EP4291087A2 - Dispositif d'analyse de gaz - Google Patents
Dispositif d'analyse de gazInfo
- Publication number
- EP4291087A2 EP4291087A2 EP22705534.0A EP22705534A EP4291087A2 EP 4291087 A2 EP4291087 A2 EP 4291087A2 EP 22705534 A EP22705534 A EP 22705534A EP 4291087 A2 EP4291087 A2 EP 4291087A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- filter
- liquid
- breath
- analytes
- analyte
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/08—Detecting, measuring or recording devices for evaluating the respiratory organs
- A61B5/082—Evaluation by breath analysis, e.g. determination of the chemical composition of exhaled breath
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/54366—Apparatus specially adapted for solid-phase testing
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
- G01N33/56983—Viruses
-
- 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
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
-
- 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
- G01N2333/005—Assays involving biological materials from specific organisms or of a specific nature from viruses
- G01N2333/08—RNA viruses
- G01N2333/11—Orthomyxoviridae, e.g. influenza virus
-
- 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
- G01N2333/005—Assays involving biological materials from specific organisms or of a specific nature from viruses
- G01N2333/08—RNA viruses
- G01N2333/165—Coronaviridae, e.g. avian infectious bronchitis virus
Definitions
- the field of the invention is a gas analysis device for detecting the presence of an analyte, such as an analyte indicative of a condition.
- the gas analysis device may be a breath analysis device.
- the gas analysis device may comprise a dissolvable filter, a reservoir for storing liquid for dissolving the filter, and an analyser for detecting the presence of a condition in dependence on an analysis of the dissolved liquid. Advantages may include the gas analysis device being inexpensive and providing quick detection results.
- the gas analysis device may be used to detect conditions such as COVID-19.
- Breath analysis devices also referred to as breath analysers
- breath analysers are convenient devices for detecting the presence of a condition. A user needs only to breathe into the breath analysis device and so the user experience is non-intrusive.
- Known techniques include using a device to collect a sample from a user’s breath and for the breath analysis to be performed in a separate apparatus.
- such techniques may not be suitable for use in the field where it is preferable for the same device to collect a sample from a user’s breath, analyse the sample, and provide the detection result.
- Figure 1 shows an implementation of a rapid detection method according to an embodiment
- Figure 2 shows schematic diagrams of a breath analysis device according to a first embodiment
- Figure 4 schematically shows components of a breath analysis device according to a second embodiment.
- Embodiments provide a breath analysis device, that may also be referred to as a breath analyser, with a number of advantages over known breath analysis devices.
- a breath analysis device may provide a simple and robust detection technique.
- the breath analysis device may be portable, such as handheld.
- the breath analysis device may comprise one or more visual indicators of the result of the detection so that the breath analysis device is suitable for use in the field. Further advantages of the breath analysis device may include the analysis process comprising a simple amplification technique so that a relatively strong detection may be made and/or the length of time required to obtain the detection result being relatively short.
- the breath analysis device may also be configured to detect a number of conditions or analytes. Such conditions include infections by pathogenic microorganisms (such as pulmonary infections) and cancer, as discussed in more detail below.
- the device may be configured to detect one or more variants of COVID19 or to detect COVID19 and/or influenza.
- the device may alternatively be configured to detect any analyte of interest that may be present in exhaled breath, such as a drug or toxin, a non-pathogenic microorganism (such as a beneficial microorganism of the respiratory tract), or an antibody, such as an antibody of a particular isotype, in particular IgA.
- a drug or toxin such as a drug or toxin
- a non-pathogenic microorganism such as a beneficial microorganism of the respiratory tract
- an antibody such as an antibody of a particular isotype, in particular IgA.
- the breath analysis device is advantageous over known breath analysis techniques that may require one or more of pipetting, solution changes, specific separate equipment to analyse an obtained sample, and/or provide the detection result, and comprise no amplification in the detection process.
- the breath analysis device comprises a filter for capturing exhaled analytes, such as exhaled particles, by a user of the breath analysis device.
- the filter is soluble, for example water-soluble, and may comprise reactants for the detection process of specific particles.
- a user of the breath analysis device breathes into the breath analysis device and particles in the user’s breath are captured in the filter;
- the water comprising the dissolved filter and reactants flows to an analyser in the breath analysis device; and 5) The analyser indicates the detection result, such as by a colour change.
- the breath analysis device may comprise a sensitive two- component amplification method embedded in the water-soluble filter.
- the detection system may comprise:
- Two distinct binding proteins with high affinity for different sites of the same microbial protein e.g. SARS-CoV-2 spike protein, or influenza HA protein.
- Each one of two binding proteins may contain (covalently attached or as continuous polypeptide) a part of a split reporter.
- the split reporter may be, for example, an enzyme or a fluorescent protein.
- the two binding proteins may not interact with each other in the absence of the microbial protein.
- the two binding proteins may be antibodies, diabodies, or other types of high affinity ligands.
- the two parts of the split reporter may be in close proximity and therefore the reporter will be active.
- Detection of reporter activity will typically be dependent on the nature of the reporter gene, but the detection may be a colorimetric reaction.
- Multiplexing may be possible by including a second set (or multiple sets) of binding proteins with different types of split reporters and different detection systems (e.g. two diabodies against the SARS-Cov-2 spike protein with a split beta-lactamase assay (red colour) and two diabodies against the influenza HA protein with a split B-Galactosidase (blue colour).
- the elements of the detection system may be included in a water-soluble filter to allow dry storage and avoid spontaneous activation during storage.
- Figure 1 shows an implementation of a rapid detection method according to an embodiment.
- Figure 1 shows a first beta-lactamase fragment 101, a second beta-lactamse fragment 102, a non-fluorescent substrate 104, a spike protein 103 and a fluorescent product 105.
- FIG. 1 shows binding proteins (diabodies to SARS-Cov-2 spike protein) fused to beta-lactamase fragments in a filter according to embodiments with the filter in a ready for use state.
- the filter is in a dry state with the fused binding protein-beta- lactamase fragments inactive.
- the fused binding protein-beta-lactamase fragments are located in close proximity to each other in the filter.
- the right side of Figure 1 shows fused binding protein-beta-lactamase fragments in the filter after the breath analysis device has been breathed through.
- the filter has captured exhaled particles and been dissolved in water.
- the captured exhaled particles include a spike protein and binding of the binding proteins to the spike protein causes enzymatic activity of the beta-lactamase fragments on a non-fluorescent substrate. This may generate a fluorescent product 105.
- the specific reactants, e.g. beta-lactamase fragments, that are comprised by the filter may be selected in dependence on a specific particle, e.g. spike protein, to be detected by the breath analysis device.
- Figure 2 shows schematic diagrams of a breath analysis device according to a first embodiment.
- subfigure A shows the breath analysis device according to the first embodiment when it is in a ready to use state.
- Subfigures B to F are schematic diagrams of the breath analysis device according to the first embodiment at different stages during use of the breath analysis device.
- the breath analysis device comprises a mouthpiece, a main chamber, a filter, a baseplate, a reservoir and an analyser.
- the mouthpiece is arranged so that a user of the breath analysis device may breath into it.
- the main chamber may be substantially elongate and tubular.
- the mouthpiece is arranged at a first end of the main chamber.
- the filter is arranged at a second end of the main chamber.
- the second end of the main chamber is opposite the first end.
- the main chamber is arranged to receive breath that enters the breath analysis device via the mouthpiece. The received breath may flow through the filter and out of the breath analysis device.
- the main chamber therefore supports a gas flow path, i.e. breath flow path, through the breath analysis device.
- the filter may be arranged across an entire cross-section of the main chamber.
- a property of the filter is that the substantial part of the gas that is breathed into the breath analysis device is able to flow through the filter. All of the gas that flows out of the main chamber may therefore be forced to flow through the filter.
- the filter may be retained in a dry state prior to use of the breath analysis device.
- the filter may comprise one or more reactants/reagents, such as binding protein-beta-lactamase fragments, in its dry state.
- the reactants/reagents are thus typically in dry form, such as lyophilised form.
- the filter may be at least partially soluble. In particular, some, or all, of the filter may be water-soluble.
- the filter may comprise filter material with any immune-enzymatic or nucleic acid detection components, as described in more detail below.
- the filter may have any, or all, of the following properties:
- the filter structure may be one or more of a meshwork, sponge, punctuated plate, or micro-sieve.
- the filter structure should let a breath flow pass but retain at least part of the exhaled particles and droplets in the breath.
- the liquid comprising the dissolved filter (which may have a high polymer concentration) should not have such a high viscosity that the liquid is unable to flow.
- Acceptable viscosities may be about 2 Pa*s or lower, preferably less than or equal to 1 Pa*s.
- the viscosity should not be as high as 1000s of Pa*s, at estimated solute concentrations of some 2-10%.
- Suitable materials for the filter to be constructed from may include lower molecular weight PEGs (polyethylene glycols), mono- and di-saccharides, or carbohydrate oligomers. These materials may easily be lyophilized to sponge-like structures, although other fabrication techniques such as molding are possible too.
- PEGs polyethylene glycols
- mono- and di-saccharides or carbohydrate oligomers.
- the filter may be a porous structure. Chemical and/or physical processes may be used to manufacture the porous structure.
- a chemical process used in the manufacture of the filter according to embodiments may include using acetic bacteria to synthesise a thin sheet of bio-cellulose.
- the pores in the sheet may be enlarged by bombarding the sheet with a carbon dioxide plasma.
- Alternative chemical processes used in the manufacture of the filter according to embodiments may include synthesising acrylamide cryogel and/or sugar cryogel.
- a physical process for manufacturing the filter may include manufacturing a filter body and then mechanically piecing the filter body.
- the filter body may first be synthesised.
- the filter body may comprise methyl-cellulose and/or salt.
- the filter body have been dried in an oven.
- the filter body may then be pierced by a plurality of nano-needles.
- the nano-needles may be a plurality of thin metallic pins with each pin having a diameter of lpm to 10pm, or less than lpm.
- the piercing may generate pores/holes in the filter body with the diameter of each pore/hole being substantially the same as the diameter of the pin that generated it.
- the filter body comprise methyl-cellulose and has pores of lpm to 10pm created by mechanical piercing of the filter body with nano-needles.
- the size and arrangement of the nano-needles allows a well defined pattern of pores/holes to be formed in the filter and this is a reliable way of achieving a desired porosity.
- the filter may comprise a methylcellulose film.
- the film may be made by dissolving methylcellulose (e.g. Sigma, M0512-250G, Lot #079K0054) at a concentration of 2% in deionized water, DI (i.e. lg of methylcellulose may be dissolved in 49g of DI). This may comprise pouring hot water, at a temperature of about 80°C, onto the methylcellulose, and then letting the solution cool down to 20°C or lower, with occasional agitation. Alternatively, the methylcellulose may be dissolved in cold water by leaving the solution overnight.
- methylcellulose e.g. Sigma, M0512-250G, Lot #079K0054
- a drop of about lmL of the methylcellulose solution may then placed onto a polypropylene surface (this is a lot more effective than glass or polystyrene surfaces that may not work).
- the polypropylene surface may be a substrate for supporting the generation of a methylcellulose film.
- Air blowing e.g. at 1 bar pressure, 5mm/50cm length
- spin-coating e.g. at 100-4000rpm
- Drying may be completed by inserting the substrate into an oven at a temperature of about 80°C for about 1 hour.
- the film may then be carefully detached from the substrate, such as with tweezers.
- the film may have a thickness of about 1-50 microns, depending on the air flow rate or spin coating speed.
- a hole stamping process may then be performed for generating holes in the methylcellulose film. This may be performed with the above-described nano-needles.
- the nano-needles may be metallic and the tip radius may be lpm or less.
- the tip opening angle may be a few degrees up to 45°.
- the film may be placed onto a substrate that is substantially softer than the tips of the nano-needles (e.g. an aluminium substrate may be used when the tips of the nano-needles are a harder material, such as tungsten carbide or silicon-carbide).
- the tips of the nano needles may be lowered onto the film and pressed into the film towards the substrate. Depending on the opening angle, the tips of the nano-needles may be lowered one to several opening diameters into the substrate. This process may create a well defined pattern of holes that may each have a diameter in the range of about 1-50 micrometers, depending on the sizes and shapes of the tips and extent of insertion through the film.
- An assembly may be generated that comprises 2% methylcellulose cast between a polypropylene sheet that has been activated by oxygen plasma (e.g. for 30s at 100W), and a polypropylene mesh with a thickness of 40 micron.
- the polypropylene mesh may be untreated and therefore hydrophobic.
- the height of the filter may be set with a spacer that may be 50 microns thick.
- the assembly may then be frozen rapidly with liquid nitrogen, after which the temperature may be raised back to -20°C in a freezer. At this temperature, the polypropylene sheets may have some flexibility so that the upper polypropylene sheet may be pealed off.
- the assembly may then be put into a lyophilizer with a temperature- controlled shelves (e.g.
- the film may be used as a filter.
- the film may be used, or tested, with the polypropylene sheet in place.
- the filter may be installed in a mouthpiece, such as a a Falcon tube with a 15mL diameter. To do this the tube may be cut open, and the edges heated with a hot air gun (set to 300°C). Once the edges are liquid, the open Flacon tube may be pressed onto the filter/backing assembly and hot welded together. After this, two lateral access holes may be drilled and filled with filter paper. With this setup, it may be possible to breathe some air through the filter, followed by dissolution with liquid after removal of one of the two filter papers. After and at the same time as the dissolution process, the liquid may be drawn into the second filter paper.
- a mouthpiece such as a a Falcon tube with a 15mL diameter.
- a hot air gun set to 300°C
- Embodiments include contiguous dissolvable substrates, such as the above-described methylcellulose films, being prepared.
- the dissolvable substrates may then be covered with a photolithographically structured mask and subsequently exposed to oxygen plasma.
- the etching parameters may be 10-100W/L of oxygen plasma.
- the etching process may generate holes in the dissolvable substrates in dependence on the pattern of the mask.
- Each filter may be backed with a polypropylene mesh that is a hydrophobic baseplate.
- the pore sizes of the baseplate are preferably in the range of 1-1000 micrometers, more preferably 10-500 micrometers, and even more preferably about 50-300 micrometers.
- Such meshes are commercially available, e.g. from PlastOK, UK. Backed with such meshes, the filters can withstand full atmospheric pressure and the expected pressures during typical use.
- the gas flow rate through the filter may be about in the 1-lOL/s/cm 2 range. This enables a large concentration of viral particles in a very low area and mass of filter. There is in fact a synergy between thin filter providing both for very low mass to be diluted and extremely low air flow resistance, and hydrophobic backing providing filter strength despite very low thickness and ease of collection of the analyte by lateral fluidic withdrawal or sampling after dilution.
- the filter may comprise a hydrophilic material.
- the filter material may be sufficiently hydrophilic to permit rapid wetting while avoiding substantial entrapment of air bubbles. Contact angles lower than 45°, or preferably lower than 20°, may be suitable.
- the filter may comprises rapidly dissolving substances. These may, for example, comprise sodium chloride or sodium bicarbonate, provided either as separate powders or dissolved during filter fabrication.
- the filter material once dissolved, preferably does not have a strong affinity to any of the assay components so that it does not interfere with the assay components, or trigger the enzymatic assembly. It may therefore be “non-fouling”, at least with respect to the enzymatic assay components. Protein interaction (“fouling”) is typically a problem with ionic substances. However, with carbohydrates it is less of a problem and some of these are indeed used to stabilize proteins during lyophilization (maltose, maltodextrin and substances of the like).
- a property of the filter material is that it is able to capture analytes, such as particles, in exhaled breath.
- the main force of adhesion for analytes, such as particles, for example viral particles, may be a capillary water film formation.
- the filter material preferably allows adsorption of a fluid film at the surface.
- the capture efficiency of analytes may be further improved by the filter being electrostatically charged. This can be as a result of its chemical composition, such as in electret materials, with orientable charged moieties.
- peptides or polysaccharides with block-co-polymer structure with schematically a positive and negative end and a neutral connection segment; or separable charged moieties may be included during synthesis of the filter material.
- Induced or permanent dipoles may then be oriented during fabrication with an applied external fieldand, fixed thereafter once the material becomes sufficiently dry, typically to achieve a glassy state with very limited molecular mobility.
- charges may be deposited secondarily by any known techniques of charge deposition, for example by means known in the art such as corona discharge, electron guns or of the like.
- the breath analysis device may further comprise an electric charger arranged to electrically charge the filter.
- the electric charge may be generated by applying an external voltage, for instance generated by a manual piezo actuator connected to a metal mesh embedded in or on the filter, or a breath-activated electrical generator likewise connected to the embedded metal mesh, the voltage being relative to a second metal mesh in or on the filter but electrically isolated from the first one.
- the analytes in exhaled breath may thus be electrostatically attracted to the filter.
- AC actuation or DC charging may be used.
- the capture efficiency of the filter may be further improved by inclusion of one or more elements having affinity for one or more analytes of interest (also described herein as capture elements or ligands) in the filter, thus assisting retention of analytes of interest in the filter.
- the filter may comprise an affinity matrix (for example a protein or nucleic acid affinity matrix).
- One or more ligands for one or more analytes of interest may be coupled to the filter, for example coupled (typically covalently coupled) to an affinity matrix.
- the breath analysis device may comprise a part that is arranged to be pressed by a user of the device.
- the part may configured so that liquid is forced out of the reservoir when the part is pressed.
- a breakable wall holding liquid within the reservoir may be broken in response to the part being pressed.
- the reservoir may be configured so that the released liquid flows to the filter.
- the filter may therefore be dissolved by the released liquid.
- the reservoir may comprise an openable, and closable, external opening so that the reservoir may be easily refilled with liquid.
- the reservoir may alternatively, or additionally, be an easily replaceable part of the breath analysis device.
- the breath analysis device may comprise one of more capillary conduits/tubes so that liquid comprising the dissolved filter may flow to the analyser.
- the breath analysis device may comprise one or more visual indicators for displaying the result of the analyser.
- the breath analysis device may comprise an electronic display configured to provide the analysis result.
- the breath analysis device may comprise one or more surfaces that comprise substances that are configured so that their colour/fluorescence/luminescence is dependent on the detection result.
- the one or more surfaces may be viewable from the outside of the breath analysis device, or the breath analysis device may be partially opened so that the surfaces may be viewed.
- embodiments include the colour of one or more of the positive control area, the negative control area and the test control area being dependent on the detection result.
- the breath analysis device is in a read to use state.
- the filter is dry.
- the breath analysis device is in the process of being used.
- a user of the breath analysis device is breathing into the mouthpiece and there is a flow of breath through the main chamber and the filter. Particles comprised by the breath may be captured in the filter.
- the activation of a liquid release mechanism may be by a manual technique, such as pushing, bending, or of the like.
- the activation may alternatively be coupled to a sufficient air volume, for example by the force of a balloon or by electronic detection of sufficient total air flow volume.
- the breath analysis device may comprise an air flow gauge for such electronic detection.
- Subfigure D shows the breath analysis device after the filter, and captured particles (such as antigens), have been dissolved by the liquid that was released from the reservoir.
- Subfigure F shows the particles that were captured by the filter undergoing enzymatic development in the analyser.
- the breath analysis device of the second embodiment may comprise a main chamber.
- a filter for capturing particles in breath may be arranged at the opposite end of the main chamber to the mouthpiece. This is indicated in the leftmost subfigure in Figure 4. The substantial gas flow through the breath analysis device may be through this filter.
- the breath analysis device may comprise a single reservoir of liquid, such as water, with liquid flow paths to each filter.
- the liquid release mechanism may be configured to release a flow of liquid from the reservoir to each filter when the liquid release mechanism is triggered. All of the first, second and third filters may thereby be dissolved at about the same time by liquid from the same reservoir.
- the breath analysis device of the second embodiment is operated in a similar way to that of the first embodiment.
- a user of the breath analysis device breathes through the mouthpiece and particles in the user’s breath are captured in the first filter.
- the liquid release mechanism is then triggered so that fluid flows from one or more reservoirs to all of the first, second and third filters. All of the first, second and third filters are dissolved by liquid.
- the liquid comprising each dissolved filter flows laterally, via capillary tubes or another technique, to separate analysers, or separate sections of the same analyser, where the liquids are analysed.
- the analyser(s) may indicate the result of the detection by their colour, or by, for example, an electronic display.
- a main implementation of embodiments is a breath analyser that provides quick in-situ virus detection and provides a visual indication of the detection result.
- the breathing of people in an environment generates airborne analytes.
- the gas analysis device of embodiments may be located anywhere that airborne analytes may be captured.
- the gas analysis device may be located in a transport hub (such as an airport or railway station), a waiting room, cinema, aircraft cabin or any other enclosed environment.
- the gas analysis device allows an environment to be monitored for specific viruses and other conditions.
- a new filter may be placed in the gas analysis device before each flight.
- the analytes captured by the filter may be analysed after each flight and used to determine if anyone present on the flight was carrying a virus, or other condition. This helps to track the spread of a virus, or other condition, without the need to perform a breath analysis of everyone on the flight.
- the analysis may also allow early detection of new viruses or new variants of viruses through, for example, RNA sequencing.
- the breath device may not comprise an analyser and thus may comprise a mouthpiece arranged to receive breath from a user of the device; a reservoir comprising a liquid; a filter configured to capture analytes in the received breath, wherein the filter is arranged in a flow path of the breath through the device and the filter is at least partially soluble in the liquid comprised by the reservoir; and a liquid release mechanism configured to release liquid in the reservoir so that the liquid flows to the filter.
- the reactants may be any reagents suitable for detection of an analyte.
- the reagents include reagents capable of specifically binding the analyte. Any suitable capture reagents or moieties for an analyte may be employed.
- the reagents may for example comprise one or more binding proteins specific for at least one antigen of the analyte or one or more nucleic acids specific for at least one target nucleic acid of the analyte.
- the reagents may also include at least one substance that is configured to change colour, fluorescence and/or luminescence in response to the analysis result. Such reagents provide for a visual indicator of the analysis result.
- these may be antibodies or antigen-binding fragments thereof.
- An antibody “specifically binds” to a protein when it binds with preferential or high affinity to that protein but does not substantially bind, does not bind or binds with only low affinity to other proteins.
- an antibody “specifically binds” a target molecule when it binds with preferential or high affinity to that target but does not substantially bind, does not bind or binds with only low affinity to other proteins.
- the one or more binding proteins are specific for at least one antigen whose presence in the analytes is to be determined.
- the one or more binding proteins may be specific for at least one epitope of an antigen whose presence in the analytes is to be determined hi some aspects, at least two binding proteins may be employed, with each binding protein specific for a different epitope of the same antigen, or specific for different antigens of the same analyte.
- the analyte may be SARS-COV2 and binding proteins for different antigens of SARS-COV2 or for different epitopes of the same antigen of SARS-COV2 (such as the spike protein) may be employed.
- binding proteins for different antigens of influenza for example influenza HA and at least one further influenza antigen
- epitopes of the same influenza antigen such as HA
- reporter are well known in the art and suitable reporters are described for example in Lim & Wells Methods in Enyzymology, 644: 275-296 (2020), whose disclosure is incorporated by reference, including reporters described in Table 1 thereof.
- suitable reporters include beta-lactamase, beta-galactosidase, dihydrofolate reductase, horse radish peroxidase, luciferase and GFP.
- the device is also applicable to detection of multiple analytes (such as different microbial or viral particles, such as SARS-COV2 as a first analyte and influenza as a second analyte) by inclusion of different sets of binding proteins for each analyte whose presence is to be determined.
- the device may comprise one or more binding proteins for at least one antigen of a first analyte and one or more binding proteins for at least one antigen of a second analyte.
- the one or more binding proteins for at least one antigen of a first analyte may comprise at least a portion of a first reporter
- the one or more binding proteins for at least one antigen of a second analyte may comprise at least a portion of a second reporter
- each said reporter when active, is capable of generating a visual indicator in response to binding of each analyte, and wherein the visual indicator for binding of each set of analyte is different.
- the visual indicator for a first analyte may be a first colour and the visual indicator for a second indicator a second, different colour.
- the first reporter may be beta-lactamase and the second reporter beta- galactosidase.
- Presence of a target nucleic acid sequence may also be determined by amplification of the sequence, as determined by colorimetric change in the presence of template-dependent amplification (for example using a pH-sensitive dye that changes colour upon acidification induced by amplification), by real-time detection of fluorescence emission with a DNA-intercalating fluorescent dye, or by analysis and/or sequencing of amplified DNA products.
- a suitable colorimetric assay is a colorimetric LAMP assay (available for example from New England Biolabs, see for example NEB #E2019).
- the oligonucleotide hybridises to the target sequence with a Tm that is at least 2 °C, such as at least 3 °C, at least 4 °C, at least 5 °C, at least 6 °C, at least 7 °C, at least 8 °C, at least 9 °C, at least 10 °C, at least 20 °C, at least 30 °C or at least 40 °C, greater than its Tm for other nucleic acids.
- the nucleic acid reagents may be specific for a target nucleic acid of a microorganism such as a virus.
- the target nucleic acid may be DNA or RNA.
- the target nucleic acid sequence may be any sequence specific to, such as unique to the target microorganism.
- the primers and/or probes may allow for amplification of a target nucleic acid sequence specific to the target microorganism such as a sequence specific to SARS-COV2 or influenza.
- Oligonucleotides specific for at least two different target nucleic acids for example for target nucleic acids from two different target microorganisms such as SARS-COV2 and influenza
- at least two sets of nucleic acid reagents may be provided, each specific for a different target nucleic acid.
- the reagents for detection may further comprise one or more reagents suitable for amplification of the target nucleic sequence.
- reagents include the presence of all four dNTPs, ATP, TTP, CTP and GTP, suitable buffering agents/pH and other factors which are required for enzyme performance or stability.
- the method of determining the presence of a condition of the invention may further comprise the use of suitable conditions for annealing primers to a target sequence (such as suitable temperature and buffer conditions).
- the method may further comprise the use of suitable conditions promoting amplification of the nucleic acid sequence (such as suitable temperature and buffer conditions).
- suitable reagents and conditions include any conditions used to provide for activity of DNA polymerase enzymes known in the art.
- amplification of the target nucleic acid sequence may take place within the analyser, particularly where isothermal amplification is employed.
- the analyser may be configured to be removable from the device and amplification then carried out separately.
- the analyser may be configured to be inserted into a thermocycler to allow for PCR amplification.
- the analyser may have suitable thermal conductivity to allow for temperature cycling, preferably allowing for reaching rapid thermal equilibrium.
- a solution comprising the reagents for detection and the analyte may be removed from the analyser and analysed in a separate analysis device.
- the liquid in each reservoir may be any liquid that is suitable for dissolving a respective filter and is in no way restricted to being water.
- the liquid may be alcohol and the filter dissolvable in alcohol.
- the analyser is comprised by the breath analysis device.
- Embodiments also include the analyser being a separate, or removable, component from the breath analysis device.
- the liquid comprising the filter may flow to a removable collection chamber that may be inserted into a separate analysis device. This may increase the number of detection methods that may be applied.
- the breath analyser may also not comprise a fluid reservoir.
- the filter that preferably comprises reactants, may be removed from the breath analyser and inserted into a separate device where it is dissolved and analysed.
- the baseplate comprises openings configured so that breath may flow through the baseplate; wherein the diameter of openings in the baseplate are in the range of about 1 pm to about 1mm, and preferably 5pm to 100 pm.
- the liquid comprised by the reservoir is water.
- the filter comprises one or more of a meshwork, a sponge, a punctuated plate or a micro-sieve.
- the filter comprises a hydrophilic material.
- the device comprises dried reagents for detection of said analytes, preferably lyophilised reagents.
- the filter comprises the reagents for detection of said analytes, optionally wherein different reagents are provided as a plurality of separate granules in the filter.
- the reservoir comprises a breakable wall and/or valve configured to retain liquid in the reservoir until the liquid is released by the liquid release mechanism.
- the device comprises a part that is arranged to be pressed by a user of the device; and the part is configured so that liquid is forced out of the reservoir when the part is pressed.
- liquid release mechanism is arranged to release liquid from the reservoir in response to a flow/volume of breath into the device.
- the reagents for detection of said analytes comprise one or more binding proteins specific for at least one antigen, optionally wherein said binding protein(s) are antibodies or antigen-binding fragments thereof.
- a said binding protein further comprises at least a portion of a reporter, wherein said reporter, when active, is capable of generating a visual indicator in response to binding of said antigen.
- 21 The device according to aspect 20, comprising at least two binding proteins specific for different antigens of an analyte or different epitopes of an antigen of an analyte, wherein the binding proteins comprise different portions of said reporter, and wherein association of the binding proteins on binding of said antigen(s) provides an active reporter capable of generating a visual indicator. 22.
- the one or more binding proteins for at least one antigen of a first analyte comprise at least a portion of a first reporter
- the one or more binding proteins for at least one antigen of a second analyte comprise at least a portion of a second reporter
- each said reporter when active, is capable of generating a visual indicator in response to binding of each analyte, and wherein the visual indicator for binding of each analyte is different.
- the positive control area comprises an immobilised antigen
- the negative control area does not comprise an immobilised antigen or a capture antibody
- the test control area comprises a capture antibody.
- the reagents for detection of said analytes comprise one or more nucleic acids specific for at least one target nucleic acid, optionally wherein said nucleic acids comprise primers and/or probes specific for a nucleic acid sequence of said target nucleic acid.
- reagents for detection of said analytes further comprise at least one nucleic acid polymerase and optionally at least one reverse transcriptase.
- each reservoir is configured to supply liquid to at least one of the first, second and third filters.
- the one or more visual indicators comprise at least one substance that is configured to change colour, fluorescence and/or luminescence in response to the analysis result.
- analytes in the received breath are microbial particles, preferably viral particles, cancer analytes, analytes of a respiratory condition, antibodies, drugs or toxins.
- the viral particles comprise SARS- COV2 and/or influenza particles.
- a filter configured for use in a breath analysis device, wherein: the filter is configured to capture analytes in received breath by the breath analysis device; the filter comprises dried reagents for detection of said analytes, preferably lyophilised reagents; and the filter is at least partially soluble in liquid, such as water; wherein the filter may be as defined in any one of aspects 6-10, the reagents may be as defined in any one of aspects 19-24 and 26-28 and/or the analytes may be as defined in aspects 36 and 37.
- a method of detecting an analyte in breath or of determining the presence of a disease or condition in a user of a breath analysis device comprising: breathing, by the user, into a breath analysis device according to any one of aspects 1-37; and determining the presence of the analyte or of the disease or condition in dependence on an analysis of analytes in the received breath.
- the method according to aspect 39 wherein the analysis is performed within the breath analysis device, optionally wherein the breath device comprises one or more visual indicators of the analysis result.
- the disease or condition is a respiratory condition, an infection by a pathogenic microorganism, a cancer, bronchiectasis, chronic obstructive pulmonary disease, asthma, acute respiratory distress syndrome, cystic fibrosis, pneumonia, pulmonary embolism, interstitial lung disease, an inherited metabolic disease, multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, schizophrenia, allograft or transplant rejection, heart disease, atherosclerosis, renal failure, liver cirrhosis, alcoholic hepatitis, non alcoholic fatty liver disease, carbohydrate malabsorption, diabetes, or sepsis.
- a respiratory condition an infection by a pathogenic microorganism, a cancer, bronchiectasis, chronic obstructive pulmonary disease, asthma, acute respiratory distress syndrome, cystic fibrosis, pneumonia, pulmonary embolism, interstitial lung disease, an inherited metabolic disease, multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, schizophrenia, allograft or transplant rejection, heart
- the infection by a pathogenic microorganism is by a virus, a bacterium or a fungus, optionally wherein (i) the virus is a respiratory virus, such as a coronavirus or an influenza virus; (ii) the infection is a bacterial respiratory infection including upper and lower respiratory tract infections, pharyngitis or tonsillitis, or is Tuberculosis, H. pylori infection or Pseudomonas infection; or (iii) the infection is any fungal respiratory infection, pneumocystis or aspergillosis, or any mould infection.
- the virus is a respiratory virus, such as a coronavirus or an influenza virus
- the infection is a bacterial respiratory infection including upper and lower respiratory tract infections, pharyngitis or tonsillitis, or is Tuberculosis, H. pylori infection or Pseudomonas infection
- the infection is any fungal respiratory infection, pneumocystis or aspergil
- a method of identifying an analyte in exhaled breath such as an analyte whose presence and/or amount correlates with presence of, or risk of developing a disease or condition, the method comprising breathing, by the user into a breath analysis device comprising a mouthpiece arranged to receive breath from a user of the device; a reservoir comprising a liquid; a filter configured to capture analytes in the received breath, wherein the filter is arranged in a flow path of the breath through the device and the filter is at least partially soluble in the liquid comprised by the reservoir; and a liquid release mechanism configured to release liquid in the reservoir so that the liquid flows to the filter, and identifying an analyte present in the received breath.
- the device comprises a baseplate as defined in any one of aspects 2-4, a reservoir as defined in aspect 5 or 14, a filter as defined in any one of aspects 6-10, a part as defined in aspect 15 and/or a liquid release mechanism as defined in aspect 16, and/or wherein the viscosity of the liquid after dissolving at least part of the filter is less than 2 Pa*s, and preferably less than or equal to 1 Pa*s.
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Abstract
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EP21156901 | 2021-02-12 | ||
PCT/EP2022/053384 WO2022171804A2 (fr) | 2021-02-12 | 2022-02-11 | Dispositif d'analyse de gaz |
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EP2706355A1 (fr) * | 2012-09-11 | 2014-03-12 | Sensa Bues AB | Système et procédé pour l'élution et le test des substances à partir d'un échantillon d'aérosol expiré |
CA2953537A1 (fr) * | 2014-06-27 | 2015-12-30 | Pulse Health Llc | Cartouche d'analyse et son procede d'utilisation |
WO2019177644A1 (fr) * | 2018-03-15 | 2019-09-19 | Chris Marsh | Ensemble de capture d'échantillon pour système d'analyse d'aldéhydes et méthode d'utilisation |
US20200124625A1 (en) * | 2018-10-19 | 2020-04-23 | SannTek Labs Inc. | Systems and methods for detecting a target analyte in a breath sample |
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