WO2020178557A1 - Dispositif de dosage - Google Patents

Dispositif de dosage Download PDF

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Publication number
WO2020178557A1
WO2020178557A1 PCT/GB2020/050467 GB2020050467W WO2020178557A1 WO 2020178557 A1 WO2020178557 A1 WO 2020178557A1 GB 2020050467 W GB2020050467 W GB 2020050467W WO 2020178557 A1 WO2020178557 A1 WO 2020178557A1
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WO
WIPO (PCT)
Prior art keywords
transport path
liquid transport
assay device
photocurrent
assay
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PCT/GB2020/050467
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English (en)
Inventor
Andrey Nikolaenko
Original Assignee
Sumitomo Chemical Company Limited
Cambridge Display Technology Limited
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Filing date
Publication date
Application filed by Sumitomo Chemical Company Limited, Cambridge Display Technology Limited filed Critical Sumitomo Chemical Company Limited
Publication of WO2020178557A1 publication Critical patent/WO2020178557A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/84—Systems specially adapted for particular applications
    • G01N21/8483—Investigating reagent band
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
    • G01N21/255—Details, e.g. use of specially adapted sources, lighting or optical systems
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6486—Measuring fluorescence of biological material, e.g. DNA, RNA, cells
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G01N33/487—Physical analysis of biological material of liquid biological material
    • G01N33/48785—Electrical and electronic details of measuring devices for physical analysis of liquid biological material not specific to a particular test method, e.g. user interface or power supply
    • 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
    • G01N33/52—Use of compounds or compositions for colorimetric, spectrophotometric or fluorometric investigation, e.g. use of reagent paper and including single- and multilayer analytical elements
    • 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
    • G01N33/5302—Apparatus specially adapted for immunological test procedures
    • 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
    • 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
    • G01N33/54386—Analytical elements

Definitions

  • Embodiments of the present disclosure relate to assay devices. More particularly, but not by way of limitation, some embodiments of the present disclosure relate to assay devices for reading the results of lateral flow immunoassay tests and/or microfluidic assays.
  • Biological testing for the presence and/or concentration of an analyte may be conducted for a variety of reasons including, amongst other applications, preliminary diagnosis, screening samples for presence of controlled substances and management of long term health conditions.
  • Lateral flow devices are one variety of biological testing. Lateral flow devices may be used to test a liquid sample, such as saliva, blood or urine, for the presence of an analyte. Examples of lateral flow devices include home pregnancy tests, home ovulation tests, tests for other hormones, tests for specific pathogens and tests for specific drugs. Lor example, EP 0 291 194 A1 describes a lateral flow device for performing a pregnancy test.
  • a liquid sample is introduced at one end of a porous strip which is then drawn along the strip by capillary action (or“wicking”).
  • a portion of the lateral flow strip is pre-treated with labelling particles which are activated with a reagent which binds to the analyte to form a complex if the analyte is present in the sample.
  • the bound complexes and also unreacted labelling particles continue to propagate along the strip before reaching a testing region which is pre-treated with an immobilised binding reagent which binds bound complexes of analyte and labelling particles and does not bind unreacted labelling particles.
  • the labelling particles have a distinctive colour, or other detectable optical or non-optical property, and the development of a concentration of labelling particles in the test regions provides an observable indication that the analyte has been detected.
  • Lateral flow test strips may be based on, for example, colorimetric labelling using gold or latex nanoparticles, fluorescent marker molecules or magnetic labelling particles.
  • Liquid assays may be measured based on colorimetry or fluorescence.
  • An advantage of some liquid based assays is that they may allow tests to be conducted using very small (e.g. picolitre) volumes.
  • Some immunoassays may be conducted in a microfluidic device.
  • WO 2008/101732 A1 describes an optical measuring instrument and measuring device.
  • the optical measuring instrument includes at least one source for providing at least one electromagnetic beam to irradiate a sample and to interact with the specimen within the sample, at least one sensor for detecting an output of the interaction between the specimen and the electromagnetic beam, an integrally formed mechanical bench for the optical and electronic components and a sample holder for holding the sample.
  • the at least one source, the at least one sensor, and the mechanical bench are integrated in one monolithic optoelectronic module and the sample holder can be connected to this module.
  • an assay device for determining the presence and/or concentration of a target analyte within a liquid transport path.
  • the assay device is adapted to at least partly receive a liquid transport path having a first end, a second end and a sample receiving portion proximate to the first end.
  • the liquid transport path is adapted to transport a liquid sample received in the sample receiving portion towards the second end.
  • the assay device includes one or more light sources.
  • the one or more light sources are arranged so that when the liquid transport path is received by the assay device, the one or more light sources illuminate one or more illuminated portions of the liquid transport path which are located between the sample receiving portion and the second end.
  • the assay device also includes one or more photodiodes.
  • the one or more photodiodes are arranged so that when the liquid transport path is received by the assay device, the one or more photodiodes receive light transmitted through an illuminated portion of the liquid transport path.
  • the assay device also includes one or more photocurrent processing channels. Each photocurrent processing channel is configured and arranged to receive a photocurrent from a corresponding photodiode, and to provide a corresponding output signal. The minimum detectable photocurrent is less than or equal to 1.5 pA for each photocurrent processing channel.
  • the assay device may be a reader device.
  • some of the illuminated portions may correspond to regions of interest, and other illuminated portions may correspond to reference regions.
  • output signals corresponding to reference regions may be used for performing background corrections for output signals corresponding to regions of interest.
  • output signals may be digital signals.
  • a minimum detectable change in the output signal may be limited by dark current of the photocurrent processing channels.
  • the minimum detectable photocurrent being less than or equal to 1.5 pA may mean that the standard error of each photocurrent processing channel is less than or equal to 1.5 pA.
  • the minimum detectable photocurrent being less than or equal to 1.5 pA may mean that the standard error of each photocurrent processing channel is less than or equal to one third of 1.5 pA. In other words, the minimum detectable photocurrent may be three times the standard error of the photocurrent processing channel(s). In some embodiments, the minimum detectable photocurrent being less than or equal to 1.5 pA may mean that the standard error of each photocurrent processing channel is less than or equal to one fifth of 1.5 pA. In other words, the minimum detectable photocurrent may be five times the standard error of the photocurrent processing channel(s).
  • the minimum detectable photocurrent may be less than or equal to 1.0 pA. In some embodiments, the minimum detectable photocurrent may be less than or equal to 0.5 pA. In some embodiments, the minimum detectable photocurrent may be less than or equal to 0.1 pA.
  • each illuminated portion may correspond to a single light source. In some embodiments, each illuminated portion may correspond to a single photodiode. In some embodiments, each illuminated portion may correspond to a single light source and a single photodiode. In some embodiments, each illuminated portion may correspond to two or more light sources having differing emission spectra. In some embodiments, each
  • each illuminated portion may correspond to two or more photodiodes having different spectral sensitivities.
  • each illuminated portion may correspond to two or more light sources having differing emission spectra, and to two or more photodiodes having different spectral sensitivities.
  • each photocurrent processing channel may include an amplifier and an analog-to-digital converter.
  • the one or more photocurrent processing channels may comprise a microcontroller, and the microcontroller may provide one or more analog-to-digital converters.
  • each analogue-to-digital convertor may have a precision greater than 8-bits, for example, each analogue-to-digital convertor may have a precision of 10-bits, 12-bits or 16-bits.
  • the amplifier may be a trans-impedance amplifier.
  • the amplifier may include an operational amplifier
  • an optical path between the one or more light sources and the one or more photodiodes may include no monochromator(s). In some embodiments, the optical path may include no beamsplitter(s) between the one or more light sources and the one or more photodiodes. In some embodiments, the optical path may include no fibre couplers and/or fibre splitters between the one or more light sources and the one or more photodiodes.
  • the light sources may take the form of one or more light emitting diodes, organic light emitting diodes, lasers, laser diodes, tungsten filament bulbs, halogen bulbs, fluorescent tubes and/or compact fluorescent bulbs.
  • organic light emitting diodes may be solution processed.
  • photodiodes may be inorganic photodiodes or organic photodiodes.
  • organic photodiodes may be solution processed.
  • the assay device may include a plurality of photodiodes arranged in an array.
  • the array may include more photodiodes in a first direction than in a second, perpendicular direction.
  • the assay device may include a single photodiode corresponding to each illuminated portion and having an area substantially corresponding to an area of the illuminated portion.
  • a slit or aperture may be included in the optical path between the one or more light sources and the illuminated portion of the liquid transport path. In some embodiments, a slit or aperture may be included in the optical path between the illuminated portion of the liquid transport path and the one or more photodiodes. In some embodiments, each slit may have adjustable width. In some embodiments, each slit may have a width of greater than or equal to 1 mm. In some embodiments, each slit may have a width of up to 2.2 mm. In some embodiments, each slit may have a width between 100 pm and 1 mm inclusive. In some embodiments, each slit may have a width between 300 pm and 500 pm inclusive.
  • a diffuser may be included in the optical path between the one or more light sources and the illuminated portion of the liquid transport path. In some embodiments, a diffuser may be included in the optical path between the illuminated portion of the liquid transport path and the one or more photodiodes.
  • the one or more processing channels may include a filtering module configured to perform averaging across a period corresponding to one or more cycles of a mains electricity signal, such that any component of interference from the mains electricity signal may be reduced or removed from the output signals.
  • the mains electricity signal may have a frequency within the range between and including 50 Hz to 60 Hz.
  • each processing channel may obtain one thousand samples during one period of the mains electricity signal, and the output signal may be based on an average across said one thousand samples.
  • samples may be obtained at regular sampling intervals.
  • samples may be obtained at irregular sampling intervals. When samples are obtained at irregular sampling intervals, samples may be interpolated onto regularly spaced time points before calculating an average of the interpolated values.
  • the filtering module may be implemented by a processor of a microcontroller executing a compiled computer program stored in a memory of the microcontroller.
  • the filtering module may be implemented using a suitably configured field-programmable gate array. In some embodiments, the filtering module may be implemented using one or more digital electronic microprocessors executing a compiled computer program. In some embodiments, the filtering module may be implemented by a microcontroller which implements the one or more analog-to-digital converters. In some embodiments, the filtering module may be implemented using a time-averaging circuit. In some embodiments, the assay device may be adapted to at least partly receive a liquid transport path having an effective transmittance T e of less than 10%, wherein the effective transmittance T e is given by the ratio:
  • S is a measured output signal from a processing channel when the liquid transport path is received in the assay device and So is a measured output signal from the same processing channel when the liquid transport path is not received in the assay device.
  • the effective transmittance T e may be less than or equal to 8%. In some embodiments, the effective transmittance T e may be less than or equal to 5%. In some embodiments, the effective transmittance T e may be less than or equal to 3%. In some embodiments, the effective transmittance T e may be less than or equal to 1%.
  • the corresponding effective transmittance T e of the liquid transport path may be less than or equal to 2.2+0.1%. In some embodiments, when an illuminated portion is defined by an aperture having a width of 2.2 mm in the direction between the first and second ends, the effective transmittance T e of the liquid transport path may be less than or equal to 4.2+0.1%.
  • the liquid transport path may include a porous strip.
  • the porous strip may include fibrous material. In some embodiments, the porous strip may include nitrocellulose. In some embodiments, the porous strip may take the form of a lateral flow immunoassay test strip. In some embodiments, the porous strip may be supported on a substrate. In some embodiments, the substrate may be opaque. In some embodiments, opaque may correspond to an effective transmittance T e for the substrate of less than or equal to 10%. In some embodiments, the effective transmittance T e of the substrate may be less than or equal to 8%. In some embodiments, the effective transmittance T e of the substrate may be less than or equal to 5%. In some embodiments, the effective transmittance T e of the substrate may be less than or equal to 3%. In some embodiments, the effective transmittance T e of the substrate may be less than or equal to 1%.
  • the liquid transport path may include one or more channels of a microfluidic device.
  • each light source may be an organic light emitting diode having an external quantum efficiency of less than or equal to 0.5%. In some embodiments, each organic light emitting diode may have an external quantum efficiency of less than or equal to 0.1% .
  • the assay device may further include a determination module configured to determine, based on the output signals, the presence and/or concentration of a target analyte within the liquid transport path.
  • the determination module may be implemented by a processor of a microcontroller executing a compiled computer program stored in a memory of the microcontroller. In some embodiments, the determination module may be implemented using a suitably configured field-programmable gate array. In some embodiments, the determination module may be implemented using one or more digital electronic processors executing a compiled computer program. In some embodiments, the determination module and the filtering module may be implemented by the same microcontroller, by the same field- programmable gate array, or by the same one or more digital electronic processors.
  • the assay device may further include a communications interface configured to provide the output signals to an external processing device.
  • the communications interface may be implemented by a microcontroller which implements the filtering module and/or the determination module.
  • the communications interface may be implemented by a field-programmable gate array which implements the filtering module and/or the determination module.
  • the external processing device may be a desktop computer, a laptop computer, a tablet computer, a mobile telephone, a handheld purpose specific computing device, and so forth.
  • an assay test may include the assay device and a liquid transport path at least partly received by the assay device.
  • the assay device and liquid transport path may be contained within, or integrated with, a casing, enclosure or package.
  • a system may include the assay device, a liquid transport path at least partly received by the assay device, and an external processing device configured to determine, based on the output signals, the presence and/or concentration of a target analyte within the liquid transport path.
  • the external processing device may determine the presence and/or concentration of a target analyte within the liquid transport path using one or more digital electronic processors executing a compiled computer program. In some embodiments, the external processing device may implement the filtering module.
  • the liquid transport path may include a porous strip supported on an opaque substrate. In some embodiments, the liquid transport path may be arranged so that the one or more light sources illuminate the porous strip through the opaque substrate.
  • a testing kit may include the assay device and a liquid transport path adapted to be received by the assay device.
  • a method of using the assay device, the assay test, the system or the testing kit includes applying a quantity of liquid sample to the liquid transport path.
  • the method includes waiting for a duration at least long enough for the liquid sample to propagate through at least one illuminated portion of the liquid transport path.
  • the method includes obtaining output signals from the one or more photocurrent processing channels.
  • the method includes determining, based on the output signals, the presence and/or concentration of a target analyte within the liquid transport path.
  • the liquid transport path is adapted to transport a liquid sample received in the sample receiving portion towards the second end.
  • the method includes illuminating, using one or more light sources, one or more illuminated portions of the liquid transport path which are located between the sample receiving portion and the second end.
  • the method includes receiving, using one or more photodiodes, light transmitted through the one or more illuminated portions of the liquid transport path.
  • the method includes generating, using one or more photocurrent processing channels which receive photocurrent from corresponding photodiodes, an output signal, wherein the resolution for detecting received photocurrent is less than or equal to 1.5 pA.
  • generating each output signal may include obtaining an average across a period corresponding to one or more cycles of a mains electricity signal, such that any contribution of interference from the mains electricity signal may be reduced or removed from the output signal.
  • the liquid transport path may have an effective transmittance T e of less than 10%, wherein the effective transmittance T e may be given by the ratio:
  • T e S/So in which S is a measured output signal from a processing channel when the liquid transport path is received between one or more light sources and one or more photodiodes, and So is a measured output signal from the same processing channel when the liquid transport path is not received between one or more light sources and one or more photodiodes.
  • Figure 1 illustrates an example of an assay device
  • Figure 2 illustrates a portion of a lateral flow test strip
  • FIG. 3 illustrates a photocurrent processing channel
  • Figure 4 illustrates dark-currents measured using photocurrent processing channels
  • Figure 5 illustrates a circuit for a photocurrent processing channel
  • Figure 6 illustrates a portion of a second example of an assay device
  • Figure 7 illustrates a portion of a third example of an assay device
  • Figure 8 illustrates a first method
  • Figure 9 illustrates a second method
  • Figure 10 illustrates a self-contained lateral flow assay device
  • Figures 11 A and 1 IB illustrate a reader device for reading a lateral flow test strip
  • Figure 12 presents measurements obtained using an assay device according to the present specification
  • Figure 13 presents comparative measurements obtained using an assay device which is not an embodiment according to the present specification
  • Figure 14 illustrates an assay device reading a channel of a microfluidic device
  • Figure 15 illustrates using an assay device to obtain background corrected measurement.
  • the words “comprise,” “comprising,” and the like are to be construed in an inclusive sense, as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to.”
  • the terms “connected,” “coupled,” or any variant thereof means any connection or coupling, either direct or indirect, between two or more elements; the coupling or connection between the elements can be physical, logical, electromagnetic, or a combination thereof.
  • the words “herein,” “above,” “below,” and words of similar import when used in this application, refer to this application as a whole and not to any particular portions of this application.
  • words in the Detailed Description using the singular or plural number may also include the plural or singular number respectively.
  • the word "or,” in reference to a list of two or more items, covers all of the following interpretations of the word: any of the items in the list, all of the items in the list, and any combination of the items in the list.
  • a material“over” a layer is meant that the material is in direct contact with the layer or is spaced apart therefrom by one or more intervening layers.
  • a material“on” a layer is meant that the material is in direct contact with that layer.
  • a layer“between” two other layers as described herein may be in direct contact with each of the two layers it is between or may be spaced apart from one or both of the two other layers by one or more intervening layers.
  • inventions introduced here can be embodied as special-purpose hardware (e.g., circuitry), as programmable circuitry appropriately programmed with software and/or firmware, or as a combination of special-purpose and programmable circuitry.
  • embodiments may include a machine-readable medium having stored thereon instructions which may be used to program a computer (or other electronic devices) to perform a process.
  • the machine-readable medium may include, but is not limited to, floppy diskettes, optical disks, compact disc read-only memories (CD-ROMs), magneto-optical disks, ROMs, random access memories (RAMs), erasable programmable read-only memories (EPROMs), electrically erasable programmable read-only memories (EEPROMs), magnetic or optical cards, flash memory, or other type of media / machine-readable medium suitable for storing electronic instructions.
  • the machine-readable medium includes non-transitory medium, where non-transitory excludes propagation signals.
  • a processor can be connected to a non-transitory computer-readable medium that stores instructions for executing instructions by the processor.
  • Quantitative detectors for biological testing methods may require optical components such as beamsplitters, lenses, monochromators, filters etc. Such components may be complex, expensive and/or bulky, and may have properties which vary considerably with the wavelength of light. Such factors have been problematic for the integration of quantitative detectors into compact, single use disposable tests for use at home or at point-of-care.
  • lateral flow immunoassays are typically prepared using nitrocellulose strips supported on opaque substrates. Consequently, quantitative readers for lateral flow immunoassays may need to either operate in a reflection mode, or use specially customized nitrocellulose strips supported on transparent substrates for a transmission mode. Operation in reflection mode adds bulk to a reader, as a reflection geometry typically needs more clearance to illuminate and read the lateral flow immunoassays compared to a transmission mode. Use of specially customized nitrocellulose strips supported on transparent substrates is impractical for a general purpose reader, as many commonly produced lateral flow
  • immunoassays may be incompatible.
  • Quantitative detectors for biological testing methods are typically configured with the assumption that the concentration of a target analyte or labels bound to said target analyte will be the limiting factor on resolution, rather than the intensity of light reaching a light detector. Consequently, the minimum detection threshold of incident light has not been considered a priority.
  • an assay device may be improved.
  • a signal processing path having improved sensitivity may improve the resolution for detecting changes in optical density, and may also improve a minimum detectable concentration of a target analyte.
  • a signal processing path having improved sensitivity may also facilitate new features.
  • a transmission mode geometry may be used even when the assay to be read is substantially opaque. This may avoid the need for specially customised transparent lateral flow test strips for integrated single use devices, and may improve the inter-compatibility of a general purpose reader.
  • cheap, low grade organic light emitting diodes i.e. low external quantum efficiency
  • an assay device for quantitative readout of an assay may be more compact, cheaper, and/or capable of reading any standard lateral flow immunoassay.
  • the inventors have further realised, surprisingly, that reading an opaque assay in a transmission geometry using assay devices having a high sensitivity signal processing path may improve a minimum detectable concentration of a target analyte by facilitating a two-colour background correction method.
  • Assay devices specifically adapted to make use of this surprising realisation are also described (see Figure 15).
  • Assay devices according to this specification may be of particular use for single use home or point-of-care testing kits, and/or for compact, general purpose handheld readers.
  • Figure 1 is a schematic illustration of an assay device 1 according to some embodiments of the present disclosure.
  • the assay device 1 is intended for use in determining the presence and/or concentration of at least one target analyte within a liquid transport path 2.
  • the assay device 1 is adapted to at least partly receive a liquid transport path 2.
  • the liquid transport path 2 has a first end 3, a second end 4 and a sample receiving portion 5 arranged proximate to the first end 2.
  • the liquid transport path 2 is adapted to transport a liquid sample 6 received in the sample receiving portion 5 in a flow direction 7 towards the second end 4.
  • the assay device 1 includes one or more light sources 8. When a liquid transport path 2 is received by the assay device 1, the light sources 8 are arranged with respect to the received liquid transport path 2 so that light 9 emitted by the light sources is incident on one or more illuminated portions 10 of the liquid transport path 2 located between the sample receiving portion 5 and the second end 4.
  • the assay device 1 also includes one or more photodiodes 11 arranged opposite (transmission geometry) to the light sources 8.
  • the photodiodes 11 receive light 9 transmitted through the illuminated portion 10 of the liquid transport path 2.
  • the assay device 1 also includes a photocurrent processing channel 12 corresponding to each photodiode 11. Each photocurrent processing channel 12 receives a photocurrent 13 from a respective photodiode 11, and processes the photocurrent 13 to provide a corresponding output signal 14.
  • Photocurrent processing channels 12 are configured to provide a minimum detectable photocurrent which is less than or equal to 1.5 pA.
  • This minimum detectable photocurrent of less than or equal to 1.5 pA may also be referred to as“ultra-high” sensitivity in the context of assay devices 1 for reading the results of biological testing assays.
  • the sensitivity of a reader has not typically been considered to be an important or limiting factor, because it has conventionally been considered that the sensitivity of biological testing assays was limited by the assays themselves, rather than by a reader used to quantify the results.
  • the output signals 14 may take the form of digital signals 29 ( Figure 3).
  • Each illuminated portion 10 may correspond to a single light source 8, or to two or more light sources 8, for example arranged to form an array.
  • Each light source 8 may take the form of one or more light emitting diodes, organic light emitting diodes, lasers, laser diodes, tungsten filament bulbs, halogen bulbs, fluorescent tubes and/or compact fluorescent bulbs.
  • Each illuminated portion 10 may correspond to a single photodiode 11, or to two or more photodiodes 11, for example arranged to form an array.
  • Each photodiode 1 l may be an inorganic photodiode or an organic photodiode.
  • each illuminated portion 10 corresponds to a single light source 9 in the form of an organic light emitting diode, and to a single photodiode 11 in the form of an organic photodiode.
  • Organic light emitting diodes and /or organic photodiodes may be solution processed.
  • the assay device 1 may include a single light source 8 and/or a single photodiode 11 having active areas substantially corresponding to the illuminated portion 10.
  • the assay device 1 may include an integrated liquid transport path 2 ( Figure 10).
  • the assay device 1 may be configured to receive a separate liquid transport path 2 in the form of a porous strip 15 (Figure 2) of a lateral flow test strip 16 ( Figure 2), or one or more channels 17 ( Figure 14) of a microfluidic device 18 ( Figure 14).
  • the liquid transport path 2 is configured to perform a colorimetric assay test such as, for example, an immunoassay test.
  • the assay device 1 may be configured to read the results of the colorimetric assay test using the pairing of one or more light sources 8 and one or more photodiodes 11.
  • the term“colorimetric assay test” includes assays conducted using non-visible wavelengths of light 9, for example infrared or ultraviolet light.
  • a flow front 19 separates a wet portion of the liquid transport path 2 from a dry portion.
  • the flow front 19 moves towards the second end 4 in the flow direction 7.
  • the liquid transport path 2 transports the liquid sample 6 in the flow direction 7 by wetting/capillary action, or similar mechanisms.
  • the liquid transport path 2 may take the form of a porous medium such as, for example, a porous strip 15 ( Figure 2).
  • a porous medium forming the liquid transport path 2 may include nitrocellulose or other fibrous materials capable of transporting an aqueous liquid by capillary action, whether inherently or following appropriate surface treatments.
  • Micro-fluidic channels 17 ( Figure 14) are sufficiently thin in at least one dimension that capillary forces may act to draw the liquid sample 6 in and along the flow direction 7.
  • the one or more light sources 8 and corresponding photodiodes 11 may be arranged relative to the illuminated portion 10 during fabrication/assembly of the assay device 1.
  • the assay device 1 may be configured with features to enable accurate and reproducible alignment of one or more regions of interest 23 (Figure 2) of the liquid transport path 2 with the one or more light sources 8 and the corresponding photodiodes 11.
  • either or both of the assay device 1 and the liquid transport path 2 may include registration indicia.
  • the assay device 1 may include a slot 60 ( Figure 11 A) having a specific length such that a liquid transport path 2 may be positioned correctly by simply being placed with the first or second end 3, 4 abutting a closed end 61 (Figure 1 IB) of the slot 60 ( Figure 11A).
  • one or more slits or apertures 53 may be included in the optical path between the one or more light sources 9 and the one or more photodiodes 11, in order to collimate the light 9.
  • each may have adjustable width.
  • slits or apertures 53 ( Figure 10) each may have a width of greater than or equal to 1 mm, between 100 pm and 1 mm inclusive, or between 300 pm and 500 pm inclusive.
  • a diffuser may be included in the optical path between the one or more light sources 9 and the one or more photodiodes 11.
  • An optical path between the one or more light sources 9 and the one or more photodiodes 11 may include no monochromator(s), no beamsplitter(s) and no fibre couplers and/or fibre splitters.
  • lateral flow immunoassay test strips are typically fabricated using opaque substrates as standard. Consequently, readers typically operate in a reflection mode, since the transmission through an opaque substrate will provide a very low signal.
  • the ultra-high ( ⁇ 1.5 pA) sensitivity of a photocurrent processing channel 12 enables measurements in transmission using an opaque liquid transport path 2.
  • the assay device 1 may include, or be adapted to at least partly receive, a liquid transport path 2 having an effective transmittance T e of less than 10%.
  • the parameter of effective transmittance T e may be defined as the ratio:
  • the ultra-high ( ⁇ 1.5 pA) sensitivity of the assay device 1 permits that in some embodiments, the effective transmittance T e of the liquid transport path 2 may be lower than 10%.
  • the assay device 1 may include, or be adapted to at least partly receive, a liquid transport path 2 having an effective transmittance T e of less than 8%, less than 5%, less than 3% or less than 1%.
  • Such sensitivity provides the capability to read lateral flow immunoassays produced using standard opaque substrates in a transmission mode. This avoids the need for customised transparent substrates, and may enable production of compact (compared to reflection mode devices) assays devices 1 which may be compatible with any type of lateral flow immunoassay test.
  • an illuminated portion 10 was defined by an aperture having a width of 1 mm in the direction x between the first and second ends 3, 4, and the corresponding effective transmittance T e of a standard, opaque lateral flow strip was measured as 2.2%.
  • the corresponding effective transmittance T e for a customized transparent lateral flow strip was measured as 25%.
  • the effective transmittance T e exhibits some dependence on the width of the illuminated portion 10. This effect is believed to be a result of scattering in the liquid flow path 2, and plateaus for wider illuminated portions 10.
  • the measurements were repeated using an illuminated portion 10 defined by an aperture having a width of 2.2 mm, and the effective transmittance T e of the standard, opaque lateral flow strip was measured as 4.2%, as compared to 41% for the customized transparent lateral flow strip.
  • the width of the illuminated portion 10 along the flow direction 7 is typically fixed for a given assay device 1.
  • each light source 8 may be an organic light emitting diode having an external quantum efficiency of less than or equal to 0.5%, or less than or equal to 0.1%.
  • Such low grade organic light-emitting diodes may not provide sufficient light 9 in many conventional readers, but may be used for the assay devices 1 according to this specification.
  • Cheap, low grade solution processed organic light-emitting diodes may provide a cost advantage for disposable, single use assay tests intended for home use or use at point-of-care.
  • Figure 2 is a schematic illustration of a lateral flow test strip 16 which may provide a liquid transport path 2 according to some embodiments of the present disclosure.
  • the liquid transport path 2 may take the form of a lateral flow test strip 16, and may be integrated into the assay device 1 ( Figure 10), or received into the assay device 1 ( Figures 11 A, 11B).
  • Lateral flow test strips 16 are a variety of biological testing kit. Lateral flow test strips 16 may be used to test a liquid sample 6, such as saliva, blood or urine, for the presence of a target analyte. Examples of lateral flow test strips 16 include home pregnancy tests, home ovulation tests, tests for other hormones, tests
  • Lateral flow test strips 16 may also be used for testing food and/or drink products to determine the presence or concentration of impurities and so forth.
  • a typical lateral flow test strip 16 includes a porous strip 15 supported on a substrate 20 which, as mentioned hereinbefore, is typically opaque, or at least not selected for the purpose of providing transparency. Portions of the porous strip 15 are treated with reagents to define a test region 21 and, optionally, a control region 22.
  • a liquid sample 6 is introduced to the sample receiving portion 5 proximate to a first end 3 of the porous strip 15, and the liquid sample 6 is then drawn along the lateral flow test strip 16 towards the second end 4 by capillary action (or“wicking”).
  • a conjugate pad 44 ( Figure 10) of the lateral flow strip 16 is pre-treated with labelling particles (not shown) which are activated with a reagent which binds to the target analyte to form a complex if the target analyte is present in the liquid sample 6.
  • the bound complexes, and also unreacted labelling particles continue to propagate along the lateral flow test strip 16 in the flow direction 7 before reaching a test region 21 which is pre-treated with an immobilised binding reagent which binds complexes of analyte bound to labelling particles and does not bind unreacted labelling particles.
  • the labelling particles have a distinctive colour, or otherwise absorb one or more ranges of ultraviolet, infrared or visible light.
  • the development of a concentration of labelling particles in the test region 20 may be measured and quantified using the assay device 1, as described herein.
  • the assay device 1 may perform measurements on developed lateral flow test strips 16, i.e. the liquid sample 6 has been left for a pre-set period to be drawn along the test strip 16.
  • the assay device 1 may perform kinetic, i.e. dynamic time resolved measurements of the absorbance (sometimes also referred to as“optical density”) of the test region 21.
  • the control region 22 is treated with an immobilised binding reagent which binds unreacted labelling particles, and optionally also complexes of analyte bound to labelling particles not bound in the test region 21.
  • a change in absorbance of the control region 22 provides an indication that the assay has operated correctly, and protects against some types of false negative results.
  • the porous strip 15 may include or be formed of nitrocellulose, or other fibrous materials capable of transporting an aqueous liquid by capillary action, whether inherently or following appropriate surface treatments.
  • the substrate 20 may be opaque.
  • the substrate 20, or the overall lateral flow test strip 16, may correspond to an effective transmittance T e for the substrate of less than or equal to 10%, less than or equal to 8%, less than or equal to 5%, less than or equal to 3%, or less than or equal to 1%.
  • As assay device 1 may be configured to illuminate more than one portion 10 of a liquid transport path 2 received or receivable by the assay device 1.
  • Each illuminated portion 10 may, in use, be illuminated by one or more light sources 8 and may correspond to one or more photodiodes 11. At least one illuminated portion 10 will correspond to a region of interest 23 of the liquid transport path 2.
  • one or more further illuminated portions 10 may correspond to reference regions 24 of the liquid transport path 2.
  • Output signals 14 corresponding to reference regions 24 may be used for performing background corrections for output signals 14 corresponding to regions of interest 23.
  • first and second regions of interest 23a, 23b may correspond to the test region 21 and control region 22 respectively.
  • first, second and third reference regions 24a, 24b, 24c may be defined before the test region 21, between the test region 21 and the control region 22, and after the control region 22 (with respect to the flow direction 7, x).
  • the reference regions 24a, 24b, 24c may be used to correct absorbance values for the regions of interest 23a, 23b for a background absorbance of the porous strip 15 and substrate 20.
  • One reference region 24 could be used.
  • Regions of interest 23 and/or reference regions 24 need not have equal widths parallel to the flow direction 7.
  • regions of interest 23 and reference regions 24 have been illustrated with reference to a liquid transport path 2 in the form of a lateral flow test strip 16. However, regions of interest 23 and reference regions 24 are equally applicable to a liquid transport path 2 in the form of a channel 17 of a microfluidic device 18 ( Figure 14).
  • Figure 3 is a schematic illustration of an example of a photocurrent processing channel 25 which may be used in assay devices 1 according to some embodiments of the present disclosure.
  • the photocurrent processing channel 25 includes an amplifier 26 and an analog-to-digital convertor (ADC).
  • the amplifier 26 receives and amplifies the photocurrent 13, and provides an amplified photocurrent 28 to the ADC 27.
  • the amplifier 26 may take the form of a trans impedance amplifier, for example an operational amplifier ( Figure 5).
  • the ADC 27 converts the amplified photocurrent 28 into a digital signal 29.
  • the digital signal 29 may correspond to the output signal 14.
  • one or more photocurrent processing channels 12 may include a microcontroller having an integrated ADC.
  • Each ADC 27 preferably has a precision greater than 8-bits, for example, each ADC 27 may have a precision of 10-bits, 12-bits or 16-bits.
  • the dynamic range of the ADC 27 is set to a level such that a quantisation step of the ADC 27 (minimum detectable shift in input) is less than, or significantly less than, an amplitude of a noise signal in the amplified photocurrent 28.
  • the photocurrent processing channel 25 may also include a filtering module 30.
  • the ADC 27 may oversample the amplified photocurrent 28.
  • the ADC 27 may sample the amplified photocurrent 28 at a sample rate which is very much higher than the typical timescale for changes in the absorbance of the test or control regions 21, 22.
  • the ADC 27 may use a sampling rate of hundreds, thousands or preferably tens of thousands of Hz.
  • the absorbance of the test or control regions 21, 22 will typically exhibit noticeable changes on timescales of the order of at least seconds or tens of seconds.
  • the filtering module 30 may apply an averaging process to the digital signal 29 in order to effectively reduce the noise in the output signal 14. This will tend to improve the signal-to-noise ratio of the output signal 14 by reducing the error by a factor of (N-l) 05 , where N is the number of samples in the digital signal 29 averaged to produce a corresponding sample of the output signal 14.
  • the period used by the filtering module 30 for obtaining an average may be set specifically to average out any interference (also sometimes called“pick-up”) corresponding to a mains electricity supply.
  • any interference also sometimes called“pick-up”
  • a mains electricity signal may have a frequency within the range between and including 50 Hz to 60 Hz.
  • the ADC 27 may obtain one thousand samples during one period of the mains electricity signal, and a corresponding sample in the output signal 14 may be based on an average across said one thousand samples.
  • the filtering module 30 may be implemented by a processor of a microcontroller executing a compiled computer program stored in a memory of the microcontroller, a suitably configured field-programmable gate array, one or more digital electronic processors executing a compiled computer program, and so forth.
  • the amplifier 26, ADC 27 and/or filtering module 30 may be integrated as a single chip, for example an application specific integrated circuit.
  • the filtering module 30 may instead be implemented in the analog domain before digitisation by the ADC 27, for example using a time- averaging circuit.
  • Figure 4 presents measurements of dark current corresponding to a pair of photocurrent processing channels 12 of an assay device 1 according to some embodiments of the present disclosure.
  • the solid black line corresponds to a first photocurrent processing channel 12, 25, and the dashed line corresponds to a second photocurrent processing channel 12, 25.
  • dark currents were measured for five separate photocurrent processing channels 12, 25, over a total duration of about 90 seconds. Parameters of the measurements are presented in Table 1:
  • the minimum detectable photocurrent based on these data is about 1.4 pA. In other examples, if even greater reliability is necessary, the minimum detectable photocurrent may be taken as five times the standard error of the photocurrent processing channel 12 dark current.
  • the minimum detectable photocurrent may be reduced further by increasing the gain of the amplifier 26, the oversampling rate of the ADC 27, the precision of the ADC (e.g. increasing the number of bits) and/or by using a higher quality photodiode 11.
  • Figure 5 schematically illustrates a non-limiting example of a circuit 35 for providing all or part of a photocurrent processing channel 12, 25 of an assay device 1 according to some embodiments of the present disclosure.
  • the amplifier 26 may be provided by a first operational amplifier Al, having an inverting input connected to a first node 31, a non-inverting input connected to a second node 32, and an output connected to a third node 33.
  • a feedback network controls the gain of the first operational amplifier Al and includes a capacitor C/ and a resistor Rf, connected in parallel between the first and third nodes 31, 33.
  • a corresponding photodiode 11 is connected between the first and second nodes 31, 32.
  • the ADC 27 has a resolution of 16 bits, and has a positive input connected to the third node 33 and a negative input connected to the second node 32.
  • a second operational amplifier A2 has an inverting input and an output both connected to the second node 32, and a non-inverting input connected to a fourth node 34.
  • the fourth node 34 corresponds to the mid-point of a voltage divider formed from a pair of resistances 3 ⁇ 4.
  • One resistance Rd connects between the fourth node 34 and ground, whilst the other resistance 3 ⁇ 4 connects between the fourth node 34 and a reference voltage terminal of the ADC 27.
  • the circuit 35 may be particularly useful when multiple photodiodes 11 are configured with a common cathode.
  • the circuit 35 may have an effect of applying half the ADC 27 reference voltage V re f to the non-inverting input of the first operational amplifier A1 and the photodiode 11 cathode, and to measure a voltage difference between the output of the first operational amplifier A1 and This may sometimes be described as using the ADC 27 in a“pseudo- differential” mode.
  • the ADC 27 output V out may provide the output signal 14. Alternatively, when a filtering module 30 is used, the ADC 27 output V out may provide the digital signal 29 to the filtering module 30.
  • Figure 6 is a schematic illustration of a second assay device 36 according to some embodiments.
  • the second assay device 36 is the same as the assay device 1, except that the second assay device 36 further includes a determination module 37. Only part of the second assay device 36 is schematically illustrated in Figure 6 in the interests of brevity.
  • the determination module 37 is configured to determine, based on the received output signals 14, the presence and/or concentration of a target analyte within the liquid transport path 2. In some examples, an absorbance measured using the output signals 14 may be converted to an estimate of a concentration of the target analyte using an empirical relationship established based on calibration experiments performed using known concentrations of the target analyte.
  • the determination module 37 may be programmed with one or more suitable empirical relationships.
  • the determination module 37 may provide an output 38 in the form of one or more concentration values for the target analyte and/or a flag denoting the presence or absence of the target analyte.
  • the determination module 37 may be implemented by a processor of a microcontroller executing a compiled computer program stored in a memory of the microcontroller, using a suitably configured field-programmable gate array, using one or more digital electronic processors executing a compiled computer program and so forth.
  • the one or more photocurrent processing channels 12 and the determination module 37 may be integrated in a single unit, for example an application specific integrated circuit.
  • Figure 7 is a schematic illustration of a third assay device 39 and an external processing device 40, according to some embodiments of the present disclosure.
  • the third assay device 39 is the same as the assay device 1, except that the third assay device 39 further includes a communications interface 41. Only part of the third assay device 39 is schematically illustrated in Figure 7 in the interests of brevity.
  • the communications interface 41 is configured to provide the output signals 14 to the external processing device 40.
  • the communications interface 41 may operate according to any suitable wired or wireless data transmission protocol, for example a wired connection via universal serial bus or a wireless connection via Bluetooth (RTM).
  • the external processing device 40 may be a desktop computer, a laptop computer, a tablet computer, a mobile telephone, a handheld purpose specific computing device, and so forth.
  • the external processing device 40 is configured to determine, based on the received output signals 14, the presence and/or concentration of a target analyte within the liquid transport path 2. In some examples, an absorbance measured using the output signals 14 may be converted to an estimate of a concentration of the target analyte using an empirical relationship established from calibration experiments performed using known concentrations of the target analyte.
  • the external processing device 40 may be programmed with one or more suitable empirical relationships. The external processing device 40 may provide the output 38 in the form of one or more concentration values for the target analyte and/or a flag denoting the presence or absence of the target analyte.
  • the external processing device 40 may be implemented by a processor of a microcontroller executing a compiled computer program stored in a memory of the microcontroller, using a suitably configured field-programmable gate array, using one or more digital electronic processors executing a compiled computer program and so forth.
  • Figure 8 is a process flow diagram which schematically illustrates a first method of using an assay device 1, 36, 39 according to some embodiments of the present disclosure.
  • a quantity of liquid sample 6 is applied to the sample receiving portion 5 of the liquid transport path 2 (step SI).
  • the liquid sample 6 is left for a duration at least long enough for the liquid sample 6 to propagate through at least one illuminated portion 13 of the liquid transport path 2 (step S2).
  • the propagation period may be a pre-set interval, for example, 5 minutes, 10 minutes, as determined from calibration experiments.
  • Output signals 14 are obtained from the one or more photocurrent processing channels 12 of the assay device l(step S3). Output signals 14 may be obtained over a second duration long enough to ensure that the flow front 19 has passed through the liquid transport path 2, and that the assay has had sufficient development time. In some examples, dynamic
  • measurements may be obtained to permit tracking the rate of change of absorbance in each region of interest 23, as well as a final value.
  • the presence and/or concentration of a target analyte within the liquid transport path 2 is determined (step S4).
  • an absorbance measured using the output signals 14 may be converted to an estimate of a concentration of the target analyte using an empirical relationship established from calibration experiments performed using known concentrations of the target analyte.
  • the determination of the presence and/or concentration of a target analyte within the liquid transport path 2 may be carried out by the determination module 37 forming part of the assay device 1, 36, or by an external processing device 40 which is separate from the assay device 1, 39.
  • the first method is repeated for a new liquid transport path 2 and/or assay device 1, 36, 39 (step S5).
  • the first method is applicable to assay devices 1, 36, 39 which incorporate an integral liquid transport path 2.
  • the first method is also applicable to assay devices 1, 36, 39 into which the liquid transport path 2 is received after application of the liquid sample 6.
  • Figure 9 is a process flow diagram which schematically illustrates a second method of using an assay device 1, 36, 39 according to some embodiments of the present disclosure.
  • the liquid transport path 2 may be received into the assay device 1, 36, 39(step S6a). In examples in which the liquid transport path 2 is integrated as part of the assay device 1, 36, 39, this step is redundant.
  • step S6b If a liquid sample 6 has not previously been introduced to the liquid transport path 2, then the liquid sample 6 is applied to the sample receiving portion (step S6b). A delay to permit propagation of the liquid sample 6 may be necessary.
  • the second method may be commenced with a liquid transport path 2 already emplaced between the light source(s) 8 and photodiode(s) 11, and having allowed time for the assay to develop.
  • the one or more light sources 8 are illuminated to direct light 9 through one or more illuminated portions 10 of the liquid transport path 2, each illuminated portion 10 being located between the sample receiving portion 5 and the second end 4 (step S7).
  • the one of more photodiodes 11 receive the light 9 transmitted through the one or more illuminated portions 10 of the liquid transport path 2 (step S8). Each photodiode 11 supplies a photocurrent 13 to a corresponding photocurrent processing channel 12.
  • the one or more photocurrent processing channels 12 receive photocurrent(s) 13 from corresponding photodiodes 11, and each photocurrent processing channel 12 processes the received photocurrent 13 to generate a corresponding an output signal (step S9).
  • the resolution of each photocurrent processing channel 12 for detecting received photocurrent 13 is less than 1.5 pA.
  • Generating each output signal 14 may include obtaining an average across a period corresponding to one or more cycles of a mains electricity signal using the filtering module 30, such that any contribution of interference/pick-up from the mains electricity signal is reduced or removed from the output signal 14.
  • the presence and/or concentration of a target analyte within the liquid transport path 2 may be determined by the determination module 37 or the external processing device 40 (step S10).
  • step Sll the second method is repeated for a new liquid transport path 2 and/or assay device 1, 36, 39.
  • the second method is applicable to assay devices 1, 36, 39 which incorporate an integral liquid transport path 2.
  • the second method is also applicable to assay devices 1, 36, 39 into which the liquid transport path 2 is received after application of the liquid sample 6.
  • Figure 10 is a schematic illustration of a self-contained assay device 42 including an integral liquid transport path 2, according to some embodiments of the present disclosure.
  • the assay device 1, 36, 39 may take the form of a self-contained lateral flow testing device 42.
  • the lateral flow testing device 42 includes a liquid transport path 2 in the form of a porous strip 15 divided into a sample pad 43, a conjugate pad 44, a test pad 45 and a wick pad 46.
  • the porous strip 15 is supported by a substrate 20, and the lateral flow test strip 16 is received into a base 47.
  • a lid 48 is attached to the base 47 to secure the lateral flow test strip 16 and cover parts of the lateral flow test strip 16 which do not require exposure.
  • the lid 48 includes a sample receiving window 49 which exposes part of the sample pad 43 to define the sample receiving portion 5.
  • the lid 48 and base 47 are made from a polymer such as, for example, polycarbonate, polystyrene, polypropylene or similar materials.
  • the base 47 includes a recess 50 into which a pair of light sources 8 are received (for example organic light-emitting diodes).
  • the lid 48 includes a recess 51 into which a pair of photodiodes 11 are received.
  • One pair of a light source 8 and a corresponding photodiode 11 are arranged on opposite sides of a test region 21 formed in the test pad 45 of the porous strip 15.
  • a second pair of a light source 8 and a corresponding photodiode 11 are arranged on opposite sides of a control region 22 formed in the test pad 45 of the porous strip 15.
  • Slit members 52 separate the light sources 8 from the porous strip 15 to define narrow slits 53 with widths typically in the range between 300 pm to 500 pm inclusive.
  • the slit members 52 define slits 53 which extend transversely across the width of the porous strip 15. For example, if the porous strip 15 extends in a first direction x and has a thickness in a third direction z, then the slits 53 extend in a second direction y. Further slit members 52 define slits 53 which separate the photodiodes 11 from the porous strip 15. The slits 53 may be covered by a thin layer of transparent material to prevent moisture entering into the recesses 50, 51.
  • Material may be considered to be transparent to a particular wavelength l, or range of wavelengths Dl, if it transmits more than 50%, more than 75%, more than 85%, more than 90% or more than 95% of the light at that wavelength l, or within the range of wavelengths Dl.
  • a diffuser (not shown) may optionally be included between each light source 8 and the corresponding slit 53.
  • a controller 54 is housed within the base 47, and integrates the functions of a pair of photocurrent processing channels 12 and the determination module 37. Alternatively, the controller 54 may be housed within the lid 48.
  • One or more output devices 55 are housed in the lid 48.
  • the one or more output devices 55 may be provided elsewhere in the lateral flow testing device 42 provided that the output devices 55 are visible and/or accessible to a user when the lateral flow testing device 42 is resting on a flat surface with the sample receiving window 49 facing up.
  • the output device(s) 55 may display an indication of the output 38 in the form of a presence or concentration of the target analyte in the liquid sample 6.
  • the output devices 55 may display the results of comparing a measured concentration of the target analyte against a threshold.
  • the output devices 55 may provide indications in the form of“positive”, or“negative” and so forth.
  • the output devices 55 may include organic or inorganic light-emitting diodes, a liquid crystal display, a buzzer or sounder, and so forth. Additionally or alternatively, the output devices 55 may also include a communications interface for outputting the results 38 via a wired or wireless connection.
  • the controller 54 is connected to the light sources 8, photodiodes 11, output devices 56 and a battery (not shown) by suitable conductors (not shown).
  • the self- contained lateral flow testing device 42 may not need a battery (not shown) and may instead be powered via a communications interface such as, for example, a universal serial bus (USB) connection.
  • USB universal serial bus
  • a liquid sample 6 suspected of containing a target analyte is introduced to the sample receiving portion 5 through the sample receiving window 49 using, for example, a dropper 56 or similar implement.
  • a liquid sample 6 may be introduced by dipping the sample receiving window 49 in a container holding liquid sample 6, or by placing the sample receiving window 49 so as to intersect a flow of liquid sample 6, and so forth.
  • the liquid sample 6 is transported along the liquid transport path 2 towards the second end 4 by a capillary, or wicking, action of the porosity of the porous strip 43, 44, 45, 46.
  • the sample pad 43 of the porous strip 15 is typically made from fibrous cellulose filter material.
  • the conjugate pad 44 has been pre-treated with at least one particulate labelled binding reagent for binding an analyte which is being tested for, to form a labehed-particle-analyte complex (not shown).
  • a particulate labelled binding reagent is typically, for example, a nanometre- or micrometre- sized label particle which has been sensitised to specifically bind to the analyte, for example, using antibodies or antigens.
  • the particles provide a detectable response, which is usually a visible optical response such as a particular colour, but may take other forms. For example, particles may be used which are visible under infrared or ultraviolet light, and so forth.
  • the conjugate pad 44 will be treated with one type of particulate labelled binding reagent to test for the presence of one type of analyte in the liquid sample 6.
  • lateral flow devices 42 may be produced which test for two or more analytes using two or more particulate labelled binding reagents concurrently (for example multiple test regions 21).
  • the conjugate pad 44 is typically made from fibrous glass, cellulose or surface modified polyester materials.
  • labelled-particle-analyte complexes and unbound label particles are carried along towards the second end 4.
  • the test pad 45 includes one or more test regions 21 and control regions 22, each of which are monitored by a corresponding light source 8 and photodiode 11 pair.
  • a test region 21 is pre-treated with an immobilised binding reagent which specifically binds the labelled-particle-analyte complexes and which does not bind the unreacted label particles.
  • concentration increase may be monitored by measuring the absorbance of the test region 21 using the corresponding light source 8 and photodiode 11 as described hereinbefore.
  • the absorbance of the test region 21 may be measured once a set duration has expired since the liquid sample 6 was added. Alternatively, the absorbance of the test region 21 may be measured continuously or at regular intervals as the lateral flow strip 16 is developed.
  • a control region 22 is often provided between the test region 21 and the second end 4.
  • the control region 22 is pre-treated with a second immobilised binding reagent which specifically binds unbound label particles and which does not bind the labelled-particle- analyte complexes.
  • the control region 22 may be pre-treated with a non specific immobilised binding reagent which binds either unbound label particles or labelled- particle-analyte complexes. In this way, if the lateral flow testing device 42 has functioned correctly and the liquid sample 6 has passed through the conjugate pad 44 and the test pad 45, the control region 22 will exhibit a change in absorbance.
  • the absorbance of the control region 22 may be measured by the second pair of a light source 8 and a photodetector 11, in the same way as the test region 21.
  • the test pad 45 is typically made from fibrous nitrocellulose, polyvinylidene fluoride, polyethersulfone (PES) or charge modified nylon materials.
  • the wick pad 46 provided proximate to the second end 4 soaks up liquid sample 6 which has passed through the test pad 45 and helps to maintain through-flow of the liquid sample 6.
  • the wick pad 46 is typically made from fibrous cellulose filter material.
  • FIGs 11 A and 1 IB are schematic illustrations of an assay device 1 in the form of a reading device 57 for receiving lateral flow test strips 16, according to some embodiments of the present disclosure.
  • the reading device 57 includes first and second light sources 8a, 8b (for example organic light emitting diodes), first and second photodiodes 11a,
  • the reading device 57 also includes a slot 60 for receiving a liquid transport path 2.
  • the slot 60 may be formed as a feature of the casing 59.
  • the slot 60 has a first end open at an exterior of the reading device 57, and a second, closed end 61.
  • the first light source 8a faces the first photodiode 1 la across the slot 60 to form a first pair 8a, 1 la.
  • the illuminated section 10 is delimited by slits 53 formed on either side of the slot 60.
  • the slits 53 may be integrally formed as features of the casing 59.
  • the second light source 8b faces the second photodiode 1 lb across the slot 60 to form a second pair 8b, 1 lb.
  • a liquid transport path 2 in the form of a lateral flow test strip 16 is received into the slot 60 and pressed into the reading device 57 until the second end 4 of the lateral flow test strip 16 abuts the closed end 61 of the slot 60.
  • the test region 21 is aligned within the illuminated portion 10 corresponding to the first light source 8a and the control region 22 is aligned with the illuminated portion 10 corresponding to the second light source 8b.
  • an absorbance of the test region 21 may be measured using the first pair 8a, 11a and an absorbance of the control region 22 may be measured using the second pair 8b, 1 lb.
  • the controller 54 determines the presence and/or concentration of the target analyte in the test region 21, and may use the control region 22 to verify that the assay has been performed correctly.
  • the results are output via the one or more output devices 55 as described hereinbefore, for example either directly to a user using one or more light emitters and/or displays, or via a wired or wireless communications interface.
  • the reading device 57 may include a pair of a light source 8 and a photodiode 11 corresponding to each region of interest 23 and optionally each reference region 24 of lateral flow test strips 16 to be measured.
  • the reading device 57 may include a single light source 8 and photodiode 11 pair, and a lateral flow test strip 16 may be passed through the illuminated portion 10 to scan the whole or a part of the length of the lateral flow test strip 16. In this way, multiple regions of interest 23 and/or reference regions 24 may be measured without requiring multiple light sources 8 and corresponding photodiodes 11.
  • Figure 11B illustrates a free-standing lateral flow test strip 16 being directly received into the reading device 57
  • the reading device 57 may be configured to receive lateral flow test strips 16 which are packaged within containers or cassettes (not shown).
  • lateral flow test strips 16 may be packaged with opaque (as previously defined) containers or cassettes and the reading device 57 may perform measurements through the opaque container or cassette.
  • the reading device 57 may include a moveable sample receiving stage (not shown) on or within which a packaged or free-standing lateral flow test strip 16 may be placed and/or secured.
  • the sample receiving stage may be moveable between a first position in which a lateral flow test strip 16 may be placed and/or secured, and one or more further positions in which one or more regions of interest 23 and/or reference regions 24 are arranged within corresponding illuminated portions (s) 10 of the reading device 57.
  • the sample receiving stage may be motorised and controlled by the controller 54.
  • Measurements may be triggered automatically when a lateral flow test strip 16 is received into the reading device 57.
  • a micro-switch or light gate may determine when the second end 4 of the lateral flow test strip 16 abuts the closed end 61 of the slot 60.
  • the reading device 57 may include an input device such as a switch or button which a user may actuate to trigger the controller 54 to obtain a measurement once a lateral flow test strip 16 has been loaded.
  • an input device such as a switch or button which a user may actuate to trigger the controller 54 to obtain a measurement once a lateral flow test strip 16 has been loaded.
  • Figure 12 presents measurements of changes in optical density (absorbance) of a test region 21 of a lateral flow test strip 16 over a duration following introduction of a liquid sample 5, and obtained using an example of an assay device 1 according to some embodiments of the present disclosure.
  • the data for Figure 12 were obtained using an assay device 1 having a photocurrent processing channel 12 which included the exemplary circuit 35 and also a filtering module 30.
  • the data were obtained using an ADC 27 sampling rate of 50 kHz.
  • Subsequent processing by the filtering module 30 obtained averages over 20 ms periods, i.e. over 1,000 samples.
  • Figure 13 presents measurements of changes in optical density (absorbance ) of a test region 21 of a lateral flow test strip 16 over the duration following introduction of a liquid sample 5, and obtained using a comparative assay device (not shown) which lacked the sensitivity according to embodiments of the present specification.
  • the data for Figure 13 were obtained using a comparative assay device (not shown) which included an amplifier 26 having the same gain and bandwidth as the exemplary circuit 35, but having a different ADC. Unlike the circuit 35, the ADC used for comparative assay device was 12-bit, was operated at a sampling rate of 12.5 kHz, and was not configured to permit effective filtering of mains electrical 50Hz noise.
  • testing kits including an assay device 1, 36, 39 or reader 57 and a liquid transport path 2 adapted to be received by the assay device 1, 36, 39 or reader 57.
  • liquid transport paths 2 in the form of lateral flow test strips 16.
  • other types of liquid transport path 2 may be used such as, for example, one or more channels 17 ( Figure 14) of a microfluidic device 18 ( Figure 14).
  • Figures 14 is a schematic illustration of a fourth assay device 62 according to some embodiments of the present disclosure.
  • the fourth assay device 62 is similar to the assay devices 1, 36, 39 described hereinbefore, except that the liquid transport path 2 takes the form of one or more channels 17 of a microfluidic device 18. Only the portions of the fourth assay device 62 which differ from previous examples are shown.
  • the one or more channels 17 are formed within a microfluidic structure 63 such as, for example, a section 64 defining the one or more channels 17, sealed with a top plate 65, for example a glass slide or a plastic sheet.
  • the section 64 may be moulded, milled, cast, and so forth.
  • First and second ports 66, 67 may be used to inject and/or extract liquid sample 5 from the channel 17.
  • Liquid sample 5 may be flowed continuously through the channel 17, for example from the first port 66 to the second port 67.
  • liquid sample 5 may be introduced into the channel 17 and left for a predetermined duration.
  • an assay may be an enzyme amplified assay (ELISA), in which a target analyte may be bound to an enzyme and also bound to the channel 17 walls.
  • the liquid sample 5 may comprise a substrate which is converted into a labelling substance by the enzyme bound to the target analyte.
  • ultra-sensitive ( ⁇ 1.5 pA) photocurrent processing channels 12 may enable improvements in sensitivity, use of opaque materials for the microfluidic structure 63 and/or use of low grade (EQE ⁇ 0.5%) organic light-emitting diodes, in a similar way as for the first, second or third assays devices 1, 36, 39, the self-contained assay device 42 and/or the reader 57.
  • Figures 15 is a schematic illustration of fifth assay device 68 according to some embodiments of the present disclosure.
  • the fifth assay device 68 is the same as the assay devices 1, 36, 39, 42 and/or reader 57 described hereinbefore, except that the fifth assay device 68 includes one or more first light sources 69 and one or more second light sources 70 corresponding to each illuminated portion 10. Only the portions of the fifth assay device 68 which differ from previous examples are shown.
  • Each first light source 69 emits first light 71 having a first spectral bandwidth DC / centred at a first wavelength 2;
  • each second light source 70 emits second light 72 having a second spectral bandwidth Dl2 centred at a second wavelength X2.
  • the first spectral bandwidth Dli corresponds to light 71 which is relatively strongly absorbed by a target analyte, or labelling particles or molecules bound to or associated with the target analyte.
  • the second spectral bandwidth Dl2 corresponds to light 72 which does not significantly interact with a target analyte, or with labelling particles or molecules bound to, or associated, with the target analyte.
  • a lateral flow test strip 16 including a substrate 20 and a porous strip 15 is between, or may be received between, the light sources 69, 70 and photodiode(s) 11, such that the substrate 20 is between the light sources 69, 70 and the porous strip 15.
  • the substrate is opaque, and strongly scatters light 71, 72 across a wide range of wavelengths. In this way, the substrate 20 may act as a diffuser, so that light sources 69, 70 which are placed side-by-side, or interdigitated, may provide relatively uniform illumination of the porous strip 15 within the illuminated portion 10.
  • the porous strip 15 is typically made of fibres (not shown) which scatter and/or absorb light across a broad range of wavelengths in an approximately similar way.
  • the proportion of light 71 at the first wavelength X which is scattered or absorbed by the porous strip 15 is approximately the same as the proportion of light 72 at the second wavelength /.2 which is scattered or absorbed by the porous strip 15.
  • the porous strip 15 is not physically uniform, and the density of fibres may vary from point to point along the porous strip 15. Such background variations of absorbance, which are due to inhomogeneity of the porous strip 15, may limit the sensitivity of a measurement.
  • the fifth assay device 68 may compensate for such background variations of absorbance due to the inhomogeneity of the porous strip 15 (or other structure(s) providing the liquid transport path 2), provided that the target analyte, or labelling particles or molecules bound to or associated with the target analyte, have an absorbance spectrum which exhibits significant differences between the first and second wavelengths li,
  • the first spectral bandwidth Dli corresponds to first light 71 which is relatively strongly absorbed by a target analyte, or labelling particles or molecules bound to or associated with the target analyte
  • the second light 72 having second spectral bandwidth Dl2 is relatively weakly absorbed.
  • the first and second light sources 69, 70 are illuminated alternately, and corresponding output signals 14 are recorded.
  • the output signals 14 may be converted into a first absorbance A; measured using the first spectral bandwidth Dli, and a second absorbance A2 measured using the second spectral bandwidth A2.
  • the first absorbance A includes contributions from the porous strip 15 and also from the target analyte, or labelling particles or molecules bound to, or associated with, the target analyte. There is also an additional contribution due to an absorbance of the substrate 20.
  • the second absorbance A2 only includes a significant contribution from the porous strip 15, in addition to a contribution from the substrate 20.
  • the relative contribution from the porous strip 15 (and the substrate) may be reduced or removed. In this way, the sensitivity of the fifth assay device 68 may be further improved.
  • the use of the opaque substrate 20 as a diffuser in order to implement a two-colour background correction is enabled by the ultra-sensitive ( ⁇ 1.5 pA) resolution of photocurrent processing channels 12 of assay devices 1, 36, 39, 42, 62, 68 and readers 57 according to the present specification.
  • the fifth assay device 68 has been described with a pair of light sources 69, 70 and a single photodiode 11.
  • a single light source 8 which emits light 71, 72 spanning, or at least including, both spectral bandwidths Dli, D/.2 may be used instead.
  • a first photodiode 11 may have a filter (not shown) which blocks the second spectral bandwidth Dl2 and a second photodiode 11 may have a filter which blocks the first spectral bandwidth Dli.
  • the lateral flow strip 16 is preferably oriented with the substrate 20 closest to the pair of filtered photodiodes 11. In this way, the substrate 20 may act as a diffuser for light 71, 72 which has passed through the porous strip 15, before the light 71, 72 reaches the first and second photodiodes 11.
  • ultra-sensitive ( ⁇ 1.5 pA) photocurrent processing channels 12 may provide further flexibility in the design of assay devices 1, 36, 39, 42, 62, 68 and/or readers 57, enabling functional modifications which might decrease photocurrent signals below a detection threshold of a less sensitive devices.
  • one or more reference regions 24 of the lateral flow test strip 16 may be made relatively narrower (for example ⁇ 1 mm wide) compared to one or more regions of interest 23.
  • the potential advantage from making reference regions 24 relatively narrower may originate from using regions of interest 23 which are at least wide enough to accommodate variability in the positions of test and control regions 21, 22 along the flow direction 7.
  • the width of regions of interest 23 can only be increased at the expense of decreasing the width of adjacent reference regions 24. Narrowing of the reference regions 24 will decrease a photocurrent 13 measured by a corresponding photodiode 11.
  • ultra-sensitive ( ⁇ 1.5 pA) photocurrent processing channels 12 may enable reference regions 24 to be relatively narrowed, whilst retaining sufficient resolution for background correction purposes. In this way, a width available for regions of interest 23 may be increased. Increasing the width of regions of interest 23 may permit relaxation of the tolerances for forming and/or positioning test and control regions 21, 22 with respect to an assay device 1, 36, 39, 42, 62, 68 or reader 57.
  • the alternative fifth assay device 68 described hereinbefore may employ a single light source 8 which emits light 71, 72 in combination with a pair of first and second photodiodes 11 having respective filters (not shown) which block light in the first or second spectral bandwidths Dli, A /.j ⁇
  • the filters (not shown) may be printed on the top of photodiodes 11. Ideal filters would provide 100% transmission for a desired pass-band, for example the first spectral bandwidth Dli, and 0% transmission outside the desired pass-band, for example the second spectral bandwidth Dl2 (complete blocking). In practice, a printed filter may absorb a significant amount of light even in the desired pass-band, which decreases a photocurrent 13 measured by a corresponding photodiode 11.
  • Ultra- sensitive ( ⁇ 1.5 pA) photocurrent processing channels 12 may enable filters used for two- colour background subtraction to be made relatively thicker in order to block more undesired light, without a corresponding decrease in the intensity of the transmitted light in the desired pass-band from becoming limiting.
  • the fifth assay device 68 (and the alternative using a pair of photodiodes) which implement a two-colour background correction works best when there is an efficient spatial intermixing of the two colours of light 71, 72 transmitted to, or received from, the liquid transport path 2.
  • improved intermixing may be achieved by increasing a distance between the liquid transport path 2 and the photodiode 11 (for examples using a single light source 8 and pair of photodiodes 11), or between the liquid transport path 2 and the first and second light sources 69, 70 (for examples using two light sources 69, 70 and a single photodiode).
  • photocurrent processing channels 12 may enable increasing the separation between optical components whilst maintaining a sufficient resolution to perform measurements of an assay.
  • a separation between a pair of light sources 69, 70 may be increased in combination with a decreased width of a reference region 24. This may compound a decrease in the photocurrent 13 corresponding to the reference region 24.
  • relatively narrowed reference regions 24 may be combined with relatively thickened printed colour filters for a two-colour background correction.
  • the use of ultra- sensitive ( ⁇ 1.5 pA) photocurrent processing channels 12 according to the present specification may provide sufficient resolution for viable measurements of an assay to be obtained.

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Abstract

L'invention concerne un dispositif de dosage (1) pour déterminer la présence et/ou la concentration d'un analyte cible au sein d'un trajet de transport de liquide (2). Le dispositif de dosage (1) est conçu pour au moins partiellement recevoir un trajet de transport de liquide (2) ayant une première extrémité (3), une seconde extrémité (4) et une partie de réception d'échantillon (5) à proximité de la première extrémité (3). Le trajet de transport de liquide (2) est conçu pour transporter un échantillon liquide (6) reçu dans la partie de réception d'échantillon (5) vers la seconde extrémité (4). Le dispositif de dosage (1) comprend une ou plusieurs sources de lumière (8). Lesdites une ou plusieurs sources de lumière (8) sont agencées de telle sorte que, lorsque le trajet de transport de liquide (2) est reçu par le dispositif de dosage (1), lesdites une ou plusieurs sources de lumière (8) éclairent une ou plusieurs parties éclairées (10) du trajet de transport de liquide (2) qui sont situées entre la partie de réception d'échantillon (5) et la seconde extrémité (4). Le dispositif de dosage (1) comprend également une ou plusieurs photodiodes (11). Lesdites une ou plusieurs photodiodes (11) sont agencées de telle sorte que, lorsque le trajet de transport de liquide (5) est reçu par le dispositif de dosage (1), lesdites une ou plusieurs photodiodes (11) reçoivent une lumière (9) transmise à travers une partie éclairée (10) du trajet de transport de liquide (2). Le dispositif de dosage (1) comprend également un ou plusieurs canaux de traitement à courant photoélectrique (12). Chaque canal de traitement à courant photoélectrique (12) est configuré et agencé pour recevoir un courant photoélectrique (13) à partir d'une photodiode correspondante (11), et pour fournir un signal de sortie correspondant (14). Le courant photoélectrique détectable minimal est inférieur ou égal à 1,5 pA pour chaque canal de traitement à courant photoélectrique (12).
PCT/GB2020/050467 2019-03-06 2020-02-27 Dispositif de dosage WO2020178557A1 (fr)

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WO2024012825A1 (fr) * 2022-07-13 2024-01-18 Ams-Osram Ag Cassette de bandelette réactive, dispositif de surveillance et procédé de fabrication d'une cassette de bandelette réactive

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