WO2016032335A1 - Micropipette ou micro-aiguille microfluidique comportant un capteur à nano-intervalle pour des applications analytiques - Google Patents

Micropipette ou micro-aiguille microfluidique comportant un capteur à nano-intervalle pour des applications analytiques Download PDF

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Publication number
WO2016032335A1
WO2016032335A1 PCT/NL2015/050601 NL2015050601W WO2016032335A1 WO 2016032335 A1 WO2016032335 A1 WO 2016032335A1 NL 2015050601 W NL2015050601 W NL 2015050601W WO 2016032335 A1 WO2016032335 A1 WO 2016032335A1
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Prior art keywords
layer
electrode
substrate
nanogap
needle
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PCT/NL2015/050601
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English (en)
Inventor
Liza RASSAEI
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Technische Universiteit Delft
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Publication of WO2016032335A1 publication Critical patent/WO2016032335A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14546—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring analytes not otherwise provided for, e.g. ions, cytochromes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
    • A61B2562/02—Details of sensors specially adapted for in-vivo measurements
    • A61B2562/0285—Nanoscale sensors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1468—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means
    • A61B5/1473—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means invasive, e.g. introduced into the body by a catheter
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6846—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
    • A61B5/6847—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive mounted on an invasive device
    • A61B5/685—Microneedles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y15/00—Nanotechnology for interacting, sensing or actuating, e.g. quantum dots as markers in protein assays or molecular motors

Definitions

  • MICRONEEDLE OR MICROPIPET COMPRISING A NANOGAP SENSOR FOR ANALYTICAL
  • the invention relates to a sensor device, especially comprising a substrate such as a (micro) needle.
  • the invention further relates to a measurement apparatus comprising such sensor device.
  • the invention also provides the use of electrochemical redox cycling within a sensor unit of such sensor device.
  • the invention also relates to a method for producing such sensor unit, especially such sensor device.
  • the invention also relates to a design of such sensor unit and sensor device.
  • a base having a sensing region is provided along with a plurality of nano-sensors.
  • Each of the plurality of nano- sensors is formed by forming a first nanoneedle along a surface of the base, forming a dielectric on the first nanoneedle, and forming a second nanoneedle on the dielectric layer.
  • the first nanoneedle of each sensor has a first end adjacent to the sensing region of the base.
  • the second nanoneedle is separated from the first nanoneedle by the dielectric and has a first end adjacent the first end of the first nanoneedle.
  • the base is provided with a fluidic channel.
  • the plurality of nano-sensors and the fluidic channel are configured and arranged with the first ends proximate the fluidic channel to facilitate sensing of targeted matter in the fluidic channel.
  • WO 96/25088 describes an insertion set for transcutaneous placement of a sensor such as a glucose sensor at a selected site within the body of a patient.
  • the insertion set comprises a slotted insertion needle extending through a mounting base adapted for mounting onto the patient's skin.
  • a flexible thin film sensor includes a proximal segment carried by the mounting base and defining conductive contacts, unnumbered, adapted for electrical connection to a suitable monitor, and a distal segment protruding from the mounting base with sensor electrodes for transcutaneous placement.
  • the distal segment of the sensor extends within a protective cannula, a portion of which is slidably disposed within the insertion needle. Placement of the mounting base onto the patient's skin causes the insertion needle to pierce the skin for transcutaneous placement of the cannula with the sensor therein.
  • the method is suited for the study of ultra small-volume systems such as the content of individual biological cells or organelles.
  • the nanochannel between the elctrodes was fabricated using a sacrificial Cr layer of 200 nm thickness that was etched by wet Cr etchant.
  • nanogap electrodes-based biomolecular measurements that can minimize electrode polarization effects since the double layers overlap and potential drop inside of the electrode gap can be reduced in nanoscale ( ⁇ 100 nm) electrode spacing.
  • the nanogap electrodes are fabricated applying a thermal oxidation layer and successiveively etching the layer by a buffered HF solution.
  • Transducers capable of transducing redox active chemical signals into electrical signals are described.
  • Transducers comprise two electrodes separated by a nanogap. At least one electrode is comprised of conducting diamond. Methods of fabricating nanogap transducers and arrays of nanogap transducers are described. Arrays of individually addressable nanogap transducers can be disposed on integrated circuit chips and operably coupled to the integrated circuit chip.
  • a problem with state of the art methods for measuring e.g. neurotransmitters is that such measurements often include an offline measurement, meaning the sample is taken from the subject and analyzed using normal lab equipment, or using micro needles which have an electrode at the end.
  • the electrode may have to be modified using different complicated strategies to be sensitive to analytes of interest in presence of undesired interferences, such as ascorbic acid. Further, the sensitivity is not very high. For environmental samples, although few handheld devices are available, most of the analysis are carried out in the lab and require big sample volumes and expensive equipment.
  • the invention provides a sensor device (“device”) comprising a substrate, especially a needle (even more especially a micro needle) with a needle tip, wherein the substrate, especially the needle, even more especially the needle tip, comprises a sensor unit, wherein the sensor unit includes a stacked layer structure including an electrode layer, wherein the stacked layer structure further includes a nanogap dividing the electrode layer in a first electrode and a second electrode with the nanogap in between, wherein the nanogap especially has a width (w) selected from the range of 10-500 nm, such as from the range of 20-200 nm, and wherein in a specific embodiment the substrate, especially the needle, further comprises a microfluidic channel structure with an orifice, wherein the orifice is especially arranged at the needle tip, for delivery or extraction of a fluid.
  • the sensor device, especially the sensor unit may be configured to sense (an analyte in) the fluid.
  • the sensor device comprises a substrate comprising a sensor unit, wherein the sensor unit comprises: (i) a base layer comprising an electrically insulating material; (ii) a stacked layer structure, with optionally one or more layers between the base layer and the stacked layer structure, the stacked layer structure comprising an adhesion layer; an electrode layer, with optionally one or more layers between the electrode layer and the adhesion layer; and an insulating layer comprising electrical insulating material, with optionally one or more layers between the insulating layer and the electrode layer; wherein the stacked layer structure is divided into two parts with a nanogap interposed between the two parts, with one part comprising a first electrode and with the other part comprising a second electrode and wherein the electrode layer is divided in the first electrode and the second electrode with the nanogap in between, wherein the surfaces of the two electrodes facing each other are mutually of equal size, wherein the width (w) of the nanogap is selected from the range of 10-500 nm.
  • a horizontal nanogap electrode As the nanogap especially divides the electrode layer, more especially substantially the entire stacked layer structure, a horizontal nanogap electrode is provided.
  • horizontal based nanogap sensors In contrast to vertical nanogap based sensors (wherein a gap is provided by etching a (sacrificial) layer between two elctrode layers) horizontal based nanogap sensors are much easier to make, and can be applied on many more substrates than the vertial nanogap sensors.
  • a horizontal based nanogap sensor e.g. may be applied on a needle-like substrate, especially alowing to transport a fluid.
  • a needle-like substrate may comprise a (micro) needle, especially a (micro) needle tip.
  • a needle-like substrate may also comprise a pipet (or pipette), especially a pipet tip. Also there is more freedom in choosing materials for the respective layers of the stack (for a horizontal nanogap electrode in comparison to a vertical nanogap electrode).
  • the sensor unit comprises a horizontal nanogap (or "horizontal nanogap electrode”).
  • the horizontal nanogap electrode divides the stack in two parts. The first part and second part are especially essentially identical in layer sequence and layer heights as they originate from the same (undivided) stack. Further, the two electrode layers, divided by the nanogap, may especialy be essentially identical in layer height and layer composition.
  • the first and the second parts may not comprise an identical layer sequence or layer height.
  • Such embodiment may e.g. be provided if one or more of the layers comprise a pluarility of materials and the materials are not homogeneously distributed over the layer.
  • Such an embodiment may also e.g. be provided if the layer thicknes changes over one of the dimensions of the layer.
  • the first and the second parts are substantially identical in layer structure and layer heights. Because of the fabrication method, substantially no dead volume is present in the sensor (wherein in a vertical nanogap sensor the fabrication procedure inherently may provide a zone where the two electrodes do not overlap).
  • the electrode layer is not necessarily divided in two halves (by the nanogap), though in general the cross-section (parallel to the layers) will be substantially equal.
  • the introduction of the nanogap provides two electrodes that have no direct physical contact, and there is (thus) no electrical contact between the two electrodes (unless an external circuit is generated, see below).
  • more than two electrodes may be provided.
  • the electrodes are especially provided from one electrode layer.
  • the horizontal nanogap sensor thus especially comprises two parallel electrodes in the same plane.
  • a vertical nanogap sensor especially comprsies two parralel electrodes in two different (parallel) planes.
  • the present sensor unit may be very sensitive (see also below), more sensitive than prior art sensors.
  • the sensor unit may make use of electrochemical redox cycling within the nanogap between the first electrode and the second electrode of the sensor unit, espeically for analysis of a first fluid.
  • first fluid is herein used to indicate the fluid that can be analyzed by the sensor unit; for instance, this can be a fluid that is extracted by a microfluidic channel structure (which may be comprised by the device, see below).
  • the microfluidic channel may comprise the sensor unit.
  • the sensor unit may be configured in the microfluidic channel.
  • a fluid (flowing) through the channel may flow along, especially over, the sensor unit, even more especially over (or along) the nanogap.
  • the microfluidic channel may be smaller than the sensor unit. Especially through the microfluidic channel a fluid may be extracted or provided near the sensor unit.
  • electrochemical redox cycling is applied.
  • This approach relies on two electrodes to reduce and oxidize redox-active molecules (i.e. all molecules that can donate or accept electrons) repeatedly and reversibly.
  • redox-active molecules comprises, e.g., many (biological) compounds, such as many enzymes, proteins, amines, metabolites, neurotransmitters, anti-oxidants, vitamins, sulfides, oxides, etc..
  • redox-active molecules may comprise proteins, amines, metabolites, neurotransmitters, anti-oxidants, vitamins, sulfides and oxides.
  • redox- active molecule may also comprise nano particles, quantum dots and any (redox-active) labelled molecules See also below for more specific examples.
  • Each analyte molecule may thus contribute several thousand electrons to the faradic current, amplifying the detected signal.
  • Electrochemical redox cycling is naturally suited for use in nanogap configuration since the degree of amplification increases by decreasing the separation between the two electrodes. Hence, especially the nanogap width is in the range of 20-200 nm.
  • each target molecule may travel between electrodes repeatedly, and reversibly changes its charge state with each electrode interaction.
  • a potential most commonly a DC potential that varies linearly in time
  • the resulting current from the redox process is measured as a function of potential.
  • concentration magnitude of the current at a certain potential
  • Electrochemical redox cycling requires at least two working electrodes (the herein indicated first electrode and second electrode).
  • the electrodes are biased at sufficiently cathodic and anodic potentials relative to the formal potential of the given reaction versus a reference electrode.
  • the product of the reduction at one electrode can diffuse to the other electrode where it can undergo oxidation and vice versa.
  • the sensor unit can be used for analysis of the presence of a predetermined (bio)molecule in said first fluid.
  • the (bio)molecule may comprise a neurotransmitter, such as a neurotransmitter selected from the groups of: amino acids, such as one or more of glutamate, aspartate, D-serine, ⁇ -aminobutyric acid (GABA), glycine; amines, such as one or more of dopamine (DA), norepinephrine (noradrenaline; E, NA), epinephrine (adrenaline), histamine, serotonin (SE, 5-HT); trace amines: such as one or more of phenethylamine, N-methylphenethylamine, tyramine, 3-iodothyronamine, octopamine, tryptamine, N,N-Dimethyltryptamine; peptides, such as one or more of somatostatin, substance P, cocaine and amphetamine regulated transcript, opioid peptides; and others, such as one or more of acetyl, amino
  • the sensor unit can be very sensitive. Even samples of less than 10 ⁇ may be anaylised. Especially, the sensor unit can be used, for analysis of the presence of a predetermined (bio)molecule in said first fluid, wherein the (first) fluid may even have a volume of 1 nanoliter or less, especially less than 0.1 nanoliter.
  • the sensor device may also be used for the analysis of the first fluid, especailly on the presence of a (bio)molecule, wherein the analysis is performed as function of the delivery via the microfluidic channel structure of a second fluid.
  • a drug in brain fluid especially cerebrospinal fluid (CSF)
  • CSF cerebrospinal fluid
  • first fluid especially cerebrospinal fluid (CSF)
  • CSF cerebrospinal fluid
  • (also) another (bio) molecule may be introduced with a second liquid, and the response may be sensed (from the first fluid) with the sensor unit.
  • the use of the sensor device may (in an embodiment) be (used) for in vivo sensing or (in another embodiment) be (used) for ex vivo sensing.
  • the use may also include sensing in an apparatus, like a chormatographic apparatus, like an LC (such as LC, HPLC, such as LC-MS, or HPLC-MS), in an electrophoresis device, etc..
  • a chormatographic apparatus like an LC (such as LC, HPLC, such as LC-MS, or HPLC-MS), in an electrophoresis device, etc.
  • the sensor device may also be used for low volume samples and for chemical forensic applications, etc.
  • the term “sensor unit” may in embodiments also refer to a plurality of (identical or different) sensor units.
  • the sensor device may include a plurality of sensor units, like two or more different sensor units at a needle tip or other substrate.
  • the term “sensor device” may in embodiments also refer to a plurality of (identical or different) sensor devices.
  • the measurment apparatus may include a plurality of sensor devices, like two or more different sensor devices, such as an array of sensor devices, which may optionally be used to measure (in) the same first fluid.
  • the invention also provides a method integrating a measurement of analytes and an extraction or injection of a fluid, the method comprising (i) providing the sensor device as described herein, (ii) connecting an electronic measuring device to the sensor unit, (iii) providing a fluid transport through the microfluidic channel structure, and (iv) measuring an analyte.
  • the term "measuring” and similar terms herein may include a qualitative measurement and optionally also a quantiative measurement.
  • the outcome of a measurement or analysis may also be that the analyte is below the detection limit, and may thus be considered not to be avialable in the (first) fluid.
  • Such method may e.g.
  • the method comprises injecting a selected amount of a selected drug locally in a brain or in brain tissue and measuring e.g. the concentration of neurotransmitters.
  • an electronic measuring device may also comprise an analysis unit.
  • first fluid or “second fluid” especially refers to a liquid, such as a body liquid like blood or brain liquid.
  • the fluid may also include (waste) water, or a fluid (carrier) from a chromatograph, etc.
  • the sensor device may also be used for measurement of an environmental pollutant, such as in water, or for food control.
  • second fluid refers to another fluid, espcially a fluid that may be delivered via the microfluidic channel structure.
  • a fluid being extracted by via the microfluidic device may comprise the first fluid that may be analysed.
  • a fluid being extracted via the microfluidic device may only comprise another fluid, (especially the "second fluid” or “fluid") and especially not the "first fluid”.
  • the sensor device as described herein especially comprises the sensor unit.
  • This sensor unit may in a specific embodiment be integrated with a needle or a pipet tip.
  • the sensor unit may be attached to the needle or a pipet tip.
  • the needle (or pipet tip) is a specific example of a substrate.
  • the sensor device may optionally comprise a plurality of sensor units.
  • the sensor device especially, may comprise an array of sensor units.
  • the sensor unit may also be applied on other substrates and may also be used in other applications than herein described especially in relation to a needle, even more especially described herein in relation to a needle (or a pipet tip) with a microfluidic channel structure.
  • the substrate comprises a needle with a needle tip, wherein the needle tip comprises the sensor unit and wherein the needle further comprises a microfluidic channel structure with an orifice at the needle top for delivery or extraction of a fluid, especially the needle may comprise a hollow needle comprising the microfluidic channel structure.
  • the substrate comprises a pipet tip, especially a micro pipet tip, even more especially the tip of a micro pipet tip, comprising the sensor unit and a microfluidic channel structure with an orifice for delivery or extraction of a fluid.
  • the needle especially comprises a micro needle, i.e. having a tip that can be used to penetrate the skin, or even bone or scalp.
  • the micro needle has (a part having) a diameter of less than 200 ⁇ over a length of at least 300 ⁇ .
  • the micro needle includes a tip having these dimensions.
  • the tip may be used to penetrate a human or animal body, such as skin, skull, bone, etc..
  • a pipet tip especially comprises a micro pipet tip having these dimensions.
  • the sensor unit comprises a base layer, optionally an adhesion layer, an electrode layer, and optionally a (first) insulating layer, which are especially arranged as a stack (on the base layer).
  • one or more layers may be arranged to the base layer, opposite to the adhesion layer, optionally one or more layers may be arranged between any set of two layers (selected from the base layer, the adhesion layer, the electrode layer, and the insulating layer), and optionally one or more layers may be arranged to the insulating layer, opposite of the electrode layer.
  • the set or stack of the adhesion layer, the electrode layer, and the insulating layer indicate in essence the necessary layers, but one or more further layers may be available.
  • the adhesion layer may be available to allow adhesion of the electrode layer on the base layer (or support).
  • the adhesion layer may be configured to allow adhesion of the electrode layer on the base layer.
  • the adhesion layer may be configured to allow adhesion between the electrode layer and an optional layer arranged between the adhesion layer and the base layer. Especially the adhesion layer may allow adhesion between the base layer and the electrode layer. Further, in general also the insulating layer will be avialable. With suitable substrates, an (additional) base layer may not necessary and the stack may be provided on the substrate (whereby the substrate can be considered a type of base layer). The substrate, especially may provide the base layer. In a further embodiment the base layer is arranged on the substrate.
  • the base layer may especially comprise one or more materials selected from the group consisting of silicon, silicon oxide, mica, quartz, glass, and a polymer.
  • a substrate of such material may be used.
  • such needle may comprise e.g. steel, glass or a polymer.
  • a micro pipet tip is used as substrate, such substrate may comprise e.g. glass or polypropylene.
  • the base layer may be provided on the substrate.
  • the base layer especially comprises an insulating material.
  • the base layer can also be used as (second) insulating layer
  • the polymer as base layer may especially be polyimide (PI).
  • a base layer when a base layer is provided on a substrate, this base layer will (thus) in general comprise an electrically insulating material.
  • a (second) insulating layer may be provided on the base layer.
  • the substrate may be any material and the base layer, when applied to the substrate, is especially selected from the herein indicated materials.
  • the substrate may provide the base layer, i.e. comprise the base layer.
  • a base layer is configured (arranged) on the substrate, i.e. on part of the substrate (which may optionally also be somewhere internal in a cavity or channel of the substrate).
  • a stack may be provided of the adhesion layer, the electrode layer, and the insulation layer, though optionally the stack may include more layers (see above).
  • the stack layer structure comprises in an embodiment the adhesion layer, the electrode layer, and the insulation layer.
  • the stack layer structure comprises the electrode and the insulation layer.
  • the adhesion layer may especially comprise one or more materials selected from the group consisting of titanium, chromium and tantalum. Also combinations, such as alloys, may be used.
  • the adhesion layer may comprise a polymer. When a polymer is used as adhesion layer, this polymer layer will in general comprise an insulating material. Hence the adhesion layer may comprise electrical conductive material. Additionally or alternatively, the adhesion layer may comprise electrically insullating material. Hence, the adhesion layer may be electrically non- conductive or electrically conductive.
  • the electrode layer which may especially be arranged on the adhesion layer, may especially comprise one or more materials selected from the group gold, carbon, graphene, graphite, platinum, ruthenium, iridium, silver, rhodium, palladium, indium tin oxide, boron doped diamond, copper, zinc, and an electrically conductive polymer. Also combinations, such as alloys, may be used. If an electrically conductive polymer be used as electrode layer on a polymer adhesion layer (or directly on a polymer base layer), then these polymers are of course different, as they have different functionalities.
  • the base layer especially comprises one or more materials selected from the group consisting of silicon, silicon oxide, mica, quartz, glass, and polymer
  • the adhesion layer especially comprises one or more materials selected from the group consisting of titanium, chromium, tantalum and a polymer
  • the electrode layer especially comprises one or more materials selected from the group consisting of gold, carbon, graphene, graphite, platinum, ruthenium, iridium, silver, rhodium, palladium, indium tin oxide, boron doped diamond, copper, zinc, and an electrically conductive polymer
  • the insulating layer especially comprises one or more materials selected from the group consisting of silica, silicon nitride and a polymer.
  • the substrate comprises one or more materials selected from the group consisting of silicon, silicon oxide, mica, quartz, glass, and a polymer
  • the substrate comprises electrical conductive material and a base layer, especially the substrate comprises a steel needle comprising said base layer , and especially wherein the stacked layer structure (comprising the adhesion layer, the electrode layer and the insulation layer) is configured on said base layer.
  • the insulating layer (or insulation layer), which may especially be arranged on the electrode layer, comprises an electrical insulating material, especially one or more materials selected from the group of silica, silicon nitride and a polymer, especially PMMA.
  • the insulating layer may especially be applied to allow the electrode surfaces facing each other be accesible to the fluid and the other part of the electrodes not being accesible to the fluid. In this way, redox cycling and electrochemical reaction may only takes place in the nanogap.
  • the terms “insulating layer” (or “insulation layer”) or "first insulation layer” (or “first insulating layer”) refer to the (electrical) isulating layer on the electrode layer (or in fact on the first and the second electrode), i.e.
  • the optional second insulation layer may be arranged anywhere between the electrode layer and the substrate, in order to provide electrical insulation (or isolation) of the electrode layer (or in fact on the first and the second electrode) from the substrate, which may optionally electrically be conductive (like a steel micro needle).
  • the base layer may also be defined as a second insulating layer. Especially the base layer may function as a second insulating layer.
  • one or more layers between the base layer and the stacked layer structure may be available, such as an (extra) insulating layer.
  • one or more layers may be arranged between the base layer and the stacked layer structure.
  • one or more layers between the electrode layer and the adhesion layer may be avialable (when the adhesion layer is available).
  • one or more layers may be arranged between the electrode layer and the adhesion layer.
  • optionally (i) one or more layers between the insulating layer and the electrode layer, and/or (ii) one or more layers on the insulating layer may be available (i.e. opposite of the electrode layer).
  • one or more layers may be arranged between the insulating layer and the electrode layer, and/or (ii) one or more layers may be arranged on the insulating layer.
  • the stacked layer structure is divided into two parts with a nanogap interposed between the two parts, with one part comprising said first electrode and with the other part comprising said second electrode, wherein the surfaces of the two electrodes facing each other are mutually of equal size, wherein the width of the nanogap is selected from the range of 10-500 nm, especially 15-300 nm, such as 20-200 nm.
  • the nanogap may be substantially have rectangular cross-sections though the edges may be (slightly) slanted (due to the carving out of the nanogap with e.g. e-beam lithography.
  • the length of the nano gap may in embodiments be at least 200 nm, such as at least 500 nm, like especially in the order of 1 ⁇ or more, like at least 10 ⁇ , such as in the range of 0.5-100 ⁇ .
  • the height of the nanogap may in embodiments be in the order of 50 nm - 5 ⁇ , such as 50-1000 nm (i.e. 50 nm - 1 ⁇ ).
  • the length of the nanogap is larger, like at least 5 times larger than the width of the nanogap.
  • the nanogap is a through hole (i.e. even through the substrate ase layer).
  • the sensor unit may be arranged adjacent to the microfluidic channel structure.
  • the nanogap may be a side channel of a larger microfluidic channel structure.
  • the term "microfluidic channel structure" may refer to a structure comprising at least one microfluidic channel. However, the structure may include more than one channel.
  • the channel structure may include a channel for delivering a (second) fluid and a channel for extracting a fluid.
  • the channel structure includes an orifice at a needle tip, when a needle or needle-like substrate is applied.
  • the term "orifice” may also refer to a plurality of orifices, e.g. an orifice for extraction of a fluid and an orifice for introduction of a (second) fluid. In such embodiments, more than one orifice may be arranged at the needle tip.
  • the needle comprises a hollow needle comprising a microfluidic channel, or especially the microfluidic channel structure.
  • the microfluidic channel structure may also be arranged at the surface of the needle.
  • the sensor unit may be arranged anywhere at a substrate, such as a needle, especially the sensor unit may be arranged at a (micro) pipet tip. When the sensor unit is used to measure in the first fluid, then especially the sensor unit may be arranged at the tip.
  • the sensor unit may be configured anywhere downstream from an orifice of the channel structure.
  • a single channel may (consecutively) be used for extraction and delivery.
  • the invention provides the sensor device per se; the invention also provides a sensor device comprising a needle, which is an embodiment of the sensor device.
  • the invention also provides a sensor device comprising a micro pipet tip.
  • the sensor device will in general also include a reference electrode.
  • the reference electrode will especially be configured to be at a relative short distance, such as e.g. at a distance smaller than 5 mm, like smaller than 2 mm, such as smaller than 0.1 mm, from the sensor unit. However, for instance non-needle applications larger distances may also be possible.
  • the reference electrode is configured to allow the reference electrode and sensor unit be in contact with the same fluid.
  • the reference electrode may extend into the nanogap.
  • the reference electrode is not in direct physical contact with first electrode and second electrode.
  • the reference electrode may e.g.
  • an Ag/AgCl electrode a standard hydrogen electrode (SHE), a normal hydrogen electrode (HE), a reversible hydrogen electrode (RHE), a saturated calomel electrode (SCE), a copper-copper (II) sulfate electrode (CSE), a silver chloride electrode, a pH-electrode, a palladium-hydrogen electrode, a dynamic hydrogen electrode (DHE), and an iridium oxide reference electrode, etc.
  • the reference electrode may further comprise a quasi reference electrode.
  • the invention provides an integrated (bio) detection with microfluidic micro needles (or microfluidic pipet tips) for analytical application.
  • the invention further provides a new design of such sensor unit and sensor device.
  • the invention also provides a measurment apparatus comprising the sensor unit.
  • the invention provides a measurement apparatus comprising (i) an electrical power source, (ii) an analysis unit, and the sensor unit as defined herein, especially the sensor device as defined herein, wherein the electrical power source is configured to apply a potential difference between the first electrode and the second electrode (versus the reference electrode), and wherein the analysis unit is functionally coupled to the first electrode and the second electrode for measuring an electrical parameter.
  • the electrical parameter may be selected from the group consisting of a voltage change, a current, a current change, a resistance, a resistance change, etc.
  • the potential difference may be modulated with one or more frequencies. Further, optionally the potential difference may be varied in time.
  • the electrical parameter may also be measured as function of time and/or modulation(s).
  • the electrical power source and analysis unit may be a single device having the above indicated functionalities.
  • the electrical power source and analysis device are - during use of the measurment apparatus - functionally coupled to the first electrode and the second electrode, and also to the reference electrode.
  • the measurment apparatus comprises a plurality of sensor devices or sensor units
  • the electrical power source and analysis device are- during use of the measurment apparatus - functionally coupled to the first electrodes and the second electrodes, and also to the reference electrode(s).
  • the measurement apparatus comprises an electrical power source, an analysis unit, a microfluidic unit for controlling delivery or extraction of a fluid, and the sensor device as defined herein comprising a microfluidic channel structure, especially wherein the base layer comprises one or more materials selected from the group consisting of silicon, silicon oxide, mica, quartz, glass, and polymer, the adhesion layer comprises one or more materials selected from the group consisting of titanium, chromium, tantalum and a polymer; the electrode layer comprises one or more materials selected from the group consisting of gold, carbon, graphene, graphite, platinum, ruthenium, iridium, silver, rhodium, palladium, indium tin oxide, boron doped diamond, copper, zinc, and an electrically conductive polymer, and the insulating layer comprises one or more materials selected from the group consisting of silica, silicon nitride and a polymer, and wherein the electrical power source is configured to apply a potential difference between the first electrode and the second
  • such sensor device comprised by such measurement apparatus may (thus) also include the microfluidic channel structure, etc.
  • the measurment apparatus may further comprising a microfluidic unit for controlling - during use of the measurement apparatus - delivery or extraction of said fluid.
  • the phrase "for controlling delivery or extraction of said fluid” may also refer to controlling delivery and (controlling) extraction of said fluid.
  • the sensor unit may be configured to sense such fluid, e.g. measure one or more analytes.
  • the invention also provides a method for producing the sensor device as defined herein, the methode comprising: (i) providing a substrate; (ii) providing an adhesion layer on at least part of the substrate; (iii) providing an electrode layer on at least part of the adhesion layer; (iv) providing an insulating layer on the electrode layer comprising electrical insulating material; and (v) generating a nanogap in the thus obtained stack to provide two separate electrodes, the nanogap having a width selected from the range of 10-500 nm.
  • the invention provides a method for producing the sensor device as defined herein, the method comprising: (i) providing a (needle like) substrate, wherein the substrate especially comprises one or more materials selected from the group consisting of silicon, silicon oxide, mica, quartz, glass, and a polymer (such as polyimide); (ii) optionally providing an adhesion layer, especially comprising one or more materials selected from the group consisting of titanium, chromium, tantalum, and a polymer, on at least part of the substrate; (iii) providing an electrode layer, on at least part of the adhesion layer, the electrode layer especially comprising one or more materials selected from the group gold, carbon, graphene, graphite, platinum, ruthenium, iridium, silver, rhodium, palladium, indium tin oxide, boron doped diamond, copper, zinc, and an electrically conductive polymer; (iv) optionally providing an insulating layer on the electrode layer comprising electrical insulating material, especially comprising
  • the layer stack including the electrode layer and especially one or more of (a) the adhesion layer at one side of the electrode layer and (b) the insulating layer at the other side of the electrode layer) to provide two separate electrodes (with a nanogap in between), the gap especially having a width (w) selected from the range of 10-500 nm, wherein in specific embodiments the (needle like) substrate comprises a microfluidic channel structure or wherein after generation of the thus obtained sensor unit a microfluidic channel structure is applied to the (needle like) substrate.
  • the method comprising (i) providing a substrate comprising a base layer comprising an electrically insulating material; (ii) providing a stacked layer structure, with optionally providing one or more layers between the base layer and the stacked layer structure, the stacked layer structure comprising (1) an adhesion layer, (2) an electrode layer, with optionally one or more layers between the electrode layer and the adhesion layer; and (iii) an insulating layer comprising electrical insulating material, with optionally (i) one or more layers between the insulating layer and the electrode layer; and (iv) generating a horizontal nanogap in the thus obtained stack to provide two separate electrodes, the nanogap having a width (w) selected from the range of 10-500 nm.
  • the substrate comprises a microfluidic channel structure or especially a microfluidic channel structure is applied to the substrate before, during or after generation of the thus obtained sensor unit.
  • the microfluidic channel structure is applied to the substrate after generation of the thus obtained sensor unit.
  • the gap may in specific embodiments be provided by one or more of e-beam lithography, focused ion beam lithography and stepper lithography, etc.. Altyernatiely or additionally, the gap may be provided by one or more of nanoskiving and nano imprint lithography.
  • the substrate may in an embodiment comprise a base layer.
  • the base layer especially comprises one or more materials selected from the group consisting of silicon, silicon oxide, mica, quartz, glass, and a polymer.
  • At least part of the substrate may be configured as the base layer.
  • Especially at least part of the substrate may be configured as the base layer if the substrate comprises electrically insulating material.
  • the substrate may comprise a (additional) base layer if the susbstrate comprises electrical conductive material, especially if the substrate comprises steel.
  • an adhesion layer may be arranged on the base layer or substrate.
  • the electrode layer may be arranged, and thereon the insulating layer. In this way the stack is provided.
  • the generation of the layers may be done with techniques known in the art, like conventional layer depositon techniques. Furhter, lithography may be used.
  • the method may further include arranging a reference electrode on the substrate (optionally on a base layer) and/or on the final insulating layer. Further, the method may include arranging electrical connections, like conductive pads, to the sensor device to allow a functional coupling between the electrodes and an electrical power source and/or an anysis unit. In this way, an electrode system may be created, including the first electrode, the second electrode, a reference electrode and contacts. In comparison to vertical nanogap sensors, the horizontal nanogap sensor production requires less lithographic steps.
  • the vertical nanogap sensor production requires at least 4 photolithographic steps, such as 4-6 steps, whereas the horizontal nanogap sensor may in embodiments require only 2-3 photolitographic steps.
  • the (gap) size between the electrodes size may be smaller, since the fabrication method is not hindered by a minimum sacrificial layer thickness that may be required to provide a good step coverage on the first electrode during the fabrication of the vertical nanogap.
  • the horizontal nangap sensor may allow better integration with many different substrates.
  • substantially herein, such as in “substantially consists”, will be understood by the person skilled in the art.
  • the term “substantially” may also include embodiments with “entirely”, “completely”, “all”, etc. Hence, in embodiments the adjective substantially may also be removed.
  • the term “substantially” may also relate to 90% or higher, such as 95% or higher, especially 99% or higher, even more especially 99.5% or higher, including 100%.
  • the term “comprise” includes also embodiments wherein the term “comprises” means “consists of.
  • the term “and/or” especially relates to one or more of the items mentioned before and after "and/or”.
  • a phrase “item 1 and/or item 2" and similar phrases may relate to one or more of item 1 and item 2.
  • the term “comprising” may in an embodiment refer to “consisting of but may in another embodiment also refer to "containing at least the defined species and optionally one or more other species”.
  • the invention further applies to a device comprising one or more of the characterizing features described in the description and/or shown in the attached drawings.
  • the invention further pertains to a method or process comprising one or more of the characterising features described in the description and/or shown in the attached drawings.
  • Figs, la-lc schematically depict some embodiments and aspects
  • Figs. 2a-2c schematically depict some embodiments and aspects in more detail
  • Fig. 3 shows the SEM picture being a basis for Fig. la.
  • the schematic drawings are not necessarily on scale.
  • Fig. la schematically depicts an embodiment of a sensor unit 100, wherein the sensor unit 100 comprises a base layer 111 and a stacked layer structure 110 (herein also indicated as stack) comprising an adhesion layer 112, an electrode layer 115 and an insulating layer 117.
  • the stacked layer structure 110 further includes a nanogap 116 dividing the electrode layer 115 in a first electrode 115a and a second electrode 115b with the nanogap 116 in between, wherein the nanogap 116 has a width w, such as selected from the range of 10-500 nm.
  • the stacked layer structure 110 or stack is divided in two parts by the horizontal nanogap. In Fig. la, these parts are substantially identical in layer composition and layer heights.
  • the height of the nanogap 116 is indicated above.
  • Reference 111 indicated a base layer, which may in embodiments be the substrate 11 10 or a layer on such substrate 1110.
  • the base layer 111 is arranged on the substrate 1110 (whereas in figure lb the substrate provides the base layer).
  • the length (1) of the nanogap 116 is in this schematically depicted embodiment larger than the height (h) or width (w).
  • the stack 110 schematically depicted in Fig. la is also depicted in Fig. lb, with an adhesion layer 112, an intermediate electrode layer 115, and the (final) insulating layer 117.
  • the sensor unit 100 may especially be used to analyze a fluid 99, especially a first fluid 199 in fluid contact with the nanogap 116.
  • a fluid 99, 199, and 299 are used to refer respectively to a fluid (in general), a first fluid (to analyze), and a second fluid (e.g. deliverable via the microfluidic channel), see also below.
  • Reference 1110 thus indicates a substrate, such as a (steel) needle or a micro pipet tip (see also below) that may either provide the base layer 1 11 or a base layer 1 11 may be provided on the substrate 1110. Especially a base layer on the substrate may be provided, especially when the substrate 1110 is electrically conductive.
  • Reference 112 indicates an adhesion layer, such as Ti. Such layer may be necessary when the electrode layer 115 does not adhere well enough to the base layer 111 or any optional extra layer (not shows).
  • Reference 115 indicates the electrode layer (see above), which may e.g. comprise gold and/or platinum. The redox cycling between the two electrodes 115a and 115b is schematically indicated with the arrows within the nanogap 116.
  • Reference 117 indicates an insulating layer (herein also indicated as first insulating layer). Electrode contacts are - for the sake of clarity - not depicted. However, this is state of the art technology.
  • the lower part of the Fig. la is based on a photograph (SEM picture), which is also shown in Fig. 3.
  • the insulating layer 117 is used to shield the electrodes from the environment except for the electrode surfaces arranged opposite to each other which (amongst others) define the nanogap 116.
  • Reference 170 indicates the surface of the substrate 1110.
  • Fig. la is a schematic drawing. In general, the insulating layer 117 will cover the entire electrode layer, and also the edges thereof (not shown in these schematic drawings). In this way, only the electrode surface in the nanogap 116 is available for electrode reactions.
  • Fig. lb schematically depicts a specific application, wherein a light transmissive substrate 1110, such as glass or mica is applied.
  • the base layer 111 may be the substrate 11 10.
  • the substrate 1110 is considered to provide the base layer 111.
  • the base layer may comprise an electrically insulating material.
  • Reference 50 indicates a fluorescence microscope, which is in this picture schematically indicated to measure in fluorescence mode. However, transmissive and reflective modes may also be applied.
  • an analysis of the first fluid 199 may be performed by means of redox cycling while simultaneously the analysis may be studied by microscope.
  • Reference 120 indicates a reference electrode out of plane for clarity.
  • Reference 130c indicates an insulated electrical wire in electrical contact with the reference electrode 120.
  • Each layer may independently from the other layers include multi-layers. Further, for instance, on top of the (first) insulating layer 117, more layers may be available. Hence, one or more layers may be arranged to the insulating layer, opposite of the electrode layer. Alternatively or additionally, also further layers may be available between this insulating layer 117 and the electrode layer 115, etc.
  • the layers at both side of the nanogap are substantially identical in order and layer heights.
  • the stacks 110 in Figs la and lb are by way of example substantially identical.
  • the (insulating) base layer 111 is arranged between the substrate 1110 and the stack, whereas in the embodiment of Fig. lb this extra layer is absent, e.g. because the substrate 1110 may already comprise the electically insulating material.
  • Figs, la/lb and the other drawings depict the nanogap 116 as a gap with a closed bottom side, being e.g. the substrate 1110 or baselayer 110. However, optionally the nanogap 116 is a through hole (i.e. even through the substrate/base layer).
  • Fig. lc schematically depicts an embodiment of the measurement apparatus 2 comprising a sensor unit 100.
  • the measuring apparatus 2 may comprise more than one sensor unit 100, such as an array of sensor units 100 (not depicted). Additionally or alternatively, embodiments of the measuring apparatus 2 may also comprise one or more sensor devices 10.
  • Reference 30 indicates an electrical power source and reference 35 indicates an analysis unit. Note that these may also be included in a single apparatus.
  • References 140 indicate contact pads, for functional connection with the electrodes 115a and 115b and the reference electrode 120.
  • Reference 200 refers to a microfluidic structure, and reference 201 to a channel comprised by such structure.
  • Reference 202 indicates an orifice.
  • the channel structure may e.g. be used to introduce a fluid 99, especially a second fluid 299.
  • the microfluidic channel 201 is schematically depicted as small channel. The channel 201 may especially be larger.
  • the sensor unit 100 may be configured within a channel such as the microfluidic channel 201. Especially, a fluid 99 flow through the channel 201 may flow along, especially over the sensor unit 100, especially the nanogap 116.
  • Reference 40 indicates a microfluidic unit; configured to control one or more of introduction and or extraction of a fluid 99 (second fluid 299 and first fluid 199, respectively). Also the micro fluid unit 40 may optionally be integrated in the analysis unit 35.
  • a needle 10 as substrate 1110 is depicted.
  • the needle includes a tip 11.
  • the sensor unit 100 is shown in an enlargement, in a cross-sectional view thereof. Further, by way of example only the first electrode 115a and second electrode 115b are indicated at the tip 11.
  • Figs. 2a and 2b schematically depict embodiments of an embodiment wherein the substrate 1110 comprises a (micro) needle 10 comprising a channel structure 200 for providing or extracting a fluid 99.
  • the needle 10 with needle tip 11 comprising the sensor unit 100 (for the sake of clarity only the location is indicated and especially peripheral devices for measuring etc. are not shown).
  • the channel(s) 201 may be enclosed by the needle 10 (Fig. 2a). Alternatively (or additionally) the channel(s) 201 may be provided to the needle surface, as is the case in fig. 2b.
  • Reference 202 indicates an orifice for fluid extraction or introduction (of fluid 99).
  • FIG 2c an embodiment wherein the substrate comprises a micro pipet tip 20 is schematically depicted.
  • the micro pipet 20 comprises a microfluidic structure 200 for transporting a fluid 99 and comprising a channel 201 and an orifice 202 and may e.g. be connected to a micro pipet 25 or another microfluidic unit 40.
  • the micro pipet tip 20 may comprise e.g. glass or other materials, especially polypropylene.
  • the micro pipet tip may comprise the sensor unit 100 and other peripheral devices (not depicted for clarity reason).
  • miniaturized analytical devices are required for on-field environmental monitoring or clinical point-of-care.
  • the current on-chip electro analytical systems rely on microelectrodes. Although their small sizes facilitate their incorporation in analytical systems and miniaturization, the small size results in difficulty to measure low analyte concentrations due to the low signal to noise level.
  • a way to circumvent such problems is to employ electrochemical redox cycling in nano confinement space.
  • a resultant high sensitivity is due to the repetitive oxidation and reduction of a redox molecule achieved by closely spacing two independently biased electrodes (one biased at oxidation and the other at reduction potentials). Due to the Brownian motion, one molecule shuttles between the electrodes and contributes to the current several thousand times before leaving the nanogap. As the current is proportional to the number of molecules (concentration) contributing to the signal, it can be, therefore, used for quantitative detection of molecules.
  • the potential benefits of paired microelectrodes in gap devices include higher sensitivity and selectivity.
  • the feedback current is free of capacitive background current.
  • This method is the base for, e.g., the electrochemical scanning electron microscope, and recently vertical nanogap sensors.
  • the vertical nanogap devices need sophisticated fabrication process, the electrode materials are limited to mostly platinum and gold widely available in the cleanrooms, introducing surface corrosion and low stability under harsh anodic and cathodic conditions.
  • their vertical structures results in the buckling of the top electrode and their structure and complicated fabrication hinders their integration with other techniques such as optical spectroscopy.
  • the invention provides a horizontal electrochemical nanogap device that can be integrated on different platforms for a variety of applications. Because of the fabrication method, these new devices allow the use of other electrode materials such as carbon or graphene in addition to gold and platinum. Horizontal electrodes do not have the problem of buckling of one electrode. Integrating the horizontal nanogap sensor on a micro needle, enables for instance real-time electrochemical monitoring of neurotransmitters metabolism in the brain, the measurement of analytes in cells or organelles, or the measurement of different biomolecules in different body fluids. Integration in other platforms may be used for applications such as environmental monitoring, food safety control, etc. For instance such platform may comprise a micro pipet tip.
  • Neurotransmitters are the primary chemical messengers secreted from neurons that relay, amplify, and modulate signals to target cells, and accordingly regulate brain function.
  • a number of psychiatric and neurodegenerative diseases and several types of drug and alcohol abuse are directly connected to abnormalities in neurotransmitters metabolism.
  • the action of neurotransmitters depends on their overall levels as well as their short burst of activity. Therefore, the real time monitoring of neurotransmitters in extracellular space of the brain and in vivo monitoring of their concentration dynamics within neural tissue are crucial especially in various neurological disorders, such as Parkinson's disease, Alzheimer's disease, depression, addiction and chronic pain.
  • nanogap electrochemical redox cycling is the measurement of chemically reversible redox molecules in presence of chemically irreversible interferences.
  • clinically important neurotransmitters such as dopamine, serotonin, and glutathione can be detected in presence of ascorbic acid - being a major interference in monitoring neurotransmitters - despite the fact that the concentration of ascorbic acid is much higher.
  • the electrode layer may comprise metals like gold, platinum, etc., see also above. It also may comprise carbon and graphene. Carbon materials are more inert compared to platinum and gold and thus provide wider potential window and can be used for a wider range of applications. Moreover, carbon electrodes can be easily modified with a wide variety of molecules, e.g., diazonium molecules, mainly due to strong carbon bonds. The surface modification can be used to tune the selectivity for the redox molecules with similar oxidation or reduction potential.
  • a membrane can be added to the entrance of the nanogap device.
  • the small gap size already behaves as a nano filter, in order to avoid possible blocking of the electrode during implanting the device in brain tissues, a membrane such as cellulose acetate or other membranes is added to the entrance of the nanogap devices.
  • the charge of the membrane can be manipulated, to selectively control the molecules entering the nanogap device.
  • the structure of the proposed micro needles sensors allows further integration of a microfluidic channel.
  • the microfluidic channel allows controlled injection of, e.g., interested drug dosage. This way neurotransmitter's fluctuation upon controlled injection can be studied.
  • One such example is in in situ monitoring of drugs such as clozapine as antipsychotic drug for treatment of schizophrenia.
  • the integrated micro needle/nanogap with a microfluidic channel enables real-time monitoring of clozapine at the point of care so that its dosage may be regulated according to the test results. Therefore, in yet another embodiment the nanogap-integrated micro needle sensor, further comprises a microfluidic channel.
  • the nanogaps senor system is integrated with other analytical tools, such as optical tools, preferably a fluorescent microscope.
  • optical tools preferably a fluorescent microscope.
  • Using this kind of embodiments enables the profiling of the chemical reactions, e.g., pH change for protonated redox active molecules such as catechol/quinone, indigo carmine, and hydroquinone/benzo- quinone during redox cycling using pH sensitive fluorescent dyes.
  • the invention further applies to a method to fabricate one or more of the devices described in the description.
  • the carbon electrodes are fabricated of a photoresist followed by vacuum carbonization.
  • the carbonization temperature and pressure are optimized to obtain high quality conductive carbon electrodes (glassy carbon electrodes).
  • the nanogap in the graphene material is also provided with different methods such as electro burning (creating a gap by removing atom by atom carbon), e-beam, focused ion beam lithography or stepper lithography. Additionally, or alternatively the nanogap may be provided by nanoskiving or nano imprint lithography.
  • the new devices can be characterized by electrochemical methods using redox model molecules such as Ru( 1 ⁇ 4)6 and Fe(CN) 6 " " to evaluate the nanogap performance and its robustness.
  • redox model molecules such as Ru( 1 ⁇ 4)6 and Fe(CN) 6 "
  • the pH in the gap can also be modulated for few milliseconds using pulse potentials by solvent electrolysis.
  • nitric oxide can be oxidized to [nitric oxide] + with a nanosecond life time.
  • phosphate buffer pH 7 it can produce nitrosonium phosphate intermediate with a life time of 1 ms that can go under redox cycling.
  • nitric oxide is a product of decomposition of S- nitroso-L-Gluthathione, this can be potentially used for the analysis of S-nitroso-L- Gluthathione in blood.
  • electrochemical nanogap sensors are particularly important for applications in multi analytes detection in complex media such as blood analysis, food control, environmental or clinical monitoring.
  • the proposed sensor is attractive as it results in a rapid on-site or point of care measurement without the need for pretreatment and offline laboratory equipment.

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Abstract

L'invention concerne un dispositif capteur comportant un substrat, en particulier une aiguille avec une pointe d'aiguille, dans lequel le substrat, en particulier l'aiguille, même plus encore en particulier la pointe de l'aiguille, comporte une unité de capteur, dans lequel l'unité de capteur comprend une structure de couches empilées comprenant une couche d'électrode, dans lequel la structure de couches empilées comprend en outre un nano-intervalle divisant la couche d'électrode en une première électrode et une deuxième électrode avec le nano-intervalle entre elles, dans lequel le nano-intervalle a une largeur (w) sélectionnée dans la plage allant de 10 à 500 nm, comme dans la plage allant de 20 à 200 nm, et dans lequel, dans un mode de réalisation spécifique l'aiguille comporte en outre une structure de canal microfluidique avec un orifice, dans lequel l'orifice est notamment agencé au niveau de la pointe de l'aiguille, à des fins d'administration ou d'extraction d'un fluide.
PCT/NL2015/050601 2014-08-30 2015-08-28 Micropipette ou micro-aiguille microfluidique comportant un capteur à nano-intervalle pour des applications analytiques WO2016032335A1 (fr)

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KR20180019451A (ko) * 2016-08-16 2018-02-26 성균관대학교산학협력단 고체 버블 및 마이크로 유체 시스템을 기반으로 한 이의 제조 방법
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WO2020234579A1 (fr) * 2019-05-23 2020-11-26 Imperial College Innovations Ltd Détecteur

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