CA2045616C - Enzyme electrochemical sensor electrode and method of making it - Google Patents
Enzyme electrochemical sensor electrode and method of making itInfo
- Publication number
- CA2045616C CA2045616C CA002045616A CA2045616A CA2045616C CA 2045616 C CA2045616 C CA 2045616C CA 002045616 A CA002045616 A CA 002045616A CA 2045616 A CA2045616 A CA 2045616A CA 2045616 C CA2045616 C CA 2045616C
- Authority
- CA
- Canada
- Prior art keywords
- enzyme
- oxidase
- conductor
- glucose
- electrochemical sensor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/001—Enzyme electrodes
- C12Q1/002—Electrode membranes
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S435/00—Chemistry: molecular biology and microbiology
- Y10S435/817—Enzyme or microbe electrode
Abstract
An electrochemical sensor electrode is formed from an electronic conductor (26) coated with a matrix (28) containing a perfluorosulfonic acid ionomer and a selected enzyme. The selected enzyme catalyzes a reaction between a predetermined substance in a solution and oxygen to form an electrochemically active compound that is detected at the electronic conductor. The resulting perfluorosulfonic acid polymer provides a stable matrix for the enzyme fox long lived enzyme activity, wherein only thin coatings are required on the metal conductor. The polymer also advantageously repels interfering substances from contacting the enzyme and contains quantities of oxygen to maintain a sensing capability during conditions of oxygen depletion in the sample. In one particular embodiment, glucose oxidase is mixed with the perfluorosulfonic acid ionomer to form an electrode for glucose detection.
Description
- WO91/09~ PCT/US90/07136 2 ~ 6 ENZY~E EL~CTRICAT. CrNSOR ~ T...CTROD~ AND ~ET~OD OF MAKTI~G TT
BACKGROUND OF INVENTION
This invention generally relates to enzyme electrochemical sensors and, more particularly, to enzyme electrodes. This invention is the result of a contract 05 with the Department of Energy (Contract No.
W-7405-ENG-36).
Enzyme electrodes are a class of devices that incorporate an enzyme as a catalyzing element on an conventional electrode. The enzyme is placed adjacent the electrode and catalyzes a reaction with a selected substance in which an electroactive species is f ormed (or consumed) and detected by the electrode to produce a signal functionally related to the amount of the selected substance adjacent the electrode. In potential medical applications of such sensors, small amounts of various substances contained in a body environment can be measured. Such substances may include glucose, urea, uric acid, triglycerides, amino acids, lactic acid, etc.
Glucose concentrations are a particularly important indicator of various body conditions, e.g., diabetes, and glucose sensors may be combined with other devices to correct abnormal conditions.
: - ~
2 û ~ 5 6 ~ 6 By way of example, the enzyme glucose oxidase catalyzes the reaction of glucose with oxygen to produce gluconic acid and hydrogen peroxide. The presence of the hydrogen peroxide can be detected by an adjacent electrode and the amount of hydrogen peroxide can be determined, whereby the glucose concentration in the material adjacent the enzyme is then known. Conventionally, a selected enzyme is held adjacent the sample material by encapsulating the enzyme between membranes of a polymer suitable for passage of the material to be measured, by including the enzyme in the pore spaces of a suitable membrane, or by forming a membrane which incorporates the enzyme.
U.S. Patent 4,415,666, issued November 15, 1983, to D'Orazio et al teaches the use of cellulose acetate and copolymers of cellulose acetate to form a multilayer membrane, incorporating an enzyme in one layer. Numerous disadvantages of the prior art are discussed therein: cellophane membranes can pass interfering high molecular weight substances adjacent the enzyme; thin filter membranes can prevent the passage of interfering materials, but must be too thin to maintain electrode responsiveness to be of practical use; laminated structures require an enzyme adhesive to bond layers together and are subject to delamination; only low enzyme loadings are possible. The sensor taught by the '666 patent attempts to solve these problems by forming a two layer membrane of a cellulose acetate where the glucose oxidase is incorporated within one of the layers to immobilize the enzyme and to allow higher loadings of enzyme to be incorporated within the membrane.
An outer layer of a higher density cellulose acetate is formed to contact the sample to preclude passage of interfering materials.
The enzyme-containing cellulose acetate layer is formed directly on A
BACKGROUND OF INVENTION
This invention generally relates to enzyme electrochemical sensors and, more particularly, to enzyme electrodes. This invention is the result of a contract 05 with the Department of Energy (Contract No.
W-7405-ENG-36).
Enzyme electrodes are a class of devices that incorporate an enzyme as a catalyzing element on an conventional electrode. The enzyme is placed adjacent the electrode and catalyzes a reaction with a selected substance in which an electroactive species is f ormed (or consumed) and detected by the electrode to produce a signal functionally related to the amount of the selected substance adjacent the electrode. In potential medical applications of such sensors, small amounts of various substances contained in a body environment can be measured. Such substances may include glucose, urea, uric acid, triglycerides, amino acids, lactic acid, etc.
Glucose concentrations are a particularly important indicator of various body conditions, e.g., diabetes, and glucose sensors may be combined with other devices to correct abnormal conditions.
: - ~
2 û ~ 5 6 ~ 6 By way of example, the enzyme glucose oxidase catalyzes the reaction of glucose with oxygen to produce gluconic acid and hydrogen peroxide. The presence of the hydrogen peroxide can be detected by an adjacent electrode and the amount of hydrogen peroxide can be determined, whereby the glucose concentration in the material adjacent the enzyme is then known. Conventionally, a selected enzyme is held adjacent the sample material by encapsulating the enzyme between membranes of a polymer suitable for passage of the material to be measured, by including the enzyme in the pore spaces of a suitable membrane, or by forming a membrane which incorporates the enzyme.
U.S. Patent 4,415,666, issued November 15, 1983, to D'Orazio et al teaches the use of cellulose acetate and copolymers of cellulose acetate to form a multilayer membrane, incorporating an enzyme in one layer. Numerous disadvantages of the prior art are discussed therein: cellophane membranes can pass interfering high molecular weight substances adjacent the enzyme; thin filter membranes can prevent the passage of interfering materials, but must be too thin to maintain electrode responsiveness to be of practical use; laminated structures require an enzyme adhesive to bond layers together and are subject to delamination; only low enzyme loadings are possible. The sensor taught by the '666 patent attempts to solve these problems by forming a two layer membrane of a cellulose acetate where the glucose oxidase is incorporated within one of the layers to immobilize the enzyme and to allow higher loadings of enzyme to be incorporated within the membrane.
An outer layer of a higher density cellulose acetate is formed to contact the sample to preclude passage of interfering materials.
The enzyme-containing cellulose acetate layer is formed directly on A
3 ~ n 4 S ~ ~ ~
the high density layer to produce a substantially integral membrane. A membrane thickness of about 1 - 10 microns for the first layer and about 40 - 80 microns for the second layer is obtained. The subject membrane is placed in a polarograph having an electrolyte containing oxygen for generating hydrogen peroxide adjacent the cell electrode for sensing. The outer layer is also required to limit the flux of glucose adjacent the enzyme to preclude nonlinear signals arising from oxygen depletion in the membrane.
It would be desirable to provide the enzyme in a thin layer, i.e. less than about lO microns thick, adjacent the electrode for a rapid response time for glucose concentration changes. The prior art electrodes also require an adjacent source of oxygen to maintain the enzyme reaction and hence, are sensitive to local oxygen concentrations. It should also be noted that any material forming the sensor must be stable and biocompatible for possible in-vivo use. In addition, it is desirable to minimize interference from other oxidizable substances in a blood environment, such as ascorbic acid and uric acid.
The use of perfluorosulfonic acid polymers and particularly Nafion (a trademark of Du Pont Company), as a protective membrane for use with glucose oxidase is taught by Harrison et al, "Characterization of Perfluorosulfonic Acid Polymer Coated Enzyme Electrodes and a Miniaturized Integrated Potentiostat for Glucose Analysis in Whole Blood,'l 60 Anal. Chem., No. 19, pp. 2002 - 2007 (October 1, 1988). Enzyme-coated ion-sensitive field effect transistors (ISFET) were coated with Nafion to form a semipermeable membrane over the enzyme layer that reduced the sensitivity to ~2 tension and provided satisfactory electrochemical performance, 30 i.e. was semipermeable to glucose, protected the enzyme WO9l/09~ PCT/US90/071~
2 ~
layer, was biocompatible, and obtained reproducible results. A device having a Nafion layer thickness of 1.7 microns was successf~lly operated in whole blood sample for about six days before the Nafion layer separated from a 05 glass shroud around the electrode. The 1.7 micron thickness of Nafion provided a signal response at glucose concentrations as low as 1.2 mM. However, a linear response was obtained at glucose concentrations only up to 28mM and the response time was 5-17 s. Harrison et al.
also note problems with adhering the Nafion. Further, any openings in the Nafion cover wc~ld expose the enzyme to the material under test, resulting in degradation of the enzyme.
These and other problems of the prior art are addressed by the present invention and an improved enzyme electrochemical sensor is provided.
one object of the present invention is to provide a suitable enzyme adjacent the sensor electrode in a matrix in which the enzyme is not subject to degradation from the material under test.
Another object of the invention is to provide a thin enzyme layer having enhanced response times.
Yet another object is to provide an enzyme in a matrix which precludes interference from undesired oxidizable components in the material to be tested.
one other object of the invention is to provide an electrochemical sensor with a greatly reduced sensitivity to the oxygen tension adjacent the membrane.
Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following or may be learned by practice of the invention. The objects and .. . I
- WO91/09~ PCT/US90/07136 2~ 6~ ~;
advantages of the invention may be realized and attained by means of the instrumentalities and combinations particularly pointed out in the appended claims.
SUMMARY OF THE INVENTION
05 TG achieve the foregoing and other objects, and in accordance with the purposes of the present invention, as embodied and broadly described herein, the apparatus of this invention may comprise an electrochemical sensor electrode having an electronic conductor with a thin coatin~ of a persulfonic acid polymer having an enzyme dispersed therein effective to catalyze a reaction between a selected substance and oxygen to generate hydrogen peroxide in said poiymer for detection by said conductor.
- In a particular embodim2nt, the perfluorosulfonic acid 15 polymer with the dispersed enz~e forms a single coating on said electronic conductor in contact with a solution ~; containing the selected substance.
In another characterization of the present invention, an electrochemical sensor electrode is fabricated from a 20 casting solution containing a perfluorosulfonic acid ionomer and an enzyme selected to determine the concentration of a predetermined substance. The perfluorosulfonic acid ionomer is provided in an alcohol solution which is neutralized to a pH which does not affect 25 the enzyme. The enzyme is then added to the ionomer solution in an amount effective to provide a desired sensitivity for the expected concentration of the predetermined substance. The ionomer solution with the enzyme is then applied to the electronic conductor to form 30 the electrochemical sensor electrode.
BRIEF DESCRIPTION OF THE DRAWINGS
The ac~o ,~nying drawings, which are incorporated in and form a part of the specification, illustrate 4 PCT/US~/071~
2~&~
embodiments of the present invention and, together with the description, serve to explain the principles of the invention. In the drawings:
FIGURE l is a schematic representation of an oS electrochemical sensor according to the present invention.
FIGURE 2 is a graphical representation showing the output stability of an electrochemical sensor in accordance with the present invention.
FIGURE 3 is a graphical representation of the output response to a range of glucose concentrations of one embodiment of an electrochemiczl sensor in accordance with the present invention.
DETAILED DESC~IPTION OF THE INVENTION
In accordance with the present invention, a casting solution of a perfluorosulfonic acid ionomer and an enzyme is prepared and an electrode conductor is coated with the solution to form a film containing the enzyme to a thickness which provides the amount of enzyme needed to obtain a preselected sensitivity with a desired response time to changes in the concentration of a selected material having a reaction with oxygen that is catalyzed by the enzyme. The integrated film can be cast as a membrane or cast directly on an electrode conductor surface without concerns for degrading the enzyme. The perfluorosulfonic acid polymer which is formed provides an insoluble biocompatible matrix for the enzyme and the enzyme is protected against bacterial degradation from an in-vivo or in-vitro environment. Further, the enzyme remains available for continued use in the electrode structure.
The perfluorosulfonic acid polymer also dissolves large quantities of oxygen that is then available adjacent the enzyme to promote hydrogen peroxide formation for signal generation.
WOgl/09304 PCT/US~/07136 In a particular embodiment, a glucose sensitive electrode was formed using perfluorosulfonic acid ionomer and glucose oxi~ase. A perfluorosulfonic acid ionomer, Nafion, is commercially available as a solution in Q5 alcohol/water mixtures, typically at 5~ by weight of Nafion. The Nafion solution was diluted a substantial amount, e.g., tenfold, by the addition of a phosphate bu~fer (pH = 7) and glucose oxidase was added to the buffered solution. The resulting solution can then be applied to an electrode by topical application for flat electrodes or by dip coating for meshes and wires. Typical layer thicknesses of 3 microns or less are satisfactory.
As hereinafter shown, the enzyme coating prepared in accordance with the present invention to form an enzyme electrode provides improved performance features over prior art electrochemical sensor electrodes. The electrode is easily fabricated, needing only a single layer of the active Nafion-enzyme material on the electrode conductor.
The resulting thin coating provides a rapid response time (2-4 seconds at most) to glucose additions and responds over a wide range of glucose concentrations (at least 1-110 mM) before saturating. The perfluorosulfonate also dissociates in the presence of water in the sample. The resulting negatively charged ions are believed to exclude interfering anions such as ascorbate or ureate. Further, the composite material is extremely stable and exhibits substantial, and nearly constant, performance over a long period of time. The high solubility of oxygen in the Nafion matrix that includes the enzyme catalyst also stabilizes the response and offers potential advantages for electrode use in hypoxic envlronments or in applications involving high glucose concentrations. The casting mixture (20 ~1) formed according to Example 1., below, was WO91/09~ PCT/US90/07136 2 ~
applied to a Pt rotating disc electrode (area = 0.531 cm2) and air dried for about 30 minutes. The resulting coating includes about 4 ~g of enzyme per 100 ~g of Nafion.
1. Dilute a commercial 5% Nafion solution (Solution Technologies) by a factor of lO using water.
2. Adjust solution to pH = 7.2 with NaOH and phosphate buffer solution.
3. Add glucose oxidase to the dilute Nafion solution (50 ~1 of 10 mg/ml glucose oxidase solution added to 2.5 ml Nafion solution).
4. Apply casting mixture to electrode structure.
It will be appreciated that the perfluorosulfonic acid (Nafion) disassociates in water to form a highly acidic solution that would denature the enzyme. According to the present invention, the enzyme activity is maintained by substantially neutralizing the acidic solution before mixing the enzyme into the perfluorosulfonic acid solution. Once the enzyme is added to form a casting solution, the mixture is promptly applied to the conductive electrode structure and cured to form the composite electrochemical sensor electrode. Surprisingly, the enzyme activity in the composite electrode is then maintained in the perfluorosulfonic acid polymer matrix containing the enzyme.
Referring now to Figure 1, electrochemical sensor assembly 10 was constructed to incorporate an enzyme electrode according to the present invention. A
conventional assembly of electrodes, i.e., reference electrode 14, counter electrode 16, and sensing electrode electrode 18, was placed in a sample solution 12, e.g.
glucose solution. Sensing electrode 18 includes signal ~ ~ 4 5 ~ ~ 6 lead 22 supported by rod 24, which may be Teflon and connected to metal conductor electrode 26. Enzyme matrix 28, formed according to Example 1, was formed on the surface of metal electrode 26 that faces solution 12 and contacts solution 12 to generate an electroactive material as hereinabove discussed.
The response of sensor electrodes constructed as above was determined for glucose additions to phosphate buffer solutions.
The response was determined for a concentration increase of 0.113 M of glucose oxidase in the phosphate buffer. The response time is defined to be the time taken from the point of glucose injection until a higher, steady state current is achieved. This was typically 2 - 4 seconds for the test sensors having a Nafion-glucose oxidase layer thickness of about 3 microns. A layer thickness of 1 - 10 microns provides adequate performance.
Further, the sensors exhibited stable performance over a test period of over 50 days, as shown in Figure 2. An initial high level of electrode performance is generally observed for the electrodes followed by a substantially constant performance showing a general maintenance of enzyme activity over the test period.
Figure 3 shows a typical response of the enzyme sensor to successive additions of glucose. The current measured at the electrode responds well to stepped increases in glucose concentrations from lmM to 113 mM. This range of glucose concentrations is substantially larger than the glucose range achievable with other known glucose sensors, indicating the capability of the perfluorosulfonic acid matrix to maintain an adequate oxygen supply adjacent the enzyme. Figure 3 also illustrates the response of the electrode to purging of oxygen from the system by bubbling argon gas through a phosphate buffer solution to which WO91/~ PCT/US~/071~
20~56~6 glucose had been added. After one hour of treatment, the electrode current was still 40% of the initial value, indicating th~ effect of oxygen retention in the Nafion and concomitant reduced sensitivity to local oxygen OS concentrations in the tested medium.
An electrochemical sensor according to the present invention, including a rotating disk electrode conductor, was also tested in human serum samples. The response of the sensor to additions of glucose to the serum was similar to the response measured with phosphate buffer solutions.
The addition of 2 mM glucose was readily detected with a response time of 2-4 seconds.
While the electrode performance shown in Figures 2 and 3 was obtained using sensors formed in accordance with the procedure of Example 1, a wide range of equivalent casting solution mixtures can be used. By way of example, the effect of alcohol content on the sensor activity was determined by replacing various fractions of the phosphate buffer diluent of the 5% Nafion solution with ethanol while 20 maintaining a constant Nafion and enzyme content. Sensors of satisfactory activity were obtained for casting solutions containing up to 40% alcohol by weight, although a limiting concentration of alcohol has not been determined.
Enzyme loadings of 4, 20, and 100 mg glucose oxidase per gram Nafion were found to respond adequately to glucose changes. Table A illustrates the sensor's response to 16mM
glucose in solution. It can be seen that the sensor sensitivity (current/loading ratio) is relatively constant.
, 2 ~ 4 5 6 ~ 6 TABLE A
mq qlucose oxidase/q Nafion Current (~) Sensitivity 4 0.70 0.175 4.0 0.20 100 19.8 0.198 A protective layer of Nafion without glucose oxidase was added to the electrochemical sensor electrode structure in order to determine the effect on the enzyme film performance. Although there was no observed effect on the electrochemical sensor electrode response time from the Nafion layer, there was a decrease of about 75~ in the sensor activity. The protective Nafion film was about 1 ~m thick over the 1 ~m thick enzyme film.
It will also be appreciated that the present invention is not limited to use with the enzyme glucose oxidase. Many other enzymes react with specific substances to produce hydrogen peroxide for generating an electrical signal functionally related to the presence of such specific substances. Suitable enzymes include galactose oxidase, alcohol oxidase, lactic acid oxidase, amino acid oxidase and cholesterol oxidase. The relative equivalence of these enzymes for use in electrochemical sensors is shown in U.S. Patent 4,795,707, issued January 3, 1989, to Niiyama et al, which may be referred to for further details. Such enzymes which produce hydrogen peroxide in the presence of a specific substance may be incorporated in a perfluorosulfonic acid polymer in accordance with the present invention to form a stable, sensitive electrochemical sensor electrode.
WO91/09304 20 4~ i PCT/US90/07136 The foregoing description of various embodiments of the invention have been presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise form disclosed, and 05 obviously many modifications and variations are possible in light of the above teaching. The embodinents were chosen and described in order to best explain the principles of the invention and its practical application to thereby enable others skilled in the art to best utilize the invention in various embodiments and with various modifications as are suited to the particular use contemplated. It is- intended that the scope of the invention be defined by the claims appended hereto.
the high density layer to produce a substantially integral membrane. A membrane thickness of about 1 - 10 microns for the first layer and about 40 - 80 microns for the second layer is obtained. The subject membrane is placed in a polarograph having an electrolyte containing oxygen for generating hydrogen peroxide adjacent the cell electrode for sensing. The outer layer is also required to limit the flux of glucose adjacent the enzyme to preclude nonlinear signals arising from oxygen depletion in the membrane.
It would be desirable to provide the enzyme in a thin layer, i.e. less than about lO microns thick, adjacent the electrode for a rapid response time for glucose concentration changes. The prior art electrodes also require an adjacent source of oxygen to maintain the enzyme reaction and hence, are sensitive to local oxygen concentrations. It should also be noted that any material forming the sensor must be stable and biocompatible for possible in-vivo use. In addition, it is desirable to minimize interference from other oxidizable substances in a blood environment, such as ascorbic acid and uric acid.
The use of perfluorosulfonic acid polymers and particularly Nafion (a trademark of Du Pont Company), as a protective membrane for use with glucose oxidase is taught by Harrison et al, "Characterization of Perfluorosulfonic Acid Polymer Coated Enzyme Electrodes and a Miniaturized Integrated Potentiostat for Glucose Analysis in Whole Blood,'l 60 Anal. Chem., No. 19, pp. 2002 - 2007 (October 1, 1988). Enzyme-coated ion-sensitive field effect transistors (ISFET) were coated with Nafion to form a semipermeable membrane over the enzyme layer that reduced the sensitivity to ~2 tension and provided satisfactory electrochemical performance, 30 i.e. was semipermeable to glucose, protected the enzyme WO9l/09~ PCT/US90/071~
2 ~
layer, was biocompatible, and obtained reproducible results. A device having a Nafion layer thickness of 1.7 microns was successf~lly operated in whole blood sample for about six days before the Nafion layer separated from a 05 glass shroud around the electrode. The 1.7 micron thickness of Nafion provided a signal response at glucose concentrations as low as 1.2 mM. However, a linear response was obtained at glucose concentrations only up to 28mM and the response time was 5-17 s. Harrison et al.
also note problems with adhering the Nafion. Further, any openings in the Nafion cover wc~ld expose the enzyme to the material under test, resulting in degradation of the enzyme.
These and other problems of the prior art are addressed by the present invention and an improved enzyme electrochemical sensor is provided.
one object of the present invention is to provide a suitable enzyme adjacent the sensor electrode in a matrix in which the enzyme is not subject to degradation from the material under test.
Another object of the invention is to provide a thin enzyme layer having enhanced response times.
Yet another object is to provide an enzyme in a matrix which precludes interference from undesired oxidizable components in the material to be tested.
one other object of the invention is to provide an electrochemical sensor with a greatly reduced sensitivity to the oxygen tension adjacent the membrane.
Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following or may be learned by practice of the invention. The objects and .. . I
- WO91/09~ PCT/US90/07136 2~ 6~ ~;
advantages of the invention may be realized and attained by means of the instrumentalities and combinations particularly pointed out in the appended claims.
SUMMARY OF THE INVENTION
05 TG achieve the foregoing and other objects, and in accordance with the purposes of the present invention, as embodied and broadly described herein, the apparatus of this invention may comprise an electrochemical sensor electrode having an electronic conductor with a thin coatin~ of a persulfonic acid polymer having an enzyme dispersed therein effective to catalyze a reaction between a selected substance and oxygen to generate hydrogen peroxide in said poiymer for detection by said conductor.
- In a particular embodim2nt, the perfluorosulfonic acid 15 polymer with the dispersed enz~e forms a single coating on said electronic conductor in contact with a solution ~; containing the selected substance.
In another characterization of the present invention, an electrochemical sensor electrode is fabricated from a 20 casting solution containing a perfluorosulfonic acid ionomer and an enzyme selected to determine the concentration of a predetermined substance. The perfluorosulfonic acid ionomer is provided in an alcohol solution which is neutralized to a pH which does not affect 25 the enzyme. The enzyme is then added to the ionomer solution in an amount effective to provide a desired sensitivity for the expected concentration of the predetermined substance. The ionomer solution with the enzyme is then applied to the electronic conductor to form 30 the electrochemical sensor electrode.
BRIEF DESCRIPTION OF THE DRAWINGS
The ac~o ,~nying drawings, which are incorporated in and form a part of the specification, illustrate 4 PCT/US~/071~
2~&~
embodiments of the present invention and, together with the description, serve to explain the principles of the invention. In the drawings:
FIGURE l is a schematic representation of an oS electrochemical sensor according to the present invention.
FIGURE 2 is a graphical representation showing the output stability of an electrochemical sensor in accordance with the present invention.
FIGURE 3 is a graphical representation of the output response to a range of glucose concentrations of one embodiment of an electrochemiczl sensor in accordance with the present invention.
DETAILED DESC~IPTION OF THE INVENTION
In accordance with the present invention, a casting solution of a perfluorosulfonic acid ionomer and an enzyme is prepared and an electrode conductor is coated with the solution to form a film containing the enzyme to a thickness which provides the amount of enzyme needed to obtain a preselected sensitivity with a desired response time to changes in the concentration of a selected material having a reaction with oxygen that is catalyzed by the enzyme. The integrated film can be cast as a membrane or cast directly on an electrode conductor surface without concerns for degrading the enzyme. The perfluorosulfonic acid polymer which is formed provides an insoluble biocompatible matrix for the enzyme and the enzyme is protected against bacterial degradation from an in-vivo or in-vitro environment. Further, the enzyme remains available for continued use in the electrode structure.
The perfluorosulfonic acid polymer also dissolves large quantities of oxygen that is then available adjacent the enzyme to promote hydrogen peroxide formation for signal generation.
WOgl/09304 PCT/US~/07136 In a particular embodiment, a glucose sensitive electrode was formed using perfluorosulfonic acid ionomer and glucose oxi~ase. A perfluorosulfonic acid ionomer, Nafion, is commercially available as a solution in Q5 alcohol/water mixtures, typically at 5~ by weight of Nafion. The Nafion solution was diluted a substantial amount, e.g., tenfold, by the addition of a phosphate bu~fer (pH = 7) and glucose oxidase was added to the buffered solution. The resulting solution can then be applied to an electrode by topical application for flat electrodes or by dip coating for meshes and wires. Typical layer thicknesses of 3 microns or less are satisfactory.
As hereinafter shown, the enzyme coating prepared in accordance with the present invention to form an enzyme electrode provides improved performance features over prior art electrochemical sensor electrodes. The electrode is easily fabricated, needing only a single layer of the active Nafion-enzyme material on the electrode conductor.
The resulting thin coating provides a rapid response time (2-4 seconds at most) to glucose additions and responds over a wide range of glucose concentrations (at least 1-110 mM) before saturating. The perfluorosulfonate also dissociates in the presence of water in the sample. The resulting negatively charged ions are believed to exclude interfering anions such as ascorbate or ureate. Further, the composite material is extremely stable and exhibits substantial, and nearly constant, performance over a long period of time. The high solubility of oxygen in the Nafion matrix that includes the enzyme catalyst also stabilizes the response and offers potential advantages for electrode use in hypoxic envlronments or in applications involving high glucose concentrations. The casting mixture (20 ~1) formed according to Example 1., below, was WO91/09~ PCT/US90/07136 2 ~
applied to a Pt rotating disc electrode (area = 0.531 cm2) and air dried for about 30 minutes. The resulting coating includes about 4 ~g of enzyme per 100 ~g of Nafion.
1. Dilute a commercial 5% Nafion solution (Solution Technologies) by a factor of lO using water.
2. Adjust solution to pH = 7.2 with NaOH and phosphate buffer solution.
3. Add glucose oxidase to the dilute Nafion solution (50 ~1 of 10 mg/ml glucose oxidase solution added to 2.5 ml Nafion solution).
4. Apply casting mixture to electrode structure.
It will be appreciated that the perfluorosulfonic acid (Nafion) disassociates in water to form a highly acidic solution that would denature the enzyme. According to the present invention, the enzyme activity is maintained by substantially neutralizing the acidic solution before mixing the enzyme into the perfluorosulfonic acid solution. Once the enzyme is added to form a casting solution, the mixture is promptly applied to the conductive electrode structure and cured to form the composite electrochemical sensor electrode. Surprisingly, the enzyme activity in the composite electrode is then maintained in the perfluorosulfonic acid polymer matrix containing the enzyme.
Referring now to Figure 1, electrochemical sensor assembly 10 was constructed to incorporate an enzyme electrode according to the present invention. A
conventional assembly of electrodes, i.e., reference electrode 14, counter electrode 16, and sensing electrode electrode 18, was placed in a sample solution 12, e.g.
glucose solution. Sensing electrode 18 includes signal ~ ~ 4 5 ~ ~ 6 lead 22 supported by rod 24, which may be Teflon and connected to metal conductor electrode 26. Enzyme matrix 28, formed according to Example 1, was formed on the surface of metal electrode 26 that faces solution 12 and contacts solution 12 to generate an electroactive material as hereinabove discussed.
The response of sensor electrodes constructed as above was determined for glucose additions to phosphate buffer solutions.
The response was determined for a concentration increase of 0.113 M of glucose oxidase in the phosphate buffer. The response time is defined to be the time taken from the point of glucose injection until a higher, steady state current is achieved. This was typically 2 - 4 seconds for the test sensors having a Nafion-glucose oxidase layer thickness of about 3 microns. A layer thickness of 1 - 10 microns provides adequate performance.
Further, the sensors exhibited stable performance over a test period of over 50 days, as shown in Figure 2. An initial high level of electrode performance is generally observed for the electrodes followed by a substantially constant performance showing a general maintenance of enzyme activity over the test period.
Figure 3 shows a typical response of the enzyme sensor to successive additions of glucose. The current measured at the electrode responds well to stepped increases in glucose concentrations from lmM to 113 mM. This range of glucose concentrations is substantially larger than the glucose range achievable with other known glucose sensors, indicating the capability of the perfluorosulfonic acid matrix to maintain an adequate oxygen supply adjacent the enzyme. Figure 3 also illustrates the response of the electrode to purging of oxygen from the system by bubbling argon gas through a phosphate buffer solution to which WO91/~ PCT/US~/071~
20~56~6 glucose had been added. After one hour of treatment, the electrode current was still 40% of the initial value, indicating th~ effect of oxygen retention in the Nafion and concomitant reduced sensitivity to local oxygen OS concentrations in the tested medium.
An electrochemical sensor according to the present invention, including a rotating disk electrode conductor, was also tested in human serum samples. The response of the sensor to additions of glucose to the serum was similar to the response measured with phosphate buffer solutions.
The addition of 2 mM glucose was readily detected with a response time of 2-4 seconds.
While the electrode performance shown in Figures 2 and 3 was obtained using sensors formed in accordance with the procedure of Example 1, a wide range of equivalent casting solution mixtures can be used. By way of example, the effect of alcohol content on the sensor activity was determined by replacing various fractions of the phosphate buffer diluent of the 5% Nafion solution with ethanol while 20 maintaining a constant Nafion and enzyme content. Sensors of satisfactory activity were obtained for casting solutions containing up to 40% alcohol by weight, although a limiting concentration of alcohol has not been determined.
Enzyme loadings of 4, 20, and 100 mg glucose oxidase per gram Nafion were found to respond adequately to glucose changes. Table A illustrates the sensor's response to 16mM
glucose in solution. It can be seen that the sensor sensitivity (current/loading ratio) is relatively constant.
, 2 ~ 4 5 6 ~ 6 TABLE A
mq qlucose oxidase/q Nafion Current (~) Sensitivity 4 0.70 0.175 4.0 0.20 100 19.8 0.198 A protective layer of Nafion without glucose oxidase was added to the electrochemical sensor electrode structure in order to determine the effect on the enzyme film performance. Although there was no observed effect on the electrochemical sensor electrode response time from the Nafion layer, there was a decrease of about 75~ in the sensor activity. The protective Nafion film was about 1 ~m thick over the 1 ~m thick enzyme film.
It will also be appreciated that the present invention is not limited to use with the enzyme glucose oxidase. Many other enzymes react with specific substances to produce hydrogen peroxide for generating an electrical signal functionally related to the presence of such specific substances. Suitable enzymes include galactose oxidase, alcohol oxidase, lactic acid oxidase, amino acid oxidase and cholesterol oxidase. The relative equivalence of these enzymes for use in electrochemical sensors is shown in U.S. Patent 4,795,707, issued January 3, 1989, to Niiyama et al, which may be referred to for further details. Such enzymes which produce hydrogen peroxide in the presence of a specific substance may be incorporated in a perfluorosulfonic acid polymer in accordance with the present invention to form a stable, sensitive electrochemical sensor electrode.
WO91/09304 20 4~ i PCT/US90/07136 The foregoing description of various embodiments of the invention have been presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise form disclosed, and 05 obviously many modifications and variations are possible in light of the above teaching. The embodinents were chosen and described in order to best explain the principles of the invention and its practical application to thereby enable others skilled in the art to best utilize the invention in various embodiments and with various modifications as are suited to the particular use contemplated. It is- intended that the scope of the invention be defined by the claims appended hereto.
Claims (9)
1. An electrochemical sensor electrode, comprising:
an electronic conductor, and a thin coating on said conductor of a perfluorosulfonic acid polymer having an enzyme dispersed therein effective to catalyze a reaction between a selected substance and oxygen to generate hydrogen peroxide in said polymer for detection at said conductor.
an electronic conductor, and a thin coating on said conductor of a perfluorosulfonic acid polymer having an enzyme dispersed therein effective to catalyze a reaction between a selected substance and oxygen to generate hydrogen peroxide in said polymer for detection at said conductor.
2. An electrochemical sensor electrode according to Claim 1, wherein said enzyme is selected from the group consisting of glucose oxidase, galactose oxidase, alcohol oxidase, lactic acid oxidase, amino acid oxidase, and cholesterol oxidase.
3. An electrochemical sensor electrode according to Claim 1, wherein said coating is 1-10 microns in thickness.
4. An electrochemical sensor electrode, consisting essentially of:
an electronic conductor, and a thin coating on said conductor of a perfluorosulfonic acid polymer having an enzyme dispersed therein effective to catalyze a reaction between a selected substance and oxygen to generate hydrogen peroxide in said polymer for detection at said conductor.
an electronic conductor, and a thin coating on said conductor of a perfluorosulfonic acid polymer having an enzyme dispersed therein effective to catalyze a reaction between a selected substance and oxygen to generate hydrogen peroxide in said polymer for detection at said conductor.
5. An electrochemical sensor electrode according to Claim 4, wherein said enzyme is selected from the group consisting of glucose oxidase, galactose oxidase, alcohol oxidase, lactic acid oxidase, amino acid oxidase, and cholesterol oxidase.
6. A method of making an electrochemical sensor electrode using a selected enzyme to determine the concentration of a predetermined substance, comprising the steps of:
providing an electronic conductor;
providing a perfluorosulfonic acid ionomer in an alcohol solution;
neutralizing said solution to form a pH which does not affect said enzyme;
adding said enzyme to said ionomer solution in an amount effective to provide a desired sensitivity for said concentration of said predetermined substance; and applying said ionomer solution with said enzyme to said conductor.
providing an electronic conductor;
providing a perfluorosulfonic acid ionomer in an alcohol solution;
neutralizing said solution to form a pH which does not affect said enzyme;
adding said enzyme to said ionomer solution in an amount effective to provide a desired sensitivity for said concentration of said predetermined substance; and applying said ionomer solution with said enzyme to said conductor.
7. A method according to Claim 6, wherein said enzyme is selected from the group consisting of glucose oxidase, galactose oxidase, alcohol oxidase, lactic acid oxidase, amino acid oxidase, and cholesterol oxidase.
8. A method according to Claim 6, wherein said ionomer solution with said enzyme is applied to form a coating of 1-10 microns in thickness on said conductor.
9. A method according to Claim 7, wherein said enzyme is glucose oxidase and said effective amount is 4-100 mg glucose oxidase/g perflurosulfonic acid ionomer.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/448,475 US5082550A (en) | 1989-12-11 | 1989-12-11 | Enzyme electrochemical sensor electrode and method of making it |
| US448,475 | 1989-12-11 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2045616A1 CA2045616A1 (en) | 1991-06-12 |
| CA2045616C true CA2045616C (en) | 1997-12-02 |
Family
ID=23780448
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002045616A Expired - Fee Related CA2045616C (en) | 1989-12-11 | 1990-12-10 | Enzyme electrochemical sensor electrode and method of making it |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US5082550A (en) |
| EP (1) | EP0457892B1 (en) |
| JP (1) | JPH04505966A (en) |
| CA (1) | CA2045616C (en) |
| DE (1) | DE69025470T2 (en) |
| WO (1) | WO1991009304A1 (en) |
Families Citing this family (249)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5593852A (en) | 1993-12-02 | 1997-01-14 | Heller; Adam | Subcutaneous glucose electrode |
| CA2050057A1 (en) | 1991-03-04 | 1992-09-05 | Adam Heller | Interferant eliminating biosensors |
| US5225064A (en) * | 1992-01-15 | 1993-07-06 | Enzyme Technology Research Group, Inc. | Peroxidase colloidal gold oxidase biosensors for mediatorless glucose determination |
| US5334296A (en) * | 1992-01-15 | 1994-08-02 | Andcare, Inc. | Peroxidase colloidal gold oxidase biosensors for mediatorless glucose determination |
| US5391272A (en) * | 1992-03-06 | 1995-02-21 | Andcare, Inc. | Electrochemical immunoassay methods |
| US5227042A (en) * | 1992-05-15 | 1993-07-13 | The United States Of America As Represented By The United States Department Of Energy | Catalyzed enzyme electrodes |
| GB9218376D0 (en) * | 1992-08-28 | 1992-10-14 | Cranfield Inst Of Tech | Media for biocatalytic electrochemical reactions in the gaseous phase |
| DE69331150T2 (en) * | 1993-04-22 | 2002-07-18 | Andcare Inc | PEROXYDASE / GOLD COLLOID / OXIDASE BIOSENSORS FOR MEDIATOR-FREE DETERMINATION OF GLUCOSE |
| FR2705148B1 (en) * | 1993-05-12 | 1995-08-04 | Lyon Ecole Centrale | ELECTROCHEMICAL ENZYMATIC ASSET TYPE SENSOR AND ASSAY DEVICE USING THE SAME. |
| US5470448A (en) * | 1994-01-28 | 1995-11-28 | United Technologies Corporation | High performance electrolytic cell electrode/membrane structures and a process for preparing such electrode structures |
| US6329139B1 (en) | 1995-04-25 | 2001-12-11 | Discovery Partners International | Automated sorting system for matrices with memory |
| US6210537B1 (en) * | 1995-06-19 | 2001-04-03 | Lynntech, Inc. | Method of forming electronically conducting polymers on conducting and nonconducting substrates |
| JP3394262B2 (en) * | 1997-02-06 | 2003-04-07 | セラセンス、インク． | Small volume in vitro analyte sensor |
| US6764581B1 (en) * | 1997-09-05 | 2004-07-20 | Abbott Laboratories | Electrode with thin working layer |
| US6893552B1 (en) | 1997-12-29 | 2005-05-17 | Arrowhead Center, Inc. | Microsensors for glucose and insulin monitoring |
| US6103033A (en) * | 1998-03-04 | 2000-08-15 | Therasense, Inc. | Process for producing an electrochemical biosensor |
| US6134461A (en) | 1998-03-04 | 2000-10-17 | E. Heller & Company | Electrochemical analyte |
| AU745414B2 (en) * | 1998-03-20 | 2002-03-21 | Lifescan, Inc. | Sensor with improved shelf life |
| US6652734B1 (en) | 1999-03-16 | 2003-11-25 | Lifescan, Inc. | Sensor with improved shelf life |
| AUPP250398A0 (en) * | 1998-03-20 | 1998-04-23 | Usf Filtration And Separations Group Inc. | Sensor with improved shelf life |
| US9066695B2 (en) * | 1998-04-30 | 2015-06-30 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
| US8480580B2 (en) * | 1998-04-30 | 2013-07-09 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
| US8974386B2 (en) | 1998-04-30 | 2015-03-10 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
| US6949816B2 (en) | 2003-04-21 | 2005-09-27 | Motorola, Inc. | Semiconductor component having first surface area for electrically coupling to a semiconductor chip and second surface area for electrically coupling to a substrate, and method of manufacturing same |
| US6175752B1 (en) * | 1998-04-30 | 2001-01-16 | Therasense, Inc. | Analyte monitoring device and methods of use |
| US8688188B2 (en) | 1998-04-30 | 2014-04-01 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
| US8465425B2 (en) | 1998-04-30 | 2013-06-18 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
| US8346337B2 (en) | 1998-04-30 | 2013-01-01 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
| US6251260B1 (en) | 1998-08-24 | 2001-06-26 | Therasense, Inc. | Potentiometric sensors for analytic determination |
| US6591125B1 (en) | 2000-06-27 | 2003-07-08 | Therasense, Inc. | Small volume in vitro analyte sensor with diffusible or non-leachable redox mediator |
| US6338790B1 (en) * | 1998-10-08 | 2002-01-15 | Therasense, Inc. | Small volume in vitro analyte sensor with diffusible or non-leachable redox mediator |
| US6391549B1 (en) * | 1999-04-01 | 2002-05-21 | Ramont University Authority For Applied Research & Industrial Development Ltd. | Monitoring gene expression |
| EP2322645A1 (en) | 1999-06-18 | 2011-05-18 | Abbott Diabetes Care Inc. | Mass transport limited in vivo analyte sensor |
| US6616819B1 (en) * | 1999-11-04 | 2003-09-09 | Therasense, Inc. | Small volume in vitro analyte sensor and methods |
| US20060091006A1 (en) * | 1999-11-04 | 2006-05-04 | Yi Wang | Analyte sensor with insertion monitor, and methods |
| WO2001088524A1 (en) * | 2000-05-12 | 2001-11-22 | Therasense, Inc. | Electrodes with multilayer membranes and methods of using and making the electrodes |
| US6560471B1 (en) | 2001-01-02 | 2003-05-06 | Therasense, Inc. | Analyte monitoring device and methods of use |
| WO2002078512A2 (en) * | 2001-04-02 | 2002-10-10 | Therasense, Inc. | Blood glucose tracking apparatus and methods |
| US7422646B2 (en) * | 2001-10-22 | 2008-09-09 | Perkinelmer Las, Inc. | Electrochemical sensor with dry ionomer membrane and methodfor making the same |
| US8260393B2 (en) * | 2003-07-25 | 2012-09-04 | Dexcom, Inc. | Systems and methods for replacing signal data artifacts in a glucose sensor data stream |
| US8010174B2 (en) | 2003-08-22 | 2011-08-30 | Dexcom, Inc. | Systems and methods for replacing signal artifacts in a glucose sensor data stream |
| US9247901B2 (en) * | 2003-08-22 | 2016-02-02 | Dexcom, Inc. | Systems and methods for replacing signal artifacts in a glucose sensor data stream |
| JP2004045373A (en) * | 2002-05-21 | 2004-02-12 | Tanita Corp | Electrochemical sensor |
| US7381184B2 (en) | 2002-11-05 | 2008-06-03 | Abbott Diabetes Care Inc. | Sensor inserter assembly |
| US7811231B2 (en) * | 2002-12-31 | 2010-10-12 | Abbott Diabetes Care Inc. | Continuous glucose monitoring system and methods of use |
| US8066639B2 (en) | 2003-06-10 | 2011-11-29 | Abbott Diabetes Care Inc. | Glucose measuring device for use in personal area network |
| US7695239B2 (en) * | 2003-07-14 | 2010-04-13 | Fortrend Engineering Corporation | End effector gripper arms having corner grippers which reorient reticle during transfer |
| US8423113B2 (en) | 2003-07-25 | 2013-04-16 | Dexcom, Inc. | Systems and methods for processing sensor data |
| US7761130B2 (en) * | 2003-07-25 | 2010-07-20 | Dexcom, Inc. | Dual electrode system for a continuous analyte sensor |
| US8160669B2 (en) | 2003-08-01 | 2012-04-17 | Dexcom, Inc. | Transcutaneous analyte sensor |
| US7774145B2 (en) | 2003-08-01 | 2010-08-10 | Dexcom, Inc. | Transcutaneous analyte sensor |
| US9135402B2 (en) | 2007-12-17 | 2015-09-15 | Dexcom, Inc. | Systems and methods for processing sensor data |
| US7494465B2 (en) * | 2004-07-13 | 2009-02-24 | Dexcom, Inc. | Transcutaneous analyte sensor |
| US8275437B2 (en) | 2003-08-01 | 2012-09-25 | Dexcom, Inc. | Transcutaneous analyte sensor |
| US20190357827A1 (en) | 2003-08-01 | 2019-11-28 | Dexcom, Inc. | Analyte sensor |
| US20140121989A1 (en) | 2003-08-22 | 2014-05-01 | Dexcom, Inc. | Systems and methods for processing analyte sensor data |
| US7920906B2 (en) | 2005-03-10 | 2011-04-05 | Dexcom, Inc. | System and methods for processing analyte sensor data for sensor calibration |
| US7306641B2 (en) * | 2003-09-12 | 2007-12-11 | Hewlett-Packard Development Company, L.P. | Integral fuel cartridge and filter |
| US7299082B2 (en) * | 2003-10-31 | 2007-11-20 | Abbott Diabetes Care, Inc. | Method of calibrating an analyte-measurement device, and associated methods, devices and systems |
| USD914881S1 (en) | 2003-11-05 | 2021-03-30 | Abbott Diabetes Care Inc. | Analyte sensor electronic mount |
| US9247900B2 (en) | 2004-07-13 | 2016-02-02 | Dexcom, Inc. | Analyte sensor |
| US8423114B2 (en) | 2006-10-04 | 2013-04-16 | Dexcom, Inc. | Dual electrode system for a continuous analyte sensor |
| WO2005057168A2 (en) | 2003-12-05 | 2005-06-23 | Dexcom, Inc. | Calibration techniques for a continuous analyte sensor |
| US11633133B2 (en) | 2003-12-05 | 2023-04-25 | Dexcom, Inc. | Dual electrode system for a continuous analyte sensor |
| WO2005089103A2 (en) | 2004-02-17 | 2005-09-29 | Therasense, Inc. | Method and system for providing data communication in continuous glucose monitoring and management system |
| US20060010098A1 (en) | 2004-06-04 | 2006-01-12 | Goodnow Timothy T | Diabetes care host-client architecture and data management system |
| US8452368B2 (en) | 2004-07-13 | 2013-05-28 | Dexcom, Inc. | Transcutaneous analyte sensor |
| US7783333B2 (en) | 2004-07-13 | 2010-08-24 | Dexcom, Inc. | Transcutaneous medical device with variable stiffness |
| US8565848B2 (en) * | 2004-07-13 | 2013-10-22 | Dexcom, Inc. | Transcutaneous analyte sensor |
| US20060270922A1 (en) * | 2004-07-13 | 2006-11-30 | Brauker James H | Analyte sensor |
| US20060020192A1 (en) * | 2004-07-13 | 2006-01-26 | Dexcom, Inc. | Transcutaneous analyte sensor |
| US8886272B2 (en) * | 2004-07-13 | 2014-11-11 | Dexcom, Inc. | Analyte sensor |
| JP4643222B2 (en) * | 2004-10-27 | 2011-03-02 | 日機装株式会社 | Biosensor and manufacturing method thereof |
| US20090105569A1 (en) * | 2006-04-28 | 2009-04-23 | Abbott Diabetes Care, Inc. | Introducer Assembly and Methods of Use |
| US8571624B2 (en) | 2004-12-29 | 2013-10-29 | Abbott Diabetes Care Inc. | Method and apparatus for mounting a data transmission device in a communication system |
| US8512243B2 (en) | 2005-09-30 | 2013-08-20 | Abbott Diabetes Care Inc. | Integrated introducer and transmitter assembly and methods of use |
| US9398882B2 (en) | 2005-09-30 | 2016-07-26 | Abbott Diabetes Care Inc. | Method and apparatus for providing analyte sensor and data processing device |
| US7883464B2 (en) | 2005-09-30 | 2011-02-08 | Abbott Diabetes Care Inc. | Integrated transmitter unit and sensor introducer mechanism and methods of use |
| US9259175B2 (en) * | 2006-10-23 | 2016-02-16 | Abbott Diabetes Care, Inc. | Flexible patch for fluid delivery and monitoring body analytes |
| US20110190603A1 (en) * | 2009-09-29 | 2011-08-04 | Stafford Gary A | Sensor Inserter Having Introducer |
| US8613703B2 (en) * | 2007-05-31 | 2013-12-24 | Abbott Diabetes Care Inc. | Insertion devices and methods |
| US9743862B2 (en) | 2011-03-31 | 2017-08-29 | Abbott Diabetes Care Inc. | Systems and methods for transcutaneously implanting medical devices |
| US9788771B2 (en) | 2006-10-23 | 2017-10-17 | Abbott Diabetes Care Inc. | Variable speed sensor insertion devices and methods of use |
| US7731657B2 (en) * | 2005-08-30 | 2010-06-08 | Abbott Diabetes Care Inc. | Analyte sensor introducer and methods of use |
| US10226207B2 (en) | 2004-12-29 | 2019-03-12 | Abbott Diabetes Care Inc. | Sensor inserter having introducer |
| US7697967B2 (en) | 2005-12-28 | 2010-04-13 | Abbott Diabetes Care Inc. | Method and apparatus for providing analyte sensor insertion |
| US9351669B2 (en) | 2009-09-30 | 2016-05-31 | Abbott Diabetes Care Inc. | Interconnect for on-body analyte monitoring device |
| US9636450B2 (en) | 2007-02-19 | 2017-05-02 | Udo Hoss | Pump system modular components for delivering medication and analyte sensing at seperate insertion sites |
| US20110073475A1 (en) * | 2009-08-29 | 2011-03-31 | Abbott Diabetes Care Inc. | Analyte Sensor |
| US8029441B2 (en) | 2006-02-28 | 2011-10-04 | Abbott Diabetes Care Inc. | Analyte sensor transmitter unit configuration for a data monitoring and management system |
| US8333714B2 (en) | 2006-09-10 | 2012-12-18 | Abbott Diabetes Care Inc. | Method and system for providing an integrated analyte sensor insertion device and data processing unit |
| US9572534B2 (en) | 2010-06-29 | 2017-02-21 | Abbott Diabetes Care Inc. | Devices, systems and methods for on-skin or on-body mounting of medical devices |
| US8133178B2 (en) | 2006-02-22 | 2012-03-13 | Dexcom, Inc. | Analyte sensor |
| WO2006110193A2 (en) | 2005-04-08 | 2006-10-19 | Dexcom, Inc. | Cellulosic-based interference domain for an analyte sensor |
| US8744546B2 (en) | 2005-05-05 | 2014-06-03 | Dexcom, Inc. | Cellulosic-based resistance domain for an analyte sensor |
| US8112240B2 (en) * | 2005-04-29 | 2012-02-07 | Abbott Diabetes Care Inc. | Method and apparatus for providing leak detection in data monitoring and management systems |
| WO2006121661A2 (en) * | 2005-05-05 | 2006-11-16 | Dexcom, Inc. | Cellulosic-based resistance domain for an analyte sensor |
| JP4880690B2 (en) * | 2005-06-21 | 2012-02-22 | ルミムーブ・インコーポレーテッド・ディー／ビー／エイ・クロスリンク・ポリマー・リサーチ | Signal active decontamination coating |
| CN101365374B (en) | 2005-08-31 | 2011-11-16 | 弗吉尼亚大学专利基金委员会 | Improving accuracy of continuous glucose sensors |
| US8880138B2 (en) | 2005-09-30 | 2014-11-04 | Abbott Diabetes Care Inc. | Device for channeling fluid and methods of use |
| US9521968B2 (en) | 2005-09-30 | 2016-12-20 | Abbott Diabetes Care Inc. | Analyte sensor retention mechanism and methods of use |
| US20090054747A1 (en) * | 2005-10-31 | 2009-02-26 | Abbott Diabetes Care, Inc. | Method and system for providing analyte sensor tester isolation |
| US7766829B2 (en) | 2005-11-04 | 2010-08-03 | Abbott Diabetes Care Inc. | Method and system for providing basal profile modification in analyte monitoring and management systems |
| EP1968432A4 (en) * | 2005-12-28 | 2009-10-21 | Abbott Diabetes Care Inc | Medical device insertion |
| US11298058B2 (en) | 2005-12-28 | 2022-04-12 | Abbott Diabetes Care Inc. | Method and apparatus for providing analyte sensor insertion |
| EP2004796B1 (en) * | 2006-01-18 | 2015-04-08 | DexCom, Inc. | Membranes for an analyte sensor |
| US7736310B2 (en) * | 2006-01-30 | 2010-06-15 | Abbott Diabetes Care Inc. | On-body medical device securement |
| US7826879B2 (en) * | 2006-02-28 | 2010-11-02 | Abbott Diabetes Care Inc. | Analyte sensors and methods of use |
| US7885698B2 (en) | 2006-02-28 | 2011-02-08 | Abbott Diabetes Care Inc. | Method and system for providing continuous calibration of implantable analyte sensors |
| EP1991110B1 (en) * | 2006-03-09 | 2018-11-07 | DexCom, Inc. | Systems and methods for processing analyte sensor data |
| US8140312B2 (en) | 2007-05-14 | 2012-03-20 | Abbott Diabetes Care Inc. | Method and system for determining analyte levels |
| US8374668B1 (en) | 2007-10-23 | 2013-02-12 | Abbott Diabetes Care Inc. | Analyte sensor with lag compensation |
| US8478557B2 (en) | 2009-07-31 | 2013-07-02 | Abbott Diabetes Care Inc. | Method and apparatus for providing analyte monitoring system calibration accuracy |
| US8226891B2 (en) | 2006-03-31 | 2012-07-24 | Abbott Diabetes Care Inc. | Analyte monitoring devices and methods therefor |
| US7653425B2 (en) | 2006-08-09 | 2010-01-26 | Abbott Diabetes Care Inc. | Method and system for providing calibration of an analyte sensor in an analyte monitoring system |
| US9326709B2 (en) | 2010-03-10 | 2016-05-03 | Abbott Diabetes Care Inc. | Systems, devices and methods for managing glucose levels |
| US7618369B2 (en) | 2006-10-02 | 2009-11-17 | Abbott Diabetes Care Inc. | Method and system for dynamically updating calibration parameters for an analyte sensor |
| US8224415B2 (en) | 2009-01-29 | 2012-07-17 | Abbott Diabetes Care Inc. | Method and device for providing offset model based calibration for analyte sensor |
| US8219173B2 (en) | 2008-09-30 | 2012-07-10 | Abbott Diabetes Care Inc. | Optimizing analyte sensor calibration |
| US7630748B2 (en) | 2006-10-25 | 2009-12-08 | Abbott Diabetes Care Inc. | Method and system for providing analyte monitoring |
| US7620438B2 (en) | 2006-03-31 | 2009-11-17 | Abbott Diabetes Care Inc. | Method and system for powering an electronic device |
| US7801582B2 (en) | 2006-03-31 | 2010-09-21 | Abbott Diabetes Care Inc. | Analyte monitoring and management system and methods therefor |
| US8346335B2 (en) * | 2008-03-28 | 2013-01-01 | Abbott Diabetes Care Inc. | Analyte sensor calibration management |
| US9675290B2 (en) | 2012-10-30 | 2017-06-13 | Abbott Diabetes Care Inc. | Sensitivity calibration of in vivo sensors used to measure analyte concentration |
| US9392969B2 (en) * | 2008-08-31 | 2016-07-19 | Abbott Diabetes Care Inc. | Closed loop control and signal attenuation detection |
| US8473022B2 (en) | 2008-01-31 | 2013-06-25 | Abbott Diabetes Care Inc. | Analyte sensor with time lag compensation |
| US20090054749A1 (en) * | 2006-05-31 | 2009-02-26 | Abbott Diabetes Care, Inc. | Method and System for Providing Data Transmission in a Data Management System |
| US20080071158A1 (en) | 2006-06-07 | 2008-03-20 | Abbott Diabetes Care, Inc. | Analyte monitoring system and method |
| US20090105571A1 (en) * | 2006-06-30 | 2009-04-23 | Abbott Diabetes Care, Inc. | Method and System for Providing Data Communication in Data Management Systems |
| GB0616566D0 (en) * | 2006-08-19 | 2006-09-27 | Rolls Royce Plc | An alloy and method of treating titanium aluminide |
| KR100770440B1 (en) * | 2006-08-29 | 2007-10-26 | 삼성전기주식회사 | Nitride semiconductor light emitting device |
| CN102772212A (en) | 2006-10-26 | 2012-11-14 | 雅培糖尿病护理公司 | Method, device and system for detection of sensitivity decline in analyte sensors |
| US8121857B2 (en) | 2007-02-15 | 2012-02-21 | Abbott Diabetes Care Inc. | Device and method for automatic data acquisition and/or detection |
| US20080199894A1 (en) * | 2007-02-15 | 2008-08-21 | Abbott Diabetes Care, Inc. | Device and method for automatic data acquisition and/or detection |
| US8732188B2 (en) * | 2007-02-18 | 2014-05-20 | Abbott Diabetes Care Inc. | Method and system for providing contextual based medication dosage determination |
| US8930203B2 (en) | 2007-02-18 | 2015-01-06 | Abbott Diabetes Care Inc. | Multi-function analyte test device and methods therefor |
| US8123686B2 (en) | 2007-03-01 | 2012-02-28 | Abbott Diabetes Care Inc. | Method and apparatus for providing rolling data in communication systems |
| CA2683721C (en) * | 2007-04-14 | 2017-05-23 | Abbott Diabetes Care Inc. | Method and apparatus for providing dynamic multi-stage signal amplification in a medical device |
| WO2009096992A1 (en) * | 2007-04-14 | 2009-08-06 | Abbott Diabetes Care, Inc. | Method and apparatus for providing data processing and control in medical communication system |
| EP2146624B1 (en) | 2007-04-14 | 2020-03-25 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in medical communication system |
| CA2683962C (en) | 2007-04-14 | 2017-06-06 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in medical communication system |
| WO2008128210A1 (en) | 2007-04-14 | 2008-10-23 | Abbott Diabetes Care, Inc. | Method and apparatus for providing data processing and control in medical communication system |
| CA2683953C (en) * | 2007-04-14 | 2016-08-02 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in medical communication system |
| US8456301B2 (en) | 2007-05-08 | 2013-06-04 | Abbott Diabetes Care Inc. | Analyte monitoring system and methods |
| US8461985B2 (en) * | 2007-05-08 | 2013-06-11 | Abbott Diabetes Care Inc. | Analyte monitoring system and methods |
| US8665091B2 (en) | 2007-05-08 | 2014-03-04 | Abbott Diabetes Care Inc. | Method and device for determining elapsed sensor life |
| US20080281179A1 (en) * | 2007-05-08 | 2008-11-13 | Abbott Diabetes Care, Inc. | Analyte monitoring system and methods |
| US7928850B2 (en) | 2007-05-08 | 2011-04-19 | Abbott Diabetes Care Inc. | Analyte monitoring system and methods |
| US8103471B2 (en) | 2007-05-14 | 2012-01-24 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in a medical communication system |
| US7996158B2 (en) | 2007-05-14 | 2011-08-09 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in a medical communication system |
| US8239166B2 (en) | 2007-05-14 | 2012-08-07 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in a medical communication system |
| US9125548B2 (en) | 2007-05-14 | 2015-09-08 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in a medical communication system |
| US10002233B2 (en) * | 2007-05-14 | 2018-06-19 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in a medical communication system |
| US8560038B2 (en) | 2007-05-14 | 2013-10-15 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in a medical communication system |
| US8260558B2 (en) | 2007-05-14 | 2012-09-04 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in a medical communication system |
| US8444560B2 (en) | 2007-05-14 | 2013-05-21 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in a medical communication system |
| US8600681B2 (en) | 2007-05-14 | 2013-12-03 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in a medical communication system |
| AU2008265541B2 (en) | 2007-06-21 | 2014-07-17 | Abbott Diabetes Care, Inc. | Health management devices and methods |
| CN101686804B (en) * | 2007-06-21 | 2013-05-08 | 雅培糖尿病护理公司 | Health monitor |
| US20080319294A1 (en) * | 2007-06-21 | 2008-12-25 | Abbott Diabetes Care, Inc. | Health management devices and methods |
| US8160900B2 (en) | 2007-06-29 | 2012-04-17 | Abbott Diabetes Care Inc. | Analyte monitoring and management device and method to analyze the frequency of user interaction with the device |
| US7768386B2 (en) * | 2007-07-31 | 2010-08-03 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in a medical communication system |
| US8834366B2 (en) | 2007-07-31 | 2014-09-16 | Abbott Diabetes Care Inc. | Method and apparatus for providing analyte sensor calibration |
| US20090036760A1 (en) * | 2007-07-31 | 2009-02-05 | Abbott Diabetes Care, Inc. | Method and apparatus for providing data processing and control in a medical communication system |
| US8216138B1 (en) | 2007-10-23 | 2012-07-10 | Abbott Diabetes Care Inc. | Correlation of alternative site blood and interstitial fluid glucose concentrations to venous glucose concentration |
| US8377031B2 (en) * | 2007-10-23 | 2013-02-19 | Abbott Diabetes Care Inc. | Closed loop control system with safety parameters and methods |
| US8409093B2 (en) * | 2007-10-23 | 2013-04-02 | Abbott Diabetes Care Inc. | Assessing measures of glycemic variability |
| US8417312B2 (en) | 2007-10-25 | 2013-04-09 | Dexcom, Inc. | Systems and methods for processing sensor data |
| US8290559B2 (en) * | 2007-12-17 | 2012-10-16 | Dexcom, Inc. | Systems and methods for processing sensor data |
| US20090164190A1 (en) * | 2007-12-19 | 2009-06-25 | Abbott Diabetes Care, Inc. | Physiological condition simulation device and method |
| US20090164239A1 (en) | 2007-12-19 | 2009-06-25 | Abbott Diabetes Care, Inc. | Dynamic Display Of Glucose Information |
| US20090259118A1 (en) * | 2008-03-31 | 2009-10-15 | Abbott Diabetes Care Inc. | Shallow Implantable Analyte Sensor with Rapid Physiological Response |
| EP3659628A1 (en) * | 2008-04-10 | 2020-06-03 | Abbott Diabetes Care, Inc. | Method and system for sterilizing an analyte sensor |
| US7826382B2 (en) | 2008-05-30 | 2010-11-02 | Abbott Diabetes Care Inc. | Close proximity communication device and methods |
| US8924159B2 (en) | 2008-05-30 | 2014-12-30 | Abbott Diabetes Care Inc. | Method and apparatus for providing glycemic control |
| US8591410B2 (en) | 2008-05-30 | 2013-11-26 | Abbott Diabetes Care Inc. | Method and apparatus for providing glycemic control |
| US20090300616A1 (en) * | 2008-05-30 | 2009-12-03 | Abbott Diabetes Care, Inc. | Automated task execution for an analyte monitoring system |
| US7943258B2 (en) * | 2008-06-04 | 2011-05-17 | Cellera, Inc. | Alkaline membrane fuel cells and apparatus and methods for supplying water thereto |
| US8876755B2 (en) | 2008-07-14 | 2014-11-04 | Abbott Diabetes Care Inc. | Closed loop control system interface and methods |
| EP2149957B1 (en) * | 2008-07-30 | 2017-06-14 | Harman Becker Automotive Systems GmbH | Priority based power distribution arrangement |
| US20100057040A1 (en) * | 2008-08-31 | 2010-03-04 | Abbott Diabetes Care, Inc. | Robust Closed Loop Control And Methods |
| US8734422B2 (en) | 2008-08-31 | 2014-05-27 | Abbott Diabetes Care Inc. | Closed loop control with improved alarm functions |
| US9943644B2 (en) * | 2008-08-31 | 2018-04-17 | Abbott Diabetes Care Inc. | Closed loop control with reference measurement and methods thereof |
| US8622988B2 (en) | 2008-08-31 | 2014-01-07 | Abbott Diabetes Care Inc. | Variable rate closed loop control and methods |
| US20100082364A1 (en) * | 2008-09-30 | 2010-04-01 | Abbott Diabetes Care, Inc. | Medical Information Management |
| US8986208B2 (en) | 2008-09-30 | 2015-03-24 | Abbott Diabetes Care Inc. | Analyte sensor sensitivity attenuation mitigation |
| US9326707B2 (en) | 2008-11-10 | 2016-05-03 | Abbott Diabetes Care Inc. | Alarm characterization for analyte monitoring devices and systems |
| WO2010067769A1 (en) | 2008-12-08 | 2010-06-17 | 日本化薬株式会社 | Biosensor for electrochemical measurement of 1,5-anhydroglucitol, and measuring method and measuring kit using the same |
| US8103456B2 (en) | 2009-01-29 | 2012-01-24 | Abbott Diabetes Care Inc. | Method and device for early signal attenuation detection using blood glucose measurements |
| US9402544B2 (en) | 2009-02-03 | 2016-08-02 | Abbott Diabetes Care Inc. | Analyte sensor and apparatus for insertion of the sensor |
| US8304368B2 (en) * | 2009-02-23 | 2012-11-06 | Cellera, Inc. | Catalyst coated membrane (CCM) and catalyst film/layer for alkaline membrane fuel cells and methods of making same |
| US20100213057A1 (en) | 2009-02-26 | 2010-08-26 | Benjamin Feldman | Self-Powered Analyte Sensor |
| DK3912551T3 (en) * | 2009-02-26 | 2023-10-30 | Abbott Diabetes Care Inc | Procedure for calibrating an analyte sensor |
| WO2010114942A1 (en) * | 2009-03-31 | 2010-10-07 | Abbott Diabetes Care Inc. | Precise fluid dispensing method and device |
| US8497777B2 (en) * | 2009-04-15 | 2013-07-30 | Abbott Diabetes Care Inc. | Analyte monitoring system having an alert |
| EP2419015A4 (en) | 2009-04-16 | 2014-08-20 | Abbott Diabetes Care Inc | Analyte sensor calibration management |
| US20100274515A1 (en) * | 2009-04-28 | 2010-10-28 | Abbott Diabetes Care Inc. | Dynamic Analyte Sensor Calibration Based On Sensor Stability Profile |
| WO2010127050A1 (en) * | 2009-04-28 | 2010-11-04 | Abbott Diabetes Care Inc. | Error detection in critical repeating data in a wireless sensor system |
| WO2010127187A1 (en) | 2009-04-29 | 2010-11-04 | Abbott Diabetes Care Inc. | Method and system for providing data communication in continuous glucose monitoring and management system |
| EP2425209A4 (en) | 2009-04-29 | 2013-01-09 | Abbott Diabetes Care Inc | Method and system for providing real time analyte sensor calibration with retrospective backfill |
| WO2010138856A1 (en) | 2009-05-29 | 2010-12-02 | Abbott Diabetes Care Inc. | Medical device antenna systems having external antenna configurations |
| US8613892B2 (en) | 2009-06-30 | 2013-12-24 | Abbott Diabetes Care Inc. | Analyte meter with a moveable head and methods of using the same |
| LT3689237T (en) * | 2009-07-23 | 2021-09-27 | Abbott Diabetes Care, Inc. | Method of manufacturing and system for continuous analyte measurement |
| US8895198B2 (en) * | 2009-08-24 | 2014-11-25 | Cellera, Inc. | Systems and methods of securing immunity to air CO2 in alkaline fuel cells |
| US9314195B2 (en) | 2009-08-31 | 2016-04-19 | Abbott Diabetes Care Inc. | Analyte signal processing device and methods |
| EP2473099A4 (en) | 2009-08-31 | 2015-01-14 | Abbott Diabetes Care Inc | Analyte monitoring system and methods for managing power and noise |
| DK3988470T3 (en) | 2009-08-31 | 2023-08-28 | Abbott Diabetes Care Inc | Display devices for a medical device |
| JP5795584B2 (en) | 2009-08-31 | 2015-10-14 | アボット ダイアベティス ケア インコーポレイテッドＡｂｂｏｔｔ Ｄｉａｂｅｔｅｓ Ｃａｒｅ Ｉｎｃ． | Medical device |
| US20110106126A1 (en) * | 2009-08-31 | 2011-05-05 | Michael Love | Inserter device including rotor subassembly |
| WO2011041469A1 (en) | 2009-09-29 | 2011-04-07 | Abbott Diabetes Care Inc. | Method and apparatus for providing notification function in analyte monitoring systems |
| WO2011044386A1 (en) * | 2009-10-07 | 2011-04-14 | Abbott Diabetes Care Inc. | Sensor inserter assembly having rotatable trigger |
| US8185181B2 (en) | 2009-10-30 | 2012-05-22 | Abbott Diabetes Care Inc. | Method and apparatus for detecting false hypoglycemic conditions |
| US20110184268A1 (en) * | 2010-01-22 | 2011-07-28 | Abbott Diabetes Care Inc. | Method, Device and System for Providing Analyte Sensor Calibration |
| US20110184258A1 (en) * | 2010-01-28 | 2011-07-28 | Abbott Diabetes Care Inc. | Balloon Catheter Analyte Measurement Sensors and Methods for Using the Same |
| USD924406S1 (en) | 2010-02-01 | 2021-07-06 | Abbott Diabetes Care Inc. | Analyte sensor inserter |
| JP5904500B2 (en) | 2010-03-24 | 2016-04-13 | アボット ダイアベティス ケア インコーポレイテッドＡｂｂｏｔｔ Ｄｉａｂｅｔｅｓ Ｃａｒｅ Ｉｎｃ． | Apparatus and system for inserting sharp member under skin surface |
| CN103026540B (en) | 2010-06-07 | 2016-08-10 | 埃尔比特系统用地C4I公司 | The chemical bond of catalyst/membrane surface bonding in film electrolyte fuel battery |
| US8635046B2 (en) | 2010-06-23 | 2014-01-21 | Abbott Diabetes Care Inc. | Method and system for evaluating analyte sensor response characteristics |
| US11064921B2 (en) | 2010-06-29 | 2021-07-20 | Abbott Diabetes Care Inc. | Devices, systems and methods for on-skin or on-body mounting of medical devices |
| US10092229B2 (en) | 2010-06-29 | 2018-10-09 | Abbott Diabetes Care Inc. | Calibration of analyte measurement system |
| US11213226B2 (en) | 2010-10-07 | 2022-01-04 | Abbott Diabetes Care Inc. | Analyte monitoring devices and methods |
| US10136845B2 (en) | 2011-02-28 | 2018-11-27 | Abbott Diabetes Care Inc. | Devices, systems, and methods associated with analyte monitoring devices and devices incorporating the same |
| EP2680754B1 (en) | 2011-02-28 | 2019-04-24 | Abbott Diabetes Care, Inc. | Devices, systems, and methods associated with analyte monitoring devices and devices incorporating the same |
| DK3575796T3 (en) | 2011-04-15 | 2021-01-18 | Dexcom Inc | ADVANCED ANALYZE SENSOR CALIBRATION AND ERROR DETECTION |
| US9069536B2 (en) | 2011-10-31 | 2015-06-30 | Abbott Diabetes Care Inc. | Electronic devices having integrated reset systems and methods thereof |
| US9622691B2 (en) | 2011-10-31 | 2017-04-18 | Abbott Diabetes Care Inc. | Model based variable risk false glucose threshold alarm prevention mechanism |
| WO2013070794A2 (en) | 2011-11-07 | 2013-05-16 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods |
| US8710993B2 (en) | 2011-11-23 | 2014-04-29 | Abbott Diabetes Care Inc. | Mitigating single point failure of devices in an analyte monitoring system and methods thereof |
| US9317656B2 (en) | 2011-11-23 | 2016-04-19 | Abbott Diabetes Care Inc. | Compatibility mechanisms for devices in a continuous analyte monitoring system and methods thereof |
| WO2013078426A2 (en) | 2011-11-25 | 2013-05-30 | Abbott Diabetes Care Inc. | Analyte monitoring system and methods of use |
| US9402570B2 (en) | 2011-12-11 | 2016-08-02 | Abbott Diabetes Care Inc. | Analyte sensor devices, connections, and methods |
| EP2890297B1 (en) | 2012-08-30 | 2018-04-11 | Abbott Diabetes Care, Inc. | Dropout detection in continuous analyte monitoring data during data excursions |
| US9968306B2 (en) | 2012-09-17 | 2018-05-15 | Abbott Diabetes Care Inc. | Methods and apparatuses for providing adverse condition notification with enhanced wireless communication range in analyte monitoring systems |
| EP2901153A4 (en) | 2012-09-26 | 2016-04-27 | Abbott Diabetes Care Inc | Method and apparatus for improving lag correction during in vivo measurement of analyte concentration with analyte concentration variability and range data |
| US9474475B1 (en) | 2013-03-15 | 2016-10-25 | Abbott Diabetes Care Inc. | Multi-rate analyte sensor data collection with sample rate configurable signal processing |
| US10433773B1 (en) | 2013-03-15 | 2019-10-08 | Abbott Diabetes Care Inc. | Noise rejection methods and apparatus for sparsely sampled analyte sensor data |
| US10076285B2 (en) | 2013-03-15 | 2018-09-18 | Abbott Diabetes Care Inc. | Sensor fault detection using analyte sensor data pattern comparison |
| US11229382B2 (en) | 2013-12-31 | 2022-01-25 | Abbott Diabetes Care Inc. | Self-powered analyte sensor and devices using the same |
| EP3865063A1 (en) | 2014-03-30 | 2021-08-18 | Abbott Diabetes Care, Inc. | Method and apparatus for determining meal start and peak events in analyte monitoring systems |
| WO2015184465A1 (en) * | 2014-05-30 | 2015-12-03 | The Regents Of The University Of California | Strip-based electrochemical sensors for quantitative analysis of analytes |
| US10674944B2 (en) | 2015-05-14 | 2020-06-09 | Abbott Diabetes Care Inc. | Compact medical device inserters and related systems and methods |
| US10213139B2 (en) | 2015-05-14 | 2019-02-26 | Abbott Diabetes Care Inc. | Systems, devices, and methods for assembling an applicator and sensor control device |
| CN113349766A (en) | 2015-07-10 | 2021-09-07 | 雅培糖尿病护理公司 | System, device and method for dynamic glucose curve response to physiological parameters |
| US11071478B2 (en) | 2017-01-23 | 2021-07-27 | Abbott Diabetes Care Inc. | Systems, devices and methods for analyte sensor insertion |
| EP3600014A4 (en) | 2017-03-21 | 2020-10-21 | Abbott Diabetes Care Inc. | Methods, devices and system for providing diabetic condition diagnosis and therapy |
| AU2018354120A1 (en) | 2017-10-24 | 2020-04-23 | Dexcom, Inc. | Pre-connected analyte sensors |
| US11331022B2 (en) | 2017-10-24 | 2022-05-17 | Dexcom, Inc. | Pre-connected analyte sensors |
| WO2022246104A1 (en) * | 2021-05-19 | 2022-11-24 | Arkansas State Universtiy-Jonesboro | Electrochemical sensor for the measurement of glucose concentration |
| CN114740069A (en) * | 2022-04-15 | 2022-07-12 | 深圳可孚生物科技有限公司 | Preparation method of microneedle glucose sensor based on CNT network layer |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4418148A (en) * | 1981-11-05 | 1983-11-29 | Miles Laboratories, Inc. | Multilayer enzyme electrode membrane |
| US4415666A (en) * | 1981-11-05 | 1983-11-15 | Miles Laboratories, Inc. | Enzyme electrode membrane |
| US4604182A (en) * | 1983-08-15 | 1986-08-05 | E. I. Du Pont De Nemours And Company | Perfluorosulfonic acid polymer-coated indicator electrodes |
| US4517291A (en) * | 1983-08-15 | 1985-05-14 | E. I. Du Pont De Nemours And Company | Biological detection process using polymer-coated electrodes |
| JPH021535A (en) * | 1987-10-05 | 1990-01-05 | Arden Medical Syst Inc | Sensor for measuring chemical seed allowing dehydrogenation from enzyme in aqueous solution |
-
1989
- 1989-12-11 US US07/448,475 patent/US5082550A/en not_active Expired - Fee Related
-
1990
- 1990-12-10 WO PCT/US1990/007136 patent/WO1991009304A1/en active IP Right Grant
- 1990-12-10 DE DE69025470T patent/DE69025470T2/en not_active Expired - Fee Related
- 1990-12-10 CA CA002045616A patent/CA2045616C/en not_active Expired - Fee Related
- 1990-12-10 JP JP3501772A patent/JPH04505966A/en active Pending
- 1990-12-10 EP EP91901386A patent/EP0457892B1/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| DE69025470T2 (en) | 1996-09-12 |
| EP0457892A1 (en) | 1991-11-27 |
| DE69025470D1 (en) | 1996-03-28 |
| WO1991009304A1 (en) | 1991-06-27 |
| EP0457892A4 (en) | 1992-10-28 |
| EP0457892B1 (en) | 1996-02-21 |
| US5082550A (en) | 1992-01-21 |
| JPH04505966A (en) | 1992-10-15 |
| CA2045616A1 (en) | 1991-06-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2045616C (en) | Enzyme electrochemical sensor electrode and method of making it | |
| US5227042A (en) | Catalyzed enzyme electrodes | |
| US5914026A (en) | Implantable sensor employing an auxiliary electrode | |
| Tamiya et al. | Micro glucose using electron mediators immobilized on a polypyrrole-modified electrode | |
| CA2274174C (en) | Glucose sensor | |
| US4415666A (en) | Enzyme electrode membrane | |
| Thevenot et al. | Enzyme collagen membrane for electrochemical determination of glucose | |
| US5746898A (en) | Electrochemical-enzymatic sensor | |
| US5356786A (en) | Interferant eliminating biosensor | |
| CA1177735A (en) | Method of polarographic analysis of lactic acid and lactate | |
| EP0025110B1 (en) | Electrochemical measuring apparatus provided with an enzyme electrode | |
| Mascini et al. | Amperometric sensor for pyruvate with immobilized pyruvate oxidase | |
| JPS63131057A (en) | Enzyme sensor | |
| JPH0210903B2 (en) | ||
| JPS5921500B2 (en) | Enzyme membrane for oxygen electrode | |
| CA1067457A (en) | Membrane for enzyme electrodes | |
| JPH0235933B2 (en) | ||
| Rishpon et al. | Amperometric glucose sensors based on glucose oxidase immobilized in Nafion | |
| CA1109374A (en) | Stabilization of activated galactose oxidase enzyme | |
| Uchiyama et al. | L‐Ascorbate sensor with polypyrrole‐coated carbon felt membrane electropolymerized in a cucumber juice solution | |
| Coulet et al. | Electrochemical study of reactions at interfaces of glucose oxidase collagen membranes | |
| Popp et al. | Sandwich enzyme membranes for amperometric multi-biosensor applications: improvement of linearity and reduction of chemical cross-talk | |
| Genshaw et al. | Whole blood glucose enzyme electrode | |
| JP3035572B2 (en) | Cholesterol sensor | |
| JPH0344653B2 (en) |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |