EP3295162A1 - Procédé de fabrication d'un dispositif de détection électrochimique de molécules au moyen de cycles redox, dispositif permettant la mise en oeuvre dudit procédé et son utilisation - Google Patents

Procédé de fabrication d'un dispositif de détection électrochimique de molécules au moyen de cycles redox, dispositif permettant la mise en oeuvre dudit procédé et son utilisation

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Publication number
EP3295162A1
EP3295162A1 EP16726763.2A EP16726763A EP3295162A1 EP 3295162 A1 EP3295162 A1 EP 3295162A1 EP 16726763 A EP16726763 A EP 16726763A EP 3295162 A1 EP3295162 A1 EP 3295162A1
Authority
EP
European Patent Office
Prior art keywords
electrode
dielectric layer
redox
pores
ink
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Withdrawn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
EP16726763.2A
Other languages
German (de)
English (en)
Inventor
Alexey YAKUSHENKO
Bernhard Wolfrum
Nouran Yehia ADLY HASSAN
Andreas Offenhäusser
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.)
Forschungszentrum Juelich GmbH
Original Assignee
Forschungszentrum Juelich GmbH
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 Forschungszentrum Juelich GmbH filed Critical Forschungszentrum Juelich GmbH
Publication of EP3295162A1 publication Critical patent/EP3295162A1/fr
Withdrawn legal-status Critical Current

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    • 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
    • G01N27/3277—Sensing specific biomolecules, e.g. nucleic acid strands, based on an electrode surface reaction being a redox reaction, e.g. detection by cyclic voltammetry
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B41—PRINTING; LINING MACHINES; TYPEWRITERS; STAMPS
    • B41J—TYPEWRITERS; SELECTIVE PRINTING MECHANISMS, i.e. MECHANISMS PRINTING OTHERWISE THAN FROM A FORME; CORRECTION OF TYPOGRAPHICAL ERRORS
    • B41J2/00—Typewriters or selective printing mechanisms characterised by the printing or marking process for which they are designed
    • B41J2/005—Typewriters or selective printing mechanisms characterised by the printing or marking process for which they are designed characterised by bringing liquid or particles selectively into contact with a printing material
    • B41J2/01—Ink jet
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D11/00—Inks
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D11/00—Inks
    • C09D11/30—Inkjet printing inks
    • C09D11/32—Inkjet printing inks characterised by colouring agents
    • C09D11/322—Pigment inks
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D11/00—Inks
    • C09D11/52—Electrically conductive inks
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D11/00—Inks
    • C09D11/54—Inks based on two liquids, one liquid being the ink, the other liquid being a reaction solution, a fixer or a treatment solution for the ink
    • 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
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • 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
    • 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
    • G01N27/3278—Sensing specific biomolecules, e.g. nucleic acid strands, based on an electrode surface reaction involving nanosized elements, e.g. nanogaps or nanoparticles
    • 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
    • G01N27/416—Systems
    • G01N27/49—Systems involving the determination of the current at a single specific value, or small range of values, of applied voltage for producing selective measurement of one or more particular ionic species
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G01N33/487—Physical analysis of biological material of liquid biological material
    • G01N33/48707—Physical analysis of biological material of liquid biological material by electrical means
    • G01N33/48721—Investigating individual macromolecules, e.g. by translocation through nanopores
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54366—Apparatus specially adapted for solid-phase testing
    • G01N33/54373—Apparatus specially adapted for solid-phase testing involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
    • G01N33/5438—Electrodes
    • H—ELECTRICITY
    • H05—ELECTRIC TECHNIQUES NOT OTHERWISE PROVIDED FOR
    • H05K—PRINTED CIRCUITS; CASINGS OR CONSTRUCTIONAL DETAILS OF ELECTRIC APPARATUS; MANUFACTURE OF ASSEMBLAGES OF ELECTRICAL COMPONENTS
    • H05K1/00—Printed circuits
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/76—Assays involving albumins other than in routine use for blocking surfaces or for anchoring haptens during immunisation
    • G01N2333/77—Ovalbumin
    • 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
    • G01N27/3276—Sensing specific biomolecules, e.g. nucleic acid strands, based on an electrode surface reaction being a hybridisation with immobilised receptors

Definitions

  • the invention relates to a method for producing a device for the electrochemical detection of molecules by means of redox cycling, and to a device for this purpose and their use.
  • Redox cycling is an electrochemical process in which electrochemically active molecules are oxidized and reduced several times. These reactions take place between two closely spaced electrodes. For this purpose, oxidizing and reducing potentials are applied to the electrodes so that the molecules are directly oxidized or reduced on contact with the electrodes. If the molecule then diffuses to the other electrode, the reverse process (reduction / oxidation) takes place. As a result of this iterative process, charge transport between the electrodes takes place through each individual molecule, which leads to an amplification of the measurable total signal.
  • Wolfrum et al. (2008), Kätelhön et al. (2010) and Zevenbergen et al. (2011) are known in the Z-axis, that is to say electrodes arranged one above the other, which have a nano-scaled gap as a so-called “nanocavity" or “nanochannel” in between.
  • the production takes place with electron beam lithography or optical Lithography comprising several etching steps and the removal of, inter alia, a chromium sacrificial layer.
  • Hüske et al. (2014) disclose in the Z-axis, that is superimposed electrodes, which have a nano-scaled dielectric between the two electrodes.
  • the electrodes are produced by optical lithography and electron beam lithography.
  • the manufacturing process comprises several deposition and etching steps, but also a so-called "soap assembly" step by anodization of aluminum.
  • Electrodes From Gross et al. (2015) are known in the Z-axis, that is to say superimposed electrodes which have a microscale gap.
  • the electrodes are made by bonding two separate electrodes with a thick-film dielectric in between.
  • the object of the invention is to provide an inexpensive and rapid method for producing a device for the electrochemical detection of molecules by means of redox cycling.
  • the method is intended to provide mechanically stable devices reproducibly and quickly at a low cost.
  • Another object of the invention is to provide a related device for the electrochemical detection of molecules by redox cycling and to show their potential uses. Solution of the task
  • the method for producing a device for the electrochemical detection of analytes by means of redox cycling is characterized by the following steps: a) a first, electrically conductive electrode is arranged on a substrate, b) a first dielectric layer is permeable to redox-active molecules c) on the dielectric layer, a second, electrically conductive electrode is arranged with conductor track, wherein at least one of the steps a) to c) with a printing method of electrically conductive and / or electrically insulating particles.
  • this provides a method in which at least one of steps a) to c) is carried out with a printing method.
  • the printing process is advantageous fast and inexpensive and very easy to reproduce.
  • the method for producing the redox cycling sensor thus comprises in particular but not exclusively a choice of conductive and / or insulating, printable particles with which the electrode and / or the dielectric layer can be arranged in a structured manner one above the other.
  • ink jet printing, aerosol jet process, screen printing, gravure printing, offset printing, nanoimprint printing or hot stamping is used.
  • Combinations of coating and ablation steps that apply the same layers can be performed in combination with various coating techniques such as slot-die, laser ablation, and so on.
  • Printable particles in the sense of the invention, preferably nanoparticles, are contained, for example, in an ink or in a paste or in another carrier medium for the particles.
  • silicon or a polymer can be selected.
  • Various polymers are particularly suitable, such as e.g. Polyethylene naphthalate, polyerylene terephthalate, polyimide, polymethyl methacrylate, polycarbonate, and so on.
  • a first electrode of conductive particles e.g. gold, silver, platinum, carbon, a conductive polymer, e.g. Poly (3,4-ethylenedioxythiophene) polystyrene sulfonates, polyaniline, polypyrols or the like and a conductor z. B. arranged by ink jet printing method or another printing method on the substrate and transferred to a finished structure.
  • the first electrode has either no or only very small pores.
  • the first electrode should be conductive and preferably show good electrochemical properties, that is z. B. have a fast electrode kinetics with standard redox mediators and be as resistant to electrode contamination by adsorption and / or corrosion.
  • a redox-active-molecule-permeable dielectric layer having access to the introduction of the redox-active molecules into the dielectric layer is arranged on the first electrode.
  • Step b) can be carried out in various ways.
  • the access can z.
  • the dielectric layer is preferably printed on the first electrode.
  • the size of the nanoparticles for the dielectric layer should be selected larger than any pores present in the first electrode, so that the nanoparticles for the structure of the dielectric do not penetrate into the pores of the first electrode.
  • the nanoparticles are in turn contained in an ink, paste or other carrier medium.
  • a porous second, electrically conductive electrode preferably with a conductor track
  • a porous second, electrically conductive electrode can be arranged on the porous dielectric layer, with the pores leading to the surface of the dielectric layer.
  • the pores of the second electrode and the dielectric form the access for the redox-active molecule.
  • the size of the nanoparticles for the second electrode should be selected to be larger than the pores present in the dielectric so that the nanoparticles for the construction of the second electrode do not penetrate into the pores of the dielectric.
  • the nanoparticles are in turn contained in an ink, paste or other carrier medium.
  • the method for producing a device for the electrochemical detection of redox-active molecules by redox cycling characterized by the steps: a) on a substrate, a first, electrically conductive electrode is arranged, b) on the first electrode a porous dielectric layer is arranged, in which the pores lead to the surface of the first electrode, c) on the dielectric layer, a porous second, electrically conductive electrode is arranged, in which the pores lead to the surface of the dielectric layer at least one of the steps a) to c) is carried out with a printing method of electrically conductive and / or electrically insulating particles.
  • a porous dielectric layer is arranged at least on the first electrode, in which the pores lead to the surface of the first electrode.
  • the pores in the dielectric layer are subsequently filled with the molecule to be converted, or analyte or redox mediator.
  • the second electrode without a pore system.
  • the access of redox-active molecules to the dielectric layer z. B. by a lateral access. Such access may alternatively be provided by a single z. B. needlepoint-like opening in the second electrode can be set.
  • an ink with dielectric nanoparticles is preferably printed on the active region of the first electrode.
  • This ink contains nanoparticles, such as polymethylmethacrylate, polystyrene, silica, titania, or the like, as a functional material.
  • the nanoparticle size in the ink for the dielectric layer should not be chosen smaller in the active region, that is to say the range of the conversion of the molecule at the first electrode, but should be chosen to be larger than any pores in the first electrode itself, so that the nanoparticles of the ink of the dielectric does not penetrate into the pores of the first electrode.
  • this can be advantageously sintered in the subsequent z.
  • thermal, photonic, by UV or similar energy input so that the nanoparticles only partially melt and form a homogeneous dielectric layer with uniformly distributed pores of defined size, which extend to the surface of the first electrode and expose them.
  • the dielectric above the first electrode can also not be sintered, so that the nanoparticles remain unchanged and in this way the porosity remains ensured down to the surface of the first electrode.
  • sol-gel inks for the production of the dielectric nanoporous layer of the sensor in step b).
  • the material or the ink for the porous dielectric layer should be prepared so that after deposition, for example by means of ink-jet printing, this layer dries out and / or hardens and has the desired porosity, so that together menumblede pores are present in the layer.
  • the layer has access to the liquid, e.g. B. on the pores.
  • Such a layer can be made by the use of sol-gel materials and a sol-gel ink. For this you can z.
  • TMOS tetramethyl orthosilicate
  • TEOS tetraethyl orthosilicate
  • TPOS tetraisopropyl ortho-silicate
  • aluminum (2-propylate) aluminum (2-butoxide
  • zirconium propylate titanium ethylate
  • solvent or active material for the condensation reaction of the sol gel different materials having OH groups can be used.
  • the ink may also contain additives such as surface tension modifiers, tackifiers, adhesion promoters, binders, and the like.
  • sol-gel formation of a silica gel on the point-like applied dielectric follows the steps described in the publication "The Sol-Gel Preparation of Silica Gels” (Buckley, AM, Greenblatt, M. 1994. Journal of Chemical Education Volume 71, No. 7, 599-602) and the contents thereof, in particular for the preparation of the sol gel, are hereby incorporated by reference into this patent application, which also achieves the object of the invention in an advantageous embodiment of the invention
  • an ink with conductive nanoparticles can advantageously be printed on a nanoporous dielectric layer and laterally further to form conductor tracks, so that this second electrode can also be contacted.
  • the nanoparticle size in the second The electrode is preferably larger than the pores in the underlying dielectric layer. This advantageously has the effect that the nanoparticles of the second electrode can not penetrate into the pores of the dielectric and can form a short circuit with the lower electrode.
  • the dielectric or dielectric layer only the region which serves as a reservoir for the molecule between the electrodes, but not optionally existing passivation layers outside the active region, is referred to as the dielectric or dielectric layer.
  • the pore system in the dielectric is the reservoir for the molecule in solution. In the reservoir, the redox reaction of the molecule takes place.
  • inks can be used, provided that they can be applied with a suitable voltage, which allows the redox reaction of the molecule.
  • the dielectric in the active region of the device is preferably made of dielectic polymers such.
  • dielectic polymers such as polyimide, polymethylmethacrylate, other acrylic-based polymers, polyvinylphenol, ceramic materials and oxides such. Silicon dioxide, titanium dioxide, silicon nitride and so on.
  • Ink jet printing is fast and inexpensive with high reproducibility of the electrodes and dielectric layers to be arranged and small dimensions.
  • inkjet printing z.
  • the particles are optionally sintered, z.
  • thermal, photonic, by UV or similar energy input This advantageously has the effect that a homogeneous conductive and / or insulating layer is formed.
  • colloidally dissolved gold or carbon or even dissolved polymers as inks.
  • the ink is optionally sintered, e.g. B. thermal, photonic, UV or similar energy input.
  • This advantageously acts to form a homogeneous conductive or insulating layer or an area with many nanopores.
  • the second, upper electrode has no ohmic or electrical contact with the lower, first electrode. This causes the two electrodes to form a pair of electrodes for the redox cycling process.
  • the active region of the device thus generally provides for the arrangement of at least one electrode and / or the dielectric by a printing process which quickly and inexpensively provides corresponding sensors for redox cycling.
  • the active region of the device is the region in which the reaction of the redox-active molecule takes place locally at the two electrodes above and below the dielectric layer or the reservoir.
  • the reservoir, of the dielectric layer is preferably limited in its area to approximately 1 ⁇ m 2 to 1 cm 2 .
  • the range in size is between 100 pm 2 to 1 mm 2 .
  • the thickness of the dielectric is preferably from 10 nm to 1000 nm.
  • all steps a) to c) are carried out by a printing process, preferably by inkjet printing. This has the advantageous effect of providing a particularly inexpensive and at the same time fast and reproducible method for producing the sensor.
  • steps a) to c) can be carried out particularly advantageously by a printing process, preferably by inkjet printing, in which particles are printed, wherein smaller particles than in step b) and / or in step b) are smaller in step a) Particles are printed as in step c).
  • An ink jet printing method is advantageous because it has a particularly high throughput with high reproducibility and accuracy.
  • B. printable pastes contained particles are then in the active area of the device of step a) after step c) increasingly larger.
  • step a) of the method inks are selected which have smaller particles than in step b) and / or in step b) of the method, inks are selected which have smaller particles than in step c).
  • pores can be produced in the second electrode which are larger than the pores in the dielectric layer and / or pores in the dielectric layer which are larger than pores in the first electrode, if they have pores at all .
  • the method may be characterized by the choice of an ink with conductive particles of gold, platinum, silver, carbon or conductive polymers, such as poly (3,4-ethylenedioxythiophene) polystyrene sulfonate, polyaniline for the preparation of the two electrodes.
  • the method can advantageously have at least one sintering process of printed conductive and / or insulating particles.
  • a passivation layer for passivating the first electrode can be arranged between the first electrode and the second electrode.
  • This passivation layer advantageously also prevents that there is no electrical contact between the electrodes.
  • the passivation layer may preferably have a cutout for the dielectric.
  • dielectric nanoparticles can be arranged on the first electrode in the active region, eg. B. of polymers such.
  • polymers such as polyimide, polymethyl methacrylate, other acrylic-based polymers, polyvinyl and also of ceramic materials and oxides such.
  • silica, titania, silicon nitride, and so on, but also from porous hydrogels can be arranged.
  • a biofunctionalized ink for the arrangement of the dielectric layer on the first electrode in the active region is selected or arranged on this. This advantageously has the effect that the sensor can be used for the indirect detection of the biological or biochemical molecules.
  • an ink with insulating particles for the production of the dielectric layer to which antibodies, receptors, DNA, enzymes zyme or other biomolecules are bound, is advantageously causes the complementary biomolecules, z.
  • antigens can be detected indirectly or electrochemically active products of enzyme activity can be detected directly.
  • the indirect detection is carried out with the aid of a redox mediator.
  • the complementary antigens partially block the pores and thereby reduce the redox cycling current of the redox mediator. Reduction of the redox cycling current quantitatively corresponds to the blocked area, that is, the concentration of the antigen.
  • a substrate is processed, thereby producing redox-active products. These redox-active products can be reduced and oxidized between the two electrodes of the redox cycling sensor, thereby amplifying the signal.
  • the redox cycling current corresponds to the concentration of the enzyme substrate.
  • the device according to the invention for the electrochemical detection of molecules by means of redox cycling thus has a first, electrically conductive electrode on a substrate.
  • a dielectric layer permeable to redox-active molecules is disposed with access to introduce the redox-active molecules into the dielectric layer.
  • Layer is disposed a second, electrically conductive electrode without electrical contact to the first electrode.
  • the redox reaction of a molecule such.
  • At least one of the two electrodes consists of printed electrically conductive particles and / or the dielectric layer consists of printed electrically insulating particles.
  • a porous dielectric layer is arranged, in which pores in the dielectric layer up to the surface of the first electrode ju-The access of the redox-active substance into the conversion region can then take place directly via the surface of the second electrode as well as the pore system of the second electrode and of the pore system of the dielectric.
  • a porous second, electrically conductive electrode without electrical contact to the first electrode is arranged on the dielectric layer.
  • the two electrodes of the device are working electrodes in a potentiostat which are in contact with a reference electrode and / or a counterelectrode.
  • the device according to the invention for the electrochemical detection of molecules by means of redox cycling then preferably has a first, electrically conductive electrode on a substrate. On the first electrode, a porous dielectric layer is arranged, in which the pores in the dielectric layer lead to the surface of the first electrode. On this dielectric layer, a porous second, electrically conductive electrode is arranged without electrical contact with the first electrode.
  • the redox reaction of the molecule or of an analyte or of a redox mediator takes place at the two electrodes.
  • the dielectric layer is a reservoir for the molecule in solution.
  • At least one of the two electrodes consists of printed electrically conductive particles and / or the dielectric layer consists of printed electrically insulating particles. This region of the device identifies the so-called active region of the device which serves to convert the molecule or analyte or redox mediator.
  • the conductive particles of the second electrode are advantageously larger than the pores in the dielectric layer below and / or the insulating particles of the dielectric layer are larger than the pores in the first electrode underneath. This also causes the electrochemical properties of the electrodes and the dielectric to be preserved.
  • the two electrodes of the device represent the working electrodes in a potentiostat, and are contacted with a reference electrode and / or a counterelectrode.
  • the reference electrode defines the voltages applied to the working electrodes. put potentials which are above and below the redox potential of the molecule or analyte and / or redox mediator so that it is alternately reduced and oxidized at the two electrodes.
  • the resulting current flow is indicated by measuring the current with a counter electrode.
  • the dielectric layer in the active region of the sensor has an area between at least 1 pm 2 to at most 1 cm 2 .
  • the range in size is between 100 pm 2 to 1 mm 2 .
  • the thickness of the dielectric is preferably from 10 nm to 1000 nm.
  • the active region of the sensor or active material is thus the region of the electrodes and of the dielectric at which the redox cycling of the molecule is carried out.
  • the active material of the dielectric is thus the region of the dielectric which is arranged directly between the active regions of the electrodes and serves as a reservoir for the molecule in solution or the analyte / redox mediator in solution.
  • the object of the invention is also achieved by the sensitive detection of redox-active molecules by means of the at least partially printed redox cycling sensor.
  • the sensitive detection of redox-active molecules by means of the at least partially printed redox cycling sensor.
  • the senor can be used by introducing a solution with a molecule or analyte or redox mediator as a redox-active molecule and for detecting the redox reaction.
  • This is in solution and is applied to the pores of the second electrode above the porous dielectric layer in Reservoir applied. Or it is z. B. by a lateral or other vertical access to the dielectric.
  • the molecule diffuses between the pores of the dielectric layer back and forth.
  • the applied voltage at the first electrode and the second electrode drives the reduction and oxidation of the molecule or analyte (redox mediator) at the two electrodes above and below the reservoir and generates a detectable current flow.
  • the redox-active molecule via another access z. B. is introduced a lateral or vertical access to the dielectric, no pore system of the second electrode is necessary.
  • the invention is not limited to this.
  • conventional ink for use in a printing process can be used to make a device for the electrochemical detection of analytes by redox cycling. This is preferably biofunctionalized.
  • a biomodified, dielectric ink can thus advantageously be present on the active region of the first electrode after step a).
  • this ink contains in step b) nanoparticles, z. Polymethyl methacrylate, polystyrene, silica, titania, and so on which are optionally loaded with antibodies, DNA, aptamers, or the like, as the active material.
  • the nanoparticle size should not be smaller than possibly existing pores in the first electrode, so that the nanoparticles do not penetrate into the electrode layer.
  • Biofunctionalized ink should only be sintered to such an extent (thermally, photonically, UV or by another method) that the biochemical units, such as antibodies, DNA, aptamers and the like, do not lose their biological recognition properties and, in particular, do not denature.
  • a sintering method must be used which does not damage the biological material.
  • Dielectric nanoparticles of an ink are preferably biofunctionalized with the following elements: • Full antibodies (eg: total IgG, IgG1, IgG2, IgG3, IgG4, IgM, IgD, IgA, IgA1, IgA2, IgE) either recombinant or human, mouse, rat, goat, rabbit or porcine antibodies.
  • Full antibodies eg: total IgG, IgG1, IgG2, IgG3, IgG4, IgM, IgD, IgA, IgA1, IgA2, IgE
  • Antibodies bound to protein A, protein G and protein L as a biorecognition element are bound to protein A, protein G and protein L as a biorecognition element.
  • Fragment antibody Fab 'fragment
  • F ab'
  • Fragment antibody generated enzymatically (eg cysteine, papain, pepsin, ficin, bromelain) or by photonic activation.
  • Enzymes that are either electrochemically active (such as glucose oxidase) and convert a substrate into a redox-active molecule that can then be amplified by redox cycling.
  • the material of the substrate is preferably selected from glass, silicon, various polymers such. Polyethylene naphthalate, polyetherethylene terephthalate, polyimide, polymethylmethacrylate, polycarbonate, and so on.
  • the electrodes are preferably made of gold, platinum, silver, carbon in various forms (carbon nanoparticles, graphite, graphene, carbon nanotubes, diamond, etc.), conductive polymers such as carbon nanoparticles.
  • conductive polymers such as carbon nanoparticles.
  • poly (3,4-ethylenedioxythiophene) polystyrene sulfonates, polyaniline etc.
  • redox-active molecules and analytes by means of redox cyclings.
  • This detection can be carried out by the immobilization of antibodies, DNA, aptamers, etc. on one or both of the electrodes and / or on the dielectric or the dielectric layer.
  • an analyte containing not only redox-active molecules, but also the containing complementary antigens, DNA, etc. these will specifically bind to the immobilized antibody, DNA, aptamers and so on.
  • the surface available for the electrochemical reactions is reduced.
  • the diffusion path of the redox-active molecule is prolonged by the blockade caused by the specific bonds. This leads to a change in the redox cycling current, which can be measured with a potentiostat. Since the blocked surface scales with the concentration of complementary antigens, DNA, etc., such a sensor can be used as a quantitative immunosensor.
  • the method presented here solves the problem by selecting a biomodified nanoparticle-containing ink from the outset in the arrangement of the dielectric layer, which in the subsequent, ie z. B. after sintering, has their biological function.
  • a device for the electrochemical detection of molecules by redox cycling in which a first, electrically conductive electrode is arranged on a substrate, on the first electrode a biofunktionalformate, porous dielectric layer is arranged, in which the pores to lead to the surface of the first electrode, and on the dielectric layer, a preferably porous second, electrically conductive electrode is disposed, wherein the nanoparticles of the second electrode, and the ink for the second electrode are larger than the pores in the dielectric.
  • the second electrode is pore-free and access of the redox-active molecule is via another access to the dielectric, e.g. B. lateral.
  • the term pores in the present patent application is defined as follows. Pores in the dielectric layer and / or in the electrodes are preferably not pinhole-like or prickly.
  • the pores are due to the printing process and in particular due to an ink jet printing process and due to an optionally subsequent sintering, preferably of a spongy nature.
  • the production method according to the invention thus requires sponge-like pore systems in the dielectric or in the electrode (s).
  • the pores should be distributed as equally as possible in the electrode (s) and / or the dielectric.
  • the pores in one of these layers can either be ordered, e.g. B. by a plurality of channel-shaped, continuous pores (variety greater than 2 pores) or by hexagonal arrangement of the nanoparticles and formation of the pores.
  • the pores can also be disordered (eg spongy porosity).
  • the particles from the upper layer should preferably always be larger than the pores of the underlying layer.
  • the pore size of the first electrode is preferably 0 to 50 nm in diameter.
  • the pore size in the dielectric is preferably 10 to 1000 nm in diameter.
  • the pore size of the second electrode is preferably 100 to 10,000 nm in diameter.
  • the second electrode as an alternative to a pore system, only a single large, z. B. annular opening may be arranged as access for the redox-active molecule.
  • a porous dielectric may consist of a spongy scaffold of optionally partially melted and non-conductive particles traversed by pores leading from the surface of the dielectric to the opposite surface to the first electrode.
  • a porous electrode in particular a porous second electrode on the dielectric
  • An access of the molecule is then possible by applying a solution with molecules on the surface of the second electrode and the pore system of the second electrode and the dielectric up to the first electrode.
  • a redox-active molecule, which is applied to the surface of the second electrode of such a sensor thus passes through the pore system of the second electrode and the pore system of the dielectric to the surface of the first electrode and can be implemented alternately. It can be reduced and oxidized according to the applied voltages on the surfaces of the two electrodes.
  • z. B. a lateral access z. B. on the passivation layer no pores in the second electrode in the active region are necessary.
  • the use of the at least partially printed redox cycling sensors is in the range of the direct detection of chemical analytes, in particular for the detection of antigens.
  • FIG. 1 A method according to the invention.
  • Figure 2 A device according to the invention.
  • a sensor with sponge-like pores in the second electrode and in the dielectric is produced by means of the method described above.
  • the conductive structures of the gold ink are printed on a polyethylene naphthalate (PEN) substrate 1 with an ink jet printer and then sintered at 125 ° C for 1 hour. In this way, a first electrode 2a is formed on the substrate 1, which either has no pores or pores with a maximum size of 20 nm.
  • PEN polyethylene naphthalate
  • FIG. 1 Shown in FIG. 1 is a right-hand region of the electrode 2 a, which defines the active measuring range for the conversion of the redox-active substance (not shown).
  • a left-hand portion of sintered gold ink 2b is shown on the substrate 1 to which a voltage is applied and thus constitutes a trace.
  • the region 2a of the first electrode runs out of the image plane to the right and is contacted with a potentiostat to apply voltage.
  • a polyimide ink is chosen. With the aid of this ink, approximately 100 ⁇ 100 ⁇ m 2 recesses 5 * are defined in the ink-jet printing as electrode regions, as shown in the right-hand part of FIG. 1 (active region).
  • the polyimide ink is arranged to passivate the first electrode 2a. As a result, the right active region of the first electrode 2a is passivated by the region 5 * .
  • the passivation ink 3a, 3b is thereby printed as a passivation layer around the later dielectric 5, so that an area 5 * for the later dielectric 5 is recessed.
  • polyimide also a part of the conductor 2b made of gold is passivated.
  • the polyimide layer 3c is arranged on the printed circuit 2b such that the printed conductor is partially exposed on the side facing the first electrode 2a and a step-shaped arrangement of polyimide 3c and printed circuit 2b results on substrate 1.
  • the passivation layers 3a, 3b and 3c are arranged in a single process step. It goes without saying that the regions of the first electrode 2a and the printed conductor 2b lying in the image depth are completely passivated.
  • Step b) Non-bio-modified polystyrene nanoparticle ink with nanoparticles of 100 nm size is deposited in the recessed area 5 * of the passivation 3a, 3b in FIG active area of the sensor arranged by ink jet printing. Due to its porosity, this dielectric 5 or this layer 5 forms a reservoir for the molecule or the analyte / redox mediator in solution and to be reacted. This layer has dimensions of about 100 m ⁇ 100 ⁇ m at a height of 500 nm.
  • the dielectric 5 is sintered at 115 ° C for 5 min, so that a homogeneous nanoporous layer 5 formed by the partial fusion of the particles.
  • the pore size is about 30 nm in diameter.
  • the ink is also partially printed on the passivation layer 3a, 3b as well as on the dielectric 5 in the region of the first electrode 2a and also in the inactive region of the sensor shown on the left in FIG. 1 and further contact points for the second electrode in FIG Form area 4b over the conductor 2b.
  • the ink is sintered at 125 ° C for 1 hour.
  • the pore size is about 100 nm in diameter.
  • the left part of FIG. 1 shows a further, particularly advantageous embodiment of the method and of a device produced in this way.
  • This left-hand area is the so-called inactive area of the sensor.
  • the inactive area comprises the track 2b made of gold, which runs out of the image plane to the left (not shown).
  • the conductor 2b is contacted with a potentiostat (not shown).
  • a voltage z. B. above the oxidation potential of the molecule or analyte / Redoxmediators be applied to the active region of the second electrode 4a, which leads to the oxidation of the molecules / the analyte at the electrode. Accordingly, a voltage which is below the reduction potential of the analyte and thus enables the alternating redox cycling process is applied to the active region of the first electrode 2a.
  • the detection can also be carried out the other way round, so that the Reduction potential on the electrode 4a and the oxidation potential is applied to the electrode 2a.
  • B. Ferrocendimethanol is brought in the form of a solution on the electrode (oxidized or reduced).
  • the lower, first electrode in region 2a and the upper, second electrode 4a are respectively contacted and set to an oxidizing potential of +600 mV and reducing potential of 0 mV against an Ag / AgCl reference electrode.
  • the detection of the analyte in different concentrations is carried out by measuring the redox cycling current at the oxidizing and / or reducing electrode.
  • a second sensor with sponge-like pores in the dielectric and the second electrode is produced as follows using a method described above (FIG. 1): Step a) and c) and the passivation follow those in Embodiment 1.
  • the gold ink conductive structures are printed on a polyethylene naphthalate (PEN) substrate 1 with an ink jet printer and then sintered at 125 ° C for one hour. In this way, a first electrode 2a is formed on the substrate 1, which either has no pores or pores with a maximum size of 20 nm.
  • PEN polyethylene naphthalate
  • FIG. 1 Shown in FIG. 1 is a right-hand region of the electrode 2 a, which defines the active measuring range for the conversion of the redox-active substance (not shown).
  • a left-hand area of sintered gold ink 2b is shown on the substrate 1, which serves for the application of voltage and thus represents a conductor track.
  • the region 2a of the first electrode runs out of the image plane to the right and is contacted with a potentiostat to apply voltage.
  • Passivation A polyimide ink is chosen. With the aid of this ink, approximately 100 ⁇ 100 ⁇ m electrode areas are defined as recess 5 * in inkjet printing, as shown in the right-hand part of FIG. 1 (active area).
  • the polyimide ink is arranged to passivate the first electrode 2a.
  • the right active region of the first electrode 2a is passivated by the region 5 *, the later reservoir.
  • the passivation ink 3a, 3b is printed as a passivation layer around the later dielectric 5, so that an area 5 * for this dielectric 5 is recessed.
  • polyimide also a part of the conductor 2b made of gold is passivated.
  • the polyimide layer 3c is arranged on the printed circuit 2b such that the printed conductor is partially exposed on the side facing the first electrode 2a and a step-shaped arrangement of polyimide 3c and printed circuit 2b results on substrate 1.
  • the passivation layers 3a, 3b and 3c are arranged in a single process step. It goes without saying that the regions of the first electrode 2a and the printed conductor 2b lying in the image depth are completely passivated.
  • the polystyrene nanoparticles are equipped with anti-ovalbumin antibody and used as a dielectric 5 or intermediate layer between the two electrodes 2a and 4a.
  • the ink is printed in the area 5 * which has been recessed by the passivation layer 3a, 3b to define the active area of the electrodes 2a, 4a.
  • the dielectric 5 is heated at 40 ° C for 30 min so that the solvents evaporate but the biological material is not damaged and maintains its function.
  • the pore size corresponds approximately to that of the first embodiment.
  • the pore size corresponds approximately to that of the first embodiment.
  • the inactive area thus otherwise corresponds to the inactive area of the first exemplary embodiment, and also the contacting of the first electrode 2a and the generated printed conductor 2b below the contact area 4b are identical.
  • the left part of FIG. 1 thus shows a further, particularly advantageous embodiment of the method and of a device produced in this way.
  • This left-hand area is the so-called inactive area of the sensor.
  • the inactive area comprises the track 2b made of gold, which runs out of the image plane to the left (not shown).
  • the conductor 2b is contacted with a potentiostat (not shown).
  • a voltage z. B. above the oxidation potential of the molecule or analyte / Redoxmediators be applied to the active region of the second electrode 4a above the dielectric 5, resulting in the oxidation of the molecules / the analyte at the electrode.
  • a voltage is applied to the active region of the first electrode 2a which lies below the reduction potential of the analyte and thus enables the redox cycling process.
  • the detection can also be performed in reverse, so that the reduction potential is applied to the electrode 4a and the oxidation potential to the electrode 2a.
  • a solution with ovalbumin and a redox mediator such. B ferrocene dimethanol is placed on the surface of the second electrode 4a.
  • the lower electrode 2a and the upper electrode 4a are respectively contacted and set to an oxidizing potential of +600 mV and a reducing potential of 0 mV against an Ag / AgCl reference electrode.
  • the detection of the analyte in different concentrations will be done by measuring the redox cycling current. At higher concentrations of ovalbumin, the redox cycling current will decrease because the available electrochemical surface also decreases with concentration.
  • FIG. 2 shows a schematically illustrated device in the active region, which is simplified compared with FIG. 1, and the cyclic conversion of an analyte at a first electrode 22a or bot. and a second electrode 24a or top. El. and their arrangement in the potentiostat.
  • the porous dielectric 25 Arranged between the two electrodes is the porous dielectric 25, which serves as a reservoir for the analyte / redox mediator in solution. Voltages are applied to the porous second electrode 4a and the first electrode 2a, which drive the cyclic redox reaction. The generated current is correspondingly measured against the counter electrode (counter electrode).
  • a nanoscale redox cycling sensor is thus produced only by means of printing technologies without additional etching steps or sacrificial layers, optionally also with biomodification without further steps.
  • the object is achieved by a design having arranged in the Z-axis superimposed electrodes having a nano-scaled dielectric between the electrodes, wherein the electrodes and / or the dielectric is completely printed. There are advantageously no etching steps in the method. This is achieved by the fact that the three layers (first first lower conductive electrode, second dielectric layer, third second upper conductive electrode) show different porosity. Each additional layer has larger particles than the underlying layer, so that the top layer 4a can not flow into the underlying layer 5 during deposition from the liquid phase (e.g., ink jet printing) and out of layer 5, not into layer 2a.
  • the liquid phase e.g., ink jet printing
  • an inkjet printer OJ300 from UniJet (Korea) was used.
  • the substrate - Teonex (PEN) was obtained from DuPont-Teijin Films (England).
  • the gold ink - Au25 was obtained from UT Dots (USA).
  • Polymer inks such as polyimide (PI) PMA-1210P-004 were obtained from Sojitz (Japan). Polystyroinanoparticle ink was mixed by itself from 200 nm polystyrene beads from Polysciences (USA).
  • Karbontinte 3800 was obtained from the company Methode (USA). Further embodiments:
  • the nanoporous dielectric can be provided as follows:
  • a non-bio-modified sol-gel-based ink is prepared.
  • TMOS 1: 1: 1 parts by weight
  • glycerol is mixed with deionized water and glycerol in a 100 ml bottle and stirred for one hour with magnetic stirrer on a magnetic disk at room temperature.
  • the sol-gel ink will be in the recessed area
  • the dielectric 5 or the layer 5, 25 forms by its porosity after hydrolysis and curing, the reservoir for the molecule in solution and to be reacted or the analyte / redox mediator.
  • This layer has dimensions of about 100 pm x 100 pm at a height of about 500 nm.
  • the dielectric 5, 25 is sintered at room temperature for 60 minutes, so that a homogeneous nanoporous layer 5 is formed by the condensation reaction in the printed sol-gel layer.
  • the pore size is then about 20-40 nm in diameter. It is understood that other sol-gel materials that undergo acid-catalyzed and / or base-catalyzed condensation reaction and hydrolysis may be used by those skilled in the art.

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Abstract

La présente invention concerne un procédé de fabrication d'un dispositif de détection électrochimique de molécules au moyen de cycles redox, ainsi qu'un dispositif permettant la mise en oeuvre dudit procédé et son utilisation. Une couche diélectrique poreuse, qui peut absorber les molécules à activité redox et qui est éventuellement biofonctionnalisée, se trouve entre deux couches électrodes. es couches individuelles sont de préférence appliquées au moyen d'un procédé d'impression à jet d'encre.
EP16726763.2A 2015-05-08 2016-04-09 Procédé de fabrication d'un dispositif de détection électrochimique de molécules au moyen de cycles redox, dispositif permettant la mise en oeuvre dudit procédé et son utilisation Withdrawn EP3295162A1 (fr)

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DE102015005781.2A DE102015005781A1 (de) 2015-05-08 2015-05-08 Verfahren zur Herstellung einer Vorrichtung zum elektrochemischen Nachweis von Molekülen mittels Redox-Cycling, sowie Vorrichtung hierzu und deren Verwendung
PCT/DE2016/000154 WO2016180385A1 (fr) 2015-05-08 2016-04-09 Procédé de fabrication d'un dispositif de détection électrochimique de molécules au moyen de cycles redox, dispositif permettant la mise en oeuvre dudit procédé et son utilisation

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