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1. WO2016176366 - DEVICE AND METHODS OF USING DEVICE FOR DETECTION OF HYPERAMMONEMIA

Примечание: Текст, основанный на автоматизированных процессах оптического распознавания знаков. Для юридических целей просьба использовать вариант в формате PDF

CLAIMS

1. A biosensor comprising:

at least a first and second vessel;

a fluid exchange opening positioned between the first and the second vessel;

a membrane positioned across or over the fluid exchange opening; and

a catalyst in solid phase within the second vessel or within a conduit in fluid communication with the second vessel;

wherein the membrane comprises an ionomer.

2. The biosensor of claim 1 further comprising a compound comprising a phenyl group in solid phase within the second vessel or within a conduit in fluid communication with the second vessel.

3. The biosensor of claim 1, wherein the catalyst is nitrorprusside with a mass of from about 5.5 micrograms to about 7.8 micrograms.

4. The biosensor of claim 2, wherein the compound comprising a phenyl group has a mass of from about 75 micrograms to about 85 micrograms.

5. The biosensor of any of claims 1 through 4, wherein at least one conduit is in fluid communication with at least the first vessel, the at least a first conduit configured to receive a fluid from a point external to the biosensor.

6. The biosensor of any of claims 1 through 4, wherein the first vessel or the second vessel: (i) comprises one or a combination of a hypohalite, an alkali buffer, and at least one: phenolic reagent or indophenol related compound; or (ii) are in fluid communication with a conduit connected to a storage vessel that comprises a fluid comprising individually or in combination: a hypohalite, an alkali buffer, and at least one: phenolic reagent or indophenol related compound.

7. The biosensor of claim 6, wherein the first vessel or the second vessel are in fluid communication with at least one reagent conduit configured to receive a fluid from a reagent storage vessel at a point distal from the first or second vessel.

8. The biosensor of claim 7, wherein the first vessel or the second vessel is in fluid

communication with: (i) a first reagent conduit configured to receive a fluid from a first reagent storage vessel comprising a compound comprising a phenyl group in liquid phase; (ii) a second reagent conduit configured to receive a fluid from a second reagent storage vessel comprising a hypohalite in liquid phase; and (iii) a third reagent conduit configured to receive a fluid from a third reagent storage vessel comprising an alkali buffer in liquid phase.

9. The biosensor of claims 7 or 8, wherein at least one reagent storage vessel is a blister pack comprising a seal covering the blister pack on a portion of that blisterpack adajcent to at least one reagent conduit.

10. The biosensor of claim 9, wherein the seal is configured for mechanical rupture, such that, upon rupture, a fluid ciruit is formed between the first vessel or the second vessel and the reagent storage vessel and fluid contents from the blisterpack are capable of fluid flow to the the first vessel or the second vessel.

11. The biosensor of claim 1, wherein either the first or the second vessels individually comprise hyohalite, an alkali buffer, a catalyst, and at least one phenolic reagent.

12. The biosensor of claim 11, wherein the first and second vessel are in fluid communication with a detection vessel by at least one reaction conduit.

13. The biosensor of claim 12, wherein the reaction conduit comprises a first portion positioned proximate to the second vessel, said first portion comprising the catalyst in solid phase.

14. The biosensor of claim 12, wherein said first portion comprises the compound comprising a phenyl group in solid phase.

15. The biosensor of any one of claims 1-14, wherein the biosensor does not comprise one or more of the following: (i) uricase or a functional fragment thereof; (ii) a hydrogel comprising dextran or a derivative thereof; (iii) a bacterial cell; (iv) an electronic dipole configured for electrophoresis; and (v) 3, 4-DHB.

16. The biosensor of claim 1, wherein the biosensor is free of a vaporizer, gas chromotograph, or a heating element configured for converting liquid ammonia into a gaseous state.

17. The biosensor of any one of claims 1-9, wherein the at least first vessel comprises a volume from about 5 μΐ to about 100 μΐ.

18. The biosensor of any one of claims 1-17, wherein the biosensor is not functionally dependent upon exposure to any stimulus external to the biosensor.

19. The biosensor of claim 1 further comprising a circuit comprising the at least one wire, and digital display operably connected to a processor configured to receive digital information from the spectrophotometer and to send digital information to the digital display.

20. The biosensor of any one of claims 1-19, wherein the biosensor further comprises a test strip comprising the first conduit configured for receiving a volume of bodily fluid.

21. The biosensor of any one of claims 1-13, wherein the alkali buffer comprises from about 0.1 M to about 5 M sodium acetate or sodium chloride.

22. The biosensor of any one of claims 1-21, wherein the membrane comprises a block polymer with a formula of FIG. 5, wherein x, y, and z are any positive integer.

23. The biosensor of any one of claims 1-22, wherein the biosensor the at least one electrically conductive support is not covered by a membrane comprising cellulose or a derivative thereof.

24. The biosensor of any one of claims 1-23, wherein the hypohalite is selected from:

hypochlorite or bleach.

25. The biosensor of any one of claims 1-24, wherein the at least one indophenol reagent or indophenol related compound is selected from: phenol, 2-phenylphenol, or napthol.

26. The biosensor of any one of claims 1-25, wherein the alkali buffer is about 1.0 M sodium chloride, calcium chloride, zinc chloride, sodium acetate, alcium acetate, or zinc acetate.

27. The biosensor of any of claims 1-26, wherein the membrane comprises Nafion.

28. The biosensor of any of claims 1-27, wherein the membrane comprises Nafion which has been pre-treated with an acid solution and/or a hydrogen peroxide solution.

29. A biosensor comprising:

at least a first and second vessel;

a fluid exchange opening positioned between the first and the second vessel;

a membrane positioned across or over the fluid exchange opening; and

a phenolic reagent stored in solid phase within the second vessel or within a conduit in fluid communication with the second vessel;

wherein the membrane comprises an ionomer.

30. The biosensor of claim 29, wherein the biosensor further comprises:

a hypohalite;

an alkali buffer;

a catalyst; and

a fluid circuit comprising, in fluid communication:

the first and second vessel; a reagent conduit; and a detection vessel positioned distal from the first and second vessel.

-I l l-

31. The biosensor of claim 29, wherein the indophenol reagent is 2-phenylphenol and has a mass of from about 75 micrograms to about 85 micrograms of 2-phenylphenol.

32. The biosensor of claim 29, stoed at about room temperature or frozen for no less than 50, 100, 150, 200, or 245 days.

33. The biosensor of any of claims 29 through 32, wherein at least one conduit is in fluid communication with at least the first vessel, the at least a first conduit configured to receive a fluid from a point external to the biosensor.

34. The biosensor of any of claims 29 through 33, wherein the first vessel or the second vessel: (i) comprises one or a combination of a hypohalite, an alkali buffer, catalyst and at least one:

phenolic reagent or indophenol related compound; or (ii) are in fluid communication with a conduit connected to a storage vessel that comprises a fluid comprising individually or in combination: a hypohalite and an alkali buffer.

35. The biosensor of claim 34, wherein the first vessel or the second vessel are in fluid communication with at least one reagent conduit configured to receive a fluid from a reagent storage vessel at a point distal from the first or second vessel.

36. The biosensor of claim 34, wherein the first vessel or the second vessel is in fluid communication with: (i) a first reagent conduit configured to receive a fluid from a first reagent storage vessel comprising a compound comprising a phenyl group in liquid phase; (ii) a second reagent conduit configured to receive a fluid from a second reagent storage vessel comprising a hypohalite in liquid phase; and (iii) a third reagent conduit configured to receive a fluid from a third reagent storage vessel comprising an alkali buffer in liquid phase.

37. The biosensor of claims 35 or 36, wherein at least one reagent storage vessel is a blister pack comprising a seal covering the blister pack on a portion of that blisterpack adajcent to at least one reagent conduit.

38. The biosensor of claim 37, wherein the seal is configured for mechanical rupture, such that, upon rupture, a fluid ciruit is formed between the first vessel or the second vessel and the reagent storage vessel and fluid contents from the blisterpack are capable of fluid flow to the the first vessel or the second vessel.

39. The biosensor of claim 29, wherein either the first or the second vessels individually or in combination comprise a hypohalite, an alkali buffer, a catalyst, at least one phenolic reagent, and a sample.

40. The biosensor of claim 29, wherein the first and second vessel are in fluid communication with a detection vessel by at least one reaction conduit.

41. The biosensor of claim 40, wherein the reaction conduit comprises a first portion positioned proximate to the second vessel, said first portion comprising the phenolic reagent in solid phase.

42. The biosensor of claim 41, wherein said first portion comprises a catalyst in solid phase.

43. The biosensor of any one of claims 29-42, wherein the biosensor does not comprise one or more of the following: (i) uricase or a functional fragment thereof; (ii) a hydrogel comprising dextran or a derivative thereof; (iii) a bacterial cell; (iv) an electronic dipole configured for electrophoresis; and (v) 3, 4-DHB.

44. The biosensor of claim 29, wherein the biosensor is free of a vaporizer, gas chromotograph, or a heating element configured for converting liquid ammonia into a gaseous state.

45. The biosensor of any one of claims 29-44, wherein the at least first vessel comprises a volume from about 5 μΐ to about 100 μΐ.

46. The biosensor of any one of claims 29-44, wherein the biosensor is not functionally dependent upon exposure to any stimulus external to the biosensor.

47. The biosensor of claim 29 further comprising a circuit comprising the at least one wire, and digital display operably connected to a processor configured to receive digital information from the spectrophotometer and to send digital information to the digital display.

48. The biosensor of any one of claims 29-47, wherein the biosensor further comprises a test strip comprising the first conduit configured for receiving a volume of bodily fluid.

49. The biosensor of any one of claims 30, wherein the alkali buffer comprises from about 0.1 M to about 5 M sodium acetate or sodium chloride.

50. The biosensor of any one of claims 29-49, wherein the membrane comprises a block polymer with a formula of FIG. 5, wherein x, y, and z are any positive integer.

51. The biosensor of any one of claims 29-49, wherein the biosensor the at least one electrically conductive support is not covered by a membrane comprising cellulose or a derivative thereof.

52. The biosensor of any one of claims 30, wherein the hypohalite is selected from: hypochlorite or bleach.

53. The biosensor of any one of claims 30, wherein the catalyst is sodium nitorpruside or a salt thereof.

54. The biosensor of any one of claims 30, wherein the alkali buffer is about 1.0 M sodium chloride, calcium chloride, zinc chloride, sodium acetate, alcium acetate, or zinc acetate.

55. The biosensor of any of claims 29-54, wherein the membrane comprises Nafion.

56. The biosensor of any of claims 29-54, wherein the membrane comprises Nafion which has been pre-treated with an acid solution and/or a hydrogen peroxide solution.

57. The biosensor of any of claims 29-54, wherein the membrane comprises Nafion which has not been pre-treated with an acid solution and/or a hydrogen peroxide solution.

58. The biosensor of claim 30, wherein the catalyst is from about 5.8 to about 7.3 micrograms for sodium nitroprusside in solid phase within the second vessel or within a conduit in fluid communication with the second vessel and with a mass of about

59. A biosensor comprising:

at least a first and second vessel configured for receving a saple from a point exterior to the biosensor;

a fluid exchange opening positioned between the first and the second vessel;

a membrane positioned across or over the fluid exchange opening; and

a catalyst in liquid phase or solid phase

a hypohalite in liquid phase;

an alkali buffer in liquid phase;

a phenolic reagent in liquid phase or solid phase; and

a fluid circuit comprising, in fluid communication:

the first and second vessel; a reagent conduit; and a detection vessel positioned distal from the first and second vessel;

wherein the catalyst is sodium nitroprusside, and, if the catalyst is in solid phase, the biosensor comprises from about 5.8 to about 7.3 micrograms of sodium nitroprusside or a salt thereof in solid phase; and, if the catalyst is in liquid phase, the sodium nitroprusside or a salt thereof is at a concentration greater than about 7 μΜ.

60. The biosensor of claim 59, wherein the catalyst is sodium nitroprusside in liquid phase at a concentration from about 7.1 μΜ to about 9.0 mM.

61. The biosensor of claim 59, wherein the catalyst is sodium nitroprusside in liquid phase at a concentration from about 1.0 mM to about 2.0 mM.

62. The biosensor of claim 59, wherein the catalyst is sodium nitroprusside in liquid phase at a concentration of about 1.9 mM.

63. The biosensor of claim 59 comprising :

a first operable condition, in which the first vessel comprises a sample;

a second operable condition, in which the first vessel comprises a sample and an aqueous buffer;

a third operable condition, in which the regeant conduit comprises a mixture of the aqueous buffer, the alkali buffer, the hypohalite, the catalyst and the phenolic reagent and the mixture moves toward the detection vessel and the catalyst mixes with the sample for a time period sufficient for the catalyst to catalyze an indophenol reaction; and

a fourth operable condition, in which the detection vessel comprises the mixture and a light source positioned proximate to the detection vessel capable of emitting light through the detection vessel sufficient to quantify the amount of ammonia in the sample.

64. The biosensor of claim 63, wherein, in the fourth operable condition, the light source is a photodiode capable of emitting light in the detection vessel and producing an amount of light sufficient to enable absorbance readings detected at a wavelength of light from about 600 to about 650 nm.

65. A system comprising the biosensor of any one of claims 1-64 in operable connection to at least one computer storage memory.

66. The system of claim 65, further comprising a sample comprising whole blood.

67. The system of claim 65, further comprising a digital display in operable connection to at least one electrically conductive support by an electrical circuit capable of carrying an a electrical signal corresponding to a measurement of a wavelength, current, and/or voltage differential from a diode, spectrophotometer, voltmeter and/or amperoeter to the digital display, wherein the digital display is a configured to display concentration value of ammonia, ammonium ion and/or an amino

acid in a sample when the at least one electrically conductive support is in contact with the sample for a time period sufficient for the at least one catalyst to catalyze the indophenol reaction.

68. The system of any one of claims 65 - 67 further comprising a computer processor in operable connection with the at least one computer storage memory.

69. The system of any one of claims 65 - 68 further comprising a computer processor in operable connection with the at least one light emitting diode (LED), amplification circuit, battery, and stepper motor.

70. The system of any one of claims 65 - 69 further comprising a computer processor in operable communication with a device capable of uploading and downloading data to and from the internet.

71. A kit comprising a biosensor or test strip comprising:

at least a first and second vessel;

a fluid exchange opening positioned between the first and the second vessel;

at least one conduit in fluid communication with the at least first vessel, the at least one conduit configured to receive a fluid from a point external to the biosensor; and

a membrane positioned at the fluid exchange opening;

a catalyst in liquid phase or solid phase

a hypohalite in liquid phase;

an alkali buffer in liquid phase;

a phenolic reagent in liquid phase or solid phase; and

a fluid circuit comprising, in fluid communication:

the first and second vessel; a reagent conduit; and a detection vessel positioned distal from the first and second vessel;

wherein the catalyst is sodium nitroprusside, and, if the catalyst is in solid phase, the biosensor comprises from about 5.8 to about 7.3 micrograms of sodium nitroprusside or a salt thereof in solid phase; and, if the catalyst is in liquid phase, the sodium nitroprusside or a salt thereof is at a concentration greater than about 7 μΜ; and

wherein the membrane comprises an ionomer.

72. The kit of claim 71, wherein the alkali buffer is about 1 M sodium chloride or sodium acetate and/or 1 M sodium hydroxide.

73. The kit of claim 71 further comprising at least one of the following: a plurality of test strips comprising one or a plurality of electrically conductive supports, a control or reference sample of bodily fluid, a set of data comprising threshold values, and a set of instructions, the set of instructions or the set of data optionally accessible remotely through an electronic medium.

74. A kit comprising a solid support that comprises:

at least a first and second vessel;

a fluid exchange opening positioned between the first and the second vessel;

at least one conduit in fluid communication with the at least first vessel, the at least one conduit configured to receive a fluid from a point external to the biosensor; and

a membrane positioned at the fluid exchange opening;

a catalyst in liquid phase or solid phase;

a hypohalite in liquid phase;

an alkali buffer in liquid phase;

a phenolic reagent in liquid phase or solid phase; and

a fluid circuit comprising, in fluid communication:

the first and second vessel; a reagent conduit; and a detection vessel positioned distal from the first and second vessel;

wherein the catalyst is sodium nitroprusside, and, if the catalyst is in solid phase, the biosensor comprises from about 5.8 to about 7.3 micrograms of sodium nitroprusside or a salt thereof in solid phase; and, if the catalyst is in liquid phase, the sodium nitroprusside or a salt thereof is at a concentration greater than about 7 μΜ; and

wherein the membrane comprises an ionomer.

75. The kit of claim 74, wherein the solid support is a test strip attached to the first and second electrodes.

76. A method of determining or identifying a concentration of an ammonia or ammonium ion in a sample comprising: contacting a sample to the biosensor of any of claims 1-64, or the system of any of claims 65-70; or any test strip disclosed herein; and determining a quantity of ammonia or ammonium ion in the sample.

77. The method of claim 76, wherein the sample is whole blood.

78. A method of quantifying a concentration of ammonia or ammonium ion in a comprising contacting a sample of bodily fluid to the biosensor of any of claims 1-64, or the system of any of claims 65-70; or any test strip disclosed herein.

79. The method of any of claims 76-78, wherein the method further comprises comparing a concentration value obtained by the quantifying or identifying steps to a threshold value associated with one or more metabolic diseases.

80. The method of any of claims 76-79, wherein the step of contacting comprises exposing the sample to the biosensor of any of claims 1-64 or the system of any of claims 65-70 for a sufficient period of time to allow modification of the indophenol reagent or indophenol related compound to become modified into a indophenol or indophenol reaction product.

81. The method of any of claims 76-80, wherein the method does not comprise exposing the sample of bodily fluid to any external stimuli or reagent prior to contacting the sample to the at least one electrically conductive supports.

82. The method of any of claims 76-81, wherein the sample of bodily fluid is whole blood from a subject.

83. The method of any of claims 76-82, wherein the sample of bodily fluid is free of urine.

84. A method of diagnosing a metabolic disease in a subject comprising:

(a) contacting a sample of bodily fluid to the to the biosensor of any of claims 1-64 or the system of any of claims 65-70 or any test strip of claims 71-75 or 87-89;

(b) quantifying one or more concentration values of ammonia in the sample;

(c) comparing the one or more concentration values of ammonia in the sample to a threshold value of ammonia concentration identified as being in a healthy range; and

(d) identifying the subject as having a metabolic disease if the one or more concentration values of ammonia in the sample exceed or fall below the threshold value.

85. The method of claim 484, wherein the metabolic disease is hyperammonemia.

86. A method of determining patient responsiveness to a therapy comprising:

(a) contacting a sample of bodily fluid to the to the biosensor of any of claims 1-64 or the system of any of claims 65-70 or the test strip of claims 71-75 or 87-89;

(b) quantifying one or more ammonia or ammonium ion concentration values;

(c) comparing the one or more concentration values to one or more threshold values associated with a metabolic disease.

87. A test strip comprising a solid support comprising:

at least a first and second vessel configured for receving a saple from a point exterior to the biosensor;

a fluid exchange opening positioned between the first and the second vessel;

a membrane positioned across or over the fluid exchange opening; and

a catalyst in liquid phase or solid phase;

a hypohalite in liquid phase;

an alkali buffer in liquid phase;

a phenolic reagent in liquid phase or solid phase; and

a fluid circuit comprising, in fluid communication:

the first and second vessel; a reagent conduit; and a detection vessel positioned distal from the first and second vessel;

wherein the catalyst is sodium nitroprusside, and, if the catalyst is in solid phase, the biosensor comprises from about 5.8 to about 7.3 micrograms of sodium nitroprusside or a salt thereof in solid phase; and, if the catalyst is in liquid phase, the sodium nitroprusside or a salt thereof is at a concentration greater than about 7 μΜ; and

wherein the membrane comprises an ionomer.

88. The test strip of claim 87, wherein the test strip is adapted for a portable device comprising a diode, spectrophotometer, voltmeter and/or amperometer and a digital display such that, when the test strip is contacted to the device, the first and second electrodes become operably connected to a closed electrical circuit comprising the voltmeter and/or amperometer and the digital display, and, upon contact with a sample, hypohalite, an alkali buffer, catalyst and at least one indophenol reagent or indophenol related compound catalyze an indophenol reaction resulting in a current on the first electrode corresponding to a concentration value of ammonia in the sample, such concentration value readable on the display of the portable device.

89. The test strip of claim 87, wherein the test strip is adapted for a tabletop device comprising a diode, spectrophotometer, voltmeter and/or amperometer and a digital display such that, when the test strip is contacted to the device, the first and second electrodes become operably connected to a closed electrical circuit comprising the voltmeter and/or amperometer and the digital display, and, upon contact with a sample, hypohalite, an alkali buffer, catalyst and at least one phenolic reagent or indophenol related compound catalyze an indophenol reaction resulting in a current on the first electrode corresponding to a concentration value of ammonia in the sample, such concentration value readable on the display of the tabletop device.

90. A method of manufacturing the biosensor of any of claims 1-64 or the system of any of claims 65-70; or any test strip of claims 71-75 or 87-89 comprising affixing the membrane between the first and/or second vessel.

92. A method of detecting the presence, absence, or quantity of amino acid in a sample comprising:

(a) contacting a sample of bodily fluid to the to the biosensor of any of claims 1-64 or the system of any of claims 65-70; or any test strip of claims 71-75 or 87-89; or any catridge disclosed herein;

(b) quantifying one or more ammonia or ammonium ion concentration values;

(c) correlating the one or more ammonia or ammonium ion concentration values to one or more quantities of an amino acid.

93. A method of treating or preventing a metabolic disease comprising:

(a) contacting a sample of bodily fluid to the to the biosensor of any of claims 1-64 or the system of any of claims 65-70 or any test strip of claims 71-75 or 87-89;

(b) quantifying one or more concentration values of ammonia in the sample;

(c) comparing the one or more concentration values of ammonia in the sample to a threshold value of ammonia concentration identified as being in a healthy range; and

(d) identifying the subject as having a metabolic disease if the one or more concentration values of ammonia in the sample exceed or fall below the threshold value;

(e) administering a therapeutically effective amount of a therapeutic agent to treat metabolic disease.

94. The method of claim 93, wherein the metabolic isease is hyperammonemia.

95. The method of claim 93, wherein the therapeutic agent is Ravicti®.

96. The method of claim 93, wherein the sample of bodily fluid is whole blood.