WO2015166246A1 - Piège à ammoniac - Google Patents
Piège à ammoniac Download PDFInfo
- Publication number
- WO2015166246A1 WO2015166246A1 PCT/GB2015/051255 GB2015051255W WO2015166246A1 WO 2015166246 A1 WO2015166246 A1 WO 2015166246A1 GB 2015051255 W GB2015051255 W GB 2015051255W WO 2015166246 A1 WO2015166246 A1 WO 2015166246A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ammonia
- trap
- acid
- ammonium ions
- collection substrate
- Prior art date
Links
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 title claims abstract description 372
- 229910021529 ammonia Inorganic materials 0.000 title claims abstract description 184
- 239000000758 substrate Substances 0.000 claims abstract description 54
- 238000001514 detection method Methods 0.000 claims abstract description 50
- 239000002253 acid Substances 0.000 claims abstract description 47
- 238000000034 method Methods 0.000 claims abstract description 36
- -1 ammonium ions Chemical class 0.000 claims abstract description 34
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 claims description 61
- 239000007789 gas Substances 0.000 claims description 59
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 238000004458 analytical method Methods 0.000 claims description 13
- CIRHGJJMQVMCQC-UHFFFAOYSA-N 2h-isoindole-1-thiol Chemical compound C1=CC=CC2=C(S)NC=C21 CIRHGJJMQVMCQC-UHFFFAOYSA-N 0.000 claims description 12
- 239000000463 material Substances 0.000 claims description 12
- 150000007513 acids Chemical class 0.000 claims description 11
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 10
- 235000011007 phosphoric acid Nutrition 0.000 claims description 9
- 230000003287 optical effect Effects 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- 239000002657 fibrous material Substances 0.000 claims description 5
- 235000011149 sulphuric acid Nutrition 0.000 claims description 5
- 238000010828 elution Methods 0.000 claims description 4
- 241001465754 Metazoa Species 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000004753 textile Substances 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 239000003929 acidic solution Substances 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 59
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 238000004255 ion exchange chromatography Methods 0.000 description 11
- 239000007864 aqueous solution Substances 0.000 description 10
- 239000000123 paper Substances 0.000 description 10
- 238000013459 approach Methods 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 239000011521 glass Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000012491 analyte Substances 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000004033 plastic Substances 0.000 description 5
- 229920003023 plastic Polymers 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 150000003555 thioacetals Chemical class 0.000 description 5
- 239000000872 buffer Substances 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 238000005070 sampling Methods 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical class [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 238000001212 derivatisation Methods 0.000 description 3
- 238000003745 diagnosis Methods 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- ZETHHMPKDUSZQQ-UHFFFAOYSA-N Betulafolienepentol Natural products C1C=C(C)CCC(C(C)CCC=C(C)C)C2C(OC)OC(OC)C2=C1 ZETHHMPKDUSZQQ-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 241000590002 Helicobacter pylori Species 0.000 description 2
- 239000007836 KH2PO4 Substances 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- PCSMJKASWLYICJ-UHFFFAOYSA-N Succinic aldehyde Chemical compound O=CCCC=O PCSMJKASWLYICJ-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000000970 chrono-amperometry Methods 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- 238000002484 cyclic voltammetry Methods 0.000 description 2
- HEOKFDGOFROELJ-UHFFFAOYSA-N diacetal Natural products COc1ccc(C=C/c2cc(O)cc(OC3OC(COC(=O)c4cc(O)c(O)c(O)c4)C(O)C(O)C3O)c2)cc1O HEOKFDGOFROELJ-UHFFFAOYSA-N 0.000 description 2
- 238000002848 electrochemical method Methods 0.000 description 2
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- 239000010439 graphite Substances 0.000 description 2
- 229910002804 graphite Inorganic materials 0.000 description 2
- 229940037467 helicobacter pylori Drugs 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 239000002608 ionic liquid Substances 0.000 description 2
- 208000017169 kidney disease Diseases 0.000 description 2
- 239000006193 liquid solution Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 150000002739 metals Chemical class 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- ZWLUXSQADUDCSB-UHFFFAOYSA-N phthalaldehyde Chemical compound O=CC1=CC=CC=C1C=O ZWLUXSQADUDCSB-UHFFFAOYSA-N 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- HNSDLXPSAYFUHK-UHFFFAOYSA-N 1,4-bis(2-ethylhexyl) sulfosuccinate Chemical compound CCCCC(CC)COC(=O)CC(S(O)(=O)=O)C(=O)OCC(CC)CCCC HNSDLXPSAYFUHK-UHFFFAOYSA-N 0.000 description 1
- 208000032484 Accidental exposure to product Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001267494 Microdes Species 0.000 description 1
- 229910021607 Silver chloride Inorganic materials 0.000 description 1
- 150000008043 acidic salts Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229910003460 diamond Inorganic materials 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000000835 electrochemical detection Methods 0.000 description 1
- 238000003487 electrochemical reaction Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000004502 linear sweep voltammetry Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002991 molded plastic Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007650 screen-printing Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 1
- 238000000348 solid-phase epitaxy Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- CWERGRDVMFNCDR-UHFFFAOYSA-M thioglycolate(1-) Chemical compound [O-]C(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-M 0.000 description 1
- 238000001075 voltammogram Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/483—Physical analysis of biological material
- G01N33/497—Physical analysis of biological material of gaseous biological material, e.g. breath
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01C—AMMONIA; CYANOGEN; COMPOUNDS THEREOF
- C01C1/00—Ammonia; Compounds thereof
- C01C1/02—Preparation, purification or separation of ammonia
- C01C1/12—Separation of ammonia from gases and vapours
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N1/00—Sampling; Preparing specimens for investigation
- G01N1/02—Devices for withdrawing samples
- G01N1/22—Devices for withdrawing samples in the gaseous state
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01C—AMMONIA; CYANOGEN; COMPOUNDS THEREOF
- C01C1/00—Ammonia; Compounds thereof
- C01C1/02—Preparation, purification or separation of ammonia
- C01C1/10—Separation of ammonia from ammonia liquors, e.g. gas liquors
-
- 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
- C12Q2304/00—Chemical means of detecting microorganisms
- C12Q2304/40—Detection of gases
- C12Q2304/48—Ammonia or volatile amines
Definitions
- the invention relates to a trap for ammonia, in particular to a trap for gaseous ammonia.
- the invention further relates to an apparatus or kit incorporating the trap, to methods of making and using the trap in particular in the detection of ammonia.
- Ammonia is a gaseous analyte present in the breath of healthy individuals. It can, however, also be indicative of illness and has the potential to be used as a screening tool for a wide range of ailments. These include kidney disease, liver cirrhosis, or infections with microorganisms such as helicobacter pylori or Candida. An increase in the ammonia in the breath can also be a stress indicator. For these reasons it would be useful to provide a simple and rapid method of measuring the presence of this compound.
- breath sampling An extremely important aspect of breath sampling, which is often overlooked, is the need to capture the analyte (such as ammonia) so that it can be detected.
- analyte such as ammonia
- many methods of ammonia analysis require that the ammonia be in solution, whether the solute be aqueous, non-aqueous, a gel or even an ionic liquid.
- the problem to be overcome is, how best to present the breath (or other gaseous) sample such that the ammonia goes into solution allowing interaction with the sensor.
- the breath sample is bubbled directly through the solute (or injected using a controlled approach), the entrapment solution needs to be of significant volume and so the ammonia is diluted. At low ammonia levels, dilution is problematic and might result in a final concentration so low it is outside the detectors range.
- a very small solute volume could be used.
- a typical breath sample from a single exhalation has a volume of roughly 500 ml. Presenting a volume of breath this large to a small volume of solute will result in solute evaporation, and not dissolution of the ammonia in the breath.
- an ammonia trap comprising, a collection substrate and an acid.
- the acid may be immobilised on the collection substrate, or be present in solution.
- This system allows the trapping of ammonia on the collection substrate by conversion of ammonia (N3 ⁇ 4) to ammonium ions (NH 4 + ) through the acquisition of a proton from the acid. This is in accordance with the following well known reaction scheme:
- the ammonia trap could, after exposure to ammonia, be said to comprise a collection substrate, ammonium ions trapped on the collection substrate and an acid, (generally present in excess) immobilised on the collection substrate.
- the ammonia will typically be gaseous, and the simple approach to ammonia collection described herein, wherein the trap just captures ammonia from the gas stream, allowing all other gases to be vented to waste, is extremely simple and very specific. Once trapped, the ammonia can be released and detected, or detected directly on the collection substrate, the exact method being dependent on the type of sensor used for detection. However, it can be seen that whether the ammonia is released or detected in situ, that a high concentration, and pure sample is obtained using the ammonia trap of the invention. This makes it much easier to reproducibly analyse the ammonia.
- the trap has been found to be highly specific for ammonia, and to be accurate, often with a 100% extraction efficiency for ammonia in breath.
- ammonia is intended to include the protonated ammonium ion. As would be clear to the skilled reader, in some cases where reference is made to ammonia detection, this may specifically be detection of the ammonium ion, as appropriate for the detection method being used. This is particularly the case as detection will often be in aqueous solution, where depending upon the pH, the ammonium ion will be formed.
- the gaseous ammonia will generally be ammonia from human or animal breath.
- breath is intended to relate to some or all the mixture of components produced by exhalation from the lungs. This may include one or both of nasal
- vapour and/or liquid components may be present, for instance water vapour or water itself. Further the vapour and/or liquid component may include dissolved substances.
- the trap of the invention is specifically intended to be able to trap ammonia in the "breath".
- the trap of the invention may trap gaseous ammonia, or it may trap ammonia from "breath condensate", which as used herein refers to the liquid component of breath and/or the condensed vapour component.
- the acid is a strong acid (or even an acidic salt), as this ensures that the ammonia gas is rapidly converted as it comes into contact with the collection substrate.
- the acid will be a mineral acid such as H3PO4, H2SO4, HC1, FINO3, or one or more organic acids such as thioglycolic acid (mercaptoacetic acid) and combinations thereof, or combination of these acids with weak acids.
- Organic acids alone have been found to be insufficiently strong to reliably trap 100% of the ammonia and in some cases could interfere with the detection method.
- the acid will be H3PO4, as HC1 and FINO3 are gaseous acids in aqueous solution.
- H2SO4 has been found to be too corrosive for many applications, often corroding the collection substrate. However, where an acid resistant collection substrate is used, so may H2SO4 be.
- H3PO4 has been found to be strong enough to trap all ammonia from the gaseous stream, without the above drawbacks, in particular H3PO4 can be used in solution and is easy to immobilise on the collection substrate as it dries to form an oil.
- H3PO4 phosphoric acid
- KH2PO4, NaH2P04 which is first dissolved in water and the filter is soaked in this solution and later dried.
- Monobasic salts of the phosphate e.g. KH2PO4, NaH2P04
- KH2PO4, NaH2P04 could be proven useful in cases where milder acidic conditions of analysis are necessary to be followed in the capture of ammonia.
- strong acid is intended to be given its usual meaning in the art, namely an acid which is essentially fully dissociated when dissolved in water. This contrasts with “weak acids” which are not.
- a typical pKa for a strong acid would be in the range -10 to -2, for weak acids in the range -2 to 12.
- the collection substrate will be porous. The collection substrate will often be selected such that it is sufficiently porous to allow the gas stream to pass through, thereby ensuring that all ammonia is trapped, strong enough not to be damaged by the gas stream, yet thin enough to provide only minimum resistance to the stream such that where the stream is breath the trap is easy to breath into.
- Porosity may be achieved through the use of a non-porous material which has been perforated (such as a plastics material), or through the use of a porous materials.
- the substrate will be a fibrous material, the fibrous material being selected in many cases from paper or textiles materials.
- the substrate will be a porous paper, such as a filter paper for reasons of cost and ready availability.
- Another approach is to utilise a solution of the above mentioned acids or combinations of acids.
- the trap will further comprise a housing for the collection substrate.
- the substrate may be placed within the housing, or suspended therein.
- the collection substrate will substantially fill the housing, often spanning a cross-section of the housing, such that any gas passing into the housing must interact with (generally by passing through) the substrate.
- the housing will be configured to allow gases to pass into and out of the trap.
- the housing will be configured with an inlet to allow gases into the trap, and an outlet to allow gases to pass out of the trap.
- the inlet(s) and outlet(s) will positioned such that the gases pass from the inlet, through the collection substrate, to the outlet.
- the housing may be fabricated from a plastics material, metal, glass or other material such as a paper product.
- the housing will be intended to be non-porous to gases. It will generally be the case that the housing be formed from a rigid material, often this material will be inert, or non-reactive to the components in the gas stream.
- the chemical trap allows a minimum volume of solution (containing the reagents) to be used for the measurement/detection.
- the trapping solution can be placed into the chamber where the breath is being collected or via another approach the breath can be transmitted into the acidic solution.
- an apparatus for ammonia detection comprising a trap according to the first aspect of the invention, and an ammonia sensor.
- Any form of ammonia sensor may be used, although often the sensor will be selected from an electroanalytical sensor, biosensor, optical sensor, fluorescent sensor, potentiometer, or combinations thereof. In many cases the sensor will be an electroanalytical sensor, and where this is the case, the indirect detection method described in our earlier application GB 1315803.5 may be used.
- the detection method of GB1315803.5 comprises indirect detection of an electroactive derivative of ammonia.
- Ammonia itself is non-electroactive except at high overpotentials, and lacks sensitivity. As such, ammonia can only be sensed directly using specialist electrochemical techniques.
- One method of addressing this is to convert the ammonia to thioisoindole using thioglycolic acid (mercaptoacetate) and o-pthalaldehyde. This combination of components are found in the well-known OPA derivatization reagent.
- the thioglycolic acid forms a thioacetal complex with the o-pthalaldehyde and in subsequent ring forming reaction with ammonia thioisoindole is formed as shown in the reaction scheme below.
- OPA o-pthalaldehyde
- the thioisoindole can act as a direct measure of the level of ammonia in the gas stream (often breath) as one molecule of thioisoindole is formed per molecule of ammonia. This allows accurate determination of ammonia concentration. Further, the use of the OPA reagent, well known to react extremely reliably, ensures that all ammonia trapped is also detected. Scheme 2 illustrates the electrochemical reaction which occurs with the thioisoindole.
- SUBSTITUTE SHEET RULE 26 As described above by reacting the ammonia with o-pthalaldehyde and thioglycolic acid to produce first the thioacetal intermediate, and then the thioisoindole, the presence and concentration of ammonia can be indirectly measured using this electroactive species. This provides for a reliable determination of the ammonia present in the breath.
- thioisoindole is formed alkaline pH as this encourages the reaction to proceed to completion more rapidly by encouraging the formation of the thioacetal.
- the classic reaction conditions for the OPA reagent are a ratio of thioglycolic:o-pthalaldehyde acid of around 2: 1 to ensure that only the single thioacetal is formed and not a diacetal as the formation of the diacetal would hinder the ring-forming reaction with ammonia. Therefore, the ratio of o-pthalaldehyde:thioglycolic acid used will typically be in the range 0.5: 1 to 5: 1. However, it has been found that a higher ratio offers a more rapid reaction rate and so often the ratio of o-pthalaldehyde:thioglycolic acid will be in the range 3.5: 1 to 4.5: 1, often around 4.
- the electrochemical potential applied between the electrodes is in the range -2.0V to 2.0V, often -1.0 to 1.0V and the invention is typically capable of detecting and measuring current between the ranges of -5.0xl0 "9 A and 1.0xlO "4 A.
- the application of a potential within these parameters leads to the favourable oxidation of thioisoindole. This transition causes a measurable current typically within the above mentioned values which corresponds to this transition.
- the apparatus will further comprise a reservoir, comprising solute for removal of the ammonia from the trap.
- the reservoir contain a simple solute, a buffer solution or a solution containing reagents to promote the further derivatisation of ammonia together with its release from the collection substrate.
- the reservoir will hold a solute or a buffer solution.
- the reservoir will often hold a buffer solution.
- the use of buffer can be avoided where a solution of OPA (dissolved in NaOH) into the trapping/capturing solution (water with thioglycolic acid) is utilised.
- the apparatus will be configured as a lateral flow device, and where this is the case the contents of the reservoir will release the ammonia from the collection substrate and these may pass in solution to the sensor. Where further reaction of the ammonia is required prior to sensing, the ammonia may first pass to a reaction chamber, and then on to the sensor.
- the apparatus will be a single use apparatus.
- the apparatus or the trap
- it is ensured that each sample is not contaminated with earlier samples, and removes the need for washing or recharging the system between uses.
- Such steps introduce the potential for user error (for instance, through inadequate rinsing of the sensor), and hence the potential for inaccurate readings.
- the trap alone is to be single use, this will be removed from the apparatus and replaced between each use of the apparatus.
- the apparatus may be disposable.
- the apparatus will be sized such that it is easily portable, ideally pocket-sized, such that the operator may carry several of the apparatus with him at one time. This provides for the possibility of use in "field” as opposed to purely clinical situations.
- Field use of the apparatus is an important aspect of the invention, as the apparatus is inexpensive to make, reliable and simple to use.
- the apparatus include a receiver.
- the receiver may be a mouthpiece, although it may also be a member configured to receive breath exhaled through the nose. The presence of such receivers allow for direct sampling of the breath, without the need for storage or diversion through pipes or other parts of an apparatus.
- the receiver may be fabricated from a wide range of materials, such as plastics, metals, glass or paper products. Where the receiver is a multi-use component, it will often be formed from metals, glass or plastics materials, most often plastics materials as these may easily and inexpensively be moulded to provide a receiver which is ergonomic and safe to use.
- a receiver with smooth contours may be beneficial as it would fit well with the mouth or nose and there would be no risk of harm to the user from sharp edges.
- the receiver is intended to be a disposable component of the apparatus, whether alone as the only disposable component of the apparatus, with the trap as a disposable unit, or with the sensor and trap, the receiver will generally be fabricated from a paper product, such as cardboard.
- a reader is connected to the sensor for displaying the results of the analysis.
- the reader may be detachable and this will be the case where the apparatus is a limited use or more typically a single use unit. In such cases, the apparatus will be reversibly connectable to the reader. Limited use refers to a number of uses fewer than the reader.
- the single use apparatus may be connected to the reader such that once removed any particular single use unit combination may not be replaced, hence preventing inadvertent reuse of a soiled unit.
- the single use unit may include a fuse component containing a material which degrades under conditions of controlled passage of charge to break the electrical contact and prevent re-use of the single use unit.
- the reader may be connected to the sensor using any of a wide range of conventional techniques known to the skilled person. Connection will typically be reversible to allow for disposal of the limited use or single use unit. Connection methods which may be used to connect the limited or single use unit to the reader include, reversible clip techniques such as snap fit configurations, adhesive, friction fit, screw fit, hook and loop fixings, the use of screw or tack fixings or combinations thereof. Reversibility of the connection between the reader and allows for the reader to be retained when the apparatus is discarded, which may be advantageous as the reader will typically be a significantly higher cost item than the reader, will readily be capable of multiple uses and is not prone to contamination in the same manner as the apparatus.
- the reader will often be a conventional product, typically the reader will be electronic and will operate using software which can convert the current output from the sensor into a results output which can be interpreted by an operator, or by the user themselves, and utilised in performing a diagnosis. Additionally or alternatively, the reader may include software which allows the reader to offer guidance as to the diagnosis. For instance, the reader may be programmed to offer a percentage likelihood that Candida is present, or a simple "yes/no" indicator.
- the software may be configured to measure the magnitude of the current, particularly where cyclic voltammetry is used. A change over a threshold value would be indicative of the presence of ammonia. Chronoamperometry may also be used, in which case the change in current with time is measured. In some embodiments, chronoamperometry is desirable as it is easier to monitor than cyclic voltammetry.
- kits for ammonia detection comprising the trap of the first aspect of the invention and an ammonia sensor.
- the kit may further comprise a solute reservoir as described above.
- the kit may be specific for breath testing, or more general.
- the kit may be disposable, or multi-use.
- the kit may comprise the sensor and trap alone, with a receiver, although typically a solute reservoir will also be present, and generally the apparatus comprising the sensor will be used in combination with a reader and optionally instructions for connection to the reader and use. As such, the kit may additionally comprise instructions for use.
- the instructions for use may be simple assembly instructions, they may include instructions for taking the concentration measurement, they may include guide levels for concentrations which are indicative of the presence of malaise in the patient, or a combination of these.
- Such a kit would provide the user and operator with a portable, rapid, easy to use point-of-use tool for assessing whether the concentration of ammonia in the breath was within expected parameters.
- a method of ammonia detection comprising the steps of: presenting gaseous ammonia to the trap of the first aspect of the invention; reacting the ammonia with the acid to form ammonium ions; and detecting the ammonium ions, typically detection is through converting these ions in-situ back to ammonia with the use of alkaline conditions (in the collecting solution).
- the method of this aspect of the invention may be used to diagnose a variety of illnesses including kidney disease, liver cirrhosis, stress, infection with fungi such as Candida, or infection with bacterium such as helicobacter pylori.
- the ammonia may be in the breath and the breath may be the breath of a human or mammal, although typically the apparatus of the invention is intended for human use.
- the step of presenting of gaseous ammonia to the trap is repeated, this increases the concentration of entrapped ammonia, ensuring that if ammonia is present it is at a concentration sufficiently high to be detected.
- repetitions would generally be in accordance with a defined protocol to ensure reproducibility of results and consistency of diagnosis.
- the trapped ammonia can then be presented to the sensor of choice. If the sensor requires a solution, the solution can be presented onto the trapped ammonia allowing the measurement to proceed, or the ammonia can be released from the collection substrate using a solute, and presented to the sensor at another point in the apparatus.
- the method may further comprise the step of releasing the ammonia/ammonium ions from the trap prior to detecting the ammonium ions; the step of releasing optionally comprising elution of the ammonia/ammonium ions from the collection substrate. Elution is the most commonly used method of release as it is the quickest and simplest method of disengaging the ammonia from the substrate.
- the step of detecting of the ammonia/ammonium ions comprises chemical transformation of the ammonium ions prior to analysis. This can have the advantage of providing an analyte which has a stronger signal for sensor detection, or alternatively simply providing a more stable analyte under detection conditions. As noted above, often the detection method is electroanalytical, optical, fluorescent, potentiometric, biological or combinations thereof.
- a fifth aspect of the invention there is provided a method of making an ammonia trap according to the first aspect of the invention, comprising immobilising an acid on a collection substrate.
- an ammonia trap comprising:
- a collection substrate optionally a porous substrate, often comprising a fibrous material, often selected from paper and textiles materials;
- an acid optionally a strong acid such as H3PO4, H2SO4, HC1, HNO3, one or more organic acids, such as thioglycolic acid, and combinations thereof, or combination of these acids with weak acids, either immobilised on the collection substrate (and/or a solution of monobasic phosphate salts); or present as an acid / diluted acid solution; and optionally a housing for the collection substrate, optionally the housing having an inlet and an outlet configured to allow gases to pass into and out of the trap, the inlet and outlet optionally being positioned such that the gases pass from the inlet, through the collection substrate, to the outlet.
- a strong acid such as H3PO4, H2SO4, HC1, HNO3
- organic acids such as thioglycolic acid, and combinations thereof, or combination of these acids with weak acids
- an apparatus for ammonia detection comprising: a trap as described;
- an ammonia sensor the sensor is selected optionally from an electroanalytical sensor, biosensor, optical sensor, fluorescent sensor, potentiometer, or combinations thereof; optionally a solute reservoir, for removal of the ammonia from the trap; and optionally a reader;
- the apparatus is optionally partly or wholly single use.
- gaseous ammonia (optionally from human or animal breath) to the trap as described, optionally repeatedly;
- the detecting optionally comprises chemical transformation of the ammonium ions prior to analysis, and wherein the detection method is optionally electroanalytical, optical, fluorescent, potentiometric, biological or combinations thereof.
- Figure 1 is a picture of the traps of the invention relative to a British pound coin for scale. Centre and bottom centre, are traps comprising collection substrates alone; left and top centre, are traps wherein the collection substrate is within a housing;
- Figures 2a, 2b and 2c are illustrations of an apparatus of the invention.
- Figure 2a is an external schematic
- Figures 2b and 2c are internal schematics;
- Figure 4 shows the effect of the amount of gas ammonia transmitted through the solution on the captured amount of ammonia by the acidic solution.
- the diamond points represent the theoretical points if the ammonia was captured 100%.
- the square points represent the measured concentration of ammonia by the ion chromatography;
- Figure 5 shows the percentage loss of the gas ammonia in relation to the amount of gas ammonia transmitted through the thioglycolic acid solution (flow rate of the gas solution 336 ml/min);
- Figure 6 shows Linear Sweep Voltammetric responses of different concentrations of gas ammonia (in solution) produced by the gas generator upon SPGE (scan rate 100 mV/s);
- Figure 8 shows the results of ion chromatography for the detection of gas ammonia in breath collected in balloons and captured in 1 ml of 120 mM thioglycolic acid solution
- Figure 9 shows the results of the electrochemical method for the detection of gas ammonia in breath collected in balloons and captured in 1 ml of 120 mM thioglycolic acid solution.
- FIG. 1 shows a trap 5 of the invention.
- the trap 5 comprises a Whatman filter paper collection substrate 10 with acid (either H3PO4 or thioglycolic acid) impregnated thereon.
- the trap can also be a single solution of the acid/diluted acid without the need for filters.
- the dried acid is visible as an oily patch 15.
- Two of the traps 5 as shown include moulded plastic housings 20 which support and encase the collection substrate 10.
- An inlet 25 and outlet 30 are present, and the trap 5 is operated by presenting human breath through inlet 25 to the collection substrate 10.
- the oily patch 15 on substrate 10 is of comparable cross-section to inlet 25 and outlet 30, which are each the same size as one another.
- the collection substrate 10 is removed from the trap 5 and placed over a screen-printed electrochemical sensor (not shown in Figure 1). A sensing solution is then added to allow the concentration of ammonia to be determined.
- the trap 5 allows a minimum volume of solution (containing the reagents) to be used for the analysis.
- the trap 5 is highly specific for ammonia and we have found a 100% extraction efficient for ammonia in breath.
- Figure 2 shows an alternative approach to sensing ammonia
- the apparatus 50 shown includes trap 5, and removes the need to take the trap 5 apart prior to analysis of the sample, as is the case for the example of Figure 1.
- the lateral flow device 50 of Figure 2 comprises a receiver 55 ( Figure 2a) over which a user would place their mouth and exhale.
- the receiver 55 directs the breath to trap 5 within ( Figures 2b and 2c).
- Adjacent the trap is a solute reservoir 60 containing buffer, after exhalation the buffer is released from reservoir 60 using reservoir release button 65.
- the buffer washes through the trap 5, eluting ammonia from the collection substrate 10 and passing by capillary action along the lateral flow device 50 towards a porous paper reaction membrane 70 including OPA reagent.
- As the ammonia passes across the reaction membrane 70 thioisoindole 85 is formed, and it is the thioisoindole 85 which is presented for detection by electrochemical sensor 75.
- Sensor 75 is plugged into reader 80 which converts the electrical signal from sensor 75 into a concentration value for interpretation by the user.
- the same device 50 could be used with an optical or other sensor 75 if required without change to the chemistry used. Examples
- the pH of the trap solution (thioglycolic acid 115-120mM) was 2.5 while the pH of the final solution (after the addition of OPA/NaOH solution) for all the measurements was 12.75 measured by Mettler Toledo Seven Compact pH meter. All voltammetric measurements were carried out using ⁇ AUTOLAB Type III potentiostat by Metrohm Autolab B.V. two minutes after the addition of all reagents unless otherwise stated.
- the screen-printed three electrode configuration had a geometric graphite working electrode area of 3 mm diameter in addition to on-board Ag/AgCl reference and graphite counter electrodes. Measurements were conducted using screen-printed three electrode configurations. Screen-printed carbon-based electrodes (denoted as SPEs) were fabricated in-house with stencil designs using a microDE 1760RS screen-printing machine (DEK, Weymouth, UK).
- the gas generator incorporated an ammonia permeation tube with ammonia permeation rate 200 ng min. Operational temperature was 30°C and the gas flow 336 ral/min. All concentrations of ammonia are given in u-g/ml (ppm) in liquid solution unless otherwise stated. The relation of the concentration of ammonia in liquid solution and in the gas solution (ex. breath) is given by the following equation:
- Y is the concentration of the analyte (ex. Ammonia) found in the aqueous solution (ppm ⁇ g/ml)
- Vaq eous is the volume of the aqueous solution with which we capture the ammonia
- 24.5 is the volume of lmol of an ideal gas at room temperature (25°C) and pressure (1 atm) (L/mol)
- M. W. is the molecular weight of the analyte (for ammonia is 17.03 g/mol)
- Vgas is the volume of the gas solution (ex. breath) (ml)
- the sodium hydroxide converts the ammonium ions back to ammonia, allowing reaction of the ammonia with the OPA.
- the solution used for capturing ammonia is roughly 0.5 ml (in these examples 0.471ml) of 115 mM thioglycolic acid unless otherwise stated.
- the gas flow is bubbled into the solution through a glass pipette.
- a solution of 69mg/ml OPA dissolved in 6M Sodium hydroxide is used for the second step .
- 0.029ml of this solution is added to the thioglycolic acid solution of the first step in order to have 0.5ml final solution.
- 0.200ml of the final solution is applied to the surface of the SPE and linear sweep voltammetry carried out (-0.6V)-(1.2V) at 100m V/s exactly 2.0 minutes after the mixing of the reagents.
- Gas Ammonia (from gas generator) detection [0073] The detection of gas ammonia produced by the gas generator was carried out by using 11 different glass vials containing 471 ⁇ _, of 120 mM thioglycolic acid. Ammonia was bubbled into the glass vials for 15 sec, 1 min 15 sec, 1 min 52 sec, 2 min 30 sec, 5 min, 7 min 30 sec, 10 min, 12 min 30 sec, 15 min, 20 min, and 25 min.
- the gas generator produces 200ng/min and as such the final concentrations (for 500uL after the addition of 29 ⁇ of 30mM of OP A in 6M Sodium hydroxide) were: 0.1, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 10 ppm ammonia in the solution.
- Figure 6 shows the linear sweep voltammograms resulting in the calibration plot shown at figure 7.
- the electrochemical technique is at least as sensitive and specific as the ion chromatography and is capable of dealing with the variation in concentration of ammonia that will inherently occur from exhalation to exhalation (in this case shown by the non-linear increase in concentration in figures 8 and 9).
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Abstract
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GB1617685.1A GB2540890A (en) | 2014-04-30 | 2015-04-30 | Ammonia trap |
CN201580000204.8A CN105431724A (zh) | 2014-04-30 | 2015-04-30 | 氨捕获器 |
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Cited By (6)
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CN105527381A (zh) * | 2016-01-07 | 2016-04-27 | 长沙三相医疗器械有限公司 | 一种氨捕获器和氨检测装置及检测氨的方法 |
CN105717187A (zh) * | 2016-02-02 | 2016-06-29 | 长沙三相医疗器械有限公司 | 一种用于幽门螺杆菌诊断的试剂和试剂盒及检测人体呼出的氨气的方法 |
CN105866224A (zh) * | 2016-03-30 | 2016-08-17 | 深圳三相生物传感科技有限公司 | 一种用于诊断人体幽门螺杆菌感染试剂盒以及检测人体呼气中氨气含量的方法 |
US11460457B2 (en) | 2018-06-27 | 2022-10-04 | Vitesco Technologies GmbH | Method and gas fuse for detecting a corrosive gas |
WO2022249061A1 (fr) * | 2021-05-28 | 2022-12-01 | 3M Innovative Properties Company | Dispositif et système de collecte d'échantillon |
WO2023073503A1 (fr) * | 2021-10-29 | 2023-05-04 | 3M Innovative Properties Company | Système de collecte d'échantillon et élément de distribution d'éluant pour celui-ci |
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CN105891405A (zh) * | 2016-03-30 | 2016-08-24 | 深圳三相生物传感科技有限公司 | 一种用于诊断人体幽门螺杆菌感染的装置及检测人体呼气中氨气含量的方法 |
CN107796795B (zh) * | 2017-10-13 | 2019-08-09 | 福州大学 | 用于气体检测的荧光传感器 |
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GB2519937A (en) * | 2013-09-05 | 2015-05-13 | Kanichi Res Services Ltd | Electrochemical sensor |
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Cited By (6)
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CN105527381A (zh) * | 2016-01-07 | 2016-04-27 | 长沙三相医疗器械有限公司 | 一种氨捕获器和氨检测装置及检测氨的方法 |
CN105717187A (zh) * | 2016-02-02 | 2016-06-29 | 长沙三相医疗器械有限公司 | 一种用于幽门螺杆菌诊断的试剂和试剂盒及检测人体呼出的氨气的方法 |
CN105866224A (zh) * | 2016-03-30 | 2016-08-17 | 深圳三相生物传感科技有限公司 | 一种用于诊断人体幽门螺杆菌感染试剂盒以及检测人体呼气中氨气含量的方法 |
US11460457B2 (en) | 2018-06-27 | 2022-10-04 | Vitesco Technologies GmbH | Method and gas fuse for detecting a corrosive gas |
WO2022249061A1 (fr) * | 2021-05-28 | 2022-12-01 | 3M Innovative Properties Company | Dispositif et système de collecte d'échantillon |
WO2023073503A1 (fr) * | 2021-10-29 | 2023-05-04 | 3M Innovative Properties Company | Système de collecte d'échantillon et élément de distribution d'éluant pour celui-ci |
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GB201617685D0 (en) | 2016-11-30 |
GB2540890A (en) | 2017-02-01 |
CN105431724A (zh) | 2016-03-23 |
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