EP0787290A1 - Detecteur selectif d'analyte - Google Patents

Detecteur selectif d'analyte

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Publication number
EP0787290A1
EP0787290A1 EP95934618A EP95934618A EP0787290A1 EP 0787290 A1 EP0787290 A1 EP 0787290A1 EP 95934618 A EP95934618 A EP 95934618A EP 95934618 A EP95934618 A EP 95934618A EP 0787290 A1 EP0787290 A1 EP 0787290A1
Authority
EP
European Patent Office
Prior art keywords
analyte
sensor according
layer
selective
selective 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.)
Withdrawn
Application number
EP95934618A
Other languages
German (de)
English (en)
Inventor
Alexandre Choulga
Benedikt Ahlers
Karl Cammann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Institut fuer Chemo und Biosensorik Muenster eV ICB
Original Assignee
Institut fuer Chemo und Biosensorik Muenster eV ICB
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
Application filed by Institut fuer Chemo und Biosensorik Muenster eV ICB filed Critical Institut fuer Chemo und Biosensorik Muenster eV ICB
Publication of EP0787290A1 publication Critical patent/EP0787290A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/28—Electrolytic cell components
    • G01N27/30—Electrodes, e.g. test electrodes; Half-cells
    • G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements
    • G01N27/3275—Sensing specific biomolecules, e.g. nucleic acid strands, based on an electrode surface reaction

Definitions

  • the invention relates to an analyte-selective sensor which consists of an analyte-specific layer which is modified such that ions or neutral species contained in solutions can come into contact with the layer, so that a change in the electrical properties then occurs.
  • the potentiometric ion-selective electrode is often used to determine ions in solutions (Cammann, K. The work with ion-selective electrodes, 2nd edition, Springer Verlag: Berlin, Hei delberg, New York, 1977).
  • Ion-selective electrodes are electrochemical sensors with which the concentration (more precisely the activity) of certain ions can be determined by means of a potential difference.
  • the ion-selective potential difference occurs at the phase boundary of active electrode material / electrolyte and depends on the activity of a particular ion in the solution according to the Nernst equation.
  • the other fundamental limitation in the potentiometric analysis methods relates to the composition of the ion-selective membrane.
  • the requirements for the nature of the specific bond and / or the complexing sites within the membrane must be such that the potential difference at the membrane / solution interface is built up selectively depending on the presence of a particular species in the solution. For example, this bond should not be too strong, so that a sufficiently rapid exchange of the detected species between the membrane phase and the solution is possible.
  • the most frequently used electrochemical analysis methods are those which measure the current flow through a suitably manufactured or modified conductive or semiconducting working electrode.
  • the potential of this electrode is determined by that of the reference electrode.
  • the measured current flow results from the electrochemical redox reaction that occurs at the interface. before working electrode / solution expires.
  • the use of these measuring methods is further restricted by the fact that the measured species must be electroactive at the working potential applied to the working electrode and thus only a limited selection of analytes can be measured.
  • this potential must be different from that of the interfering species. The latter often poses a problem, since many chemical or large groups of chemical compounds have very similar redox properties.
  • the required electropotentials for many connections lie outside the practical range.
  • liquid chromatography belongs to the non-electrochemical methods most commonly used for the specific detection of landed and neutral species.
  • the sample to be analyzed is brought into contact with a so-called stationary phase, e.g. a polymer layer that specifically binds or retains the detected species.
  • stationary phase e.g. a polymer layer that specifically binds or retains the detected species.
  • the strength of this bond determines the retention time of the analyte within the chromatographic column.
  • a large number of species can be identified using tailor-made stationary phases.
  • this type of analytical measuring arrangement is very complex and expensive.
  • WO 93/06 237 describes the use of IDEs for measuring the change in conductivity of a layer of electroactive conductive polymers (polyaniline, polypyrrole). These changes result from the interaction of the functional redox groups of the polymer with the species of interest which are used in the solution or with species which result from an enzyme reaction result in the layer of the immobilized enzyme which is applied from above to the layer of said polymer.
  • Layer for a specific non-aqueous substance is permeable in a solution, which causes a change in the capacitance of the capacitor by entering the electric field between the IDE's.
  • the second layer contains valinomycin, which is selectively permeable to potassium ions.
  • the interdigital electrodes measure the changes in capacitance as a result of the specific uptake of ions in the valinomycin layer.
  • GB 21 37 361 does not provide a description of the membrane composition, ie there is no information on the conditions which are necessary to ensure the permeability of the sensitive second layer in relation to the species of interest. On the other hand, such conditions severely limit the number of detectable species.
  • the need to shield the senior Electrodes through an insulating layer complicates the manufacture of the transducer because of the high demands on the quality of such a layer and at the same time worsens sensor sensitivity.
  • Another problem is a sudden change in the dielectric constant of the measuring layer, which cannot be ruled out, depending on the composition of the solution to be analyzed.
  • a sensor which has an analyte-specific layer made of a liquid, solid or semi-solid material on a support, which is designed such that it is in contact with the ions or substances contained in the solution their bulk electrical properties, such as resistance, conductivity, admittance or impedance, change.
  • the analyte-specific layer For the measurement of the electrical properties of the analyte-specific layer, it is provided that preferably at least two electrodes are used which are in contact with the analyte-specific layer.
  • the analyte-specific Layer formed directly on the conductor surface. Standard two- or four-electrode arrangements can be used for this type of measurement.
  • the conductive materials used for the production of the solid or semi-solid or porous measuring electrons can be substances which, owing to the mobility of electrodes or defect sites, have properties of an electrical conductor, a semiconductor or a defect site conductor. Examples for this are:
  • noble metals Au, Au, Pt, Pd, ...
  • Carbon-based materials carbon fibers, glassy carbon, graphite
  • highly doped silicon poly-Si
  • the conductors can be free-standing, for example in the form of rods, wires or meshes, or embedded in plastic or other insulating supports which only leave the membrane contact area free.
  • the exposed part can be in the form of disks or bands, for example.
  • the conductors can also be on an insulating support in the form of thick or thin Layers are formed, produced with the aid of screen printing, by chemical or electrochemical polymerisation or deposition (the latter in the case of metals), by vacuum evaporation, sputtering or other techniques of thick and thin layer technologies.
  • the conductors applied to an insulating support can be in the form of ribbons, circles, disks or interdigital electrodes (IDE), for example.
  • the conductors can be arranged on the same or opposite sides of the carrier, in a plane or vertically separated from one another.
  • the surface of the measuring electrode need not necessarily be smooth or polished. It can be made rough to make better contact with the layer and to lower the interface resistance. A possible way is the use of platinized platinum electrodes or of chloridized silver electrodes.
  • a further preferred embodiment proposes to apply an additional layer between the conductors and the analyte-selective layer in the event that increased electrochemical resistance between the conductors and the layer occurs, which has redox-pair-forming substances to suppress the interface resistance.
  • Such redox pair-forming substances which suppress the interfacial resistance have already been described in CH 677 295.
  • the disclosure content is therefore expressly referred to.
  • the layer thickness of this layer is in the range from 0.1 ⁇ m to 100 ⁇ .
  • Layer to be separated from the analyte-selective layer with the so-called phenomenon of capacitive coupling It is also possible to use the inductive coupling for contactless measurements of the electrical properties of layers. In this case the layer is placed in a coil through which a current then flows. Eddy currents are built up in the layer and cause a loss of performance depending on the layer conductivity. Another possibility is to use two coils which are connected by a circulating current in the sample.
  • the analyte-specific layer is essential to the invention in the analyte-selective sensors proposed here.
  • This layer is modified so that it changes its electrical properties in the presence of ions or substances contained in solutions.
  • the change in the electrical properties of the analyte-specific layer can be attributed to the distribution of the ion or substance to be determined between the solution and the layer. This changes the electrical properties, such as resistance, conductivity, admittance or impedance.
  • the analyte-selective sensors according to the invention have the following decisive advantages over the prior art: 1.
  • no reference electrode is required, since the measurements of such electrical properties as conductivity or admittance, in contrast to, for example, potential measurements in potentiometry, are absolute measurements.
  • the sensors can be constructed as highly integrated solid-state complete systems, which simplifies their manufacture, miniaturization and use.
  • the sensor design is compatible with microelectronics, in particular with IC technology, and thus allows the production of such sensors in large quantities at low costs, including disposable sensors.
  • Possible sensor arrays can be easily integrated on a substrate together with the signal processing electronics.
  • the method of operation of the sensors leads to an expansion of the detection range of the species to be determined in comparison to traditional electrochemical detection techniques and to an enlarged selection of materials which can be used as selectively binding components in the sensors.
  • these sensors allow the determination of analyte concentrations in solutions with very high ionic strength.
  • the sensors described in the present invention can then be used as dosimeters. An example of this is the determination of traces of toxic components, for example heavy metal ions.
  • the sensors can be used to measure the solution composition in closed vessels, e.g. in sealed glass ampoules possible.
  • the prerequisite is that the sensitive membrane is inside the vessel, e.g. on the inner surface of the walls, and that the changes in the electrical properties of the membrane are measured from outside the vessel, using contactless measuring techniques.
  • the layer consists of a liquid, semi-solid or solid component (material), so that the layer is able, due to its bulk properties or due to the presence of analyte-specific coupling elements, to remove the analyte from a
  • the analyte-specific layer preferably consists of a polymer which has or contains ion-selective or molecule-selective coupling elements, so that the analyte is selectively extracted from the solution into this polymer membrane layer.
  • coupling elements include functional groups, ion exchangers, complexing groups or chelate groups, cage compounds (for example cyelophans, crown ethers, antibiotics, cyclodextrins), antigens or antibodies, natural or synthetic polypeptides, lectins , understood specifically binding proteins, receptor proteins, lipids and surfactants.
  • the term coupling elements thus encompasses all of these compounds or residues which are capable of containing the analyte to bind ions or neutral particles.
  • the layer can be a polymer which itself has these coupling elements, ie the polymer itself has corresponding radicals or functional groups, or these coupling components are added to the polymer.
  • the selective extraction then involves a selective change in the ionic conductivity. It is not critical whether a reversible or irreversible analyte extraction or binding takes place in the analyte-specific layer, since the measurements of the layer properties, such as the resistance or the conductivity, are absolute measurements.
  • the senor according to the invention can be used as a dosimeter, ie the change in the electrical properties of the layer is to be understood as the sum parameter (dose) of the analyte traces in a medium to which the sensor is exposed over a longer period of time.
  • the analyte-specific layer is placed on a support, e.g. is applied to glass, metal, ceramic, sapphire, plastic or polymer in the form of films.
  • a support e.g. is applied to glass, metal, ceramic, sapphire, plastic or polymer in the form of films.
  • the techniques for applying the polymer membrane layer are known per se from the prior art. Suitable separation processes include:
  • a porous Matrix / carrier eg filter papers, fabric, microporous glass
  • a liquid to act as an analyte-specific layer.
  • the specificity in the extraction of the target analyte can be determined by certain bulk properties of the liquid, e.g. Lipophilia.
  • This liquid can be an organic solvent which is not or only slightly soluble in water, so that target analytes are extracted from aqueous media into this liquid, which forms the analyte-specific layer.
  • the following liquids are mentioned as examples:
  • Non-polar solvents such as carbon tetrachloride, chloroform, hexane, toluene and most aromatic and saturated aliphatic hydrocarbons.
  • the invention it is possible to control the specificity in the extraction of the target analyte by certain bulk properties of the analyte-specific polymer membrane layer, such as the polarity.
  • lipophilic components can be extracted from an aqueous phase into a membrane phase, which likewise consists of lipophilic components.
  • the polymer is an aliphatic main chain with non- or low polar substituents.
  • Polymers which form the polymer layer on the transducer are to be mentioned here. These homopolymers or copolymers, which originate from the monomer units of alkenes and are given carry non-polar or less polar substituents:
  • R j Rj — H, -F, -Cl, -BR, -N0 2 , -COR, -COOR (bonded to the main polymer chain via the oxygen atom or carbon atom), carboxylic acid nitrile groups, carboxamide groups, a1iphatic / aro atisehe ether groups, aromatic / hetero-aromatic radicals.
  • the polymer material can be of low molecular weight to very high molecular weight composition, but preferably high molecular weight.
  • the halogen atom is preferably a chlorine atom.
  • polymer materials are also suitable as the polymer of the solid or semisolid membrane:
  • Polyurethanes silicon-containing polymer material preferably a silicone resin or silicone rubber, cellulose derivatives such as cellulose ether or cellulose ester
  • Solid or semi-solid layers produced from such polymers can also contain organic, lipophilic, water-insoluble liquids, preferably ethers and esters of aliphatic alcohols.
  • the polymer of the layer should be a polymer or copolymer with strongly hydrophilic side groups or should have only small proportions of low-polar or hydrophobic groups.
  • Solid or semi-solid layers made from such polymers can also contain an aqueous electrolyte solution.
  • Such a film can be, for example, a solid polyethylene oxide film which contains alkali salts as ionic additives (conductive salts), preferably lithium salts with the anions CF 3 C0 2 -, CF 3 S0 3 -, C 6 F 13 S0 3 -, Hgl 3 - , AsF 6 -.
  • alkali salts as ionic additives (conductive salts), preferably lithium salts with the anions CF 3 C0 2 -, CF 3 S0 3 -, C 6 F 13 S0 3 -, Hgl 3 - , AsF 6 -.
  • the other suitable polymers which have a high chain mobility are, for example, polyphosphazenes (1) and polysiloxanes (2) with the side groups R, which have cation complexation and ion pair separation properties, as is the case, for example, with oligoalkyl ethers.
  • the polymers mentioned can be described by the following general formulas:
  • a layer can also be produced in such a way that the specific extraction of the analyte into the membrane phase is determined by the affinity of the analyte molecule for morphologically (structurally) defined binding sites within the layer.
  • This can e.g. in that the layer is obtained in the presence of free analyte molecules, e.g. by chemical, photochemical or electrochemical polymerization.
  • a non-covalent attachment of the analyte to monomeric units is obtained, i.e. via ionic, hydrogen bridge, hydrophobic or charge transfer interactions, opposite to the respective sides of the analyte molecule.
  • the analyte is later removed by washing or hydrolysis, leaving behind its "impressions" generated on the molecular scale during layer formation.
  • impressions now act as binding sites with increased affinity for the analyte.
  • the Affinity depends on the distribution of the charge or other functional groups in the analyte molecule as well as on its shape and size.
  • the affinity of such layers for certain species can be controlled inter alia via the conditions of the layer formation or via the ratio of the layer components.
  • the degree of occupancy of the "impression" binding sites by analyte molecules can, for example, influence the ionic conductivity of the layer, and these changes can be measured using the means belonging to the invention.
  • the layers based on the affinity principle can be prepared in such a way that they are able to bind specifically charged or neutral species or to distinguish between optical isomers.
  • Such membranes can e.g. consist of electrochemically produced polymer films.
  • films made of polypyrrole and polyaniline it is e.g. known from the prior art that the order of selectivity of the anion exchange is determined by the counterion taken up in the synthesis from the aqueous or organic solution.
  • Heteroaromatic / arotamic compounds e.g. Thiophenes, pyrroles, phenols, anilines, naphthenes, anthracenes, carbazoles.
  • the counterions used in electropolymerization can be, for example, inorganic or organic ions be, polyions, biomolecules and their fragments.
  • the hydrophobicity of such a material can be controlled either by using monomer units modified with hydrophobic groups or by taking up hydrophobic counterions.
  • the molecular recognition properties can be optimized by adding functional groups to the base monomers, by changing the ratio of the monomer units in copolymers or by changing the extent of crosslinking.
  • the polymer films can be overoxidized electrochemically, thereby producing an electronically non-conductive but ionically conductive material. Such a treatment simultaneously prevents an excess of anionic species in the polymer film.
  • the molecular selectivity of the film can also be tuned by controlling it via the redox state, ie by applying a DC potential.
  • the analyte-specific layer consists of a polymer which has ion-selective or molecule-selective coupling sites, so that the analyte can be selectively extracted from the solution into the layer. It is proposed for this embodiment that the polymer layer is an ion conductor.
  • these polymers can be complex-forming polymers which are polymeric chelating agents, that is to say products which can form chelates. They contain corresponding chelating functional groups in covalent bond to polymers that can be uncrosslinked or crosslinked. These groups can be complexed with metal ions both intramolecularly and intermolecularly.
  • Complexing groups (ligands) of conventional complex-forming polymers are iminodiacetic acid, hydroxyquinoline, thiourea, guanidine, dithiocarbamate, hydroxamic acid, amidoxime, aminophosphoric acid, (cycl.) Polyamino, mercapto, 1,3 - Dicarbonyl, u. Crown ether residues, some of which have very specific activities towards ions of different metals.
  • Basic polymers of the complex-forming polymers are, in addition to polystyrenes, polyacrylates, polyacrylonitriles, polyvinyl alcohols and polyethyleneimines.
  • the complex-forming polymers are preferably produced in polymer-analogous reactions on crosslinked polyvinyl compounds.
  • complex-forming polymers can be made from both natural polymers and cellulose.
  • the compounds can also be covalently bound to the polymer, such as cage compounds (for example cyelophans, crown ethers, antibiotics, cyclodextrins), antigens or antibodies, natural or synthetic polypeptides, lectins, specifically binding proteins, lipids and surfactants.
  • polysaccharides with active ligands examples include: polysaccharides with active ligands; Poly crown ether; Poly crown vinyls; Polyether copolymers with active ligands; Polysaccharides, polysiloxanes and polyacrylates with chiral selectors.
  • Surfactants, colloidal gold, graphite, glass or inorganic microparticles or pearls can be included in the polymer films as molecular carriers.
  • the selective binding of neutral or charged species, for example alkali metal ions, Mg 2 "1" , Ca 2+ or transition metal ions, to specifically functional groups in the polymer layer can bring about a change in the morphology and the pore size, specifically
  • Changes in morphology can lead to changes in the electrical properties of the membrane layer, e.g. ionic conductivity. This is the case with some gels, proteins, especially receptor proteins, lipids and surfactants, which contain functional groups which are capable of binding anions or cations or which are sensitive to lipophilic components of the sample.
  • polymer films can be used which contain ligands covalently bound to the polymer backbone, which are able to complex ions. These films can be cross-linked, e.g. by transition metal ions if these ions form complexes or chelates with the ligands contained in the polymer at different points in the polymer chain.
  • Cation receptor polymer layers for example multi-phase polymer layers, which are sensitive to Ca 2+ .
  • polyions such as proteins and synthetic or natural polypeptides should be mentioned.
  • polyanionic macromolecules proteoglycans and acidic glycoproteins
  • These macromolecules are polyanions, in accordance with their carboxylated, sialic or sulfate groups.
  • the conductive particles preferably have a size smaller than 10 ⁇ m, at best smaller than 1 ⁇ m and consist e.g. made of a semiconductor, metal or graphite.
  • the analyte-specific layer can have an ordered structure (ie the components of the medium form a liquid crystal phase), a partially ordered one (eg in the multi-double structures of films formed from polyionic complexes) or an amorphous one.
  • an effect on the conditioning of the membrane phase is possible, for example disorganization, as a result of which its bulk electrical properties are influenced.
  • the above-mentioned multi-double structures can be formed, for example, from polyionic complexes between quaternary ammonium ions, including surfactants and lipids, and from polyions, such as, for example, polystyrene sulphonate and polyvinyl sulphonate.
  • the components of such a film are, for example, dioctadegyldimethylammonium bromide (2C, 8 N + 2CBr ”) and sodium polystyrene sulfonate (PSS-Na + ).
  • Ion exchangers and ionic polymers can also be used as a sensitive layer material in the sense of the present invention, provided that the ion exchange for the detected ion results in a change in the electrical properties of the layer.
  • the characteristic feature of an ion exchanger and ionic polymer is the presence of a large amount of hydrophilic groups which are bound to the polymer. These groups can be, for example, -S0 3 H and -COOH in cation exchange resins, and quaternary ammonium groups in anion exchange resins.
  • Such polymers for example persulfone polymers such as Nafion or Eastman Kodak AQ polymers, can also contain essential hydrophobic regions. As a result, films are formed with a heterogeneous structure, with separately hydrophilic and hydrophobic regions. A characteristic of these materials is the fact that they contain themselves internally due to the inclusion of water. thin and prevent local ionization, which results in a conductivity close to that of aqueous electrolytes.
  • ionic polymers refers to polymers which have basic or acidic functional groups attached to or in the basic structure of the polymer.
  • ionic groups of the ionic polymers i.a. Salts of carboxy, sulfonic acid, phosphonic acid, ammonium or phosphonium groups act.
  • the ionomers forming the sensitive layer can belong in particular to the following groups:
  • Terpolymers Terpolymer ethylene propylene diene sulfonate; substituted polyvinyls such as polyacrylates, in particular polyacetates or butyrals or polyvinylimidazole;
  • Perfluoropolymers especially perfluorosulfonates.
  • the analyte-specific layer additionally of the polymer materials and / or liquids described above also contains ion-selective or molecule-selective coupling elements.
  • the analyte-specific polymer layer can consist of a polymer, the corresponding one
  • Coupling elements to enable a selective extraction of the analyte but on the other hand it is also possible that the layer, as described above, contains a polymer material and / or liquid and that ion-selective or molecule-selective coupling elements are additionally added.
  • Such coupling elements are preferably complexing agents for cations / anions / neutral particles. Such complexing agents then enable complexing and transfer mobility of ions or neutral molecules in the lipophilic, sensitive layer.
  • This complexing agent should have lipophilic properties and form complexes which are charged or uncharged with cations / anions / neutral particles.
  • anion / cation exchangers also represent components in the layer, which bring about the mobility of ions within the layer. Both the complexing agents for cations / anions / neutral particles and anion / cation exchangers with their lipophilic properties can be present side by side in the layer.
  • ion-selective or molecule-selective components with lipophilic properties are described in the literature, for example those used in ion-selective membranes of ion-selective electrodes, extraction or washing processes.
  • ion-selective components are described in the literature, for example those used in ion-selective membranes of ion-selective electrodes, extraction or washing processes.
  • Cation exchangers diacyl phosphates, tetraaryl borates and their salts, e.g. Tetraphenyl borate and its silver and alkali salts, such as sodium tetraphenyl borate.
  • the phenyl nuclei of the tetraphenyl borates can be unsubstituted or substituted, preferably monochloro-substituted in the para position.
  • Anion exchanger trialkylmethylammonium salts, cationic metal complexes
  • -cyclic for example macrocycles such as crown ether (alkali selectivity), natural antibiotics (valinomycin - potassium selectivity, nonactin - ammonium selectivity)
  • non-cyclic for example dicarboxylic acid diamides (high selectivities towards alkali / alkaline earth ions), tridodecyl laminate (H + Sensitivity)
  • Complexing agents for anions e.g. Guanidine compounds, complexation of oxo anions such as phosphate or nitrate
  • boric acid such as boronic acid (complex formation with glucose), calixarenes
  • plasticizers be added to the solid or semi-solid polymer. These plasticizers also preferably have lipophilic properties. The use of such plasticizers is known from the literature. Examples for this are:
  • Ether e.g. o-nitrophenyloctyl ether ester plasticizers, particularly Dicar diester diester plasticizers, tetracarboxylic acid tetraester plasticizers, the esterifying component being an aliphatic alcohol, generally having at least five carbon atoms, e.g. Bis (2-ethyl hexyl) sebacate, diester of phosphoric acid or phosphonic acid.
  • the ion-selective or molecule-selective layers preferably consist of the following composition of the individual components:
  • Polymer membrane layers particularly preferably have the following composition:
  • Solid materials for example crystalline bodies, single crystals such as LaF 3 doped with EU 2+ for F, polycrystalline Ag 2 S compacts, ionic conductors (for example NASICON) or ion-selective glass (for example pH-pNa electrode glass) can also be used .
  • Another variant of the invention now proposes to additionally provide an analyte-specific polymer membrane layer as described above with an enzyme-containing layer.
  • Appropriate biosensors can now be produced as a result.
  • at least one further layer is formed on the analyte-specific polymer membrane layer, which contains an enclosed or immobilized enzyme and, if necessary, also a redox mediator.
  • the operation of such a bio-sensor is based on the detection of the change in the electrical properties of the analyte-specific polymer membrane layer as a result of the biocatalytic Activity of the enzyme in the additional enzyme-containing layer.
  • the material forming the layer preferably contains at least one macromolecular component, which is preferably a protein, polysaccharide or synthetic polymer or copolymer.
  • non-enzymatic proteins such as collagens and albumins. These proteins can be cross-linked to form a membrane for enzyme immobilization.
  • Polysaccharides have the advantage that inorganic catalysts are not present in the polymerization, which can be the case with synthetic polymers. Diethylaminoethyl dextran (DEAE dextran) or polyethyleneimine could be used. Polysaccharides with a molecular weight of 5,000 to 500,000, preferably 5,000 to 50,000, should be selected.
  • Suitable polymers include polyacrylamide gels; likewise vinyl polymers, in particular vinyl acetates; Polyvinyl alcohols, preferably polyvinyl butyral.
  • polyurethanes and polysiloxanes also heteropolysiloxanes which contain functional groups, for example amino groups.
  • the crosslinking is preferably carried out using bifunctional or multifunctional reagents, for example glutaralaldehyde and its oligomers. It should be mentioned here that the crosslinking depends on the exposure time to the glutaralaldehyde, and this should be between 10 and 90 minutes, preferably 30 minutes at room temperature.
  • the ratio enzyme / (matrix component) is important for the diffusion properties of the membrane.
  • the ratio is in the range from 5 to 100% by weight, preferably between 10 and 50% by weight.
  • the mechanical and adhesive properties of the enzymatic membranes can be improved if the solution forming the membrane contains a polyhydric alcohol, preferably glycerol or sorbitol or lactitol.
  • a polyhydric alcohol preferably glycerol or sorbitol or lactitol.
  • the preferred concentration of the polyhydric alcohol is in the range from 5 to 30% by volume.
  • the presence of a polyhydric alcohol or polysaccharide in the solution from which the membrane is formed can lead to better preservation of the enzyme activity during immobilization and thus to an extended service life of the sensor.
  • the enzymatic membrane may contain oxidizing or reduced agents (e.g. ferrocenes) which are able to recycle the active center of the enzyme.
  • oxidizing or reduced agents e.g. ferrocenes
  • the enzyme can also be immobilized on the analyte-selective layer by covalent binding. This can take place if the analyte-selective measurement it carries suitable functional groups (eg -OH, -NH 2 , or -COOH), or if an additional layer, which contains corresponding functional groups, is formed on the analyte-selective membrane layer, so that the enzyme is bound to the additional layer .
  • suitable functional groups eg -OH, -NH 2 , or -COOH
  • differential measurements can be carried out.
  • a difference signal is measured between the ASIS with and without the enzyme.
  • Another layer of cross-linked proteins or synthetic / natural polymer can be applied to the enzymatic layer. This layer improves the biosensor properties in the following way:
  • the additional layer In order to suppress the negative influence of the buffer capacity for a buffer with weakly acidic groups and pK ⁇ 7, the additional layer must carry functional groups which are negatively charged at a given pH of the sample. For buffers with weakly basic residues and pK> 7, the functional groups must be positively charged under the assay conditions. Further details, features and advantages of the present invention result from the following description of exemplary embodiments and from the drawings.
  • FIG. 1 shows the schematic structure of a first embodiment of an analyte-selective sensor with an analyte-specific polymer membrane layer (sensor)
  • FIG. 2 shows the schematic structure of an analyte-selective sensor in the form of a biosensor
  • FIG. 3 shows exemplary measuring electrode arrangements in which the conductors are formed in the form of wires or in the form of thick or thin layers
  • FIG. 4 shows exemplary measuring electrode arrangements in which the conductors are designed in the form of disk electrodes
  • FIG. 5 shows schematically the structure of the measuring electrodes in the form of IDE and a measuring arrangement for measuring the admittance of the sensor
  • FIG. 6 shows the dependency of the real part of the admittance, Re (Y), of the ASA based on IDE using PVC membranes containing valinomycin for determining the concentration of K + in the solution. The measurements were carried out at 100 kHz. 1 M NaN0 3 was used as the background electrolyte. 7 shows the dependence of the real part of the admittance, Re (Y), of the ASA based on two coated wire electrodes using valinomycin-containing membranes for determining the concentration of K + in the solution. The measurements were carried out at 100 kHz. 1 M NaN0 3 was used as the background electrolyte.
  • FIG. 1 shows in section the schematic structure of an analyte-selective sensor 1 according to the invention.
  • Sensor 1 is in direct contact with solution 4 and is constructed in such a way that the analyte-specific polymer membrane layer 3 is applied to an inert support 7.
  • the layer thickness of the sensitive layer 3 can be in the range from 0.1 ⁇ m to 1 mm.
  • the electrodes 5, 6 have direct contact with the layer 3.
  • this layer has the following composition: 32% by weight of polymer material, 66% by weight of plasticizer and
  • K lium-selective membrane High molecular weight polyvinyl chloride homopolymer was used as polymer material, plasticizer was o-nitrophenyl octyl ether. As a potassium-selective component, one is known from the prior art
  • Component used the natural antibiotic valinomycin.
  • Ammonium-selective membrane High molecular weight polyvinyl chloride homopolymer was used as the polymer material, plasticizer was dibutyl sebacate. A component known from the prior art, the natural antibiotic nonactin, was used as the ammonium-selective component.
  • H + -selective membrane high-molecular polyvinyl chloride homopolymer was used as polymer material, plasticizer was o-nitrophenylloctyl ether.
  • H + selective component de uses a component known from the prior art, ionophore ETH 1907 (4-nonadecylpyridine).
  • Ca 2+ -selective membrane High molecular weight polyvinyl chloride homopolymer was used as the polymer material.
  • the plasticizer was o-nitrophenyl octyl ether.
  • FIG. 2 now shows the schematic structure of a biosensor according to the invention analogous to the exemplary embodiment according to FIG. 1.
  • the biosensor 2 consists of an analyte-specific polymer membrane layer 8 applied to a carrier 7.
  • the electrodes 5, 6 are now provided with an additional layer 10, which suppresses the interface resistance .
  • This layer 10 contains redox-pair-forming substances according to CH 677 295.
  • the enzyme-containing polymer membrane layer 9 is not applied directly to the analyte-specific polymer membrane layer 8, but rather A further layer 11 is provided between these two layers, which serves to better bind layer 9 to layer 8.
  • this layer 11 consists of carboxylated or aluminized PVC and has a layer thickness of 10 ⁇ m to 1 mm.
  • the enzyme-containing polymer membrane layer 9 can be in the thickness range from 1 ⁇ m to 1 mm.
  • the thickness of this layer is preferably 10 ⁇ m to 500 ⁇ m.
  • a further layer 12 made of cross-linked protein or synthetic or natural polymer is now provided on the enzyme-containing polymer membrane layer 9.
  • This layer advantageously improves the biosensor properties.
  • this layer consists of Nafion or acetate cellulose and has a thickness of 100 ⁇ m.
  • biosensors were produced in accordance with the structure according to FIG. 2:
  • Biosensors for urea and amino acid the enzyme-containing polymer membrane layer 9 consisting of urease or amino acid oxidase and the analyte-specific polymer membrane layer 8 consisting of ammonium-selective PVC membrane (ammonium ionophores).
  • glucose oxidase or acetylcolinesterase There is glucose oxidase or acetylcolinesterase and the analyte-specific polymer membrane layer 8 is a pH-selective PVC membrane (H + ionophore).
  • FIG 3 now shows, by way of example, measuring electrode arrangements as can be used for the sensors according to the invention.
  • the practical implementation of the measurements of the electrical properties of the layer can preferably be distinguished between two basic types of measuring cells, as is shown in FIG. 3: 1. Both conductors (11) are covered by the layer (13), which in this way forms a continuous bulk phase. (Fig. 3 a, b);
  • the conductivity of the sample is much larger than the conductivity of the analyte-specific membranes used.
  • the sensor characteristics were determined in a standard solution of known or adjusted conductivity before and after the measurement in a solution. * Parallel measurements of the conductivity of the sample were made and considered.
  • Case 1.2 corresponds to the situation when the proportion of the volume conductivity of the sample to the sensor output signal is minimal, so that the measured signal mainly corresponds to the bulk conductivity of the analyte-selective layer.
  • the invention basically includes the following design options for the sensor:
  • the sensor consists of two metal wires (11) that are covered with an electrically insulating polymer (e.g. TFPE, PVC) or an inorganic (glass) layer
  • an electrically insulating polymer e.g. TFPE, PVC
  • each wire (11) is connected to the measuring device (15).
  • the analyte-selective layer (13) is applied to the other exposed end of each wire (13).
  • the thickness of the analyte-selective layer (13) formed in this way should preferably be less than that of the insulating layer (14) covering the rest of the wire, especially in the event that the layer has a very low conductivity.
  • B disc electrodes fFi ⁇ . 4 Two interconnected wires or strips (16) are pressed on or embedded in an electrically insulating plastic block (17), as shown in FIG. 4. The conductor ends protruding on one side of the block are connected to the measuring device (15). The other side of the block (17) is polished so that the working electrodes form a flat surface in one plane with the surrounding surface of the plastic block.
  • the analyte-selective layer is applied to both electrodes simultaneously or separately on each.
  • Such a sensor probe can be immersed directly in the test solution or pressed onto a micro-flow measuring cell using an O-ring.
  • One of the advantages of this design is the ease of renewing the probe simply by polishing the electrode surface.
  • interdigital electrodes Two interdigital electrodes (IDE) or conduction bands (19) are applied to an insulating substrate (20) (FIG. 5).
  • the latter can in particular be a polymer tape (eg polyimide), glass, ceramic (eg molten aluminum or sital) or sapphire.
  • the electrode materials can be selected from what has been described above, just like the analyte-specific layer (22).
  • the regions of the electrodes connecting the measuring part to the contact surfaces of the sensor chip must be covered by an electrically insulating layer (21) which only leaves the electrical tap and the sensitive surface of the electrode (19) free.
  • This passivation layer (21) can either be a polymer film (eg silicone rubber, high-temperature cross-linked polyimide or photoresists) or inorganic films such as pyrolytic silicon oxide, CVD silicon nitride or applied glass films.
  • a polymer film eg silicone rubber, high-temperature cross-linked polyimide or photoresists
  • inorganic films such as pyrolytic silicon oxide, CVD silicon nitride or applied glass films.
  • the advantage of using an IDE lies in the possibility of a dense arrangement of the electrodes (dimensions a and b can be reduced down to the submicro scale) with a large periphery at the same time, which leads to an increase in the sensitivity of the measurement in a small area.
  • the lowest achievable limit for the dimensions a and b is 0.1 ⁇ m, 2 ⁇ m and 50 ⁇ m, respectively, if electron photolithography, optical photolithography or screen printing technology are used for the electrode production.
  • the thickness of the electrodes, h is usually between 0.01 ⁇ m and 10 ⁇ m.
  • the analyte-selective layer (22) is applied to the measuring surface of the IDE, which is free of passivation.
  • the layer must cover the entire sensitive area of the electrodes (19). Since the electrical conductivity of the layer can be rather low (the resistance of a lipophilic ion-selective membrane based on PVC can reach a height of 10 8 ⁇ cm 2 , for example), even small parts of the electrode which are directly exposed to the solution make one reliable measurement of membrane conductivity impossible because its resistance is less than the membrane resistance themselves, and thus they can short-circuit the current flow in the measuring circuit.
  • the sensitive layer absorbs water and has the same conductivity as the solution
  • the requirements for the quality of the passivation layer are of less importance, so that in some cases passivation is not necessary. This is e.g. the case when the surface of the measuring electrodes with the covering layer is much larger than the area of other parts of the electrode which are exposed to the solution.
  • the dimensions of a, b and h should be chosen so that the ratio 1.2 (see above) is met, i.e. the layer thickness d should ideally be greater than a as well as b and h.
  • the thickness of the passivation layer covering the central part of the chip should preferably be greater than that of the measuring layer. In this case, changes in the background conductivity of the sample interfere to the smallest extent with the measurement of the conductivity of the selective layer.
  • the invention comprises not only individual, but also multi-analyte probes, which are produced by combining or integrating multiple electrodes on a sensor unit or a support, coated with layers specific for different analytes.
  • Sensors with moderate selectivity can also be integrated in a multisensor unit, which leads to the obtaining of so-called "fingerprints" which correspond to the different compositions of the sample solutions.
  • fingerprints which correspond to the different compositions of the sample solutions.
  • a corresponding sample composition can be assigned to the respective response patterns.
  • the preferred construction of the multisensor is based on the use of microelectronic chips with the required number of the above-described integral digital electrode pairs, each pair being coated with the appropriate layer. Such a design has the advantage of technological compatibility with IC technologies and the simplicity of miniaturization.
  • FIG. 5 One of the simplest electrical arrangements used for measuring the admittance (impedance) of the sensor and thus the conductivity of the layer is shown in FIG. 5.
  • the load resistance, R is connected in series with the sensor to be examined and the voltage drop at R L supplies the output signal.
  • the condition for the use of such an arrangement is that that inner ⁇ half of the frequency range of the input voltage used, the impedance of the tested sensor ⁇ sensor "should be much greater than R L.
  • the current flow towards the load resistance is mainly determined by the impedance of the sensor and can easily be according to the formula
  • ⁇ is the angular frequency of the input voltage, V m . and U out - the output voltage.
  • the first term on the right side represents the real part of the sensor admittance
  • the impedance Z of the sensor is measured instead of the admittance Y.
  • the impedance Z of a system represents the reciprocal of the associated admittance. Impedance measurements can therefore also be used to characterize the conductivity of a layer.
  • the measurements of the admittance or alternatively, a phase component of the output signal of the measurement order from FIG. 5, are used in the preferred implementation of the invention. These values also depend on the frequency, and this dependency can vary in the different frequency ranges.
  • the usual operating frequency is selected taking into account these factors with the aim of optimizing the sensor sensitivity, reducing the requirements for the measuring device and suppressing unspecific disturbances.
  • the preferred working range for contact measurements is at frequencies between 1 Hz and 100 kHz.
  • the preferred frequencies for contactless measurements of membrane conductivity are: from 1 MHz to 100 MHz if capacitive coupling is used; - from 10 Hz to 10,000 Hz if inductive coupling is used.
  • Two identical pairs of interdigital metal electrodes (Ni, PT or Au) were produced by vacuum evaporation on a 0.5 mm thick ceramic substrate.
  • the dimensions of a sensor chip are 5mm 20mm.
  • an intermediate layer made of chrome (0.1 ⁇ m thick) was applied.
  • Each electrode finger was 70 ⁇ m wide and approximately 1 mm long with a 70 ⁇ m spacing between the electrode fingers of a pair.
  • the sentive area of each pair of electrodes forming the impediometric transducer was approximately 1 mm 1.5 mm.
  • the central part of the chip was encapsulated with a layer of Dow Corning silicone rubber. The complete chip layout is shown schematically in FIG.
  • the ion-selective membrane was applied to the sensitive surface of the IDE and CWE by means of dip coating from the solution of the membrane components in THF.
  • the sensor admittance measurements were carried out using an ONO SOKKI dual channel analyzer CF 940 or a lock-in amplifier EG & G 5209 in accordance with the measuring arrangement in FIG. 5.
  • the IDE were coated with PVC membranes containing valinomycin.
  • Re (Y) and the imaginary part Im (Y) -the admittance of the sensor from the potassium concentration was checked in a frequency range from 0.05 Hz to 100 kHz. It has been observed that Re (Y) at frequencies from 100 Hz to 100 kHz, corresponding to the industry speed increases with increasing potassium concentration. The detection limit was in the range of 10 "5 M and this even with 1 M sodium nitrate solution as an interfering ion electrolyte. At a frequency of 100 Hz, the dependence Re (Y) against pK + was quasi linear for pK + in the range from 1 to 4 (FIG. 6 ).
  • the ASA based on CWE (coated wire electrodes) using PVC membranes containing valinomycin showed a quasi-linear dependence of the Re (Y) on the pK + in the range from 0 to 4 with 1 M sodium nitrate solution as the interference ion electrolyte , measured at a frequency of 100 kHz ( Figure 7).
  • the ASA based on IDE (interdigital electrodes) using PVC membranes containing nonactin showed a dependence of the Re (Y) on the pNH 4 + in the range from 0 to 5 with 1 M sodium nitrate solution as the interfering ion electrolyte, measured at a frequency of 100 kHz (FIG. 8).
  • Example 4 The ASS based on IDE (interdigital electrodes) using pH-sensitive PVC membranes (Ionophore ETH 1907) showed quasi-linear dependence of the Re (Y) on the pH in the range from 2 to 8, measured at a Frequency of 100 kHz ( Figure 9). Standard Merck buffers of different pH values were used.
  • the ASA based on IDE using Ca-IV ionophore from Fluka containing PVC membranes showed a dependence of the Re (Y) on the Ca 2+ concentration in the range from 10 " 7 to 0.1 M at 1 M Sodium nitrate solution as an interfering ion electrolyte, measured at a frequency of 100 kHz (FIG. 10).

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Abstract

L'invention concerne un détecteur sélectif d'analyte, servant à la détermination qualitative et/ou quantitative d'ions ou de substances contenus dans des solutions. Ce détecteur (1) comprend au moins une couche (3) spécifique de l'analyte, déposée sur un substrat inerte (7) et en contact avec la solution, cette couche, constituée d'un matériau liquide, solide ou semi-solide, étant raccordée au moins à deux électrodes (5, 6). Cette couche (3) retire de façon sélective l'analyte de la solution, de sorte que l'absorption de l'analyte modifie les propriétés électriques de la couche (3), telles que la résistance, la conductivité, l'admittance ou l'impédance.
EP95934618A 1994-10-18 1995-10-17 Detecteur selectif d'analyte Withdrawn EP0787290A1 (fr)

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DE4437274A DE4437274C2 (de) 1994-10-18 1994-10-18 Analytselektiver Sensor
DE4437274 1994-10-18
PCT/DE1995/001458 WO1996012176A1 (fr) 1994-10-18 1995-10-17 Detecteur selectif d'analyte

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US6004442A (en) 1999-12-21
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DE4437274C2 (de) 1998-11-05

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