WO2016161430A1 - Dispositifs microfluidiques tridimensionnels à attribut de soulèvement - Google Patents

Dispositifs microfluidiques tridimensionnels à attribut de soulèvement Download PDF

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Publication number
WO2016161430A1
WO2016161430A1 PCT/US2016/025884 US2016025884W WO2016161430A1 WO 2016161430 A1 WO2016161430 A1 WO 2016161430A1 US 2016025884 W US2016025884 W US 2016025884W WO 2016161430 A1 WO2016161430 A1 WO 2016161430A1
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Prior art keywords
zone
pop
sample
detection
paper
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PCT/US2016/025884
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English (en)
Inventor
Chien-Chung Wang
George M. Whitesides
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President And Fellows Of Harvard College
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Publication of WO2016161430A1 publication Critical patent/WO2016161430A1/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
    • G01N33/483—Physical analysis of biological material
    • G01N33/487—Physical analysis of biological material of liquid biological material
    • G01N33/49—Blood
    • G01N33/4915—Blood using flow cells
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5023—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures with a sample being transported to, and subsequently stored in an absorbent for analysis
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502707—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the manufacture of the container or its components
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B81—MICROSTRUCTURAL TECHNOLOGY
    • B81B—MICROSTRUCTURAL DEVICES OR SYSTEMS, e.g. MICROMECHANICAL DEVICES
    • B81B3/00—Devices comprising flexible or deformable elements, e.g. comprising elastic tongues or membranes
    • B81B3/0062—Devices moving in two or more dimensions, i.e. having special features which allow movement in more than one dimension
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B81—MICROSTRUCTURAL TECHNOLOGY
    • B81C—PROCESSES OR APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OR TREATMENT OF MICROSTRUCTURAL DEVICES OR SYSTEMS
    • B81C1/00—Manufacture or treatment of devices or systems in or on a substrate
    • B81C1/00015—Manufacture or treatment of devices or systems in or on a substrate for manufacturing microsystems
    • B81C1/00023—Manufacture or treatment of devices or systems in or on a substrate for manufacturing microsystems without movable or flexible elements
    • B81C1/00119—Arrangement of basic structures like cavities or channels, e.g. suitable for microfluidic systems
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/001—Enzyme electrodes
    • C12Q1/002—Electrode membranes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/001—Enzyme electrodes
    • C12Q1/005—Enzyme electrodes involving specific analytes or enzymes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G01N33/487—Physical analysis of biological material of liquid biological material
    • G01N33/48707—Physical analysis of biological material of liquid biological material by electrical means
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/04—Closures and closing means
    • B01L2300/041—Connecting closures to device or container
    • B01L2300/043—Hinged closures
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • B01L2300/0645—Electrodes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0874—Three dimensional network
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/12—Specific details about materials
    • B01L2300/126—Paper
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0406—Moving fluids with specific forces or mechanical means specific forces capillary forces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/505—Containers for the purpose of retaining a material to be analysed, e.g. test tubes flexible containers not provided for above
    • B01L3/5055—Hinged, e.g. opposable surfaces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B81—MICROSTRUCTURAL TECHNOLOGY
    • B81B—MICROSTRUCTURAL DEVICES OR SYSTEMS, e.g. MICROMECHANICAL DEVICES
    • B81B2201/00—Specific applications of microelectromechanical systems
    • B81B2201/05—Microfluidics
    • B81B2201/058—Microfluidics not provided for in B81B2201/051 - B81B2201/054
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/902—Oxidoreductases (1.)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/902—Oxidoreductases (1.)
    • G01N2333/904—Oxidoreductases (1.) acting on CHOH groups as donors, e.g. glucose oxidase, lactate dehydrogenase (1.1)

Definitions

  • This technology relates generally to paper-based microfluidic devices.
  • this invention relates to medical diagnostics and point-of-care devices.
  • microfluidic devices were initially fabricated in silicon and glass using photolithography and etching techniques adapted from the microelectronics industry.
  • Current microfluidic devices are constructed from plastic, silicone, or other polymeric materials, e.g.
  • PDMS polydimethylsiloxane
  • Point-of-care devices can bring the diagnostic test conveniently and immediately to patients, thus allowing for immediate clinical decisions to be made.
  • POC testing since the 1980s has led to a revolution in clinical medicine and patient care.
  • Those point-of-care devices include glucose meters (glucometer), cholesterol meters, pregnancy test strips, and so on.
  • DKA diabetic ketoacidosis
  • POC point-of-care
  • point-of-care devices should be simple to use and readable on site.
  • the devices represent a new class of "paper machines” - three-dimension microfluidic/electrochemical devices in "pop-up” form.
  • Pop-up also known as "kirigami”
  • 3-D three-dimensional
  • the integration of a pop-up structure into paper-based microfluidic devices provides both a reconfigurable path for analytes to flow, and the ability to spatially separate— and then reconnect— layers of the device, enabling time-controlled valving of the fluid flow.
  • a flap of patterned paper creates an electrochemical cell or single reaction zone.
  • 3-D microfluidic connectivity changes through multiple configurations as it is folded.
  • a pop-up three dimensional microfluidic device includes at least one porous, hydrophilic sheet comprising a fluid-impermeable material that defines at least a first sample zone and a detection zone within the porous, hydrophilic layer, wherein the sample zone and the detection zone are not in fluidic contact with each other on the sheet; the device having at least one crease line and at least one score line capable of manipulation to provide:
  • a first open state forms a pop-up element in which the sample zone and the detection zone are spaced from one another and are located in different planes;
  • a pop-up three dimensional microfluidic device includes at least one porous, hydrophilic sheet comprising a fluid-impermeable material that defines at least a first zone and a second zone within the porous, hydrophilic layer, the sheet having at least one crease line and at least one score line to delineate a pop up element capable of being erected upon bending; wherein one of the first zone or the second zone is located on the pop up element; wherein the device includes an open state having a pop-up element wherein the first zone and the second zone are spaced from one another; and
  • the spaced apart relationship of the first zone and the second zone includes the first zone and the second zone being located in different planes. [0019] In any of the preceding embodiments, the first zone is in alignment with the second zone in the folded state.
  • the open state forms a 90°, 180° or 360° pop up element.
  • the device is configured and arranged to cause the pop up element to move laterally and vertically as the device is manipulated between the open state and the folded state.
  • the porous, hydrophilic sheet includes cellulosic paper.
  • At least one of the first zone and the second zone include a reagent selected for the detection of an analyte of interest.
  • the first zone is configured to receive a sample and the second zone includes a plurality of assay regions, at least one of the assay regions in fluidic contact with the first zone in the second folded state.
  • the assay components in each of the plurality of assay regions are the same or different.
  • the detection zone includes reagents to provide an optically detectable output.
  • the detection zone incudes reagents to provide an visually detectable output.
  • the detection zone includes reagents to provide an electrochemically detectable output. [0029] In any of the preceding embodiments, the detection zone includes electrodes.
  • the electrode is integratable with a portable electroreader.
  • the electrode pair is integratable with a benchtop device such as a voltammeter, ammeter, cyclovoltammeter, or potentiometer.
  • the electrode pair is integratable with a glucose meter.
  • the device further includes a fluid reservoir.
  • the device includes at least two pop-up elements.
  • the device includes at least two pop-up elements, wherein the two pop-up elements are in the same plane when erected.
  • the device includes at least two pop-up elements, wherein the two pop-up elements are in different planes when erected.
  • a method of analyzing a sample including providing a pop-up three dimensional microfluidic device according to any preceding embodiment, wherein at least one of the first zone and the second zone includes a reagent selected for the detection of an analyte of interest;
  • the condition is the presence or absence of an analyte of interest.
  • the condition is the concentration of an analyte of interest.
  • the analyte of interest is beta- hydroxybutyrate.
  • the detection is an visual detection.
  • the detection is an electrical detection.
  • the device includes at least two pop-up elements, wherein the two pop-up elements are in the same plane when erected.
  • the device includes at least two pop-up elements, wherein the two pop-up elements are in different planes when erected.
  • the first pop-up element includes the first zone
  • the second pop-up element includes the second zone
  • manipulating the device into the first folded state causes the first zone to come into fluidic contact with the second zone, and further manipulating the device to a second folded state in which the second zone is in fluidic contact with a third zone.
  • all three zones are in fluidic contact after the further manipulation of the device.
  • a pop up test strip for measuring analyte including a folded porous, hydrophilic sheet comprising a fluid- impermeable material that defines at least a first sample zone and a detection zone within the porous, hydrophilic layer, the sheet having at least one crease line and at least one score line to delineate a pop up portion capable of being erected upon bending, electrodes extending from the sheet and in electrical communication with the detection zone, wherein the electrodes are configured to be insertable into a glucose meter; wherein the one or both of the first sample zone and the detection zones includes reagents for electrochemical detection of beta-hydroxy-butyrate, wherein the device includes a first open state having a pop-up element wherein the sample zone and the detection zone are spaced from one another; and a second folded state in which the sample zone and the detection zone are in fluidic contact with each other.
  • the reagent includes 3-hydrozybutyrate dehydrogenase.
  • the reagent is located in the firs sample zone.
  • Integrating a pop-up structure into paper-based diagnostic devices provides more freedom and flexibility in design and use than previous devices made using the principle of origami.
  • the 3D structure allows the path of the liquid flow, and of the electrical conductivity, to be reconfigured by spacially separating the layers by folding and unfolding the device.
  • the concept of using a 3D pop-up structure provides five key functions for the analystical device: i) controlling timing and enabling multistep
  • pop-up-structures can be made that include, for example, arbitrary fluidic paths (e.g., multi-step fluidic programming during the course of an analysis) or other sensing
  • Figures 1A-1D is a schematic representation of a three dimensional pop-up microfluidic device according to one or more embodiments in an (A and C) open and (B and D) closed configuration.
  • Figure 2 is a representation of a three dimensional pop-up microfluidic device according to one or more embodiment.
  • Figure 3 (i)-(v) illustrates the fabrication of a three dimensional pop-up microfluidic device according to one or more embodiments.
  • Figure 4 illustrates the scoring and folding of a sheet to create a pop-up feature according to one or more embodiments.
  • Figure 5A is a side view and Figure 5B is a top view of a pop-up three dimensional microfluidic device that includes multiple reagent zones.
  • Figure 6 is a series of photographs illustrating the folding of a pop-up three dimensional microfluidic device according to one or more embodiments.
  • Figure 7 is a schematic illustration of a method of testing a sample using a pop-up three dimensional device according to one or more embodiments.
  • Figure 8 is a concentration titration of nicotinamide adenine dinucleotide (NADH) using cyclic voltammetry for a device according to one or more
  • Figures 9A and 9B are plots of glucose display values (arbitrary) vs.
  • beta-hydroxybutyrate (BHB) concentration for the analysis of solutions of BHB in Tris buffer using pop-up paper devices (9 A) and commercial test strips (9B) demonstrating the linear relationship between concentration and readout. .
  • Figures 10A and 10B are a plot of glucose display values (arbitrary) vs. beta-hydroxybutyrate (BHB)-spiked blood are different concentrations
  • Pop-up paper-based microfluidic devices are provided for performing chemical analyses using hand-held devices. Paper devices are less expensive, and easier to fabricate than open-channel microfluidic chips (normally fabricated in polymers), and do not require pumps and electrical power to manipulate fluids.
  • the pop-up structure acts as a reversible, mechanical valve to change the fluidic connectivity of the system. When the device is 'closed' using a modest mechanical pressure (i.e., when squeezed between the thumb and forefinger or placed on a flat surface with a weight on top), the valve goes from an 'off to an 'on' state because the contact between the separate paper components allows a fluid connection, with liquid flowing from one sheet to another. This connection is insensitive to the applied pressure, since it requires, primarily, fluidic contact and capillarity to establish the fluidic path, not consistent reproducible mechanical contact between the surfaces of the paper.
  • FIG. 1A is a schematic illustration of the device in an open configuration
  • FIG. IB is a schematic illustration of the device in a closed configuration. The device is able to move, optionally
  • FIGs. 1C and ID are photographs showing the valve capabilities of the popup paper microfluidic device when it is open and closed.
  • the paper structures can be folded and unfolded to change the fluidic connectivity of the system.
  • the device is prepared from paper sheets that have suitable fluidic channels, reaction zone and electrodes and electronic circuitry, when required, built into the layer. The sheet is then folded and scored, e.g., cut, to allow the different regions of the device move into and out of contact.
  • the open position provides a spaced apart
  • the application zone 100 includes a fluid accepting region 110 that can be used for sample application.
  • the region includes a fluid- impermeable material 120 that defines at least a fluid-accepting region 110 within a porous, hydrophilic layer.
  • the application zone can also include reagents such as buffers, lysing agents, enzymes, coenzymes and reactive chemicals that are used to prepare the sample for analysis, that can also be located in the fluid-accepting region 110.
  • reagents such as buffers, lysing agents, enzymes, coenzymes and reactive chemicals that are used to prepare the sample for analysis, that can also be located in the fluid-accepting region 110.
  • buffers e.g., lysing agents, enzymes, coenzymes and reactive chemicals that are used to prepare the sample for analysis
  • a lysis buffer e cells before analysis.
  • the reagents necessary for chemical analyses can be stored in the pores between the cellulose fibers of the paper either as a dry powder (usually included in a solid stabilizing agent such as dextran or trehalose), or suspended in a hydrogel; there is thus very little manipulation required by the users.
  • the sample zone can include separate regions for sample application 220 and sample mixing and/or reacting 210. See, e.g., FIG. 2.
  • the sample application and mixing regions 220, 210 can be in fluidic contact.
  • the sample is applied as a fluid at the sample application region, the sample moves by fluidic, e.g., capillary, action through a porous hydrophilic channel (e.g., defined by the fluid-impermeable fluid) 230 towards the mixing zone.
  • the mixing zone can include additional reagents for sample preparation and/or sample reaction.
  • the device also includes a lower portion that has a reaction and/or detection zone 150.
  • the reaction and/or detection zone 150 has a sample accepting region 160 that can optionally have additional reagents, e.g., assay reagents, that interact with the sample to provide a detectable indicator.
  • the indicator can be optically detected by instrumentation or the human eye.
  • the reagents can be selected to provide a signal that is detectable by color change, ultraviolet radiation, fluorescence, chemiluminescence, electroluminescence and the like.
  • the regents can be selected to produce an electrically detectable signal, e.g., an electrochemical response that is detectable as a current or voltage reading.
  • the reaction/detection zone 150 can include a sample accepting region 160 that is in fluidic contact with one or more assay regions 170.
  • the reaction/detection zone includes a fluid- impermeable material 180 that defines one or more of a sample acceptance region 160 and assay region 170 within a porous, hydrophilic layer.
  • the sample accepting region can include assaying reagents and the analysis is carried out at the same location.
  • An additional fluid reservoir 190 can be located below the reach on/detecti on zone to provide addition fluid to ensure adequate fluidic flow.
  • the fluid reservoir can be constructed by embossing in hydrophobic paper or materials, as is described in Anal. Chem., 2014, 86 (24), pp 11999-12007, which is incorporated by reference in its entirety.
  • the pop-up feature of the device allows the user to move the upper and lower regions into and out of contact with each other.
  • fluid accepting region 110 located in application zone 100 (upper portion of the device) contacts sample accepting region 160 located in the
  • sample can flow to assay regions for detection; or the device can be connected to a readout device in cases where an electrical signal is used for detection and measurement.
  • the interaction time can be accurately controlled and multistage interaction processes can be monitored and controlled.
  • the user simply adds the sample and a solution of electrochemical mediator (if the assay is an electrochemical assay) or other reagents to the popped up (unfolded) device, folds the device as instructed, and reads the results.
  • FIG. 2 is a photograph of a pop-up three dimensional microfluidic device designed to produce an electrically detectable signal, e.g., an electrochemical response that is detectable as a current or voltage reading according to one or more embodiments
  • the device has an application zone 200 (upper portion of the device) that includes porous hydrophilic regions, indicated as white regions in the device, e.g., the sample port (220), reaction zone (210) and non-electrode portion of the detection zone 250.
  • the porous hydrophilic regions are bounded by a fluid- impervious region 240, indicated by a dark grey.
  • the device also has a
  • the electrodes 260 are printed onto the paper substrate and are shown in black in FIG. 2.
  • the electrodes can be a working electrode, a counter electrode, a reference electrode, ion-selective electrodes, as well as additional auxiliary electrodes.
  • the electrodes are shown extending from and beyond the detection zone.
  • the electrodes can be sized to be connectable to an electronic reader, e.g., a voltmeter, ammeter or other similar device.
  • the sample application and detection regions are made from a single paper sheet. In the open configuration the sample application zone is spaced above and apart from the detection zone.
  • the pop-up 3D pop-up device can be prepared from a single sheet of paper (although more complex systems be involving multiple folding steps can use more than one sheet).
  • a 'pop-up' structure is one in which a two dimensional (2D) is transformed into a 3D geometry by a folding or opening operation. Pop-ups can classified by the angle of opening two base pages or surfaces when the pop-up feature is fully erected, for example, when the base sheets are at 90°, 180° and 360°.
  • a 90° pop-up structure is one that erects fully when two adjacent base pages, on which it sits, are opened to a right angle.
  • the device illustrated in FIGs. 2 and 4 is an example of a 90° pop-up structure.
  • two parallel score lines 400, 400' intersect a fold line 410.
  • Fold lines 420, 420' and 420" establish the fold lines of the pop up element 430 (that creates the upper sample application zone) when the two bases 440, 450 are rotated to 90° (shown by arrow).
  • An additional pop-up feature (housing the application zone) is formed along the score line 460.
  • the fabrication process of such structures is simple and is based on the principles of paper cutting and folding. A portion of a device, or even the entire device, can be fabricated on a single sheet of paper and then assembled by paper folding. In one or more embodiments, the device is made entirely from one sheet of paper that is pattered by defined hydrophobic/hydrophilic area and electrode components.
  • FIG. 3 The manufacture and assembly of a pop-up three dimensional diagnostic device including electrodes is demonstrated in FIG. 3. The method is described for a pop-up paper-based device configured for electrochemical detection of analytes. Electrochemistry offers three advantages as the basis for bioanalysis: i) It provides quantitative measurements, ii) It is independent of lighting and color (both good lighting and a colorless solution are usually required for colorimetric and
  • spectrophotometric assays iii) It allows easy interfacing with electronic medical- records systems.
  • the fabrication of a chemical or optical based pop-up paper-based device is prepared with suitable modification to accommodate the different detection mode, e.g., addition of assaying regions with suitable reagents in the reach on/detecti on layer.
  • step (i) a flat sheet 300 to be used as a substrate is selected.
  • the sheet is porous and most often hydrophilic, as the fluid is typically water;
  • hydrophilic layers include any hydrophilic substrate that wicks fluids by
  • the porous, hydrophilic layer is paper.
  • porous, hydrophilic layers include
  • porous, hydrophilic layers include Whatman chromatography paper No. 1.
  • the paper can be chemically treated to modify the water absorbing properties (or other properties) of the paper.
  • a fluid impermeable layer 310 is deposited to define the fluidic structures such as the sample and reaction zones as well as any interconnecting channels. Lines indicating future score lines and fold lines are shown for illustration purposes.
  • a single substrate sheet can be used to make multiple individual foldable devices.
  • the microfluidic channel, and reaction zone(s) are deposited on hydrophilic layers patterned by fluid-impermeable materials that define one or more hydrophilic channels or regions on the patterned hydrophilic layer. Fluid flow can be controlled in a paper-based microfluidic device by wax barriers (i.e. channels) patterned using a solid-wax printer. This is done by wax printing or any other suitable method.
  • An exemplary method of preparing patterned hydrophilic layers is described in detail in WO 2008/049083, the content of which is incorporated in its entirety by reference.
  • the electrode assembly e.g., electrodes and associated circuitry 320
  • the electrode assembly is deposited by stenciling or screen printing or other suitable method.
  • an ion selective membrane can be deposited to make ion-selective electrodes. See, e.g., Lan, W.; Zou, X. U.; Hamedi, M. M.; Hu, J.; Parolo, C.; Maxwell, E. J.; Bu, P.; Whitesides, G. M. Anal. Chem. 2014, 86, 9548-9553.
  • One or more electrode pairs can be used, in addition to reference electrodes, as is conventionally practiced. Stencil-printing carbon or silver onto wax- printed paper can be used to make working, counter, and reference electrodes.
  • Electrodes can be screen-printed electrodes using conductive carbon ink, and wires using silver ink because of its good conductivity. Carbon ink can also be used for wire material as well.
  • the electrodes made from conductive ink have several advantages: (i) they are less expensive, compared to Au or Pt electrodes; (ii) the fabrication process is simple, and has less requirements on cleanroom facilities; (iii) those materials are well developed, and easy to obtain, because they are widely used in both industrial and academic research; (iv) screen printing is capable of mass production at low cost.
  • a portion of the upper sample zone may also include conductive material to improve electrical contact on folding.
  • the electrode assembly is deposited on a portion of the hydrophilic layer that is shaped so that it may fit into an electrochemical reader, such as a glucose meter. Alternatively, electrical contacts can be provided to create an electrical connection with other readers. Fabrication of microfluidic devices including one or more electrode assemblies is described in details in PCT
  • electrochemical pop-up paper-based analytical devices can perform a wide range electrochemical methods (e.g., potentiometry,
  • step (iv) reagents that will be used in the diagnostic assay are applied to either the sample deposition and mixing regions 330 and/or the reaction and detection regions (not shown in this example) as is required by the test of interest.
  • Any known method or assay can be adapted to this device and includes rapid detection of electrolyte, metabolites and enzymes, such as sodium, potassium, and chloride ions, glucose, ketone, blood urea nitrogen, ammonia levels in blood, aspartate transaminase (AST), alanine transaminatse (ALT) or bilirubin.
  • disease-specific biomarkers/ antibodies/immunoassay or disease -specific nucleic acid, DNA amplification can be used.
  • the materials can be applied as a solution or suspension and can be dried prior to further processing.
  • step (v) the sheet is cut into individual devices and each device is scored and folded.
  • FIG. 4 is a schematic illustration of the scoring and foling of the flat sheet along indicated lines and the erection of the pop up structure on folding of a single device prepared according to the above-described steps.
  • the device is scored along thick vertical dashed lines and folded along thin dashed lines. Once folded, the sample application zone pops up out of the plane of the paper and is positioned separate from and above the detection zone.
  • the device will provide 3-D switchable 90 degree- "pop-up" structures.
  • to improve the cut-and-fold techniques will provide 3-D switchable 90 degree- "pop-up" structures.
  • an additional sheet of paper can be adhered to the bottom of the device.
  • the device In use or in storage, the device can be completely folded. This is
  • the arrangement can be used in a dry, inactive state for storing and shipping.
  • the device can be sealed in a protective sleeve or layer.
  • the folded arrangement is also used in a wet, active state for assay, detection and measurement.
  • the device may include a number of pop up elements and a number of foldable flaps, each associated with score lines and fold lines to change the 3D structure and fluid connectivity of the device.
  • the 3D connectivity changes as the flaps are folded.
  • FIG. 5 is a (A) side view and (B) top view of a pop-up three dimensional microfluidic device that includes multiple reagent zones and electrodes.
  • the device includes multiple pop-up zones, which permit separate multi-steps reactions with spatial and time control.
  • different chemical reagents are applied in different zones. The sample can be exposed sequentially or simultaneously to the different reagents by folding the pop-up regions in a prescribed order.
  • FIG. 6 illustrates a step-wise folding of the device to its flat form, suitable for storage or use.
  • the sample is applied to the application region 600 in the "open" configuration and flows to the reaction mixing region 605.
  • a first-folding step folds a top flap 610 over the application region 600 to perform the first analyses detection.
  • the sample is transferred from the application region 600 to a branched fluidic channel 615.
  • the fluidics direct a sample go a second level containing a second analysis region 625, and permit separate second-steps reactions with spatial and time control.
  • a second-folding step lowers a second flaps 630, 630' over the second analysis region 625, and the second analyses detection is performed.
  • the detection is
  • the device may be made up of more than one foldable sheet. This permits to device to execute more complex actions.
  • the device can be configured to have a first element, e.g., a sample application zone, to move out of the way of a second element, e.g., as second application zone, so the two analysis can take place without bumping into one another.
  • the pop up element of the device is capable of rotation as it is manipulated between the open state and closed state.
  • the structures can be further elaborated by computer-aided designs. Because there are many possible configurations for folding, we can test reactions sequentially at different points, or perform multistage or multiplexed detection processes. Certain embodiments provide a simple to operate, portable, versatile and multiplexed paper machine for blood and urine samples. This eliminates the necessity for conventional bench top analysis process that requires professional clinicians and instruments.
  • a method of detecting an analyte includes opening a device from its flat storage position and fold to 'pop up' the sample preparation region spaced apart and above the detection region.
  • the device is typically pretreated with the appropriate chemical reagents for the assay of interest.
  • a sample e.g., a biological sample such as blood, saliva or urine is applied to the sample area. Additional components, such as buffer, can be added to provide sufficient solvent for reaction and mixing.
  • the method may call for a time period sufficient for the sample to mix and/or react. Because there is no fluidic contact with the detection zone, the user is able to determine the delay or reaction time, independent of the time for fluidic transport of the reagents to the detection zone.
  • the device is folded into a closed position, bringing the sample into fluidic contact with the detection zone.
  • the zone may have addition reagents that permit detection, e.g., optical detection of the test results.
  • the detection zone may include electrodes and associated circuitry to allow
  • the read out can be integrated with hand-held (portable) electrochemical readers; i.e. glucometer, or integrated with benchtop electrochemical analyzer; i.e. potentiostate, amperometry, voltammetry, or potentiometry.
  • hand-held electrochemical readers i.e. glucometer
  • benchtop electrochemical analyzer i.e. potentiostate, amperometry, voltammetry, or potentiometry.
  • electrochemical reader refers to an amperometric device which detects the existence of certain analytes. Once the electrode portion of the device is inserted in the port of an electrochemical reader, such as a
  • the glucometer can detect the sample and launch the 10 sec
  • a combination of auxiliary electrodes can be used in addition to the two electrodes used for the electrochemical measurement.
  • the additional electrodes allows the detection of fluid in different areas of the detection zone. This system prevents the user from re-using a test strip or invalidates a result (display errors) if too small a volume of sample is deposited e.g., when the whole volume of the detection zone is not filled after a certain elapsed time of the countdown, which would result in insufficient contact of the fluid with all the electrodes of the assembly).
  • a method of testing using a diagnostic device integrated with a commercial reader is described with reference to FIG 7.
  • a pop up device having the appropriate reagents is inserted into a reader in the closed stage.
  • the reader recognizes the device and indicates that it is ready to proceed.
  • the user then opens the device and the sample application region pops up and is accessible for use.
  • the sample here blood
  • the sample application region has been preheated with the appropriate reagents to test react with the blood to form a readable output.
  • the reagents include those appropriate for the detection of beta- hydroxybutyrate, as is discussed in greater detail below.
  • the user is in control of the reaction time. The user allows the sample to react for the selected time.
  • the device When reaction is complete, the device is closed, thereby bringing the sample in contact with the electrodes. Electrodes are above to detect an electrical signal, which is displayed as a readout on the portable reader.
  • the pop-up structure can be used to electrochemically detect concentration of beta-HB (3- -hydroxybutyrate).
  • electrochemical analytical device is connected to a commercial glucometer (or other commercial device), the electronics immediately start the measurement (sometimes after only a 5 - 10 s reaction period).
  • This automatic (and immediate) electrical response limits the time allowed for a reaction.
  • concentration of the enzyme stored in the device can be increased, but using more enzyme also increases cost. For some applications, there are no enzymes that can react rapidly enough to work with conventional electrochemical analytical devices.
  • the electrochemical pop-up analytical devices address these limitations by decoupling the enzymatic reaction from the specific timing sequence for analysis imposed by commercial glucometers.
  • the devices can be designed to integrate with a commercially available glucometers.
  • the device can be a more versatile, portable, electrochemical reader capable of a wide variety of electrochemical measurements with transmission of data over the audio channel of any cellphone, with any mobile network.
  • the pop-up electrochemical analytical device includes a sample port, a reaction zone where enzymes can be stored, and a detection zone that is spatially separated from the first two zones.
  • the detection zone interfaces with a glucometer, through three stencil-printed electrodes: i) a working electrode, ii) a common counter and reference electrode, and iii) an indicator electrode. See, e.g., FIG. 2.
  • the time-dependent assay is true and the accuracy of the assay usually need to be read out within a specific time period.
  • the device, kit, and method described herein can be used to analyze glucose or non-glucose analytes.
  • Other non-glucose analytes include lactate, ethanol, urea, creatinine, creatine, uric acid, cholesterol, pyruvate, creatinine, ⁇ -hydroxybutyrate, alanine aminotrasferase, aspartate aminotransferase, alkaline phosphatase, and acetylcholinesterase (or its inhibitors).
  • Suitable reagents pre-deposited on the hydrophilic regions of the microfluidic device for these non-glucose analytes are chosen so that the reaction between the non-glucose analyte and the reagent will generate a current readable by the glucose meter or other commercial electrochemical readers, where a potential is applied by the electrochemical reader.
  • the reactions occur in the reaction zones are enzymatic-based reactions.
  • the enzyme can be specific to the analyte to be quantified and an electrochemical mediator (such as Fe(CN)6 3 ) may undergo a concomitant reaction (to become Fe(CN)6 4 ⁇ ) and then be electrochemically quantified by the glucose meter.
  • any other electroactive species able to react at the potential applied by the glucometer is suitable.
  • a potential of 0.5V can be applied.
  • the glucose meter is CVS glucometer TrueTrackTM glucose meter.
  • Different potential range for other electrochemical reader can be used.
  • Other examples of such chemical species include ruthenium hexamine and Os(III) complex. These chemical species can be recognized by a commercial electrochemical reader, e.g., a glucose meter, and thus one or more reagent can be selected to be predeposited in the hydrophilic regions to react with non-glucose analytes to generate
  • Fluidic channels and cutting guides were generated by wax printing onto chromatography paper (Whatman 1 Chr). A total of 12 devices were printed on each sheet of paper. A PDF of the file used to print the devices is available for download from http://pubs.acs.org. After the devices were printed, the wax was melted by baking the devices in an oven at 120 e C for 45 seconds.
  • the electrodes were fabricated by stencil-printing carbon ink (C2050106P7, Gwent Electronic Materials Ltd., United Kingdom). The stencil pattern was generated using AutoCAD® 2012, and cut from a frisket film (Grafix, low tack) using a laser- cutter (Versal/LASER VLS3.5, Universal Laser Systems).
  • the stencil was adhered on the top of the paper, and filled the openings of the stencil with graphite ink and allowed the ink to dry at room temperature for 30 minutes in a laminar flow hood.
  • Both the electrodes and detection zone of the pop-up device were treated with a solution of 0.5 wt% 3-aminopropyldimethyl-ethoxysilane (APDES) in water to enhance the hydrophilicity.
  • APDES 3-aminopropyldimethyl-ethoxysilane
  • a l,10-phenanthroline-5,6-dione (1,10-PD) mediated graphite ink can be directly screen-printed onto the working electrode.
  • the enzyme solution were made to 2 U/mL by reconstituting the content of one vial with 0.6 mL Tris-buffer (100 mM, pH 8.0); this concentration was higher than the final concentration of activity (0.12 U/mL) of a solution made by following the enzyme manufacturer's instructions (i.e., to use 10 mL of solution for re-constitution) for use in a laboratory analyzer (i.e., RX DaytonaTM clinical chemistry analyzer, Randox Laboratories Ltd.).
  • a laboratory analyzer i.e., RX DaytonaTM clinical chemistry analyzer, Randox Laboratories Ltd.
  • the procedure for cutting and folding the pop-up devices is modeled after the method used to make pop-up greeting cards.
  • the dry pop-up device was inserted into the glucometer and waited for the reader to indicate it recognized the device.
  • 15 of sample either BHB in buffer or whole blood
  • 35 of mediator solution 2.5 mg/mL 1,10 PD in water
  • BHB solutions were prepared by diluting a 60-mM BHB stock solutions with water. Theses BHB aqueous solution were then spiked into whole blood in a range of 0.1 mM to 6.0 mM. Before use, unspiked whole blood was tested with commercial BHB test strips to ensure the sample had BHB levels below the LOD of the test strips (0.1 mM).
  • the Precision Xtra ® meter uses different test strips for glucose and for BHB; the device recognizes the type of strip automatically based on a recognition electrode on the back side of the BHB strip. That is, the glucose strips have no electrodes on the backside; the BHB strips have a recognition electrode patterned onto their backside.
  • a device for BHB that could be read by simple glucose meters should not require this type of recognition of strips.
  • the pop-up-electrochemical analytical devices for detecting BHB mimic the configuration of commercial glucose strips in term of the configuration at the junction between the strip and the meter, and, thus, trick the meter into operating as a glucometer.
  • Strips were also design for use with a commercial glucometer (CVS Truetrack ® glucometer), which did not include a mode for measuring BHB.
  • the number displayed by the reader is a representation of the actual BHB concentration value and not the exact concentration; the true value of BHB can be calculated from the reading on the meter using a calibration curve, or against an empirical scale. In a device intended for POC use, the conversion could be easily accomplished by the electrochemical reader.
  • the pop-up devices could be used with other glucometers and electrochemical detectors with simple modifications of the electrodes, and other design aspects required to generate the electrochemical interface designed for that device.
  • Using the Precision Xtra ® we were able to make a direct comparison of our measurements of BHB, made with paper devices, to those made with commercial, plastic test strips using the same reader in different test modes.
  • the Pop-up Device Enables Controlled Valving and Timing
  • the pop-up structure provides spatial separation in the "open” configuration; it enables the operator to wait for the enzymatic reaction to reach completion before changing the path of the fluid (i.e. 'closing' the pop-up) and enabling the fluid flow that triggers the initiation of the electrochemical measurement sequence by the glucometer.
  • the pop-up-device structure enables the controlled timing of the enzymatic reaction and therefore the total amount of the 3-HBHD required can be reduced by allowing a longer reaction time, and thus reduce the cost of each test strip (with the trade-off being that the analysis is slower).
  • This design also allows reagents to be stored in the paper and to be activated by the fluid flow; no premixing of the components is needed.
  • amperometric assay for BHB was designed on the pop-up-electrochemical paper analytical device to have three steps: i) 3-HBDH catalyzes the oxidation of BHB (present in the sample) to acetoacetate (AcAc), with a corresponding reduction of NAD + to NADH; ii) the NADH produced donates two electrons to the electron- transfer mediator, l,10-phenanthroline-5,6-dione (1,10-PD), and generates the reduced form of 1,10-PD; iii) the working electrode oxidizes the reduced form of 1,10-PD at a potential of +0.2V (set automatically by the hand-held reader), and the resulting current is displayed as a numerical quantity on the electrochemical reader.
  • the quantity of enzyme and the cofactor NAD + was varied to ensure that the signal for appropriate BHB concentrations would correspond to the linear range of the glucose output; if a concentration were out of this range, the reader would display an out-of-range error message rather than a number.
  • FIG. 8 shows a concentration- dependent increase in the height of the anodic peak in a mixed solution of 1,10- PD and NADH.
  • the dependence of peak current on the concentration of NADH demonstrates that stencil-printed carbon electrodes on paper behave similarly to the screen-printed electrodes on plastic test strips.
  • the "pop-up" format allowed an enzymatic assay for BHB to be read with a commercial glucometer.
  • the pop-up-electrochemical paper based analytical device is primed with enzyme and cofactor reagents.
  • enzyme/cofactor solution was prepared to a final concentration of 2 U/mL of 3- HBDH and 42 mM NAD + in Tris-buffer (pH 8.0), spotted onto the reaction zone of pop-up-devices, and dried at 4 e C for six hours in the dark.
  • the volume of the enzyme/cofactor solution was chosen to be 45 ⁇ , by titration to ensure that the signal for appropriate BHB concentrations would correspond to the linear range of the glucose output as shown in Table 1.
  • the dry pop-up-device was inserted into the glucometer in the open configuration and waited for the reader to indicate it recognized the device. Then the sample (BHB in buffer) and a separate mediator solution (2.5 mg/mL 1,10-PD) was loaded onto the reaction zone in the top layer of paper device. The sample fluid was retained in the top layer of paper, and the bottom layer remained dry (because there is no fluidic connection between the two zones— top and bottom— in the "open” configuration). After the enzymatic reaction was completed (at a specified time based on the level of enzymatic activity in the devices), the fluidic connectivity was changed by simply closing the device. The liquid from the reaction zone could then wick into the detection zone. Once the sample reached the electrodes, the glucometer initiated the amperometric measurement at a potential of +0.2 V and displayed a number for the measured analyte. See, e.g. FIGs. 7A-7E.
  • the Precision Xtra® reader was used in glucometer mode to analyze the concentrations of BHB in Tris buffer (100 mM Tris-HCI, pH 8.0).
  • the normal range of BHB in healthy individuals is less than 0.4 to 0.5 mM, and diabetics with a BHB concentration greater than 3 mM are advised to seek medical attention immediately.
  • FIG. 10 A and 10B are a plot of glucose display values (arbitrary) vs. beta- hydroxybutyrate (BHB)-spiked blood are different concentrations demonstrating the linear relationship between concentration and readout for (A) a pop-up electrochemical paper-based analytical device according to one or more embodiments, and (b) commercially available test strips (Abbot, Precision Xtra® Blood Ketone Test Strip).
  • Figure 10 shows a linear response for BHB concentrations on both the pop-up devices (10A) and the commercial test strips (10B).
  • the limit of detection (LOD) was calculated to be the concentration that produced a display value three times the standard deviation displayed for a blank sample. While the commercial test strips result in a smaller standard deviation than the paper devices, the LOD values of our devices for BHB (0.3 mM) were comparable to these of commercial test strips (0.12 mM, Table 1). Unlike the commercial test strips that were made in a manufacturing environment, the pop-up devices were fabricated by hand in a laboratory. With additional automation and quality systems for manufacturing, the standard deviation for measurements with different test strips should decrease.
  • mediator/enzyme/cof actor concentrations it should be possible to reduce the volume of sample and improve performance.
  • Percentages or concentrations expressed herein can represent either by weight or by volume.
  • first, second, third, etc. may be used herein to describe various elements, these elements are not to be limited by these terms. These terms are simply used to distinguish one element from another. Thus, a first element, discussed below, could be termed a second element without departing from the teachings of the exemplary embodiments.
  • Spatially relative terms such as “above,” “below,” “left,” “right,” “in front,” “behind,” and the like, may be used herein for ease of description to describe the relationship of one element to another element, as illustrated in the figures. It will be understood that the spatially relative terms, as well as the illustrated configurations, are intended to encompass different
  • orientations of the apparatus in use or operation in addition to the orientations described herein and depicted in the figures.
  • elements described as “below” or “beneath” other elements or features would then be oriented “above” the other elements or features.
  • the exemplary term, "above,” may encompass both an orientation of above and below.
  • the apparatus may be otherwise oriented (e.g., rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted

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Abstract

L'invention concerne un dispositif microfluidique tridimensionnel à soulèvement qui inclut au moins une feuille hydrophile poreuse comprenant un matériau imperméable aux fluides qui définit au moins une première zone d'échantillon et une zone de détection à l'intérieur de la couche hydrophile poreuse, la zone d'échantillon et la zone de détection n'étant pas en contact fluidique entre elles sur la feuille ; le dispositif comportant au moins une ligne de pli et au moins une zone de marquage capable de manipulation pour produire : (i) un premier état plié dans lequel la zone d'échantillon et la zone de détection sont séparées l'une de l'autre et sont situées dans des plans différents pour former une zone de soulèvement et (ii) un second état plié dans lequel la zone d'échantillon et la zone de détection sont en contact fluidique entre elles.
PCT/US2016/025884 2015-04-02 2016-04-04 Dispositifs microfluidiques tridimensionnels à attribut de soulèvement WO2016161430A1 (fr)

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WO2022253108A1 (fr) * 2021-06-02 2022-12-08 厦门为正生物科技股份有限公司 Appareil de test pliant et son procédé d'utilisation
EP4257981A1 (fr) * 2022-04-07 2023-10-11 CSEM Centre Suisse d'Electronique et de Microtechnique SA - Recherche et Développement Dispositif de détection à sensibilité de détection améliorée pour détecter la présence d'une entité chimique, biologique ou biochimique prédéfinie dans un échantillon de fluide
CN116550402A (zh) * 2023-07-03 2023-08-08 中国农业大学 一种快速检测马拉硫磷的3d纸基微流控装置与方法
CN116550402B (zh) * 2023-07-03 2023-09-22 中国农业大学 一种快速检测马拉硫磷的3d纸基微流控装置与方法

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