CA2229509C - Chemical signal-impermeable mask - Google Patents
Chemical signal-impermeable mask Download PDFInfo
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- CA2229509C CA2229509C CA002229509A CA2229509A CA2229509C CA 2229509 C CA2229509 C CA 2229509C CA 002229509 A CA002229509 A CA 002229509A CA 2229509 A CA2229509 A CA 2229509A CA 2229509 C CA2229509 C CA 2229509C
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- mask
- working electrode
- chemical signal
- mils
- conductive material
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/1486—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/20—Applying electric currents by contact electrodes continuous direct currents
- A61N1/30—Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
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- 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
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- 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
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- 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
- C12Q1/005—Enzyme electrodes involving specific analytes or enzymes
- C12Q1/006—Enzyme electrodes involving specific analytes or enzymes for glucose
Abstract
A chemical signal-impermeable mask (1) is positioned in the electrolyte flow such that the mask is between a source of chemical signal and a working electrode (4) which senses the chemical signal transported from the source (e.g., by diffusion). The configuration of the mask is such that the mask prevents substantially all chemical signal transport from the chemical signal source/having a radial vector component relative to a plane of the mask/and the catalytic face of the working electrode, thus allowing primarily only chemical signal transport that is substantially perpendicular to the place of the mask and the catalytic surface (6) of the working electrode. By reducing or eliminating chemical signal radial transport toward the working electrode, the mask thus significantly reduces or eliminates edge effects. By substantially reducing edge effects created by radial transport of chemical signal, it is possible to obtain a more accurate measurement of the amount (e.g., concentration) of chemical signal that is transported from a given area of source material.
Description
CHEMICAL SIGNAL-IMPERMZa~ABLE MASK
Field of the Invention s This invention relates generally to the detection of chemical signals that are diffused through a solid or semi-solid, or quiescent liquid surface, particularly where the chemical signals are associated with a medically important molecule.
se Backctroun3 of the Inverctian An electrode is the component in the electrochemical cell in contact with an electrolyte through which current can flow by electronic movement.
Electrodes, which are essential components of both 15 galvanic (current producing) and electrolytic (current using) cells, can be composed of a number of electrically conductive materials, e.g., lead, zinc, aluminum, copper, iron, nickel, mercury, graphite, gold, or platinum.
Examples of electrodes are found in electric cells, where 2o they are dipped in the electrolyte; in medical devices, where the electrode is used to detect electrical impulses emitted by the heart or the brain; and in semiconductor devices, where they perform one or more of the functions of emitting, collecting, or controlling the movements of 2s electrons and ions.
The electrolyte can be any substance that provides ionic conductivity, and through which electrochemically active species can be transported (e. g., by diffusion).
Electrolytes can be solid, liquid, or semi-solid (e. g., so in the form of a gel). Common electrolytes include sulfuric acid and sodium chloride, which ionize in solution. Electrolytes used in the medical field must ~ have a pH which is sufficiently close to that of the WO 97/10356 PC'1'/US96/11776 tissue in contact with the electrode (e.g., skin) so as not to cause harm to the tissue over time.
Electrochemically active species that are present in the electrolyte can undergo electrochemical reactions (oxidation or reduction) at the surface of the electrode.
The rate at which the electrochemical reactions take place is related to the reactivity of the species, the electrode material, the electrical potential applied to the electrode, and the efficiency at which the to electrochemically active species is transported to the electrode surface.
In unstirred electrolyte, such as quiescent liquid solutions and gel electrolytes, diffusion is the main process of transport of electrochemically active species is to the electrode surface. The exact nature of the diffusion process is determined by the geometry of the electrode (e. g., planar disk, cylindrical, or spherical), and the geometry of the electrolyte (e. g., semi-infinite large volume, thin disk of gel, etc.). For example, 2o diffusion of electrochemically active species to a spherical electrode in a semi-infinite volume of electrolyte differs from diffusion of electrochemically active species to a planar disk electrode. A constant and predictable pattern of diffusion (i.e., a diffusion 2s pattern that can be predicted by a simple equation) is critical in determining a correlation between the electrochemical current collected, and the concentration of the electrochemically active species in the electrolyte.
3o However, diffusion of electrochemically active species toward an electrode can not be predicted by a simple equation for every situation. For example, where the electrochemically active species diffuses through a disk-shaped electrolyte toward a smaller disk-shaped 35 electrode in contact with the electrolyte, the current observed at the electrode can not be predicted by a simple equation. In this latter situation, the inaccuracy in the diffusion model is caused by the combination of two different diffusion models. First, in the center of 0 5 the disk electrode the diffusion of the electroactive species towards the electrode is in a substantially perpendicular direction. Secondly, at the edges of the disk electrode the diffusion comes from both perpendicular and radial directions. The combination of 1o these two different diffusion patterns makes the total current collected at the disk electrode difficult to predict. In addition, the relative contributions of the diffusion fluxes from the axial and radial directions may change over time, causing further errors in predicted 1s current.
Summary of the Invention A mask which is substantially impermeable to the transport of a chemical signal is positioned in the chemical signal transport path moving toward a working 2o electrode which senses an electrochemical signal diffused through a material which is sonically conductive, which material comprises water and an electrolyte. More particularly, the mask of the invention is positioned on or in the sonically conductive material, such as an ion-25 containing gel, between an area from which the chemical signal is transported and the catalytic face of the working electrode used to sense the chemical signal. The configuration of the mask (e. g., shape, thickness, mask component(s)) is such that the mask prevents so substantially all chemical signal transport (from the chemical signal source) having a radial vector component ' relative to a plane of the mask and the catalytic face of the working electrode, thus allowing primarily only chemical signal transport (e.g., diffusion) that is substantially perpendicular to the place of the mask and the catalytic surface of the working electrode. The mask thus minimizes radial transport of the chemical signal to the working electrode and accumulation of chemical signal at the periphery of the working electrode. The mask thus ti significantly reduces or eliminates edge effects, since the chemical signal that reaches the electrode is primarily only that chemical signal that is transported in a direction substantially perpendicular to the 1o catalytic face of the working electrode. Substantially all transport of chemical signal to the working electrode surface via a path which includes an radial vector component (i.e., is not a path substantially perpendicular to the working electrode catalytic surface) 1s is prevented from occurring by the mask, since the mask blocks entry of potentially radially transported chemical signal at the source. By substantially reducing edge effects created by radial transport of chemical signal, it is possible to obtain a more accurate measurement of 2o the amount (e. g., concentration) of chemical signal that is transported from a given area of source material.
In one embodiment, the working electrode~is a closed polygon or closed circle. The mask has an outer perimeter which is equal to or greater than (i.e., 2s extends beyond) the outer perimeter of the working electrode. The mask has an opening, the opening being sufficiently small so that chemical signal that passes through the opening to the catalytic surface of the working electrode in a direction that is substantially 3o perpendicular to the plane of the mask, and thus, substantially perpendicular to the working electrode catalytic face.
In another embodiment, the working electrode is annular and the mask is composed of a solid, circular 3s piece concentrically positioned with respect to the working electrode such that the outer perimeter of the solid circular piece is circumscribed substantially within the inner perimeter of the annular working electrode. Thus chemical signal that passes with the s electrolyte flow and through the plane of the mask is substantially only that chemical signal that is transported from the chemical signal source in a direction that is substantially perpendicular to the working electrode catalytic face.
io In another embodiment, the mask is attached to a surface of a hydrogel patch, and the mask and hydrogel patch are provided as a single unit.
In another embodiment, the mask is an integral part of the housing for the sensor portion of a device i5 for monitoring the chemical signal.
In another embodiment, the mask is independent of any portion of the device with which it is to be used, i.e., the mask is not bound to another component but merely placed, by the user, in.contact with the 2o electrolyte containing material prior to use.
aspect of the invention is to provide a means that can be used with virtually any surface-contacting working electrode, and can enhance the performance of the electrode and the accuracy of measurements from the 2s working electrode.
Another aspect of the invention is to provide a means for accurately and consistently measuring the amount of a chemical signal present in a sample by minimizing the error created by chemical signal which 3o moves to the electrode with a radial vector component.
Another aspect of the invention is to provide a means for quickly, accurately, and continually measuring a chemical signal transported through an electrolyte containing ion conducting material, e.g., a hydrogel. By 3s using the mask of the invention with a working electrode as described herein, measurement of the chemical signal transported through the material in a path perpendicular to the electrode is achieved within a matter of seconds to minutes.
In accordance with an aspect of the present invention, there is provided an assembly for use in a monitoring device for monitoring a chemical signal, the chemical signal being a compound which diffuses through the skin of a subject, the assembly comprising:
a) an sonically conductive material having a first face having a chemical signal target area, the sonically conductive material comprising water and an electrolyte; and b) a mask characterized by being substantially impermeable to a chemical signal, the mask being positioned on a second face of the sonically conductive material opposite the first material face such that chemical signal transported through a plane of the mask, through the sonically conductive material, and toward the chemical signal target area is substantially only that chemical signal transported in a direction substantially perpendicular to the chemical signal target area.
In accordance with another aspect of the present invention , the mask has an opening through which chemical signal flows in a direction substantially perpendicular to the target area.
In accordance with another aspect of the present invention, the opening in the mask constitutes an area which is in a range of 1~ to 90~ of an area encompassed by the entire mask plus opening.
In accordance with another aspect of the present invention, the opening in the mask has a perimeter equal to or circumscribed within an outer 6a perimeter of the target area.
In accordance with another aspect of the present invention, the mask is solid and the target area is annular.
In accordance with another aspect of the present invention, the sonically conductive material comprises:
i) a hydrophilic compound which forms a gel in water, which compound is present in an amount of about 4~ or more by weight based on the weight of the sonically conductive material;
ii) a hydrogel comprising about 955 or less water; and iii) a chloride containing salt.
In accordance with another aspect of the present invention, the sonically conductive material comprises glucose oxidase and the chemical signal is glucose.
In accordance with another aspect of the present invention, the first and second faces of the sonically conductive material are coplanar and each has a surface area in a range of from about 0.5 to about 10 cm2 and the material has a thickness in a range of from about mils to about 50 mils.
In accordance with another aspect of the present invention, the mask has a thickness in a range of about 0.5 mil to 10 mils and the sonically conductive material has a thickness in a range of about 10 mils to 50 mils.
In accordance with another aspect of the present invention, the mask has a thickness in a range of about 0.5 mil to 10 mils and the sonically conductive 6b material has a thickness in a range of about 10 mils to 60 mils.
In accordance with another aspect of the present invention, the mask has a thickness in a range of about 0.01 mil to 5 mils and the sonically conductive material has a thickness in a range of about 5 mils to 60 mils.
In accordance with another aspect of the present invention, the mask has a thickness in a range of about 0.01 mil to 10 mils and the sonically conductive material has a thickness in a range of about 10 mils to 60 mils.
In accordance with another aspect of the present invention, the mask has a thickness in a range of about 0.5 mil to 5 mils and the sonically conductive material has a thickness in a range of about 5 mils to 60 mils.
In accordance with another aspect of the present invention, there is provided a sensor assembly for use with a chemical signal monitoring device, comprising;
a sensor housing having a top portion and a bottom portion, the bottom portion defining a bottom portion opening a chemical signal impermeable mask positioned between the top portion and the bottom portion, the mask having a surface area greater than or equal to the surface area of the bottom portion opening, and defining a mask opening, the mask being positioned so that the mask opening and the bottom portion opening are aligned;
and 6~
a working electrode positioned in the top portion of the sensor housing;
wherein prior to use of the device a hydrogel is inserted between the sensor housing bottom portion and top portion such that when the sensor assembly is closed, the top portion is positioned directly over the bottom portion such that a first hydrogel face contacts the mask, and the working electrode is in contact with a second hydrogel face opposite the first hydrogel face, the working electrode being positioned directly opposite the bottom portion opening, wherein chemical signal transported through a plane of the mask, through the hydrogel and toward the working electrode is substantially only that chemical signal transported in a direction substantially perpendicular to the working electrode.
In accordance with another aspect of the present invention, the hydrogel comprises glucose oxidase, the mask is impermeable to glucose, and the working electrode comprises platinum.
In accordance with another aspect of the present invention, the surface area of each the first and second hydrogel faces is in a range of about 0.5 cm2 to 10 cm2 .
In accordance with another aspect of the present invention, the mask has a thickness in a range of about 0.5 mils to 10 mils.
In accordance with another aspect of the present invention, the mask has a thickness in the range of about 0.01 mils to 10 mils.
In accordance with another aspect of the present invention, the hydrogel has a thickness in a 6a range of about 10 mils to 50 mils.
In accordance with another aspect of the present invention, the hydrogel has a thickness in a range of about 5 mils to 60 mils.
In accordance with another aspect of the present invention, the assembly has a total thickness in a range of about 5 mils to 50 mils.
In accordance with another aspect of the present invention, the assembly has a total thickness in the range of about 5 mils to 70 mils.
In accordance with another aspect of the present invention, there is provided an assembly for use in monitoring a chemical signal, comprising:
a) an sonically conductive material comprised of water, electrolyte and an enzyme;
b) a working electrode having a catalytic surface comprised of a material selected from the group consisting of platinum, palladium, nickel, and oxides, dioxides and alloys thereof, the catalytic surface contacting a first face of the sonically conductive material; and c) a chemical signal impermeable mask positioned on a second face of the sonically conductive material (a) opposite the first sonically conductive material face and opposite the catalytic surface of the electrode (b), the mask having an outer perimeter which is equal to or extends beyond an outer perimeter of the working electrode (b) and having an opening therein which has a perimeter which is equal to or circumscribed within the outer perimeter of the working electrode, wherein chemical signal transported through a plane of the mask, through the sonically conductive material, and toward the 6e catalytic surface of the electrode is substantially only that chemical signal transported in a direction substantially perpendicular to the catalytic surface of the electrode.
In accordance with another apsect of the present invention, in the assembly for use in monitoring a chemical signal, the material (a), electrode (b), and mask (c) are such that the mask blocks substantially all chemical signal flowing to the catalytic surface which is not flowing in a direction substantially perpendicular to the catalytic surface and allows substantially all chemical signal to flow to the catalytic surface which is flowing to that surface in a substantially perpendicular path.
In accordance with another apsect of the present invention, in the assembly for use in monitoring a chemical signal, the first and second faces of the sonically conductive material each have a geometric surface area in a range of about 0.5 cm2 to 10 cm2 and the material has a thickness in range of about 5 to about 50 mils, further wherein the working electrode (b) has a geometric surface area in a range of about 0.25 to about 5.0 cm2, and still further wherein the mask (c) has a thickness in a range of about 0.5 mil to about 10 mils.
In accordance with another apsect of the present invention, in the assembly for use in monitoring a chemical signal, the first and second faces of the sonically conductive material each have a geometric surface area in a range of about 0.5 cmz to 10 cm2 and the material has a thickness in range of about 5 to about 60 mils, further wherein the working electrode (b) has a geometric surface area in a range of about 0.05 cm2 to 6f about 8 cm2, and still further wherein the mask (c) has a thickness in a range of about 0.01 mil to about 10 mils.
In accordance with another aspect of the present invention, there is provided an assembly for use in a monitoring device for monitoring a chemical signal, comprising:
a) an sonically conductive material;
b) a mask characterized by being impermeable to the chemical signal, the mask being positioned between sonically conductive material and a source of chemical signal; and c) a working electrode which measures chemical signal transported from the source of chemical signal wherein the mask is concentric to the working electrode and further wherein the chemical signal that passes through a plane of the mask is that chemical signal that is transported from the source to the catalytic surface in a manner which is substantially perpendicular to the catalytic surface.
In accordance with another aspect of the present invention, in the assembly for use in a monitoring device for monitoring a chemical signal, the sonically conductive material is a hydrogel having an enzyme therein and the catalytic surface is comprised of a material selected from the group consisting of platinum, palladium, nickel, oxides thereof, dioxides thereof and alloys thereof.
In accordance with another aspect of the present invention, there is provided a method of measuring a concentration of a chemical present in a bloodstream of a mammalian subject, comprising the steps of:
6g contacting a mammalian subject's skin with a sensor assembly comprising;
a) an sonically conductive material in contact with the skin;
b) a working electrode in contact with the sonically conductive material the working electrode having a catalytic surface; and c) a mask having an opening therein wherein the mask is positioned between the skin and the working electrode;
transporting a chemical through the skin and sonically conductive material whereby the mask blocks flow to the catalytic surface except for flow substantially axial to the catalytic surface;
monitoring an electrical signal generated at the working electrode by catalytic conversion into an electric signal at the catalytic surface of the working electrode;
wherein the electrical signal generated at the working electrode over a given period of time is correlated with a concentration of chemical present in the bloodstream of the mammalian subject.
In accordance with another aspect of the present invention, in the method of measuring a concentration of a chemical present in a bloodstream of a mammalian subject, the assembly further comprises:
d) an electroosmotic electrode in contact with the sonically conductive material and said transporting is accomplished by applying an electrical current to the electroosmotic electrode.
6h In accordance with another aspect of the present invention, in the method of measuring a concentration of a chemical present in a bloodstream of a mammalian subject, the chemical is glucose, the sonically conductive material is a hydrogel, and the catalytic surface of the working electrode comprises a material selected from the group consisting of platinum oxide and platinum dioxide.
In accordance with another aspect of the present invention, in the method of measuring a concentration of a chemical present in a bloodstream of a mammalian subject,the chemical is glucose, the hydrogel comprises a hydrophilic polymer, water and glucose oxidase.
In accordance with another aspect of the present invention, there is provided a method of measuring a glucose concentration in a mammalian subject, the method comprising:
contacting a first surface of an sonically conductive material with a skin surface wherein the sonically conductive material comprises water and glucose oxidase;
contacting a second surface of the conductive material with a working electrode;
applying current to the skin in an amount sufficient to draw glucose into the conductive material whereby the glucose is converted to gluconic acid and hydrogen peroxide and the hydrogen peroxide is drawn to the working electrode; and positioning a mask impermeable to the hydrogen peroxide between the skin surface and a surface of the working electrode so as to shield the working electrode surface from hydrogen peroxide moving to the working 6i electrode surface via any path other than a path substantially axial to the working electrode surface.
In accordance with another aspect of the present invention, the mammalian subject is a human.
An aspect of the invention is to provide a disposable assembly which makes it possible to proportionally measure a chemical signal by conversion into an electrical signal, where the electrical signal can be measured and accurately correlated with the amount of chemical signal present in a given source (e.g., the amount of chemical signal present in and/or below a section of skin, or in a hydrogel patch in contact with the working electrode).
An advantage of the invention is that use of the mask with a working electrode and hydrogel allows for measurement of very small amounts of an electrochemical signal. For example, the mask of the invention can be used in conjunction with a working electrode, electroosmotic electrode and hydrogel system for monitoring glucose levels in a subject. An electroosmotic electrode (e. g., reverse iontophoresis electrode) can be used to electrically draw glucose into the hydrogel. Glucose oxidase (GOD) contained in the hydrogel catalyzes the conversion of glucose to generate a reaction product (hydrogen peroxide) which can be proportionally converted to an electrical signal. The electroosmotic electrode is switched off and the working electrode of the invention is turned on. The working electrode catalyzes the resulting chemical signal into an electrical signal which is correlated to the amount of chemical signal. This system allows for the continuous and accurate measurement of an inflow of a very small amount of glucose (e. g., glucose concentrations 10, 500, or 1,000 or more times less than the concentration of glucose in blood).
Another advantage is that the mask is easily and economically produced and is disposable.
A feature of the mask and the device used therewith is that it is flat (e. g., a disk with s substantially planar surfaces), thin (e. g., 0.5 to. l0 mils), impermeable to chemical signal flow with the electrode/mask/hydrogel assembly having a surface area on each face in the range of about 0.5 cm2 to l0 cm2.
A feature of the mask is that where the mask 1o includes an opening, the opening has substantially the same dimensions or smaller as the working electrode i.e., the outer perimeter of the opening is circumscribed within the outer perimeter of the catalytic surface of the working electrode.
1s These and other aspects, advantages and features of the present invention will become apparent to those persons skilled in the art upon reading the details of the composition, components and size of the invention as set forth below reference being made to the accompanying 2o drawings forming a part hereof wherein like numbers refer to like components throughout.
Hrje Descriot;on of the Drawin_Q
Figure 1 is an overhead schematic view of a disc or donut shaped embodiment of the mask of the invention.
25 Figures 2A and 28 are cross-sectional views of embodiments of an electroosmotic electrode/working electrode/hydrogel patch assembly with a mask according to the invention.
Figure 3 is a cross-sectional view of an 3o electroosmotic electrode/sensing electrode/hydrogel patch assembly without a mask according to the invention.
Figure 4 is a schematic representation of the reaction which glucose oxidase (GOD) catalyzes to produce gluconic acid and hydrogen peroxide; hydrogen peroxide is then catalyzed at the working electrode into molecular oxygen, 2 hydrogen ions, and 2 electrons, the latter of which generates an electrical current. ., Figure 5 is a cross-sectional schematic~view of a mask of the invention provided below a hydrogel patch.
Figure 6 is an overhead schematic view of a sensor housing containing electroosmotic and working electrodes and a mask. .
Figure 7 is a graph~showing the measured 1o electrical current at the working electrode in the absence of the mask for different intervals as a function of time:
Figure 8 is a graph showing the measured electrical current at the~working electrode in the presence of the mask for different intervals as a function of time.
Figure 9 is a graph showing a comparison of the measured electrical-current at the working electrode either with the mask or without the mask as a function of 2o interval number.
Besc~iption of the Preferred Embodiments Before the mask of the present invention and assembly comprising such is described and disclosed it is to be understood that this invention is not limited to the particular components or composition described as such may, of course, vary. It is also to be understood that the terminology used herein~is for the purpose of describing particular embodiments only, and is not intended to be limiting since the scope of the present 3o invention will be limited only by the appended claims.
It must be noted that as used in this specification and the appended claims, the singular forms ''a", "an" and "the" include plural referents unless the context clearly dictates otherwise. .Thus, for example, _ g _ reference to "a molecule" includes a plurality of molecules and different types of molecules.
Unless defined otherwise all technical and scientific terms used herein have the same meaning as s commonly understood by one of ordinary skill in the art to which this invention belongs. Although any materials or methods similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials io are now described. All publications mentioned herein are incorporated herein by reference for the purpose of describing and disclosing the particular information for which the publication was cited in connection with.
pef initions 1s The term "mask," '~impermeable mask," or "mask of the invention" means a thin (less than 50 mils, preferably 0.5 mil to 5 mils in thickness), substantially flat piece of material that, when,positioned within the transport path of chemical,signal moving toward a working 2o electrode, reduces or prevents transport of chemical signal in a radial direction from the chemical signal source. The mask can be positioned on a face of the sonically conductive material, or can~be positioned at any position within the sonically conductive material 2s (e.g., such that the mask is contacted by material on each of its planar surfaces). In one exemplary configuration, the mask has an opening, which opening is substantially. the same shape and size (e. g., smaller than or equal to) that of the working electrode. Thus, the 30 outer perimeter of the opening is circumscribed substantially within~the outer perimeter of the 'catalytic ' surface of the working electrode. When the opening is circular, the diameter is equal to or less than the ' diameter of the circular catalytic surface of a working electrode with which.the mask is to used. In an alternative exemplary configuration, the mask is a solid piece of material (i.e., does not-have an opening), and is used in conjunction with, for example, an annular working electrode. This type of mask is concentrically .
positioned with respect to the working electrode, s'o that chemical signal does not'enter the region substantially concentric to the annular working electrode. The mask is composed of a material that is substantially impermeable to to the flow of chemical signal that, is to be detected.
The mask and/or the mask opening are of a size sufficient to allow a detectable amount of chemical signal to reach the working electrode, while reducing or preventing entry of chemical signal into the electrolyte flow path that has a potential to be transported (eg., by diffusion) in a radial direction toward an edge of~the working electrode. Thus, the mask substantially eliminates "edge effect" flow, i.e., the chemical signal impermeable mask area prevents chemical signal from contacting the 2o electrode unless the signal flows substantially perpendicular to the surface of the working electrode.
The term "working electrode" means an electrode that detects a chemical signal by catalyzing the conversion of a chemical. compound into an electrical signal (e.g., conversion of hydrogen peroxide into 2 electrons, molecular oxygen, and 2 hydrogen ions).
The term "catalytic surface'.' or "catalytic face"
means the surface of the working electrode that: 1) is in contact with the surface of an ionically conductive 3o material which comprises an electrolyte and allows for the flow of chemical signal; 2) is composed of a catalytic material (e. g., carbon, platinum,~palladium, nobel metal, or nickel and/or oxides and dioxides of any of these); and 3) catalyzes the.conversion of the chemical signal into an electrical signal (i.e., an electrical current) that is monitored and correlated with an amount of chemical signal present at the electrode.
."Chemical signal," ''electrochemical signal," or "electrochemically active compound" means the chemical compound that is ultimately converted to an electrical signal and measured by the working electrode in conjunction with a monitoring device. Chemical signal which moves toward the working electrode at an angle, i.e., includes a radial vector component, is blocked by to the mask. "Chemical_signals" can be:, 1) directly converted into an electrical signal by chemical reaction at the catalytic face of the electrode; or 2) indirectly converted into an electrical signal'by the action of one or more catalysts. For example, the chemical signal glucose is indirectly. converted into an electrical signal by reactions driven by two catalysts. A first catalyst, the enzyme glucose oxidase (GOD), converts glucose into gluconic acid and hydrogen peroxide. Hydrogen peroxide is then converted to an electrical signal by a second 2o catalyst which second catalyst is the catalytic material (e.g., metal.or metal oxide on the catalytic face of the working electrode.
"Ionically conductive material" means a material that provides ionic conductivity, and through which electrochemically active species can~be transported (e.g.,.by diffusion). The ionically conductive material can be, for example, a solid, liquid, or semi-solid (e.g., in the form cf a gel) material that contains an electrolyte, which can be composed primarily of water and 3o ions (e. g., sodium chloride). Generally, the material comprises water at 50% or more by weight of the total material weight. The material can be in the form of a gel, a sponge or pad (e. g., soaked with an electrolytic solution), or any other material~that can contain an ' 3s electrolyte and allow passage of electrochemically active species, especially the chemical signal of interest, through it. An exemplary sonically conductive material in the form of a hydrogel is described in PcT wo 97/o2s11, published January 30, 1997.
A "chemical signal target area" is an area on a surface of an sonically conductive material toward which chemical signal transport is desired. The chemical signal target area is~generally an area of the sonically to conductive material. that, during chemical signal monitoring, is in contact with a chemical signal sensing means (e. g., a catalytic face of a'working electrode), and is of the same size and shape as the portion of the chemical signal sensing means in contact with the is sonically conductive material surface (e. g., the same size and shape as the catalytic face of the working electrodej. For example, where the chemical sensing means to be used with the sonically conductive material is a circular working electrode, the chemical signal.
2o target area is a circular area of the sonically conductive material face that contacts the catalytic surface of the circular working electrode during chemical signal monitoring. In another example, where the chemical sensing means to be used with the sonically 2s conductive material is an annular working electrode, the chemical signal target area is an annular area of the sonically conductive material face that contacts the catalytic surface of the circular working electrode during chemical signal monitoring.
3o Mask lGeneraW
The invention must provide some basic characteristics in order to be useful for its intended purpose, which is to inhibit contact between a working electrode and radially inward transported chemical signal, particularly the form of the chemical signal that can be catalyzed into an electrical signal at the catalytic surface of the electrode (e. g., hydrogen peroxide that results from conversion of the chemical signal glucose).
For example, the mask of the invention can be used in connection with any metabolite monitoring device, where the device contains a working electrode that detects a chemical signal that is transported from one area (e. g., the skin and tissues: below the skin) through an ion conducting material (e.g., a hydrogel) to the electrode surface. Examples of such devices include those described in PCT application serial no.
PCT/GB93/00982.
Further exemplary devices, hydrogels, and additional components for use with the present invention are deSCribed in PCT WO 97/02811, published January 30, 1997 and in PCT WO 97/10499, published March 20, 1997.
which applications disclose inventions which were invented under an obligation to assign rights to the same entity to which the rights in the present invention were invented under an obligation to assign a An exemplary sonically conductive material suitable for use with the invention is a hydrogel composed of a hydrophilic compound, water, and a salt.
The hydrophilic compound forms a gel in the presence of water, and is generally present in the gel in an amount of about 4% or more by weight based. on the total gel weight. The gel contains water in an amount of about 95%
or less based on the weight of the hydrogel. The salt can be any salt that ionizes readily in water and facilitates electric conductivity through the gel, WO 97/10356 PCTlUS96/11776 preferably a chloride containing salt (e. g., NaCl, KC1, etc. ) .
Regardless of the composition of the sonically conductive material, one face of the material has a s chemical signal target area. The target area is the area .
on a face of the material toward which chemical signal transport is desired, e.g., the area of the material face that will be in contact with the catalytic face of'a working electrode during chemical signal sensing.
to Preferably, the target area of the.ionically conductive material is used with a working electrode that has a catalytic face.having approximately the same shape and size as the target area (e. g., circular, annular,. etc.).
During monitoring, the mask is positioned on a second 15 sonically, conductive , material face opposite the first material face having the target area, such that chemical signal that diffuses from the chemical signal source, through a plane of the mask, through the sonically conductive material, and toward the chemical signal 2o target area is substantially only that chemical signal that is transported in a direction substantially perpendicular to the chemical signal target area.
An exemplary monitoring device that can be used in connection with the mask of the invention is generally 25 composed of: 1) a hydrogel patch, one face of which is contacted with a source of biologically important molecules such as the skin of a mammalian subject; 2) an electroosmotic electrode which is positioned on the face of the hydrogel patch opposite the face in contact with 3o the mammalian subject s skin; 3) a working electrode having a catalytic material on at least. its catalytic face, the catalytic face of the electrode being that face in contact with the same face of the hydrogel as the electroosmotic electrode; 4) a means for generating an 35 electrical current, through the electroosmotic electrode, the electrical current serving to electrically draw molecules through the mammalian subject's skin, into the hydrogel patch, and toward_the catalytic face of the working electrode; and 5) a monitoring means for monitoring, electrical current generated at the catalytic face..of 'the working electrode. Alternatively, the chemical signal can enter the hydrogel by passive diffusion, i.e., the assembly can be used without an electroosmotic electrode.
1o Such a monitoring device can be used to monitor levels of a metabolically important compound in, for example, the bloodstream of a mammalian subject (e.g., a human subject). As used herein, the metabolic compound in this example is termed the "chemical signal." For example, the metabolic~compound (and chemical signal) can be glucose. That chemical signal is converted to.a useful chemical signal and then converted to.an electrical signal as shown in Figure 4. The electroosmotic electrodes are used to electrically draw 2o glucose~molecules through the mammalian subject's skin, into the hydrogel, and toward the catalytic face of the working electrode. The hydrogel contains the enzyme glucose oxidase (GOD), which converts the glucose into gluconic acid and hydrogen peroxide. The hydrogen 2s peroxide is then converted into molecular oxygen, 2 hydrogen ions, and 2 electrons, the latter of which generates an electrical current in the working electrode (see.Figure 4)~. The electrical current is measured by the attached monitoring device,_and correlated with the 3o amount of glucose present in the subject's bloodstream.
An assembly of the invention comprised of an electrode~and mask positioned on either side of a.
hydrogel is used with a monitoring device as described above by positioning the mask between mammalian subject's 35 skin and the face of the hydrogel in contact with the subject's skin, such that chemical signal that diffuses from the subject's skin and past the plane of~the mask is only that chemical signal that is transported in a path substantially perpendicular to the catalytic face of the working electrode. It is important that the mask does not completely occlude contact of the ionically conductive material (e.g., the hydrogel) with the chemical signal source (e. g., the subject's skirt).
An exemplary assembly of the invention is shown in 1o Fig. 2A, where the working electrode 4 and mask 1 are circular, and .the mask has an opening 2 that is positioned so that it is directly beneath the working electrode 4 on the opposite face of the gel 3. Because the mask is impermeable to the chemical signal (e. g., 1s glucose), chemical signal is electrically drawn via a substantially perpendicular path only through the opening in the mask. An additional exemplary assembly of the invention is shown in Fig. 2B, where the working electrode is annular (circular with a circular opening in 2o the center), and the mask 1 is a solid, circular piece positioned concentric to the working electrode such that the outer perimeter of the mask 1 is substantially circumscribed within the inner perimeter of the annular working electrode 4. In this embodiment, the annular 2s working electrode extends from approximately the.outer perimeter of the mask~to the outer perimeter of the ionically~conductive material (e.g., hydrogel) used in conjunction with the mask 1 and working electrode 4. For example, where the radius of the a circular hydrogel is 30 0.95 cm, the radius of the mask can be about 0.5 cm and the width of the working~electrode is about o.45 cm.
The position of the mask, and the inhibition of the entry of glucose into gel areas other than that directly beneath the working electrode minimizes the 35 radial component of chemical~signal transport. Reduction of radial transport of the chemical signal toward the working electrode reduces accumulation of such radially transported compound at the periphery.of the electrode, thereby reducing the edge effects~associated with. this s phenomenon. . It is recognized that the mask can allow for a small amount of radial chemical signal transport from the chemical signal source toward the working electrode where, for example, the error in measured electrical current associated with electrochemical conversion of the to radially transported chemical signal is of a magnitude that does not significantly affect the accuracy of the measurement of the amount of chemical signal (e.g., the concentration of chemical signal in a subjects bloodstream). Thus, for example, where the mask has an is opening, the opening can be slightly larger than the diameter of the working electrode used in conjunction with the mask.
The (ij size or geometric surface area of the working electrode, (2) thickness of the gel, (3) size of 2o the opening in the mask, and (4) width of the mask surrounding the opening are all interrelated to each other. For example, when the thickness of the gel is~
increased the size of the opening must be decreased to obtain the same degree of. elimination of radially 2s transported chemical signal.. The smaller the opening in the mask the greater the ability to block radial transport of chemical signal. Although it is desirable to decrease radial transport of the chemical signal, it is also desirable to maximize the chemical signs-1 3o received and the chemical signal is decreased by a smaller opening in the mask.
For reasons that may relate to factors such as the build up of undesired materials, components such as the hydrogel, mask and the electrodes must be easi~.y 3s replaceable by a patient in a convenient manner.
Accordingly, an assembly of these components must have some structural integrity, and provide for the detection of the chemical signal of interest. In that the device is preferably small (e.g., hand held, e.g., the size of a s watch to be worn on the wrist of a patient), it is necessary that the assembly of components be particularly thin. The mask generally has a thickness of about 0.5 to mils (1 mil equals one thousandth of an inch) and the hydrogel has a thickness in the range of about 5 mils to 10 60 mils, generally about 10 mils to 60 mils, normally about~600 microns (about 24 mils).
In order to accurately measure the amount of a chemical. signal (e. g., the amount of hydrogen peroxide generated by GOD catalysis of glucose) and be 1s sufficiently large to be manipulated, the device cannot be too thin and cannot be too small. The overall surface area of the hydroge~l on a single surface should_be in the range of about 0.25 cm2 to about 10 cm2, preferably about 0.50 cm2 to 5 cm2. The electrodes of the entire 2o monitoring device, which include both electroosmotic and working.electrodes, must have a total.surface area that is less than that of the hydrogel patch. In general, the surface area of a mask (the area of the mask, and the opening where applicable) suitable for use in the 25 monitoring device ranges from about 0.1 cm2 to about 6 cm2, preferably about 0.25 cm2 to 2.0 cm2, more preferably about 1.0 cm2.
l~sic Structure Figure 1 is an overhead schematic view of an 3o exemplary mask of the invention. The mask may be any configuration but is.preferably donut shaped as per Figure 1, with an outer perimeter that is equal to or larger than that of the working electrode and/or is substantially the same as the hydrogel patch used in conjunction with the mask. The mask opening is generally equal in. size to about 50% of the area of the working electrode,~ 20%. In general, the mask opening constitutes an area that is in the range of 1% to 90% of the area encompassed by.the mask plus the opening. The mask 1 is disc-shaped, and has a diameter equal to or less than the diameter of the hydrogel patch used in conjunction with the mask, the diameter being in the general range of about 0.5 cm to 3.0 cm, generally about l0 1.9 cm. In general, the range of the surface area of the hydrogel patch used in conjunction with the mask is from about 0.5 cm2 to about 10 cm', preferably in the range of about 1 cm2 to about 5 cm2. The mask 1 defines.an opening 2 positioned~substantially in the center of the mask 1.
The diameter of opening 2 is less than or equal to the diameter of the catalytic surface. of the working electrode that is to be used in conjunction with the mask, generally in the range of about 0.4 cm. Normally, the mask opening constitutes-an area that is about 5/8 ~ 15% of the total area encompassed by the catalytic face of the working electrode, equal to, or slightly larger than the catalytic face of the working electrode (e. g., 100.5% to 105% of the catalytic surface area).
Alternatively, the mask can be a composed of a 2s solid, circular piece for use with, for example, an annular working electrode. The solid, circular mask is concentrically positioned with respect to an annular working electrode such that the outer perimeter of the solid circular piece is circumscribed substantially 3o within the inner perimeter of the annular working electrode. Thus'chemical signal that diffuses from the chemical signal source and through the masks) is substantially only that chemical signal that diffuses from the chemical signal source in a direction that is 3s substantially perpendicular to the plane of the mask, and thus, substantially perpendicular to the annular working electrode catalytic face.
The mask is preferably thin, generally having a thickness in the range of aboutØ01 mil to 10 mils, normally about 0.5 mil to 5 mils (1 mil equals one-thousandth of an inch).. The working electrode used in conjunction with the mask of the invention generally has a geometric surface about 5% to 90%, preferably about 10%
to 80% of the geometric surface of the~hydrogel.
1o The mask is composed of a material that is substantially impermeable to the.chemical signal to be detected (e.g., glucose), and can be permeable to substances other than the chemical signal of interest.
By "substantially impermeable" is meant that.the~mask 1s material reduces or eliminates chemical signal transport (e. g., by diffusion). The mask can allow for a low level of chemical signal transport, with the proviso that chemical signal that passes through the material of the mask does not cause significant edge effects at the 2o working electrode use in conjunction with the mask.
Examples of materials that can be used to form the impermeable mask include mylar, polyethylene, nylon and various other synthetic polymeric material. The mask can be composed of a.single material, or can be composed of 2s two or more materials (e.g., the mask is composed of multiple layers of the same or different materials) to form a-chemical signal-impermeable composition.
In general, the size of the mask (i.e., diameter, surface area, thickness, etc.), the geometry of the mask 30 (e.g., circular, oval, annular, polygonal, etc.), the size (e. g., diameter; surface area, etc.) and/or geometry (e. g., annular, circular, oval, polygonal) of a mask opening through which the chemical~signal is to be detected, compositions of the mask (e. g., type and number 35 of materials, number of layers, chemical signal to which the mask is permeable), the number of mask used in an assembly of the invention (i.e., the number and position of the masks in the electrolyte flow path between the catalytic surface of the working electrode and the s chemical signal source) and other characteristics of .the mask will vary according to a variety of factors such as, for example, the diameter of the hydrogel patch, the diameter of the working electrode, the diameter of the electroosmotic/working electrode assembly, the chemical to signal to be detected, the characteristics of the chemical signal's path of transport (e. g., the diffusion characteristics of the chemical signal), and the geometry and size of the monitoring device.
Methods for making the mask include die cutting 15 and stamping. according to methods well known in the art.
Most preferably, the mask is manufactured in a manner that'is the most economical without compromising performance of the mask (e.g, the impermeability of the mask to the chemical signal of interest, the ability to 2o manipulate the mask by hand without breaking or otherwise compromising its operability). The mask may have an adhesive including a pressure sensitive adhesive coated on one or both surfaces. Further, the mask may be coated with a material which absorbs one~.or more compounds or 25 ions flowing in the hydrogel.
~onf ig~urations The mask can be supplied in several different configurations. Examples of these configurations include: 1) the mask supplied in connection with a 3o hydrogel patch; 2) the mask supplied as an integral component of a monitoring device; or 3) the mask supplied as an independent component.
Fig. 5 illustrates how the mask of the invention can be supplied with a hydrogel patch as a hydrogel/mask assembly 12. The mask 1 is.positioned on one face of the gel 3. The mask can be attached to the gel 3 by any suitable chemical means (e.g., adhesive) that do not -affect the impermeability of the mask to the chemical signal of interest or the conductivity of the gel for electrically-induced movement of the chemical signal through the mask opening and into and through the hydrogel. Release liner components 9 and 10 are positioned on opposite surfaces of the assembly 12 to 1o provide improved handleability of the assembly 12 in that the assembly 12 may be slightly fragile (e. g., may tear during shipping or repeated handling) and/or wet and sticky The release liner 10 may include a perforated cut (e. g., an S-shaped cut) or may include two portions 11 and l3.that overlap one another to allow easy removal of the release liner, l0. Prior to use, the release liners 9 and 10 are removed from the assembly 12, and the assembly 12 positioned in the sensor~housing of a monitoring device so that the mask will be in contact 2o with the subject s skin, and the hydrogel will be in contact with the electroosmotic and working electrodes.
In another embodiment, the mask is an integral component of the sensor housing of a monitoring device.
An example of a sensor housing of a.monitoring device is illustrated in Fig. 6~. The sensor housing 16 of the monitoring device includes a top portion 15 containing electroosmotic 5 and working 4 electrodes, and a bottom portion 14 defining an opening 17, the opening having a diameter at least slightly less than that of the mask 1 3o so that the mask fits tightly in the recess 19. The top portion 15 and the bottom portion 14 can be connected by a hinge 18 that permits opening and closing of the sensor housing. The mask 1 is either permanently or re~aovably fitted over this sensor housing opening 17. The edges of the sensor housing opening 17 can define a recess 19 so as to easily receive the mask 1 and seat the mask 1 within the recess 19. The mask can be secured into position in the bottom portion 14 of the sensor housing 16 by any suitable chemical means (e.g., adhesive) or . s physical means (e.g., physically attaching the mask to the opening by melting the edges of the mask 1 edges to the edges of the opening 17), provides that the operability of the mask, the hydrogel, the sensor housing, and/or the monitoring device are not io significantly affected.
The entire assembly is used by inserting a hydrogel patch (as per the gel 3 of Fig. 5) over the mask 1 in the bottom portion 14, and bringing the top portion 15 into position over the bottom portion 14 so that the 15 electroosmotic electrode 5 and working electrodes 4 contact the central portion of the hydrogel. The top portion 15 and the bottom portion l4 can be held together by interconnecting portions of a securing means 19 (e. g., a latch) which can be closed and opened repeatedly, 2o preferably for the life of the sensor housing. The bottom portion 14 is then positioned on the subject's skin so that the hydrogel contained within the bottom portion 14 is in contact with the skin through opening 2.
When properly aligned, the opening 2 in the mask 1 is 25 positioned beneath the approximate center of the catalytic face 6 of the working electrode 4, so that chemical signal that is transported axially through the hydrogel accessible through the mask opening 2 and will come in contact with the central portion of the catalytic 3o face 6 of the working electrode 4. In another embodiment, the mask is supplied as an independent component, e.g. for insertion into a sensor housing as exemplified in Fig. 6. The mask is inserted in the device prior to use as described above and in Fig. 6, the 35 hydrogel inserted within the bottom portion of the sensor housing and on top of the mask, and the device assembled as described above.
Regardless of the embodiment used, all of the masks of the invention: 1) are impermeable to the s chemical signal to be detected; 2) have a diameter that is at least the same or.greater than the diameter of the hydrogel patch used-in conjunction with the mask; and either 3) are configured for use with a working electrode so that when positioned in the path of electrolyte flow io from the chemical signal source, substantially only chemical signal that flows from the source in a direction substantially perpendicular to the working electrode is allowed to enter the electrolyte flow path.
The mask is generally used in conjunction with an 1s electroosmotic electrode (e.g., an iontophoresis or reverse iontophoresis electrode). An electroosmotic electrode suitable for use with the invention is deSCrlbed In PCT W0 96/00109, published January 4, 1996 20 (which discloses an invention invented under an obligation to assign to the same entity as that to which the rights in the present application are assigned)..
The electroosmotic electrode is used to create an 2s electrical field which transports material such as ions and non-polar molecules from one area (e. g., skin, blood and flesh) to the area of the working electrode. It is important the electroosmotic electrode and the working electrode be used alternately (i.e., current is present 3o in the electroosmotic electrode or the electrical current generated at the working electrode is measured -- not both at once).
Working electrodes suitable for use with the invention include any electrode having a catalytic 3s surface for detection of a chemical signal. An example of a suitable working electrode is described in PcT wo 97/10499, published March 20, 1997.
A standard bipotentiostat circuit can be used to bias~the working and scavenging electrodes independently versus the reference electrode.
Based on the description above and in the figures, it will be recognized that the working electrode of the io invention can be configured in a variety of different forms, and from a variety of different materials. The mask will change with the working electrode so as to maintain certain defined mechanical, electrical, chemical and transport (e. g., diffusion) characteristics.
i5 Mechanically the mask will have sufficient structural integrity such that it can be readily handled by human fingers without significant handling difficulties or significantly compromising the performance of the mask. Preferably, the mask will be 2o somewhat flexible so that it can bend at least slightly during.handling without creasing, breaking, or being otherwise compromised in, for example, its impermsability to the chemical signal of interest. The relative mechanical requirements of the mask may vary with the 2s particular mask embodiment. For example, where the mask is an integral part~of the sensor housing, it may be desirable to design the mask so that it can be separated from the patch without significantly tearing the patch, or adhering to the patch in a manner that makes it , 3o difficult to completely remove all patch material from the face of the mask.
The mask must maintain its impermeability to the chemical signal of interest. Preferably, the mask will optimally function at a pH which is relatively close to that from which the chemical signal is withdrawn (e. g, human skin (about 7)) and at least within a range of from about pH 4 to pH 9.
Utili~
The present invention is useful in connection with the detection of biologically significant molecules such as glucose which is moved through human skin using a technique known as electroosmosis. The basic concept of moving a molecule such as a glucose through human skin is disclosed within U.S. PatBnt 5,362,307, issued November 8, 1994 and U.S. Patent 5,279.,543, issued January 18, for disclosing the basic concept of moving molecules such as glucose through human skin by means of electroosmosis.
The concept of converting the very small amounts of molecules such as glucose which can be extracted through the skin in order to create a current by use of glucose OXidaSe is dlsclOSed in PCT WO 96/00109, published January 4, 1996; PCT WO 96/001100 published January 4, 1996;
PCT WO 97/02811, published January 30, 1997 and PCT WO 97/1Q~99, published March 20, 1997, (which applications disclose inventions which were invented under an obligation to assign rights to the same entity to which the rights in the present invention were invented under an obligation to assign.
Fig. 2A illustrates how an exemplary mask of the invention is used in conjunction with a hydrogel/electroosmotic electrode/working electrode system, such as that used in a metabolite monitoring device (e.g., a glucose monitoring device). The mask 1 is positioned on a face of the gel 3 with the opening 2 substantially in the center of the gel 3. A working - 5 electrode 4 and electroosmosis electrode 5 are positioned on the face of the gel 3 opposing the mask 1. The catalytic surface 6 of the working electrode 4 is positioned on the gel 3 so that the working electrode 4 is.directly opposite the opening 2 of the mask 1. The 1o face of the gel 3 attached to the mask 1 is placed on the surface 7 through which the chemical signal is to be diffused (e. g., mammalian skin, e.g., human skin).
During use in monitoring levels of a chemical signal of interest (e. g., glucose), an electrical current 15 is sent through the electroosmotic electrode, thereby drawing molecules through.the patient s skin and into the hydrogel patch. The mask permits entry of the chemical signal into the gel only at the opening 2, thus reducing the amount of chemical signal.that is radially 2o transported into the.patch, as well as the amount of chemical signal that is capable of being transported radially toward the working electrode. The mask creates a column-like flow through the gel to. the working electrode and substantially prevents any material from 25 flowing to the electrode if that material includes a radial vector as a component of its movement, i.e., the material must move axially or perpendicular to the working electrode. The chemical signal permitted into the patch by entry through the opening in the mask is 3o transported in a substantially axial direction toward the catalytic surface 6 of the working electrode 4, where it is converted to an electrical signal. Alternatively, the ' chemical signal is converted into an intermediate compound by a component in the gel 3. The intermediate ' 35 compound in turn is transported to the catalytic surface 6 of the working electrode 4, where it is converted into an electrical signal. The electrical signal is detected by switching off the electroosmotic electrode, and monitoring the electrical current generated at the working electrode.
The use of the mask and advantages associated therewith are.further illustrated by comparing the flow of glucose in a monitoring system either with (Figs. 2A
and 2B) or without (Fig. 3) the mask of the invention.
1o Fig. 3 illustrates an electroosmotic electrode/working electrode/hydrogel patch assembly (without a mask of the invention) for monitoring glucose levels in a mammalian subject (e.g., a human subject). As described above, the electroosmotic electrodes (e. g., iontophoresis electrodes) 5 are activated to electrically draw , glucose 8 through the subject's skin 7 and into the hydrogel 3. The iontophoresis electrode 5 is used-to electrically draw glucose 8 through the subject's skin 7 and into the hydrogel 3. Glucose 8 is permitted to enter 2o the gel 3 over the entire face of the gel 3 in contact with the subject's skin 7. As a result, glucose is present throughout the entire gel 3, rather than in a region substantially perpendicular to the catalytic face 6 of the working electrode 4. The gel 3 contains the enzyme glucose oxidase (GOD), which converts the glucose to hydrogen peroxide and gluconic acid. The conversion of glucose to hydrogen peroxide by GOD is illustrated schematically in Fig. 3. The hydrogen peroxide is transported (e.g., by diffusion) toward the so catalytic face 6 of the working electrode 4, where it is converted into molecular oxygen, 2 hydrogen ions, and 2 electrons, the latter of which provides an electrical signal.
Because glucose is present throughout the entire 3s gel 3, the hydrogen peroxide resulting from enzymatic conversion of glucose is also present throughout the entire gel 3. Because the surface area of the gel is greater~than that of the working electrode, uncatalyzed hydrogen peroxide accumulates at the working electrode 4 s periphery due to radial transport of the compound toward the catalytic~surface 6. Accumulation of peroxide at the working electrode periphery produces a variable hydrogen peroxide flux (i.e.,,the amount of peroxide present over the working_ electrode at a given time is not directly 1o correlated with the actual peroxide flux through. the hydrogel), and thus produces a flux or error in the measured electrical current at the working electrode.
In contrast, and as illustrated in Figs. 2A and 2B, the mask 1 of the invention permits entry of 1s glucose 8 only at the opening 2 (in Fig. 2A) or the non-mask.contacting portion of the gel 3 (as in Figs. 2A and 2B). The opening and/or non-mask contacting gel surface is directly opposite the catalytic surface 6 of the working electrode 4. The glucose 8 is converted into 2o hydrogen peroxide and gluconic acid by GOD, which is contained in the gel 3. The hydrogen peroxide produced is generally positioned within the gel in a region that is beneath and substantially perpendicular to the catalytic.face 6 of the working electrode 4. Thus, the 2s radial transport component of hydrogen peroxide illustrated in Fig. 3 is eliminated, and an increased flux or error in current measured at the working electrode 4 periphery does not occur.
The composition, size and thickness of the mask 3o and other components can be varied and such variance can affect the time over which the components can be used.
For example, the hydrogel patches may be connected to the mask and are generally designed to provide utility over a period of about 24 hours. After that time some ' 35 deterioration in characteristics, sensitivity, and accuracy of the measurements from the electrode can be expected (e. g., due to reduced effectiveness of an enzyme in the hydrogel). Due to other problems the working .
electrode and hydrogel patch, preferably the entire device, should be replaced. The invention contemplates , components,.assemblies and devices which are used over a shorter period of time e.g., 8 to 12 hours or a longer period of time e.g., 1 to 30 days.
In its broader sense, a mask of the invention can 1o be used to carry out a method which comprises extracting any biomedically significant substance through the skin of a human patient and reacting that substance with another substance or substances (which reaction is greatly accelerated by the use of an.enzyme e.g., 10 to 100 times or more as fast) to form a product which is detectable electrochemically by the production of a signal which signal is generated proportionally based on the amount of a biologically important or biomedically significant substance drawn into the patch. As indicated in the above-cited patents the ability to withdraw biochemically significant substances such as glucose through skin has been established (see U.S. Patent Nos.
5,362,307 and 5,279,543). However, the amount of compound withdrawn is often so small that it is not possible to make meaningful use of such methodology in that the withdrawn material cannot be precisely measured and~related to any standard.
Moreover, conventional hydrogel/working electrode assemblies are severely compromised in their ability to 3o accurately, quickly, and continuously monitor levels of the chemical signal. As described above, in devices without a mask chemical signal is radially transported toward the catalytic surface of the working electrode and accumulates at the working electrode periphery, thus causing the flux or error of chemical signal to be greater. at the electrode edges than at the electrode center, a phenomenon termed "edge effects." The edge effects result in varying electrical signals, and thus varying and inadequate measurement of the flux of the ' s chemical signal. The present invention provides an electrode that is capable of detecting the electrochemical signal at very low levels in a manner that allows for direct, accurate correlation between the amount of signal generated and the amount of the molecule (e.g.,, glucose) in the area from which it is moved (e. g., in the human subject).
The invention is remarkable in that it allows for the noninvasive detection and measuring of amounts of a biomedically relevant compound, e.g.,.glucose, at levels i5 that are 1, 2, or even 3 orders of magnitude less than the concentration of that compound in, for example, blood. For example, glucose might be present in blood in a concentration of about 5 millimolar. However, the concentration of glucose in a hydrogel patch which 2o withdraws glucose through skin as described in the system above is on the order of 2 to 100 micromolar. Micromolar amounts are 3 orders of magnitude less than millimolar amounts. The ability to accurately and quickly detect glucose in such small concentrations is attained by 2s constructing the working electrode with the mask and other, components described herein.
~PLES
The foll-owing examples are put forth so as to provide those of ordinary skill.in the art with a 3o complete disclosure and description of how to make and use various specific'asse~blies of the present invention and are not intended to limit the scope of what the inventors regard as their invention. The data presented in these examples are computer-simulated (i.e., the data is generated from a computer model of the mask and electrode assembly described herein). The computer model of the invention uses the following parameters:
glucose diffusivity: 1.3 x 10-6 cm2/sec;
peroxide diffusivity: 1.2 x 10-5 cm2/sec;
enzyme rate constant: 735 sec-l;
KM for glucose: 1.1 .x 105 nmol/ml;
KM for glucose: 200 nmol/ml;
initial oxygen concentration: 240 nmol/ml;
1o enzyme loading in gel: 100 U/ml; and glucose flux: 5 nmol/cm2 hr.
Efforts have been made to~ensure accuracy with respect to numbers used, (e. g., amounts, particular components, etc.) but some deviations should be accounted for. .Unless indicated otherwise, parts are parts by weight, surface area is geometric surface area, temperature is in degrees centigrade, and pressure is at or near atmospheric pressure.
EX~PLE 1 Lg lucose monitoring 'device - no mask) 2o The peroxide flux or. current error at the surface of a platinum working electrode in a glucose monitoring device comprising an iontophoresis electrode/platinum working electrode/hydrogel assembly (no mask) was simulated by computer. The~computer-based experiments were designed to simulate the use of the device in vivo (e. g., the manner in which the device is used to monitor glucose in a .human subject). The computer simulation was based upon a continuous glucose flux into the hydrogel (5 nmol/cm2 hr), 18 U/ml glucose oxidase loaded into the 3o gel, a gel thickness of 600 microns, and alternate intervals of: 1) iontophoresis (i.e., the iontophoresis electrodes are activated, and glucose molecules are electrically drawn through the subject s skin and into and through the hydrogel patch); and 2) detection of an electrical current at the working electrode (i.e., the iontophoresis_electrode is switched off and the sensing unit'to detect electrical current at the working electrode is on). The experimental protocol is shown in s Table 1.
Table 1_: Experimental Protocol for Computer Simulation Interval Interval Length Iontophoresis Working No.' (min) Electrode Electrode 1 15 on of f 2 5 off on 3 15 on of f '4 5 . off on 5 15 on off 6 . 5 off on is This protocol was repeated for a total of 20 intervals.
The results of the computer model are shown in Fig. 7.
These data indicate that the electrical current measured at the working electrode is a function of the interval number, i.e., peroxide flux at the working 2o electrode increases with increasing interval number.
This is a direct result of the accumulation of hydrogen peroxide at the periphery of the working electrode as a result of radial transport of hydrogen peroxide within the gel.toward the electrode. As a result, the device is 25 never able to provide a steady state measurement profile in the presence of a continuous flow of glucose and hydrogen peroxide.
lPLE 2 - with a mask The computer model described in Example 1 was repeated with the same parameters, except that the device included a mask of the invention positioned between the s subjects skin and the hydrogel. The position of the mask.allows transport of glucose toward the working electrode only in a direction that is substantially axial to the catalytic face of the working electrode, and thus production of hydrogen peroxide only in a region of the to hydrogel that is directly beneath the working electrode.
Therefore, the amount of hydrogen peroxide that. is produced at a position outside the perimeter of the working electrode is essentially eliminated.
The results of the computer model, expressed as 1s the measured electrical current as a function of interval number, are shown in Fig. 8. These data indicate that after interval 2, the is independent of interval number.
Thus, within only 2 to 4 intervals, the device provides a steady state profile of the measurement of a continuous 2o flux of hydrogen peroxide.
EXZ~tumhE 3 - with and without a mask The data from the computer simulations of measurement of a constant glucose flux (5 nmol/cm2 hr) using a glucose monitoring device without the mask 25 (Example. l) and with the mask (Example 2) were analyzed to plot the electrical current measured at the working electrode after 5 minutes of measurement versus the interval number (Fig. 9). This analysis shows that in the absence of the mask, there is a strong dependence of 3o the measured electrical current on the interval number.
When the mask of the invention is included in the device, the profile of the measured electrical current is essentially linear, and thus independent of interval number (see "with mask" line of Fig. 9). ' The instant invention is shown and described herein in what is considered to be the most practical, . and preferred embodiments. It is recognized, however, that departures may be made therefrom which are within the scope bf the invention, and that modifications will occur to one skilled in the art upon reading this disclosure.
Field of the Invention s This invention relates generally to the detection of chemical signals that are diffused through a solid or semi-solid, or quiescent liquid surface, particularly where the chemical signals are associated with a medically important molecule.
se Backctroun3 of the Inverctian An electrode is the component in the electrochemical cell in contact with an electrolyte through which current can flow by electronic movement.
Electrodes, which are essential components of both 15 galvanic (current producing) and electrolytic (current using) cells, can be composed of a number of electrically conductive materials, e.g., lead, zinc, aluminum, copper, iron, nickel, mercury, graphite, gold, or platinum.
Examples of electrodes are found in electric cells, where 2o they are dipped in the electrolyte; in medical devices, where the electrode is used to detect electrical impulses emitted by the heart or the brain; and in semiconductor devices, where they perform one or more of the functions of emitting, collecting, or controlling the movements of 2s electrons and ions.
The electrolyte can be any substance that provides ionic conductivity, and through which electrochemically active species can be transported (e. g., by diffusion).
Electrolytes can be solid, liquid, or semi-solid (e. g., so in the form of a gel). Common electrolytes include sulfuric acid and sodium chloride, which ionize in solution. Electrolytes used in the medical field must ~ have a pH which is sufficiently close to that of the WO 97/10356 PC'1'/US96/11776 tissue in contact with the electrode (e.g., skin) so as not to cause harm to the tissue over time.
Electrochemically active species that are present in the electrolyte can undergo electrochemical reactions (oxidation or reduction) at the surface of the electrode.
The rate at which the electrochemical reactions take place is related to the reactivity of the species, the electrode material, the electrical potential applied to the electrode, and the efficiency at which the to electrochemically active species is transported to the electrode surface.
In unstirred electrolyte, such as quiescent liquid solutions and gel electrolytes, diffusion is the main process of transport of electrochemically active species is to the electrode surface. The exact nature of the diffusion process is determined by the geometry of the electrode (e. g., planar disk, cylindrical, or spherical), and the geometry of the electrolyte (e. g., semi-infinite large volume, thin disk of gel, etc.). For example, 2o diffusion of electrochemically active species to a spherical electrode in a semi-infinite volume of electrolyte differs from diffusion of electrochemically active species to a planar disk electrode. A constant and predictable pattern of diffusion (i.e., a diffusion 2s pattern that can be predicted by a simple equation) is critical in determining a correlation between the electrochemical current collected, and the concentration of the electrochemically active species in the electrolyte.
3o However, diffusion of electrochemically active species toward an electrode can not be predicted by a simple equation for every situation. For example, where the electrochemically active species diffuses through a disk-shaped electrolyte toward a smaller disk-shaped 35 electrode in contact with the electrolyte, the current observed at the electrode can not be predicted by a simple equation. In this latter situation, the inaccuracy in the diffusion model is caused by the combination of two different diffusion models. First, in the center of 0 5 the disk electrode the diffusion of the electroactive species towards the electrode is in a substantially perpendicular direction. Secondly, at the edges of the disk electrode the diffusion comes from both perpendicular and radial directions. The combination of 1o these two different diffusion patterns makes the total current collected at the disk electrode difficult to predict. In addition, the relative contributions of the diffusion fluxes from the axial and radial directions may change over time, causing further errors in predicted 1s current.
Summary of the Invention A mask which is substantially impermeable to the transport of a chemical signal is positioned in the chemical signal transport path moving toward a working 2o electrode which senses an electrochemical signal diffused through a material which is sonically conductive, which material comprises water and an electrolyte. More particularly, the mask of the invention is positioned on or in the sonically conductive material, such as an ion-25 containing gel, between an area from which the chemical signal is transported and the catalytic face of the working electrode used to sense the chemical signal. The configuration of the mask (e. g., shape, thickness, mask component(s)) is such that the mask prevents so substantially all chemical signal transport (from the chemical signal source) having a radial vector component ' relative to a plane of the mask and the catalytic face of the working electrode, thus allowing primarily only chemical signal transport (e.g., diffusion) that is substantially perpendicular to the place of the mask and the catalytic surface of the working electrode. The mask thus minimizes radial transport of the chemical signal to the working electrode and accumulation of chemical signal at the periphery of the working electrode. The mask thus ti significantly reduces or eliminates edge effects, since the chemical signal that reaches the electrode is primarily only that chemical signal that is transported in a direction substantially perpendicular to the 1o catalytic face of the working electrode. Substantially all transport of chemical signal to the working electrode surface via a path which includes an radial vector component (i.e., is not a path substantially perpendicular to the working electrode catalytic surface) 1s is prevented from occurring by the mask, since the mask blocks entry of potentially radially transported chemical signal at the source. By substantially reducing edge effects created by radial transport of chemical signal, it is possible to obtain a more accurate measurement of 2o the amount (e. g., concentration) of chemical signal that is transported from a given area of source material.
In one embodiment, the working electrode~is a closed polygon or closed circle. The mask has an outer perimeter which is equal to or greater than (i.e., 2s extends beyond) the outer perimeter of the working electrode. The mask has an opening, the opening being sufficiently small so that chemical signal that passes through the opening to the catalytic surface of the working electrode in a direction that is substantially 3o perpendicular to the plane of the mask, and thus, substantially perpendicular to the working electrode catalytic face.
In another embodiment, the working electrode is annular and the mask is composed of a solid, circular 3s piece concentrically positioned with respect to the working electrode such that the outer perimeter of the solid circular piece is circumscribed substantially within the inner perimeter of the annular working electrode. Thus chemical signal that passes with the s electrolyte flow and through the plane of the mask is substantially only that chemical signal that is transported from the chemical signal source in a direction that is substantially perpendicular to the working electrode catalytic face.
io In another embodiment, the mask is attached to a surface of a hydrogel patch, and the mask and hydrogel patch are provided as a single unit.
In another embodiment, the mask is an integral part of the housing for the sensor portion of a device i5 for monitoring the chemical signal.
In another embodiment, the mask is independent of any portion of the device with which it is to be used, i.e., the mask is not bound to another component but merely placed, by the user, in.contact with the 2o electrolyte containing material prior to use.
aspect of the invention is to provide a means that can be used with virtually any surface-contacting working electrode, and can enhance the performance of the electrode and the accuracy of measurements from the 2s working electrode.
Another aspect of the invention is to provide a means for accurately and consistently measuring the amount of a chemical signal present in a sample by minimizing the error created by chemical signal which 3o moves to the electrode with a radial vector component.
Another aspect of the invention is to provide a means for quickly, accurately, and continually measuring a chemical signal transported through an electrolyte containing ion conducting material, e.g., a hydrogel. By 3s using the mask of the invention with a working electrode as described herein, measurement of the chemical signal transported through the material in a path perpendicular to the electrode is achieved within a matter of seconds to minutes.
In accordance with an aspect of the present invention, there is provided an assembly for use in a monitoring device for monitoring a chemical signal, the chemical signal being a compound which diffuses through the skin of a subject, the assembly comprising:
a) an sonically conductive material having a first face having a chemical signal target area, the sonically conductive material comprising water and an electrolyte; and b) a mask characterized by being substantially impermeable to a chemical signal, the mask being positioned on a second face of the sonically conductive material opposite the first material face such that chemical signal transported through a plane of the mask, through the sonically conductive material, and toward the chemical signal target area is substantially only that chemical signal transported in a direction substantially perpendicular to the chemical signal target area.
In accordance with another aspect of the present invention , the mask has an opening through which chemical signal flows in a direction substantially perpendicular to the target area.
In accordance with another aspect of the present invention, the opening in the mask constitutes an area which is in a range of 1~ to 90~ of an area encompassed by the entire mask plus opening.
In accordance with another aspect of the present invention, the opening in the mask has a perimeter equal to or circumscribed within an outer 6a perimeter of the target area.
In accordance with another aspect of the present invention, the mask is solid and the target area is annular.
In accordance with another aspect of the present invention, the sonically conductive material comprises:
i) a hydrophilic compound which forms a gel in water, which compound is present in an amount of about 4~ or more by weight based on the weight of the sonically conductive material;
ii) a hydrogel comprising about 955 or less water; and iii) a chloride containing salt.
In accordance with another aspect of the present invention, the sonically conductive material comprises glucose oxidase and the chemical signal is glucose.
In accordance with another aspect of the present invention, the first and second faces of the sonically conductive material are coplanar and each has a surface area in a range of from about 0.5 to about 10 cm2 and the material has a thickness in a range of from about mils to about 50 mils.
In accordance with another aspect of the present invention, the mask has a thickness in a range of about 0.5 mil to 10 mils and the sonically conductive material has a thickness in a range of about 10 mils to 50 mils.
In accordance with another aspect of the present invention, the mask has a thickness in a range of about 0.5 mil to 10 mils and the sonically conductive 6b material has a thickness in a range of about 10 mils to 60 mils.
In accordance with another aspect of the present invention, the mask has a thickness in a range of about 0.01 mil to 5 mils and the sonically conductive material has a thickness in a range of about 5 mils to 60 mils.
In accordance with another aspect of the present invention, the mask has a thickness in a range of about 0.01 mil to 10 mils and the sonically conductive material has a thickness in a range of about 10 mils to 60 mils.
In accordance with another aspect of the present invention, the mask has a thickness in a range of about 0.5 mil to 5 mils and the sonically conductive material has a thickness in a range of about 5 mils to 60 mils.
In accordance with another aspect of the present invention, there is provided a sensor assembly for use with a chemical signal monitoring device, comprising;
a sensor housing having a top portion and a bottom portion, the bottom portion defining a bottom portion opening a chemical signal impermeable mask positioned between the top portion and the bottom portion, the mask having a surface area greater than or equal to the surface area of the bottom portion opening, and defining a mask opening, the mask being positioned so that the mask opening and the bottom portion opening are aligned;
and 6~
a working electrode positioned in the top portion of the sensor housing;
wherein prior to use of the device a hydrogel is inserted between the sensor housing bottom portion and top portion such that when the sensor assembly is closed, the top portion is positioned directly over the bottom portion such that a first hydrogel face contacts the mask, and the working electrode is in contact with a second hydrogel face opposite the first hydrogel face, the working electrode being positioned directly opposite the bottom portion opening, wherein chemical signal transported through a plane of the mask, through the hydrogel and toward the working electrode is substantially only that chemical signal transported in a direction substantially perpendicular to the working electrode.
In accordance with another aspect of the present invention, the hydrogel comprises glucose oxidase, the mask is impermeable to glucose, and the working electrode comprises platinum.
In accordance with another aspect of the present invention, the surface area of each the first and second hydrogel faces is in a range of about 0.5 cm2 to 10 cm2 .
In accordance with another aspect of the present invention, the mask has a thickness in a range of about 0.5 mils to 10 mils.
In accordance with another aspect of the present invention, the mask has a thickness in the range of about 0.01 mils to 10 mils.
In accordance with another aspect of the present invention, the hydrogel has a thickness in a 6a range of about 10 mils to 50 mils.
In accordance with another aspect of the present invention, the hydrogel has a thickness in a range of about 5 mils to 60 mils.
In accordance with another aspect of the present invention, the assembly has a total thickness in a range of about 5 mils to 50 mils.
In accordance with another aspect of the present invention, the assembly has a total thickness in the range of about 5 mils to 70 mils.
In accordance with another aspect of the present invention, there is provided an assembly for use in monitoring a chemical signal, comprising:
a) an sonically conductive material comprised of water, electrolyte and an enzyme;
b) a working electrode having a catalytic surface comprised of a material selected from the group consisting of platinum, palladium, nickel, and oxides, dioxides and alloys thereof, the catalytic surface contacting a first face of the sonically conductive material; and c) a chemical signal impermeable mask positioned on a second face of the sonically conductive material (a) opposite the first sonically conductive material face and opposite the catalytic surface of the electrode (b), the mask having an outer perimeter which is equal to or extends beyond an outer perimeter of the working electrode (b) and having an opening therein which has a perimeter which is equal to or circumscribed within the outer perimeter of the working electrode, wherein chemical signal transported through a plane of the mask, through the sonically conductive material, and toward the 6e catalytic surface of the electrode is substantially only that chemical signal transported in a direction substantially perpendicular to the catalytic surface of the electrode.
In accordance with another apsect of the present invention, in the assembly for use in monitoring a chemical signal, the material (a), electrode (b), and mask (c) are such that the mask blocks substantially all chemical signal flowing to the catalytic surface which is not flowing in a direction substantially perpendicular to the catalytic surface and allows substantially all chemical signal to flow to the catalytic surface which is flowing to that surface in a substantially perpendicular path.
In accordance with another apsect of the present invention, in the assembly for use in monitoring a chemical signal, the first and second faces of the sonically conductive material each have a geometric surface area in a range of about 0.5 cm2 to 10 cm2 and the material has a thickness in range of about 5 to about 50 mils, further wherein the working electrode (b) has a geometric surface area in a range of about 0.25 to about 5.0 cm2, and still further wherein the mask (c) has a thickness in a range of about 0.5 mil to about 10 mils.
In accordance with another apsect of the present invention, in the assembly for use in monitoring a chemical signal, the first and second faces of the sonically conductive material each have a geometric surface area in a range of about 0.5 cmz to 10 cm2 and the material has a thickness in range of about 5 to about 60 mils, further wherein the working electrode (b) has a geometric surface area in a range of about 0.05 cm2 to 6f about 8 cm2, and still further wherein the mask (c) has a thickness in a range of about 0.01 mil to about 10 mils.
In accordance with another aspect of the present invention, there is provided an assembly for use in a monitoring device for monitoring a chemical signal, comprising:
a) an sonically conductive material;
b) a mask characterized by being impermeable to the chemical signal, the mask being positioned between sonically conductive material and a source of chemical signal; and c) a working electrode which measures chemical signal transported from the source of chemical signal wherein the mask is concentric to the working electrode and further wherein the chemical signal that passes through a plane of the mask is that chemical signal that is transported from the source to the catalytic surface in a manner which is substantially perpendicular to the catalytic surface.
In accordance with another aspect of the present invention, in the assembly for use in a monitoring device for monitoring a chemical signal, the sonically conductive material is a hydrogel having an enzyme therein and the catalytic surface is comprised of a material selected from the group consisting of platinum, palladium, nickel, oxides thereof, dioxides thereof and alloys thereof.
In accordance with another aspect of the present invention, there is provided a method of measuring a concentration of a chemical present in a bloodstream of a mammalian subject, comprising the steps of:
6g contacting a mammalian subject's skin with a sensor assembly comprising;
a) an sonically conductive material in contact with the skin;
b) a working electrode in contact with the sonically conductive material the working electrode having a catalytic surface; and c) a mask having an opening therein wherein the mask is positioned between the skin and the working electrode;
transporting a chemical through the skin and sonically conductive material whereby the mask blocks flow to the catalytic surface except for flow substantially axial to the catalytic surface;
monitoring an electrical signal generated at the working electrode by catalytic conversion into an electric signal at the catalytic surface of the working electrode;
wherein the electrical signal generated at the working electrode over a given period of time is correlated with a concentration of chemical present in the bloodstream of the mammalian subject.
In accordance with another aspect of the present invention, in the method of measuring a concentration of a chemical present in a bloodstream of a mammalian subject, the assembly further comprises:
d) an electroosmotic electrode in contact with the sonically conductive material and said transporting is accomplished by applying an electrical current to the electroosmotic electrode.
6h In accordance with another aspect of the present invention, in the method of measuring a concentration of a chemical present in a bloodstream of a mammalian subject, the chemical is glucose, the sonically conductive material is a hydrogel, and the catalytic surface of the working electrode comprises a material selected from the group consisting of platinum oxide and platinum dioxide.
In accordance with another aspect of the present invention, in the method of measuring a concentration of a chemical present in a bloodstream of a mammalian subject,the chemical is glucose, the hydrogel comprises a hydrophilic polymer, water and glucose oxidase.
In accordance with another aspect of the present invention, there is provided a method of measuring a glucose concentration in a mammalian subject, the method comprising:
contacting a first surface of an sonically conductive material with a skin surface wherein the sonically conductive material comprises water and glucose oxidase;
contacting a second surface of the conductive material with a working electrode;
applying current to the skin in an amount sufficient to draw glucose into the conductive material whereby the glucose is converted to gluconic acid and hydrogen peroxide and the hydrogen peroxide is drawn to the working electrode; and positioning a mask impermeable to the hydrogen peroxide between the skin surface and a surface of the working electrode so as to shield the working electrode surface from hydrogen peroxide moving to the working 6i electrode surface via any path other than a path substantially axial to the working electrode surface.
In accordance with another aspect of the present invention, the mammalian subject is a human.
An aspect of the invention is to provide a disposable assembly which makes it possible to proportionally measure a chemical signal by conversion into an electrical signal, where the electrical signal can be measured and accurately correlated with the amount of chemical signal present in a given source (e.g., the amount of chemical signal present in and/or below a section of skin, or in a hydrogel patch in contact with the working electrode).
An advantage of the invention is that use of the mask with a working electrode and hydrogel allows for measurement of very small amounts of an electrochemical signal. For example, the mask of the invention can be used in conjunction with a working electrode, electroosmotic electrode and hydrogel system for monitoring glucose levels in a subject. An electroosmotic electrode (e. g., reverse iontophoresis electrode) can be used to electrically draw glucose into the hydrogel. Glucose oxidase (GOD) contained in the hydrogel catalyzes the conversion of glucose to generate a reaction product (hydrogen peroxide) which can be proportionally converted to an electrical signal. The electroosmotic electrode is switched off and the working electrode of the invention is turned on. The working electrode catalyzes the resulting chemical signal into an electrical signal which is correlated to the amount of chemical signal. This system allows for the continuous and accurate measurement of an inflow of a very small amount of glucose (e. g., glucose concentrations 10, 500, or 1,000 or more times less than the concentration of glucose in blood).
Another advantage is that the mask is easily and economically produced and is disposable.
A feature of the mask and the device used therewith is that it is flat (e. g., a disk with s substantially planar surfaces), thin (e. g., 0.5 to. l0 mils), impermeable to chemical signal flow with the electrode/mask/hydrogel assembly having a surface area on each face in the range of about 0.5 cm2 to l0 cm2.
A feature of the mask is that where the mask 1o includes an opening, the opening has substantially the same dimensions or smaller as the working electrode i.e., the outer perimeter of the opening is circumscribed within the outer perimeter of the catalytic surface of the working electrode.
1s These and other aspects, advantages and features of the present invention will become apparent to those persons skilled in the art upon reading the details of the composition, components and size of the invention as set forth below reference being made to the accompanying 2o drawings forming a part hereof wherein like numbers refer to like components throughout.
Hrje Descriot;on of the Drawin_Q
Figure 1 is an overhead schematic view of a disc or donut shaped embodiment of the mask of the invention.
25 Figures 2A and 28 are cross-sectional views of embodiments of an electroosmotic electrode/working electrode/hydrogel patch assembly with a mask according to the invention.
Figure 3 is a cross-sectional view of an 3o electroosmotic electrode/sensing electrode/hydrogel patch assembly without a mask according to the invention.
Figure 4 is a schematic representation of the reaction which glucose oxidase (GOD) catalyzes to produce gluconic acid and hydrogen peroxide; hydrogen peroxide is then catalyzed at the working electrode into molecular oxygen, 2 hydrogen ions, and 2 electrons, the latter of which generates an electrical current. ., Figure 5 is a cross-sectional schematic~view of a mask of the invention provided below a hydrogel patch.
Figure 6 is an overhead schematic view of a sensor housing containing electroosmotic and working electrodes and a mask. .
Figure 7 is a graph~showing the measured 1o electrical current at the working electrode in the absence of the mask for different intervals as a function of time:
Figure 8 is a graph showing the measured electrical current at the~working electrode in the presence of the mask for different intervals as a function of time.
Figure 9 is a graph showing a comparison of the measured electrical-current at the working electrode either with the mask or without the mask as a function of 2o interval number.
Besc~iption of the Preferred Embodiments Before the mask of the present invention and assembly comprising such is described and disclosed it is to be understood that this invention is not limited to the particular components or composition described as such may, of course, vary. It is also to be understood that the terminology used herein~is for the purpose of describing particular embodiments only, and is not intended to be limiting since the scope of the present 3o invention will be limited only by the appended claims.
It must be noted that as used in this specification and the appended claims, the singular forms ''a", "an" and "the" include plural referents unless the context clearly dictates otherwise. .Thus, for example, _ g _ reference to "a molecule" includes a plurality of molecules and different types of molecules.
Unless defined otherwise all technical and scientific terms used herein have the same meaning as s commonly understood by one of ordinary skill in the art to which this invention belongs. Although any materials or methods similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials io are now described. All publications mentioned herein are incorporated herein by reference for the purpose of describing and disclosing the particular information for which the publication was cited in connection with.
pef initions 1s The term "mask," '~impermeable mask," or "mask of the invention" means a thin (less than 50 mils, preferably 0.5 mil to 5 mils in thickness), substantially flat piece of material that, when,positioned within the transport path of chemical,signal moving toward a working 2o electrode, reduces or prevents transport of chemical signal in a radial direction from the chemical signal source. The mask can be positioned on a face of the sonically conductive material, or can~be positioned at any position within the sonically conductive material 2s (e.g., such that the mask is contacted by material on each of its planar surfaces). In one exemplary configuration, the mask has an opening, which opening is substantially. the same shape and size (e. g., smaller than or equal to) that of the working electrode. Thus, the 30 outer perimeter of the opening is circumscribed substantially within~the outer perimeter of the 'catalytic ' surface of the working electrode. When the opening is circular, the diameter is equal to or less than the ' diameter of the circular catalytic surface of a working electrode with which.the mask is to used. In an alternative exemplary configuration, the mask is a solid piece of material (i.e., does not-have an opening), and is used in conjunction with, for example, an annular working electrode. This type of mask is concentrically .
positioned with respect to the working electrode, s'o that chemical signal does not'enter the region substantially concentric to the annular working electrode. The mask is composed of a material that is substantially impermeable to to the flow of chemical signal that, is to be detected.
The mask and/or the mask opening are of a size sufficient to allow a detectable amount of chemical signal to reach the working electrode, while reducing or preventing entry of chemical signal into the electrolyte flow path that has a potential to be transported (eg., by diffusion) in a radial direction toward an edge of~the working electrode. Thus, the mask substantially eliminates "edge effect" flow, i.e., the chemical signal impermeable mask area prevents chemical signal from contacting the 2o electrode unless the signal flows substantially perpendicular to the surface of the working electrode.
The term "working electrode" means an electrode that detects a chemical signal by catalyzing the conversion of a chemical. compound into an electrical signal (e.g., conversion of hydrogen peroxide into 2 electrons, molecular oxygen, and 2 hydrogen ions).
The term "catalytic surface'.' or "catalytic face"
means the surface of the working electrode that: 1) is in contact with the surface of an ionically conductive 3o material which comprises an electrolyte and allows for the flow of chemical signal; 2) is composed of a catalytic material (e. g., carbon, platinum,~palladium, nobel metal, or nickel and/or oxides and dioxides of any of these); and 3) catalyzes the.conversion of the chemical signal into an electrical signal (i.e., an electrical current) that is monitored and correlated with an amount of chemical signal present at the electrode.
."Chemical signal," ''electrochemical signal," or "electrochemically active compound" means the chemical compound that is ultimately converted to an electrical signal and measured by the working electrode in conjunction with a monitoring device. Chemical signal which moves toward the working electrode at an angle, i.e., includes a radial vector component, is blocked by to the mask. "Chemical_signals" can be:, 1) directly converted into an electrical signal by chemical reaction at the catalytic face of the electrode; or 2) indirectly converted into an electrical signal'by the action of one or more catalysts. For example, the chemical signal glucose is indirectly. converted into an electrical signal by reactions driven by two catalysts. A first catalyst, the enzyme glucose oxidase (GOD), converts glucose into gluconic acid and hydrogen peroxide. Hydrogen peroxide is then converted to an electrical signal by a second 2o catalyst which second catalyst is the catalytic material (e.g., metal.or metal oxide on the catalytic face of the working electrode.
"Ionically conductive material" means a material that provides ionic conductivity, and through which electrochemically active species can~be transported (e.g.,.by diffusion). The ionically conductive material can be, for example, a solid, liquid, or semi-solid (e.g., in the form cf a gel) material that contains an electrolyte, which can be composed primarily of water and 3o ions (e. g., sodium chloride). Generally, the material comprises water at 50% or more by weight of the total material weight. The material can be in the form of a gel, a sponge or pad (e. g., soaked with an electrolytic solution), or any other material~that can contain an ' 3s electrolyte and allow passage of electrochemically active species, especially the chemical signal of interest, through it. An exemplary sonically conductive material in the form of a hydrogel is described in PcT wo 97/o2s11, published January 30, 1997.
A "chemical signal target area" is an area on a surface of an sonically conductive material toward which chemical signal transport is desired. The chemical signal target area is~generally an area of the sonically to conductive material. that, during chemical signal monitoring, is in contact with a chemical signal sensing means (e. g., a catalytic face of a'working electrode), and is of the same size and shape as the portion of the chemical signal sensing means in contact with the is sonically conductive material surface (e. g., the same size and shape as the catalytic face of the working electrodej. For example, where the chemical sensing means to be used with the sonically conductive material is a circular working electrode, the chemical signal.
2o target area is a circular area of the sonically conductive material face that contacts the catalytic surface of the circular working electrode during chemical signal monitoring. In another example, where the chemical sensing means to be used with the sonically 2s conductive material is an annular working electrode, the chemical signal target area is an annular area of the sonically conductive material face that contacts the catalytic surface of the circular working electrode during chemical signal monitoring.
3o Mask lGeneraW
The invention must provide some basic characteristics in order to be useful for its intended purpose, which is to inhibit contact between a working electrode and radially inward transported chemical signal, particularly the form of the chemical signal that can be catalyzed into an electrical signal at the catalytic surface of the electrode (e. g., hydrogen peroxide that results from conversion of the chemical signal glucose).
For example, the mask of the invention can be used in connection with any metabolite monitoring device, where the device contains a working electrode that detects a chemical signal that is transported from one area (e. g., the skin and tissues: below the skin) through an ion conducting material (e.g., a hydrogel) to the electrode surface. Examples of such devices include those described in PCT application serial no.
PCT/GB93/00982.
Further exemplary devices, hydrogels, and additional components for use with the present invention are deSCribed in PCT WO 97/02811, published January 30, 1997 and in PCT WO 97/10499, published March 20, 1997.
which applications disclose inventions which were invented under an obligation to assign rights to the same entity to which the rights in the present invention were invented under an obligation to assign a An exemplary sonically conductive material suitable for use with the invention is a hydrogel composed of a hydrophilic compound, water, and a salt.
The hydrophilic compound forms a gel in the presence of water, and is generally present in the gel in an amount of about 4% or more by weight based. on the total gel weight. The gel contains water in an amount of about 95%
or less based on the weight of the hydrogel. The salt can be any salt that ionizes readily in water and facilitates electric conductivity through the gel, WO 97/10356 PCTlUS96/11776 preferably a chloride containing salt (e. g., NaCl, KC1, etc. ) .
Regardless of the composition of the sonically conductive material, one face of the material has a s chemical signal target area. The target area is the area .
on a face of the material toward which chemical signal transport is desired, e.g., the area of the material face that will be in contact with the catalytic face of'a working electrode during chemical signal sensing.
to Preferably, the target area of the.ionically conductive material is used with a working electrode that has a catalytic face.having approximately the same shape and size as the target area (e. g., circular, annular,. etc.).
During monitoring, the mask is positioned on a second 15 sonically, conductive , material face opposite the first material face having the target area, such that chemical signal that diffuses from the chemical signal source, through a plane of the mask, through the sonically conductive material, and toward the chemical signal 2o target area is substantially only that chemical signal that is transported in a direction substantially perpendicular to the chemical signal target area.
An exemplary monitoring device that can be used in connection with the mask of the invention is generally 25 composed of: 1) a hydrogel patch, one face of which is contacted with a source of biologically important molecules such as the skin of a mammalian subject; 2) an electroosmotic electrode which is positioned on the face of the hydrogel patch opposite the face in contact with 3o the mammalian subject s skin; 3) a working electrode having a catalytic material on at least. its catalytic face, the catalytic face of the electrode being that face in contact with the same face of the hydrogel as the electroosmotic electrode; 4) a means for generating an 35 electrical current, through the electroosmotic electrode, the electrical current serving to electrically draw molecules through the mammalian subject's skin, into the hydrogel patch, and toward_the catalytic face of the working electrode; and 5) a monitoring means for monitoring, electrical current generated at the catalytic face..of 'the working electrode. Alternatively, the chemical signal can enter the hydrogel by passive diffusion, i.e., the assembly can be used without an electroosmotic electrode.
1o Such a monitoring device can be used to monitor levels of a metabolically important compound in, for example, the bloodstream of a mammalian subject (e.g., a human subject). As used herein, the metabolic compound in this example is termed the "chemical signal." For example, the metabolic~compound (and chemical signal) can be glucose. That chemical signal is converted to.a useful chemical signal and then converted to.an electrical signal as shown in Figure 4. The electroosmotic electrodes are used to electrically draw 2o glucose~molecules through the mammalian subject's skin, into the hydrogel, and toward the catalytic face of the working electrode. The hydrogel contains the enzyme glucose oxidase (GOD), which converts the glucose into gluconic acid and hydrogen peroxide. The hydrogen 2s peroxide is then converted into molecular oxygen, 2 hydrogen ions, and 2 electrons, the latter of which generates an electrical current in the working electrode (see.Figure 4)~. The electrical current is measured by the attached monitoring device,_and correlated with the 3o amount of glucose present in the subject's bloodstream.
An assembly of the invention comprised of an electrode~and mask positioned on either side of a.
hydrogel is used with a monitoring device as described above by positioning the mask between mammalian subject's 35 skin and the face of the hydrogel in contact with the subject's skin, such that chemical signal that diffuses from the subject's skin and past the plane of~the mask is only that chemical signal that is transported in a path substantially perpendicular to the catalytic face of the working electrode. It is important that the mask does not completely occlude contact of the ionically conductive material (e.g., the hydrogel) with the chemical signal source (e. g., the subject's skirt).
An exemplary assembly of the invention is shown in 1o Fig. 2A, where the working electrode 4 and mask 1 are circular, and .the mask has an opening 2 that is positioned so that it is directly beneath the working electrode 4 on the opposite face of the gel 3. Because the mask is impermeable to the chemical signal (e. g., 1s glucose), chemical signal is electrically drawn via a substantially perpendicular path only through the opening in the mask. An additional exemplary assembly of the invention is shown in Fig. 2B, where the working electrode is annular (circular with a circular opening in 2o the center), and the mask 1 is a solid, circular piece positioned concentric to the working electrode such that the outer perimeter of the mask 1 is substantially circumscribed within the inner perimeter of the annular working electrode 4. In this embodiment, the annular 2s working electrode extends from approximately the.outer perimeter of the mask~to the outer perimeter of the ionically~conductive material (e.g., hydrogel) used in conjunction with the mask 1 and working electrode 4. For example, where the radius of the a circular hydrogel is 30 0.95 cm, the radius of the mask can be about 0.5 cm and the width of the working~electrode is about o.45 cm.
The position of the mask, and the inhibition of the entry of glucose into gel areas other than that directly beneath the working electrode minimizes the 35 radial component of chemical~signal transport. Reduction of radial transport of the chemical signal toward the working electrode reduces accumulation of such radially transported compound at the periphery.of the electrode, thereby reducing the edge effects~associated with. this s phenomenon. . It is recognized that the mask can allow for a small amount of radial chemical signal transport from the chemical signal source toward the working electrode where, for example, the error in measured electrical current associated with electrochemical conversion of the to radially transported chemical signal is of a magnitude that does not significantly affect the accuracy of the measurement of the amount of chemical signal (e.g., the concentration of chemical signal in a subjects bloodstream). Thus, for example, where the mask has an is opening, the opening can be slightly larger than the diameter of the working electrode used in conjunction with the mask.
The (ij size or geometric surface area of the working electrode, (2) thickness of the gel, (3) size of 2o the opening in the mask, and (4) width of the mask surrounding the opening are all interrelated to each other. For example, when the thickness of the gel is~
increased the size of the opening must be decreased to obtain the same degree of. elimination of radially 2s transported chemical signal.. The smaller the opening in the mask the greater the ability to block radial transport of chemical signal. Although it is desirable to decrease radial transport of the chemical signal, it is also desirable to maximize the chemical signs-1 3o received and the chemical signal is decreased by a smaller opening in the mask.
For reasons that may relate to factors such as the build up of undesired materials, components such as the hydrogel, mask and the electrodes must be easi~.y 3s replaceable by a patient in a convenient manner.
Accordingly, an assembly of these components must have some structural integrity, and provide for the detection of the chemical signal of interest. In that the device is preferably small (e.g., hand held, e.g., the size of a s watch to be worn on the wrist of a patient), it is necessary that the assembly of components be particularly thin. The mask generally has a thickness of about 0.5 to mils (1 mil equals one thousandth of an inch) and the hydrogel has a thickness in the range of about 5 mils to 10 60 mils, generally about 10 mils to 60 mils, normally about~600 microns (about 24 mils).
In order to accurately measure the amount of a chemical. signal (e. g., the amount of hydrogen peroxide generated by GOD catalysis of glucose) and be 1s sufficiently large to be manipulated, the device cannot be too thin and cannot be too small. The overall surface area of the hydroge~l on a single surface should_be in the range of about 0.25 cm2 to about 10 cm2, preferably about 0.50 cm2 to 5 cm2. The electrodes of the entire 2o monitoring device, which include both electroosmotic and working.electrodes, must have a total.surface area that is less than that of the hydrogel patch. In general, the surface area of a mask (the area of the mask, and the opening where applicable) suitable for use in the 25 monitoring device ranges from about 0.1 cm2 to about 6 cm2, preferably about 0.25 cm2 to 2.0 cm2, more preferably about 1.0 cm2.
l~sic Structure Figure 1 is an overhead schematic view of an 3o exemplary mask of the invention. The mask may be any configuration but is.preferably donut shaped as per Figure 1, with an outer perimeter that is equal to or larger than that of the working electrode and/or is substantially the same as the hydrogel patch used in conjunction with the mask. The mask opening is generally equal in. size to about 50% of the area of the working electrode,~ 20%. In general, the mask opening constitutes an area that is in the range of 1% to 90% of the area encompassed by.the mask plus the opening. The mask 1 is disc-shaped, and has a diameter equal to or less than the diameter of the hydrogel patch used in conjunction with the mask, the diameter being in the general range of about 0.5 cm to 3.0 cm, generally about l0 1.9 cm. In general, the range of the surface area of the hydrogel patch used in conjunction with the mask is from about 0.5 cm2 to about 10 cm', preferably in the range of about 1 cm2 to about 5 cm2. The mask 1 defines.an opening 2 positioned~substantially in the center of the mask 1.
The diameter of opening 2 is less than or equal to the diameter of the catalytic surface. of the working electrode that is to be used in conjunction with the mask, generally in the range of about 0.4 cm. Normally, the mask opening constitutes-an area that is about 5/8 ~ 15% of the total area encompassed by the catalytic face of the working electrode, equal to, or slightly larger than the catalytic face of the working electrode (e. g., 100.5% to 105% of the catalytic surface area).
Alternatively, the mask can be a composed of a 2s solid, circular piece for use with, for example, an annular working electrode. The solid, circular mask is concentrically positioned with respect to an annular working electrode such that the outer perimeter of the solid circular piece is circumscribed substantially 3o within the inner perimeter of the annular working electrode. Thus'chemical signal that diffuses from the chemical signal source and through the masks) is substantially only that chemical signal that diffuses from the chemical signal source in a direction that is 3s substantially perpendicular to the plane of the mask, and thus, substantially perpendicular to the annular working electrode catalytic face.
The mask is preferably thin, generally having a thickness in the range of aboutØ01 mil to 10 mils, normally about 0.5 mil to 5 mils (1 mil equals one-thousandth of an inch).. The working electrode used in conjunction with the mask of the invention generally has a geometric surface about 5% to 90%, preferably about 10%
to 80% of the geometric surface of the~hydrogel.
1o The mask is composed of a material that is substantially impermeable to the.chemical signal to be detected (e.g., glucose), and can be permeable to substances other than the chemical signal of interest.
By "substantially impermeable" is meant that.the~mask 1s material reduces or eliminates chemical signal transport (e. g., by diffusion). The mask can allow for a low level of chemical signal transport, with the proviso that chemical signal that passes through the material of the mask does not cause significant edge effects at the 2o working electrode use in conjunction with the mask.
Examples of materials that can be used to form the impermeable mask include mylar, polyethylene, nylon and various other synthetic polymeric material. The mask can be composed of a.single material, or can be composed of 2s two or more materials (e.g., the mask is composed of multiple layers of the same or different materials) to form a-chemical signal-impermeable composition.
In general, the size of the mask (i.e., diameter, surface area, thickness, etc.), the geometry of the mask 30 (e.g., circular, oval, annular, polygonal, etc.), the size (e. g., diameter; surface area, etc.) and/or geometry (e. g., annular, circular, oval, polygonal) of a mask opening through which the chemical~signal is to be detected, compositions of the mask (e. g., type and number 35 of materials, number of layers, chemical signal to which the mask is permeable), the number of mask used in an assembly of the invention (i.e., the number and position of the masks in the electrolyte flow path between the catalytic surface of the working electrode and the s chemical signal source) and other characteristics of .the mask will vary according to a variety of factors such as, for example, the diameter of the hydrogel patch, the diameter of the working electrode, the diameter of the electroosmotic/working electrode assembly, the chemical to signal to be detected, the characteristics of the chemical signal's path of transport (e. g., the diffusion characteristics of the chemical signal), and the geometry and size of the monitoring device.
Methods for making the mask include die cutting 15 and stamping. according to methods well known in the art.
Most preferably, the mask is manufactured in a manner that'is the most economical without compromising performance of the mask (e.g, the impermeability of the mask to the chemical signal of interest, the ability to 2o manipulate the mask by hand without breaking or otherwise compromising its operability). The mask may have an adhesive including a pressure sensitive adhesive coated on one or both surfaces. Further, the mask may be coated with a material which absorbs one~.or more compounds or 25 ions flowing in the hydrogel.
~onf ig~urations The mask can be supplied in several different configurations. Examples of these configurations include: 1) the mask supplied in connection with a 3o hydrogel patch; 2) the mask supplied as an integral component of a monitoring device; or 3) the mask supplied as an independent component.
Fig. 5 illustrates how the mask of the invention can be supplied with a hydrogel patch as a hydrogel/mask assembly 12. The mask 1 is.positioned on one face of the gel 3. The mask can be attached to the gel 3 by any suitable chemical means (e.g., adhesive) that do not -affect the impermeability of the mask to the chemical signal of interest or the conductivity of the gel for electrically-induced movement of the chemical signal through the mask opening and into and through the hydrogel. Release liner components 9 and 10 are positioned on opposite surfaces of the assembly 12 to 1o provide improved handleability of the assembly 12 in that the assembly 12 may be slightly fragile (e. g., may tear during shipping or repeated handling) and/or wet and sticky The release liner 10 may include a perforated cut (e. g., an S-shaped cut) or may include two portions 11 and l3.that overlap one another to allow easy removal of the release liner, l0. Prior to use, the release liners 9 and 10 are removed from the assembly 12, and the assembly 12 positioned in the sensor~housing of a monitoring device so that the mask will be in contact 2o with the subject s skin, and the hydrogel will be in contact with the electroosmotic and working electrodes.
In another embodiment, the mask is an integral component of the sensor housing of a monitoring device.
An example of a sensor housing of a.monitoring device is illustrated in Fig. 6~. The sensor housing 16 of the monitoring device includes a top portion 15 containing electroosmotic 5 and working 4 electrodes, and a bottom portion 14 defining an opening 17, the opening having a diameter at least slightly less than that of the mask 1 3o so that the mask fits tightly in the recess 19. The top portion 15 and the bottom portion 14 can be connected by a hinge 18 that permits opening and closing of the sensor housing. The mask 1 is either permanently or re~aovably fitted over this sensor housing opening 17. The edges of the sensor housing opening 17 can define a recess 19 so as to easily receive the mask 1 and seat the mask 1 within the recess 19. The mask can be secured into position in the bottom portion 14 of the sensor housing 16 by any suitable chemical means (e.g., adhesive) or . s physical means (e.g., physically attaching the mask to the opening by melting the edges of the mask 1 edges to the edges of the opening 17), provides that the operability of the mask, the hydrogel, the sensor housing, and/or the monitoring device are not io significantly affected.
The entire assembly is used by inserting a hydrogel patch (as per the gel 3 of Fig. 5) over the mask 1 in the bottom portion 14, and bringing the top portion 15 into position over the bottom portion 14 so that the 15 electroosmotic electrode 5 and working electrodes 4 contact the central portion of the hydrogel. The top portion 15 and the bottom portion l4 can be held together by interconnecting portions of a securing means 19 (e. g., a latch) which can be closed and opened repeatedly, 2o preferably for the life of the sensor housing. The bottom portion 14 is then positioned on the subject's skin so that the hydrogel contained within the bottom portion 14 is in contact with the skin through opening 2.
When properly aligned, the opening 2 in the mask 1 is 25 positioned beneath the approximate center of the catalytic face 6 of the working electrode 4, so that chemical signal that is transported axially through the hydrogel accessible through the mask opening 2 and will come in contact with the central portion of the catalytic 3o face 6 of the working electrode 4. In another embodiment, the mask is supplied as an independent component, e.g. for insertion into a sensor housing as exemplified in Fig. 6. The mask is inserted in the device prior to use as described above and in Fig. 6, the 35 hydrogel inserted within the bottom portion of the sensor housing and on top of the mask, and the device assembled as described above.
Regardless of the embodiment used, all of the masks of the invention: 1) are impermeable to the s chemical signal to be detected; 2) have a diameter that is at least the same or.greater than the diameter of the hydrogel patch used-in conjunction with the mask; and either 3) are configured for use with a working electrode so that when positioned in the path of electrolyte flow io from the chemical signal source, substantially only chemical signal that flows from the source in a direction substantially perpendicular to the working electrode is allowed to enter the electrolyte flow path.
The mask is generally used in conjunction with an 1s electroosmotic electrode (e.g., an iontophoresis or reverse iontophoresis electrode). An electroosmotic electrode suitable for use with the invention is deSCrlbed In PCT W0 96/00109, published January 4, 1996 20 (which discloses an invention invented under an obligation to assign to the same entity as that to which the rights in the present application are assigned)..
The electroosmotic electrode is used to create an 2s electrical field which transports material such as ions and non-polar molecules from one area (e. g., skin, blood and flesh) to the area of the working electrode. It is important the electroosmotic electrode and the working electrode be used alternately (i.e., current is present 3o in the electroosmotic electrode or the electrical current generated at the working electrode is measured -- not both at once).
Working electrodes suitable for use with the invention include any electrode having a catalytic 3s surface for detection of a chemical signal. An example of a suitable working electrode is described in PcT wo 97/10499, published March 20, 1997.
A standard bipotentiostat circuit can be used to bias~the working and scavenging electrodes independently versus the reference electrode.
Based on the description above and in the figures, it will be recognized that the working electrode of the io invention can be configured in a variety of different forms, and from a variety of different materials. The mask will change with the working electrode so as to maintain certain defined mechanical, electrical, chemical and transport (e. g., diffusion) characteristics.
i5 Mechanically the mask will have sufficient structural integrity such that it can be readily handled by human fingers without significant handling difficulties or significantly compromising the performance of the mask. Preferably, the mask will be 2o somewhat flexible so that it can bend at least slightly during.handling without creasing, breaking, or being otherwise compromised in, for example, its impermsability to the chemical signal of interest. The relative mechanical requirements of the mask may vary with the 2s particular mask embodiment. For example, where the mask is an integral part~of the sensor housing, it may be desirable to design the mask so that it can be separated from the patch without significantly tearing the patch, or adhering to the patch in a manner that makes it , 3o difficult to completely remove all patch material from the face of the mask.
The mask must maintain its impermeability to the chemical signal of interest. Preferably, the mask will optimally function at a pH which is relatively close to that from which the chemical signal is withdrawn (e. g, human skin (about 7)) and at least within a range of from about pH 4 to pH 9.
Utili~
The present invention is useful in connection with the detection of biologically significant molecules such as glucose which is moved through human skin using a technique known as electroosmosis. The basic concept of moving a molecule such as a glucose through human skin is disclosed within U.S. PatBnt 5,362,307, issued November 8, 1994 and U.S. Patent 5,279.,543, issued January 18, for disclosing the basic concept of moving molecules such as glucose through human skin by means of electroosmosis.
The concept of converting the very small amounts of molecules such as glucose which can be extracted through the skin in order to create a current by use of glucose OXidaSe is dlsclOSed in PCT WO 96/00109, published January 4, 1996; PCT WO 96/001100 published January 4, 1996;
PCT WO 97/02811, published January 30, 1997 and PCT WO 97/1Q~99, published March 20, 1997, (which applications disclose inventions which were invented under an obligation to assign rights to the same entity to which the rights in the present invention were invented under an obligation to assign.
Fig. 2A illustrates how an exemplary mask of the invention is used in conjunction with a hydrogel/electroosmotic electrode/working electrode system, such as that used in a metabolite monitoring device (e.g., a glucose monitoring device). The mask 1 is positioned on a face of the gel 3 with the opening 2 substantially in the center of the gel 3. A working - 5 electrode 4 and electroosmosis electrode 5 are positioned on the face of the gel 3 opposing the mask 1. The catalytic surface 6 of the working electrode 4 is positioned on the gel 3 so that the working electrode 4 is.directly opposite the opening 2 of the mask 1. The 1o face of the gel 3 attached to the mask 1 is placed on the surface 7 through which the chemical signal is to be diffused (e. g., mammalian skin, e.g., human skin).
During use in monitoring levels of a chemical signal of interest (e. g., glucose), an electrical current 15 is sent through the electroosmotic electrode, thereby drawing molecules through.the patient s skin and into the hydrogel patch. The mask permits entry of the chemical signal into the gel only at the opening 2, thus reducing the amount of chemical signal.that is radially 2o transported into the.patch, as well as the amount of chemical signal that is capable of being transported radially toward the working electrode. The mask creates a column-like flow through the gel to. the working electrode and substantially prevents any material from 25 flowing to the electrode if that material includes a radial vector as a component of its movement, i.e., the material must move axially or perpendicular to the working electrode. The chemical signal permitted into the patch by entry through the opening in the mask is 3o transported in a substantially axial direction toward the catalytic surface 6 of the working electrode 4, where it is converted to an electrical signal. Alternatively, the ' chemical signal is converted into an intermediate compound by a component in the gel 3. The intermediate ' 35 compound in turn is transported to the catalytic surface 6 of the working electrode 4, where it is converted into an electrical signal. The electrical signal is detected by switching off the electroosmotic electrode, and monitoring the electrical current generated at the working electrode.
The use of the mask and advantages associated therewith are.further illustrated by comparing the flow of glucose in a monitoring system either with (Figs. 2A
and 2B) or without (Fig. 3) the mask of the invention.
1o Fig. 3 illustrates an electroosmotic electrode/working electrode/hydrogel patch assembly (without a mask of the invention) for monitoring glucose levels in a mammalian subject (e.g., a human subject). As described above, the electroosmotic electrodes (e. g., iontophoresis electrodes) 5 are activated to electrically draw , glucose 8 through the subject's skin 7 and into the hydrogel 3. The iontophoresis electrode 5 is used-to electrically draw glucose 8 through the subject's skin 7 and into the hydrogel 3. Glucose 8 is permitted to enter 2o the gel 3 over the entire face of the gel 3 in contact with the subject's skin 7. As a result, glucose is present throughout the entire gel 3, rather than in a region substantially perpendicular to the catalytic face 6 of the working electrode 4. The gel 3 contains the enzyme glucose oxidase (GOD), which converts the glucose to hydrogen peroxide and gluconic acid. The conversion of glucose to hydrogen peroxide by GOD is illustrated schematically in Fig. 3. The hydrogen peroxide is transported (e.g., by diffusion) toward the so catalytic face 6 of the working electrode 4, where it is converted into molecular oxygen, 2 hydrogen ions, and 2 electrons, the latter of which provides an electrical signal.
Because glucose is present throughout the entire 3s gel 3, the hydrogen peroxide resulting from enzymatic conversion of glucose is also present throughout the entire gel 3. Because the surface area of the gel is greater~than that of the working electrode, uncatalyzed hydrogen peroxide accumulates at the working electrode 4 s periphery due to radial transport of the compound toward the catalytic~surface 6. Accumulation of peroxide at the working electrode periphery produces a variable hydrogen peroxide flux (i.e.,,the amount of peroxide present over the working_ electrode at a given time is not directly 1o correlated with the actual peroxide flux through. the hydrogel), and thus produces a flux or error in the measured electrical current at the working electrode.
In contrast, and as illustrated in Figs. 2A and 2B, the mask 1 of the invention permits entry of 1s glucose 8 only at the opening 2 (in Fig. 2A) or the non-mask.contacting portion of the gel 3 (as in Figs. 2A and 2B). The opening and/or non-mask contacting gel surface is directly opposite the catalytic surface 6 of the working electrode 4. The glucose 8 is converted into 2o hydrogen peroxide and gluconic acid by GOD, which is contained in the gel 3. The hydrogen peroxide produced is generally positioned within the gel in a region that is beneath and substantially perpendicular to the catalytic.face 6 of the working electrode 4. Thus, the 2s radial transport component of hydrogen peroxide illustrated in Fig. 3 is eliminated, and an increased flux or error in current measured at the working electrode 4 periphery does not occur.
The composition, size and thickness of the mask 3o and other components can be varied and such variance can affect the time over which the components can be used.
For example, the hydrogel patches may be connected to the mask and are generally designed to provide utility over a period of about 24 hours. After that time some ' 35 deterioration in characteristics, sensitivity, and accuracy of the measurements from the electrode can be expected (e. g., due to reduced effectiveness of an enzyme in the hydrogel). Due to other problems the working .
electrode and hydrogel patch, preferably the entire device, should be replaced. The invention contemplates , components,.assemblies and devices which are used over a shorter period of time e.g., 8 to 12 hours or a longer period of time e.g., 1 to 30 days.
In its broader sense, a mask of the invention can 1o be used to carry out a method which comprises extracting any biomedically significant substance through the skin of a human patient and reacting that substance with another substance or substances (which reaction is greatly accelerated by the use of an.enzyme e.g., 10 to 100 times or more as fast) to form a product which is detectable electrochemically by the production of a signal which signal is generated proportionally based on the amount of a biologically important or biomedically significant substance drawn into the patch. As indicated in the above-cited patents the ability to withdraw biochemically significant substances such as glucose through skin has been established (see U.S. Patent Nos.
5,362,307 and 5,279,543). However, the amount of compound withdrawn is often so small that it is not possible to make meaningful use of such methodology in that the withdrawn material cannot be precisely measured and~related to any standard.
Moreover, conventional hydrogel/working electrode assemblies are severely compromised in their ability to 3o accurately, quickly, and continuously monitor levels of the chemical signal. As described above, in devices without a mask chemical signal is radially transported toward the catalytic surface of the working electrode and accumulates at the working electrode periphery, thus causing the flux or error of chemical signal to be greater. at the electrode edges than at the electrode center, a phenomenon termed "edge effects." The edge effects result in varying electrical signals, and thus varying and inadequate measurement of the flux of the ' s chemical signal. The present invention provides an electrode that is capable of detecting the electrochemical signal at very low levels in a manner that allows for direct, accurate correlation between the amount of signal generated and the amount of the molecule (e.g.,, glucose) in the area from which it is moved (e. g., in the human subject).
The invention is remarkable in that it allows for the noninvasive detection and measuring of amounts of a biomedically relevant compound, e.g.,.glucose, at levels i5 that are 1, 2, or even 3 orders of magnitude less than the concentration of that compound in, for example, blood. For example, glucose might be present in blood in a concentration of about 5 millimolar. However, the concentration of glucose in a hydrogel patch which 2o withdraws glucose through skin as described in the system above is on the order of 2 to 100 micromolar. Micromolar amounts are 3 orders of magnitude less than millimolar amounts. The ability to accurately and quickly detect glucose in such small concentrations is attained by 2s constructing the working electrode with the mask and other, components described herein.
~PLES
The foll-owing examples are put forth so as to provide those of ordinary skill.in the art with a 3o complete disclosure and description of how to make and use various specific'asse~blies of the present invention and are not intended to limit the scope of what the inventors regard as their invention. The data presented in these examples are computer-simulated (i.e., the data is generated from a computer model of the mask and electrode assembly described herein). The computer model of the invention uses the following parameters:
glucose diffusivity: 1.3 x 10-6 cm2/sec;
peroxide diffusivity: 1.2 x 10-5 cm2/sec;
enzyme rate constant: 735 sec-l;
KM for glucose: 1.1 .x 105 nmol/ml;
KM for glucose: 200 nmol/ml;
initial oxygen concentration: 240 nmol/ml;
1o enzyme loading in gel: 100 U/ml; and glucose flux: 5 nmol/cm2 hr.
Efforts have been made to~ensure accuracy with respect to numbers used, (e. g., amounts, particular components, etc.) but some deviations should be accounted for. .Unless indicated otherwise, parts are parts by weight, surface area is geometric surface area, temperature is in degrees centigrade, and pressure is at or near atmospheric pressure.
EX~PLE 1 Lg lucose monitoring 'device - no mask) 2o The peroxide flux or. current error at the surface of a platinum working electrode in a glucose monitoring device comprising an iontophoresis electrode/platinum working electrode/hydrogel assembly (no mask) was simulated by computer. The~computer-based experiments were designed to simulate the use of the device in vivo (e. g., the manner in which the device is used to monitor glucose in a .human subject). The computer simulation was based upon a continuous glucose flux into the hydrogel (5 nmol/cm2 hr), 18 U/ml glucose oxidase loaded into the 3o gel, a gel thickness of 600 microns, and alternate intervals of: 1) iontophoresis (i.e., the iontophoresis electrodes are activated, and glucose molecules are electrically drawn through the subject s skin and into and through the hydrogel patch); and 2) detection of an electrical current at the working electrode (i.e., the iontophoresis_electrode is switched off and the sensing unit'to detect electrical current at the working electrode is on). The experimental protocol is shown in s Table 1.
Table 1_: Experimental Protocol for Computer Simulation Interval Interval Length Iontophoresis Working No.' (min) Electrode Electrode 1 15 on of f 2 5 off on 3 15 on of f '4 5 . off on 5 15 on off 6 . 5 off on is This protocol was repeated for a total of 20 intervals.
The results of the computer model are shown in Fig. 7.
These data indicate that the electrical current measured at the working electrode is a function of the interval number, i.e., peroxide flux at the working 2o electrode increases with increasing interval number.
This is a direct result of the accumulation of hydrogen peroxide at the periphery of the working electrode as a result of radial transport of hydrogen peroxide within the gel.toward the electrode. As a result, the device is 25 never able to provide a steady state measurement profile in the presence of a continuous flow of glucose and hydrogen peroxide.
lPLE 2 - with a mask The computer model described in Example 1 was repeated with the same parameters, except that the device included a mask of the invention positioned between the s subjects skin and the hydrogel. The position of the mask.allows transport of glucose toward the working electrode only in a direction that is substantially axial to the catalytic face of the working electrode, and thus production of hydrogen peroxide only in a region of the to hydrogel that is directly beneath the working electrode.
Therefore, the amount of hydrogen peroxide that. is produced at a position outside the perimeter of the working electrode is essentially eliminated.
The results of the computer model, expressed as 1s the measured electrical current as a function of interval number, are shown in Fig. 8. These data indicate that after interval 2, the is independent of interval number.
Thus, within only 2 to 4 intervals, the device provides a steady state profile of the measurement of a continuous 2o flux of hydrogen peroxide.
EXZ~tumhE 3 - with and without a mask The data from the computer simulations of measurement of a constant glucose flux (5 nmol/cm2 hr) using a glucose monitoring device without the mask 25 (Example. l) and with the mask (Example 2) were analyzed to plot the electrical current measured at the working electrode after 5 minutes of measurement versus the interval number (Fig. 9). This analysis shows that in the absence of the mask, there is a strong dependence of 3o the measured electrical current on the interval number.
When the mask of the invention is included in the device, the profile of the measured electrical current is essentially linear, and thus independent of interval number (see "with mask" line of Fig. 9). ' The instant invention is shown and described herein in what is considered to be the most practical, . and preferred embodiments. It is recognized, however, that departures may be made therefrom which are within the scope bf the invention, and that modifications will occur to one skilled in the art upon reading this disclosure.
Claims (41)
1. An assembly for use in a monitoring device for monitoring a chemical signal, the chemical signal being a compound which diffuses through the skin of a subject, the assembly comprising:
a) an ionically conductive material having a first face having a chemical signal target area, the ionically conductive material comprising water and an electrolyte; and b) a mask characterized by being substantially impermeable to a chemical signal, the mask being positioned on a second face of the ionically conductive material opposite the first material face such that chemical signal transported through a plane of the mask, through the ionically conductive material, and toward the chemical signal target area is substantially only that chemical signal transported in a direction substantially perpendicular to the chemical signal target area.
a) an ionically conductive material having a first face having a chemical signal target area, the ionically conductive material comprising water and an electrolyte; and b) a mask characterized by being substantially impermeable to a chemical signal, the mask being positioned on a second face of the ionically conductive material opposite the first material face such that chemical signal transported through a plane of the mask, through the ionically conductive material, and toward the chemical signal target area is substantially only that chemical signal transported in a direction substantially perpendicular to the chemical signal target area.
2. The assembly of claim 1, wherein the mask has an opening through which chemical signal flows in a direction substantially perpendicular to the target area.
3. The assembly of claim 2, wherein opening in the mask constitutes an area which is in a range of 1% to 90% of an area encompassed by the entire mask plus opening.
4. The assembly of claim 2, wherein the opening in the mask has a perimeter equal to or circumscribed within an outer perimeter of the target area.
5. The assembly of claim 1, wherein the mask is solid and the target area is annular.
6. The assembly of claim 1, wherein the ionically conductive material comprises:
i) a hydrophilic compound which forms a gel in water, which compound is present in an amount of about 4% or more by weight based on the weight of the ionically conductive material;
ii) a hydrogel comprising about 95% or less water; and iii) a chloride containing salt.
i) a hydrophilic compound which forms a gel in water, which compound is present in an amount of about 4% or more by weight based on the weight of the ionically conductive material;
ii) a hydrogel comprising about 95% or less water; and iii) a chloride containing salt.
7. The assembly of claim 1, wherein the ionically conductive material comprises glucose oxidase and the chemical signal is glucose.
8. The assembly of claim 1, wherein the first and second faces of the ionically conductive material are coplanar and each has a surface area in a range of from about 0.5 to about 10 cm2 and the material has a thickness in a range of from about 5 mils to about 50 mils.
9. The assembly of claim 1, wherein the mask has a thickness in a range of about 0.5 mil to 10 mils and the ionically conductive material has a thickness in a range of about 10 mils to 50 mils.
10. The assembly of claim 1, wherein the mask has a thickness in a range of about 0.5 mil to 10 mils and the ionically conductive material has a thickness in a range of about 10 mils to 60 mils.
11. The assembly of claim 1, wherein the mask has a thickness in a range of about 0.01 mil to 5 mils and the ionically conductive material has a thickness in a range of about 5 mils to 60 mils.
12. The assembly of claim 1, wherein the mask has a thickness in a range of about 0.01 mil to 10 mils and the ionically conductive material has a thickness in a range of about 10 mils to 60 mils.
13. The assembly of claim 1, wherein the mask has a thickness in a range of about 0.5 mil to 5 mils and the ionically conductive material has a thickness in a range of about 5 mils to 60 mils.
14. A sensor assembly for use with a chemical signal monitoring device, comprising;
a sensor housing having a top portion and a bottom portion, the bottom portion defining a bottom portion opening a chemical signal impermeable mask positioned between the top portion and the bottom portion, the mask having a surface area greater than or equal to the surface area of the bottom portion opening, and defining a mask opening, the mask being positioned so that the mask opening and the bottom portion opening are aligned;
and a working electrode positioned in the top portion of the sensor housing;
wherein prior to use of the device a hydrogel is inserted between the sensor housing bottom portion and top portion such that when the sensor assembly is closed, the top portion is positioned directly over the bottom portion such that a first hydrogel face contacts the mask, and the working electrode is in contact with a second hydrogel face opposite the first hydrogel face, the working electrode being positioned directly opposite the bottom portion opening, wherein chemical signal transported through a plane of the mask, through the hydrogel and toward the working electrode is substantially only that chemical signal transported in a direction substantially perpendicular to the working electrode.
a sensor housing having a top portion and a bottom portion, the bottom portion defining a bottom portion opening a chemical signal impermeable mask positioned between the top portion and the bottom portion, the mask having a surface area greater than or equal to the surface area of the bottom portion opening, and defining a mask opening, the mask being positioned so that the mask opening and the bottom portion opening are aligned;
and a working electrode positioned in the top portion of the sensor housing;
wherein prior to use of the device a hydrogel is inserted between the sensor housing bottom portion and top portion such that when the sensor assembly is closed, the top portion is positioned directly over the bottom portion such that a first hydrogel face contacts the mask, and the working electrode is in contact with a second hydrogel face opposite the first hydrogel face, the working electrode being positioned directly opposite the bottom portion opening, wherein chemical signal transported through a plane of the mask, through the hydrogel and toward the working electrode is substantially only that chemical signal transported in a direction substantially perpendicular to the working electrode.
15. The sensor assembly of 14, wherein the hydrogel comprises glucose oxidase, the mask is impermeable to glucose, and the working electrode comprises platinum.
16. The sensor assembly of claim 14, wherein the surface area of each the first and second hydrogel faces is in a range of about 0.5 cm2 to 10 cm2.
17. The sensor assembly of claim 14, wherein the mask has a thickness in a range of about 0.5 mils to 10 mils.
18. The sensor assembly of claim 14, wherein the mask has a thickness in the range of about 0.01 mils to 10 mils.
19. The sensor assembly of claim 14, wherein the hydrogel has a thickness in a range of about 10 mils to 50 mils.
20. The sensor assembly of claim 14, wherein the hydrogel has a thickness in a range of about 5 mils to 60 mils.
21. The sensor assembly of claim 14, wherein the assembly has a total thickness in a range of about 5 mils to 50 mils.
22. The sensor assembly of claim 14, wherein the assembly has a total thickness in the range of about 5 mils to 70 mils.
23. An assembly for use in monitoring a chemical signal, comprising:
a) an ionically conductive material comprised of water, electrolyte and an enzyme;
b) a working electrode having a catalytic surface comprised of a material selected from the group consisting of platinum, palladium, nickel, and oxides, dioxides and alloys thereof, the catalytic surface contacting a first face of the ionically conductive material; and c) a chemical signal impermeable mask positioned on a second face of the ionically conductive material (a) opposite the first ionically conductive material face and opposite the catalytic surface of the electrode (b), the mask having an outer perimeter which is equal to or extends beyond an outer perimeter of the working electrode (b) and having an opening therein which has a perimeter which is equal to or circumscribed within the outer perimeter of the working electrode, wherein chemical signal transported through a plane of the mask, through the ionically conductive material, and toward the catalytic surface of the electrode is substantially only that chemical signal transported in a direction substantially perpendicular to the catalytic surface of the electrode.
a) an ionically conductive material comprised of water, electrolyte and an enzyme;
b) a working electrode having a catalytic surface comprised of a material selected from the group consisting of platinum, palladium, nickel, and oxides, dioxides and alloys thereof, the catalytic surface contacting a first face of the ionically conductive material; and c) a chemical signal impermeable mask positioned on a second face of the ionically conductive material (a) opposite the first ionically conductive material face and opposite the catalytic surface of the electrode (b), the mask having an outer perimeter which is equal to or extends beyond an outer perimeter of the working electrode (b) and having an opening therein which has a perimeter which is equal to or circumscribed within the outer perimeter of the working electrode, wherein chemical signal transported through a plane of the mask, through the ionically conductive material, and toward the catalytic surface of the electrode is substantially only that chemical signal transported in a direction substantially perpendicular to the catalytic surface of the electrode.
24. The assembly of claim 23, wherein the material (a), electrode (b), and mask (c) are such that the mask blocks substantially all chemical signal flowing to the catalytic surface which is not flowing in a direction substantially perpendicular to the catalytic surface and allows substantially all chemical signal to flow to the catalytic surface which is flowing to that surface in a substantially perpendicular path.
25. The assembly of claim 23, wherein the first and second faces of the ionically conductive material each have a geometric surface area in a range of about 0.5 cm2 to 10 cm2 and the material has a thickness in range of about 5 to about 50 mils, further wherein the working electrode (b) has a geometric surface area in a range of about 0.25 to about 5.0 cm2, and still further wherein the mask (c) has a thickness in a range of about 0.5 mil to about 10 mils.
26. The assembly of claim 23, wherein the first and second faces of the ionically conductive material each have a geometric surface area in a range of about 0.5 cm2 to 10 cm2 and the material has a thickness in range of about 5 to about 60 mils, further wherein the working electrode (b) has a geometric surface area in a range of about 0.05 cm2 to about 8 cm2, and still further wherein the mask (c) has a thickness in a range of about 0.01 mil to about 10 mils.
27. An assembly for use in a monitoring device for monitoring a chemical signal, comprising:
a) an ionically conductive material;
b) a mask characterized by being impermeable to the chemical signal, the mask being positioned between ionically conductive material and a source of chemical signal; and c) a working electrode which measures chemical signal transported from the source of chemical signal wherein the mask is concentric to the working electrode and further wherein the chemical signal that passes through a plane of the mask is that chemical signal that is transported from the source to the catalytic surface in a manner which is substantially perpendicular to the catalytic surface.
a) an ionically conductive material;
b) a mask characterized by being impermeable to the chemical signal, the mask being positioned between ionically conductive material and a source of chemical signal; and c) a working electrode which measures chemical signal transported from the source of chemical signal wherein the mask is concentric to the working electrode and further wherein the chemical signal that passes through a plane of the mask is that chemical signal that is transported from the source to the catalytic surface in a manner which is substantially perpendicular to the catalytic surface.
28. The assembly of claim 27, wherein the ionically conductive material is a hydrogel having an enzyme therein and the catalytic surface is comprised of a material selected from the group consisting of platinum, palladium, nickel, oxides thereof, dioxides thereof and alloys thereof.
29. A method of measuring a concentration of a chemical present in a bloodstream of a mammalian subject, comprising the steps of:
contacting a mammalian subject's skin with a sensor assembly comprising;
a) an ionically conductive material in contact with the skin;
b) a working electrode in contact with the ionically conductive material the working electrode having a catalytic surface; and c) a mask having an opening therein wherein the mask is positioned between the skin and the working electrode;
transporting a chemical through the skin and ionically conductive material whereby the mask blocks flow to the catalytic surface except for flow substantially axial to the catalytic surface;
monitoring an electrical signal generated at the working electrode by catalytic conversion into an electric signal at the catalytic surface of the working electrode;
wherein the electrical signal generated at the working electrode over a given period of time is correlated with a concentration of chemical present in the bloodstream of the mammalian subject.
contacting a mammalian subject's skin with a sensor assembly comprising;
a) an ionically conductive material in contact with the skin;
b) a working electrode in contact with the ionically conductive material the working electrode having a catalytic surface; and c) a mask having an opening therein wherein the mask is positioned between the skin and the working electrode;
transporting a chemical through the skin and ionically conductive material whereby the mask blocks flow to the catalytic surface except for flow substantially axial to the catalytic surface;
monitoring an electrical signal generated at the working electrode by catalytic conversion into an electric signal at the catalytic surface of the working electrode;
wherein the electrical signal generated at the working electrode over a given period of time is correlated with a concentration of chemical present in the bloodstream of the mammalian subject.
30. The method of claim 29, wherein the assembly further comprises:
d) an electroosmotic electrode in contact with the ionically conductive material and said transporting is accomplished by applying an electrical current to the electroosmotic electrode.
d) an electroosmotic electrode in contact with the ionically conductive material and said transporting is accomplished by applying an electrical current to the electroosmotic electrode.
31. The method of claim 29, wherein the chemical is glucose, the ionically conductive material is a hydrogel, and the catalytic surface of the working electrode comprises a material selected from the group consisting of platinum oxide and platinum dioxide.
32. The method of claim 31, wherein the hydrogel comprises a hydrophilic polymer, water and glucose oxidase.
33. The method of claim 32, wherein the mammalian subject is a human.
34. The method of claim 29, wherein the mammalian subject is a human.
35. The method of claim 29, wherein the chemical is glucose.
36. The method of claim 29, wherein the ionically conductive material comprises glucose oxidase.
37. The method of claim 29, wherein the catalytic surface of the working electrode is comprised of a material selected from the group consisting of platinum oxide and platinum dioxide.
38. The method of claim 29, wherein the mammalian subject is a human, the chemical is glucose, the ionically conductive material comprises glucose oxidase, and the surface of the working electrode is comprised of a material selected from the group consisting of platinum oxide and platinum dioxide.
39. A method of measuring a glucose concentration in a mammalian subject, comprising:
contacting a first surface of an ionically conductive material with a skin surface wherein the ionically conductive material comprises water and glucose oxidase;
contacting a second surface of the conductive material with a working electrode;
applying current to the skin in an amount sufficient to draw glucose into the conductive material whereby the glucose is converted to gluconic acid and hydrogen peroxide and the hydrogen peroxide is drawn to the working electrode; and positioning a mask impermeable to the hydrogen peroxide between the skin surface and a surface of the working electrode so as to shield the working electrode surface from hydrogen peroxide moving to the working electrode surface via any path other than a path substantially axial to the working electrode surface.
contacting a first surface of an ionically conductive material with a skin surface wherein the ionically conductive material comprises water and glucose oxidase;
contacting a second surface of the conductive material with a working electrode;
applying current to the skin in an amount sufficient to draw glucose into the conductive material whereby the glucose is converted to gluconic acid and hydrogen peroxide and the hydrogen peroxide is drawn to the working electrode; and positioning a mask impermeable to the hydrogen peroxide between the skin surface and a surface of the working electrode so as to shield the working electrode surface from hydrogen peroxide moving to the working electrode surface via any path other than a path substantially axial to the working electrode surface.
40. The method of claim 39, wherein the mammalian subject is a human.
41. The method of claim 39, wherein the working electrode is comprised of a material selected from the group consisting of platinum oxide and platinum dioxide.
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PCT/US1996/011776 WO1997010356A1 (en) | 1995-09-12 | 1996-07-16 | Chemical signal-impermeable mask |
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Families Citing this family (275)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5593852A (en) | 1993-12-02 | 1997-01-14 | Heller; Adam | Subcutaneous glucose electrode |
US5771890A (en) | 1994-06-24 | 1998-06-30 | Cygnus, Inc. | Device and method for sampling of substances using alternating polarity |
US20040062759A1 (en) * | 1995-07-12 | 2004-04-01 | Cygnus, Inc. | Hydrogel formulations for use in electroosmotic extraction and detection of glucose |
US5735273A (en) | 1995-09-12 | 1998-04-07 | Cygnus, Inc. | Chemical signal-impermeable mask |
US8734339B2 (en) | 1996-12-16 | 2014-05-27 | Ip Holdings, Inc. | Electronic skin patch for real time monitoring of cardiac activity and personal health management |
US7899511B2 (en) | 2004-07-13 | 2011-03-01 | Dexcom, Inc. | Low oxygen in vivo analyte sensor |
US6001067A (en) | 1997-03-04 | 1999-12-14 | Shults; Mark C. | Device and method for determining analyte levels |
US9155496B2 (en) | 1997-03-04 | 2015-10-13 | Dexcom, Inc. | Low oxygen in vivo analyte sensor |
US8527026B2 (en) | 1997-03-04 | 2013-09-03 | Dexcom, Inc. | Device and method for determining analyte levels |
US6862465B2 (en) | 1997-03-04 | 2005-03-01 | Dexcom, Inc. | Device and method for determining analyte levels |
US7657297B2 (en) * | 2004-05-03 | 2010-02-02 | Dexcom, Inc. | Implantable analyte sensor |
US6139718A (en) | 1997-03-25 | 2000-10-31 | Cygnus, Inc. | Electrode with improved signal to noise ratio |
BR9811609A (en) * | 1997-09-05 | 2000-09-05 | Abbott Lab | Electrochemical sensor with equalized electrode areas |
US7066884B2 (en) * | 1998-01-08 | 2006-06-27 | Sontra Medical, Inc. | System, method, and device for non-invasive body fluid sampling and analysis |
US8287483B2 (en) | 1998-01-08 | 2012-10-16 | Echo Therapeutics, Inc. | Method and apparatus for enhancement of transdermal transport |
US20060015058A1 (en) * | 1998-01-08 | 2006-01-19 | Kellogg Scott C | Agents and methods for enhancement of transdermal transport |
US6134461A (en) * | 1998-03-04 | 2000-10-17 | E. Heller & Company | Electrochemical analyte |
US6587705B1 (en) | 1998-03-13 | 2003-07-01 | Lynn Kim | Biosensor, iontophoretic sampling system, and methods of use thereof |
US6175752B1 (en) | 1998-04-30 | 2001-01-16 | Therasense, 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 |
US8480580B2 (en) | 1998-04-30 | 2013-07-09 | 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 |
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 |
US9066695B2 (en) | 1998-04-30 | 2015-06-30 | Abbott Diabetes Care 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 |
WO1999058190A1 (en) * | 1998-05-13 | 1999-11-18 | Cygnus, Inc. | Collection assemblies for transdermal sampling system |
EP1077634B1 (en) | 1998-05-13 | 2003-07-30 | Cygnus, Inc. | Monitoring of physiological analytes |
ATE246356T1 (en) | 1998-05-13 | 2003-08-15 | Cygnus Therapeutic Systems | DEVICE FOR PREDICTING PHYSIOLOGICAL MEASUREMENTS |
WO1999058050A1 (en) | 1998-05-13 | 1999-11-18 | Cygnus, Inc. | Signal processing for measurement of physiological analytes |
US6532386B2 (en) | 1998-08-31 | 2003-03-11 | Johnson & Johnson Consumer Companies, Inc. | Electrotransort device comprising blades |
CA2342801A1 (en) | 1998-09-04 | 2000-03-16 | Powderject Research Limited | Monitoring methods using particle delivery methods |
US6602678B2 (en) | 1998-09-04 | 2003-08-05 | Powderject Research Limited | Non- or minimally invasive monitoring methods |
ATE254877T1 (en) | 1998-09-17 | 2003-12-15 | Cygnus Therapeutic Systems | DEVICE FOR PRESSING A GEL/SENSOR UNIT |
DE69908602T2 (en) | 1998-09-30 | 2004-06-03 | Cygnus, Inc., Redwood City | METHOD AND DEVICE FOR PREDICTING PHYSIOLOGICAL MEASUREMENTS |
US6180416B1 (en) | 1998-09-30 | 2001-01-30 | Cygnus, Inc. | Method and device for predicting physiological values |
US6391643B1 (en) | 1998-10-28 | 2002-05-21 | Cygnus, Inc. | Kit and method for quality control testing of an iontophoretic sampling system |
US20040171980A1 (en) | 1998-12-18 | 2004-09-02 | Sontra Medical, Inc. | Method and apparatus for enhancement of transdermal transport |
EP1135052A1 (en) | 1999-02-12 | 2001-09-26 | Cygnus, Inc. | Devices and methods for frequent measurement of an analyte present in a biological system |
US6959211B2 (en) | 1999-03-10 | 2005-10-25 | Optiscan Biomedical Corp. | Device for capturing thermal spectra from tissue |
ATE290902T1 (en) | 1999-04-16 | 2005-04-15 | Johnson & Johnson Consumer | DEVICE FOR IONTOPHORETIC ADMINISTRATION OF MEDICATION WITH INTERNAL SENSORS |
CA2369336A1 (en) | 1999-04-22 | 2000-11-02 | Cygnus, Inc. | Hydrogel in an iontophoretic device to measure glucose |
US6379324B1 (en) | 1999-06-09 | 2002-04-30 | The Procter & Gamble Company | Intracutaneous microneedle array apparatus |
US6256533B1 (en) | 1999-06-09 | 2001-07-03 | The Procter & Gamble Company | Apparatus and method for using an intracutaneous microneedle array |
US6312612B1 (en) | 1999-06-09 | 2001-11-06 | The Procter & Gamble Company | Apparatus and method for manufacturing an intracutaneous microneedle array |
US20050009717A1 (en) * | 1999-07-01 | 2005-01-13 | Lukenbach Elvin R. | Foaming make-up removing cleansing compositions |
US7074747B1 (en) | 1999-07-01 | 2006-07-11 | Johnson & Johnson Consumer Companies, Inc. | Cleansing compositions |
WO2001001949A1 (en) | 1999-07-01 | 2001-01-11 | Johnson And Johnson Consumer Companies, Inc. | Cleansing compositions |
US6762158B2 (en) | 1999-07-01 | 2004-07-13 | Johnson & Johnson Consumer Companies, Inc. | Personal care compositions comprising liquid ester mixtures |
JP3655587B2 (en) * | 1999-09-20 | 2005-06-02 | ロシュ ダイアグノスティックス コーポレーション | Small biosensor for continuous analyte monitoring |
US7045054B1 (en) * | 1999-09-20 | 2006-05-16 | Roche Diagnostics Corporation | Small volume biosensor for continuous analyte monitoring |
EP1235611B1 (en) * | 1999-11-15 | 2005-09-07 | Velcro Industries B.V. | Skin attachment member |
CA2374751C (en) * | 2000-03-17 | 2009-10-13 | Sontra Medical, Inc. | System, method, and device for non-invasive body fluid sampling and analysis |
US6885883B2 (en) * | 2000-05-16 | 2005-04-26 | Cygnus, Inc. | Methods for improving performance and reliability of biosensors |
US6565532B1 (en) | 2000-07-12 | 2003-05-20 | The Procter & Gamble Company | Microneedle apparatus used for marking skin and for dispensing semi-permanent subcutaneous makeup |
US6540675B2 (en) * | 2000-06-27 | 2003-04-01 | Rosedale Medical, Inc. | Analyte monitor |
WO2002015777A1 (en) * | 2000-08-18 | 2002-02-28 | Cygnus, Inc. | Methods and devices for prediction of hypoglycemic events |
WO2002017210A2 (en) | 2000-08-18 | 2002-02-28 | Cygnus, Inc. | Formulation and manipulation of databases of analyte and associated values |
US20020026111A1 (en) * | 2000-08-28 | 2002-02-28 | Neil Ackerman | Methods of monitoring glucose levels in a subject and uses thereof |
US20120191052A1 (en) | 2000-10-06 | 2012-07-26 | Ip Holdings, Inc. | Intelligent activated skin patch system |
US7828827B2 (en) * | 2002-05-24 | 2010-11-09 | Corium International, Inc. | Method of exfoliation of skin using closely-packed microstructures |
US6821281B2 (en) | 2000-10-16 | 2004-11-23 | The Procter & Gamble Company | Microstructures for treating and conditioning skin |
US7131987B2 (en) * | 2000-10-16 | 2006-11-07 | Corium International, Inc. | Microstructures and method for treating and conditioning skin which cause less irritation during exfoliation |
US6560471B1 (en) | 2001-01-02 | 2003-05-06 | Therasense, Inc. | Analyte monitoring device and methods of use |
US6663820B2 (en) * | 2001-03-14 | 2003-12-16 | The Procter & Gamble Company | Method of manufacturing microneedle structures using soft lithography and photolithography |
US7041468B2 (en) | 2001-04-02 | 2006-05-09 | Therasense, Inc. | Blood glucose tracking apparatus and methods |
US6748250B1 (en) * | 2001-04-27 | 2004-06-08 | Medoptix, Inc. | Method and system of monitoring a patient |
US20090137888A9 (en) * | 2001-04-27 | 2009-05-28 | Berman Herbert L | System for monitoring of patients |
US6591124B2 (en) | 2001-05-11 | 2003-07-08 | The Procter & Gamble Company | Portable interstitial fluid monitoring system |
US6503209B2 (en) | 2001-05-18 | 2003-01-07 | Said I. Hakky | Non-invasive focused energy blood withdrawal and analysis system |
WO2003000127A2 (en) * | 2001-06-22 | 2003-01-03 | Cygnus, Inc. | Method for improving the performance of an analyte monitoring system |
CN1273075C (en) * | 2001-07-13 | 2006-09-06 | 爱科来株式会社 | Analyzing apparatus, piercing element integrally installed body for temperature measuring device with analyzing apparatus, and body fluid sampling apparatus |
US20030032874A1 (en) * | 2001-07-27 | 2003-02-13 | Dexcom, Inc. | Sensor head for use with implantable devices |
US6631282B2 (en) | 2001-08-09 | 2003-10-07 | Optiscan Biomedical Corporation | Device for isolating regions of living tissue |
US20040087992A1 (en) * | 2002-08-09 | 2004-05-06 | Vladimir Gartstein | Microstructures for delivering a composition cutaneously to skin using rotatable structures |
US6952604B2 (en) | 2001-12-21 | 2005-10-04 | Becton, Dickinson And Company | Minimally-invasive system and method for monitoring analyte levels |
US7004928B2 (en) | 2002-02-08 | 2006-02-28 | Rosedale Medical, Inc. | Autonomous, ambulatory analyte monitor or drug delivery device |
US7828728B2 (en) | 2003-07-25 | 2010-11-09 | Dexcom, Inc. | Analyte sensor |
DE60334365D1 (en) | 2002-03-22 | 2010-11-11 | Animas Technologies Llc | INCREASED PERFORMANCE OF AN ANALYSIS MONITORING DEVICE |
US6801804B2 (en) | 2002-05-03 | 2004-10-05 | Aciont, Inc. | Device and method for monitoring and controlling electrical resistance at a tissue site undergoing iontophoresis |
US7150975B2 (en) * | 2002-08-19 | 2006-12-19 | Animas Technologies, Llc | Hydrogel composition for measuring glucose flux |
EP1540351A4 (en) * | 2002-08-30 | 2007-06-06 | Biochec Co Ltd | Glucose extraction patch and its manufacturing process |
US20040122500A1 (en) * | 2002-12-19 | 2004-06-24 | Kimberly-Clark Worldwide, Inc. | Electrode for utilizing edge effect to create uniform current density |
US7174198B2 (en) * | 2002-12-27 | 2007-02-06 | Igor Trofimov | Non-invasive detection of analytes in a complex matrix |
US7811231B2 (en) | 2002-12-31 | 2010-10-12 | Abbott Diabetes Care Inc. | Continuous glucose monitoring system and methods of use |
US8771183B2 (en) | 2004-02-17 | 2014-07-08 | Abbott Diabetes Care Inc. | Method and system for providing data communication in continuous glucose monitoring and management system |
US7578954B2 (en) * | 2003-02-24 | 2009-08-25 | Corium International, Inc. | Method for manufacturing microstructures having multiple microelements with through-holes |
US7052652B2 (en) * | 2003-03-24 | 2006-05-30 | Rosedale Medical, Inc. | Analyte concentration detection devices and methods |
JP4381705B2 (en) * | 2003-03-26 | 2009-12-09 | シスメックス株式会社 | Transcutaneous analyte extraction system and analysis system, and transcutaneous analyte extraction method and analysis method |
US7587287B2 (en) | 2003-04-04 | 2009-09-08 | Abbott Diabetes Care Inc. | Method and system for transferring analyte test data |
US7134999B2 (en) * | 2003-04-04 | 2006-11-14 | Dexcom, Inc. | Optimized sensor geometry for an implantable glucose sensor |
US7415299B2 (en) * | 2003-04-18 | 2008-08-19 | The Regents Of The University Of California | Monitoring method and/or apparatus |
JP2004343275A (en) * | 2003-05-14 | 2004-12-02 | Murata Mach Ltd | Image processing system and scanner |
US7258673B2 (en) * | 2003-06-06 | 2007-08-21 | Lifescan, Inc | Devices, systems and methods for extracting bodily fluid and monitoring an analyte therein |
US8066639B2 (en) | 2003-06-10 | 2011-11-29 | Abbott Diabetes Care Inc. | Glucose measuring device for use in personal area network |
JP2007500336A (en) * | 2003-07-25 | 2007-01-11 | デックスコム・インコーポレーテッド | Electrode system for electrochemical sensors |
US7108778B2 (en) * | 2003-07-25 | 2006-09-19 | Dexcom, Inc. | Electrochemical sensors including electrode systems with increased oxygen generation |
JP4708342B2 (en) | 2003-07-25 | 2011-06-22 | デックスコム・インコーポレーテッド | Oxygen augmentation membrane system for use in implantable devices |
US7761130B2 (en) | 2003-07-25 | 2010-07-20 | Dexcom, Inc. | Dual electrode system for a continuous analyte sensor |
US20190357827A1 (en) | 2003-08-01 | 2019-11-28 | Dexcom, Inc. | Analyte sensor |
US8275437B2 (en) | 2003-08-01 | 2012-09-25 | Dexcom, Inc. | Transcutaneous analyte sensor |
US8060173B2 (en) | 2003-08-01 | 2011-11-15 | Dexcom, Inc. | System and methods for processing analyte sensor data |
US8676287B2 (en) | 2003-08-01 | 2014-03-18 | Dexcom, Inc. | System and methods for processing analyte sensor data |
US20050069925A1 (en) * | 2003-08-15 | 2005-03-31 | Russell Ford | Microprocessors, devices, and methods for use in monitoring of physiological analytes |
US7189341B2 (en) * | 2003-08-15 | 2007-03-13 | Animas Technologies, Llc | Electrochemical sensor ink compositions, electrodes, and uses thereof |
US7920906B2 (en) | 2005-03-10 | 2011-04-05 | Dexcom, Inc. | System and methods for processing analyte sensor data for sensor calibration |
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 |
US9247900B2 (en) | 2004-07-13 | 2016-02-02 | Dexcom, Inc. | Analyte sensor |
DE602004029092D1 (en) | 2003-12-05 | 2010-10-21 | Dexcom Inc | CALIBRATION METHODS FOR A CONTINUOUSLY WORKING ANALYTIC SENSOR |
US8364231B2 (en) | 2006-10-04 | 2013-01-29 | Dexcom, Inc. | Analyte sensor |
US8287453B2 (en) | 2003-12-05 | 2012-10-16 | Dexcom, Inc. | Analyte sensor |
US8423114B2 (en) | 2006-10-04 | 2013-04-16 | Dexcom, Inc. | Dual electrode system for a continuous analyte sensor |
US8532730B2 (en) | 2006-10-04 | 2013-09-10 | Dexcom, Inc. | Analyte sensor |
US11633133B2 (en) | 2003-12-05 | 2023-04-25 | Dexcom, Inc. | Dual electrode system for a continuous analyte sensor |
US8017145B2 (en) * | 2003-12-22 | 2011-09-13 | Conopco, Inc. | Exfoliating personal care wipe article containing an array of projections |
US8165651B2 (en) * | 2004-02-09 | 2012-04-24 | Abbott Diabetes Care Inc. | Analyte sensor, and associated system and method employing a catalytic agent |
WO2005084257A2 (en) * | 2004-02-26 | 2005-09-15 | Vpn Solutions, Llc | Composite thin-film glucose sensor |
WO2005094526A2 (en) * | 2004-03-24 | 2005-10-13 | Corium International, Inc. | Transdermal delivery device |
US20050245799A1 (en) * | 2004-05-03 | 2005-11-03 | Dexcom, Inc. | Implantable analyte sensor |
US8792955B2 (en) | 2004-05-03 | 2014-07-29 | Dexcom, Inc. | Transcutaneous analyte sensor |
US20160192880A9 (en) * | 2004-05-28 | 2016-07-07 | David Scott Utley | Intra-Oral Detector and System for Modification of Undesired Behaviors and Methods Thereof |
US20060010098A1 (en) | 2004-06-04 | 2006-01-12 | Goodnow Timothy T | Diabetes care host-client architecture and data management system |
GB2414675B (en) * | 2004-06-05 | 2006-09-06 | Dewan Fazlul Hoque Chowdhury | Transdermal drug delivery device |
US20080242961A1 (en) * | 2004-07-13 | 2008-10-02 | Dexcom, Inc. | Transcutaneous analyte sensor |
US8886272B2 (en) | 2004-07-13 | 2014-11-11 | Dexcom, Inc. | Analyte sensor |
US8565848B2 (en) | 2004-07-13 | 2013-10-22 | Dexcom, Inc. | Transcutaneous analyte sensor |
US7946984B2 (en) | 2004-07-13 | 2011-05-24 | Dexcom, Inc. | Transcutaneous analyte sensor |
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 |
WO2006127694A2 (en) | 2004-07-13 | 2006-11-30 | Dexcom, Inc. | Analyte sensor |
US20060016700A1 (en) | 2004-07-13 | 2006-01-26 | Dexcom, Inc. | Transcutaneous analyte sensor |
IL163796A0 (en) * | 2004-08-30 | 2005-12-18 | Gribova Orna A | Device for detecting changes in blood glucose level or dardiovacular condition |
JP5502279B2 (en) * | 2004-10-28 | 2014-05-28 | エコー セラピューティクス, インコーポレイテッド | System and method for analyte sampling and analysis using hydrogels |
US20060094945A1 (en) * | 2004-10-28 | 2006-05-04 | Sontra Medical Corporation | System and method for analyte sampling and analysis |
JP2006167428A (en) * | 2004-11-16 | 2006-06-29 | Sysmex Corp | Analyte extraction device, analyzer, analyte extraction method, and analysis method |
US8512243B2 (en) | 2005-09-30 | 2013-08-20 | Abbott Diabetes Care Inc. | Integrated introducer and transmitter assembly and methods of use |
US8029441B2 (en) | 2006-02-28 | 2011-10-04 | Abbott Diabetes Care Inc. | Analyte sensor transmitter unit configuration for a data monitoring and management system |
US8133178B2 (en) | 2006-02-22 | 2012-03-13 | Dexcom, Inc. | Analyte sensor |
US20090076360A1 (en) | 2007-09-13 | 2009-03-19 | Dexcom, Inc. | Transcutaneous analyte sensor |
CA2602259A1 (en) * | 2005-03-29 | 2006-10-05 | Arkal Medical, Inc. | Devices, systems, methods and tools for continuous glucose monitoring |
WO2007081378A1 (en) * | 2005-04-29 | 2007-07-19 | Byrne Norman R | Center connect single-sided junction block |
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 |
US20060281187A1 (en) | 2005-06-13 | 2006-12-14 | Rosedale Medical, Inc. | Analyte detection devices and methods with hematocrit/volume correction and feedback control |
KR100692783B1 (en) * | 2005-07-19 | 2007-03-12 | 케이엠에이치 주식회사 | Patch for extracting glucose |
US8801631B2 (en) | 2005-09-30 | 2014-08-12 | Intuity Medical, Inc. | Devices and methods for facilitating fluid transport |
EP1928304B1 (en) | 2005-09-30 | 2012-10-24 | Intuity Medical, Inc. | Catalysts for body fluid sample extraction |
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 |
US7432069B2 (en) * | 2005-12-05 | 2008-10-07 | Sontra Medical Corporation | Biocompatible chemically crosslinked hydrogels for glucose sensing |
JP2009520187A (en) * | 2005-12-16 | 2009-05-21 | バイエル・ヘルスケア・エルエルシー | Transcutaneous analyte sensor assembly and method of use thereof |
US9757061B2 (en) | 2006-01-17 | 2017-09-12 | Dexcom, Inc. | Low oxygen in vivo analyte sensor |
US7736310B2 (en) | 2006-01-30 | 2010-06-15 | Abbott Diabetes Care Inc. | On-body medical device securement |
US7885698B2 (en) | 2006-02-28 | 2011-02-08 | Abbott Diabetes Care Inc. | Method and system for providing continuous calibration of implantable analyte sensors |
US7981034B2 (en) | 2006-02-28 | 2011-07-19 | Abbott Diabetes Care Inc. | Smart messages and alerts for an infusion delivery and management system |
JP2009528121A (en) * | 2006-03-01 | 2009-08-06 | ジー.アール. エンライトンメント エルティーディー. | Apparatus and method for measuring parameters related to electrochemical processes |
US20090131778A1 (en) * | 2006-03-28 | 2009-05-21 | Jina Arvind N | Devices, systems, methods and tools for continuous glucose monitoring |
US20080154107A1 (en) * | 2006-12-20 | 2008-06-26 | Jina Arvind N | Device, systems, methods and tools for continuous glucose monitoring |
US20100049021A1 (en) * | 2006-03-28 | 2010-02-25 | Jina Arvind N | Devices, systems, methods and tools for continuous analyte monitoring |
US7620438B2 (en) | 2006-03-31 | 2009-11-17 | Abbott Diabetes Care Inc. | Method and system for powering an electronic device |
US8226891B2 (en) | 2006-03-31 | 2012-07-24 | Abbott Diabetes Care Inc. | Analyte monitoring devices and methods therefor |
WO2007143225A2 (en) | 2006-06-07 | 2007-12-13 | Abbott Diabetes Care, Inc. | Analyte monitoring system and method |
US8206296B2 (en) | 2006-08-07 | 2012-06-26 | Abbott Diabetes Care Inc. | Method and system for providing integrated analyte monitoring and infusion system therapy management |
US8932216B2 (en) | 2006-08-07 | 2015-01-13 | Abbott Diabetes Care Inc. | Method and system for providing data management in integrated analyte monitoring and infusion system |
US20080058726A1 (en) * | 2006-08-30 | 2008-03-06 | Arvind Jina | Methods and Apparatus Incorporating a Surface Penetration Device |
GB2441784A (en) * | 2006-09-13 | 2008-03-19 | Rtc North Ltd | Device for obtaining and analysing a biological fluid |
US7831287B2 (en) * | 2006-10-04 | 2010-11-09 | Dexcom, Inc. | Dual electrode system for a continuous analyte sensor |
WO2008091602A2 (en) * | 2007-01-22 | 2008-07-31 | Corium International, Inc. | Applicators for microneedle arrays |
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 |
US8812071B2 (en) * | 2007-03-07 | 2014-08-19 | Echo Therapeutics, Inc. | Transdermal analyte monitoring systems and methods for analyte detection |
US20080234562A1 (en) * | 2007-03-19 | 2008-09-25 | Jina Arvind N | Continuous analyte monitor with multi-point self-calibration |
CA2681412A1 (en) | 2007-03-26 | 2008-10-02 | Dexcom, Inc. | Analyte sensor |
US9114238B2 (en) | 2007-04-16 | 2015-08-25 | Corium International, Inc. | Solvent-cast microprotrusion arrays containing active ingredient |
US8386027B2 (en) | 2007-04-27 | 2013-02-26 | Echo Therapeutics, Inc. | Skin permeation device for analyte sensing or transdermal drug delivery |
US7928850B2 (en) | 2007-05-08 | 2011-04-19 | 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 |
US8456301B2 (en) | 2007-05-08 | 2013-06-04 | Abbott Diabetes Care Inc. | Analyte monitoring system and methods |
US20080312518A1 (en) * | 2007-06-14 | 2008-12-18 | Arkal Medical, Inc | On-demand analyte monitor and method of use |
US8641618B2 (en) | 2007-06-27 | 2014-02-04 | Abbott Diabetes Care Inc. | Method and structure for securing a monitoring device element |
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 |
US9968742B2 (en) | 2007-08-29 | 2018-05-15 | Medtronic Minimed, Inc. | Combined sensor and infusion set using separated sites |
US20120046533A1 (en) | 2007-08-29 | 2012-02-23 | Medtronic Minimed, Inc. | Combined sensor and infusion sets |
WO2009048607A1 (en) | 2007-10-10 | 2009-04-16 | Corium International, Inc. | Vaccine delivery via microneedle arrays |
JP5178132B2 (en) * | 2007-10-11 | 2013-04-10 | キヤノン株式会社 | Image processing system and image processing method |
US20090099427A1 (en) * | 2007-10-12 | 2009-04-16 | Arkal Medical, Inc. | Microneedle array with diverse needle configurations |
US8417312B2 (en) | 2007-10-25 | 2013-04-09 | Dexcom, Inc. | Systems and methods for processing sensor data |
CA2702799A1 (en) | 2007-10-25 | 2009-04-30 | Dexcom, Inc. | Systems and methods for processing sensor data |
US8396528B2 (en) | 2008-03-25 | 2013-03-12 | Dexcom, Inc. | Analyte sensor |
CN102047101A (en) | 2008-03-28 | 2011-05-04 | 德克斯康公司 | Polymer membranes for continuous analyte sensors |
WO2009131738A2 (en) * | 2008-04-23 | 2009-10-29 | Elc Management Llc | Microcurrent-generating topical or cosmetic systems, and methods of making and using the same |
US8591410B2 (en) | 2008-05-30 | 2013-11-26 | Abbott Diabetes Care Inc. | Method and apparatus for providing glycemic control |
US8924159B2 (en) | 2008-05-30 | 2014-12-30 | Abbott Diabetes Care Inc. | Method and apparatus for providing glycemic control |
WO2009145920A1 (en) | 2008-05-30 | 2009-12-03 | Intuity Medical, Inc. | Body fluid sampling device -- sampling site interface |
EP2299904B1 (en) | 2008-06-06 | 2019-09-11 | Intuity Medical, Inc. | Medical measurement method |
US9636051B2 (en) | 2008-06-06 | 2017-05-02 | Intuity Medical, Inc. | Detection meter and mode of operation |
GB0811874D0 (en) * | 2008-06-30 | 2008-07-30 | Nemaura Pharma Ltd | Patches for reverse iontophoresis |
WO2010009172A1 (en) | 2008-07-14 | 2010-01-21 | Abbott Diabetes Care Inc. | Closed loop control system interface and methods |
US8103456B2 (en) | 2009-01-29 | 2012-01-24 | Abbott Diabetes Care Inc. | Method and device for early signal attenuation detection using blood glucose measurements |
GB2467377A (en) | 2009-02-02 | 2010-08-04 | Nemaura Pharma Ltd | Transdermal patch with extensor means actuated to expel drug towards the skin of a patient |
US9402544B2 (en) * | 2009-02-03 | 2016-08-02 | Abbott Diabetes Care Inc. | Analyte sensor and apparatus for insertion of the sensor |
CA2759850C (en) * | 2009-04-24 | 2019-10-22 | Corium International, Inc. | Methods for manufacturing microprojection arrays |
US9226701B2 (en) | 2009-04-28 | 2016-01-05 | Abbott Diabetes Care Inc. | Error detection in critical repeating data in a wireless sensor system |
US8483967B2 (en) | 2009-04-29 | 2013-07-09 | Abbott Diabetes Care Inc. | Method and system for providing real time analyte sensor calibration with retrospective backfill |
US9184490B2 (en) | 2009-05-29 | 2015-11-10 | Abbott Diabetes Care Inc. | Medical device antenna systems having external antenna configurations |
US8498694B2 (en) * | 2009-07-13 | 2013-07-30 | Entrotech, Inc. | Subcutaneous access device and related methods |
EP3936032A1 (en) | 2009-07-23 | 2022-01-12 | Abbott Diabetes Care, Inc. | Real time management of data relating to physiological control of glucose levels |
EP3923295A1 (en) | 2009-08-31 | 2021-12-15 | Abbott Diabetes Care, Inc. | Medical devices and methods |
US9314195B2 (en) | 2009-08-31 | 2016-04-19 | Abbott Diabetes Care Inc. | Analyte signal processing device and methods |
WO2011026148A1 (en) | 2009-08-31 | 2011-03-03 | Abbott Diabetes Care Inc. | Analyte monitoring system and methods for managing power and noise |
WO2011041469A1 (en) | 2009-09-29 | 2011-04-07 | Abbott Diabetes Care Inc. | Method and apparatus for providing notification function in analyte monitoring systems |
US20110082356A1 (en) | 2009-10-01 | 2011-04-07 | Medtronic Minimed, Inc. | Analyte sensor apparatuses having interference rejection membranes and methods for making and using them |
US20110288388A1 (en) | 2009-11-20 | 2011-11-24 | Medtronic Minimed, Inc. | Multi-conductor lead configurations useful with medical device systems and methods for making and using them |
EP3106871B1 (en) | 2009-11-30 | 2021-10-27 | Intuity Medical, Inc. | A method of verifying the accuracy of the operation of an analyte monitoring device |
US8660628B2 (en) | 2009-12-21 | 2014-02-25 | Medtronic Minimed, Inc. | Analyte sensors comprising blended membrane compositions and methods for making and using them |
EP2533694A1 (en) | 2010-02-10 | 2012-12-19 | Baylor University | Ultra-wide band non-invasive biological sensor and method |
US10448872B2 (en) | 2010-03-16 | 2019-10-22 | Medtronic Minimed, Inc. | Analyte sensor apparatuses having improved electrode configurations and methods for making and using them |
ES2881798T3 (en) | 2010-03-24 | 2021-11-30 | Abbott Diabetes Care Inc | Medical device inserters and medical device insertion and use procedures |
WO2011140274A2 (en) | 2010-05-04 | 2011-11-10 | Corium International, Inc. | Method and device for transdermal delivery of parathyroid hormone using a microprojection array |
GB201008448D0 (en) | 2010-05-20 | 2010-07-07 | Univ Strathclyde | Transdermal device |
US9215995B2 (en) | 2010-06-23 | 2015-12-22 | Medtronic Minimed, Inc. | Sensor systems having multiple probes and electrode arrays |
CA2803797A1 (en) | 2010-06-25 | 2011-12-29 | Intuity Medical, Inc. | Analyte monitoring methods and systems |
US9029168B2 (en) * | 2010-06-28 | 2015-05-12 | The Trustees Of Princeton University | Use and making of biosensors utilizing antimicrobial peptides for highly sensitive biological monitoring |
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 |
DK3575796T3 (en) | 2011-04-15 | 2021-01-18 | Dexcom Inc | ADVANCED ANALYZE SENSOR CALIBRATION AND ERROR DETECTION |
US9008744B2 (en) | 2011-05-06 | 2015-04-14 | Medtronic Minimed, Inc. | Method and apparatus for continuous analyte monitoring |
EP3407064B1 (en) | 2011-08-03 | 2020-04-22 | Intuity Medical, Inc. | Body fluid sampling arrangement |
WO2013032940A1 (en) | 2011-08-26 | 2013-03-07 | Dexcom, Inc. | Polymer membranes for continuous analyte sensors |
US9980669B2 (en) | 2011-11-07 | 2018-05-29 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods |
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 |
US9493807B2 (en) | 2012-05-25 | 2016-11-15 | Medtronic Minimed, Inc. | Foldover sensors and methods for making and using them |
US20140012115A1 (en) | 2012-07-03 | 2014-01-09 | Medtronic Minimed, Inc. | Plasma deposited adhesion promoter layers for use with analyte sensors |
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 |
US9788765B2 (en) | 2012-09-28 | 2017-10-17 | Dexcom, Inc. | Zwitterion surface modifications for continuous sensors |
US10194840B2 (en) | 2012-12-06 | 2019-02-05 | Medtronic Minimed, Inc. | Microarray electrodes useful with analyte sensors and methods for making and using them |
ES2743404T3 (en) | 2012-12-21 | 2020-02-19 | Corium Inc | Matrix for therapeutic agent supply and manufacturing method |
US10426383B2 (en) | 2013-01-22 | 2019-10-01 | Medtronic Minimed, Inc. | Muting glucose sensor oxygen response and reducing electrode edge growth with pulsed current plating |
EP2968887B1 (en) | 2013-03-12 | 2022-05-04 | Corium, Inc. | Microprojection applicators |
AU2014237279B2 (en) | 2013-03-15 | 2018-11-22 | Corium Pharma Solutions, Inc. | Microarray with polymer-free microstructures, methods of making, and methods of use |
CA2903459C (en) | 2013-03-15 | 2024-02-20 | Corium International, Inc. | Multiple impact microprojection applicators and methods of use |
EP2968118B1 (en) | 2013-03-15 | 2022-02-09 | Corium, Inc. | Microarray for delivery of therapeutic agent and methods of use |
EP2968119B1 (en) | 2013-03-15 | 2019-09-18 | Corium International, Inc. | Microarray for delivery of therapeutic agent, methods of use, and methods of making |
US10729386B2 (en) | 2013-06-21 | 2020-08-04 | Intuity Medical, Inc. | Analyte monitoring system with audible feedback |
US20150122647A1 (en) | 2013-11-07 | 2015-05-07 | Medtronic Minimed, Inc. | Enzyme matrices for use with ethylene oxide sterilization |
CA2933166C (en) | 2013-12-31 | 2020-10-27 | Abbott Diabetes Care Inc. | Self-powered analyte sensor and devices using the same |
EP3188714A1 (en) | 2014-09-04 | 2017-07-12 | Corium International, Inc. | Microstructure array, methods of making, and methods of use |
US10213139B2 (en) | 2015-05-14 | 2019-02-26 | Abbott Diabetes Care Inc. | Systems, devices, and methods for assembling an applicator and sensor control device |
US10857093B2 (en) | 2015-06-29 | 2020-12-08 | Corium, Inc. | Microarray for delivery of therapeutic agent, methods of use, and methods of making |
ITUB20154036A1 (en) * | 2015-09-30 | 2017-03-30 | St Microelectronics Srl | BIOSENSOR FOR DETECTION OF ANALYTES IN SWEAT, AND METHOD OF MANUFACTURE OF THE BIOSENSOR |
JP6116075B1 (en) * | 2015-11-20 | 2017-04-19 | 日本航空電子工業株式会社 | Electrochemical measurement method, electrochemical measurement apparatus and transducer |
WO2017117472A1 (en) | 2015-12-30 | 2017-07-06 | Dexcom, Inc. | Biointerface layer for analyte sensors |
US10324058B2 (en) | 2016-04-28 | 2019-06-18 | Medtronic Minimed, Inc. | In-situ chemistry stack for continuous glucose sensors |
US11179078B2 (en) | 2016-06-06 | 2021-11-23 | Medtronic Minimed, Inc. | Polycarbonate urea/urethane polymers for use with analyte sensors |
US11134868B2 (en) | 2017-03-17 | 2021-10-05 | Medtronic Minimed, Inc. | Metal pillar device structures and methods for making and using them in electrochemical and/or electrocatalytic applications |
US10856784B2 (en) | 2017-06-30 | 2020-12-08 | Medtronic Minimed, Inc. | Sensor initialization methods for faster body sensor response |
US20190223771A1 (en) | 2018-01-23 | 2019-07-25 | Medtronic Minimed, Inc. | Implantable polymer surfaces exhibiting reduced in vivo inflammatory responses |
US11186859B2 (en) | 2018-02-07 | 2021-11-30 | Medtronic Minimed, Inc. | Multilayer electrochemical analyte sensors and methods for making and using them |
US11220735B2 (en) | 2018-02-08 | 2022-01-11 | Medtronic Minimed, Inc. | Methods for controlling physical vapor deposition metal film adhesion to substrates and surfaces |
US11583213B2 (en) | 2018-02-08 | 2023-02-21 | Medtronic Minimed, Inc. | Glucose sensor electrode design |
EP3794135A1 (en) | 2018-05-16 | 2021-03-24 | Medtronic MiniMed, Inc. | Thermally stable glucose limiting membrane for glucose sensors |
USD1002852S1 (en) | 2019-06-06 | 2023-10-24 | Abbott Diabetes Care Inc. | Analyte sensor device |
US11718865B2 (en) | 2019-07-26 | 2023-08-08 | Medtronic Minimed, Inc. | Methods to improve oxygen delivery to implantable sensors |
US11523757B2 (en) | 2019-08-01 | 2022-12-13 | Medtronic Minimed, Inc. | Micro-pillar working electrodes design to reduce backflow of hydrogen peroxide in glucose sensor |
US20220031205A1 (en) | 2020-07-31 | 2022-02-03 | Medtronic Minimed, Inc. | Sensor identification and integrity check design |
US20220133190A1 (en) | 2020-10-29 | 2022-05-05 | Medtronic Minimed, Inc. | Glucose biosensors comprising direct electron transfer enzymes and methods of making and using them |
USD999913S1 (en) | 2020-12-21 | 2023-09-26 | Abbott Diabetes Care Inc | Analyte sensor inserter |
US20220240823A1 (en) | 2021-01-29 | 2022-08-04 | Medtronic Minimed, Inc. | Interference rejection membranes useful with analyte sensors |
CN113008966B (en) * | 2021-03-04 | 2021-09-28 | 西南交通大学 | Non-enzymatic electrochemical sensor capable of simultaneously detecting glucose and uric acid |
US20220338768A1 (en) | 2021-04-09 | 2022-10-27 | Medtronic Minimed, Inc. | Hexamethyldisiloxane membranes for analyte sensors |
US20230053254A1 (en) | 2021-08-13 | 2023-02-16 | Medtronic Minimed, Inc. | Dry electrochemical impedance spectroscopy metrology for conductive chemical layers |
US20230113175A1 (en) | 2021-10-08 | 2023-04-13 | Medtronic Minimed, Inc. | Immunosuppressant releasing coatings |
US20230123613A1 (en) | 2021-10-14 | 2023-04-20 | Medtronic Minimed, Inc. | Sensors for 3-hydroxybutyrate detection |
US20230172497A1 (en) | 2021-12-02 | 2023-06-08 | Medtronic Minimed, Inc. | Ketone limiting membrane and dual layer membrane approach for ketone sensing |
CN115165984B (en) * | 2022-07-15 | 2023-06-06 | 中国科学院海洋研究所 | Ocean environment hydrogen permeation monitoring sensor with working face being plane and monitoring method |
US20240023849A1 (en) | 2022-07-20 | 2024-01-25 | Medtronic Minimed, Inc. | Acrylate hydrogel membrane for dual function of diffusion limiting membrane as well as attenuation to the foreign body response |
Family Cites Families (35)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4633879A (en) * | 1979-11-16 | 1987-01-06 | Lec Tec Corporation | Electrode with disposable interface member |
US4477971A (en) * | 1981-11-06 | 1984-10-23 | Motion Control, Inc. | Iontophoretic electrode structure |
US4457748A (en) * | 1982-01-11 | 1984-07-03 | Medtronic, Inc. | Non-invasive diagnosis method |
DK8601218A (en) * | 1984-07-18 | 1986-03-17 | ||
US4702732A (en) * | 1984-12-24 | 1987-10-27 | Trustees Of Boston University | Electrodes, electrode assemblies, methods, and systems for tissue stimulation and transdermal delivery of pharmacologically active ligands |
US4960467A (en) * | 1985-02-11 | 1990-10-02 | The United States Of America As Represented By The Secretary Of The Army | Dermal substance collection device |
US4909256A (en) * | 1985-02-11 | 1990-03-20 | The United States Of America, As Represented By The Secretary Of The Army | Transdermal vapor collection method and apparatus |
US4657748A (en) * | 1985-03-18 | 1987-04-14 | Exxon Research And Engineering Company | Crystalline zeolite (ECR-1) and process for preparing it |
US4732155A (en) * | 1985-08-27 | 1988-03-22 | The Children's Medical Center Corporation | Implantable chemoattractant system |
US4894339A (en) * | 1985-12-18 | 1990-01-16 | Seitaikinouriyou Kagakuhin Sinseizogijutsu Kenkyu Kumiai | Immobilized enzyme membrane for a semiconductor sensor |
US4722726A (en) * | 1986-02-12 | 1988-02-02 | Key Pharmaceuticals, Inc. | Method and apparatus for iontophoretic drug delivery |
US4752285B1 (en) * | 1986-03-19 | 1995-08-22 | Univ Utah Res Found | Methods and apparatus for iontophoresis application of medicaments |
US4722761A (en) * | 1986-03-28 | 1988-02-02 | Baxter Travenol Laboratories, Inc. | Method of making a medical electrode |
US5250022A (en) * | 1990-09-25 | 1993-10-05 | Rutgers, The State University Of New Jersey | Iontotherapeutic devices, reservoir electrode devices therefore, process and unit dose |
US4731049A (en) * | 1987-01-30 | 1988-03-15 | Ionics, Incorporated | Cell for electrically controlled transdermal drug delivery |
US4821733A (en) * | 1987-08-18 | 1989-04-18 | Dermal Systems International | Transdermal detection system |
AU614092B2 (en) * | 1987-09-11 | 1991-08-22 | Paul Max Grinwald | Improved method and apparatus for enhanced drug permeation of skin |
WO1989006989A1 (en) * | 1988-01-29 | 1989-08-10 | The Regents Of The University Of California | Iontophoretic non-invasive sampling or delivery device |
US5362307A (en) * | 1989-01-24 | 1994-11-08 | The Regents Of The University Of California | Method for the iontophoretic non-invasive-determination of the in vivo concentration level of an inorganic or organic substance |
US5203327A (en) * | 1988-09-08 | 1993-04-20 | Sudor Partners | Method and apparatus for determination of chemical species in body fluid |
US5076273A (en) * | 1988-09-08 | 1991-12-31 | Sudor Partners | Method and apparatus for determination of chemical species in body fluid |
US5057072A (en) * | 1988-10-28 | 1991-10-15 | Medtronic, Inc. | Iontophoresis electrode |
US4968297A (en) * | 1989-05-09 | 1990-11-06 | Iomec, Inc. | Iontophoretic electrode with solution containment system |
US5139023A (en) * | 1989-06-02 | 1992-08-18 | Theratech Inc. | Apparatus and method for noninvasive blood glucose monitoring |
US5140985A (en) * | 1989-12-11 | 1992-08-25 | Schroeder Jon M | Noninvasive blood glucose measuring device |
US5036861A (en) * | 1990-01-11 | 1991-08-06 | Sembrowich Walter L | Method and apparatus for non-invasively monitoring plasma glucose levels |
US5161532A (en) * | 1990-04-19 | 1992-11-10 | Teknekron Sensor Development Corporation | Integral interstitial fluid sensor |
WO1992007609A1 (en) * | 1990-10-29 | 1992-05-14 | Angeion Corporation | Digital display system for balloon catheter |
US5158537A (en) * | 1990-10-29 | 1992-10-27 | Alza Corporation | Iontophoretic delivery device and method of hydrating same |
US5156591A (en) * | 1990-12-13 | 1992-10-20 | S. I. Scientific Innovations Ltd. | Skin electrode construction and transdermal drug delivery device utilizing same |
DK0592418T3 (en) * | 1991-07-12 | 1995-10-09 | Grimma Masch Anlagen Gmbh | Process and apparatus for detecting combustion gases from waste incineration plants |
US5322063A (en) * | 1991-10-04 | 1994-06-21 | Eli Lilly And Company | Hydrophilic polyurethane membranes for electrochemical glucose sensors |
DE69519023T2 (en) * | 1994-06-24 | 2001-06-13 | Cygnus Therapeutic Systems | IONTOPHORETIC SAMPLING DEVICE |
US5771890A (en) * | 1994-06-24 | 1998-06-30 | Cygnus, Inc. | Device and method for sampling of substances using alternating polarity |
US5735273A (en) * | 1995-09-12 | 1998-04-07 | Cygnus, Inc. | Chemical signal-impermeable mask |
-
1995
- 1995-09-12 US US08/527,061 patent/US5735273A/en not_active Expired - Lifetime
-
1996
- 1996-07-16 DE DE69612398T patent/DE69612398T2/en not_active Expired - Lifetime
- 1996-07-16 PT PT96924546T patent/PT876501E/en unknown
- 1996-07-16 EP EP96924546A patent/EP0876501B1/en not_active Expired - Lifetime
- 1996-07-16 AT AT96924546T patent/ATE200305T1/en not_active IP Right Cessation
- 1996-07-16 WO PCT/US1996/011776 patent/WO1997010356A1/en active IP Right Grant
- 1996-07-16 JP JP51192497A patent/JP3366646B2/en not_active Expired - Lifetime
- 1996-07-16 AU AU64973/96A patent/AU703849B2/en not_active Ceased
- 1996-07-16 CA CA002229509A patent/CA2229509C/en not_active Expired - Lifetime
- 1996-07-16 DK DK96924546T patent/DK0876501T3/en active
- 1996-07-16 KR KR10-1998-0701816A patent/KR100438509B1/en not_active IP Right Cessation
- 1996-07-16 ES ES96924546T patent/ES2155615T3/en not_active Expired - Lifetime
-
1997
- 1997-10-29 US US08/959,599 patent/US5827183A/en not_active Expired - Lifetime
-
1998
- 1998-08-04 US US09/128,891 patent/US6141573A/en not_active Expired - Lifetime
-
2000
- 2000-03-13 US US09/523,826 patent/US6201979B1/en not_active Expired - Lifetime
-
2001
- 2001-01-18 US US09/764,550 patent/US6370410B2/en not_active Expired - Lifetime
- 2001-06-27 GR GR20010400995T patent/GR3036141T3/en not_active IP Right Cessation
- 2001-12-06 US US10/006,769 patent/US6529755B2/en not_active Expired - Lifetime
-
2002
- 2002-12-20 US US10/324,818 patent/US6771995B2/en not_active Expired - Fee Related
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US6529755B2 (en) | 2003-03-04 |
JPH11512316A (en) | 1999-10-26 |
DE69612398T2 (en) | 2001-07-12 |
WO1997010356A1 (en) | 1997-03-20 |
AU6497396A (en) | 1997-04-01 |
KR19990044567A (en) | 1999-06-25 |
DK0876501T3 (en) | 2001-05-14 |
US20030120138A1 (en) | 2003-06-26 |
PT876501E (en) | 2001-07-31 |
US5827183A (en) | 1998-10-27 |
US20020062073A1 (en) | 2002-05-23 |
EP0876501B1 (en) | 2001-04-04 |
CA2229509A1 (en) | 1997-03-20 |
KR100438509B1 (en) | 2004-11-16 |
GR3036141T3 (en) | 2001-09-28 |
ES2155615T3 (en) | 2001-05-16 |
US20010020125A1 (en) | 2001-09-06 |
EP0876501A1 (en) | 1998-11-11 |
US6370410B2 (en) | 2002-04-09 |
US6201979B1 (en) | 2001-03-13 |
AU703849B2 (en) | 1999-04-01 |
DE69612398D1 (en) | 2001-05-10 |
US6771995B2 (en) | 2004-08-03 |
US5735273A (en) | 1998-04-07 |
JP3366646B2 (en) | 2003-01-14 |
US6141573A (en) | 2000-10-31 |
ATE200305T1 (en) | 2001-04-15 |
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