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Title:
SYSTEM FOR DETECTION OF VOLATILE ORGANIC COMPOUNDS (VOC) IN EXHALED BREATH FOR HEALTH MONITORING
Document Type and Number:
WIPO Patent Application WO/2020/049438
Kind Code:
A4
Abstract:
The present invention relates to a system for detection of volatile organic compounds (VOC) in exhaled breath for health monitoring. It can be used for screening, diagnosis, monitoring onset and relapse of diseases. Certain volatile compounds, in exhaled breath 5 of a person, which are the markers of the disease under consideration, will be analysed by the sensor array. The presence and concentration of these markers will be determined by a sensor array specific for the set of markers for the disease. Depending on the presence or absence and concentration levels of these VOCs health status of a person can be analysed. The present invention also relates to a device for monitoring health conditions of an 10 individual and screening for presence or relapse of diseases.

Inventors:
PERUVANGAT JILMA (IN)
Application Number:
PCT/IB2019/057383
Publication Date:
September 03, 2020
Filing Date:
September 02, 2019
Export Citation:
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Assignee:
KOZHNOSYS PRIVATE LTD (IN)
International Classes:
G01N33/497; A61B5/097
Attorney, Agent or Firm:
MAJUMDAR, Subhatosh et al. (IN)
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Claims:
AMENDED CLAIMS

received by the International Bureau on 09 July 2020 (09.07.2020)

1. A molecularly imprinted polymer (MIP) coated piezoelectric sensor for detection of volatile organic compounds (VOCs) comprising: A polymer film or polymer nanoparticles molecularly imprinted with the VOC target molecule and coated on a piezoelectric crystal having frequency change sensitive to binding with the said VOC target molecule.

2. The sensor according to claim 1, wherein the molecularly imprinted polymer (MIP) layer is composed of a monomer selected from Acrolein, Acrylamide, 2-Acrylamido-2- methylpropane sulfonic acid (AMPSA),Acrylicacid, Acrylonitrile, Allylamine,m- divinylbenzene(DVB ) ,p-divinylbenzene(D VB ) ,N,N -Dimethyl Aminoethyl

Methacrylate, Ethylene glycol dimethacrylate, 2 hydroxyethyl methacrylate (HEMA), Itaconic acid, Methacrylic acid, N,N'-Methylenebisacrylamide,Urocanic acid, Urocanic acid, ethyl ester, vinylbenzene, 1-Vinylimidazole, 2-Vinylpyridine, 4-Vinylpyridine, 2- (Trifluoromethyl) acrylic acid, 4-Vinylbenzoic acid, 4-vinylbenzeneboronic acid, N- vinylpyrrolidone (NVP), Methyl methacrylate, Acrylonitrile or combinations thereof.

3. The sensor according to claim 2, wherein the monomers are cross-linked by a crosslinker selected from Ethylene glycol dimethacrylate(EGDMA),m- divinylbenzene(DVB), p-divinylbenzene(DVB),N,0 bismethacryloyl ethanolamine,N,N’ -methylenebisacrylamide(MDAA),p-divinylbenzene (DVB),N,N’ - 1 ,3-phenylenebis(2-methyl-2-propenamide),(PDBMP) 3,5- bisacryloylamidobenzoicacid,N,0-bisacryloyl-Lphenylalaninol,l,3- diisopropenylbenzene(DIP),pentaerythritoltriacrylate(PETRA),pentaerythritol pentacrylate(PRTEA),triethylolpropane, trimethacrylate(TRIM), tetramethylenedimethacrylate (TDMA), 2,6-bisacryloylamidopyridine, 1 ,4- phenylenediacrylamide, 1 ,4-diacryloyl piperazine(DAP), N,N' -ethylene bismethacrylamide,N,N'-tetramethylene, bismethacryl amide, N,N'-hexamethylene, bismethacrylamide, anhydroerythritol dimethacrylate, Ag-LaFe03 or l,4;3,6-dianhydro- Dsorbitol -2, 5 -dimethacrylate. 4. The sensor according to claim 1, wherein the piezoelectric crystal is a micro/nano cantilever, quartz crystal microbalance (QCM) or surface acoustic wave sensors.

5. The sensor according to claim 1, wherein the target VOCs are selected from ammonia, hydrogen disulphide, ketones, Benzene, Ethylbenzene, 4-ethylbenzamaide, undecanal, diethyl carbitol, isoborneol, n-propylbenzene, 1 -Butanol, 2-Butanone, 2-Pentanone, n- pentane, n-hexane, n-heptane, n-octane, n-dodecane, 2-Methylpentane, 3- Methylpentane, Cyclohexane, Propanal, n-butanal, n-pentanal, n-hexanal, n-octanal, n- nonanal, n-decanal, Naphthalene, 1 -methyl-, Cyclohexane 1,4-dimethyl, Cyclohexane, 1, 3-dimethyl -trans-, Cyclohexane, 1 -ethyl -2 -methyl -trans-, Heptane, 3 -ethyl -2-methyl-, Benzene, 1,2,3,4-tetramethyl-, Benzene, 1,4-dichloro-, 2-Propanol, 1-Propanol, 2,2- dimethyl, n-hexanol, Methylene chloride, Styrene, Tetrachloroethylene, Toluene, m,p- Xylene, o-Xylene, p-dichlorobenzene, 4,6-Dimethyl-dodecane, 2,2-Dimethyl-propanoic acid, 5 -Methyl-3 -hexanone, 2,2-Dimethyl-decane, Limonene, 2,2,3-Erimethyl-,exo- bicyclo[2.2.1]heptane, Ammonium acetate, 3 -Methyl -hexane, 2,4-Dimethyl -heptane, 4- Methyl-octane, 2,6,6-Trimethyl-octane, 3-Methyl-nonane, 2,3 -dihydro- 1 -phenyl -4(1- H)-quinazolinone, 1 -Phenyl -ethanone, Heptanal, Isopropyl myristate, Hydrazine- carboxamide, Methyl hydrazine, Ethyl alcohol, 1 -Methyl -4-(l-methylethyl)-benzene, Dimethyl ether, Butylated hydroxytoluene, Carbonic dihydrazide, l-Methyl-2-(l- methylethyl)-benzene, l-Methyl-3-(l-methylethyl)-benzene, 1,2,3-Cycloheptatriene, 3- Ethyl -pentane, 1,3,5 ,7-Cyclooctatetraene, Bicyclo[4.2.0]octa-l,3,5-triene, 2, 3,4-

Trimethyl -hexane, 2,6-Bis(l,l-dimethylethyl)-4-methyl-methylcarbamate, phenol, 4,7- Dimethyl -undecane, 2, 4, 6-Tris(l,l -dimethyl -ethyl)-4-methylcyclohexa-2,5-dien-l-one, Hydrazine , 1,3-Pentadiene, 3, 3-Dimethyl -pentane, 3, 3-Dimethyl -hexane, 2-Methyl- hexane, 3 -Ethyl -hexane, 2,2,3 -Trimethyl -hexane, Ethylidene cyclopropane, 2-Ethyl-l- hexanol, 2-Ethyl-4-methyl-l-pentanol, 2,3,4-Trimethyl-pentane, 2,3 -Dimethyl -hexane, 3-Ethyl-3-methyl -2-pentanone, 2-Methyl -4, 6-octadiyn-3 -one, 2 -Propyl- 1-pentanol,

6,10-Dimethyl-5,9-dodecadien-2-one, 2-propenenitrile, 2-butoxy-ethanol, furfural, 6- Methyl-5-hepten-2-one, Isoprene, 1,2-Propanediol, 2- Acetyl aminopropionic acid, Cyclopentanone, Methylacrylic acid, Butyl acetate, Trans-2 -Butene Oxide, Dimethylacetamide, Benzocyclobutene, Cyclohexanone, Butyl Glycol , 4-

Hydroxybutanoic acid, 1,3,5 ,7-Tetroxane, Ethylene Carbonate, l,4-Dimethoxy-2,3- butanediol, 2,5,6-Trimethyl-octane, 3,4,5,6-Tetramethyloctane, 2, 3, 4-Trimethyl - heptane, 5-Methyl-3-hexanol, 5-Butylnonane, 2,3,6-Trimethyl-octane, Benzenemethanol, alpha, alpha-dimethyl, Ethylaniline, Cyclooctanemethanol, trans-2- Dodecen-l-ol, 2,5 -Dimethylhexane -2, 5 -dihydroperoxide, Tetradecane, Hexadecane, butane, 2-methyl, Ethanol, Acetone, Isopropyl alcohol, Acrolein, Furan, tetrahydro-, Heptane , Carene, Tetradecanal, 3,3-dimethylhex-l-ene, 2-buten-l-ol, N-methyl-2- methylpropylamine, n-octene, Benzothiazole, Propane, 2-methyl-, 1,3 -Butadiene, Acetonitrile, n-Butane, 2-Propenal, Furan, Dimethyl sulphide, 2-Pentene, (Z)-, 1,3- Pentadiene, (E)-, 1,3-Pentadiene, (Z)-, 2-Propenal, 2-methyl-, 3-Buten-2-one, Furan, 2- methyl-, 2,3-Butanedione, Furan, 3-methyl-, Ethyl acetate, Thiophene, Pentane, 2- methyl-, 1-Pentene, 2-methyl-, 1-Hexene, Pentane, 3-methyl-, Pyrrole, Pyrimidine, Furan, 2,5-dimethyl-, Sulfide, allyl methyl (ams), Pyridine, Sulfide, methyl propyl (mps), Hexane, 2-methyl-, 1-Heptene, 2-Heptene, (E)-, 2-Hexanone, Heptane, 2- methylene, 3-Octene, (E)-, 2-Cyclohexen-l-one, 4-Heptanone, 3-Heptanone, 2- Heptanone, Heptane, 2,4-dimethyl-, -Pinene, Furan, 2-pentyl-, 3 -Carene, m-Cymene, p- Cymene, Eucalyptol, Pyrrolidine, 2,4-Dimethyl-l-heptene, 2,2-Dimethyl-butane, 1,3- Di-tert-butylbenzene, 2-Xylene, 2-Nonanone, 4-Methyl-2-heptanone, 2-Dodecanone, Isobutyric acid, allyl ester, 2-Ethyl-hexanol, Benzaldehyde, Cyclohexanol, 3- methylbutanal, Propanoic acid, Octane, Terpene,l-hexadecanol, Dimethyl disulphide, Xylene, Ethane, Propane, Methanol, 2,3,4-Trimethylhexane, 2,6,8-Trimethyldecane, Tridecane, Undecane, 2,4-Dimethylheptane, 4-Methyloctane, 2,2,4-Trimethylhexane, Decane, 3, 3 -Dimethyl -heptane, 2,4-Dimethyl-octane, 3-Ethyl-3-methyl-heptane, 2, 3,7- Trimethyl -decane, 2,3 -Dimethyl-decane, 3,9-Dimethyl-undecane, 3, 6-Dimethyl -decane, 2,5,6-Trimethyl-decane, Tetradecane, Pentadecane, 2-Methyl-tridecane, 2-Methyl- pentadecane, Acetophenone, Acetic Acid, 2-Methyl- 1,3 -butadiene, Phenylethyl acetate, Phenol, Carbon dioxide, Nonadecane, Phthalic anhydride, Sulphur dioxide, Acetaldehyde, Acrylonitrile, Carbon disulphide, 1-Decene, 1-Nonene, 1-Octene, 3- Methyl-hexane, (E)-2-Nonene, Ammonia, Hydrogen sulphide, Triethyl amine, Trimethyl amine, 2,6,10-Trimethyldodecane, 3,7-Dimethyl-decane, 2,3-Dimethyl- heptane, 2,2,4,6,6-Pentamethyl-heptane, 5 -Ethyl -2-methyl -octane, 2,6,10,14-

Tetramethyl-, hexadecane, 3,7-Dimethyl-propanoate(E)-2,6-octadien-l-ol, 2,3,5- Trimethyl-hexane, (l-methylethyl)benzene, (l-methylpropyl)cyclooctane, 2-Ethylhexyl tetradecyl ester oxalic acid, 2-Butyl- 1-octanol, 1-Chloro-nonadecane, 3-Ethyl-2,2- dimethyl-pentane, I,G-oxybis-octane, 2,3,6,7-Tetramethyl-octane, Decamethyl- cyclopentasiloxane, 1 -Propanol , Methanethiol, 2-Butene, Isobutane, 2-Methyl- 1- propene, Pentafluoroe thane, Ethyl ether, Methyl acetate, 2,3-Butadiene, Dichlorofluoroethane, 2-Methylbutane, 2-Pentene , Trichloro-methane, Cyclopentane, 2-Methylpropanal, 2-Methylfuran, 2-Methyl- 1-pentene, 2-Methyl- 1 -propanol, Methylcyclopentane, Mercaptoacetone, 2-Ethoxy-2-methylpropane, 1-Pentanol, 4- Methylpentane, Methylcyclohexane, Tetrahydro-2,2,4,4-tetramethylfuran, Nonane, 3,5- Dimethyloctane, 3-Ethyloctane or combinations thereof.

6. A modular sensor array for detection of VOCs from exhaled breath comprising: i. One or more molecularly imprinted polymer (MIP) coated piezoelectric sensor comprising a polymer film or polymeric nanoparticle molecularly imprinted with the VOC target molecule and coated on; a piezoelectric sensor having frequency sensitive to binding with the said VOC target molecule, and ii. A reference sensor comprising a non-polymer or non-imprinted polymer film coated on; a piezoelectric sensor , for measuring a change in the frequency;

Wherein, the said sensor array is configured to quantify the difference between the frequency of the MIP sensors and the frequency of the reference sensor to determine a concentration of the target VOC molecule.

7. A device for detection of VOCs from exhaled breath comprising:

i. An inlet port for collecting exhaled breath;

ii. A pre-concentrator connected to receive the exhaled breath sample from the sample inlet port to form a concentrated sample;

iii. A heating unit arranged for desorbing the captured VOCs from the adsorbent material of the pre -concentrator;

iv. A sensor chamber connected to receive the concentrated sample from the pre-concentrator and configured to detect and quantify VOCs therein; Wherein the sensor chamber comprises a sensor array comprising a plurality of molecularly imprinted polymer (MIP) coated piezoelectric sensor for detecting the VOCs and a non-imprinted polymer film or a non polymer film coated reference sensor;

v. A gas handling system for transporting the sample from the sample inlet port to the pre -concentrator and the concentrated sample from the pre concentrator to the sensor array and from the sensor array to an outlet; and vi. A control unit for controlling operation of the device and an output unit for displaying the results.

8. The device according to claim 7, wherein the pre -concentrator comprises an adsorbent material for reversibly capturing the VOCs of exhaled breath and removing carbon dioxide, moisture and other unwanted constituents of exhaled breath.

9. The device according to claim 8, wherein the adsorbent is selected from molecular imprinted polymer, polymer resins, activated charcoal, divinylbenzene, polydimethylsiloxane, polyacrylate, polyethylene glycol or graphitized carbon black.

10. The device according to claim 7, wherein the pre-concentrator is connected to a carbon- dioxide sensor for determining the carbon-dioxide in the exhaled breath.

11. The device according to claim 7, wherein the gas handling system includes an air intake port to purge the pre -concentrator with dry air.

12. The device according to claim 11, wherein the air intake port is connected to an air filter.

13. The device according to claim 7, wherein the gas handling system includes a flow sensor connected to the sample inlet and sensor chamber and means to select a desired portion of a stream of breath exhaled into the sample inlet.

14. The device according to claim 7, wherein the gas handling system comprises plurality of valves.

15. The device according to claim 7, wherein the device comprises temperature sensors for sensing temperature of the air in pre -concentrator. 16. The device according to claim 7, wherein the inlet port is adapted to receive exhaled breath directly from the subject by the subject exhaling into the inlet.

17. The device according to claim 7, wherein the sample inlet is adapted to receive exhaled breath from a receptacle.

18. The device according to claim 7, wherein the said device is bench-top, stand-alone and portable device.

19. The device according to any one of the preceding claims, wherein the said device simultaneously screens for multiple diseases from exhaled breath of a person.

20. The device according to any one of the preceding claims, wherein the said device has one or more sensor module.

21. The device according to claim 20, wherein the sensor module unit can be replaced.

22. The device according to claim 20, wherein the modular sensor has array of sensor specific for the diseases to be detected.

23. The device according to claim 7, wherein the said device has a software algorithm to analyse and process signal from the sensor array.

24. A method for detecting and quantifying volatile organic compounds (VOCs) in breath using the device as claimed in any one of the claims 7 to 23 comprising the steps of:

I. Exhaling into an inlet port for collecting exhaled breath;

II. Directing the exhaled breath to the pre-concentrator; Purging the pre concentrator with dry air while heating the pre -concentrator to a first temperature;

III. Sealing the pre-concentrator and heating it to a second temperature higher than the first temperature to release volatile organic compounds;

IV. Passing the released volatile organic compounds to the sensor chamber to detect and quantify the volatile organic compounds; Wherein the said sensor chamber comprises a sensor array comprising a plurality of molecularly imprinted polymer (MIP) coated piezoelectric sensor for detecting the VOCs and a non-imprinted polymer film or a non polymer film coated reference sensor; and

V. Purging the pre-concentrator while heating it to an elevated temperature to remove any remaining volatile organic compounds.

25. The method according to claim 24, wherein the method further comprises the step, before and/or after analyzing the concentrated sample, of controlling the gas handling system to admit ambient air into the sensor chamber for calibration.