties (e.g. the pH) of the media in which the coated electrode is used for analytical or monitoring purposes.
  • surface active agent has been used, but if desired the term “surfactant” may be regarded as equally satisfactory.

Abstract

L'invention concerne des électrodes présentant une revêtement de surface comportant un composé de résine phénolique oxydée possédant un agent de surface. Le revêtement est formé de préférence par dépôt d'une solution contenant l'agent de surface. Les électrodes sont de préférence en platine et peuvent servir d'anodes pour la détection électrochimique de peroxyde d'hydrogène, tout particulièrement par méthode ampérométrique. Le peroxyde d'hydrogène peut être formé par action d'une enzyme, et est situé en principe sur ou près de l'électrode. Les électrodes peuvent être entourées d'une membrane servant à réguler l'apparition d'impuretés et à minimiser les dommages mécaniques du revêtement. La membrane peut être constituée d'une couche de polymère perméable, agissant par porosité ou par perméabilité sélective. Elle peut être combiinée à un assemblage d'une électrode (ou anode) revêtue et d'une cathode pour constituer une unité hermétique convenable. L'invention sert principalement à analyser un mélange, tout particulièrement un mélange à base de glucose lors de son interaction avec de l'oxydase de glucose, tout particulièrement dans des environnements biologiques, et spéciallement des mesures des composés du sang et du sérum lors d'élimination d'interférants.
PCT/GB2000/003108 1999-08-14 2000-08-11 Dispositif et procede analitique WO2001013103A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU64599/00A AU6459900A (en) 1999-08-14 2000-08-11 Analytical apparatus and method

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9919192.6 1999-08-14
GBGB9919192.6A GB9919192D0 (en) 1999-08-14 1999-08-14 Analytical apparatus and method
GBGB9928633.8A GB9928633D0 (en) 1999-12-04 1999-12-04 Analytical apparatus and method
GB9928633.8 1999-12-04

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WO2001013103A1 true WO2001013103A1 (fr) 2001-02-22

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10211741A1 (de) * 2002-03-14 2003-10-09 November Ag Molekulare Medizin Verfahren zur Behandlung einer Kohlenstoff-Elektrode
DE10229210A1 (de) * 2002-06-28 2004-01-29 november Aktiengesellschaft Gesellschaft für Molekulare Medizin Vorrichtung zur Detektion eines Analyten
DE10340275B3 (de) * 2003-08-29 2005-05-25 november Aktiengesellschaft Gesellschaft für Molekulare Medizin Verfahren zur Herstellung einer Elektrode
EP2149790A1 (fr) * 2007-04-12 2010-02-03 Arkray, Inc. Outil d'analyse
WO2014181260A1 (fr) * 2013-05-09 2014-11-13 Schlumberger Technology Corporation Mesure de ph electrochimique
US9097659B2 (en) 2013-03-14 2015-08-04 Bayer Healthcare Llc Maintaining electrode function during manufacture with a protective layer

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EP0326081A2 (fr) * 1988-01-25 1989-08-02 New Oji Paper Co., Ltd. Electrode enzymatique
WO1994002629A1 (fr) * 1992-07-28 1994-02-03 The Victoria University Of Manchester Procede et dispositif d'analyse

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10211741A1 (de) * 2002-03-14 2003-10-09 November Ag Molekulare Medizin Verfahren zur Behandlung einer Kohlenstoff-Elektrode
DE10211741B4 (de) * 2002-03-14 2005-12-01 November Ag Verfahren zum elektrochemischen Detektieren eines Analyten
DE10229210A1 (de) * 2002-06-28 2004-01-29 november Aktiengesellschaft Gesellschaft für Molekulare Medizin Vorrichtung zur Detektion eines Analyten
DE10340275B3 (de) * 2003-08-29 2005-05-25 november Aktiengesellschaft Gesellschaft für Molekulare Medizin Verfahren zur Herstellung einer Elektrode
EP2149790A1 (fr) * 2007-04-12 2010-02-03 Arkray, Inc. Outil d'analyse
EP2149790A4 (fr) * 2007-04-12 2013-10-09 Arkray Inc Outil d'analyse
US9097659B2 (en) 2013-03-14 2015-08-04 Bayer Healthcare Llc Maintaining electrode function during manufacture with a protective layer
WO2014181260A1 (fr) * 2013-05-09 2014-11-13 Schlumberger Technology Corporation Mesure de ph electrochimique

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