WO2012177114A1 - Système détecteur d'analyte - Google Patents

Système détecteur d'analyte Download PDF

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Publication number
WO2012177114A1
WO2012177114A1 PCT/MY2012/000125 MY2012000125W WO2012177114A1 WO 2012177114 A1 WO2012177114 A1 WO 2012177114A1 MY 2012000125 W MY2012000125 W MY 2012000125W WO 2012177114 A1 WO2012177114 A1 WO 2012177114A1
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WO
WIPO (PCT)
Prior art keywords
sensor system
analyte sensor
body fluid
sensing device
analyte
Prior art date
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Ceased
Application number
PCT/MY2012/000125
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English (en)
Inventor
Mohd Rais Ahmad
Airul Azha ABD. RAHMAN
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Mimos Bhd
Original Assignee
Mimos Bhd
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Filing date
Publication date
Application filed by Mimos Bhd filed Critical Mimos Bhd
Publication of WO2012177114A1 publication Critical patent/WO2012177114A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/28—Electrolytic cell components
    • G01N27/30—Electrodes, e.g. test electrodes; Half-cells
    • G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements
    • G01N27/3271—Amperometric enzyme electrodes for analytes in body fluids, e.g. glucose in blood
    • G01N27/3273—Devices therefor, e.g. test element readers, circuitry

Definitions

  • the present invention relates to an analyte sensor system for measuring concentration of a targeted analyte in a body fluid.
  • Determination of body metabolites such as uric acid, lactate, pyruvate and ketone bodies is useful to indicate overall health condition and to diagnose specific health problems.
  • Urine, blood and sweat are commonly analysed during medical screening and diagnosis of diseases.
  • Enzyme based sensor have been widely used to analyse body metabolites.
  • the enzyme based sensor comprises of an enzyme disposed on a transducer.
  • the enzyme reacts with a targeted analyte to produce a reaction product.
  • the transducer converts the concentration of the reaction product into electrical signal.
  • Table 1 shows frequently employed enzymes for medical sensors and the respective target analytes.
  • the enzyme based sensor poses a few drawbacks. Firstly, the protein structure of the enzyme is sensitive to denaturation by temperature, pH or aging. The denaturing of enzymes causes inaccurate sensor readings of the targeted analyte concentration. Secondly, the enzyme tends to leach out from the transducer. Thus, additional precautions must be taken to ensure the mechanical stability of the enzyme, so that it is always attached to the surface of the transducer and does not tear under agitation.
  • the method used to immobilize the enzyme affects the stability of the sensor.
  • Enzyme based sensor that uses soluble enzymes trapped in dialysis membranes are generally less stable than those using enzymes trapped in gels. Therefore, there is a need to provide a sensor system for determining concentration of an analyte that addresses the aforementioned drawbacks.
  • the present invention provides an analyte sensor system (100) to determine concentration of a targeted analyte in a body fluid.
  • the analyte sensor system (100) is characterised by a sensing device (110); a current measurement circuit (130) connected to the sensing device (110), wherein the current measurement circuit (130) is configured to amplify voltage signal from the sensing device (110) and convert the voltage signal to oxidation current; a biasing circuit (150) connected to the sensing device (110), wherein the biasing circuit (150) is configured to provide a voltage bias for selectively oxidize the targeted analyte; and a voltage reference circuit (170) connected to the sensing device (110), wherein the voltage reference circuit (170) is configured to provide a reference voltage in measuring the oxidation current.
  • the sensing device (110) comprises of a substrate (111); a conductor layer (112) disposed on the substrate (111); an insulator (113) disposed on the conductor layer (112); a counter electrode (114) disposed on the conductor layer (112), wherein the counter electrode (114) is used to provide stable supply of electron across the body fluid, and wherein the counter electrode (114) is connected to the biasing circuit (150); a sensing electrode (115) disposed on the conductor layer (112), wherein the sensing electrode (115) is used to selectively oxidize the targeted analyte, and wherein the sensing electrode (115) is connected to the current measurement circuit (130); a reference electrode (116) disposed on the conductor layer (112), wherein the reference electrode (116) is used to provide reference voltage for current measurement, and wherein the reference electrode (116) is connected to the voltage reference circuit (170); a buffer layer (1 7) disposed on the electrodes (114, 115, 116) and the insulator (113), where
  • the counter electrode (114), the sensing electrode (115) and the reference electrode (116) are provided in close proximity to each other.
  • the counter electrode (114) is made of one or any combination of the following materials: platinum, graphite, glassy carbon, or pyrolitic carbon.
  • the sensing electrode (115) is made of 1 to 90% by weight of graphite, 1 to 90% by weight of carbon nanotubes, 1 to 90% by weight of pyrolitic carbon, 0.1 to 10% by weight of ferrocene, 0.1 to 10% by weight of platinum nanoparticles and 2 to 30% by weight of organic binder.
  • the organic binder is suitably selected from one or any combination of the following binders: Bisphenol A propoxylate didlycidyl ether, methyl methacrylate-glycidyl methacrylate- tetrahydrofurfuryl acrylate copolymer, or glycidyl methacrylate-tetrahydrofurfuryl acrylate copolymer.
  • the reference electrode (116) is made of silver-silver chloride, platinum-silver, platinum, mercury-mercury chloride, or any combination thereof.
  • the buffer layer (117) comprises of one or any combination of the following chemicals: hydrochloric acid, acetic acid, boric acid, citric acid, sodium hydroxide, sodium citrate, sodium acetate, potassium hydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen phosphate, or sodium dihydrogen phosphate.
  • the filter layer (118) is made out of one or any combination of the following materials: cellulose acetate, ethyl cellulose, cellulose, Nafion, polystyrene sulfonic acid, poly (N-vinyl pyrrolidone), poly (N-vinyl imidazole), or poly (4-vinyl pyrridine).
  • the conductor layer (112) is made of screen printed silver or carbon.
  • the insulator ( 13) is made of screen printed solder mask or epoxy paste.
  • a method of measuring concentration of a targeted analyte in a body fluid by using the analyte sensor system (100) comprises the steps of providing a body fluid to a sensing device (110); filtering unwanted substance or molecules from the body fluid by a filter layer (118); buffering current path of the body fluid by a buffer layer (117); determining a voltage bias by a biasing circuit (150) and providing the voltage bias from a biasing circuit (150) to a counter electrode (114); oxidizing the targeted analyte in the body fluid by a sensing electrode (115); converting voltage signal from the sensing electrode (115) to oxidation current signal by a current measurement circuit (130); and referencing the oxidation current with a calibrated data of oxidation current against concentration of the targeted analyte.
  • the body fluid is provided to the sensing device (110) by immersing the sensing device (110) in the body fluid.
  • the analyte sensor system provided by the present invention can be repeatedly used without suffering from denaturation which causes inaccurate measurement of the analyte sensor system.
  • the analyte sensor system provided by the present invention can be stored in ambient conditions. BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 illustrates a block diagram of an analyte sensor system (100) according to an embodiment of the present invention.
  • FIG. 2 illustrates a cross sectional view of a sensing device (110) of the analyte sensor system (100) of FIG. 1.
  • FIG. 3 illustrates a flow chart for measuring concentration of a targeted analyte in a body fluid by using the analyte sensor system (100) of FIG. 1.
  • FIG. 4 illustrates a graph plot of oxidation current (mA) versus concentration of uric acid.
  • FIG. 1 illustrates an analyte sensor system (100) in accordance with an embodiment of the present invention.
  • the analyte sensor system (100) is used to determine concentration of a targeted analyte in a body fluid.
  • the sensor system (100) generally comprises of a sensing device (110), a current measurement circuit (130), a biasing circuit (150), and a voltage reference circuit (170).
  • the analyte sensor system (100) selectively oxidizes the targeted analyte and consequently, produces an oxidation current which is an indicative of the concentration level of the targeted analyte in the body fluid.
  • FIG. 2 illustrates a cross sectional view of the sensing device (110) of the analyte sensor system (100) of FIG. 1.
  • the sensing device (110) comprises of a substrate (111), a conductor layer (112), an insulator (113), a counter electrode (114), a sensing electrode (115), a reference electrode (116), a buffer layer (117), and a filter layer (118).
  • the conductor layer (112) is disposed on the substrate (111).
  • the conductor layer (112) is used to conduct electrical signal to the current measurement circuit (130), the biasing circuit (150), and the voltage reference circuit (170).
  • the conductor layer ( 12) is made of screen printed silver or carbon.
  • the insulator (113) is disposed on the conductor layer (112). Moreover, the insulator (113) fills the gaps in between the electrodes (114, 115, 116) to insulate them from each other. Preferably the insulator (113) is made of screen printed solder mask or epoxy paste.
  • the counter electrode (114), the sensing electrode (115) and the reference electrode (116) are disposed on the conductor layer (112) and preferably, the electrodes are provided in close proximity to each other. This is so that when a small volume of body fluid is disposed on the sensing device (110), all the electrodes are able to react with it to determine the concentration level of the targeted analyte.
  • the counter electrode (114) functions as an inert electrode to provide stable supply of electron across the body fluid.
  • the counter electrode (114) is made of one or any combination of the following materials: platinum, graphite, glassy carbon, or pyrolitic carbon.
  • the counter electrode ( 4) is connected to the biasing circuit (150) through wire trace of the conductor layer (112).
  • the biasing circuit (150) is configured to provide a stable voltage bias for selectively oxidize the targeted analyte.
  • the sensing electrode (115) is used to selectively oxidize the targeted analyte in the body fluid.
  • the sensing electrode (115) is made of 1 to 90% by weight of graphite, 1 to 90% by weight of carbon nanotubes, 1 to 90% by weight of pyrolitic carbon, 0.1 to 10% by weight of ferrocene, 0.1 to 10% by weight of platinum nanoparticles and 2 to 30% by weight of organic binder.
  • the organic binder is suitably selected from one or a combination of the following binders: Bisphenol A propoxylate didlycidyl ether, methyl methacrylate-glycidyl methacrylate- tetrahydrofurfuryl acrylate copolymer, or glycidyl methacrylate-tetrahydrofurfuryl acrylate copolymer.
  • the sensing electrode (115) is connected to the current measurement circuit (130) through wire trace of the conductor layer (112).
  • the current measurement circuit (130) is configured to amplify the voltage signal from the sensing electrode (115) and thereon, convert the voltage signal to current signal which is the oxidation current.
  • the oxidation current is an indicative of the concentration of the targeted analyte whereby the oxidation current values is in linear relationship with the concentration of the analyte.
  • the reference electrode (116) is used to provide a reference voltage for measuring the oxidation current.
  • the reference electrode (116) is made of silver-silver chloride, platinum-silver, platinum, mercury-mercury chloride, or any combination thereof.
  • the reference electrode (116) is connected to the voltage reference circuit (170) through wire trace of the conductor layer (112).
  • the voltage reference circuit (170) is configured to provide a stable reference voltage in measuring the oxidation current.
  • the buffer layer (117) is disposed on the electrodes (114, 115, 116) and the conductor layer (112).
  • the buffer layer (117) is used to control the pH level of the body fluid.
  • the buffer layer (117) is also used to control and reduce the electrical resistance across the body fluid provided to the sensing device.
  • the buffer layer (117) comprises one or any combination of the following chemicals: hydrochloric acid, acetic acid, boric acid, citric acid, sodium hydroxide, sodium citrate, sodium acetate, potassium hydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen phosphate, or sodium dihydrogen phosphate.
  • the filter layer (118) is disposed on the buffer layer (117).
  • the filter layer (118) is used to physically and chemically prevent unwanted materials and molecules from entering the electrodes' surfaces. For instance, the filter layer (118) physically filters out unwanted substance such as blood proteins due to its molecular size.
  • the filter layer (118) is polarized by using ionic pendant group and thus, allowing only ionic analytes with the opposite polarity to flow through to the electrodes' surfaces while filtering out ionic analytes with the same polarity as the pendant group.
  • the filter layer (118) is made out of one or a combination of the following materials: cellulose acetate, ethyl cellulose, cellulose, Nafion, polystyrene sulfonic acid, poly (N-vinyl pyrrolidone), poly (N-vinyl imidazole), or poly (4-vinyl pyrridine).
  • cellulose acetate ethyl cellulose
  • cellulose cellulose
  • Nafion polystyrene sulfonic acid
  • poly (N-vinyl pyrrolidone) poly (N-vinyl imidazole), or poly (4-vinyl pyrridine).
  • the sensing device (110) can be immersed in the body fluid to measure the targeted analyte.
  • unwanted substance or molecule is filtered out from the sample as the sample flows through the filter layer (118).
  • current path of the sample is buffered as the sample resides in the buffer layer (117) by providing electrical conductivity across the buffer layer (117).
  • a voltage bias is determined by examining its oxidation potential in cyclic voltammetry plots between 0 to 1 V and the voltage bias is provided by the biasing circuit (150) to the counter electrode (114).
  • the sensing electrode (115) selectively oxidizes the targeted analyte in the sample.
  • the voltage signal from the sensing electrode (115) supplied by the biasing circuit (150) is converted to oxidation current signal by the current measurement circuit (130).
  • the oxidation current value obtained is then referenced to a plotted graph of oxidation current versus the analyte concentration level to determine the concentration level of the targeted analyte in the body fluid as in step 206.
  • the determined concentration level of the targeted analyte can be transmitted to a centralized system for storing and monitoring the concentration level of the targeted analyte over a period of time.
  • the trend of the analyte concentration level can be used to trigger an alert if the analyte concentration level surpasses or approaching a threshold concentration level.
  • An exemplary method of preparing a sensing device (110) of the analyte sensor system (100) is provided herein below.
  • the analyte sensor system (100) is used for measuring concentration of uric acid in a body fluid.
  • Graphite-CNT-ferrocene composite paste was screen printed over metal stencil onto a silver layer in a sensing electrode window.
  • the composite thick film was cured in the oven at 120 °C under continuous flow of nitrogen for 15 minutes to afford a dry thickness of 60 ⁇ .
  • matte carbon paste and silver-silver chloride paste were printed on a counter electrode window and a reference electrode window respectively. Each printed paste was cured in the oven at 120 °C under continuous flow of nitrogen for 15 minutes to afford a dry thickness of 60 ⁇ .
  • Example 2 Calibration Measurement of Body Metabolite
  • An exemplary method of calibrating the analyte sensor system (100) for measuring concentration of uric acid is provided herein below.
  • Four calibration solutions were prepared by sparingly diluting soluble uric acid of varying concentrations in deionized water and buffered with phosphate at pH7.
  • the calibration solutions were dropped onto the sensing device or alternatively the sensing device could be immersed into each solution. In the latter approach it is important to avoid electrical shorting at the electrical contacts as the sensing device is immersed into the solutions.
  • a direct current (DC) voltage of 0.6 VDC was provided during the measurement of concentration level of the uric acid in each calibration solution.
  • Table 2 shows oxidation voltage and current peaks at a biasing voltage of 0.6 VDC for the calibration solutions
  • FIG. 4 shows a graph plot of oxidation current (mA) versus concentrations of uric acid (mM) of the calibration solutions.
  • Table 2 shows oxidation current (mA) versus concentrations of uric acid (mM)
  • the analyte sensor system (100) can be applied as a wearable sensor system whereby the sensing device (110) is directly in contact with sweat to allow direct measurement of analytes in a body fluid such as sweat.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Electrochemistry (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hematology (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Investigating Or Analyzing Materials By The Use Of Electric Means (AREA)

Abstract

La présente invention concerne un système détecteur d'analyte (100) pour déterminer la concentration d'un analyte ciblé dans un fluide corporel. Le système détecteur d'analyte (100) se compose d'un dispositif de détection (110), d'un circuit de mesure de courant (130) connecté au dispositif de détection (110), d'un circuit de polarisation (150) connecté au dispositif de détection (110), et d'un circuit de référence de tension (170) connecté au dispositif de détection (110). Le système détecteur d'analyte (100) oxyde de façon sélective l'analyte ciblé et, en conséquence, produit un courant d'oxydation qui est indicateur de la concentration de l'analyte ciblé dans le fluide corporel.
PCT/MY2012/000125 2011-06-20 2012-06-18 Système détecteur d'analyte Ceased WO2012177114A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
MYPI2011700092 2011-06-20
MYPI2011700092 2011-06-20

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WO2012177114A1 true WO2012177114A1 (fr) 2012-12-27

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102013201705A1 (de) * 2013-02-01 2014-08-07 Schunk Wien Gesellschaft M.B.H. Überwachungseinrichtung zum Nachweis einer Flüssigkeit
CN104990971A (zh) * 2015-01-29 2015-10-21 河南工业大学 一种用于磺胺类兽药残留检测的电化学传感器制备方法
DE212014000253U1 (de) 2014-03-03 2016-11-18 Obschestvo S Ogranichennoi Otvetstvennostju Taksi Kobra Mobile anschauliche Werbung auf Landfahrzeugen (Varianten)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6241862B1 (en) * 1996-02-14 2001-06-05 Inverness Medical Technology, Inc. Disposable test strips with integrated reagent/blood separation layer
EP1197751A2 (fr) * 2000-10-14 2002-04-17 Endress + Hauser Conducta Gesellschaft für Mess- und Regeltechnik mbH + Co. Procédé ampérométrique de mesure et de détection et appareil pour son utilisation
US6966977B2 (en) * 2000-07-31 2005-11-22 Matsushita Electric Industrial Co., Ltd. Biosensor
US20080169800A1 (en) * 2007-01-17 2008-07-17 Wen-Yaw Chung Signal readout circuit for amperometric sensor

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6241862B1 (en) * 1996-02-14 2001-06-05 Inverness Medical Technology, Inc. Disposable test strips with integrated reagent/blood separation layer
US6966977B2 (en) * 2000-07-31 2005-11-22 Matsushita Electric Industrial Co., Ltd. Biosensor
EP1197751A2 (fr) * 2000-10-14 2002-04-17 Endress + Hauser Conducta Gesellschaft für Mess- und Regeltechnik mbH + Co. Procédé ampérométrique de mesure et de détection et appareil pour son utilisation
US20080169800A1 (en) * 2007-01-17 2008-07-17 Wen-Yaw Chung Signal readout circuit for amperometric sensor

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102013201705A1 (de) * 2013-02-01 2014-08-07 Schunk Wien Gesellschaft M.B.H. Überwachungseinrichtung zum Nachweis einer Flüssigkeit
DE212014000253U1 (de) 2014-03-03 2016-11-18 Obschestvo S Ogranichennoi Otvetstvennostju Taksi Kobra Mobile anschauliche Werbung auf Landfahrzeugen (Varianten)
CN104990971A (zh) * 2015-01-29 2015-10-21 河南工业大学 一种用于磺胺类兽药残留检测的电化学传感器制备方法
CN104990971B (zh) * 2015-01-29 2017-09-26 河南工业大学 一种用于磺胺类兽药残留检测的电化学传感器制备方法

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