WO2022018452A1 - Capteur à transistor organique à effet de champ à porte étendue - Google Patents

Capteur à transistor organique à effet de champ à porte étendue Download PDF

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Publication number
WO2022018452A1
WO2022018452A1 PCT/GB2021/051902 GB2021051902W WO2022018452A1 WO 2022018452 A1 WO2022018452 A1 WO 2022018452A1 GB 2021051902 W GB2021051902 W GB 2021051902W WO 2022018452 A1 WO2022018452 A1 WO 2022018452A1
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Prior art keywords
sensor
electrode
sensor electrode
region
gate
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PCT/GB2021/051902
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English (en)
Inventor
Shashi PANDYA
Olga EFREMOVA
Dominique RICHARDSON
Gowan-Hugh WALLEY
Rebecca DEY
Mahdi ARABNEJAD
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Neudrive Limited
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Publication of WO2022018452A1 publication Critical patent/WO2022018452A1/fr

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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
    • G01N27/403—Cells and electrode assemblies
    • G01N27/414—Ion-sensitive or chemical field-effect transistors, i.e. ISFETS or CHEMFETS
    • G01N27/4145—Ion-sensitive or chemical field-effect transistors, i.e. ISFETS or CHEMFETS specially adapted for biomolecules, e.g. gate electrode with immobilised receptors
    • 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
    • G01N27/307—Disposable laminated or multilayered electrodes
    • 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
    • G01N27/3271—Amperometric enzyme electrodes for analytes in body fluids, e.g. glucose in blood
    • G01N27/3272—Test elements therefor, i.e. disposable laminated substrates with electrodes, reagent and channels
    • 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
    • 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
    • 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

Definitions

  • the present invention relates to an organic thin-film transistor-based sensor. More specifically, the present invention relates to a sensor arrangement comprising disposable sensor elements for the detection of target analytes including nucleic acid strands, proteins, peptides and others.
  • Target analytes may be small molecules and embodiments may provide a pH sensor in biologically relevant ranges.
  • Thin film transistors may be employed in capacitive sensor systems by using a gate electrode as a sensor, whereby changes in the environment of the gate electrode alter a source-drain current. If changes in the source-drain current are measureable then a measurement may be related to the presence or absence of a target analyte at the gate electrode.
  • Organic thin-film transistors or organic field effect transistors (OFET) are a type of thin film transistor comprising organic or polymeric layers.
  • OTFTs have been investigated for their suitability as gate electrode sensors.
  • several properties affect the versatility of such organic field effect transistors in practical scenarios.
  • One issue concerns the stability of OTFT devices and their materials when exposed to harsh chemical environments, such as the low acidity encountered in some biological samples or some food compositions.
  • organic field effect transistors tend to exhibit so-called “drift”, meaning a change of the baseline signal independently of the presence of target analytes at the gate electrode.
  • Reasons for this behaviour are believed to include the geometry of conductor connections, hysteresis effects, temperature fluctuations, sensitivity to light, and other influences. Such influences can alter baseline signals significantly more than a signal expected from a target analyte at the gate electrode.
  • the present invention is concerned with providing an improved sensor setup to at least partially mitigate the aforementioned difficulties.
  • the sensor arrangement comprises a transistor body comprising an organic field effect transistor, the organic field effect transistor comprising a source region, a drain region, and a gate region, and further comprising a sensor electrode attachment that is detachably connectable to the gate region to provide an extended gate sensor, wherein a part of the sensor electrode attachment is provided with a sensor electrode and another part of the sensor electrode attachment is provided with a reference electrode.
  • the sensor arrangement is connected or connectable to a driver/read-out device configured to drive (bias) the transistor regions (source/drain/gate regions) to maintain these at a known setting (voltage or current, respectively) and to obtain data from the transistor regions, respectively.
  • the read-out device may be integral with the sensor arrangement.
  • the read-out device may be remote and connectable via a wired or wireless data connection.
  • a detachably connectable sensor attachment is a component that can be removed from the sensor arrangement without practically affecting repeated use of the remaining device (e.g., the main transistor body) and is suitable as a consumable, such as a disposable sensor element, which may be a multi-use sensor element or a single use sensor element.
  • the detachably connectable sensor attachment may be constituted by a sample harvesting device that has been used to collect a sample or specimen for subsequent use with the sensor arrangement. As such, the sensor attachment may be brought in contact with a target analyte before being attached to the sensor arrangement. Alternatively, the sensor electrode attachment may be connected to the sensor arrangement before contacting a target analyte.
  • the sensor electrode attachment comprises a substrate, such as a sheet providing a support surface, on which the electrodes, such as a sensor electrode or a reference electrode, are provided in the form of conductive lanes.
  • the lanes will comprise a connector region to be attached to corresponding regions of the sensor arrangement and an exposed region.
  • the exposed region of the sensor electrode provides a sensing element.
  • the exposed region of the reference electrode exposes a reference electrode material for immersion in an analyte.
  • the area between the connector region and the exposed region may be covered by a non-conducting, or dielectric, material.
  • the sensor electrode and the reference electrode may be isolated from one another unless the exposed regions are brought into contact with conductive sample fluid.
  • the contacts may be at least partially surrounded by an isolating area that is non- conductive (dielectric), or inside an isolating housing, sufficiently large for a human finger to hold the disposable element without accidentally touching a conductive surface.
  • the non-conductive area may be at least 1 cm 2 or more.
  • the reference electrode may be located on the same substrate as the sensor electrode. This allows the sensor element to be used as a single disposable component together with a reference electrode.
  • the electrical contacts to the gate electrode and to the reference electrode may be arranged such that they can be connected in a single operation.
  • the electrical contacts may all be provided at one side, in particular at one edge, of the substrate, in the manner of an electrical plug or multi-pin connector.
  • the electrical contacts may be provided at one surface (top or bottom) of the substrate. This allows a contact region to be provided for a simple connection to the sensor arrangement.
  • the reference electrode may be manufactured by evaporation, etching, screen printing, photolithography, chemical vapour deposition (CVD), sputtering, electrodeposition, or other suitable methods.
  • the reference electrode is understood to comprise a different material composition to the sensor electrode.
  • the sensor electrode may comprise gold (Au) and the reference electrode may comprise silver/silver chloride (Ag/AgCI).
  • substrates are provided with a heat-stabilising layer as a coating that is often referred to as a “planarising layer”, to provide a heat-stabilised substrate, typically before the conductor lane material is deposited.
  • the heat-stabilising layer improves heat stability to allow the substrate to be exposed to temperatures over about 100°C, and reduces shrinkage and blooming effects (‘blooming’ being the migration of small oligomers towards the substrate surface during heating).
  • the heat-stabilising layer is intended to also provide a smoother, more planar, surface than the underlying substrate compared to a substrate without “planarising layer”.
  • Materials used as heat-stabilising coatings are typically organic materials, e.g., sol-gel derived coatings based on siloxane chemistry, or polyfunctional acrylate coatings.
  • the sensor element is characterised by a substrate layer comprising a heat-stabilising layer for both the gate (i.e., sensor) electrode and the reference electrode.
  • the same heat-stabilising layer material may be used for the gate (sensor) electrode and for the reference electrode.
  • the gate and reference electrodes may be located on the same heat-stabilising layer.
  • a surface of the sensor electrode is provided with a self- assembled monolayer.
  • Self-assembly molecules are, typically, elongate molecules with two end groups: a head group and a functional group.
  • the head group is a region of the molecule to attach to a carrier surface to immobilise thereon.
  • the functional group is a region of the molecule not attached to the carrier surface and therefore available for reacting with its surroundings. The functional group tends to stick away from the carrier surface, such that a large number of self-assembly molecules tend to arrange themselves in the form of what could be described as ‘bristles’.
  • Functionalising a detachable sensor electrode attachment avoids the need for functionalising a component that is integrated with the main transistor components.
  • the sensor arrangement comprises a transistor body comprising an organic field effect transistor, the organic field effect transistor comprising a source region, a drain region, and a gate region, and further comprising a sensor element provided with a sensor electrode that is detachably connectable to the gate region of the transistor body.
  • a surface of the sensor electrode is provided with a self-assembled monolayer.
  • a recognition region is provided by moieties of molecules constituting the self-assembled monolayer.
  • the expression “moiety” is understood to refer to regions of a molecule.
  • the moieties may be the terminal (free) ends of the molecules constituting the self-assembled layer.
  • specificity to a particular target analyte, such as a target ion or target molecule may be integral with a moiety of the self-assembly molecules of a layer, particularly with their functional groups.
  • the moieties may be ion-sensitive.
  • the moieties may be capable of protonation and deprotonation.
  • a self- assembly molecule may comprise a carboxyl group that can alter between a protonated state (-COOH) and a de-protonated state (-COO ) depending on the number of hydrogen ions in its environment (i.e. , depending on the pH).
  • the affinity to a target molecule i.e. the energy balance that favours either attachment or removal of a target molecule from the sensor molecule, may be altered by the choice and/or design of the functional groups of the monolayer molecules.
  • the recognition region of the sensor electrode is an area with an affinity for a target analyte.
  • the moieties may be designed to be pH-sensitive in a pre-defined range, for instance, the monolayer may be changing the current at an operating voltage of -0.2 V to -1.0 V corresponding to a pH range from 2 to 12.
  • Embodiments may be able to measure a pH as low as pH 2, pH 2.5, pH 3, pH 3.5, pH 4, pH 4.5, pH 5, pH 5.5, pH 6, or pH 6.5.
  • Embodiments may be able to measure a pH as high as pH 10, pH 9.5, pH 9, pH 8.5, pH 8, pH 8.5, pH 7.5, or pH 7.
  • Embodiments may measure pH increments in steps (resolution) smaller than a single pH, eg. smaller than pH 0.1, pH 0.2, pH 0.25, pH 0.3, pH 0.4, pH 0.5.
  • embodiments may measure a pH range of 5 to 8.5 with increments (with a resolution) of 0.5.
  • a recognition region is provided by capture molecules attached to the self-assembled monolayer.
  • the self-assembled layer is an intermediate layer for attaching (e.g., conjugating or anchoring) a capture molecule via the self-assembled layer to the sensor electrode.
  • a capture molecule is understood to be a molecule with an affinity for a target molecule that is higher than an affinity for non-target molecules.
  • the attachment will be in the form of a covalent chemical bond. Other suitable attachment mechanisms may be used.
  • the capture molecules are linked to the monolayer after formation of the monolayer.
  • the recognition region comprises a molecule selected from the group of: deoxyribonucleic acid (DNA), ribonucleic acid (RNA), enzymes, peptides, ionophores, molecularly imprinted polymers, proteins and their fragments, antibodies, aptamers, sequences that are at least partially complementary to any one or more thereof, or antibodies specific to any one of or more thereof.
  • DNA deoxyribonucleic acid
  • RNA ribonucleic acid
  • enzymes enzymes
  • peptides peptides
  • ionophores molecularly imprinted polymers
  • proteins and their fragments proteins and their fragments
  • antibodies aptamers, sequences that are at least partially complementary to any one or more thereof, or antibodies specific to any one of or more thereof.
  • the binding of a molecule on an electrode gate alters the gate properties compared to a gate surface without a bound molecule.
  • the binding event creates a change that may be measured and correlated with the pH value at the sensor, with the redox state, and/or with the presence of a molecule.
  • a self-assembled monolayer By incorporating a self-assembled monolayer, this enables a possibility to arrange capture molecules in an ordered manner, further improving the signal-to-noise ratio of target molecules.
  • a carboxyl (-COOH) terminated self-assembled layer may capture an amine (-NH2) moiety of another molecule.
  • amine (-NH2) moiety may be provided on a 5’ end of single strand nucleic acid that is to be used as capture molecule.
  • nucleic acid capture molecules are bound with their 5’ end to the self-assembled layer.
  • the self-assembled layer seems to also provide a certain level of shielding against random deposition and against random orientation of target molecules.
  • the recognition layer achieves not only the selective capture of target molecules, but also that the molecules are captured in an expected orientation. The inventors appreciated that this effect may be exploited to further improve the signal uniformity across different sensor electrode attachments.
  • the sensor electrode attachment comprises a flexible substrate.
  • a substrate of the sensor element can be suitable for both the gate electrode material and the reference electrode material.
  • Example substrate materials comprise polyethylene terephthalate (PET), polyester film, polyethylene naphthalate (PEN), polycarbonate (PC), polyethersulphone (PES), aromatic fluorene containing polyarylates (PAR), or polyimide (PI).
  • PET polyethylene terephthalate
  • PEN polyethylene naphthalate
  • PC polycarbonate
  • PES polyethersulphone
  • PAR aromatic fluorene containing polyarylates
  • PI polyimide
  • the substrate materials can be provided as a flexible sensing element, in particular as a Tollable sensor element.
  • the thickness of a flexible substrate layer, or substrate film may be in the region of several 10 pm to several 100 pm, ranging from 25 pm to 1,000 pm.
  • a typical flexible substrate thickness may be 50 pm or 75 pm. This is about one or two orders of magnitude thinner than glass substrates which may have a thickness in the region of 1 mm.
  • flexible sensor element it is meant that the substrate can be subjected to bending as defined by a roll test, repeatedly, without for practical purposes suffering a loss in performance.
  • a roll test such as the “Flex-E test” (Austrian Academy of Sciences, 8700 Leoben, Austria). The Flex-E test involves driving a flexible substrate (sheet) around rolls of a pre-defined radius, e.g.
  • 1 mm roll radius simulating a bending/unbending, and/or simulating bending from a plane at a first angle into a first direction, bending at a second angle into another direction opposite the first direction, and bending back into the plane, and allowing multi-layer films to be subjected to both compression forces (at the inner roll radius) and tension forces (at the outer roll radius).
  • the forces can be repeated over multiple cycles, e.g. 1000, 5000 or 10000 cycles to bring about material defects leading to performance loss.
  • An example metric for performance loss may be the behaviour of an OTFT sheet, e.g. a change of turn-on voltage or drain current, of OTFTs on a sheet substrate before and after rolling.
  • a performance loss may be observed, for instance, after formation of cracks resulting in discontinuities of electrode lanes. Tests of the applicant’s OTFT devices showed a performance loss of less than 5 % after 10,000 cycles (bending/unbending) with a 1 mm bend radius. It will be understood that the performance loss may depend on the bend radius, number of rolls and number of changes of bending direction, the layer thickness, type, number and material composition, temperature and other factors. “Flexible” substrates as understood in the art are differentiated particularly over rigid substrates such as glass substrates which are for practical purposes unable to maintain performance after having been subjected to a 1 mm bend angle.
  • Flexible substrates as understood herein may have a performance loss of less than 30% after being subjected to 100 cycles of a roll test with a 2 mm radius, or stricter criteria.
  • the performance loss may be less than 25%, 20%, 15%, 10%, or less than 5%.
  • the number of cycles may be 100, 500, 1000, 5000, or 10000.
  • the roll radius for a test may be 0.5 mm, 1 mm, or 2 mm.
  • the substrate layer is no thicker than 1000 pm, 900 pm, 800pm, 700 pm, 600 pm, 500 pm, 400 pm, 300 pm, 200 pm, or 100 pm.
  • a sensor element that is flexible can be more readily incorporated with medical equipment, such as wound dressings, flexible wall pouches, collection bags and the like, as well as with wearable devices (“wearables”).
  • a flexible substrate allows for a relatively larger element to be provided than a rigid substrate material. By being able to provide a larger surface area of the sensor component, this may allow a larger number of sensor electrodes to be provided, a number of sensor electrodes to be distributed over a larger area, and/or providing a longer connector region to the gate electrode.
  • the sensor electrode comprises a layer thickness sufficient to provide an electrode surface that is smoother than an electrode-carrying surface beneath.
  • a sensor electrode comprising a layer thickness of at least 15 nm, 20 nm, 30 nm, 40 nm, 50 nm, 60 nm, 70 nm, 80 nm, 90 nm, 100 nm, 150nm, 200 nm, 0.3 pm, 0.4 pm, 0.5 pm, 0.6 pm, 0.7 pm, 0.8 pm, 0.9 pm, 1 pm, 1.1 pm, 1.2 pm, 1.3 pm, 1.4 pm, or at least 1.5 pm.
  • the substrate is typically provided with a heat-stabilising layer to improve heat stability (when exposed to temperatures above about 100°C), scratch resistance, and shrinkage prevention and/or hygroscopic expansion relative to a substrate layer without heat-stable layer, before electrode material is provided on the substrate.
  • the heat- stabilising layer therefore constitutes the electrode-carrying layer that is directly beneath the electrode.
  • An example material suitable as a heat-stabilising layer is polyethylene terephthalate (PET, such as Melinex® ST504 obtainable from DuPont Teijin Films U.S., Chester, VA, USA).
  • Other materials, such as polyethylene naphthalate (PEN) may be used so long as they are thermally stable, to withstand a temperature of at least 100°C.
  • a heat-stabilising layer may indeed exhibit a rougher surface than the pre-stabilised substrate, i.e. the surface topology of the heat-stabilising layer comprises, in a profile section, more vertical variation than was measurable in the underlying substrate prior to heat-stabilising (see Figure 6 and accompanying description below). This is surprising because one of the purposes of a heat-stabilising layer is conventionally believed to include the smoothing of the underlying surface.
  • the surface roughness of a PET film substrate is typically in the region of a few nanometres (3-4 nm to 20 nm).
  • a heat-stabilising layer may have a surface roughness (of the heat-stabilising layer as applied on the PET substrate surface) in the region of 40-100 nanometres.
  • the surface roughness may be measured with conventional surface profilometry such as interferometry, or atomic force microscopy.
  • An electrode material such as gold typically conforms to the roughness of the underlying substrate.
  • An observation made by the inventors was that a gold layer deposited on the heat-stabilising layer, when deposited in a gold (electrode) layer thickness of about 10 nm, was often rougher than the underlying PET substrate.
  • Depositing a thicker layer of electrode material helped to even out surface unevenness of the underlying substrate surface. This allows a smoother electrode surface to be provided. This in turn is believed to assist in the formation of a self-assembled monolayer, when the electrode surface is so thick to be sufficiently smooth to be suitable as a substrate for a self-assembled monolayer.
  • the particular surface roughness and electrode layer thickness applied to achieve a desired degree of electrode surface roughness may depend on the materials used as the substrate, as the heat protective layer, as the electrode layer, and on the type of self-assembly molecules. For instance, a gold electrode layer of about 100 nm thickness resulted in a gold electrode surface roughness of about 4 nm even though the heat-stabilising layer, i.e. the electrode-carrying layer underneath, had a surface roughness in the region of 40-100 nm.
  • a typical layer thickness of silver/silver chloride (Ag/AgCI) paste may be in the region of a few micrometres, for instance between 6 pm and 10 pm.
  • the sensor electrode attachment comprises a fluid passage in which a surface of the sensor electrode is located.
  • the fluid passage may be provided by a structure on the sensor electrode attachment.
  • the structure may be integral with the sensor electrode attachment.
  • a fluid channel may be provided on the sensor element to pass across one or more sensor electrodes.
  • An example material for a fluid channel is PDMS (polydimethylsiloxane), which is suitable because of its compatibility with sensor element substrate materials and its non-conductive properties. However, other materials may be used.
  • the integrated fluid passage may provide an “on-the-chip” sensor electrode with defined fluid flow characteristics.
  • An integrated fluid passage may improve the signal quality by reducing fluid flow effects.
  • the sensor arrangement comprises a plurality of sensor electrodes.
  • the sensor electrodes are, typically, electrically isolated from each other unless immersed in a conductive medium, such as a sample fluid to be measured.
  • the sensor arrangement may comprise an array of organic field effect transistors, each comprising a gate region connectable to a sensor electrode to be provided. It will be understood that in many instances a separate transistor element will be used in the sensor arrangement for each gate electrode that is to be operated, each transistor element with a source region, a drain region arranged to measure a change at its gate region, when connected with the sensor element. However, in some arrangements a transistor element may be used with a plurality of gate electrodes measurable in parallel.
  • the sensor element comprises one or more sensor electrodes without a self-assembled monolayer.
  • a sensor electrode attachment may comprise at least one sensor electrode with a self- assembled monolayer and at least one sensor electrode without a self-assembled monolayer.
  • a sensor electrode that is not provided with a self-assembled monolayer may be used as a negative control electrode.
  • one or more sensor electrodes are provided with a self- assembled monolayer comprised of different molecules than another sensor electrode of the sensor element.
  • this allows a control sensor electrode to be provided.
  • This allows a reference signal, and/or a baseline noise level, to be measured contemporaneously with another sensor electrode, to provide a possibility to correct for signal variations arising from thermal variation, drift, or other influences.
  • a negative control sensor electrode may be inert, or practically insensitive to the target molecule.
  • the control electrode may be practically insensitive to protonation and deprotonation in the pH region of the sensor electrode.
  • this allows one or more positive control sensor electrodes to be provided.
  • the positive control sensor electrodes may comprise a different density (higher or lower) of capture molecules or capture molecules with a different affinity (higher or lower) for a target analyte. This allows a qualitative measurement to be combined with a quantitative measurement.
  • the baseline control element may be sensitive to the target molecule, but may have a different affinity to the target molecule. This may allow differences in attachment dynamics and detachment dynamics to be observed.
  • two or more of the sensor electrodes, or one or more sensor electrodes and a reference electrode may be provided in the same flow passage.
  • a sensor electrode attachment as defined in claim 12, for use with a sensor arrangement according to the first aspect and/or according to the second aspect.
  • the sensor electrode attachment comprises a flexible substrate material, a heat- stabilising layer comprising a heat-stabilising layer surface on which there is provided a sensor connector region and a sensor electrode region conductively linked with the sensor connector region.
  • the sensor electrode attachment further comprises a reference electrode connector region and reference electrode region conductively linked with the reference electrode connector region.
  • a sensor electrode attachment as defined in claim 13, for use with a sensor arrangement according to the first aspect and/or according to the second aspect.
  • the sensor electrode attachment comprises a flexible substrate material, a heat- stabilising layer comprising a heat-stabilising layer surface on which there is provided a sensor connector region and a sensor electrode region conductively linked with the sensor connector region.
  • a surface of the sensor electrode is smoother than the heat- stabilising layer surface.
  • a surface of the sensor electrode region is provided with a self-assembled monolayer.
  • a sensor electrode attachment as defined in claim 15, for use with a sensor arrangement according to the first aspect and/or according to the second aspect.
  • the sensor electrode attachment comprises a flexible substrate material, a heat- stabilising layer comprising a heat-stabilising layer surface on which there is provided a sensor connector region and a sensor electrode region conductively linked with the sensor connector region.
  • a surface of the sensor electrode region is provided with a self-assembled monolayer.
  • the sensor element can be provided as a consumable, or disposable, component of the sensor arrangement.
  • the sensor element can be provided without transistor stack architecture, i.e. without source/drain regions and channel regions. The manufacture of a sensor element is therefore considerably simpler compared to an architecture integrated with a functionalised transistor.
  • an insulating layer may cover a region between the connector region and the sensor electrode region and/or the reference electrode, respectively. Electrode material is between the insulating layer (on top of the electrode material) and the substrate (beneath the electrode material).
  • a surface of the sensor electrode is smoother than the heat- stabilising layer surface.
  • the flexible substrate material has a flexibility characterised by a performance loss, if used as a OTFT substrate, of less than 30% of drain current after 100 cycles of a roll test with a 2 mm roll radius.
  • the sensor element comprises a plurality of sensor electrodes each sensor electrode conductively isolated from the other sensor electrodes. In some embodiments, different sensor electrodes are provided with different types of self-assembled monolayer.
  • the sensor electrode attachment is comprised in a medical apparatus, wound dressing, bandage, cast structure, implantable device, or prosthetic device.
  • the sensor electrode attachment is comprised in a wristband, watch, harness, strap, garment, cap, glove, head gear, in-ear piece, over-ear wearable, contact lens, or glasses.
  • Sensor electrode attachments according to the third, fourth and/or fifth aspects may be incorporated in wearable devices (“wearables”), for instance as a replaceable consumable.
  • the fourth aspect and/or the fifth aspect may comprise one or more of the features described in relation to the first aspect and/or the second aspect, as well as combinations thereof. Likewise, one or more features described in relation to the third aspect, the fourth aspect and/or the fifth aspect may be used in embodiments of the first aspect and/or the second aspect.
  • FIG. 1 shows an isometric view of a schematic setup of an organic field effect transistor (OFET) architecture
  • Figure 2 shows a schematic setup of a measurement device incorporating a detachable extended gate structure in accordance with embodiments of the invention
  • Figures 3A to 3C each show a top-view of a portion of a sensor electrode
  • Figure 4 shows a top view photograph of a dual-sensor electrode embodiment
  • Figure 5 shows a top view photograph of a batch of multiple pairs of sensor electrodes and reference electrodes
  • Figure 6 shows a graph illustrating the surface roughness of different substrate layers
  • Figures 7 A to 7C show exemplary steps in a sequence of functionalising a part of a surface of a sensor electrode
  • Figure 8 shows a schematic diagram of connections between a dual-sensor element according to Figure 4 and its connections to signal measurement units;
  • Figure 9 shows a graph illustrating a successive multi-sample measurement protocol
  • Figure 10 shows multiple graphs of samples measured, successively, in accordance with the Figure 9 protocol
  • FIG 11 shows multiple graphs of samples measured, successively, in accordance with the Figure 9 protocol
  • Figure 12 shows a graph illustrating another successive multi-sample measurement protocol
  • Figure 13 shows multiple graphs of samples measured, successively, in accordance with the Figure 12 test protocol using a sensor embodiment
  • Figure 14 shows a summed graph of the Figure 13 measurements combined
  • Figure 15 shows a graph comparing results of a DNA sample measurement series
  • Figure 16 shows a graph comparing results of a series of redox-active samples.
  • FIG. 1 shows a schematic illustration of a structure of an organic field effect transistor (OFET) 10.
  • the transistor 10 comprises, on a substrate layer 12, a source region 14, a drain region 16, an organic semiconductor layer 18, a dielectric 20 and a gate 22.
  • the architecture of the transistor 10 is a top-gate architecture as the gate 22 is located distally of the substrate layer 12. However, bottom-gate architectures may be used.
  • the transistor 10 is understood to be a three-terminal device, the three terminals being constituted by the source region 14, the drain region 16, and the gate 22.
  • the transistor 10 can be used as a switch and/or an amplifier.
  • the practical relevance in relation of the present disclosure is that changes in the electrical charge at the gate 22 affect, and practically amplify, the amount of current able to flow as source-drain current I S D between the source region 14 and the drain region 16.
  • small changes at the gate 22 can result in a large change of source-drain current I S D.
  • a gate bias voltage applied to the gate 22 (here: a negative voltage) induces a conducting channel across the semiconductor layer 18 (here: illustrated by positive charges 19).
  • the width of the channel layer is controlled by a gate voltage Vg applied on the gate 22.
  • Figure 2 shows a schematic illustration of a sensor arrangement designed to utilise a sensitivity of a gate layer 22a to monitor for changes of an environment in a sensing region 31 using an extended sensing pad 26, constituting a sensor electrode attachment.
  • elements corresponding to those in Figure 2 are provided with the same numeral as in Figure 1 and an additional suffix “-a”, without repeating the description thereof.
  • Figure 2 shows a transistor 10a that comprises a main transistor body 11a comprising a substrate layer 12a, a source region 14a, a drain region 16a, an organic semiconductor layer 18a, a dielectric 20a, and a gate layer 22a.
  • the gate layer 22a comprises a conductor link 24 effectively extending the gate surface, or the effective location of the gate surface, from the main transistor body 11a, to an extended sensing pad 26.
  • the extended sensing pad 26 is conductively connected to the gate layer 22a and therefore a surface of the sensing pad 26 constitutes an electrode surface of the gate layer 22a.
  • the sensing pad 26 is remote from the main transistor body 11a, extending into a sensing region 31.
  • the sensing pad 26 may be part of a probe to be brought into contact with a sample while avoiding contact of the sample with the main transistor body 11a.
  • the extended sensing pad 26 is located within a flow passage 30 constituting a measurement chamber.
  • the flow passage 30 is defined by channel walls that are non-conductive.
  • the flow passage walls may be constituted by dielectric material.
  • a reference electrode 28 Within the flow passage 30 there is provided a reference electrode 28.
  • the sensing pad 26 may not be integral with a flow passage.
  • the Figure 2 arrangement may be considered an extended gate field effect transistor (EGFET) because the sensing pad 26 is located not directly on the main transistor body 11a.
  • the sensing pad 26 may be a few centimetres, e.g. 5 cm, 4 cm, 3 cm, 2 cm, or 1 cm, from the main transistor body 11a.
  • the measurement chamber in the form of the flow passage 30 is arranged to receive the sensing pad 26.
  • the gate voltage V G is applied by way of a reference electrode.
  • the reference electrode may be a silver electrode located within the flow passage 30, allowing the voltage to be applied via the sample solution to the extended gate 22.
  • the reference electrode may be provided by a simple silver (Ag) wire or as Ag/AgCI reference electrode.
  • both the gate electrode and the reference electrode may be provided together on the same sensor element. This facilitates a contemporaneous connection of sensor elements and reference electrode upon attachment of a disposable sensing element.
  • the gate electrode and the reference electrode may be provided as separate elements, each separately connectable and/or disposable. For instance, a disposable Ag/AgCI reference electrode substrate may be used repeatedly for measurements made with different gate electrode elements.
  • the source-drain current I S D is measured in a practical manner by continuously measuring I S D and observing changes over time during introduction of an analyte into the flow passage 30.
  • the presence of an analyte may be measured by providing a sample on the sensing pad 26, or by placing the sensing pad 26 into a sample.
  • the reference electrode 28 is positioned in the flow passage 30 upstream of the extended sensing pad 26, i.e. it is arranged such that fluid is allowed to pass the reference electrode 28 before it passes the extended sensing pad 26.
  • the reference electrode 28 may be located downstream, or at practically the same location with reference to the flow direction, e.g. on opposite walls at the same location of the flow passage 30.
  • a gate voltage Vg can be applied via the reference electrode, relying on conductive properties of a sample fluid in the flow passage 30.
  • the sample fluid may be a sample fluid stationary in the flow passage 30 or passing through the flow passage 30. In the absence of a sample fluid there may be no conductive path between the sensing pad 26 and the reference electrode 28.
  • the transistor 10 may be designed to operate with a current range from about 50 mA to 100 pA with a gate voltage Vg of -1, or in another variant may be designed to operate with a current range from about 1 pA to 5 pA.
  • the main transistor bodies 10, 10a are a thin-film transistor (TFT), particularly an organic thin-film transistor (OTFT) and the electrodes (source, drain, gate) may be connectable by way of conductive regions on a substrate.
  • TFT thin-film transistor
  • ONT organic thin-film transistor
  • a typical electrode material is gold but other suitable electrically conducting materials may be used, such as aluminium, silver, copper, chromium, tungsten, and alloys thereof, as well as carbon or graphene.
  • the source- drain voltage V S D to the source-drain region is maintained constant.
  • the gate voltage Vg To calibrate the sensor, for instance to determine a useful sensing range of the sensor, it is practical to vary the gate voltage Vg and to measure a resulting transfer curve. It is understood that a transfer curve is a record of the resulting source-drain current I S D in response to the gate voltage Vg (gate bias) for a given source-drain voltage V S D.
  • the relation of I S D as a function V G at a given V S D may be presented or stored as a transfer curve.
  • the source-drain current I S D is monitored while applying a constant source-drain voltage V SD and a constant gate voltage V G . In some embodiments, it may be appropriate to maintain another one of the quantities constant and to measure a variation of a remaining variable.
  • a plurality of different transfer functions may be determined at different source-drain voltage levels V S D.
  • At least the main transistor body 11a, and optionally also the electrodes and/or the fluid passage are light-shielded, for instance by being located beneath a light-shielding structure, such as a light-shielding layer, or inside a light-shielded housing, to avoid effects on light-sensitive components.
  • Light exposure is expected to affect the transfer curve (transfer function), for instance light exposure may be indicated e.g. by a high turn-on voltage. If a high turn-on voltage can be related to light exposure (e.g. by observation), this behaviour of the transfer curve can be utilised to measure a degree of light exposure, or to confirm the adequacy of the light-shielding structure.
  • a window in a light-shielding structure may be noticeable in a transfer curve. This behaviour may be used to improve the light-shielding structure if required. Apertures may be maintained in the light-shielding structure if it is found that these are not practically affecting the transfer curve.
  • the extended sensing pad 26 comprises a physical connection via the conductor link 24 to the gate layer 22a.
  • the sensing pad 26 is not integrally connected with the transistor main body 11a. Rather, the sensing pad 26 is detachably connected with the gate layer 22a via a gate connection 23.
  • the physical connection is attachable and detachable repeatedly without impeding multiple use of the transistor main body 11a with different attachable sensing pads.
  • the gate connection 23 may be directly on the gate layer 22a or part of the gate layer 22a. The gate connection 23 may extend from the gate layer 22a, for instance for ease of handling.
  • connections may be attached manually for each connection by crocodile clips clamping a screen-printed pad, or bayonet connections.
  • other connections may be used.
  • the connection of the extended sensing pad 26 with the gate layer 22a can be made by a one-step actuation, in a single action in the manner of a plug/socket.
  • the extended sensing pad 26 constitutes a replaceable sensor electrode attachment.
  • the detachable connection allows the sensing pad 26 to be provided as a disposable or single-use component.
  • the sensing pad 26 can be removed for disposal, for re purposing and/or for further use, such as use in further analysis or for harvesting of captured sample molecules.
  • Figures 3A-3C each show a different top view of a portion of an electrode pad 40a-c with a conductor lane 42a-b (visible in Figures 3A and 3B).
  • the electrode pad 40a of Figure 3A might constitute a portion of the sensing pad 26 of Figure 2, and the conductor lane 42a (Figure 3A) might constitute a conductor link 24 ( Figure 2).
  • Figures 3A-3C show part of a gold (Au) electrode pad 40a, 40b, 40c provided on a heat-stabilised substrate layer 44 and connected with a gold (Au) conductor lane 42a, 42b.
  • the electrode pads 40a-c are generally circular (in the Figures, only part of the pad circle is visible).
  • the arrangements of Figures 3A -3C are covered with a dielectric material 48 with a layer boundary 50a, 50b, 50c. By design, it is typically intended that the dielectric material 48 covers the conductor lane, but leaves the electrode pads 40a- c exposed for use.
  • Figures 3A-3C show variations in the quality of the dielectric covering.
  • the dielectric material 48 covers practically the entire conductor lane 42a while leaving the electrode pad 40a exposed, and so the layer boundary 50a coincides with the pad- adjoining end of the conductor lane 42a and leaving a nearly perfectly circular electrode area exposed.
  • Figures 3B and 3C show examples of the layer boundary 50b, 50c being offset relative to the example of Figure 3A.
  • the layer boundary 50b is further away from the electrode pad 40b, and so an uncovered portion 46 of the conductor lane 42b is exposed, being not covered by the dielectric material 48.
  • dielectric material 48 is deposited over a covered portion 41 of the electrode pad 40c, such that the layer boundary 50c extends through the electrode pad 40c. It will be appreciated that despite the same geometry of the pad circle, the available surface area of the electrode pads 40a, 40b, 40c may differ, and so the behaviour of a functionalised surface of the electrode pads may differ significantly, particularly for low levels of analytes. Even though the offsets illustrated in Figures 3B and 3C may be larger than usually tolerated in a production environment, the Figures illustrate just one of many aspects that may present as inter-batch variation and/or as intra-batch variation.
  • Figures 4 and 5 show different sensor layouts that may be used in a sensor arrangement as shown in Figure 2.
  • FIG 4 shows an arrangement of a dual sensing element 60 constituting a sensor electrode attachment.
  • the dual sensing element 60 may be used in the manner of a disposable extended gate as illustrated in Figure 2.
  • the dual sensing element 60 comprises a first gate connector pad 62 comprising a first conductor connection 63 to a first sensing pad 64, and a second gate connector pad 66 comprising a second conductor connection 67 to a second sensing pad 68.
  • the sensors of the dual sensing element 60 are provided on a single, common, substrate layer 61.
  • the dual sensing element 60 is designed with two sensors (the first sensing pad 64 and the second sensing pad 68) which can therefore be designed to be located at a pre-determined distance from each other, which may be in close proximity.
  • a plurality of electrodes allows simultaneous measurements to be made from within a small sample volume, or from within a small flow passage.
  • one electrode may be a sensing electrode and one electrode may be a control electrode, to allow contemporaneous measurements of one or more calibration values and/or of one or more samples.
  • a sensing element may comprise a single sensing area.
  • a sensing element may comprise a plurality of sensing areas, arranged linearly, e.g. 1 *5 sensing areas, or as a two-dimensional matrix, e.g. 2 x 4 sensing areas, 3 x 3 sensing areas, or any number of an n c m array.
  • the sensing electrodes have a generally round circumference. However, other geometries may be used.
  • one (or more) of the sensor pads may be used to obtain a calibration value.
  • a calibration value may be obtained in the form of a ‘negative’ control (or blind control) and/or in the form of a positive control.
  • a calibration value may be obtained from a reference sample, e.g. a sample known to comprise no measurable amount of a target analyte, or of a known amount of a target analyte.
  • a calibration value may be obtained by way of a non-functionalised sensor electrode. For instance, one sensor electrode may be functionalised with an active sensing area, sensitive for an analyte, and another sensor electrode may be active without being functionalised to be sensitive for the analyte.
  • Figure 5 shows a portion of a sensor sheet 70 comprising on a single substrate 71 both a sensing electrode and a reference electrode.
  • the sensing electrode comprises a first gate connector 72 connecting via a first conductor connection 73 to a sensing pad 74.
  • the reference electrode comprises a reference electrode connector 76 connecting via a reference lane 77 to a reference electrode pad 78.
  • the first conductor connection 73 and the reference lane 77 are covered by a dielectric layer whereas the connectors 73, 76 and the pads 74, 78 are exposed to allow an electrical connection to be made.
  • Figure 5 shows three pairs of a sensing electrode and a corresponding reference electrode. It is an option to separate the substrate 71 to provide sensor strips each comprising one electrode pair (i.e. the pair comprising one sensing electrode and one corresponding reference electrode on a common sensor electrode attachment).
  • the lane layout is designed to allow rectangular strips to be cut out, each rectangular strip comprising a sensing electrode and a reference electrode.
  • the sheet could be cut differently, to comprise a plurality of pairs on one strip.
  • the sensor layout could be arranged to have sensors and connector pads in closer proximity to provide a sensor element with a plurality of sensing electrodes, each with an individual reference electrode.
  • the substrate could be prepared with a plurality of sensing electrodes with a common reference electrode.
  • the gate connector 72 and the reference electrode connector 76 are in a fixed spatial relationship, at a pre-determined distance from each other, both at the same surface (here: top) of the substrate 71 and at the same edge (here: the left edge in the reading orientation of Figure 5), allowing both connectors 72 and 76 to be ‘plugged’ into a corresponding socket in a single action.
  • the sensing pad 74 and the reference electrode pad 78 are in a fixed spatial relationship, at a pre-determined distance from each other. Thereby, the reference electrode is spatially aligned with the sensing electrode when setting up a sensor device for a measurement.
  • the sensing pads 26, 40a-c, 64, 68 and 74 comprise a sensor surface that can be provided with a self-assembled monolayer, providing a functionalised sensor surface.
  • a functionalised an arrangement is meant that allows the presence of an analyte to be detected more effectively than by exposure to a non-functionalised electrode surface.
  • a functionalised arrangement may comprise molecules or molecule moieties with a binding affinity for a target analyte to be detected, wherein the binding affinity is greater than that of a non-functionalised electrode surface.
  • the functionalised arrangement may constitute a recognition region.
  • Figure 6 shows a graph 80 illustrating the surface roughness measured from an example substrate film prior to application of the electrode lanes.
  • the graph 80 shows, on the horizontal axis, a distance in micrometres (here: 200 pm) along which a surface profile is measured. On its vertical axis, the graph 80 shows the surface profile measured in nanometres (here, ranging from -20 nm to +40 nm).
  • a first line 82 illustrates the surface profile of a PET substrate. The first line 82 varies vertically between -10 nm and +10 nm (a range of about 20 nm)
  • a second line 84 illustrates the surface profile of a heat-stabilising layer (or “planarising” layer) applied on top of the PET substrate.
  • the second line 84 varies vertically from -15 nm to + 40 nm (a range of about 65 nm). Note the lines 82 and 84 overlap in the graph 80 to facilitate their comparison, although it will be understood the heat-stabilising layer is in practice on top of the PET layer. Figure 6 shows that not only is there a rougher surface profile of the heat-stabilising layer 84 compared to the PET layer 82. In addition, the heat-stabilising layer may also comprise steeper deposits or ridges illustrated (in profile) by individual spikes 86. The profile of line 84 with individual spikes 86 and troughs can be understood as the surface profile onto which electrode material is to be deposited.
  • FIGS 7 A to 7C illustrate schematically a manufacturing sequence 100 for a sensing electrode functionalised with self-assembled monolayer.
  • step 102 depicted in Figure 7A, an electrode surface 110 is provided.
  • the electrode surface 110 may be a sensor pad such as the sensing pad 26 (Fig. 2), 40a-c (Fig. 3), the first and second sensing pads 64, 68 (Fig. 4) or the sensing pad 74 (Fig. 5).
  • the electrode surface provides a monolayer support on which a self-assembly monolayer is allowed to be formed.
  • the electrode surface 110 is provided with self- assembly molecules 112 and kept in a condition allowing a self-assembled monolayer 114 to form.
  • the self-assembled monolayer may at that stage have a carboxyl (-COOH) terminated functional surface, as depicted in Figure 7B, however other functional groups may be used.
  • the self-assembled monolayer 114 may be activated to act as a sensor surface, for instance by de-protonation.
  • the arrangement of Figure 7B may constitute a sensor electrode surface on which a recognition layer is provided by moieties of molecules constituting the self-assembled monolayer.
  • the terminal ends of the self-assembled monolayer 114 are provided with capture molecules 116.
  • the capture molecules 116 may be selected to exhibit a known specificity and/or sensitivity for a target analyte.
  • the capture molecules 116 may be biomolecules, such as antibodies, cross-linked (bioconjugated) to the self-assembled monolayer 114.
  • suitable reagents for cross-linking carboxyl groups include 1-ethyl-3-(3-dimethylamino- propyl)carbodiimide hydrochloride and N-hydroxysulfosuccinimide (EDC/sulfo-NHS).
  • Example moieties include protein groups, such as a lysine group (providing a -NH2 group for cross-linking). Other cross-linking mechanisms may be used.
  • the electrode surface 110 may be a gold electrode surface.
  • monolayers may be formed on other electrode surface materials such as silver (Ag), aluminium (Al), copper (Cu), chromium (Cr) or tungsten (W), and alloys thereof, as well as carbon and/or graphene, which may be used in embodiments of the invention.
  • gold (Au) electrodes are reliable both as an OTFT electrode surface and as a monolayer substrate for a self-assembled layer, allowing stable bonds to be formed, for instance Au-S bonds when using thiol groups for anchoring.
  • Gold layer bonds such as Au-S bonds can be designed to be sufficiently robust for subsequent use, particularly sufficiently stable to exposure of sample fluids.
  • the self-assembly molecules may be provided with any suitable anchorage group to attach them to the electrode surface, such as a thiol group or amino group. It will be appreciated that the head group (anchoring group) will be selected for its bond properties with the electrode material, e.g. Gold, Silver, Copper, Chrome, Tungsten, etc.
  • An exemplary self-assembly molecule is 8-mercaptooctanoic acid, comprising a thiol (-SH) group as the head group to form an Au-S bond with the electrode surface, and comprising a carboxyl end as the functional group. The carboxyl end may be used as a pH-sensitive region (corresponding to Figure 7B).
  • the carboxyl end may be used for bioconjugation of capture molecules, to allow a capture molecule to be cross-linked to the carboxyl end of the 8-mercaptooctanoic acid.
  • the monolayer may be constituted by molecules comprising an immobilising moiety and a conjugation region.
  • the immobilising moiety is understood to provide a bond with the electrode surface.
  • the conjugation region is a functional region of the molecule permitting interactions with an intermediate molecule.
  • the intermediate molecule may comprise a recognition moiety.
  • the recognition moiety may be a functional region for a defined protein-protein interaction, for a defined peptide chain, or for a defined nucleic acid sequence.
  • Figure 8 shows a schematic layout of a measurement setup to read out data from a dual sensor element 60 (see Figure 4) connected to a first transistor body 10c and to a second transistor body 10d.
  • the first gate connector pad 62a is conductively connected to a gate region 22c of the first transistor body 10c.
  • the source region 14c and the drain region 16c are connected to a first signal measurement unit to control the source-drain voltage and to measure changes in the source-drain current in response to changes in the environment of the first sensing pad 64a.
  • the second gate connector pad 66a is conductively connected to a gate region 22d of the first transistor body 10d.
  • the source region 14d and the drain region 16d are connected to a second signal measurement unit to control the source-drain voltage and to measure changes in the source-drain current in response to changes in the environment of the first sensing pad 68a.
  • a reference electrode 28a such as an Ag/AgCI reference electrode is located within the sample volume, for instance within the same fluid passage as the first and second sensing pads 64a and 68a.
  • a reference electrode is provided on a different element than the sensor element 60.
  • the reference electrode is provided as an electrode with the sensor electrode attachment, integrally on the same sensor electrode attachment as the sensor electrode.
  • An example of such a sensor electrode attachment is shown in Figure 5, showing a reference electrode 78 co-located with a sensor electrode 74 on the same substrate 71.
  • a plurality of sensor electrodes such as electrode element 60 of Figure 4 or electrode element 70 of Figure 5, are provided.
  • Each electrode element comprises a conductive electrode surface suitable for connection to a transistor gate layer. At least a portion of the electrode surface remains exposed (for instance, not covered by a dielectric layer) and is therefore available for surface processing.
  • Electrode Batch 1 A first batch of extended gates is prepared by immersing electrode surface in 4ml_ self-assembled monolayer (SAM) solution (1mM 8-mercaptooctanoic acid in ethanol) and left for 1 hour to allow a self-assembled monolayer (SAM) to be formed on the electrode pad. After formation of the SAM, each extended gate is washed by immersion in 4ml_ H 2 0 for 5 minutes before placing into holders.
  • SAM self-assembled monolayer
  • Electrode Batch 2 A second batch of extended gates is prepared similarly to the first batch, but using 1-hexadecanethiol as a control self-assembled monolayer.
  • 8-mercaptooctanoic acid comprises a carboxyl (-COOH) terminal group that can be deprotonated or protonated and is therefore sensitive to pH changes in its environment.
  • 1-hexadecanehtiol comprises a methyl (-CH3) terminal group that is not as sensitive to pH changes as a carboxyl group.
  • SAM molecules for both Batch 1 and Batch 2 are otherwise structurally similar, i.e. they comprise a thiol group as a head group for attachment to a gold surface and both molecules have a similar molecule length, and can be expected to cover the underlying electrode surface in a similar manner. Therefore, differences in behaviour can to be attributed to the presence of a carboxyl group or methyl group, respectively.
  • Test Solution Batches Several batches of commercially available pH buffered solution were used. The examples described herein use the following pH buffers: pH 2, pH 4.01, ph 6, pH 6.5, pH 7, pH 7.5, pH 8, pH 9.21. However, other buffers may be used and pH buffers could also be mixed in-house to provide a specific pH value.
  • Measurement protocol 1A was to investigate the ability to measure a wide pH range, in this case from pH 2 to pH 9, including highly acidic pH.
  • Figure 9 shows a sequence 120 of exposure of each gate sensor electrode to different Test Solution Batches. Each sensor electrode was exposed to one pH solution for a 1 -minute measurement period, thereafter the extended gate was washed and used to measure another pH solution. Eight measurement periods 121 to 128 were carried out. The sequence of pH solutions was as follows: period 121: pH 2, followed by period 122: pH 4.01, followed by period 123: pH 7, followed by period 124: pH 9.21, followed by period 125: pH 7, followed by period 126: pH 4.01, followed by period 127: pH 2, followed by period 128 pH 9.21.
  • Figure 10 shows a graph 130 of the results of the measurements obtained from the 8MOA electrodes.
  • Figure 11 shows a graph 140 of the results of the measurements obtained from the HDE electrodes.
  • each graph 130, 140 shows a plurality of (here: 10) curves each representing the measurements of a different sensor electrode.
  • Each curve is a ISD curve corresponding to current changes due to the different pH values at the extended gate electrode.
  • the electrode elements were from different production batches and the measurements were taken each at a different time throughout the day. Measurements at different times of the day may introduce variation due to differences in light exposure, temperature, humidity. Measurements using different electrodes may introduce variation due to batch-to-batch variations.
  • the curves for the graphs 130, 140 have been normalised (e.g. vertically offset) to start at the same y-Axis zero point, but are otherwise not processed.
  • Graph 130 shows that the curves correspond, although inverted on the vertical axis, qualitatively to the measurement sequence 120 (Figure 9), i.e., a first 8MOA current level 131 corresponds to the exposure period 121 (pH 2), a second 8MOA current level 132 can be discerned as a discrete current level corresponding to the exposure period 122 (pH 4), and subsequent 8MOA current levels 133 to 138 correspond to the exposure periods 123 to 128.
  • Spikes, such as spike 139 (only one of many spikes being annotated in Figure 10) between the levels are a consequence of changing the measurement solutions and washing the electrodes.
  • graph 140 shows that the curves tend to correspond somewhat to the exposure periods, i.e. , a first HDE current level 141 corresponds to the exposure period 121 (pH 2), a second HDE current level 142 corresponds to the exposure period 122 (pH 4), and subsequent HDE current levels 143 to 148 correspond to the exposure periods 123 to 128.
  • the step height between two levels is not as pronounced as in graph 130.
  • Measurement protocol 1B was to investigate the ability to measure pH values in small increments (here: steps of pH 0.5), within a physiologically relevant range, in this case from pH 6 to pH 8.
  • Each of the five extended gates were from the Electrode Batch 1 , activated with 8- mercaptooctanoic acid SAM, and were investigated as a pH-sensitive electrode (8MOA Electrodes).
  • Figure 12 shows a sequence 150 of successive exposures of each extended gate to the different Test Solution Batches.
  • Each extended gate electrode was exposed to a pH solution for a 1 -minute measurement period, thereafter the extended gate was washed and used to measure another pH solution.
  • Six measurement periods 151 to 156 were carried out.
  • the sequence of pH solutions was as follows: Period 151: pH 6.0, followed by period 152: pH 6.5, followed by period 153: pH 7.0, followed by period 154: pH 7.5, followed by period 155: pH 8.0, followed by period 156: pH 6.0.
  • Results of Measurement Protocol 1B Results of Measurement Protocol 1B:
  • Figure 13 shows a graph 160 of the results of the measurements obtained from 8MOA electrodes. Each curve is a I S D curve corresponding to current changes due to the different pH values at the extended gate electrode. Each curve was obtained with a different sensor electrode and at different times of the day (including morning and afternoon, as drift behaviour can vary throughout the day).
  • the individual graphs 160 show that the curves correspond, although inverted on the y- axis, qualitatively to the measurement sequence 150 (Figure 12), i.e., a first 8MOA current level 161 corresponds to the exposure period 151 (pH 6), a second 8MOA current level 162 corresponds to the exposure period 152 (pH 6.5), and subsequent 8MOA current levels 163 to 166 correspond to the exposure periods 153 to 156.
  • Spikes and steeper steps, such as spike 167 (only one of many spikes being annotated in Figure 14) between the levels are a consequence of the changing the measurement solutions and washing the electrodes.
  • Figure 14 shows a graph 170 depicting results of the Figure 13 measurements that were y-axis normalised (e.g. vertically offset to start at the same y-axis position) and summed (thereby for practical purposes averaging the Figure 13 curves). This shows that despite the use of different sensor elements, the curves of Figure 13 are qualitatively similar enough to allow averaging as a means of reducing the noise level.
  • the first 8MOA current level 171 corresponds to the exposure period 151
  • the second 8MOA current level 172 corresponds to the exposure period 152
  • current levels 173 to 176 correspond to the exposure periods 153 to 156.
  • Figures 10 and 14 illustrate that the magnitude of drift can exceed the resolution of a non-calibrated measurement. It is therefore surprising that the qualitative behaviour is similar despite the use of different electrode elements, measured at different times of the day. This supports the improvement of the signal quality by functionalising gate electrodes, despite using different disposable sensor elements.
  • each sensor electrode is washed with ethanol and water and dried under a stream of nitrogen (N 2 ) gas. Thereafter, each sensor electrode is oxygen plasma cleaned (oxygen flow rate 8sccm, at 100% power for 5 minutes using a HPT-200 Henniker Plasma Cleaner. Other suitable cleaning protocols may be used). Then, each sensor electrode is immersed in 4m L SAM solution (1mM 8-mercaptooctanoic acid in ethanol) and left for 1 hour to allow a self-assembled monolayer to be formed on the sensor electrode. After formation of the SAM, each sensor electrode is washed by immersion in 4m L H 2 0 for 5 minutes before placing into holders.
  • the capture molecule is a test single-strand DNA Sequence 1.
  • the capture molecule is complementary to a target molecule (Sequence 2) and not complementary to a negative control molecule (Sequence 3).
  • Sequence 1 (SEQ ID_NO 1 - Capture molecule):
  • Sequence 2 (SEQ ID_NO 2 - Target molecule complementary to Sequence 1):
  • Each sensor electrode was washed with water before adding 100 pl_ DNA sequence 2 in TrisEDTA buffer (TrisEDTA + 150mM NaCL + 5nM MgCI 2 ), 100 nM DNA sequence 2 in TrisEDTA buffer, pH 7.2, DNA sequence 2 being complementary to the test DNA sequence 1, both obtained from Eurofins Genomics, Eurofins Genomics Europe Sequencing Gmbh, Constance, Germany). Thereafter, each sensor electrode was quenched (quenching is the process of ‘inactivating’ monolayer molecules that were activated for functionalising but were then not functionalised) with 1 M ethanolamine (1 M ethanolamine in H20, pH 8.5) for 15 minutes. Lastly each sensor electrode was washed 5Xwith TrisEDTA buffer.
  • Each sensor electrode comprised a self-assembled layer carrying a bio-conjugated single stranded DNA (DNA sequence 1) sensitive to a target sample (DNA sequence 2).
  • Measurement protocol 2 was to investigate the ability to obtain DNA-specific measurements.
  • the measurements were obtained by comparing two transfer curves for each sensor element.
  • the first of the two transfer curves is a pre-hybridisation transfer curve.
  • the second of the two transfer curves is a post-hybridisation transfer curve.
  • Each sensor element was used for the measurements (pre-hybridisation and post-hybridisation) of one sample, and thereafter discarded.
  • the electrodes were provided with TrisEDTA buffer solution (400 pl_) and a transfer curve was prepared for each sensor electrode, for a gate voltage from -1.0 V to -2.5 V. Thereafter, the TrisEDTA buffer solution was removed from the sensor element.
  • the TrisEDTA buffer solution comprised no known quantities of DNA.
  • Hybridisation phase Three sensor elements were provided with a solution of 1 mM target DNA (DNA Sequence 2). Three sensor elements were provided with a solution of 1 mM off-target DNA (DNA Sequence 3, 100 mI_). Each DNA solution (target sample DNA Sequence 2 and negative control DNA Sequence 3) was exposed to hybridisation conditions with the functionalised self-assembled monolayer (DNA Sequence 1), for a hybridisation period of 1 hour.
  • Graph 180 shows the averaged voltage response (change) of three measurements of the non-complementary (negative control) DNA strands (DNA Sequence 3).
  • a bar 182 illustrates the standard deviation of the graph 180 values.
  • Graph 184 shows the averaged voltage response of three measurements of the complementary DNA strands (DNA Sequence 2).
  • a bar 186 illustrates the standard deviation of the graph 184 values.
  • the voltage change of graph 184 was significantly different (here: larger) to the voltage change of the graph 180.
  • the difference in signal is believed to arise from the controlled binding of the complementary DNA strand compared to the non-specific interactions of the non-complementary sample. In other words, the signals allow a binding event to be distinguished from a non-binding event.
  • DNA Sequences 1-4 was 24 bases, other lengths may be used. Longer sequences are considered to provide better specificity but may require consideration as to avoiding entanglement or formation of hairpin structures.
  • Electrode Batch 3 A third batch of extended gates is prepared similarly to the first batch (see Example 1 above), but using 11-ferro-cenyl-1-undecanethiol (11FcUT) as a control self-assembled monolayer. To this end, solid 11-(Ferrocenyl)undecanethiol was dissolved in ethanol to form a 1 mM 11-(Ferrocenyl)undecanethiol solution.
  • the extended gate electrodes were cleaned in oxygen plasma (plasma cleaning conditions as in Examples 1 and 2 above), and their purity confirmed by subsequent characterisation using cyclic voltammetry with [Fe(CN) 6 ] 3 /4 in PBS buffer.
  • the gate electrodes were then washed with water and ethanol.
  • To functionalise the extended gold electrodes they were then immersed in the 1 mM 11 FcUT solution at room temperature for 12 hours. After functionalisation, the electrodes were rinsed with pure ethanol at room temperature and immersed in ethanol for 15 minutes, followed by a washing step for 1 minute in a fresh ethanol bath.
  • the 11 FcUT functionalisation of the gate electrodes was confirmed by cyclic voltammetry measurement in saturated KCI0 4 , which recorded a reversible RedOx potential at 0.27V vs a Ag/AgCI reference electrode, which is a potential associated with a Ferrocenyl group.
  • Electrode Batch 4 A fourth batch of extended gates was prepared analogously to the third batch, using 1-hexadecanethiol (HDE) as a non redox-active control electrode.
  • HDE 1-hexadecanethiol
  • Test Solution Batches for example 3 Several batches of commercially available Cr(VI) solution were prepared using (NH 4 ) 2 Cr 2 0 7 (10 3 M) mixed with HCI0 4 (0.1 M) to obtain a series of test solutions with concentrations of 10 4 M, 10 5 M, and 10 6 M Cr(VI).
  • a 10 4 M Cr(VI) solution was obtained by mixing 4ml_ (NH 4 ) 2 Cr 2 0 7 and 4ml_ HCI0 4 .
  • a 10 5 Cr(VI) solution was obtained by mixing 0.4ml_ (NH 4 ) 2 Cr 2 0 7 and 4ml_ HCI0 4 .
  • a 10 6 Cr(VI) solution was obtained by mixing 0.04ml_ (NH 4 ) 2 Cr 2 0 7 and 4ml_ HCI0 4 . HCI0 4 without Cr was used as a reference solution.
  • 4 ml_ of aqueous K 2 [Fe(CN) 6 ] (0.01 M) was added and filled with distilled water to a volume of 40 ml_.
  • Ferrocenyl (Fc) is used as an example with redox-active properties for the detection of Cr(VI) and other oxidants, following the known redox reaction Cr 2 0 7 2 + 6 Fc + 14 H + 2 Cr 3+ +6 Fc + + 7 H 2 0.
  • [Fe(CN) 6 ] 4 was added as a mediator, as this is easily oxidised by Cr(VI) to [Fe(CN) 6 ] 3 .
  • the content of Cr(VI) in solution thus determines the ratio of [Fe(CN) 6 ] 3 7 4 ⁇ Therefore, the ratio [Fe(CN) 6 ] 3 /4 in the solution is believed to determine in a measurable manner the redox status (Fc+/Fc) of the ferrocenyl groups of the functionalised electrode.
  • Measurement protocol 3 was to investigate the responsiveness to a redox-active compound.
  • the extended gate electrodes from electrode batch 3 were exposed to a reference solution (HCI0 4 ), and to different concentrations of (NH 4 ) 2 Cr 2 07 in HCIO4.
  • the concentrations were 10 4 M, 10 5 M, and 10 6 M, as set out above.
  • the graph 190 shows the voltage response of different analyte concentrations, provided in the form of differently diluted samples. The exposure lasted for about 1 minute per sample.
  • a first sample level 191 corresponds to an exposure to (HCj0 4 ) as reference without Cr(VI).
  • a second sample level 192 corresponds to 10 '6 Cr(VI).
  • a third sample level 193 corresponds to 10 '5 Cr(VI).
  • a fourth sample level 194 corresponds 10 '4 Cr(VI).
  • a fifth sample level 195 corresponds to 10 '5 Cr(VI), i.e. the same concentration as the third sample level 193.
  • a sixth sample level 196 corresponds to 10 '6 Cr(VI), i.e. the same concentration as the second sample level 192.
  • a seventh sample level 197 corresponds to HCI0 4 . Spikes and steeper steps, such as spike 198 (only one of many spikes being annotated in Figure 16) between the levels are a consequence of the changing the measurement solutions and washing the electrode
  • Figure 16 shows visually distinct steps corresponding to different voltage response levels measured with test solutions of different Cr(VI) concentrations.
  • the graphs show irregularities believed to be the consequence of a poor physical electrode connection.
  • the sixth sample level 196 shows a voltage response between the second and sample levels 192 and 193.
  • Figure 16 illustrates an immediately measurable qualitative response sensitive to changes in concentration.
  • the target analyte was label-free, by which is meant that the analyte was detected without further markers to assist its detection at the gate electrode.
  • the pH value itself was measurable by a mono-layer comprising carboxyl groups as terminal free ends.
  • binding of the strand was measurable by the sensor directly from a sample without labelling (e.g. without attaching an immuno-label to the nucleic acid strand).
  • the sensors in accordance with embodiments of the invention can be functionalised for sensing small target analytes, including pH sensitive measurements, and larger biomolecules, such as DNA strands.
  • the surface-modified gate electrodes were stable throughout the test series.
  • the mono-layer remained stable after repeated exposure to low (i.e., strongly acidic) pH buffers as low as pH 2.
  • typical pH ranges are in the region of pH 5 to pH 8.5.
  • the pH stability avoids having to further coat the electrode pad with a pH protective material.
  • the present invention is particularly useful for organic field effect transistors using a separate gate electrode component that is attachable and detachable, in particular for extended gate electrodes.
  • the invention shows a robustness that allows it to be used in organic transistor architectures and, in particular, in flexible (for example Tollable) electronics.
  • This enables sensors of the invention to be manufactured as organic thin film transistor (OTFT) devices, which can be manufactured in comparatively simple conditions, which include mostly non-vacuum processes at temperatures often not exceeding 115°C. This means the per-sensor cost of a sensor element can be kept comparatively low.
  • OTFT organic thin film transistor
  • Sensor elements of the present invention may be used as disposable sensors, for example real-time sensors allowing changes in analyte presence at the sensing electrode to be measured as a function of time.
  • the sensor elements may also be used as sample harvesting units to contact a sample for subsequent readout at a later stage.
  • the transistor main unit may be used with a plurality of sensing electrodes each sensitive to a different analyte, for instance to a different pH range, to a different analyte concentration or concentration range, and/or to a different analyte composition.
  • the present invention address a particular issue with the practicality of using extended gate organic field effect transistors, making them suitable for real-world situations, such as pH wound monitoring, where it can be impractical to rely on complicated laboratory setup protocols such as for ensuring a standard connection has been made.
  • a sensing element may be provided with different types of capture molecules.
  • a sensing element may be provided with a single type of capture molecule. This allows the manufacture of individual sensing elements to be facilitated. However, different sensing pads on the same sensing element may comprise different types of capture molecules. This allows a sensing array to be provided for the simultaneous measuring of multiple different analytes.
  • a sensing pad may be used to first monitor the pH of a wound to indicate if the wound has a pH consistent with wound healing. If necessary, the sensing electrode may be exchanged to monitor for the presence of bacterial markers to determine the presence or absence of pathogenic organisms. Furthermore, different sensor electrodes, such as for pH and for a bacterial marker, may be present on the same sensor array.
  • the invention may be adopted in an array of multiple sensing elements, with as few as 2 sensing elements, or any size of n x m arrayed sensing elements.

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Abstract

L'invention concerne un agencement de capteur qui comprend un transistor organique à effet de champ (10a) avec des régions de source (14a), de drain (16a) et de porte (22a) ; et qui comprend en outre une fixation d'électrode de capteur (23, 24) qui peut être connectée de manière détachable à la région de porte (22a) pour fournir un capteur à porte étendue, une partie de la fixation d'électrode de capteur étant pourvue d'une électrode de capteur (26) et une autre partie de la fixation d'électrode de capteur étant pourvue d'une électrode de référence (28). Les modes de réalisation concernent des pastilles de capteur jetables (70 ; figure 5) sur des substrats flexibles (71 ; figure 5) et des électrodes fonctionnalisées avec des monocouches autoassemblées. Des exemples de mesures ont permis de distinguer la présence et l'absence de différents analytes, de mesurer les concentrations d'analytes ainsi que l'activité redox et/ou le pH des solutions.
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