WO2023180691A1 - Appareil et procédés de biocapteur à base de polymère superabsorbant - Google Patents

Appareil et procédés de biocapteur à base de polymère superabsorbant Download PDF

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Publication number
WO2023180691A1
WO2023180691A1 PCT/GB2023/050623 GB2023050623W WO2023180691A1 WO 2023180691 A1 WO2023180691 A1 WO 2023180691A1 GB 2023050623 W GB2023050623 W GB 2023050623W WO 2023180691 A1 WO2023180691 A1 WO 2023180691A1
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Prior art keywords
dry
sap
absorbent
superabsorbent polymer
sensing material
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PCT/GB2023/050623
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English (en)
Inventor
David Howarth
Gavin Macfie
Andrew TREWEEKE
Ian Megson
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iDE8 Limited
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Publication of WO2023180691A1 publication Critical patent/WO2023180691A1/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
    • G01N33/52—Use of compounds or compositions for colorimetric, spectrophotometric or fluorometric investigation, e.g. use of reagent paper and including single- and multilayer analytical elements
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/60—Liquid-swellable gel-forming materials, e.g. super-absorbents
    • 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
    • C12Q1/54—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving glucose or galactose
    • 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
    • G01N33/64—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving ketones
    • 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
    • G01N33/66—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood sugars, e.g. galactose

Definitions

  • the invention relates to an absorbent sensing material, which may be in particulate form, for interrogation of sample liquid to detect analyte, use of absorbent sensing material in absorbent articles, and in test sensors such as test strips, absorbent articles, test sensors such as test strips, and methods of manufacture of absorbent articles and test sensors such as test strips, as well as processes for detecting analyte in sample liquid using absorbent sensing material.
  • Absorbent articles such as diapers comprising biosensing capabilities are known.
  • KR20180085577 LEE describes an attachment-type sensor comprising first and second hydrogel membranes and adhesive film. The flow of the sample does not directly affect the test strip, so the reaction agent is less likely to be washed off.
  • WOOO/65348 ROE Proctor and Gamble
  • US2015025347 SONG describes a separate lateral flow device attached to an absorbent article.
  • W02015085024 NELSON describes a disposable hygienic article with means for diagnostic testing stating typically in the form of a separate test strip visible through a port.
  • WO2015/127528 JOLLEZ describes a chromogenic absorbent material for animal litter comprising a water-absorbing first polysaccharide, and a structural second polysaccharide.
  • WO2017/165953 JOLLEZ describes a water absorbing material and uses thereof.
  • JPH11295306 BISEIKEN describes test materials for urine inspection using cellulose.
  • JP2017187336A KOGA SHIN describes a urinary ketone body detecting paper diaper with an indicator embedded between and absorbent body and a transparent window.
  • W02018/141017 RAJAPAKSA describes an absorbent article with indicator.
  • Bilirubin oxidase catalyses a colorimetric reaction visible when urine with bilirubin is present.
  • a separate absorbent material is used within the absorbent body capable of collecting and retaining urine.
  • the bilirubin oxidase may be encapsulated in a micro-capsule such as polysaccharide or the bilirubin oxidase and may be stabilised by covalently binding to polyacrylic acid. Neither is an easy to manufacture or cost-effective route to long term stability.
  • US2006/0253047 FOX describes a device for non-invasively monitoring a medical condition of a mammal and in particular marker ingredients to generate a colour in a non- invasive wearable device for a collecting bodily fluid.
  • marker ingredients to generate a colour in a non- invasive wearable device for a collecting bodily fluid.
  • Several options for marking ingredient application are described, but application in a liquid carrier to the inner or outer surface of the next -to-skin water permeable layer is preferred.
  • WO2016191372 MEEK describes an indicator panel which may be in contact with an absorbent core. The problem of highly concentrated urine affecting perceived indicator colour is noted. W02008/072116 LONG is similar to MEEK describing absorbent articles that can detect medical conditions.
  • LIS2015260658 SONG describes multi-layered devices for analyte collection using a control layer to inhibit the reaction at a sensing layer and acknowledges problems of repeated insults of bodily fluid. A separate absorption layer is required.
  • LIS2017/0172933 HARDER describes loadable polymeric particles for therapeutic and diagnostic applications.
  • Diaper Detective System 2014 is a diaper with an insert lateral flow channels for two biosensing tests. This is complex to manufacture.
  • W02007073139 and MXNL05000103 GONZALEZ describe a diagnostic disposable diaper including: a plurality of urine-sensitive indicator reagents to detect levels of glucose, ketone bodies, heavy metals and which are fixed to the internal absorbent lining of the diaper.
  • SHIBATA et. Al. 17894-17898 I PNAS I October 19, 2010 describes injectable hydrogel microbeads for fluorescence based in vivo continuous glucose monitoring.
  • WO2012043177 EP2623530
  • SHIBATA describes injectable hydrogel particles.
  • US6203496 GAEL describes providing one or more chemical reagents near an absorbent region of a diaper and examples of various detection regimes, reagents and colour changes that may be useful in embodiments of the present invention.
  • JANKOWSKA et al. describe a wound pad for non-invasive monitoring using sensing molecules in a biocompatible hydrogel matrix.
  • WO2019245468 SISMAN describes a method of manufacture to introduce chemicals to non-woven bulk product for diagnosing a disease.
  • Non-biosensing applications include treatment.
  • No signalling component is required or provided, or in several examples, possible.
  • US6051749(A) SCHULZ describes a fabric incorporating organophilic clay, preferably dispersed in a matrix of a superabsorbent polymer for diapers that can prevent skin irritation.
  • US2012/0058074 BRAIG describes dry odour-inhibiting compositions comprising water absorbing polymer particles and at least one oxidase and a substrate of the oxidase e.g. P-D-Glucose for glucose oxidase.
  • KR930002270(B1) IM describes disposable absorbents with anti-bacterial enzyme.
  • WO2019/077335 HALL describes antimicrobial super-absorption compositions comprising an enzyme, a substrate for the enzyme, and a superabsorbent component, such as a superabsorbent polymer, in the form of a powder.
  • WO2013116358 STAMPER describes insecticidal hydrogel feeding spheres.
  • US2017348162 ARIZTI describes an absorbent device and a detector device to indicate the presence or absence of bodily oxidates in an absorbent system but does not discuss disease detection.
  • US5226902 BAE describes a device for dispensing biologically active material into the surrounding environment in which hydrogel deswells or shrinks in response to contact by external physical or chemical stimuli.
  • WO2017178417A1 DONG describes swelling of polymer beads to close an inlet to a sample chamber.
  • Ghanem, A., & Ghaly, A. describe Immobilization of glucose oxidase in chitosan gel beads. Journal of Applied Polymer Science, 91(2), 861-866 (2003).
  • the concentration of analyte in sample liquid may vary with time;
  • test strip sensors attached to diapers may be configured to limit volume to address some of these issues but may suffer from other issues, such as cost and complexity of manufacture and use; test strips or other biosensor components placed on or attached to wearable articles e.g. diapers, are often rigid and may break (leaking fluid) and/or be uncomfortable to wear, they also add significantly to cost: providing enzyme substrates e.g. glucose for glucose oxidase prevents the detection of such substrates;
  • a surrounding medium that provides a diffusion gradient is required, this is undesirable in many commercial applications; hydrogel-sensing systems degrade relatively quickly and are unstable over the time periods for long term storage required for commercial products; defining a volume for liquid sample can be a challenge in manufacturing complex structures with layers are difficult to manufacture and control, and may require pre-processing of analyte before a conjugate or the like is received in an absorbent layer.
  • the present invention seeks to alleviate one or more of the above problems, and/or other problems of the prior art.
  • an absorbent sensing material for interrogation of sample liquid to detect analyte (e.g. the presence and/or concentration of analyte) (e.g. in an absorbent article),
  • dry superabsorbent polymer (e.g. dry super absorbent polymer material which may be known as modified e.g. pre-loaded dry superabsorbent polymer) configured to receive a sample liquid (e.g. in vitro)’, the absorbent material comprising, within the (modified e.g. pre-loaded) dry superabsorbent polymer, (e.g. dried within the superabsorbent polymer to form modified, e.g. pre-loaded, dry superabsorbent polymer material) at least one dry reaction component for (e.g.
  • SAP dry superabsorbent polymer
  • analyte e.g. in vitro
  • the dry (modified) superabsorbent polymer absorbs sample liquid
  • the at least one dry reaction component dissolves and, if analyte is present in the sample liquid, its presence is detected and signalled (e.g. within the SAP, from within the SAP).
  • the dry superabsorbent polymer (SAP) (which may be known as modified, e.g. pre-loaded, dry superabsorbent polymer) changes colour and/or fluoresces.
  • the absorbent sensing material preferably comprises at least 50%, more preferably at least 75%, more preferably at least 90%, more preferably at least 95% by weight of dry superabsorbent polymer comprising the at least one dry reaction component.
  • the (modified) dry superabsorbent polymer material preferably comprises at least 95% by weight, more preferably at least 97% by weight of dry superabsorbent polymer and may comprise up to 5% by weight, more preferably 3% by weight, of one or more dry reaction component(s).
  • At least one dry first reaction component is provided for detecting analyte and at least one dry second reaction component is provided for signalling the presence of the detected analyte.
  • the (modified) dry superabsorbent polymer is configured to receive a discrete (e.g. limited) amount of a sample liquid (e.g. in vitro)’,
  • the (modified) dry superabsorbent polymer provides (e.g. defines) a sample chamber.
  • the (modified) dry superabsorbent polymer provides (e.g. defines) a sample chamber of limited mass.
  • the (modified) dry superabsorbent polymer provides (e.g. defines) a sample chamber of limited volume (e.g. in a dry state and/or in a swollen hydrated state).
  • the (modified) dry superabsorbent polymer is in the form of a continuous bulk medium, having a discrete (e.g. limited) absorption capacity per unit mass providing, in effect, sample chamber of limited volume per unit mass.
  • the (modified) dry superabsorbent polymer comprises particles, preferably dry, preferably discrete particles.
  • the SAP particles each provide a discrete quantity of SAP into which a limited, albeit large, volume of liquid can be absorbed.
  • the SAP is preferably formed as particles (e.g. beads, pellets, flakes, grains of any shape e.g. spherical, cylindrical) of small mass and so (relatively) small swelling capability. SAP particles do tend to have very rapid and large swelling capability although this slows very quickly following after initial exposure to liquid.
  • the SAP particles are preferably 3 dimensional (3D) although they may be generally 2 dimensional, and/or have limited size in one dimension e.g. flakes. They may be hollow.
  • the (modified) dry SAP of the invention may also be referred to as pre-loaded dry SAP.
  • the dry particles are of similar mass e.g. at least 90% by weight are within a range of ⁇ +/- 10% the average dry mass. Preferably, at least 90% by weight of the particles are within ⁇ 10% or ⁇ 5% or ⁇ 2% of the average dry weight of the particles.
  • 1 mm size particles e.g. beads
  • 2.5 mm diameter particles e.g. beads
  • 4 mm diameters particles e.g. beads
  • the particles are of similar size.
  • at least 90% by weight of the particles are within ⁇ 10% or ⁇ 5% or ⁇ 2% of the average dimension (e.g. length or diameter or radius).
  • the particles may be of the order of tens or hundreds of nanometres e.g. submicron so for example ⁇ 100 nanometres, or 100 to 1000 nanometres, or may span the nanometre and micron range so for example 100 to 5000 nanometres, or may be of order of tens or hundreds of microns, so submillimetre e.g. from 5 to 1000 microns, or 5 to 500 microns, 5 to 250 microns, or ⁇ 500 microns, or above the half millimetre range so e.g.
  • each SAP particle may therefore have substantially or generally the same mass and so the same liquid absorption capacity.
  • the absorptive capacity per unit mass, or per particle defines a ‘sample chamber’.
  • a main dimension of dry SAP particles such as length or diameter, preferably an average main dimension over a known number of particles, is, preferably ⁇ 100 nanometres, or preferably 100 to 1000 nanometres, or preferably 100 to 5000 nanometres, 5 to 1000 microns, 5 to 500 microns, 5 to 250 microns, ⁇ 500 microns or preferably ⁇ 0.1 mm (100 micrometres), or preferably ⁇ 0.05 mm ( ⁇ 50 micrometres), or preferably ⁇ 0.01 mm ( ⁇ 10 micrometres), or preferably ⁇ 0.005 mm ( ⁇ 5 micrometres), 0.5 to 5 mm, or from 1 mm to 4 mm, or from 0.5 mm to 3 mm, or from 0.5 mm to 2 mm, or from 1 mm to 2 mm.
  • At least 50%, or at least 80%, at least 85%, or at least 90%, or at least 95% or at least 99% of particles have such a corresponding main dimension e.g. within +/- 10% or within +/- 5%.
  • SAP particles The purpose of selecting such a small main dimension (for example for the majority such as >50%, or >75%, or >90%, or >95%, in other words, preferably most) for SAP particles is so that the volume of the sample chamber provided by each particle is more easily delimited or defined to be of particular size or of a particular range of sizes as described elsewhere herein.
  • the effective size of the sample chamber from one particle to the next is preferably similar or the same within a similar range of tolerances.
  • the limited volume e.g. per particle
  • the limited volume is less than an expected volume of sample liquid.
  • the limited volume e.g. per particle
  • the limited volume is at least an order of magnitude less than an expected volume of sample liquid.
  • the at least one dry reaction component comprises at least one dry transducing component for detecting an analyte; and, at least one dry signalling component responsive to the detection of analyte for signalling the presence of analyte.
  • the at least one reaction component or the at least one transducing component comprises at least one of an electrochemical assay; a colorimetric assay; a nitrate assay; a ketone assay; a glucose assay; a bilirubin assay; a component capable of photometric detection; a component capable of spectrometric detection.
  • the at least one reaction component or the at least one transducing component comprises a colorimetric assay comprising a chromogen (and/or dye).
  • the at least one dry transducing component is selected from: one or more enzymes;
  • Glucose Oxidase GOD
  • HRP Horseradish Peroxidase
  • the at least one signalling component is selected from a chromogen a colourless chromogen potassium iodide (e.g. to provide brown colours)
  • TMB tetramethylbenzidine
  • a Benedict’s solution will change from a transparent blue colour to orange or brick red precipitate depending on the level of glucose present, whereas green represents normal glucose.
  • the superabsorbent polymer is a synthetic superabsorbent polymer, or a naturally-derived superabsorbent polymer, or a biodegradable superabsorbent polymer, or any combination thereof.
  • the superabsorbent polymer comprises, or consists of, one or more SAPs recognised or determined by international standards such as: ISO 17190:2019 which refers to ‘Polymeric material capable of absorbing and retaining large quantities of aqueous solutions, saline solutions, and body fluids’ or ISO 12687:2019 which refers to ‘Polymeric materials, based on acrylic acid, acrylamide or their derivatives, that can absorb and retain water and aqueous solutions to a degree that the resulting hydrogel products can absorb at least 10 times their own weight of water under pressure’ or ASTM F2221-15 which refers to ‘polymeric material that, when hydrated, swells and retains large amounts of liquid, such as water or aqueous solutions, as a result of the action of capillary forces or hydrogen bonding or both.’
  • ISO 17190:2019 which refers to ‘Polymeric material capable of absorbing and retaining large quantities of aqueous solutions, saline solutions, and body fluids’
  • ISO 12687:2019 which
  • the superabsorbent polymer comprises at least one of: polymerised acrylic acid or salts thereof or the like, sodium polyacrylate, polyacrylamide copolymer, ethylene maleic anhydride copolymer, cross-linked carboxymethylcellulose, polyvinyl alcohol copolymers, cross-linked polyethylene oxide, and starch grafted copolymer of polyacrylonitrile, e.g. at least 50% or at least 75% or at least 90% by weight of one or more of these.
  • a disposable absorbent article for sample e.g. bodily
  • fluid interrogation e.g. urine, interstitial fluid, tears, saliva, plasma, serum, blood etc
  • absorbent core at least a portion of the absorbent core comprising the absorbent material of any of claims 1 to 20 or as described.
  • the limited volume e.g. per particle
  • the limited volume is less than an expected volume of sample liquid.
  • the limited volume e.g. per particle
  • the limited volume is at least an order of magnitude less than an expected volume of sample liquid.
  • At least a portion of the (modified e.g. pre-loaded) dry superabsorbent polymer (SAP) of the absorbent material comprises particles of (modified e.g. pre-loaded) superabsorbent polymer (SAP).
  • the dry superabsorbent polymer (SAP) of the absorbent material comprises superabsorbent polymer (SAP) fibres e.g. to provide or be added to fibres in, for example, absorbent sheets, such as nappy liners, hygiene liners, kitchen roll, toilet roll, tissues etc.
  • SAP superabsorbent polymer
  • the absorbent material is provided within a compartment of limited volume, having at least one impervious wall (e.g. a rear wall, or rear and one or both side walls) to resist further ingress of sample liquid once full.
  • at least one impervious wall e.g. a rear wall, or rear and one or both side walls
  • an absorbent sensing material for detecting and for signalling the presence of one or more analytes in a sample liquid (e.g. in vitro), preferably in which the superabsorbent polymer is used as a sample chamber to absorb a predetermined amount of the at least one reaction component, and/or preferably in which the superabsorbent polymer is used as a sample chamber to absorb a predetermined amount of sample liquid.
  • a sample liquid e.g. in vitro
  • an absorbent sensing material comprising: preparing SAP (e.g. particles of a predetermined dimension or range of dimensions e.g. volume or length or diameter to provide, when swollen, a predetermined swollen volume or range of swollen volumes), optionally, of known or predictable size or range of sizes as discussed in various example herein; drying SAP particles; in the absence of an analyte, introducing at least one wet reaction component for detecting and signalling the presence of the analyte, to the dry SAP; drying the SAP to form dry SAP pre-loaded with the at least one dry reaction component for detecting and signalling the presence of an analyte.
  • SAP e.g. particles of a predetermined dimension or range of dimensions e.g. volume or length or diameter to provide, when swollen, a predetermined swollen volume or range of swollen volumes
  • drying SAP particles in the absence of an analyte, introducing at least one wet reaction component for detecting and signalling the presence of the
  • an absorbent sensing material comprising: preparing SAP particles; drying SAP particles; in the absence of an analyte, introducing at least one wet reaction component for detecting and signalling the presence of the analyte, to the dry SAP particles; drying the SAP particles to form dry SAP particles pre-loaded with the at least one dry reaction component for detecting and signalling the presence of an analyte.
  • a process for detecting analyte in a fluid comprising: a) providing absorbent material according to any of the claims to absorbent material
  • the SAP within the SAP to detect and signal the presence (and/or concentration) of analyte in the sample liquid; f) detecting and signalling the presence of analyte in the sample liquid (e.g. by visual indication within the SAP such as a change of colour of the SAP).
  • the invention provides dry SAP beads encapsulating a detection chemistry that activates within the limited volume of the beads upon intake of a liquid, e.g. biological fluid in an absorbent product, to provide a visible result and methods of manufacturing and uses of same.
  • a liquid e.g. biological fluid in an absorbent product
  • any one or more features of any one or more embodiments may be used in any one or more aspects of the invention as described herein as would be understood by someone skilled in the art.
  • the features of the claims and/or those described herein may be used in any aspect of the invention, the different aspects of the invention making use of the features of embodiments described with reference to a different aspect.
  • SAP particles and in particular SAP beads are described in several examples below, it will be understood that technical features of the SAP particles and in particular the SAP may be adapted to SAP in non-particulate form or in other shapes (e.g. SAP bulk medium, and/or SAP fibres etc.) with suitable changes, mutatis mutandis, as would be understood by someone skilled in the art.
  • Figure 1 shows a perspective view of 10 SAP beads when initially dry (lower) and when completely swollen (upper).
  • Figure 2 shows a perspective view of groups of 10 SAP beads in Experiment 1 with beads pre-treated (hydrated) with buffer only (left) and beads pre-treated (hydrated) with liquid reaction mix (right)
  • Figure 3 and Figure 4 show perspective view of groups of 10 SAP beads in Experiments 2 and 3 showing respectively heat-dried beads (Figure 3) and freeze-dried beads (Figure 4).
  • Figure 5 shows perspective view of groups of 10 SAP beads in Experiment 4.
  • Figure 6 is a table of results.
  • Figure 7 is a flow chart outlining one or more processes of the invention.
  • Figure 8 is an example chemical detection and signalling regime for detection of glucose in one or more example embodiments of any aspect of the invention.
  • any quantities, dimensions, or shapes used herein are to be understood to lie within the tolerances, ranges, and variations expected or understood within the particular field.
  • beads are usually spherical but need not be so, and spherical beads may vary in their sphericity.
  • the term ‘beads’ is used as one example of the more general term ‘particles’, which are discrete, independently movable from one another, each having a limited mass, which may vary from one to the next.
  • SAP may refer to SAP alone, or, where the context so indicates, to modified SAP material comprising both SAP and at least one reaction component and the present text is to be read with this in mind.
  • SAPs are defined in several standards including ISO standards referred to elsewhere in this text.
  • Hydrogel Biosensors have generated considerable interest over the past few years, with respect to the excellent alternative systems to detect a wide range of biomolecules, including small biochemicals, pathogenic proteins, and disease-specific genes.
  • hydrogels Due to the excellent physical properties of hydrogels, such as the high water-content and stimuli-responsive behavior of cross-linked network structures, this system can offer substantial improvement for the design of novel detection systems for various diagnostic applications.
  • the other main advantage of hydrogels is the role of biomimetic three- dimensional (3D) matrix immobilizing enzymes and aptamers within the detection systems, which enhances their stability.
  • This provides ideal reaction conditions for enzymes and aptamers to interact with substrates within the aqueous environment of the hydrogel.
  • a super absorbent polymer is a hydrogel without the water content.
  • a SAP is dry.
  • SAP comprises water-absorbing polymers which when cross-linked, absorb aqueous solutions through hydrogen bonding with water molecules.
  • a SAP is ability to absorb water, liquid or a biological fluid depends on the ionic concentration of the aqueous solution.
  • a SAP superabsorbent polymer
  • a SAP is intended to refer to such a polymer in dry form. This may be entirely dry (H2O ⁇ 0.5% by weight), essentially dry ( ⁇ 5% H2O by weight), substantially dry ( ⁇ 15% H2O by weight), or sufficiently dry (e.g.
  • the stability of the SAP and its contents do not degrade to any significant extent over the period of preferably > 6 months, more preferably > 1 year, even more preferably > 18 months, even more preferably > 2 years.
  • the SAP does not comprise enough or sufficient water to enable the transducer component e.g. enzyme to activate or to activate the signalling component.
  • a hydrogel is intended to refer to a SAP (superabsorbent polymer) in wet form. This may be partially swollen with liquid e.g. (>25% H2O by weight), or substantially swollen with liquid e.g. (>50% H2O by weight or >60% H2O by weight or >70% H2O by weight) or sufficiently swollen with liquid e.g. H2O that further absorption of liquid is substantially reduced and/or prevented e.g. within the timescale of exposure to liquid.
  • SAP superabsorbent polymer
  • a SAP may absorb 300 times its weight (from 30 to 60 times its own volume), but when put into a 0.9% saline solution, the absorbency may drop to 50 times its weight.
  • the swift initial swelling in the first 200 seconds and the much slower absorption thereafter see Zohuriaan-Mehr et al 2008.
  • the present inventors have appreciated that this variation in speed of swelling can be used in shortlived disposable hygiene absorption products or interrogation mechanisms in sensors such as test sensors e.g. test strips to deliver an indicator of the presence of an analyte or of a disease or state or, indeed in some embodiments, a test result.
  • analytes include but are not limited to glucose, lactate, urea and cholesterol.
  • Biosensor systems typically comprise: i. a biologically active receptor element e.g. enzymes, optionally with one or more co-factor(s), antibodies, antigens, cells, nucleic acids, DNA etc.; ii. a base material which may be a base substrate in the form of a layer of polymer or paper or other suitable material; iii. a transducer element based on, for example, optical signalling (e.g. colour change, absorbance, luminescence, electrochemical (e.g. amperometric, conductometric, potentiometric, impedimetric etc.; iv. a detection or observation element.
  • a biologically active receptor element e.g. enzymes, optionally with one or more co-factor(s), antibodies, antigens, cells, nucleic acids, DNA etc.
  • a base material which may be a base substrate in the form of a layer of polymer or paper or other suitable material
  • iii. a transducer element based on, for example
  • glucose and glucose oxidase in a colorimetric system as examples of an analyte I receptor system with a transducer capability, but it will be understood that in other embodiments, other biosensor chemistries can be used in the different aspects of the invention.
  • the superabsorbent polymer that provides the ‘vessel’ or ‘sample chamber’ within which the reaction takes place between the biologically-active receptor and an analyte and, preferably also, within which the visual signalling occurs.
  • This combination of the dry biologically-active receptor and dry transducer element within a single dry component (the superabsorbent polymer) greatly simplifies the manufacture of wearable products and, indeed, biosensors which provide a disease state indication or, indeed, measurement and is particularly useful for wearable hygiene products such as diapers, sanitary napkins and, indeed, non-wearable hygiene products such as absorptive sheets for beds.
  • the approach of the present inventors is to use the properties of a SAP and combine this with a number of known bio reagents so that, when presented with a biological fluid sample, the super absorbent reagent will, firstly, capture and contain the biological sample and, secondly, will react to provide an indication of the presence or concentration of the analyte e.g. of elevated glucose or ketones.
  • the indication may be directly observable e.g. visible by eye such as a change in colour, or may be provided after interrogation e.g. direct or indirect interrogation.
  • Superabsorbent polymers are commonly made from the polymerization of acrylic acid blended with sodium hydroxide in the presence of an initiator to form a poly-acrylic acid sodium salt (sometimes referred to as sodium polyacrylate). This polymer is the most common type of SAP made in the world today.
  • a superabsorbent polymer such as polyacrylamide copolymer, ethylene maleic anhydride copolymer, cross-linked carboxymethylcellulose, polyvinyl alcohol copolymers, cross-linked polyethylene oxide, and starch grafted copolymer of polyacrylonitrile to name a few.
  • polyacrylamide copolymer ethylene maleic anhydride copolymer
  • ethylene maleic anhydride copolymer cross-linked carboxymethylcellulose
  • polyvinyl alcohol copolymers cross-linked polyethylene oxide
  • starch grafted copolymer of polyacrylonitrile to name a few.
  • the latter is one of the oldest SAP forms created (see CALO et al 2015).
  • Gel polymerization A mixture of acrylic acid, water, cross-linking agents and UV initiator chemicals are blended and placed either on a moving belt or in large tubs. The liquid mixture then goes into a ‘reactor’ which is a long chamber with a series of strong UV lights. The UV radiation drives the polymerization and cross-linking reactions. The resulting ‘logs’ are sticky gels containing 60-70% water. The logs are shredded or ground and placed in various sorts of driers. Additional cross-linking agent may be sprayed on the particles' surface; this ‘surface cross-linking’ increases the product’s ability to swell under pressure — a property measured as Absorbency Under Load (AUL) or Absorbency against Pressure (AAP). The dried polymer particles are then screened for proper particle size distribution and packaging.
  • the gel polymerization (GP) method is currently the most popular method for making the sodium polyacrylate superabsorbent polymers now used in baby diapers and other disposable hygienic articles.
  • Solution polymerization - Solution polymers offer the absorbency of a granular polymer supplied in solution form. Solutions can be diluted with water prior to application, and can coat most substrates or used to saturate them. After drying at a specific temperature for a specific time, the result is a coated substrate with super absorbency. For example, this chemistry can be applied directly onto wires and cables, though it is especially optimized for use on components such as rolled goods or sheeted substrates.
  • Solution-based polymerization is commonly used today for SAP manufacture of copolymers, particularly those with the toxic acrylamide monomer. This process is efficient and generally has a lower capital cost base.
  • the solution process uses a water-based monomer solution to produce a mass of reactant polymerized gel.
  • the polymerization s own exothermic reaction energy is used to drive much of the process, helping reduce manufacturing cost.
  • the reactant polymer gel is then chopped, dried and ground to its final granule size. Any treatments to enhance performance characteristics of the SAP are usually accomplished after the final granule size is created.
  • the invention provides a system in which a biological fluid is diffused into a SAP (e.g. into initially dry) SAP material, and more preferably into (e.g. initially dry) SAP particles, which has/have been bonded with a wide variety of chemical reagents during or after manufacture e.g. as outlined in any of the three types of SAP manufacture above.
  • a biological fluid is diffused into a SAP (e.g. into initially dry) SAP material, and more preferably into (e.g. initially dry) SAP particles, which has/have been bonded with a wide variety of chemical reagents during or after manufacture e.g. as outlined in any of the three types of SAP manufacture above.
  • a biological fluid is diffused into a SAP (e.g. into initially dry) SAP material, and more preferably into (e.g. initially dry) SAP particles, which has/have been bonded with a wide variety of chemical reagents during or after manufacture e.g. as outlined in any of the three types of SAP manufacture above.
  • the invention provides SAP + Reagent which when insulted by a sample liquid e.g., a biological fluid provides a hydrogel sample for interrogation.
  • a sample liquid e.g., a biological fluid provides a hydrogel sample for interrogation.
  • the biological sample acts as the wetting material within the superabsorbent polymer.
  • the invention aims to solve and improve upon methods of capturing a biological sample within a specific mechanical carrier (e.g. microfluidic or nanofluidic cell, paper-based assay I dipstick) to measure including small biochemicals, pathogenic proteins, and disease-specific genes.
  • a specific mechanical carrier e.g. microfluidic or nanofluidic cell, paper-based assay I dipstick
  • One or more embodiments of the invention allow for diffusion of the specific sample that is under interrogation and allows for the act of absorption to mix the biological sample with the predefined reagent.
  • SAPs once swollen with liquid, particularly once swollen to near or final capacity, are resistant to pneumatic compression, such as might occur in a sanitary article for example a female hygiene pad or diaper for a child or adult, or indeed an absorbent incontinence sheet for use in beds.
  • the present inventors have recognised the usefulness of this capability in developing embodiments of the present invention.
  • SAP particles have a limited mass, they therefore also have a limited, although great, ability to absorb liquid. So, in this sense, they have a limited volume, a limited volume into which sample can be absorbed. This may be thought of as a sample chamber. Thus, once the SAP particles are ‘full’ they cannot ‘easily’ absorb more liquid. Further, they do not give up their liquid contents easily either, particularly if they are isolated within a surrounding ‘dry’ environment. As explained above, once even partially swollen, their swelling rate decreases (see Zohuriaan-Mehr et al 2008), further liquid insults may be merely slightly absorbed. To some extent, further insults of liquid may bypass, at least in part, already swollen SAP particles.
  • in vivo SAP particles When in vivo SAP particles are constantly surrounded by wet conditions, and diffusion can occur into and out of the particles.
  • the particles are, in essence, isolated from one another, particularly when spherical or swollen. Indeed, no matter the initial shape, sphericity is increased in swollen SAP particles.
  • typically in between the SAP particles is essentially dry, the liquid having been absorbed. Even when close-packed, swollen SAP particles may only touch one another at but a few points about their surface. Therefore, diffusion into and out of each SAP particle is low in such dry conditions. What has been absorbed, stays absorbed.
  • each SAP particle provides a limited volume which the present inventors have appreciated can be thought of as a sample chamber resistant to further ingress of liquid.
  • each subdivision of SAP provides a limited volume for absorption related to its mass within that subdivision.
  • each subdivision forms a sample chamber, each sample chamber being adjacent to a neighbouring one.
  • SAP is actually physically subdivided into individual particles, preferably beads, more preferably spherical beads.
  • Particles of other such shapes may be used such as, grains, rods, flakes and the like etc.
  • volume limitation to the assay is provided by notional, or actual, subdivision of SAP into particles. These subdivisions may be thought of as first sample chambers.
  • a second sample chamber within the physical configuration of an absorbent article or test sensor such as a test strip.
  • a second sample chamber may have one or more impermeable (optionally flexible) walls and/or a closable entrance and so on.
  • Such a second sample chamber may have one or more rigid walls. It may have a pre-defined sample chamber volume (e.g. of the second sample chamber volume).
  • absorbent sensing material of the invention in combination with such a second sample chamber, eases the manufacturing challenges of such a chamber (e.g. in volume definition and/or surface properties and so on). Indeed, capillary surface size and/or properties may not be required.
  • the liquid that has entered the SAP particles (or subdivisions of bulk SAP), notionally first sample chambers, remains there. It is not easily washed away or diluted even by further insults of liquid sample. This is particularly the case in absorbent articles for mammalian e.g. human wear, which are usually replaced every 2 to 6 hours, more usually every 2 to 3 hours. And even more the case in point-of-care or home test sensors where results are expected within seconds up to around 30 minutes to an hour.
  • a main lateral dimension of dry SAP particles e.g. a length or diameter
  • a main lateral dimension of dry SAP particles may be ⁇ 0.1 mm ( ⁇ 100 micrometres, which would give a volume of a cube or sphere of or of the order of, 1 nL), or ⁇ 0.05 mm ( ⁇ 50 micrometres, which would give a volume of a cube or sphere of, or of the order of, 65 picolitres), or ⁇ 0.01 mm ( ⁇ 10 micrometres, which would give a volume of a cube or sphere of, or of the order of, 1 picolitre), or ⁇ 0.005 mm ( ⁇ 5 micrometres, which would give a volume of a cube or sphere of, or of the order of, 0.065 picolitres).
  • At least e.g. 90% of the particles (or other proportion of the particles as disclosed elsewhere) may be of the stated dry volume e.g. within expected tolerances.
  • a suitable dimension of swollen SAP particles into which a liquid sample has been absorbed may be ⁇ 5 mm ( ⁇ 5000 micrometres which would give a volume of a cube or sphere of, or of the order of, 6.5 microlitres), ⁇ 1 mm ( ⁇ 1000 micrometres which would give a volume of a cube or sphere of, or of the order of, 1 microlitres), or ⁇ 0.5 mm ( ⁇ 500 micrometres which would give a volume of a cube or sphere of, or of the order of, 65 nanolitres).
  • the volume and/or other suitable dimension of the corresponding dry SAP particles which would absorb these amounts of liquid as a liquid sample of generally or substantially predetermined size is related to this swollen volume by the swelling ratio.
  • the swelling ration depends on, amongst other things, the material from which the SAP is made. Examples of materials are shown in Table 1.
  • the volume of the sample chamber provided by a single SAP particle is defined to be a particular size or in a particular range for example by defining a particular dimension e.g. diameter or other suitable dimension.
  • table 2 examples are shown in which example cube and sphere sizes are shown, and table 3 in which ranges of sphere sizes, here swollen sphere sizes Vmax, are shown:
  • the purpose of selecting such dimension, in some embodiments at one end of the range e.g. a small dimension, for the majority (e.g. >50%, or >75%, or >90%, or >95% >99%, in other words, preferably most) SAP particles is so that the volume of the sample chamber provided by each particle is more defined to be in a particular size for a selected application.
  • the actual volume of such a sample chamber is in effect limited by the size of the initial dry particle.
  • the volume of a fully swollen SAP bead is closely based on its initial dimensions when dry, and so for spherical particles, its dry diameter, as well as to a lessor extent, the SAP type, the sample liquid, and to a even lessor extent the temperature, pressure, humidity, surrounding air flow etc.
  • Vmax the maximum volume of the fully swollen particle (Vmax) depends on the SAP material, the swelling factor of the SAP material, the initial dry particle size, and environmental conditions (temperature, humidity, surrounding, air flow etc)
  • the swelling volume (Vmax) represents the size of the sample chamber.
  • the size of the sample chamber presented by the SAP particle has a volume equivalent to the amount of liquid that that SAP bead has absorbed. This in turn depends on various factors such as the type of SAP, the composition of the liquid, and the environmental conditions etc..
  • the benefits of this may be particularly useful where a very limited amount of sample chamber volume is available within one SAP particle, or a majority, or most, or all, where more than one is provided.
  • individualised modified/preloaded SAP particles can provide a sample chamber of, in effect, a limited pre-definable volume.
  • the calculation for determining the diameter of a spherical SAP bead to achieve a certain volume can be done based on
  • V 1/6 TT D 3 F
  • D the diameter
  • F the Swelling Factor, or swelling ratio
  • TT (pi) is a mathematical constant with a value of approximately 3.14.
  • Swelling factor F is a dimensionless quantity that represents the amount of water absorbed per gram of dry SAP.
  • the swelling factor F can vary depending on the specific type of SAP used and the conditions of the swelling. Therefore, in certain embodiments or scenarios, or for certain applications, it can be important to use the appropriate swelling ratio for the specific SAP material being used and/or specific conditions.
  • Table 4 shows various example of particle size (assuming as an example spherical particles, and various swelling factors F).
  • a dry SAP bead with a diameter D of 0.5 microns has a volume of approximately 0.065 picolitres. If this has a swelling ratio of 500, then it absorbs (0.065 x 500) picolitres of liquid, so 3270 picolitres or 3.27 nanolitres. This is in effect the sample volume per particle.
  • SAP particles of various anticipated sample chamber volumes can be provided for different purposes, and/or different diagnostic techniques and/or different sample types.
  • a dry SAP bead of 1.24 cm could provide absorption of 100cm A 3 if the swelling factor is 100.
  • One or more embodiments of this invention relate to medical diagnostics, specifically to the screening of large populations of infants for indicators of chronic diseases, for example diabetes. Such screening enables prompt medical intervention and the avoidance of complications resulting from late diagnosis.
  • chronic conditions are diagnosed using measurements of the concentration of analytes in biofluids.
  • the most relevant analyte is glucose in blood or urine.
  • Such measurements may be made using either disposable test strips or laboratory analysers. Disposable test strips can measure glucose in both blood and urine.
  • Diabetes screening shows 60% of under 2s are already in diabetic ketoacidosis at the time of diagnosis. Some subjects present with ketoacidosis-related cerebral oedema at diagnosis leading to permanent, severe disability requiring wheelchairs and residential care.
  • the absorbent sensing material may be configured to display a ‘traffic light’ type output for one or more analytes, indicating that the urine is either Normal (in which case no action is required), Alert (in which case a Health Care Professional should be consulted for follow-up tests) and Alarm (in which case immediate medical attention should be sought).
  • One embodiment of the invention is a disposable wearable article such as a nappy (diaper) liner, or a nappy (diaper), containing absorbent sensing material capable of detecting and indicating a level of analyte e.g. glucose and, optionally, other analytes in urine based on one or more sensing element(s) which indicate, e.g. change colour or otherwise provide an indication, when in contact with the relevant analyte.
  • a key challenge to overcome is discriminating between a small amount of more concentrated sample fluid e.g. urine and a larger amount of less concentrated sample fluid e.g. urine, both of which may contain the same absolute quantity of analyte.
  • This challenge is addressed using a fluid capture system such as the absorbent sensing material which, as explained above, over the time scale of use is capable of receiving a finite amount of urine.
  • the absorbent sensing material is located between the source of the urine and an impermeable layer, typically located beneath the absorbent matrix. The impermeable layer may prevent further ingress of fluid once the absorbent sensing material is saturated.
  • the capacity of each part (e.g. particles) of the absorbent sensing material is preferably configured such that it is saturated with a limited urine volume. Due to the finite fluid capacity of the absorbent sensing material, the reaction components come into contact with a more defined amount of analyte.
  • Each SAP particle is in one sense capable of receiving only a more defined volume of urine. Therefore, the amount of analyte that is delivered to each SAP particle is more closely proportional to the concentration in the bulk fluid. Once the SAP particle is full or partially full, it is configured to resist further ingress of fluid. Without wishing to be bound by theory, it is thought this may be due to a reduction in swelling rate over time.
  • the reaction components consist of a sensing chemistry immobilised internally.
  • a two-stage dual enzyme system may be used in which Glucose Oxidase (GOD) and Horseradish Peroxidase (HRP) are provided.
  • Glucose Oxidase (GOD) catalyses the reaction of glucose to gluconic acid and hydrogen peroxide.
  • Horseradish Peroxidase (HRP) catalyses the reaction of peroxide with the initially colourless chromogen (dye precursor) and a colour develops.
  • the colour will depend on the chromogen selected. For example, with potassium iodide, green to brown colours are accessible. With 3,3’,5,5’-tetramethylbenzidine (TMB) blue colours are accessible. Other colours are accessible using different chromogens (see Figure 8 and Examples below).
  • Each level is indicated by a separate sensing compartment containing SAP particles, one each for Normal, Alert and Alarm. These may be differentiated on the basis of colour, achieved by selecting a different coloured chromophore for each sensing compartment.
  • the contents (SAP particles) of all three sensing compartments are white.
  • the Normal sensing SAP particles would turn green and the Alert and Alarm sensing elements would remain white.
  • the Normal SAP particles would turn green
  • the Alert SAP particles would turn orange and the Alarm SAP particles would remain white.
  • the Normal SAP particles would turn green
  • the Alert SAP particles would turn orange and the Alarm SAP particles would turn red.
  • each group of SAP particles contains increasing loadings of chromogen, such that a normal glucose concentration is indicated by one light coloured e.g. blue dot, an intermediate Alert concentration is indicated by one light coloured, e.g. blue, dot and a coloured, e.g. blue, dot of medium intensity, while a higher Alarm concentration is indicated by one light coloured, e.g. blue, dot, one coloured, e.g. blue, dot of medium intensity and a further coloured, e.g. blue, dot of greater intensity.
  • the same level of the same type of chromogen would be present in each group of SAP particles, with the sensing performance of each differentiated on the basis of the enzyme system and loadings, such that the sensing elements’ SAP particles in each compartment each reach the same colour end point, such that a normal glucose concentration is indicated by one blue dot, an intermediate Alert concentration is indicated by two blue dots, while a higher Alarm concentration is indicated by three blue dots.
  • At least two groups of SAP particles are provided, at least one group configured to be indicative of a first level of analyte, and a second group configured to be indicative of a second level of analyte.
  • SAP beads sensing elements
  • SAP beads were prepared using two-stage dip process in which SAP beads were first impregnated with enzymes, a dye fixer and a colour enhancer, then impregnated with the chromogen and a film-forming agent.
  • SAP beads were dipped into Solution 1, a 25 % ethanol solution buffered to pH 4.8 with citrate buffer, containing the enzymes GOD and HRP, the dye fixer Gantrez AN-139, and the colour enhancer polyyinylpyrrolidone. The SAP beads were then allowed to dry.
  • the SAP beads were then dipped into Solution 2, consisting of the chromogen TMB and a film forming agent ethyl cellulose in chloroform. The SAP beads were then dried.
  • the variant described herein is that in which the same chromogen is used in the Normal, Alert and Alarm sensing elements.
  • Each of the three portions of sensing elements contains increasing loadings of the same chromogen, TMB.
  • Absorbent polymer (SAP) beads were stably loaded with reagents that would react with a glucose solution to produce a visually detectable colour change.
  • the ability of loaded beads to react with glucose, even after the beads had been dried to their native state has been demonstrated. In their native state they are typically ⁇ 0.5% water by weight.
  • a pre-existing commercial assay was loaded onto the beads using a reaction mix containing an enzyme and a reagent which produces a visible colour change in the presence of the product of the reaction between the enzyme and glucose.
  • the stability of the loaded beads was tested for freezing at -80°C and subsequently for loaded beads that underwent freeze-drying or thermal drying. The number of beads for each assay and the volume of reagent required was determined.
  • the sensitivity of this approach can be demonstrated using a number of glucose concentrations (relatively low to relatively high) to transect the physiological glucose concentration range. Furthermore, the beads remain active after drying. Furthermore, long-term stability and potential for suitability for long term storage is indicated after early stage accelerated stability testing.
  • Absorbent beads in the form of a super absorbent polymer consisting of sodium polyacrylate was used. This has no known toxicity or hazard.
  • a glucose assay kit (colorimetric/fluorometric) was used e.g. from Abeam (product ab65333). This is a well-characterized, simple and rapid assay used to quantify glucose levels in biological samples.
  • the supplied enzyme mix oxidises glucose, generating a product that reacts with a dye which generates a red colour which is visible to the naked eye.
  • Glucose Assay Kit ab65333 is a rapid, simple and sensitive assay used to quantify glucose levels in biological samples such as serum, plasma, and other body fluids, food, growth medium, etc.
  • the kit detects glucose in the range 1-10000 pM. The detection regime is shown in Figure 8 using
  • the assay is designed for use with a plate reader to detect and quantify colour or fluorescence. This study was adapted to function with the beads in the in vitro environment selected to provide a visual assessment of an end point.
  • the volumes used were adjusted using additional buffer, while at the same time retaining the recommended proportions between the reaction mix (enzyme and probe) with the glucose solution.
  • Coated beads were freeze-dried using a CHRIST ALPHA1-2 LDPI US freeze drier, according the manufacturer’s instructions.
  • the initially dry SAP beads are much smaller in diameter than the water swollen SAP beads (now hydrogel beads).
  • test beads Two sets of beads were prepared, a test set imbibed with 250 pl of reaction mix (described as test beads (right)) and a control set coated with assay buffer only (described as control 1 beads (left)).
  • the beads readily absorbed the reagents after 30 min incubation in the dark at room temperature. Addition of 250 pl of 1mM glucose solution to both test and control beads, followed by 30 min incubation at 37°C in the dark produced a strong reaction in the test beads (pink/brown colour), while the control beads remained colourless (see Figure 2).
  • Figure 2 shows groups of 10 SAP beads in Experiment 1 which have been (hydrated) pre-loaded with buffer only (left image) and then exposed to glucose solution for 30 minutes at 37° C, or (hydrated) pre-loaded with liquid reaction mix (right), and then exposed to glucose solution for 30 minutes at 37° C.
  • the beads on the left remain colourless and a clear colour change to pink brown is visible on the right.
  • Test beads treated with reaction mix
  • control beads control 1 treated with assay buffer only were prepared as described above, along with a second control (control 2) treated with reaction mix to give three sets of beads in total. Based on an optimisation experiment (not shown), the volume of reaction mix used was reduced to 200 pl.
  • the beads were transferred to individual tubes and placed in a rotating heating block set to 35°C for 18 hours in the dark, after which the beads were reduced in size but not dry.
  • the beads required a total incubation at 35°C, with rotation, of 48 hours in the dark, by which time the beads were further reduced in size, with test and control 2 beads slightly pink in colour.
  • the beads were sticky and difficult to manipulate but decanted onto weighing boats for assay.
  • the assay was performed by adding 200 pl of 1 mM glucose solution to control 1 and test beads, or assay buffer to control 2 beads.
  • the results indicate a relatively high background colour in the absence of glucose (control 2), but the test bead positivity is sufficiently strong to differentiate it from this control (see Figure 3).
  • Figure 3 and Figure 4 show perspective view of groups of 10 SAP beads in Experiments 2 and 3 showing respectively heat-dried beads (Figure 3) and freeze-dried beads ( Figure 4): control 1 (top) treated with buffer, dried, then incubated with glucose solution for 30 minutes at 37° C, no colour is seen; control 2 (middle) treated with liquid reaction mix, dried, then incubated with buffer for 30 minutes at 37° C, a light pink colour is seen; test beads (lower) treated with liquid reaction mix, dried, then and incubated with glucose solution for 30 minutes at 37° C, a deeper purple colour is seen.
  • test beads retained their reactivity with glucose. d. Effect of freeze-drying of loaded beads on assay function.
  • the second method selected for drying the beads was freeze drying. This presented a specific difficulty in that the initial step requires freezing of the coated beads at -80°C; freezing of the beads is not recommended by the manufacturer. However, a pilot study revealed that freezing and thawing of beads loaded with 200 pl of reaction mix did not cause visible disruption of the bead structure or cause loss of activity of the reaction mix (not shown).
  • control 1 beads were colourless, control 2 had a light pink background, while test beads were a deeper pinkish brown colour, with some white patches, which is indicative of a strongly positive result (see Figure 4) as also described above.
  • freeze-drying was a much more effective method than heat-drying.
  • the results show that modified or pre-loaded beads retain their structure and function after both freezing at -80°C and the freeze-drying process.
  • pre-loaded dried beads can be formed.
  • Test and control beads that were freeze dried had a change in appearance (described above). It was thought that the surface changes and opacity may be due to the accumulation of buffer salts on the beads following drying. This may have an adverse effect on readability or interpretation so water was substituted for buffer in the reaction mix; glucose would be delivered in buffer, as previously.
  • FIG. 5 shows groups of 10 SAP beads in Experiment 4 showing respectively: control 1 (top) treated with liquid water, freeze-dried, then incubated with glucose solution for 30 minutes at 37° C, no colour is seen; control 2 (middle) treated with reaction mix, freeze-dried, then incubated with buffer for 30 minutes at 37° C, almost no colour is seen.
  • test beads (lower) treated with reaction mix, freeze-dried, then and incubated with glucose solution for 30 minutes at 37° C, a purple colour is seen.
  • the sensitivity of the assay, relative to a range of concentrations of glucose will provide a different depth of colour, or using Benedict’s solution, a range of colours.
  • shelf-life The retention of activity of treated, freeze-dried, dry SAP beads over time (“shelf-life”) is much longer than for undried loaded, swollen hydrogel beads.
  • the beads can absorb the glucose assay reaction mix.
  • the reaction mix retains activity after absorption.
  • Heat-dried test beads retain their reactivity with glucose. • Freeze-dried test beads retain their reactivity with glucose.
  • Test beads retain their structure and function after undergoing both freezing at -80°C and the freeze-drying process.
  • buffer is not used in the reaction mix.
  • water is used, particularly if freeze-drying is to be used.
  • the invention provides a method for manufacturing absorbent articles or test sensors and a method for carrying out detection of analyte using the absorbent articles or test sensors as shown in Figure 7.
  • step 10 initially dry SAP I SAP particles are pre-loaded with at least one wet reaction component e.g. in solution, to cause the SAP particles to form swollen hydrogel particles.
  • step 20 primarily water is driven off from the SAP I SAP particles by drying these e.g. by heat and/or freeze-drying e.g. until a desired residual water content is achieved.
  • step 30 the now dry SAP I SAP particles pre-loaded with at least one reaction component are added to an absorptive item, e.g. a disposable hygiene item or to a test sensor, during manufacture of same.
  • absorptive item e.g. a disposable hygiene item or to a test sensor
  • the dry pre-loaded SAP I SAP particles are used as an indicator or diagnostic of an analyte in sample liquid, by exposing this/these to liquid, and detecting and indicating the presence or concentration of the analyte.
  • dry superabsorbent polymer (SAP) /SAP particles containing dry reaction component(s) in other words dry modified (preloaded) SAP can be extended to other detection scenarios, and interrogation techniques for example those that require a limited sample chamber volume (e.g. a ‘second’ sample chamber in addition to the notional sample chamber provided by the SAP).
  • the present inventors have appreciated a simple solution for indicating or monitoring a disease state using a body fluid or, more generally, for indicating the presence of an analyte in a sample liquid.
  • the present invention does not use a separate sensor.
  • the present invention does not (initially at least) use hydrogel (in the sense of wet SAP).
  • SAP particles such as beads are used, their shape may be spherical, cylindrical, irregular, regular, cubic, flakes, prismatic, fibre-like, hollow, or any 2 or 3-dimensional structure.
  • SAP particles are positioned within an article e.g. a wearable article, which has a window e.g.
  • the window may be on the inside (hidden during use) or outside (visible during use) of the article.
  • SAP particles are included in such articles as before, however, the SAP particles have undergone a previous manufacturing step, namely impregnation or pre- loading with one or more reagents (reaction components) in one or more reagent mixes and then drying as usual, preferably, freeze-drying.
  • the now pre-loaded SAP (e.g. beads) swollen with wet reaction mix may be dried by any suitable method. For example, heating in an oven, optionally on a conveyor passing through an oven, or by freeze drying or freezer.
  • the residual moisture content in dry SAP for use in one or more embodiments of the invention is typically 0.5% to 15% by weight, or 1% to 10% by weight, or less than 15% by weight or less than 10% by weight or less than 5% by weight.
  • the residual moisture content may be determined by EDANA (European Disposables and Non-Woven Association) recommended test method No. NWSP 230.0. R2 ‘Moisture Content’.
  • the SAP particle size may be determined by means of EDANA (European Disposables and Non-Woven Association) recommended test method No. NWSP 220.0.R2 ‘Particle Size Distribution’.
  • the swelling capacity of the SAP e.g. of particles may be determined by EDANA recommended test method No. NSWP 240.02. R2 ‘Free Swell Capacity’.
  • the fluid retention capacity may be determined by the EDANA recommended test method No. NWSP 241.0.R2.
  • Other parameters may be determined from the EDANA test methods or adapted test methods if required e.g. swelling rate. Other recognised standard test methods may be used.
  • SAP beads dry SAP beads are used in a process for detection of an analyte.
  • the SAP itself is not responsive to specific molecules.
  • the SAP is not required to give back the imbibed solution or maintain the imbibed solution around it to allow diffusion.
  • the detection (transduction) mechanism is independent of the carrier membrane i.e. independent of the SAP.
  • the present invention aims to provide a simple to use, and/or simple to manufacture, and/or simple to implement, and/or simple to read system for detecting analytes.
  • an absorbent article may comprise absorbent sensing material comprising pre-loaded SAP in a portion of the absorbent article e.g. in a central portion, or in an indicator portion which may be at the front or rear or base of an article, and the remaining absorbent material may be regular dry SAP particles that do not have a sensing capability.
  • a separate fluid compartment may be provided for absorbent sensing material, separate from that containing regular SAP particles. Different compartments may be provided with absorbent sensing material of the present invention, with different sensing capabilities e.g. different reagent components for different assays (e.g.
  • the absorbent material may be used in a test strip or other sensors technologies for interrogation by visual or other methods.
  • the SAP particles are of limited volume and solve the problem of requiring a limited volume in a different way - the internal volume or rather swelling capacity of each SAP bead limits the volume of sample that can be interrogated in each particle, particularly in vitro, where the presence of other surrounding SAP particles tend to main a dry environment outside each SAP particle.
  • dry SAP particles is known in absorbent articles, its use as a medium for interrogating sample liquids, particularly for interrogating sample liquids in absorbent articles or other sensors technologies, is not known.
  • This ability to combine the use of SAP as an absorbent and as a carrier for one or more dry detection and signalling components facilitates very simple use.
  • the signalling component is observable by eye, although other measurable or observable regimes can be used.
  • SAP particles are pre- loaded with reagent mix comprising one or more dry detection and signalling components (in the absence of any substrates or analytes being detected) and then dried as usual. These may be air-dried, heat-dried or freeze-dried or use any suitable drying method to form absorbent sensing material that can be used in multiple applications.
  • the absorbent material in the form of pre-loaded SAP, preferably SAP particles can therefore, as is usual now, be manufactured separately in advance of the absorbent articles. The manufacturing process of absorbent articles does not need to be charged, save that a viewing window may be provided, preferably on the exterior to the absorbent article.
  • the absorbent article may have a permeable interior (in wearable articles skin facing) layer, and an impermeable exterior (in wearable articles outer) layer.
  • the absorbent material with sensing capability may be used in many different applications, both in human and animal healthcare and in liquid analysis applications.
  • the absorbent material of the invention e.g. in the form of SAP particles may be manufactured in advance ready for use in other sensors technologies, other than absorbent articles. It will be further clear to those skilled in the art that the invention is not limited to sensing elements which are based on colorimetric detection.
  • the invention could be applied to other analytes besides glucose and other disease states besides diabetes.
  • a similar dual enzyme detection method may be used to detect ketones in urine, indicative of diabetic ketoacidosis.
  • protein in urine is indicative of kidney inflammation
  • nitrite and white blood cells are indicative of bacterial infection
  • bilirubin and urobilinogen are indicative of liver damage.
  • Each analyte may be detected in a manner analogous to that described for glucose above. Multiple analytes may be detected simultaneously by combining a series of sensing elements. It will also be clear to those skilled in the art that the invention is not limited to the detection of analytes in urine.
  • any biofluid for example it could also be applied in a transdermal patch in which interstitial fluid is drawn into the fluid capture system, or indeed a dry tissue for blowing a nose or wiping away tears, or a nasal or throat swab for sampling nasal or throat fluids.
  • the absorbent material may, in these examples, be in the form of fibres
  • the present invention at least partially addresses one or more problems of the art: variability of concentration of analyte in sample liquid, and/or a variable flow, e.g. of urine, and/or a variable contact time do not render the test invalid; additional insults of bodily fluid do not render the test invalid; sample fluid discharged into an absorbent matrix may not affect the remaining liquid presented to any test element;
  • SAP or SAP particles or sensors using SAP or SAP particles attached to diapers may more easily limit sample volume. These may also address cost and complexity of manufacture and use;
  • SAP e.g. SAP particles do not break and/or are comfortable to wear, they also relatively cheap; detection of enzyme substrates is possible; a diffusion gradient is not required; dry SAP sensing systems are stable over the time periods for long term storage required for commercial products; a controlled sample volume, e.g. a ‘second’ sample chamber in addition to the notional chamber(s) provided by SAP, can be more easily manufactured.
  • the invention provides, within the dry superabsorbent polymer, at least one reaction component for detecting and signalling the presence of analyte, and/or, in some embodiments, for detecting and signalling the concentration, e.g. the relative level of concentration of analyte, and/or, , in some embodiments, for detecting and signalling the relative quantity of analyte; wherein upon insult of sample liquid, the dry super absorbent polymer absorbs sample liquid, the dry reaction component, dissolves, preferably within the SAP, and if analyte is present in the sample liquid, its presence is detected and signalled within the SAP itself.

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Abstract

L'invention concerne un matériau de détection absorbant pour l'interrogation d'un échantillon de liquide afin de détecter un analyte, comprenant : un polymère superabsorbant sec (SAP) configuré pour recevoir un échantillon de liquide ; le matériau absorbant comprenant, dans le polymère superabsorbant sec, au moins un composant de réaction sec destiné à détecter et signaler la présence de l'analyte. Lors de l'agression de l'échantillon liquide, le polymère superabsorbant sec absorbe l'échantillon liquide, ledit composant de réaction sec se dissout et, si l'analyte est présent dans l'échantillon liquide, sa présence est détectée et signalée. L'invention concerne également l'utilisation du matériau de détection absorbant, des articles absorbants et des procédés de fabrication d'articles absorbants et de capteurs d'essai tels que des bandes d'essai.
PCT/GB2023/050623 2022-03-23 2023-03-16 Appareil et procédés de biocapteur à base de polymère superabsorbant WO2023180691A1 (fr)

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