WO2021178760A1 - Dispositifs et procédés de détection d'un analyte cible d'intérêt - Google Patents

Dispositifs et procédés de détection d'un analyte cible d'intérêt Download PDF

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Publication number
WO2021178760A1
WO2021178760A1 PCT/US2021/021027 US2021021027W WO2021178760A1 WO 2021178760 A1 WO2021178760 A1 WO 2021178760A1 US 2021021027 W US2021021027 W US 2021021027W WO 2021178760 A1 WO2021178760 A1 WO 2021178760A1
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WIPO (PCT)
Prior art keywords
filter
receptor
binding
sensor
indicator
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PCT/US2021/021027
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English (en)
Inventor
Min Hu
Jacob TREVINO
Brendan Walker
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Drinksavvy, Inc.
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Application filed by Drinksavvy, Inc. filed Critical Drinksavvy, Inc.
Publication of WO2021178760A1 publication Critical patent/WO2021178760A1/fr

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    • 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
    • G01N33/536—Immunoassay; Biospecific binding assay; Materials therefor with immune complex formed in liquid phase
    • G01N33/542—Immunoassay; Biospecific binding assay; Materials therefor with immune complex formed in liquid phase with steric inhibition or signal modification, e.g. fluorescent quenching
    • 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
    • G01N21/55—Specular reflectivity
    • G01N21/552—Attenuated total reflection
    • G01N21/553—Attenuated total reflection and using surface plasmons
    • G01N21/554—Attenuated total reflection and using surface plasmons detecting the surface plasmon resonance of nanostructured metals, e.g. localised surface plasmon resonance
    • 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
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N21/7703—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator using reagent-clad optical fibres or optical waveguides
    • G01N21/774—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator using reagent-clad optical fibres or optical waveguides the reagent being on a grating or periodic structure
    • G01N21/7743—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator using reagent-clad optical fibres or optical waveguides the reagent being on a grating or periodic structure the reagent-coated grating coupling light in or out of the waveguide
    • 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
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N21/78—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator producing a change of colour
    • 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
    • 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
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N2021/7756—Sensor type
    • G01N2021/7763—Sample through flow
    • 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
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N2021/7769—Measurement method of reaction-produced change in sensor
    • G01N2021/7786—Fluorescence

Definitions

  • the present invention relates to devices and methods for the detection of analytes in a liquid sample. More specifically, the devices and methods have a high affinity for an analyte, are capable of detecting analytes in low concentrations, such as protein biomarkers, drugs, or toxins, and provide either an optical or electrical signal as a notification to an end user upon detection.
  • the devices and methods have a high affinity for an analyte, are capable of detecting analytes in low concentrations, such as protein biomarkers, drugs, or toxins, and provide either an optical or electrical signal as a notification to an end user upon detection.
  • Point-of-care (POC) diagnostics in particular is one of the fastest growing markets in life sciences, with the benefits including quick and efficient testing and the abilities to reach more patients, eliminate follow-up visits, and ultimately save money and lives in the healthcare system.
  • POC diagnostics have many direct applications in hospital systems, pharmacies, critical care settings, mobile settings, and resource-limited settings.
  • ELISA enzyme-linked immunoassay
  • LFA lateral flow immunoassay
  • RNA ribonucleic acid
  • RT-PCR real time reverse transcription polymerase chain reaction
  • the binding condition is a binding of the analyte of interest to the binding material, or, in the alternative, a lack of binding of the analyte of interest to the binding material.
  • the receptor may be or include a filter.
  • the filter may have, in various embodiments, a plurality of: air voids, pores, openings, channels, nanoholes, microholes, holes, nanopillars, micropillars, pillars, microfins, nanofins, fins, nanostructures, microstructures, and/or structures with millimeter scale.
  • the filter may also be a portion of a microchannel coated with a film or layer of the binding material.
  • the binding material may be a MIP material, an aptamer material, a SOMAmer, an affirmer, an antibody, a peptide, DNA,
  • the binding material may include at least one of a specific binding enhancement layer or an additional layer to reduce non-specific binding from non-target substances in the fluid.
  • the binding material may include hydrophobic components, hydrophilic components coated with a hydrophobic layer, or combinations thereof.
  • the indicator may be either a colorimetric indicator or an electric transducer.
  • the colorimetric indicator may be or include, for example, a plurality of nanoparticles, a Bragg reflective coating, a photonic crystal, an interference based thin film reflector, a plasmonic array of pillars, a plasmonic nanoparticle thin film, a chromophore, a fluorophore, a dye, a pigment, a hydrochromic ink, a material coated with the hydrochromic ink, and combinations thereof.
  • the electric transducer may be configured to measure, for example, a variable such as resistance, capacitance, voltage, current, pressure, and combinations thereof.
  • the senor may also include a sample introduction chamber and a microchannel providing fluidic communication between the sample introduction chamber and the indicator.
  • the receptor may be disposed in the microchannel.
  • the sensor includes a plurality of microchannels, each of which contains a corresponding receptor, and a plurality of indicators, each of which is in fluidic communication with a corresponding microchannel and its respective receptor. In some variations of this latter embodiment, at least one of the receptors differs from at least one other receptor and/or at least one of the indicators differs from at least one other indicator.
  • FIGURE 1 A shows a plan (top) view of an exemplary (e.g., analyte) filter-based sensor, in accordance with some embodiments of the present invention
  • FIGURE IB shows a side (elevation) view of the (e.g., analyte) filter-based sensor of FIGURE 1 A, in accordance with some embodiments of the present invention
  • FIGURE 2A shows a side (elevation) view of an exemplary composite sensor under hydrophobic conditions, in accordance with some embodiments of the present invention
  • FIGURE 2B shows a plan (top) view of the (e.g., analyte) filter portion of the composite sensor of FIGURE 2A, in accordance with some embodiments of the present invention
  • FIGURE 3A shows a side (elevation) view of an exemplary composite sensor under hydrophilic conditions, in accordance with some embodiments of the present invention
  • FIGURE 3B shows a side (elevation) view of the composite sensor of FIGURE 3 A under hydrophobic conditions, in accordance with some embodiments of the present invention
  • FIGURE 3C shows a plan (top) view of the (e.g., analyte) filter portion of the composite sensor of FIGURE 3 A, in accordance with some embodiments of the present invention
  • FIGURE 4 A shows a side (elevation) view of an exemplary (e.g., analyte) filter- based sensor having a pillar array, in accordance with some embodiments of the present invention
  • FIGURE 4B shows a plan (top) view of the (e.g., analyte) filter-based sensor of FIGURE 4A, in accordance with some embodiments of the present invention
  • FIGURE 5A shows a side (elevation) view of an exemplary filter-based sensor having a pillar array under hydrophobic conditions, in accordance with some embodiments of the present invention
  • FIGURE 5B shows a side (elevation) view of the filter-based sensor of FIGURE 5 A under hydrophilic conditions, in accordance with some embodiments of the present invention
  • FIGURE 6A shows a side (elevation) view of an exemplary lateral, filter-based sensor, in accordance with some embodiments of the present invention
  • FIGURE 6B shows a plan (top) view of the exemplary lateral, filter-based sensor shown in FIGURE 6A, in accordance with some embodiments of the present invention
  • FIGURE 7A shows an exemplary composite sensor having a lateral filter and a structural color indicator under hydrophobic conditions, in accordance with some embodiments of the present invention
  • FIGURE 7B shows the composite sensor of FIGURE 7A under hydrophilic conditions, in accordance with some embodiments of the present invention
  • FIGURE 8A shows a plan (top) view of an exemplary sensor having a filter disposed in a microchannel and a colorimetric indicator, in accordance with some embodiments of the present invention
  • FIGURE 8B shows a side (elevation) view of the exemplary sensor shown in FIGURE 8A, in accordance with some embodiments of the present invention
  • FIGURE 8C shows a cross-section of an exemplary Bragg reflective coating used as the colorimetric indicator shown in FIGURE 8A, in accordance with some embodiments of the present invention
  • FIGURE 8E shows a cross-section of exemplary nanoparticles used as the colorimetric indicator shown in FIGURE 8A, in accordance with some embodiments of the present invention
  • FIGURES 9A through 9C show schematically the operation of the sensor shown in FIGURE 8A, in accordance with some embodiments of the present invention.
  • FIGURE 10A shows a plan (top) view of an exemplary sensor having a filter, including an array of micropillars/nanopillars, disposed in a microchannel and a colorimetric indicator, in accordance with some embodiments of the present invention
  • FIGURE 10B shows a side (elevation) view of the exemplary sensor shown in FIGURE 10A, in accordance with some embodiments of the present invention
  • FIGURES 11A through 11C show schematically the operation of the sensor shown in FIGURE 10A, in accordance with some embodiments of the present invention.
  • FIGURE 12A shows a plan view of an exemplary sensor having a filter, including a microstructure or nanostructure, disposed in a microchannel and a colorimetric indicator, in accordance with some embodiments of the present invention
  • FIGURE 12B shows a side (elevation) view of the exemplary sensor shown in FIGURE 12A, in accordance with some embodiments of the present invention
  • FIGURES 13A through 13C show schematically the operation of the sensor shown in FIGURE 12A, in accordance with some embodiments of the present invention.
  • FIGURE 14 shows an exemplary sensor having a plurality of microchannels with corresponding filters and colorimetric indicators, in accordance with some embodiments of the present invention;
  • FIGURE 17A shows a plan (top) view of an exemplary sensor having a filter disposed in a microchannel and an electric transducer, in accordance with some embodiments of the present invention
  • FIGURES 18A and 18B show schematically the operation of the sensor shown in FIGURES 17A and 17B, in accordance with some embodiments of the present invention
  • FIGURE 22 shows an exemplary receptor fabricated with aptamers, in accordance with some embodiments of the present invention.
  • FIGURE 24 shows a schematic of an exemplary binding process using another exemplary receptor fabricated with aptamers, in accordance with some embodiments of the present invention.
  • compositions and devices such as a sensor are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions and devices of the present disclosure that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present disclosure that consist essentially of, or consist of, the recited processing steps.
  • the in-flow and/or presence of a specific fluid such as a fluid containing a target analyte of interest (e.g., fuel containing contaminants, blood containing certain biomarkers for certain diseases, liquid containing certain drugs, and the like), may be detected using filter-based colorimetric devices having colorimetric (e.g., dye, pigment, photonic crystal, and the like) indicators that are structured and arranged to exhibit an observable change in color upon contact with the fluid.
  • a filter-based colorimetric sensing device, or sensor, 100 is shown.
  • the three-dimensional (3D) sensor 100 includes a receptor 140 (e.g., a 3D filter 140) and an indicator 150 (e.g., a colorimetric indicator 150) that are physically spaced from one another and that are structured and arranged to verify or confirm the presence (or absence) of the specific fluid (e.g., a fluid containing the target analyte of interest).
  • a receptor 140 e.g., a 3D filter 140
  • an indicator 150 e.g., a colorimetric indicator 150
  • the (e.g., 3D) filter 140 may include a base substrate 110 in which a plurality of air voids, pores, openings, channels, holes (e.g., nanoholes or microholes), or the like (collectively “openings”) 120 may be formed (e.g., in an array).
  • the base substrate 110 may be a solid structure having a plurality of faces.
  • the base substrate 110 may be manufactured of a dielectric or insulative material (e.g., silica, titanium dioxide, silicon nitride, and the like), a (e.g., organic, inorganic, or hybrid) molecularly-imprinted polymer (MIP) material, a metallic material (e.g., gold, silver, aluminum, and the like), a metallic material coated with an MIP material, and combinations thereof.
  • a dielectric or insulative material e.g., silica, titanium dioxide, silicon nitride, and the like
  • MIP molecularly-imprinted polymer
  • metallic material e.g., gold, silver, aluminum, and the like
  • a metallic material coated with an MIP material e.g., gold, silver, aluminum, and the like
  • openings 120 are flow-through channels through which a liquid may flow from the top surface of the filter 140 through the openings 120 to the bottom surface of the filter 140, where the colorimetric indicator 150 is disposed a spatial distance 160 from the filter 140.
  • the surface of the openings 120 may be coated with a (e.g., thin) layer of a binding material 130 (e.g., analyte receptor 130), such as MIP material, aptamer material, slow off-rate modified aptamers (SOMAmers), affirmers, antibodies, peptide, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), peptide nucleic acid (PNA), oligonucleotides, coordination complex, metal organic framework (MOF) materials, porous coordination polymer materials, and so forth, or combinations thereof.
  • a binding material 130 e.g., analyte receptor 130
  • MIP material e.g., MIP material, aptamer material, slow off-rate modified aptamers (SOMAmers), affirmers, antibodies, peptide, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), peptide nucleic acid (PNA), oligonucleotides, coordination complex, metal
  • the thickness of the analyte receptor coating 130 may range from about 1 Angstrom (e.g., in the case of a molecular monolayer) to about a thickness of approximately the radius of the (e.g., circular) opening 120.
  • the analyte receptor coating 130 may also include a binding material produced from hydrophobic components, so that the binding material is hydrophobic, or produced from hydrophilic binding materials coated with a hydrophobic layer, or combinations thereof.
  • the analyte receptor coating 130 may also include a specific binding enhancement layer or an additional layer to reduce non-specific binding from non-target substances in the liquid. Non-limiting examples of such a layer include polymer brushes, zwitterionic polymers, and so forth.
  • FIGURE 1A shows a square, 3 by 3 array of circular openings 120, that is done for the purpose of illustration rather than limitation. Indeed, any number of openings 120, any shape of openings, and any arrangement or distribution of openings 120 on the filter 140 may be used.
  • openings 120 may be formed in the filter 140 in a periodic, aperiodic, and/or random array.
  • the openings 120 may be separated from each other, interconnected, or a combination of the two. Separation distances between (e.g., adjacent) openings may be as close as about 0.275 nanometers (“nm”).
  • the diameter of the (e.g., circular) openings 120 may range from about 0.001 nm to about 10,000 microns. Those skilled in the art can appreciate that selection of the size (e.g., diameter or other dimension) of the openings 120 may depend on the target analyte of interest; hence, the size of the openings 120 may be smaller than 0.001 nm or larger 10,000 microns.
  • the (e.g., circular) opening diameters or widths shown in FIGURE 1 A appear to be uniform in dimension, that, too, is done for the purpose of illustration rather than limitation. Indeed, in some variations, a variety of opening diameters or other dimensions may be formed on a single filter 140. Moreover, the diameters or dimensions of the openings 120 may vary within a single filter 140.
  • a hydrophobic material e.g., Teflon, silane, and the like
  • the hydrophobic coating is designed to repel all fluids that do not contain the target analyte of interest, thereby preventing the fluid from infiltrating the openings 120.
  • the openings 120 may be coated with a hydrophobic material as well as with the analyte receptor 130.
  • the colorimetric indicator 150 is structured and arranged to exhibit a color change upon passage of a fluid through the openings 120 of the filter 140 and into contact with the colorimetric indicator 150.
  • the colorimetric indicator 150 is a structural color indicator.
  • Exemplary structural color indicators include Bragg reflective coatings, photonic crystals, interference based thin film reflectors, and plasmonic arrays of micropillars or nanopillars, such as, for example, the plasmonic array of micropillars or nanopillars described below with reference to FIGURE 2C.
  • the detectable visible color difference i.e., the change of color
  • the detectable visible color difference i.e., the change of color
  • a structural color change is generally referred to as a structural color change.
  • the colorimetric indicator 150 there may be a color change in the visible spectrum of light refracted by the colorimetric indicator 150 once the fluid is introduced in to (e.g., photonic crystals associated with) the colorimetric indicator 150.
  • the introduction of the fluid may lead to a difference in the refractive index of the colorimetric indicator 150.
  • the difference in the refractive index may be used to identify the nature of the fluid passing through the openings 120 of the filter 140.
  • Another suitable structural color indicator may be, for example, a thin film that includes plasmonic nanoparticles (e.g., gold nanoparticles) dispersed in a matrix of a liquid absorbent material (e.g., a superabsorbent polymer).
  • plasmonic nanoparticles e.g., gold nanoparticles
  • a liquid absorbent material e.g., a superabsorbent polymer
  • the plasmonic color is determined by the interparticle distance.
  • a swelling may be induced in the liquid absorbent material, thereby leading to an interparticle distance change and, thus, a visual color change.
  • a structural color indicator is a thin film of dielectric/metallic/semi conductor material deposited on another dielectric/metallic/semiconductor material (e.g., a silicon oxide thin film deposited on silicon or gold, or a germanium thin film deposited on silicon).
  • the colorimetric indicator 150 is or includes a chromophore, a fluorophore, a hydrochromic ink, a hydrochromic ink-coated material, or the like that is adapted to change color in contact with a liquid or when wet with water or any liquid.
  • the colorimetric indicator 150 may be or include any substance that exhibits an observable change in color upon wetting, such as a dye, a pigment, or another indicator.
  • the colorimetric indicator 150 may include a chromophore, fluorophore, or the like in combination with a structural color indicator.
  • the filter 140 may be used without the colorimetric indicator 150.
  • a fluid flowing through the openings 120 may be visualized upon the binding of a target analyte of interest with the binding material 130 of the filter 140.
  • a fluid dripping through the openings 120 may be directly visualized by the naked human eye or, alternatively, indirectly visualized with an observable change in color by employing an auxiliary material at the exit of the openings 120.
  • the auxiliary material may be, for example, a color change chemical compound such as Copper (II) sulfate, which shows white color in a dehydrated state, but blue color in a hydrated state after absorbing water.
  • Another exemplary auxiliary material is Cobalt (II) chloride, which shows blue color in a dehydrated state, but red color in a hydrated state.
  • FIGURES 2A and 2C illustrative embodiments of a composite sensor 200 under hydrophobic and hydrophilic conditions, respectively, are shown.
  • the receptor portion i.e., the filter 240
  • the indicator portion i.e., the structural color indicator 270
  • the filter 240 may be separated from the structural color indicator 270 by a spatial distance 160 of at least 1 micron; although those of ordinary skill in the art can appreciate that the separation distance 160 may be greater than or less than 1 micron.
  • the filter 240 may be similar to (and implemented in a similar fashion to) the filter 140 previously described with reference to FIGURES 1 A and IB. In other words, the previous description of the filter 140 is equally applicable to the filter 240.
  • the structural color indicator 270 includes a substrate 210 on which a plurality of nanopillars 280 are formed in an array.
  • the nanopillars 280 may be manufactured of a dielectric or insulative material (e.g., silica, titanium dioxide, silicon nitride, and the like).
  • the nanopillars 280 are manufactured from a material that, upon absorbing liquid (e.g., water), swells solely based on the wetness.
  • Non-limiting examples of such a material are a superabsorbent material (e.g., a superabsorbent polymer) and a composite material that includes plasmonic nanoparticles (e.g., gold nanoparticles) dispersed in a matrix of a superabsorbent material (e.g., a superabsorbent polymer). Swelling of the nanopillars 280 may be induced when liquid contacts the superabsorbent material or the composite material that includes the superabsorbent material.
  • Metal 220 may be deposited on the upper surface of the substrate 210, as well as on the upper surface of each of the nanopillars 280.
  • the structural color indicator 270 is a plasmonic array of nanopillars 280.
  • This exemplary structural color indicator 270 exhibits a visual color change when a fluid 250 passes through the openings 120 of the filter 240 and into the gaps 290 between the nanopillars 280, as shown in FIGURE 2C. More particularly, the effective refractive index in the localized environment of the structural color indicator 270 changes due to the infiltration of the fluid 250 into the gaps 290 between the nanopillars 280. In many cases, this change in the effective refractive index affects the dipole interaction between the metallic surfaces 220 deposited on the upper surface of the substrate 210, as well as on the upper surface of each of the nanopillars 280. This dipole interaction determines the scattered hybridized plasmon resonance, i.e., the color.
  • the fluid 250 may induce a swelling of the nanopillars 280 (e.g., when the nanopillars 280 are manufactured from a material that is capable of swelling), which consequently increases the distance between the metallic surface 220 deposited on the upper surface of the substrate 210 and the metallic surface 220 deposited on the upper surface of each of the nanopillars 280.
  • the dipole interaction between the metallic surfaces 220 is also impacted by this swelling effect, which also leads to a color change.
  • the nanopillars 280 are manufactured from the composite material described above, the swelling may increase the distance between the nanoparticles of the composite material, which can also lead to a color change.
  • a hydrophobic coating on the filter 240 is designed to repel all fluids that do not contain a target analyte of interest, thereby preventing the fluid from infiltrating the openings 120.
  • a fluid e.g., liquid 250
  • some portion of the target analytes of interest 230 may specifically bind 235 (FIGURE 2C) to the binding material 130 disposed (e.g., coated) on the filter 240 and in the openings 120 of the filter 240.
  • the binding 235 of the target analytes of interest 230 to the binding material 130 may result in a change (e.g., an increase) in surface energy.
  • the surface energy of the openings 120 may increase after the binding 235 of the target analytes of interest 230 to the binding material 130, triggering a wettability change.
  • Such a wettability change may produce a hydrophilic condition (FIGURE 2C) by which the liquid 250 containing the target analytes of interest 230 is allowed to flow through the openings 120.
  • Liquid 250 flowing through the bottom surface of the filter 240 and contacting the structural color indicator 270 results in a visible color change, as described above.
  • the filter 240 may instead be designed such that the surface energy of the openings 120 decreases after the binding 235 of target analytes of interest 230 to the analyte receptor coating 130. More specifically, as shown in FIGURE 3A, under hydrophilic conditions, a fluid 250 (e.g., liquid 250) without a target analyte of interest present therein may flow through the filter 240 and into the gaps 290 between the nanopillars 280 of the colorimetric indicator 270.
  • a fluid 250 e.g., liquid 250
  • the target analytes of interest 230 may bind 235 to the analyte receptor coating 130 on the openings 120 of the filter 240, causing a decrease in surface energy and a resulting hydrophobic condition.
  • a wettability change is triggered that results in a repelling of the fluid 250 from the openings 120 (i.e., the fluid 250 will not be permitted to pass through the filter 240).
  • FIGURES 4A and 4B depict an exemplary filter-based colorimetric sensor 400 that includes (i) a receptor (or filter) that includes an array of taller pillars 410 (e.g., micropillars, nanopillars, and the like) formed on a (e.g., planar) substrate 460 and (ii) a colorimetric indicator 440 of shorter pillars 450. As illustrated, the colorimetric indicator 440 of shorter pillars 450 is spatially separated from the filter of taller pillars 410.
  • a receptor or filter
  • taller pillars 410 e.g., micropillars, nanopillars, and the like
  • a colorimetric indicator 440 of shorter pillars 450 is spatially separated from the filter of taller pillars 410.
  • the taller filter pillars 410 may be manufactured of a dielectric or insulative material (e.g., silica, titanium dioxide, silicon nitride, and the like), a (e.g., organic, inorganic, or hybrid) molecularly- imprinted polymer (MIP) material, a dielectric material coated with a MIP material (or other types of molecular receptors or ion receptors (e.g., aptamers, SOMAmers, affirmers, and so forth)), a metallic material (e.g., gold, silver, aluminum, and the like), a metallic material coated with a MIP material (or other types of molecular receptors or ion receptors (e.g., aptamers, SOMAmers, affirmers, and so forth)), and combinations thereof.
  • a dielectric or insulative material e.g., silica, titanium dioxide, silicon nitride, and the like
  • MIP molecularly- imprinted polymer
  • the taller filter pillars 410 are structured and arranged on the substrate 460 to act as a selective filter, controlling when liquid may flow from the top surface of the taller filter pillars 410 down to the shorter pillars 450 of the colorimetric indicator 440 located in the gaps 470 between the taller filter pillars 410.
  • the taller filter pillars 410 may be coated with a (e.g., thin) layer of a binding material 420 (e.g., analyte receptor 420), such as a (e.g., organic, inorganic, or hybrid) molecularly-imprinted polymer (MIP) material, aptamer material, peptide, DNA, RNA, PNA, oligonucleotides, coordination complex, and so forth, or combinations thereof.
  • MIP molecularly-imprinted polymer
  • the thickness of the coating 420 may range from about 1 Angstrom (e.g., in the case of a molecular monolayer) to a thickness that almost closes the gap 470 between adjacent taller filter pillars 410.
  • the coating 420 may also include a binder material produced from hydrophobic components, so that the binder material is hydrophobic, or produced from hydrophilic binding materials coated with a hydrophobic layer, or combinations thereof.
  • taller filter pillars 410 shown in FIGURES 4A and 4B are cylindrical in shape and have a periodic spacing, this is done for illustrative purposes only. Those skilled in the art can appreciate that the taller filter pillars 410 may have any reasonable shape and may be arrayed in a pattern that is periodic, aperiodic, random, or a combination thereof. Moreover, the taller filter pillars 410 may be separated from one another, may be interconnected, or a combination thereof. In some implementations, the spacing between (e.g., adjacent) taller filter pillars 410 may be any distance greater than about 1 nm.
  • each taller filter pillar 410 may be any size greater than 1 nm and, more preferably, may range between about 1 um (micron) to about 10,000 pm.
  • a hydrophobic material e.g., Teflon, silane, and the like
  • the hydrophobic coating may be designed to repel all fluids that do not contain the target analyte of interest, thereby preventing the fluid from infiltrating the gaps 470 between the taller filter pillars 410.
  • the colorimetric indicator 440 includes an array of colorimetric pillars 450 (e.g., micropillars, nanopillars, and the like) formed on the top surface of the substrate 460.
  • the colorimetric pillars 450 are shorter than the filter pillars 410.
  • the height, dimensions, and spacing of the colorimetric pillars 450 may be in the optical wavelength range (i.e., about 200 nm to about 1,000 nm).
  • the colorimetric pillars 450 shown in FIGURES 4A and 4B are cylindrical in shape and have a periodic distribution, this is done for illustrative purposes only.
  • the colorimetric pillars 450 may have any reasonable shape and may be arrayed in a pattern that is periodic, aperiodic, random, or a combination thereof. Moreover, the colorimetric pillars 450 may be separated from one another, may be interconnected, or a combination thereof.
  • metal 430 is deposited on a top surface of the colorimetric pillars 450, as well as on the top surface of the substrate 460.
  • the colorimetric pillars 450 may be manufactured of a dielectric or insulative material (e.g., silica, titanium dioxide, silicon nitride, and the like).
  • the colorimetric pillars 450 are manufactured from a material that swells upon absorbing a liquid (e.g., as previously described for the nanopillars 280 of FIGS. 2A and 2C).
  • the colorimetric indicator 440 is a plasmonic array of colorimetric pillars 450 and exhibits a visual color change when a fluid passes through the gaps 470 between the taller filter pillars 410 and into the spaces between the shorter colorimetric pillars 450, for the same reason as described above with reference to FIGURE 2C.
  • This detectable visible color difference i.e., the change of color
  • the colorimetric indicator 440 may be or include a chromophore, a fluorophore, or the like that is adapted to change color when contacted with a liquid or when wet with water or any liquid.
  • the colorimetric indicator 440 may include any substance that exhibits an observable change in color upon wetting, such as a dye, a pigment, or another indicator.
  • the colorimetric indicator 440 may include a chromophore, fluorophore, or the like in combination with any type of structural color indicator.
  • the colorimetric indicator 440 may also be absent in a case in which the liquid is able to flow through the gaps 470 and is capable of being visually observed at the bottom of the filter.
  • a liquid dripping through the gaps 470 between the micropillars or nanopillars 410 of the filter may be directly visualized by the naked human eye or indirectly visualized with an observable change by employing an auxiliary material (e.g., dry powders, cellulose paper, materials coated with hydrochromic ink, a special chemical compound that changes color from a dehydrated state to a hydrated state, and so forth) to facilitate observation at the bottom of the filter.
  • an auxiliary material e.g., dry powders, cellulose paper, materials coated with hydrochromic ink, a special chemical compound that changes color from a dehydrated state to a hydrated state, and so forth
  • FIGURES 5A and 5B depict the operation of the filter-based colorimetric sensor 400 (described above with reference to FIGURES 4A and 4B) under hydrophobic and hydrophilic conditions, respectively.
  • Target analytes of interest 520 contained in a fluid (e.g., a liquid) 510 may specifically bind to or be absorbed by 535 the binding material 420 (e.g., analyte receptor 420) disposed on the taller filter pillars 410.
  • the binding material 420 e.g., analyte receptor 420
  • the wettability of the surfaces upon which the binding material 420 is disposed is modified to a degree great enough to overcome the initial hydrophobicity of the surfaces.
  • the liquid 510 flows into and between the air gaps 470 defined by the taller filter pillars 410, as well as between the colorimetric pillars 450, as shown in FIGURE 5B.
  • the target analytes of interest 520 bind to the binding material 420 disposed on the taller filter pillars 410
  • such binding may enable a change in surface energy.
  • the surface energy of the taller filter pillars 410 may increase after the target analytes of interest are bound to the binding material 420.
  • the binding may trigger a wettability change, such that the liquid 510 flows through the air gaps 470 defined between the taller filter pillars 410 to the colorimetric pillars 450 below.
  • a color change is expected due to the infiltration of the liquid 510.
  • FIGURES 6A and 6B depict an embodiment of an exemplary lateral, filter-based colorimetric sensor 600.
  • the sensor 600 includes a (e.g., planar) substrate 610 on which a receptor 650 (e.g., filter 650) of taller pillars and a separate, physically spaced, indicator 690 (e.g., colorimetric indicator 690) of shorter pillars are formed.
  • the substrate 610 may also be configured to include an area 670 for the introduction of a fluid (e.g., liquid).
  • the colorimetric indicator 690 may be structured and arranged to confirm the presence (or absence) of a specific fluid (i.e., a fluid containing target analytes of interest).
  • the filter 650 includes an array of micropillars or nanopillars 620.
  • the pillars 620 may be manufactured of a dielectric or insulative material (e.g., silica, titanium dioxide, silicon nitride, and the like), a (e.g., organic, inorganic, or hybrid) MIP material, a dielectric material coated with a MIP material (or other types of molecular receptors or ion receptors (e.g., aptamers, SOMAmers, affirmers, and so forth)), a metallic material (e.g., gold, silver, aluminum, and the like), a metallic material coated with a MIP material (or other types of molecular receptors or ion receptors (e.g., aptamers, SOMAmers, affirmers, and so forth)), and combinations thereof.
  • a dielectric or insulative material e.g., silica, titanium dioxide, silicon nitride, and the like
  • a MIP material e.g
  • the filter pillars 620 shown in FIGURES 6A and 6B are cylindrical in shape and have a periodic (e.g., three by three) array, this is done for illustrative purposes only. Those skilled in the art can appreciate that the filter pillars 620 may have any reasonable shape and may be arrayed in a pattern that is periodic, aperiodic, random, or a combination thereof. Moreover, the filter pillars 620 may be separated from one another, may be interconnected, or a combination thereof. In some implementations, the spacing between (e.g., adjacent) filter pillars 620 may be any distance greater than about 1 nm.
  • the filter pillars 620 may be coated with a (e.g., thin) layer of binding material 630 (e.g., analyte receptor 630), such as MIP material, aptamer material, peptide, DNA, RNA, PNA, oligonucleotides, coordination complex, and so forth, or combinations thereof.
  • binding material 630 e.g., analyte receptor 630
  • the thickness of the coating 630 may range from about 1 Angstrom (e.g., in the case of a molecular monolayer) to a thickness that almost closes a gap 680 between one pillar 620 and another, adjacent pillar 620.
  • the surficial walls of the filter pillars 620 may also be coated with a hydrophobic material (e.g., Teflon, silane, or the like) that is adapted to repel such fluids.
  • the coating 630 may include a binding material produced from hydrophobic components, so that the binding material is hydrophobic, or produced from hydrophilic binding materials coated with a hydrophobic layer, or combinations thereof.
  • the colorimetric indicator 690 may also include an array of micropillars or nanopillars 660.
  • the colorimetric pillars 660 are shorter than the filter pillars 620.
  • the colorimetric pillars 660 shown in FIGURES 6A and 6B are cylindrical in shape and have a periodic (e.g., four by four) array, this is done for illustrative purposes only. Those skilled in the art can appreciate that the colorimetric pillars 660 may have any reasonable shape and may be arrayed in a pattern that is periodic, aperiodic, random, or a combination thereof.
  • the colorimetric pillars 660 may be separated from one another, may be interconnected, or a combination thereof. In some implementations, the spacing between (e.g., adjacent) colorimetric pillars 660 may be any distance greater than about 1 nm.
  • metal 640 is deposited on a top surface of the colorimetric pillars 660, as well as on a top surface of the substrate 610 in the vicinity of the colorimetric pillars 660.
  • the colorimetric pillars 660 may be manufactured of a dielectric or insulative material (e.g., silica, titanium dioxide, silicon nitride, and the like).
  • the colorimetric pillars 660 are manufactured from a material that swells upon absorbing a liquid (e.g., as previously described for the nanopillars 280 of FIGS. 2A and 2C).
  • the colorimetric indicator 690 is a plasmonic array of colorimetric pillars 660 and exhibits a visual color change when a fluid passes through the gaps 680 between the filter pillars 620 and into the spaces between the colorimetric pillars 660, for the same reason as described above with reference to FIGURE 2C.
  • This detectable visible color difference i.e., the change of color
  • the colorimetric indicator 690 may include any other type of structural color indicator, such as, for example, photonic crystals.
  • a color change may be exhibited in the visible spectrum of light refracted by the colorimetric indicator 690 due to, inter alia, a difference in the refractive index of the colorimetric indicator 690.
  • the colorimetric indicator 690 may be or include a chromophore, a fluorophore, a hydrochromic ink, a material coated with a hydrochromic ink, or the like that is adapted to change color when contacted with a liquid or when wet with water or any liquid.
  • the colorimetric indicator 690 may include a chromophore, a fluorophore, or the like in combination with a structural color indicator.
  • the colorimetric indicator 690 may include any substance that exhibits an observable change in color upon wetting, such as a dye, a pigment, or another indicator.
  • FIGURES 6A and 6B Although the embodiment depicted in FIGURES 6A and 6B was described as having a filter 650 and a colorimetric indicator 690 that was spatially separated from the filter 650, the filter 650 may alternatively be used without the colorimetric indicator 690. Indeed, fluid flowing through the gaps 680 in the filter 650 may be directly visualized by the naked human eye upon exiting the filter 650.
  • FIGURES 7A and 7B depict operation of the lateral, filter-based colorimetric sensor 600 (described above with reference to FIGURES 6A and 6B) under hydrophobic 700 and hydrophilic 710 conditions, respectively.
  • a fluid 720 is placed on the first area 670 of the substrate 610 and caused to flow laterally (e.g., horizontally) towards the filter 650.
  • Target analytes of interest 730 contained in the fluid 720 may specifically bind to or be absorbed by the binding materials 630 (e.g., analyte receptors 630) disposed on the surfaces of the filter pillars 620. Such binding may result in a change in surface energy in the surfaces of the filter pillars 620.
  • the wettability of the surfaces of the filter pillars 620 may be modified. Resultingly, the flowing fluid 720 may overcome the initial hydrophobicity of the surfaces of the filter pillars 620, allowing the fluid 720 to flow (e.g., wick) through the gaps 680 to the colorimetric indicator 690 as shown in FIGURE 7B.
  • the fluid 720 containing the target analytes of interest 730 comes into contact with the colorimetric indicator 690, a color change may therefore result.
  • the in-flow of a specific fluid i.e., a fluid containing a target analyte of interest (e.g., a fuel containing contaminants, blood or other bodily fluids containing certain biomarkers for certain diseases, liquid containing certain drugs, and so forth)
  • a target analyte of interest e.g., a fuel containing contaminants, blood or other bodily fluids containing certain biomarkers for certain diseases, liquid containing certain drugs, and so forth
  • an analyte receptor coating e.g., a single film containing molecular receptors
  • a plurality of faces coated with receptor e.g., molecular
  • the microchannel may be structured and arranged to operate as a receptor, filter, smart gate, or the like (e.g., using any of the receptors / filters described above) and be adapted to control the flow of liquid.
  • the microchannels may range between about 1 micron and about 10,000 microns in width and about 1 micron and greater in height. Those skilled in the art can appreciate that the width and height ranges are illustrative and not limiting. Widths less than 1 micron or greater than 10,000 microns and heights less than 1 micron are also possible.
  • the microchannels shown in the figures described below have a substantially rectangular shape, that is done for illustrative purposes only. Those of ordinary skill in the art can appreciate that embodiments of the invention may be practiced with a microfluidic channel having other shapes and other dimensions.
  • the device When combined with a colorimetric indicator (e.g., nanoparticles, photonic crystals, plasmonic arrays of pillars, plasmonic nanoparticle thin films, dyes and pigments, hydrochromic ink, materials coated with hydrochromic ink, Bragg reflective coatings, and the like, including any of the colorimetric indicators described above) disposed at the output of the microchannel filter and spatially separated from the microchannel filter, the device may be used to verify or confirm the presence (or absence) of a specific fluid (e.g., a fluid containing a target analyte of interest).
  • a colorimetric indicator e.g., nanoparticles, photonic crystals, plasmonic arrays of pillars, plasmonic nanoparticle thin films, dyes and pigments, hydrochromic ink, materials coated with hydrochromic ink, Bragg reflective coatings, and the like, including any of the colorimetric indicators described above
  • a specific fluid e.g., a fluid containing a target
  • the colorimetric indicator may be structured and arranged to exhibit an observable color change in the visible spectrum of light refracted by the colorimetric indicator due to, inter alia, a difference in the refractive index of the colorimetric indicator upon the introduction therein of the specific fluid.
  • the difference in refractive index may be used to identify the nature of the specific fluid passing through the microchanneTs filter.
  • the colorimetric indicator may be or include a chromophore, a fluorophore, or the like that is adapted to change color when contacted with a liquid or when wet with water or any liquid.
  • the colorimetric indicator may include any substance that exhibits an observable change in color upon wetting, such as a dye, a pigment, a material coated with hydrochromic ink, or another indicator.
  • the colorimetric indicator may be absent.
  • the sensor may include a (e.g., transparent) window through which one may observe the liquid flowing through the microchanneTs filter.
  • a liquid passing through the microchanneTs filter may be directly visualized by the naked human eye or, alternatively, may be indirectly visualized with an observable color change by employing auxiliary material (e.g., dry powders, cellulose paper, materials coated with hydrochromic ink, a special chemical compound that changes color from a dehydrated state to a hydrated state, and so forth) to facilitate the observation at or near the exit of the microchanneTs filter.
  • auxiliary material e.g., dry powders, cellulose paper, materials coated with hydrochromic ink, a special chemical compound that changes color from a dehydrated state to a hydrated state, and so forth
  • FIGURES 8 A and 8B show an illustrative embodiment of a microfluidic filter-based colorimetric sensor 800 that, in some implementations, includes a sample introduction chamber 810 and a colorimetric indicator 840 that are in fluidic communication via a microfluidic channel 820 containing a receptor or filter 830
  • the colorimetric indicator 840 is spatially separated from the filter 830
  • the filter 830 may be a section or portion of the microfluidic channel 820 whose surface has been coated with a (e.g., thin) layer or film of an analyte (e.g., molecular) receptor, such as MIP material, aptamer material, antibodies, peptide, DNA, RNA, PNA, oligonucleotides, SOMAmers, and so forth, or combinations thereof.
  • analyte e.g., molecular
  • Typical thickness of the molecular receptor film may range between 1 Angstrom (e.g., for a molecular monolayer) to the thickness approaching the height and/or width of the microchannel 820 .
  • the molecular receptor film may also include a binding material produced from hydrophobic components, so that the binding material itself is hydrophobic; a hydrophilic binding material coated with a hydrophobic layer; or any combination thereof.
  • a hydrophobic material e.g., Teflon, silane, and the like
  • the hydrophobic coating is designed to repel all fluids that do not contain the target analyte of interest, thereby preventing the fluid from infiltrating beyond the filter 830 of the microchannel 820.
  • the colorimetric indicator 840 may be disposed near the exit of the microfluidic channel 820 and the filter 830.
  • Exemplary colorimetric indicators 840 may include a Bragg reflective coating 870 (FIGURE 8C), a plurality of photonic crystals 880 (FIGURE 8D), a plurality of nanoparticles 890 (FIGURE 8E), dyes and pigments, hydrochromic ink, and so forth.
  • FIGURES 9A through 9C operation of the microfluidic filter-based colorimetric sensor 800 shown in FIGURES 8A and 8B will now be described.
  • the colorimetric indicator 840 is spatially separated from the filter 830, e.g., by a distance of at least 1 micron.
  • a fluid 900 e.g., a liquid
  • the hydrophobicity of the filter 830 disposed in the microchannel 820 repels the fluid 900 (e.g., liquid), thereby preventing the fluid 900 (e.g., liquid) from passing through the filter 830 and reaching the colorimetric indicator 840.
  • a fluid 900 e.g., a liquid
  • target analytes of interest 850 come into contact with the binding material (e.g., analyte receptor) disposed on the outer surface of the filter 830 disposed in the microchannel 820.
  • the binding material e.g., analyte receptor
  • the target analytes of interest 850 will begin to specifically bind to the analyte receptor, which enables a change in surface energy.
  • the surface energy of the filter 830 may increase after binding with the target analytes of interest, which may result in a wettability change sufficient to overcome the initial hydrophobicity of the surface of the filter 830, resulting in the fluid 900 (e.g., liquid) passing from the sample introduction chamber 810 through the microchannel 820 and the filter 830, before reaching the colorimetric indicator 840.
  • the fluid 900 e.g., liquid
  • a discemable color change provides an indication of the presence of the target analyte of interest 850 in the fluid 900.
  • FIGURES 10A and 10B show an illustrative embodiment of a microfluidic filter- based colorimetric sensor 1000 that, in some implementations, includes a sample introduction chamber 1010 and a colorimetric indicator 1040 that are in fluidic communication via a microfluidic channel 1020 containing a receptor 1030 (e.g., filter 1030).
  • the filter 1030 may contain a patterned array of microstructures or nanostructures 1035.
  • the filter 1030 may contain a patterned array of structures on the millimeter scale.
  • the colorimetric indicator 1040 is spatially separated from the filter 1030.
  • the microstructures or nanostructures 1035 may be micropillars, nanopillars, and the like, or combinations thereof, whose surface(s) have been coated with a (e.g., thin) layer of an analyte (e.g., molecular) receptor 1038, such as MIP material, aptamer material, peptide, DNA, RNA, PNA, clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR associated proteins (Cas) mediated binding materials, SOMAmers, affirmers, oligonucleotides, antibodies, coordination complex, MOF materials, porous coordination polymer materials, and so forth, or combinations thereof.
  • analyte e.g., molecular receptor 1038
  • MIP material e.g., MIP material, aptamer material, peptide, DNA, RNA, PNA, clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR associated proteins (Cas) mediated binding
  • the molecular receptor film 1038 may be a binding material produced from hydrophobic components, so that the binding material itself is hydrophobic; a hydrophilic binding material coated with a hydrophobic layer; or any combination thereof.
  • the micropillars, nanopillars, and the like 1035 shown in FIGURES 10A and 10B appear to be substantially cylindrical in shape, this is done for illustrative purposes only. Those of ordinary skill in the art can appreciate that the micropillars, nanopillars, and the like 1035 may be designed to have any reasonable shape.
  • a hydrophobic material e.g., Teflon, silane, and the like
  • the hydrophobic coating is designed to repel all fluids that do not contain the target analyte of interest, thereby preventing the fluid from infiltrating beyond the filter 1030 of the microchannel 1020.
  • the colorimetric indicator 1040 may be disposed near the exit of the microfluidic channel 1020 and the filter 1030, such that it is spatially separated from the filter 1030.
  • Exemplary colorimetric indicators 1040 include nanoparticles, Bragg reflective coatings, photonic crystals, interference based thin film reflectors, plasmonic arrays of micropillars or nanopillars, plasmonic nanoparticle thin films, dyes and pigments, hydrochromic ink, materials coated with hydrochromic ink, and the like.
  • the colorimetric indicator 1040 is spatially separated from the filter 1030, e.g., by a distance of at least 1 micron.
  • the filter 1030 disposed in the microchannel 1020 repels the fluid 900 (e.g., liquid), thereby preventing the fluid 900 (e.g., liquid) from passing through the filter 1030 and reaching the colorimetric indicator 1040.
  • a fluid 900 e.g., a liquid
  • target analytes of interest 1050 come into contact with the binding material 1038 (e.g., analyte receptor 1038) disposed on the outer surface of the micropillars, nanopillars, and the like 1035 disposed in the microchannel 1020.
  • the target analytes of interest 1050 begin to specifically bind to the analyte receptor 1038, which enables a change in surface energy.
  • the surface energy of the filter 1030 may increase after binding with the target analytes of interest 1050, which may result in a wettability change sufficient to overcome the hydrophobicity of the surfaces of the filter 1030.
  • the fluid 900 e.g., liquid
  • the fluid 900 passes from the sample introduction chamber 1010 through the microchannel 1020 and the filter 1030, before reaching the colorimetric indicator 1040.
  • a discemable color change provides an indication of the presence of the target analyte of interest 1050 in the fluid 900.
  • FIGURES 12A and 12B show an illustrative embodiment of a microfluidic filter- based colorimetric sensor 1200 that, in some implementations, includes a sample introduction chamber 1210 and a colorimetric indicator 1240 that are in fluidic communication via a microfluidic channel 1220 containing a receptor 1230 (e.g., filter 1230).
  • the filter 1230 may include a plurality of microstructures or nanostructures 1235 (e.g., nanofms, microfms, and the like, or combinations thereol).
  • the filter 1230 may contain a patterned array of structures on the millimeter scale (e.g., fins with millimeter scale).
  • the colorimetric indicator 1240 is spatially separated from the filter 1230.
  • the microstructures or nanostructures 1235 are manufactured of a dielectric or insulative material (e.g., silica, titanium dioxide, silicon nitride, and the like), a (e.g., organic, inorganic, or hybrid) molecularly-imprinted polymer (MIP) material, a dielectric material coated with a MIP material (or other types of molecular receptors or ion receptors (e.g., aptamers, SOMAmers, affirmers, and so forth)), a metallic material (e.g., gold, silver, aluminum, and the like), a metallic material coated with a MIP material (or other types of molecular receptors or ion receptors (e.g., aptamers, SOMAmers, affirmers, and so forth)), and combinations thereof.
  • a dielectric or insulative material e.g., silica, titanium dioxide, silicon nitride, and the like
  • MIP molecularly-imprinted polymer
  • surfaces of the microstructures or nanostructures 1235 are coated with a (e.g., thin) layer of analyte (e.g., molecular) receptor 1238, such as MIP material, aptamer material, SOMAmers, affirmers, antibodies, peptide, DNA, RNA, PNA, CRISPR-Cas mediated binding materials, oligonucleotides, coordination complex, MOF materials, porous coordination polymer materials, and so forth, or combinations thereof.
  • analyte e.g., molecular receptor 1238
  • the molecular receptor film 1238 may also include a binding material produced from hydrophobic components, so that the binding material itself is hydrophobic; a hydrophilic binding material coated with a hydrophobic layer; or any combination thereof.
  • the molecular receptor film 1238 may also include a specific binding enhancement layer or an additional layer to reduce non-specific binding from non-target substances in the fluid. Non-limiting examples of such a layer include polymer brushes, zwitterionic polymers, and so forth.
  • a hydrophobic material e.g., Teflon, silane, and the like
  • the hydrophobic coating is designed to repel all fluids that do not contain the target analyte of interest, thereby preventing the fluid from infiltrating beyond the filter 1230 of the microchannel 1220
  • the microstructures or nanostructures 1235 may be periodically-distributed, randomly-distributed, or a combination thereof within the microchannel 1220.
  • the microstructures or nanostructures 1235 may be disposed spatially distant from one another, such that each microstructure or nanostructure 1235 is isolated from every other microstructure or nanostructure 1235.
  • the spacing between adjacent microstructures or nanostructures 1235 may be at least 1 nm.
  • selected microstructures or nanostructures 1235 may be interconnected to one or more other microstructures or nanostructures 1235.
  • a first portion of the microstructure or nanostructure 1235 may be isolated from other microstructures or nanostructures 1235, while a second portion of microstructures or nanostructures 1235 may be interconnected to other microstructures or nanostructures 1235.
  • the colorimetric indicator 1240 may be disposed near the exit of the microfluidic channel 1220 and the filter 1230, and may be spatially separated from the filter 1230.
  • Exemplary colorimetric indicators 1240 include Bragg reflective coatings, photonic crystals, nanoparticles, interference based thin film reflectors, plasmonic arrays of micropillars or nanopillars, plasmonic nanoparticle thin films, dyes and pigments, hydrochromic ink, materials coated with hydrochromic ink, and the like.
  • the colorimetric indicator 1240 is spatially separated from the filter 1230, e.g., by a distance of at least 1 micron.
  • the filter 1230 disposed in the microchannel 1220 repels the fluid 900 (e.g., liquid), thereby preventing the fluid 900 (e.g., liquid) from passing through the filter 1230 and reaching the colorimetric indicator 1240.
  • a fluid 900 e.g., a liquid
  • target analytes of interest 1250 come into contact with the binding material 1238 (e.g., analyte receptor 1238) disposed on the outer surface of the microstructures or nanostructures 1235 disposed in the microchannel 1220.
  • the target analyte of interest 1250 begins to specifically bind to the analyte receptor 1238, which enables a change in surface energy.
  • the surface energy of the filter 1230 may increase after binding with the target analytes of interest 1250, which may result in a wettability change sufficient to overcome the hydrophobicity of the surfaces of the filter 1230.
  • the fluid 900 e.g., liquid
  • the fluid 900 passes from the sample introduction chamber 1210 through the microchannel 1220 and the filter 1230, before reaching the colorimetric indicator 1240.
  • a discemable color change provides an indication of the presence of the target analyte of interest 1250 in the fluid 900.
  • FIGURES 8A-8B, 10A-10B, and 12A-12B were described as having a single microchannel, a single filter, and a single colorimetric indicator, this was done for the purpose of illustration, rather than limitation.
  • additional embodiments of the invention may include a sensor device having multiple microchannels, multiple filters, and multiple colorimetric indicators.
  • the sensor device may be structured and arranged to detect a plurality of different target analytes of interest contained in a single fluid (e.g., liquid) using different filters and colorimetric indicators associated with different microchannels.
  • a sensor device 1400 for detecting a plurality of individually targeted analytes of interest contained in a common fluid (e.g., liquid) using multiple microchannels 1420a, 1420b, 1420c, . . . 1420n is shown.
  • each of the multiple microchannels 1420a, 1420b, 1420c, . . . 1420n may have a corresponding filter 1430a, 1430b, 1430c, . . . 1430n disposed therein and a corresponding, spatially separated (e.g., by a distance of at least 1 micron), colorimetric indicator 1440a, 1440b, 1440c, . . .
  • FIGURE 14 shows four integrated microchannels, there can be any number (n) of microchannels.
  • each combination of microchannel, corresponding filter, and respective colorimetric indicator may be structured and arranged to detect a discrete target analyte of interest at the exclusion of other analytes of interest that may be present in the fluid (e.g., liquid).
  • each combination of microchannel, corresponding filter, and respective colorimetric indicator may be structured and arranged as shown in FIGURES 8A-8B, 10A-10B, or 12A-12B or, in the alternative, differently.
  • a first microchannel 1420a may include a filter 1430a and be associated with a colorimetric indicator 1440a similar to the ones shown and described in connection with FIGURES 8A-8B;
  • the second microchannel 1420b may include a filter 1430b and be associated with a colorimetric indicator 1440b similar to the ones shown and described in connection with FIGURES 10A-10B;
  • the third microchannel 1420c may include a filter 1430c and be associated with a colorimetric indicator 1440c similar to the ones shown and described in connection with FIGURES 12A-12B.
  • FIGURES 15 and 16 operation of the microfluidic filter-based colorimetric sensor 1400 shown in FIGURE 14 will now be described.
  • a fluid 900 e.g., a liquid
  • the filters 1430a, 1430b, 1430c, . . . 1430n repel the fluid 900 (e.g., liquid), thereby preventing the fluid 900 (e.g., liquid) from passing through any of the filters 1430a, 1430b, 1430c, . . . 1430n and from reaching their respective colorimetric indicators 1440a, 1440b, 1440c, . . . 1440n.
  • a fluid 900 e.g., a liquid
  • a binding material e.g., analyte receptor
  • a binding material e.g., analyte receptor
  • the fluid 900 passes from the sample introduction chamber 1410, through the corresponding microchannel 1420a, 1420c and filter 1430a, 1430c, before reaching the associated colorimetric indicator 1440a, 1440c.
  • the fluid 900 makes contact with colorimetric indicators 1440a, 1440c, a discemable color change in those colorimetric indicators provides an indication of the presence of the respective target analytes of interest 1450a, 1450c in the fluid 900.
  • indicia e.g., an audible signal, a visible (e.g., light source) signal, a haptic signal, a message displayed on a display device, and the like, or combinations thereol.
  • indicia e.g., an audible signal, a visible (e.g., light source) signal, a haptic signal, a message displayed on a display device, and the like, or combinations thereol.
  • Embodiments of filter-based sensing devices used in combination with electric transducers may include microchannels and filters similar to any of those filter-based sensing devices described previously. More specifically, in some variations, the filter may include one or more of: a receptor-coated microchannel surface, an (e.g., patterned, random, or combination thereol) array of receptor-coated microstructures or nanostructures (e.g., micropillars, nanopillars, and the like, or combinations thereol), and/or a receptor-coated microfin or nanofin arrangement whose surface(s) have been coated with a (e.g., thin) layer of an analyte (e.g., molecular) receptor, such as MIP material, aptamer material, SOMAmers, affirmers, antibodies, peptide, DNA, RNA, PNA, CRISPR-Cas mediated binding materials, oligonucleotides, coordination complex, MOF materials, porous coordination polymer materials, and so forth, or
  • the electrical transducer(s) 1740 may include metal or semiconductor electrodes placed in the chamber 1735 in close proximity to each other.
  • the electric (or conductive) wires 1750 for transmitting signals between the electric transducer(s) 1740 and the processing device 1760 may be manufactured, for example, from metals, semiconductor materials, conductive materials, and so forth. In the alternative, the electric transducer 1740 may communicate with the processing device 1760 wirelessly.
  • a hydrophobic material e.g., Teflon, silane, and the like
  • the hydrophobic coating is designed to repel all fluids 900 that do not contain the target analyte of interest, thereby preventing the fluid 900 from infiltrating the filter 1730.
  • the filter 1730 may be coated with a hydrophobic material as well as with a binding material (e.g., an analyte receptor).
  • a fluid 900 e.g., a liquid
  • target analytes of interest 1770 come into contact with the binding material disposed on the outer surface of the filter 1730 disposed in the microchannel 1720.
  • the target analytes of interest 1770 begin to specifically bind to the binding material disposed on the filter 1730, which enables a change in surface energy in the filter 1730.
  • the surface energy of the filter 1730 may increase after binding with the target analytes of interest 1770, which may result in a wettability change sufficient to overcome the hydrophobicity of the surface of the filter 1730.
  • the fluid 900 passes from the sample introduction chamber 1710 through the microchannel 1720 and the filter 1730, before reaching the chamber 1735.
  • the electrical transducer(s) 1740 may measure a change in one or more of resistance, capacitance, voltage, current, pressure, and so forth indicative of the presence of the target analytes of interest 1770 in the fluid 900.
  • the electrical transducer(s) may further communicate (e.g., data) signals of the measurements to the processing device 1760.
  • the processing device 1760 may then process the (e.g., data) signals from the electric transducer(s) 1740 and calculate that there has been a change in resistance, capacitance, voltage, current, pressure, and so forth indicative of the presence of the target analytes of interest 1770 in the fluid 900.
  • the processing device 1760 may alert the end user of the presence of the target analytes of interest 1770 in the fluid 900 using, for example, an audible signal or alarm, a haptic signal or alarm, an image or message on a display device, a visible (e.g., light source) signal or alarm, and so forth.
  • the receptors (e.g., filters) of the sensor devices described herein may be manufactured in a variety of manners.
  • a hydrophobic coating or layer may be applied to the receptors (e.g., filters), as well as a coating or layer of binding material (e.g., a MIP or aptamer).
  • the hydrophobic coating may be applied to the surficial walls defining each of the openings or gaps in the filters in a variety of manners. For example, where the hydrophobic coating includes silane molecules, the hydrophobic coating may be applied via vapor phase deposition.
  • the hydrophobic coating may be applied via, for example: atomic layer deposition (ALD), plasma-enhanced chemical vapor deposition (PECVD), or physical vapor deposition (PVD).
  • ALD atomic layer deposition
  • PECVD plasma-enhanced chemical vapor deposition
  • PVD physical vapor deposition
  • the hydrophobic coating may be applied via, e.g., an electron-beam evaporation process.
  • the additional hydrophobic coating may be unnecessary.
  • the MIP material for a MIP coating or a MIP layer may be manufactured by polymerization, e.g., by thermal and/or photochemical initiation, of a mixture of monomers, cross-linkers, initiators, and/or porogens, or combinations thereof and the like.
  • polymerization e.g., by thermal and/or photochemical initiation, of a mixture of monomers, cross-linkers, initiators, and/or porogens, or combinations thereof and the like.
  • the choice of components for the mixture depends on the type and end use of the MIP material.
  • Typical monomers include, for the purpose of illustration and not limitation, carboxylic acids (e.g., acrylic acid, methacrylic acid, vinylbenzoic acid, and trifluoromethyl acrylic acid (TFMAA)), sulphonic acids (e.g., 2-acrylamido-2-methylpropane sulphonic acid), heteroaromatic bases (e.g., vinylpyridine and vinylimidazole), acrylamide, 2-hydroxy ethylmethacrylate (HEMA), and the like.
  • carboxylic acids e.g., acrylic acid, methacrylic acid, vinylbenzoic acid, and trifluoromethyl acrylic acid (TFMAA)
  • sulphonic acids e.g., 2-acrylamido-2-methylpropane sulphonic acid
  • heteroaromatic bases e.g., vinylpyridine and vinylimidazole
  • acrylamide 2-hydroxy ethylmethacrylate
  • Typical cross-linkers include, for the purpose of illustration and not limitation, ethylene glycol dimethacrylate (EGDMA), trimethylolpropane trimethacrylate (TRIM), divinylbenzene (DVB), pentaerythritol triacrylate (PETRA), and the like.
  • Typical initiators include, for the purpose of illustration and not limitation, acetyl peroxide, lauroyl peroxide, decanoyl peroxide, caprylyl peroxide, benzoyl peroxide, tertiary butyl peroxypivalate, sodium percarbonate, tertiary butyl peroctoate, azobis-isobutyronitrile (AIBN), and the like.
  • Typical porogens include, for the purpose of illustration and not limitation, methanol, acetonitrile, toluene, mineral oil, and combinations thereof.
  • a MIP layer or coating may be applied as a coating to the surficial walls defining all or a select number of the openings or gaps in the filters.
  • a soluble and processible MIP layer is developed as shown in FIGURE 19.
  • the soluble and processible MIP layer is made from a polymer with cross-linkable arms, e.g., a star-shaped polymer with cross-linkable arms, or a dendrimer with cross-linkable arms.
  • the cross-linkable arms may contain one or more vinyl groups or other suitable functional groups that may be initiated and/or participate in a polymerization reaction.
  • the soluble and processible MIP layer may be made from crosslinkable star polymers synthesized using controlled free radical polymerization methods such as RAFT (reversible-addition fragmentation chain-transfer) or ATRP (atom transfer radical polymerization), or by grafting end-functionalized polymer chains onto a multifunctional central core.
  • RAFT irreversible-addition fragmentation chain-transfer
  • ATRP atom transfer radical polymerization
  • the polymerization may incorporate a functional monomer into the chain that can be used to form crosslinks (e.g., 4- butenylstyrene, 2-(allyloxy)ethyl acrylate, and N-(hex-5-enyl)acrylamide).
  • Crosslinking the star polymer in the presence of the target analytes of interest may form selective receptor binding sites around the target analytes.
  • Crosslinking may be accomplished catalytically (e.g., by cross metathesis of olefin-terminated side chains).
  • the terminal functional groups may allow the MIP polymers or coating or layer to be bound to the surface of, for example, the filter 140 shown in FIGURE 1 A.
  • thiol groups facilitate bonding to metal surfaces
  • polymers functionalized with a silanizing reagent may bond to glass.
  • the MIP layer may be attached to the filter surfaces using, for example, covalent bonds, non-covalent forces, ionic bonds, van der Waals forces, electrostatic forces, hydrogen bonding, Pi-Pi stacking interactions, and the like.
  • the soluble and processible MIP coating layer can be replaced by a coating of aptamers or other binding materials such as coordination complex that specifically bind to analyte molecules, proteins, or ions.
  • Aptamers generally, are oligonucleotide molecules that bind to a specific target (such as small molecules, proteins, and ions) and they can be produced in a process similar to a molecularly imprinted polymer.
  • ketamine can be used as the analyte template to form aptamers via an imprinting and SELEX (systematic evolution of ligands by exponential enrichment) process to determine the desired oligonucleotide sequence.
  • the terminal functional groups may be modified to allow the coating of aptamers to be bound to the surficial walls of the openings or gaps in the filters.
  • the monomers (in the case of MIP) or nucleic acids library (in the case of aptamer) can be selected to exhibit desired hydrophilic or hydrophobic nature of the final binding materials.
  • the MIP layer may be produced, grown, or grafted in situ on the inner surfaces or surficial walls of the filters.
  • An exemplary grafting process is illustrated in FIGURE 20.
  • a silanization process is employed to functionalize the surficial wall surface with vinyl groups, from which a macromonomer can be grown via a “grafted” approach (as shown in the top row of FIGURE 20 to the structure in the bottom row, right hand side).
  • Target analyte molecules can be subsequently imprinted in situ in a MIP thin layer, e.g., using the soluble and processible MIP approach described herein, where the MIP thin layer may be on and/or attached to the surficial wall surface of the filter. Subsequently, the target analyte molecules may be removed to form the MIP thin layer (as shown in the structure in the bottom row, left hand side of FIGURE 20).
  • the filter itself depicted in, for example, FIGURE 1 A may be, for example, synthesized from a homogenous liquid precursor of a polymer material, which may be an organic, inorganic, or hybrid polymer material, under suitable reaction conditions.
  • a polymer material which may be an organic, inorganic, or hybrid polymer material, under suitable reaction conditions.
  • the base substrate may be formed from its sol-gel precursor tetraethyl orthosilicate (TEOS) under suitable conditions.
  • TEOS tetraethyl orthosilicate
  • the base substrate may be formed from its precursors tetraiso-propylorthotitanate (i.e., Ti(OC 3 H 7 ) 4 or “TIPT”) and/or titanium tetrachloride (i.e., TiCl 4 ) under suitable conditions.
  • tetraiso-propylorthotitanate i.e., Ti(OC 3 H 7 ) 4 or “TIPT”
  • titanium tetrachloride i.e., TiCl 4
  • a liquid precursor of the appropriate organic, inorganic, or hybrid (e.g., TEOS, (3- aminopropyl)triethoxysilane (APTES), or suitable silane molecules) polymer material may be mixed homogeneously with target analyte molecules of interest that act as templates for molecularly imprinting purposes, e.g., to create cavities for recognition of the target analyte molecule.
  • this mixed liquid precursor of the organic, inorganic or hybrid polymer material may be mixed with and include porogens (e.g., microcylinders), which may be fugitive materials, for creating the openings or gaps in the filter.
  • the shape of the openings or gaps in the filters may be cylindrical or whatever is the shape of the porogen.
  • the mixed liquid precursor can include metal nanoparticles (e.g., gold, silver, and/or platinum nanoparticles) via, e.g., a sol-gel process.
  • the mixed liquid precursor then may be solidified under suitable reaction conditions, such as under moderate temperature (e.g., a temperature from room temperature to 300 °C) to lock in the porogens in the solidified precursor matrix.
  • Solidification methods may include, but are not limited to, thermal treatment, photo-induced solidification, radiation-induced solidification, and chemical reaction- induced solidification.
  • the target analyte molecules of interest that act as cavity templates may then be removed to form the molecularly imprinted cavities of the MIP.
  • Analyte molecule templates may be removed using, for example, a Soxhlet extraction process, a sonication process, a washing process with suitable solvent (e.g., methanol/acetic acid or other solvents and combinations thereol).
  • suitable solvent e.g., methanol/acetic acid or other solvents and combinations thereol.
  • the porogens that form the cylindrical or other shaped openings or gaps in the filters, such as colloidal porogens (e.g., cylindrical latex microparticles) may be removed using a thermal process (e.g., sintering above 500 °C) or by dissolution using a suitable solvent or solvent system.
  • the resulting cylindrical or other shaped openings or gaps in the filters may be interconnected or, alternatively, the resulting cylindrical or other shaped openings or gaps in the filters may be isolated from one another (or combinations thereof).
  • the porogens used to form the openings or gaps in the filters may have a shape other than cylindrical such that the resulting openings or gaps in the filters have a shape other than cylindrical.
  • a hydrophobic coating may be applied to the surficial walls defining each of the openings or gaps in the filters in a variety of manners.
  • the hydrophobic coating may be applied via vapor phase deposition.
  • the hydrophobic coating includes dielectric materials (e.g., titanium dioxide, silicon dioxide, hafnium oxide, etc.)
  • the hydrophobic coating may be applied via atomic layer deposition (ALD), plasma-enhanced chemical vapor deposition (PECVD), or physical vapor deposition (PVD).
  • the hydrophobic coating includes metallic materials (e.g., gold, silver, aluminum, copper, and the like)
  • the hydrophobic coating may be applied via an electron-beam evaporation process.
  • the MIP layer may be produced, grown, or grafted in situ on the inner surfaces or surficial walls of the filters via a controlled polymerization process.
  • An exemplary grafting process is illustrated in FIGURE 21.
  • an initiator e.g., a bromide based ATRP initiator, disulfide RAFT agent, etc.
  • the hydrophobicity/hydrophilicity of the resulting MIP can be tuned by selecting suitable hydrophobic or hydrophilic monomers.
  • the binding materials may be aptamers (or other type of binding material).
  • a probe aptamer may be utilized as the coating to replace the MIP layer without losing the binding properties.
  • Aptamers generally, are specific nucleic acid sequences identified from the SELEX process against the target, so they have high binding affinity with the target molecules.
  • a complementary aptamer (c-aptamer) sequence can be used to hybridize with the probe aptamer (p-aptamer).
  • the c- aptamer may be modified with a hydrophilic functional group or hydrophilic sequence while the p-aptamer is modified with a hydrophobic functional group or hydrophobic sequence.
  • the hydrophobic p-aptamer may fall off the solid surface due to the conformational change of the p-aptamer as shown in FIGURE 23.
  • the remaining c-aptamer tagged with the hydrophilic functional group becomes exposed, thus leading to a hydrophilic surface with a detectable wettability change.
  • the wettability change can also be a change from a hydrophilic to a hydrophobic state.
  • the p-aptamer may be modified with an additional folding sequence (e.g., a hairpin structure or other types of folding structures).
  • the hydrophilic (or hydrophobic) functional groups may be incorporated into the hairpin structure. Binding of target leads to a conformational change of the hairpin, which results in the exposure of the hydrophilic (or hydrophobic) groups as shown in FIGURE 24. For example, a conformational change from hairpin to linear DNA chain or a conformational change from a large hairpin to a small hairpin with part of the sequence exposed. Therefore, a wettability change can be observed upon binding of target.
  • MIPs and aptamers are described, any types of receptors may be used without departing from the scope of the present disclosure. As such, the use of MIPs and/or aptamers should be taken as exemplary only and not to otherwise limit the scope of the present disclosure.

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Abstract

Un capteur permettant de détecter un analyte d'intérêt dans un échantillon de fluide comprend un récepteur et un indicateur qui est physiquement espacé du récepteur. Le récepteur, qui peut être un filtre, comprend un matériau de liaison qui se lie à un analyte d'intérêt. Le récepteur peut être configuré de telle sorte que, lorsque l'analyte d'intérêt se lie au matériau de liaison, un changement d'énergie de surface entraîne au moins une partie du récepteur. Le récepteur peut en outre être configuré pour permettre, lors de la satisfaction d'une condition de liaison, le passage d'un échantillon de fluide à travers celui-ci. L'indicateur rapporte le passage de l'échantillon de fluide à travers le récepteur.
PCT/US2021/021027 2020-03-06 2021-03-05 Dispositifs et procédés de détection d'un analyte cible d'intérêt WO2021178760A1 (fr)

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WO2018231962A1 (fr) * 2017-06-13 2018-12-20 Drinksavvy, Inc. Capteurs colorimétriques et leurs procédés de fabrication

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Publication number Priority date Publication date Assignee Title
WO2018231962A1 (fr) * 2017-06-13 2018-12-20 Drinksavvy, Inc. Capteurs colorimétriques et leurs procédés de fabrication

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DING SHUSHU ET AL: "Rational Design of a Stimuli-Responsive Polymer Electrode Interface Coupled with in Vivo Microdialysis for Measurement of Sialic Acid in Live Mouse Brain in Alzheimer's Disease", ACS SENSORS, vol. 2, no. 3, 24 March 2017 (2017-03-24), pages 394 - 400, XP055812385, ISSN: 2379-3694, Retrieved from the Internet <URL:https://pubs.acs.org/doi/pdf/10.1021/acssensors.6b00772> DOI: 10.1021/acssensors.6b00772 *
DING SHUSHU ET AL: "Wettability Switching of Electrode for Signal Amplification: Conversion of Conformational Change of Stimuli-Responsive Polymer into Enhanced Electrochemical Chiral Analysis", ANALYTICAL CHEMISTRY, vol. 88, no. 24, 20 December 2016 (2016-12-20), US, pages 12219 - 12226, XP055812382, ISSN: 0003-2700, Retrieved from the Internet <URL:https://pubs.acs.org/doi/pdf/10.1021/acs.analchem.6b03278> DOI: 10.1021/acs.analchem.6b03278 *
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