CA2502277A1 - Analyte sensors and methods for making them - Google Patents
Analyte sensors and methods for making them Download PDFInfo
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- CA2502277A1 CA2502277A1 CA002502277A CA2502277A CA2502277A1 CA 2502277 A1 CA2502277 A1 CA 2502277A1 CA 002502277 A CA002502277 A CA 002502277A CA 2502277 A CA2502277 A CA 2502277A CA 2502277 A1 CA2502277 A1 CA 2502277A1
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- layer
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- glucose oxidase
- glucose
- enzyme
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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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- 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
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/28—Electrolytic cell components
- G01N27/30—Electrodes, e.g. test electrodes; Half-cells
- G01N27/307—Disposable laminated or multilayered electrodes
Abstract
Embodiments of the invention provide analyte sensors (100) having stabilized coating compositions and methods for making such sensors. Illustrative embodiments include electrochemical glucose sensors (100) having stabilized glucose oxidase coatings (110) that are generated for example, via spin coating processes.
Description
ANALYTE SENSORS AND METHODS FOR MAKING THEM
Cross Reference To Related Applications This application is related to U.S. Patent No. 6,413,393 "SENSOR
INCLUDING UV-ABSORBING POLYMER AND METHOD OF
MANUFACTURE"; U.S. Patent No. 6,368,274 "REUSABLE ANALYTE SENSOR
SITE AND METHOD OF USING THE SAME"; U.S. Patent No. 5,786,439 "HYDROPHILIC, SWELLABLE COATINGS FOR IMPLANTABLE DEVICES";
U.S. Patent No. 5,777,060 "SILICON CONTAINING BIOCOMPATIBLE
MEMBRANES"; U.S. Patent No. 5,391,250 "METHOD OF FABRICATING THIN
FILM SENSORS"; PCT ' International Publication Number WO 01/58348 "IMPROVED ANALYTE SENSOR AND METHOD OF MAKING THE SAME", and U.S. Patent No. 5,390,671 "TRANSCUTANEOUS SENSOR INFUSION SET", the contents of each of which are incorporated herein by reference.
Background of the Invention 1. Field of the Invention.
The present invention relates to sensors for the detection and measurement of analytes such as glucose and methods for making them.
Cross Reference To Related Applications This application is related to U.S. Patent No. 6,413,393 "SENSOR
INCLUDING UV-ABSORBING POLYMER AND METHOD OF
MANUFACTURE"; U.S. Patent No. 6,368,274 "REUSABLE ANALYTE SENSOR
SITE AND METHOD OF USING THE SAME"; U.S. Patent No. 5,786,439 "HYDROPHILIC, SWELLABLE COATINGS FOR IMPLANTABLE DEVICES";
U.S. Patent No. 5,777,060 "SILICON CONTAINING BIOCOMPATIBLE
MEMBRANES"; U.S. Patent No. 5,391,250 "METHOD OF FABRICATING THIN
FILM SENSORS"; PCT ' International Publication Number WO 01/58348 "IMPROVED ANALYTE SENSOR AND METHOD OF MAKING THE SAME", and U.S. Patent No. 5,390,671 "TRANSCUTANEOUS SENSOR INFUSION SET", the contents of each of which are incorporated herein by reference.
Background of the Invention 1. Field of the Invention.
The present invention relates to sensors for the detection and measurement of analytes such as glucose and methods for making them.
2. Description of Related Art.
Analyte sensors such as electrochemical sensors are manufactured according to a variety of processes for use in a wide niunber of specialized sensor applications. For example, electrochemical sensors are typically manufactured using thin filin processes known in the art. Such thin film sensors generally comprise one or more thin conductors applied by thin film deposition processes and subsequently patterned by photolithographic mask and/or etch techniques in combination with layers of nonconductive film materials, such as polyimide film. The conductors are typically shaped to define distal end sensor tips having an appropriate electrode material thereon, in combination with proximal end contact pads adapted for conductive connection with appropriate electronic monitoring equipment. Additional layers of coatings having various functional properties axe typically included in such sensors. In recent years, thin film sensors of this general type have been designed fox use as transcutaneous sensors in medical applications. As one example, thin filin sensors have been designed for use in monitoring blood glucose levels in a diabetic patient.
A wide variety of methods for producing sensors, such as those used in sensor sets designed for the determination of a body characteristic such as blood glucose levels, are known in the art. Examples of such sensors, sensor sets and methods for their production axe described, fox example, in commonly assigned U.S. Patent Nos.
5,390,691, 5,391, 250, 5,482,473, 5,299,571, 5,568,806 as well as PCT
International Publication Number WO 01 /58348, the contents of each of which axe incorporated herein by reference.
While a number of sensor designs and processes for making such sensors are known in the art, there continues to be a need for sensors having improved characteristics such as enhanced longevity, linearity and regularity, as well as optunized signal to noise ratios. There is also a need fox the identification of the methods and processes that allow fox the generation of sensors having these optimized qualities. The present invention fulfills these needs and provides further related advantages.
Summary of the Invention Embodiments of the invention disclosed herein provide methods for producing sensors of the type used, for example, in subcutaneous or transcutaneous monitoring of blood glucose levels in a diabetic patient. More specifically, the disclosure provided herein teaches methods for applying very thin enzyme coatings to these types of sensors as well as sensors produced by such processes. Preferable methods fox producing the sensors of the invention include coating processes. Surprisingly, sensors having enzyme coatings formed by such processes have a number of superior qualities including enhanced longevity, linearity and regularity, as well as improved signal to noise ratios. In addition, certain sensor embodiments of the invention that utilize glucose oxidase coatings formed by such processes are designed to recycle hydrogen peroxide and improve the biocompatibility profiles of such sensors.
An illustrative embodiment of the invention is a sensor designed for implantation within a body that consists of a base layer, a sensor layer disposed upon the base layer which includes a plurality of sensor elements, an enzyme layer (preferably less than 2 microns in thickness disposed upon the sensor layer which coats sensing elements on the sensor layer, and a cover layer. Typically the enzyme layer comprises glucose oxidase, preferably in a substantially fixed ratio with a carrier protein.
Typically the carrier protein comprises albumin, preferably in an amount of about 5% by weight. In preferred embodiments of the invention, the cover layer is an analyte contacting layer which is disposed on the sensor so as to regulate the amount of analyte that can contact the enzyme layer. Preferably the analyte contacting layer is a glucose limiting layer that limits the amount of glucose analyte that can contact the glucose oxidase coating on the sensor. In highly preferred embodiments, the sensor includes an adhesion promoter layer disposed between the enzyme layer and the glucose limiting layer.
Another embodiment of the invention is an electrochemical glucose sensor having hydrogen peroxide recycling capabilities. Typically, such sensors include a base layer, a sensor layer disposed upon the base layer, wherein the sensor layer includes at least one working electrode and at least one counter electrode, a glucose oxidase layer disposed upon the sensor layer that coats at least a portion of the working electrode and at least a portion of the counter electrode in a manner such that the working electrode oxidizes hydrogen peroxide that is produced by glucose oxidase upon reaction with glucose, and a glucose limiting layer disposed on the sensor so as to regulate the amount of glucose that can contact the glucose oxidase layer and to inhibit the diffusion of hydrogen peroxide into the environment in which the sensor is placed.
Optionally such sensor embodiments further include a reference electrode on the sensox layer, wherein the glucose oxidase layer is disposed upon the sensor layer so as to coat at least a portion of the reference electrode.
The disclosure herein provides methods for making the sensor embodiments of the invention. A preferred embodiment of the invention is a method of making a sensor by pxoviding a base layer, forming a sensor layer on the base layer, spin coating an enzyme layer on the sensor layer and then forming an analyte contacting layer on the sensor, wherein the analyte contacting layer regulates the amount of analyte that can contact the enzyme layer. While the preferred process for applying very thin enzyme coatings is a spin coating processes, such very thin coatings can also be applied by dip and dry processes, low-shear spraying processes, ink-jet printing processes, silk screen processes and the like. In preferred methods, the enzyme layer is vapor crosslinked on the sensor layer. In a typical embodiment of the invention, the sensor layer is formed to include at least one working electrode and at least one counter electrode. In highly preferred embodiments, the enzyme layer is formed on at least a portion of the working electrode and at least a portion of the counter electrode. Typically, the enzyme layer that is formed on the sensor layer is less than 2, 1, 0.5, 0.25 ox 0.1 microns in thickness.
Preferably the enzyme layer comprises glucose oxidase, glucose dehydrogenase, lactose oxidase, hexokinase ox lactose dehydrogenase. In a specific method, the enzyme layer comprises glucose oxidase that is stabilized by coating it on the sensor layer in combination with a carrier protein in a fixed ratio. Typically the carrier protein is albumin. Preferably such methods include the step of forming an adhesion promoting layer disposed between the glucose oxidase layer and the analyte contacting layer.
Optionally, the adhesion promoting layer is subjected to a curing process prior to the formation of the analyte contacting layer.
The invention also provides additional articles of manufacture including sensor sets and kits. In one such embodiment of the invention, a kit and/or sensor set, useful fox the sensing an analyte as is described above, is provided. The kit and/or sensor set typically comprises a container, a label and a sensor having an extremely thin enzyme coating as described above.
Other objects, features and advantages of the present invention will become apparent to those skilled in the art from the following detailed description.
It is to be understood, however, that the detailed description and specific examples, while indicating preferred embodiments of the present invention are given by way of illustration and not limitation. Many changes and modifications within the scope of the present invention may be made without departing from the spirit thereof, and the invention includes all such modifications.
Analyte sensors such as electrochemical sensors are manufactured according to a variety of processes for use in a wide niunber of specialized sensor applications. For example, electrochemical sensors are typically manufactured using thin filin processes known in the art. Such thin film sensors generally comprise one or more thin conductors applied by thin film deposition processes and subsequently patterned by photolithographic mask and/or etch techniques in combination with layers of nonconductive film materials, such as polyimide film. The conductors are typically shaped to define distal end sensor tips having an appropriate electrode material thereon, in combination with proximal end contact pads adapted for conductive connection with appropriate electronic monitoring equipment. Additional layers of coatings having various functional properties axe typically included in such sensors. In recent years, thin film sensors of this general type have been designed fox use as transcutaneous sensors in medical applications. As one example, thin filin sensors have been designed for use in monitoring blood glucose levels in a diabetic patient.
A wide variety of methods for producing sensors, such as those used in sensor sets designed for the determination of a body characteristic such as blood glucose levels, are known in the art. Examples of such sensors, sensor sets and methods for their production axe described, fox example, in commonly assigned U.S. Patent Nos.
5,390,691, 5,391, 250, 5,482,473, 5,299,571, 5,568,806 as well as PCT
International Publication Number WO 01 /58348, the contents of each of which axe incorporated herein by reference.
While a number of sensor designs and processes for making such sensors are known in the art, there continues to be a need for sensors having improved characteristics such as enhanced longevity, linearity and regularity, as well as optunized signal to noise ratios. There is also a need fox the identification of the methods and processes that allow fox the generation of sensors having these optimized qualities. The present invention fulfills these needs and provides further related advantages.
Summary of the Invention Embodiments of the invention disclosed herein provide methods for producing sensors of the type used, for example, in subcutaneous or transcutaneous monitoring of blood glucose levels in a diabetic patient. More specifically, the disclosure provided herein teaches methods for applying very thin enzyme coatings to these types of sensors as well as sensors produced by such processes. Preferable methods fox producing the sensors of the invention include coating processes. Surprisingly, sensors having enzyme coatings formed by such processes have a number of superior qualities including enhanced longevity, linearity and regularity, as well as improved signal to noise ratios. In addition, certain sensor embodiments of the invention that utilize glucose oxidase coatings formed by such processes are designed to recycle hydrogen peroxide and improve the biocompatibility profiles of such sensors.
An illustrative embodiment of the invention is a sensor designed for implantation within a body that consists of a base layer, a sensor layer disposed upon the base layer which includes a plurality of sensor elements, an enzyme layer (preferably less than 2 microns in thickness disposed upon the sensor layer which coats sensing elements on the sensor layer, and a cover layer. Typically the enzyme layer comprises glucose oxidase, preferably in a substantially fixed ratio with a carrier protein.
Typically the carrier protein comprises albumin, preferably in an amount of about 5% by weight. In preferred embodiments of the invention, the cover layer is an analyte contacting layer which is disposed on the sensor so as to regulate the amount of analyte that can contact the enzyme layer. Preferably the analyte contacting layer is a glucose limiting layer that limits the amount of glucose analyte that can contact the glucose oxidase coating on the sensor. In highly preferred embodiments, the sensor includes an adhesion promoter layer disposed between the enzyme layer and the glucose limiting layer.
Another embodiment of the invention is an electrochemical glucose sensor having hydrogen peroxide recycling capabilities. Typically, such sensors include a base layer, a sensor layer disposed upon the base layer, wherein the sensor layer includes at least one working electrode and at least one counter electrode, a glucose oxidase layer disposed upon the sensor layer that coats at least a portion of the working electrode and at least a portion of the counter electrode in a manner such that the working electrode oxidizes hydrogen peroxide that is produced by glucose oxidase upon reaction with glucose, and a glucose limiting layer disposed on the sensor so as to regulate the amount of glucose that can contact the glucose oxidase layer and to inhibit the diffusion of hydrogen peroxide into the environment in which the sensor is placed.
Optionally such sensor embodiments further include a reference electrode on the sensox layer, wherein the glucose oxidase layer is disposed upon the sensor layer so as to coat at least a portion of the reference electrode.
The disclosure herein provides methods for making the sensor embodiments of the invention. A preferred embodiment of the invention is a method of making a sensor by pxoviding a base layer, forming a sensor layer on the base layer, spin coating an enzyme layer on the sensor layer and then forming an analyte contacting layer on the sensor, wherein the analyte contacting layer regulates the amount of analyte that can contact the enzyme layer. While the preferred process for applying very thin enzyme coatings is a spin coating processes, such very thin coatings can also be applied by dip and dry processes, low-shear spraying processes, ink-jet printing processes, silk screen processes and the like. In preferred methods, the enzyme layer is vapor crosslinked on the sensor layer. In a typical embodiment of the invention, the sensor layer is formed to include at least one working electrode and at least one counter electrode. In highly preferred embodiments, the enzyme layer is formed on at least a portion of the working electrode and at least a portion of the counter electrode. Typically, the enzyme layer that is formed on the sensor layer is less than 2, 1, 0.5, 0.25 ox 0.1 microns in thickness.
Preferably the enzyme layer comprises glucose oxidase, glucose dehydrogenase, lactose oxidase, hexokinase ox lactose dehydrogenase. In a specific method, the enzyme layer comprises glucose oxidase that is stabilized by coating it on the sensor layer in combination with a carrier protein in a fixed ratio. Typically the carrier protein is albumin. Preferably such methods include the step of forming an adhesion promoting layer disposed between the glucose oxidase layer and the analyte contacting layer.
Optionally, the adhesion promoting layer is subjected to a curing process prior to the formation of the analyte contacting layer.
The invention also provides additional articles of manufacture including sensor sets and kits. In one such embodiment of the invention, a kit and/or sensor set, useful fox the sensing an analyte as is described above, is provided. The kit and/or sensor set typically comprises a container, a label and a sensor having an extremely thin enzyme coating as described above.
Other objects, features and advantages of the present invention will become apparent to those skilled in the art from the following detailed description.
It is to be understood, however, that the detailed description and specific examples, while indicating preferred embodiments of the present invention are given by way of illustration and not limitation. Many changes and modifications within the scope of the present invention may be made without departing from the spirit thereof, and the invention includes all such modifications.
Brief Description of the Figures Figure 1 provides a diagrammatic view of a glucose sensor of the current invention.
Figure 2 provides a schematic of the well known reaction between glucose and oxygen in the presence of glucose oxidase. As shown in a stepwise manner, this reaction involves glucose oxidase (GO~, glucose and oxygen in water. In the reductive half of the reaction, two protons and electrons are transferred ~rom ~3-D-glucose to the enzyme yielding d-gluconolactone. In the oxidative half of the reaction, the enzyme is oxidized by molecular oxygen yielding hydrogen peroxide. The d-gluconolactone then reacts with water to hydrolyze the lactone ring and produce gluconic acid. In typical electrochemical sensors of the invention, the hydrogen peroxide produced by this reaction is oxidized at the working electrode (HaOz -~ 2H+ + O~ + 2e-).
Detailed Description of the Preferred Embodiments Unless otherwise defined, all terms of art, notations and other scientific terms ox terminology used herein axe intended to have the meanings commonly understood by those of skill in the art to which this invention pertains. In some cases, terms with commonly understood meanings axe deftned herein fox clarity and/or for ready reference, and the inclusion of such defuvtions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art. Many of the techniques and procedures described or referenced herein are well understood and commonly employed using conventional methodology by those skilled in the art. As appropriate, procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer defined protocols and/or parameters unless otherwise noted.
Embodiments of the invention disclosed herein provide methods for producing electrochemical sensors of the type used, for example, in subcutaneous or transcutaneous monitoring of blood glucose levels in a diabetic patient. More specifically, the disclosure provided herein teaches methods for applying very thin enzyme coatings to specific elements within these sensors. The disclosure further provides sensors produced by such processes. Methods for producing the sensors of the invention include spin coating processes, dip and dry processes, low-shear spraying processes, ink-jet printing processes, silk screen processes and the like. Surprisingly, sensors having thin enzyme coatings produced by such processes have a number of improved qualities itacluding enhanced longevity, linearity, regularity as well as improved signal to noise ratios.
~Uhile preferred embodiments of the invention pertain to glucose sensors, such thin enzyme coating can be adapted for use with any one of the wide variety of sensors known in the art. A number of enzyme sensors (e.g., glucose sensors which the enzyme glucose oxidase to effect a reaction of glucose and oxygen) are known in the art, and are within the skill in the art to fabricate. See, for example, U.S. Pat. Nos.
5,165,407, 4,890,620, 5,390,671 and 5,391,250, the disclosures of each being incorporated herein by reference. Sensors for monitoring glucose concentration of diabetics are further described in Shichiri, et al.,: "In Vivo Characteristics of Needle-Type Glucose Sensor-Measurements of Subcutaneous Glucose Concentrations in Human Volunteers,"
Horm.
Metab. Res., Suppl. Ser. 20:17-20 (1988); Bruckel, et al.,: "In Vivo Measurement of Subcutaneous Glucose Concentrations with an Enzymatic Glucose Sensor and a ~Uick Method," Klin. Wochenschr. 67:491-495 (1989); and Pickup, et al.,: "In Vivo Molecular Sensing in Diabetes Mellitus: An Implantable Glucose Sensor with Direct Electron Transfer," Diabetologia 32:213-217 (1989). Other sensors are described in, fox example Reach, et al., in ADVANCES IN IMPLANTABLE DEVICES, A. Turner (ed.), JAI
Press, London, Chap. 1, (1993), incorporated herein by reference. Specific aspects of the invention are discussed in detail in the following sections.
A. EXTREMELY THIN ENZYMATIC COATINGS OF THE INVENTION
A significant aspect of the present invention involves processes for making sensors having improved electrode chemistry coatings (e.g., enzyme coatings of less than 2 microns in thickness) with enhanced material properties. Methods for producing the extremely thin. enzyme coatings of the invention include spin coating processes, dip and dty processes, low shear spraying processes, ink-jet printing processes, silk screen processes and the like. Typically, such coatings are vapor crosslinked subsequent to their application. Sul.-prisingly, sensors produced by these processes have material properties that exceed those of sensors having coatings produced by electrodeposition including enhanced longevity, linearity, regularity as well as improved signal to noise ratios. In addition, certain sensor embodiments of the invention that utilize glucose oxidase coatings formed by such processes are designed to recycle hydrogen peroxide and improve the bi.ocompatibility profiles of such sensors.
While not being bound by a specific scientific theory, it is believed that sensors produced by such processes have surprisingly enhanced characteristics as compared to those generated by electrodeposition because electrodeposition produces 3-5 micron duck enzyme layers in which only a fraction of the reactive enzyme within the coating layer is able to access the analyte to be sensed. In sensors utilizing glucose oxidase, the thick coatings produced by electYOdeposition may hinder the ability of hydrogen peroxide generated at the reactive interface of the 3-5 micron thick enzyme layer to contact the sensor surface and thereby generate a signal. In addition, hydrogen peroxide that is unable to reach a sensor surface due to such thick coatings can diffuse away from the sensor into the environment in which the sensor is placed, thereby decreasing the biocompatibility of such sensors.
In addition, while not being bound by a specific scientific theory, it is believed that the unexpected properties of sensors produced by such processes further results from the fact that processes such as spin coating, or the like, allow for a precise control over the enzyme coating's ratio of glucose oxidase to albumin (which is used as a carrier protein to stabilize the glucose oxidase in the enzyme layer). Specifically, because glucose oxidase and albumin have different isoelect~i.c points, electrodeposition processes may result in a surface coating in which an optimally determined ratio of enzyme to carrier protein is detrimentally altered in the electrodeposition process and further wherein the glucose oxidase and the carrier protein are not distributed in a substantially uniform manner throughout the disposed enzyme layer.
In this context, a preferred embodiment of the invention is a method of making a less than about 2 micron coating of stabilized glucose oxidase on the surface of a matrix such as an electrode comprising combining glucose oxidase with albumin in a fixed ratio (one that is typically optimized for glucose oxidase stabilizing properties) and applying the glucose oxidase and albumin mixture to the surface of the matrix by a process selected from the group consisting of a spin coating process, a dip and dry process, a microdeposition process, a jet punter deposition process, a screen printing process or a doctor blading process. Preferably the stabilized glucose oxidase coating is applied to the surface of an electrode by a spin coating process. In lvghly preferred embodiments, the glucose oxidase/albumin is prepared in a physiological solution (e.g., phosphate buffered saline at neutral pH) with the albumin being present in an amount of about 5%
albumin by weight. Optionally the stabilized glucose oxidase layer that is formed on the sensor layer is less than 2, 1, 0.5, 0.25 ox 0.1 microns in thickness. A closely related embodiment of the invention is a stabilized glucose oxidase layer for coating the surface of an electrode wherein the glucose oxidase is mixed with a carrier protein in a fixed ratio within the layer, the glucose oxidase and the carrier protein are distzibuted in a substantially uniform manner throughout the layer. Preferably the layer is less than 2 microns in thickness.
B. ANALYTE SENSORS OF THE INVENTION
The invention disclosed herein includes a number of embodiments including sensors having very thin enzyme coatings. Illustrative general embodiments of the sensor disclosed herein include a base layer, a cover layer and at least one sensor layer having a sensor element such as an electrode disposed between the base and cover layers.
Typically, an exposed portion of one or more sensor elements (e.g., a worl~ing electrode, a counter electrode, reference electrode, etc.) is coated with a very thin layer of material having an appropriate electrode chemistry. For example, an enzyme such as glucose oxidase, glucose dehydrogenase or hexokinase, can be disposed on the exposed portion of the sensor element within an opening or aperture defined in the cover layer. FIG. 1 illustrates a cross-section of a typical sensor structure 100 of the present invention. The sensor is formed from a plurality of layers of various conductive and non-conductive constituents disposed on each other according to a method of the invention to produce a sensor structure 100.
A preferred embodiment of the invention is shown in FIG. 1. This embodiment includes an electrically insulating base layer 102 to support the sensor 100.
The electrically insulating layer base 102 can be made of a material such as a polyimide substrate, which may be self supporting or further supported by another material as is known in the art. In one embodiment, the electrically insulating layer 102 comprises a polyimide tape, dispensed from a reel. Providing the layer 102 in this form can facilitate clean, high density mass production. Further, in some production processes using such a polyimide tape, sensors 100 can be produced on both sides of the tape.
Typical embodiments of the invention include a sensor layer disposed on the base layer 102. In a preferred embodiment as shown in FIG. 1 the sensor layer comprises a conductive layer 104 which is disposed on insulating base layer 102.
Preferably the conductive layer 104 comprises one or more electrodes. The conductive layer 104 can be applied using many known techniques and materials as will be described hereafter, however, the electrical circuit of the sensor 100 is typically defined by etching the disposed conductive layer 104 into a desired pattern of conductive paths.
A typical electrical circuit for the sensor 100 comprises two ox more adjacent conductive paths with regions at a proximal end to form contact pads and regions at a distal end to form sensor electrodes. An electrically insulating protective layer 106 such as a polymer coating is typically disposed on portions of the conductive layer 104.
Acceptable polymer coatings for use as the insulating protective layer 106 can include, but are not limited to, non-toxic biocompatible polymers such as polyimide, biocompatible solder masks, epoxy acrylate copolymers, or the like. Further, these coatings can be photo imageable to facilitate photolithographic forming of apertures 108 through to the conductive layer 104.
In the sensors of the present invention, one or more exposed regions or apertures 108 can be made through the protective layer 106 to the conductive layer 104 to define the contact pads and electrodes of the sensor 100. In addition to photolithograplv.c development, the apertures 108 can be formed by a number of techniques, including laser ablation, chemical milling or etching ox the like.
A secondary photoresist can also be applied to the protective layer 106 to define the regions of the protective layer to be removed to form the apertures 108. An operating sensor typically includes a plurality of electrodes such as a working electrode and a counter electrode electrically isolated from each other, however typically situated in close proximity to one another. Other embodiments may also include a reference electrode.
Still other embodiments may utilize an separate reference not formed on the sensor. The exposed electrodes and/or contact pads can also undergo secondary processing through the apertures 108, such as additional plating processing, to prepare the surfaces and/or strengthen the conductive regions.
A dvn sensor chemistry layer 110 is typically disposed on one or more of the exposed electzodes of the conductive layer 104 through the apertures 108.
Preferably, the sensor chemistry layer 110 is an enzyme layer. Most preferably, the sensor chemistry layer 110 comprises the enzyme glucose oxidase. In such embodiments, the sensor chemistry layer 110 reacts with glucose to produce hydrogen peroxide which modulates a current to the electrode which can be monitored to measure an amount of glucose present. The sensor chemistry layer 110 can be applied over portions of the sensor layer or over the entire region of the sensor layer, including the protective layer 106 as shown in FIG. 1. Preferably the sensor chemistry layer 110 is disposed on portions of a working electrode and a counter electrode that comprise the sensor layer. Preferred methods fox generating the thin sensor chemistry layer 110 include spin coating processes, dip and dry processes, low shear spraying processes, ink-jet printing processes, silk screen processes and the like. Most preferably the thin sensor chemistry layer 110 is applied using a spin coating process.
Typically, the thin sensor chemistry layer 110 is coated with one or more cover layers. In preferred embodiments of the invention, the cover layer comprises a membrane which can regulate the aanount of analyte that can contact the enzyme of the sensor layer. Fox example, the cover layer can comprise a glucose limiting membrane, which regulates the amount of glucose that contacts the glucose oxidase enzyme layer on an electrode. Such glucose limiting membranes can be made from a wide variety of materials known to be suitable for such purposes, e.g., silicone, polyurethane, polyurea r cellulose acetate, Nafion, polyester sulfonic acid (Kodak AQ), hydxogels or any other membrane known to those skilled in the art.
In preferred embodiments of the invention, the cover layer is a glucose limiting membrane layer 112 which is disposed above the sensor chemistry layer 110 to regulate S glucose contact with the sensor chemistry layer 110. In some embodiments of ; the invention, an adhesion promoter layer 114 is disposed between the membrane layer 112 and the sensor chemistry layer 110 as shown 'vl FIG. 1 iii order to facilitate their contact and/or adhesion. The adhesion promoter layer 114 can be made from any one of a wide variety of materials known in the art to Facilitate the bonding between such layers.
Preferably, the adhesion promoter layer 114 comprises a silane compound. In alternative embodiments, protein or like molecules in the sensor chemistry layer 110 can be sufficiently crosslinked or otherwise prepared to allow the membrane layer 112 to be disposed in direct contact with the sensor chemistry layer 110 in the absence of an adhesion promoter layer 114.
The sensors of the invention can have any desired configuration, fox example planar or cyftndxical. The base layer 102 can be self supportive, such as a rigid polymeric layer, or non-self supportive, such as a flexible film. The latter embodiment is desirable in that it permits continuous manufacture of sensors using, for example, a roll of a polymeric film which is continuously unwound and upon which sensor elements, cover layers and functional coating layers are continuously applied.
As noted above, embodiments of the invention typically include a sensor layer having one or more sensor elements. According to the present invention, useful sensor elements (referred to herein as conductive elements) include thin film conductors ox other electrically conductive elements that produce detectable electrical signals.
Preferably, such conductive elements axe electrodes. Preferably, an enzyme, such as glucose oxidase, is disposed in the aperture 108 defined above the sensor element.
According to a specific preferred embodiment, the sensor element is an electrically conductive sensor element. However, sensor elements of the present invention are not lirxiited to conductive elements. Other useful sensor elements can be formed from any material that is capable of producing a detectable signal after interacting with a preselected analyte whose presence is to be detected (referred to herein as reactive elements). The detectable signal can be, for example, an optically detectable change, such as a color change or a visible accumulation of the desired analyte (e.g., cells).
Exemplary materials include polymers that bind specific types of cells; single-strand DNA; antigens; antibodies and reactive fragments thereof; etc. Sensor elements can also be formed from materials that are essentially non-reactive (i.e., controls).
The foregoing alternative sensor elements are beneficially included, for example, in sensors for use in cell-sorting assays and assays for the presence of pathogenic organisms, such as viruses (HIV, hepatitis-C, etc.), bacteria, protozoa and the like.
Embodiments of the present invention can include one or more functional coating layers. As used herein, the term "functional coating layer" denotes a layer that coats at least a portion of at least one surface of a sensor, more preferably substantially all of a surface of the sensor, and that is capable of interacting with one or more analytes, such as chemical compounds, cells and fragments thereof, etc., in the environment in which the sensor is disposed. Non-limiting examples of functional coating layers include sensor chemistry layers (e.g., enzyme layers), analyte limiting layers, biocompatible layers; layers that increase the slipperiness of the sensor; layers that promote cellular attachment to the sensor; layers that reduce cellular attachment to the sensor; and the like.
Typically analyte limiting layers operate to prevent or restrict the diffusion of one or more analytes, such as glucose, through the layers. Optionally such layers can be formed to prevent or restrict the diffusion of one type of molecule through the layer (e.g.
glucose), while at the same time allowing or even facilitating the diffusion of other types of molecules through the layer (e.g. Oz). An illustrative functional coating layer is a hydrogel such as those disclosed in U.S. Patent Nos. 5,786,439 and 5,391,250, the disclosures of each being incorporated herein by reference. The hydrogels described therein are particularly useful with a variety of implantable devices for which it is advantageous to provide a surrounding water layer.
The sensor embodiments disclosed herein can include layers having UV-absorbing polymers. In accordance with one aspect of the present invention, there is provided a sensor including at least one functional coating layer including a UV-absorbing polymer. In preferred embodiments, the UV-absorbing polymer is a polyurethane, a polyuxea ox a polyuxethane/polyurea copolymer. More preferably, the selected UV-absorbing polymer is formed from a reaction mixture including a diisocyanate, at least one diol, diainine or mixture thereof, and a polyfunctional UV
absorbing monomer.
UV-absorbing polymers are used with advantage in a variety of sensor fabrication methods, such as those described in U.S. Pat. No. 5,390,671, to Lord et al., entitled "Transcutaneous Sensor Insertion Set"; No. 5,165,407, to Wilson et al., entitled "Implantable Glucose Sensor"; and U.S. Pat. No. 4,890,620, to Gough, entitled "Two-Dimensional Diffusion Glucose Substrate Sensing Electrode", which are incorporated herein in their entireties by reference. However, any sensor production method which includes the step of forming a UV-absorbing polymer layer above ox below a sensor element is considered to be within the scope of the present invention. In particular, the inventive methods axe not limited to thin-film fabrication methods, and can work with other sensor fabrication methods that utilize UV-laser cutting. Embodiments can work with tlvck-film, planar ox cylindrical sensors and the like, and other sensor shapes requiring laser cutting.
As disclosed herein, the sensors of the present invention are particularly designed for use as subcutaneous ox txanscutaneous glucose sensors for monitoring blood glucose levels in a diabetic patient. Typically each sensor comprises a plurality of sensor elements, for example electrically conductive elements such as elongated thin film conductors, formed between an underlying insulative thin film base layer and an overlying insulative thin film cover layer.
If desired, a plurality of different sensor elements can be included in a single sensor. For example, both conductive and reactive sensor elements can be combined in one sensor, optionally with each sensor element being disposed on a different portion of the base layer. One or more control elements can also be provided. In such embodiments, the sensor can have defined in its cover layer a plurality of openings ox apertures. One or more openings can also be defined in the cover layer directly over a portion of the base layer, in order to provide for interaction of the base layer with one or more analytes in the environment in which the sensor is disposed. The base and cover layers can be comprised of a vaxiety of materials, typically polymers. In more specific embodiments the base and cover layers are comprised of an insulative material such as a polyicoide. Openings are typically formed in the cover layer to expose distal end electrodes and proximal end contact pads. In a glucose monitoring application, for example, the sensor is placed transcutaneously so that the distal end electrodes are in contact with patient blood or extracellular fluid, and the contact pads axe disposed externally for convenient connection to a monitoring device.
An illustrative embodiment of the invention is a sensor designed for implantation within a body that comprises a base layer, a sensor layer disposed upon the base layer which includes a plurality of sensor elements, an enzyme layer (preferably less than 2 microns in thickness) disposed upon the sensor layer which coats all of the plurality of sensing elements on the sensor layer, and a cover layer. Typically the enzyme layer comprises glucose oxidase, preferably in a substantially fixed ratio with a carrier protein.
In a specific embodiment, the glucose oxidase and the carrier protein are distributed in a substantially uniform manner throughout the disposed enzyme layer. Typically the carrier protein comprises albumin, preferably in an amount of about 5% by weight. As used herein, "albumin" refers to those albumin proteins typically used by artisans to stabilize polypeptide compositions such as human senun albumin, bovine serum albumin and the like. In highly preferred embodiments of the invention, the cover layer is an analyte contacting layer which is disposed on the sensor so as to regulate the amount of analyte that can contact the enzyme-layer. In further highly preferred embodiments, the sensor includes an adhesion promoter layer disposed between the enzyme layer and the analyte contacting layer and the enzyme layer is less than 1, 0.5, 0.25 or 0.1 microns in thickness.
A related embodiment of the invention is an electrochemical analyte sensor which includes a base layer, a sensor layer disposed upon the base layer that includes at least one working electrode and at least one counter electrode, an enzyme layer disposed upon the sensor layer, wherein the enzyme layer is less than 2 microns in thickness; and an analyte contacting layer that regulates the amount of analyte that contacts the enzyme layer. In a specific embodiment of the invention, the working electrode and/or the coated surface of the working electrode is larger than counter electrode and/or the coated surface of the counter electrode. In preferred embodiments, the enzyme layer comprises glucose oxidase stabilized by coating it on the working electrode and the counter electrode in combination with a carrier protein in a fixed ratio. In a highly preferred embodiment, the enzyme layer substantially covers the sensor layer.
Embodiments where the glucose oxidase enzyme layer is disposed in a uniform coating over the whole sensor layer are preferred because they may avoid problems associated with sensors having multiple different coatings on a single layer such as the selective delamination of different coatings having different material properties.
Optionally, the sensor includes an adhesion promoting layer disposed between the enzyme layer and the analyte contacting layer.
A related embodiment of the invention is an electrochemical analyte sensor which includes a base layer, a sensor layer disposed upon the base layer that includes at least one working electrode, at least one reference electrode and at least one counter electrode, an enzyme layer disposed upon the sensor layer, and an analyte contacting cover layer that regulates the amount of analyte that contacts the enzyme layer. In preferred embodiments, the enzyme layer is less than 2 microns in thickness and is coated on at least a portion of the working electrode, the reference electrode and the counter electrode. In a highly preferred embodiment, the enzyme layer substantially covers the working electrode, the reference electrode and the counter electrode.
Optionally, the enzyme layer comprises glucose oxidase in combination with a carrier protein (e.g, albumin) in a fixed ratio. Typically, the sensor includes an adhesion promoting layer disposed between the enzyme layer and the analyte contacting layer.
Yet another embodiment of the invention comprises a glucose sensor for implantation within a body which includes a base layer, a sensor layer disposed upon the base layer, a glucose oxidase layer disposed upon the sensor layer, wherein the glucose oxidase is stabilized by combining it with albumin in a defined ratio and further wherein the glucose oxidase and the albumin are distributed in a substantially uniform manner throughout the disposed layer, and a glucose limiting layer that regulates the amount of glucose that contacts the glucose oxidase layer. In preferred embodiments, the sensor layer includes a plurality of sensor elements including at least one working electrode and at least one counter electrode. In such sensor embodiments, the glucose oxidase layer is preferably less than 2, 1, 0.5, 0.25 or 0.1 microns in thickness and the albl»'!'m?n in the layer is present in an amount of about 5% albumin by weight. Preferably the sensor includes an adhesion promoting layer disposed between the glucose oxidase layer and the glucose )uniting layer.
A highly preferred embodiment of the invention is an electrochemical glucose sensor having hydrogen peroxide recycling capabilities. Typically such sensors include a , base layer, a sensor layer disposed upon the base layer, wherein the sensor layer includes at least one working electrode and at least one counter electrode, a glucose oxidase layer disposed upon the sensor layer, wherein the glucose oxidase layer coats at least a portion of the working electrode and at least a portion of the counter electrode in a manner such that the working electrode oxidizes hydrogen peroxide that is produced by glucose oxidase upon reaction with glucose, and a glucose limiting layer disposed on the sensor so as to regulate the amount of glucose that can contact the glucose oxidase layer and to inhibit die diffusion of hydrogen peroxide into the environment in which the sensor is placed. Typically such sensors include an adhesion promoting layer disposed between the glucose oxidase layer and the glucose limiting layer. In addition such sensors usually include an insulation layer between the base layer and the glucose oxidase layer. The embodiments of the invention relating to electrochemical glucose sensors having hydrogen peroxide recycling capabilities are particularly preferred because the recycling of this molecule reduces the amount of hydrogen peroxide that can escape from the sensor into the environment in which it is placed. In this context, implantable sensors that are designed to reduce the release of tissue irritants such as hydrogen peroxide will have improved biocompatibility profiles. Consequently, yet another embodiment of the invention is a method of improving the biocompatibility of a glucose oxidase sensor by designing the sensor to incorporate the hydrogen peroxide recycling elements disclosed herein.
In certain embodiments of the invention disclosed herein (e.g., those having hydrogen peroxide recycling capabilities) the sensor layer has a plurality of electzodes including a working electrode and a counter electrode, both of which are coated with a layer of glucose oxidase. Such sensor designs have surprising properties including an enhanced sensitivity. Without being bound by a specific theory, these properties may result from the enhanced oxidation of hydrogen peroxide at the surface of the electrode which produces additional oxygen that can be utilized in the glucose sensing reaction (see, e.g., FIG. 2). Therefore this recycling effect may reduce the oxygen dependent limitations of such sensors. Moreover, this design may result in a sensor having a counter electrode that can readily reduce available hydrogen peroxide and consequently has a lower electrode potential. Sensors designed to function with lower electrode potentials are preferred embodiments of the invention because high electrode potentials in sensors of this type can result in a gas producing hydrolysis reaction which can destabilize the sensors (due to the disruption of sensor layers from gas bubbles produced by hydrolysis reactions). In addition, in sensor embodiments designed so that the counter electrode is coated with a very thin layer of glucose oxidase, the hydrogen peroxide generated when glucose reacts with glucose oxidase is very close to the reactive surface of the counter electrode. This can increase the overall efficiency of the sensor in a manner that allows for the production of compact sensor designs which include for example, counter electrodes with smaller reactive surfaces.
A variety of art-accepted methods and materials can be utilized to generate such sensors. For example, while a variety adhesion promoting compounds axe known in the art, typically this layer comprises a silane compound. In preferred embodiments of the invention, the base layer comprises a polyixnmide, the insulation layer comprises a polyimmide, an electrode comprises platinum black and the glucose limiting layer comprises a hydroplvlic polymer. Preferably, the glucose oxidase layer is vapor crosslinked on the sensor layer.
C. METHODS FOR PRODUCING ANALYTE SENSORS OF THE INVENTION
The disclosure provided herein teaches methods for applying very thin enzyme coatings to these types of sensors as well as sensors produced by such processes. In this context, preferred embodiments of the invention include methods for making such sensors on a substrate according to art accepted processes. In certain embodiments, the substrate comprises a rigid and flat structure suitable for use in photolithogxaphic mask and etch processes. In this regard, the substrate typically defines an upper surface having a high degs:ee of uniform flatness. A polished glass plate may be used to define the smooth upper surface. Alternative substrate materials include, for example, stainless steel, aluminum, and plastic materials such as delrin, etc. In other embodiments, the substrate is non-rigid and can be another layer of filth or insulation that is used as a substrate, fox example plastics such as polyi~nides and the like.
An W itial step in the methods of the invention t~rpically includes the formation of a base layer of the sensor. The base layer can be disposed on the substrate by any desired means, fox example by controlled spin coating. In addition, an adhesive may be used if there is not sufficient adhesion between the substrate layer and the base layer. A base layer of insulative material is formed on the substrate, typically by applying the base layer material onto the substrate in liquid form and thereafter spinning the substrate to yield fine base layer of thin, substantially uniform thickness. These steps are repeated to build up the base layer of sufficient thickness, followed by a sequence of photolithogxaphic and jor chemical mask and etch steps to form the conductors discussed below.
In a preferred form, the base layer comprises a thin film sheet of insulative material, such as polyicoide having a filin thickness on the order of about 0.003 inch.
The methods of the invention further include the generation of a. sensor layer having one or more sensor elements. Typically these sensor elements are electrodes that are formed by one of the variety of methods known in the art such as photoresist, etching and rinsing to define the geometry of the active electrodes. The electrodes can then be made electrochemically active, for example by elect~odeposition of Pt 'black for the working and counter electrode, and silver followed by silver chloride on the reference electrode. The enzyme layer is then disposed on the sensor layer by a method other than electrochemical deposition, followed by vapor cxosslinking, for example with a dialdehyde (glutaraldehyde) ox a carbodi-imide.
In an exemplary embodiment of the invention, the base layer is initially coated I
with a thin film conductive layer by electrode deposition, surface sputtering, or other suitable process step. In the preferred form, this conductive layer may be provided as a plurality of thin film conductive layers, such as an initial chrome-based layer suitable for chemical adhesion to a polyicoide base layer followed by subsequent formation of thin film gold-based and chrome-based layers in sequence. In alternative embodiments, other electrode layer conformations or materials can be used. The conductive layer is then covered,-in accordance with conventional photolithographic techniques, with a selected photoxesist coating, and a contact mask can be applied over the photoresist coating fox suitable photoimaging. The contact mask typically includes one ox more conductor trace patterns for appropriate exposure of the photoresist coating, followed by an etch step resulting in a plurality of conductive sensor traces remaining on the base layer. In an illustrative sensor construction designed for use as a subcutaneous glucose sensor, each sensor trace can include three parallel sensor elements corresponding with three separate electrodes such as a working electrode, a counter electrode and a reference electrode.
Portions of the conductive sensors axe typically covered by a insulative layer, preferably of a material such as a polyicoide. The insulative layer can be applied in any desired manner. In an exemplary procedure, the insulative layer is applied in a liquid layer over the sensor traces, after which the substrate is spun to distribute the liquid material as a thin film overlying the sensor traces and extending beyond the marginal edges of the sensor traces in sealed contact with the base layer. This liquid material can then be subjected to one or more suitable radiation and/or chemical and/or heat curing steps as axe known in the art. In alternative embodiments, the liquid material can be applied using spray techniques ox any other desired means of application.
Various insulative layer materials may be used such as photoixnagable epoxyacrylate, with a preferred material comprising a photoimagable polyicoide available from OCG, Inc. of West Patexson, N.J., under the product number 7020.
Appropriate electrode chemistries defining the distal end electrodes can be applied to the sensor tips, optionally subsequent to exposure of the sensor tips through the openings. In an illustrative sensor embodiment having three electrodes for use as a glucose sensor, an enzyme (preferably glucose oxidase) is provided within one of the openings, thus coating one of the sensor tips to define a working electrode.
One ox both of die other electrodes can be provided with d1e same coating as the working electrode.
Alternatively, the other two electrodes can be provided with other suitable chemistries, such as other enzymes, left uncoated, or provided with chemistries to define a reference electrode and a counter electrode for the electrochemical sensor.
A significant aspect of the present invention involves processes for making sensors having extremely thin coatings for electrode chemistries (e.g., enzyme coatings of less than 2 microns in thickness) with enhanced material properties. Methods for producing the extremely thin enzyme coatings of the invention include spin coating processes, dip and dry processes, low shear spraying processes, ink-jet printing processes, silk screen processes and the like. As artisans can readily determine the thickness of an enzyme coat applied by process of the art, they can readily identify those methods capable of generating the extremely thin coatings of the invention. Typically, such coatings are vapor cxosslinked subsequent to their application. Surprisingly, sensors produced by these processes have material properties that exceed those of sensors having coatings produced by electrodeposition including enhanced longevity, linearity, regularity as well as improved signal to noise ratios. In addition, embodiments of the invention that utilize glucose oxidase coatings formed by such processes are designed to recycle hydrogen peroxide and improve the biocompatibility profiles of such sensors.
~Xlhile not being bound by a specific scientific theory, it is believed that the surprising properties of sensors produced by such processes have enhanced characteristics as compared to those generated by electrodeposition because electrodeposition produces 3-5 micron thick enzyme layers in which only a fraction of the reactive enzyme is able to access the analyte to be sensed. Moreover, in sensors utilizing glucose oxidase, the thick coatings produced by electrodeposition may hinder the ability of hydrogen peroxide generated at the reactive interface to reach the sensor surface and thereby generate a signal. Moreover, hydrogen peroxide that is unable to reach a sensor surface due to such thick coatings typically diffuses away from the sensor into the environment in which the sensor is placed, thereby decreasing the biocompatibility of such sensors. In addition, as glucose oxidase and albumin have different isoelectric points, electrodeposition processes can result in a surface coating in which an optimally determined ratio of enzyme to carrier protein is detrimentally altered and further wherein the glucose oxidase and the carrier protein are not distributed in a substantially uniform manner throughout the disposed enzyme layer. The thin coating processes utilized to produce the sensors disclosed herein avoid these problems associated with electrodeposition.
Sensors generated by processes such as spin coating processes also avoid other problems associated with electrodeposition, such as those pertaining to the material stresses placed on the sensor during the electrodeposition process. In particular, the process of electrodeposition is observed to produce mechanical stresses on the sensor, for example mechanical stresses that result from tensile andjor compression forces. In certain contexts, such mechanical stresses may result in sensors having coatings with some tendency to crack or delaminate. Tllis is not observed in coatings disposed on sensor via spin coating or other low-stress processes. Consequently, yet another embodiment of the invention is a method of avoiding the electrodeposition influenced cracking and ox delamination of a coating on a sensor comprising applying the coating via a spin coating process.
Subsequent to treatment of the sensor elements, one or more additional functional coating or cover layers can then be applied by any one of a wide variety of methods known in the art, such as spraying, dipping, etc. In preferred embodiments of the invention, the sensor is made by methods which apply a cover layer that comprises a hydrophilic membrane coating which can regulate the amount of analyte that can contact the enzyme of the sensor layer. For example, the cover layer that is added to the glucose sensors of the invention can comprise a glucose limiting membrane, which regulates the amount of glucose that contacts glucose oxidase enzyme layer on an electrode.
Such glucose linvting membranes can be made from a wide variety of materials known to be suitable for such purposes, e.g., silicone, polyurethane, cellulose acetate, Nafion, polyester sulfonic acid (Kodak AQ), hydrogels or any other membrane known to those skilled in the art. In certain embodiments of the invention pertaining to sensors having hydrogen peroxide recycling capabilities, the membrane layer is disposed on the glucose oxidase enzyme layer to inhibit the release of hydrogen peroxide into the environment in which the sensor is placed and to facilitate the contact between the hydrogen peroxide molecules and the electrode sensing elements.
In some embodunents of the methods of invention, an adhesion promoter layer is disposed between the cover layer and the sensor chemistry layer in order to facilitate their contact. The adhesion promoter layer can be made from any one of a wide variety of materials known in the art to facilitate the bonding between such layers and can be applied by any one of a wide variety of methods known in the art. Preferably, the adhesion promoter layer comprises a silane compound. Like certain other coating layers of the sensor, the adhesion promoter layer can then be subjected to one or more suitable radiation andf ox chemical and/or heat curing steps as are known in the art.
In alternative embodiments, the enzyme layer can be sufficiently crosslinked or otherwise prepared to allow the membrane cover layer to be disposed in direct contact with the sensor chemistry layer in the absence of an adhesion promoter layer.
A preferred embodiment of the invention is a method of making a sensor by providing a base layer, forming a sensor layer on the base layer, spin coating an enzyme layer on the sensor layer and then foxmixig an analyte contacting layer on the sensor, wherein the analyte contacting layer regulates the amount of analyte that can contact the enzyme layer. In preferred methods, the enzyme layer is vapor cxosslinked on the sensor layer. In a typical embodiment of the invention, the sensor layer is formed to include at least one working electrode and at least one counter electrode. In highly preferred embodiments, the enzyme layer is formed on at least a portion of the working electrode and at least a portion of the counter electrode. Typically, the enzyme layer that is formed on the sensor layer is less than 2, 1, 0.5, 0.25 or 0.1 microns in thickness.
Preferably, the enzyme layer comprises glucose oxidase, glucose dehydrogenase, lactose oxidase, hexokinase or lactose dehydxogenase. In a specific method, the enzyme layer comprises glucose oxidase that is stabilized by coating it on the sensor layer in combination with a carrier protein in a ~txed ratio. Typically the carrier protein is albumin.
Preferably such methods include the step of forming an adhesion promoter layer disposed between the glucose oxidase layer and the analyte contacting layer. Optionally, the adhesion promoter layer is subjected to a curing process prior to the formation of the analyte contacting layer.
,A related embodiment of the invention is a method of making a glucose sensor by providing a base layer, forming a sensor layer on the base layer that includes at least S one working electrode and at least one counter electrode, forming a glucose oxidase layer on the sensor layer by a spin coating process (a layer which is preferably stabilized by combining the glucose oxidase with albumin in a fixed ratio), wherein the glucose oxidase layer coats at least a portion of the working electrode and at least a portion of the counter electrode, and then forming an glucose limiting layer on the glucose sensor so as to regulate the amount of glucose that can contact the glucose oxidase layer.
In such processes, the glucose oxidase layer that is formed on the sensor layer is preferably less than 2, 1, 0.5, 0.25 or 0.1 microns in thickness. Typically, the glucose oxidase coating is vapor crosslinked on the sensor layer. Optionally, the glucose oxidase coating covers the entire sensor layer. In highly preferred embodiments of the invention, an adhesion promoter layer disposed between the glucose oxidase layer and the analyte contacting layer The finished sensors produced by such processes are typically quickly and easily removed from a supporting substrate (if one is used), for example, by cutting along a line surrounding each sensor on the substrate. The cutting step can use methods typically used in this art such as those that include a W laser cutting device that is used to cut through the base and cover layers and the functional coating layers along a line surrounding or circumscribing each sensor, typically in at least slight outward spaced relation from the conductive elements so that the sufficient interconnected base and cover layer material remains to seal the side edges of the finished sensor.
Since the base layer is typically not physically attached or only minimally adhered directly to the underlying supporting substrate, the sensors can be lifted quickly and easily from the supporting substrate, without significant further processing steps or potential damage due to stresses incurred by physically pulling or peeling attached sensors from the supporting substrate. The supporting substrate can thereafter be cleaned and reused, or otherwise discarded. Alternatively, the functional coating layers) can be applied after the sensor including base layer, sensor elements and cover layer is removed from the supporting substrate by cutting.
D. KITS AND SENSOR SETS OF THE INVENTION
In another embodiment of the invention, a kit and/or sensor set, useful for the sensing an analyte as is described above, is provided. The kit and/or sensor set typically comprises a container, a label and a sensor having an extremely thin enzyme coating as described above. Suitable containers include, for example, an easy to open package made from a material such as a metal foil, bottles, vials, syringes, and test tubes. The containers may be formed from a variety of materials such as metals (e.g.
foils) paper products, glass or plastic. The container preferably holds a glucose sensor coated with a layer of glucose oxidase that is less than 2 microns in thickness. The label on, or associated with, the container indicates that the sensor is used for assaying the analyte of choice. The kit and/or sensor set may further include other materials desirable from a commercial and user standpoint, including elements or devices designed to facilitate the introduction of the sensor into the analyte environment, other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.
Various citations are referenced throughout the specification. In addition, certain text from related art is reproduced herein to more clearly delineate the various embodiments of the invention. The disclosures of all citations in the specification are expressly incorporated herein by reference.
Figure 2 provides a schematic of the well known reaction between glucose and oxygen in the presence of glucose oxidase. As shown in a stepwise manner, this reaction involves glucose oxidase (GO~, glucose and oxygen in water. In the reductive half of the reaction, two protons and electrons are transferred ~rom ~3-D-glucose to the enzyme yielding d-gluconolactone. In the oxidative half of the reaction, the enzyme is oxidized by molecular oxygen yielding hydrogen peroxide. The d-gluconolactone then reacts with water to hydrolyze the lactone ring and produce gluconic acid. In typical electrochemical sensors of the invention, the hydrogen peroxide produced by this reaction is oxidized at the working electrode (HaOz -~ 2H+ + O~ + 2e-).
Detailed Description of the Preferred Embodiments Unless otherwise defined, all terms of art, notations and other scientific terms ox terminology used herein axe intended to have the meanings commonly understood by those of skill in the art to which this invention pertains. In some cases, terms with commonly understood meanings axe deftned herein fox clarity and/or for ready reference, and the inclusion of such defuvtions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art. Many of the techniques and procedures described or referenced herein are well understood and commonly employed using conventional methodology by those skilled in the art. As appropriate, procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer defined protocols and/or parameters unless otherwise noted.
Embodiments of the invention disclosed herein provide methods for producing electrochemical sensors of the type used, for example, in subcutaneous or transcutaneous monitoring of blood glucose levels in a diabetic patient. More specifically, the disclosure provided herein teaches methods for applying very thin enzyme coatings to specific elements within these sensors. The disclosure further provides sensors produced by such processes. Methods for producing the sensors of the invention include spin coating processes, dip and dry processes, low-shear spraying processes, ink-jet printing processes, silk screen processes and the like. Surprisingly, sensors having thin enzyme coatings produced by such processes have a number of improved qualities itacluding enhanced longevity, linearity, regularity as well as improved signal to noise ratios.
~Uhile preferred embodiments of the invention pertain to glucose sensors, such thin enzyme coating can be adapted for use with any one of the wide variety of sensors known in the art. A number of enzyme sensors (e.g., glucose sensors which the enzyme glucose oxidase to effect a reaction of glucose and oxygen) are known in the art, and are within the skill in the art to fabricate. See, for example, U.S. Pat. Nos.
5,165,407, 4,890,620, 5,390,671 and 5,391,250, the disclosures of each being incorporated herein by reference. Sensors for monitoring glucose concentration of diabetics are further described in Shichiri, et al.,: "In Vivo Characteristics of Needle-Type Glucose Sensor-Measurements of Subcutaneous Glucose Concentrations in Human Volunteers,"
Horm.
Metab. Res., Suppl. Ser. 20:17-20 (1988); Bruckel, et al.,: "In Vivo Measurement of Subcutaneous Glucose Concentrations with an Enzymatic Glucose Sensor and a ~Uick Method," Klin. Wochenschr. 67:491-495 (1989); and Pickup, et al.,: "In Vivo Molecular Sensing in Diabetes Mellitus: An Implantable Glucose Sensor with Direct Electron Transfer," Diabetologia 32:213-217 (1989). Other sensors are described in, fox example Reach, et al., in ADVANCES IN IMPLANTABLE DEVICES, A. Turner (ed.), JAI
Press, London, Chap. 1, (1993), incorporated herein by reference. Specific aspects of the invention are discussed in detail in the following sections.
A. EXTREMELY THIN ENZYMATIC COATINGS OF THE INVENTION
A significant aspect of the present invention involves processes for making sensors having improved electrode chemistry coatings (e.g., enzyme coatings of less than 2 microns in thickness) with enhanced material properties. Methods for producing the extremely thin. enzyme coatings of the invention include spin coating processes, dip and dty processes, low shear spraying processes, ink-jet printing processes, silk screen processes and the like. Typically, such coatings are vapor crosslinked subsequent to their application. Sul.-prisingly, sensors produced by these processes have material properties that exceed those of sensors having coatings produced by electrodeposition including enhanced longevity, linearity, regularity as well as improved signal to noise ratios. In addition, certain sensor embodiments of the invention that utilize glucose oxidase coatings formed by such processes are designed to recycle hydrogen peroxide and improve the bi.ocompatibility profiles of such sensors.
While not being bound by a specific scientific theory, it is believed that sensors produced by such processes have surprisingly enhanced characteristics as compared to those generated by electrodeposition because electrodeposition produces 3-5 micron duck enzyme layers in which only a fraction of the reactive enzyme within the coating layer is able to access the analyte to be sensed. In sensors utilizing glucose oxidase, the thick coatings produced by electYOdeposition may hinder the ability of hydrogen peroxide generated at the reactive interface of the 3-5 micron thick enzyme layer to contact the sensor surface and thereby generate a signal. In addition, hydrogen peroxide that is unable to reach a sensor surface due to such thick coatings can diffuse away from the sensor into the environment in which the sensor is placed, thereby decreasing the biocompatibility of such sensors.
In addition, while not being bound by a specific scientific theory, it is believed that the unexpected properties of sensors produced by such processes further results from the fact that processes such as spin coating, or the like, allow for a precise control over the enzyme coating's ratio of glucose oxidase to albumin (which is used as a carrier protein to stabilize the glucose oxidase in the enzyme layer). Specifically, because glucose oxidase and albumin have different isoelect~i.c points, electrodeposition processes may result in a surface coating in which an optimally determined ratio of enzyme to carrier protein is detrimentally altered in the electrodeposition process and further wherein the glucose oxidase and the carrier protein are not distributed in a substantially uniform manner throughout the disposed enzyme layer.
In this context, a preferred embodiment of the invention is a method of making a less than about 2 micron coating of stabilized glucose oxidase on the surface of a matrix such as an electrode comprising combining glucose oxidase with albumin in a fixed ratio (one that is typically optimized for glucose oxidase stabilizing properties) and applying the glucose oxidase and albumin mixture to the surface of the matrix by a process selected from the group consisting of a spin coating process, a dip and dry process, a microdeposition process, a jet punter deposition process, a screen printing process or a doctor blading process. Preferably the stabilized glucose oxidase coating is applied to the surface of an electrode by a spin coating process. In lvghly preferred embodiments, the glucose oxidase/albumin is prepared in a physiological solution (e.g., phosphate buffered saline at neutral pH) with the albumin being present in an amount of about 5%
albumin by weight. Optionally the stabilized glucose oxidase layer that is formed on the sensor layer is less than 2, 1, 0.5, 0.25 ox 0.1 microns in thickness. A closely related embodiment of the invention is a stabilized glucose oxidase layer for coating the surface of an electrode wherein the glucose oxidase is mixed with a carrier protein in a fixed ratio within the layer, the glucose oxidase and the carrier protein are distzibuted in a substantially uniform manner throughout the layer. Preferably the layer is less than 2 microns in thickness.
B. ANALYTE SENSORS OF THE INVENTION
The invention disclosed herein includes a number of embodiments including sensors having very thin enzyme coatings. Illustrative general embodiments of the sensor disclosed herein include a base layer, a cover layer and at least one sensor layer having a sensor element such as an electrode disposed between the base and cover layers.
Typically, an exposed portion of one or more sensor elements (e.g., a worl~ing electrode, a counter electrode, reference electrode, etc.) is coated with a very thin layer of material having an appropriate electrode chemistry. For example, an enzyme such as glucose oxidase, glucose dehydrogenase or hexokinase, can be disposed on the exposed portion of the sensor element within an opening or aperture defined in the cover layer. FIG. 1 illustrates a cross-section of a typical sensor structure 100 of the present invention. The sensor is formed from a plurality of layers of various conductive and non-conductive constituents disposed on each other according to a method of the invention to produce a sensor structure 100.
A preferred embodiment of the invention is shown in FIG. 1. This embodiment includes an electrically insulating base layer 102 to support the sensor 100.
The electrically insulating layer base 102 can be made of a material such as a polyimide substrate, which may be self supporting or further supported by another material as is known in the art. In one embodiment, the electrically insulating layer 102 comprises a polyimide tape, dispensed from a reel. Providing the layer 102 in this form can facilitate clean, high density mass production. Further, in some production processes using such a polyimide tape, sensors 100 can be produced on both sides of the tape.
Typical embodiments of the invention include a sensor layer disposed on the base layer 102. In a preferred embodiment as shown in FIG. 1 the sensor layer comprises a conductive layer 104 which is disposed on insulating base layer 102.
Preferably the conductive layer 104 comprises one or more electrodes. The conductive layer 104 can be applied using many known techniques and materials as will be described hereafter, however, the electrical circuit of the sensor 100 is typically defined by etching the disposed conductive layer 104 into a desired pattern of conductive paths.
A typical electrical circuit for the sensor 100 comprises two ox more adjacent conductive paths with regions at a proximal end to form contact pads and regions at a distal end to form sensor electrodes. An electrically insulating protective layer 106 such as a polymer coating is typically disposed on portions of the conductive layer 104.
Acceptable polymer coatings for use as the insulating protective layer 106 can include, but are not limited to, non-toxic biocompatible polymers such as polyimide, biocompatible solder masks, epoxy acrylate copolymers, or the like. Further, these coatings can be photo imageable to facilitate photolithographic forming of apertures 108 through to the conductive layer 104.
In the sensors of the present invention, one or more exposed regions or apertures 108 can be made through the protective layer 106 to the conductive layer 104 to define the contact pads and electrodes of the sensor 100. In addition to photolithograplv.c development, the apertures 108 can be formed by a number of techniques, including laser ablation, chemical milling or etching ox the like.
A secondary photoresist can also be applied to the protective layer 106 to define the regions of the protective layer to be removed to form the apertures 108. An operating sensor typically includes a plurality of electrodes such as a working electrode and a counter electrode electrically isolated from each other, however typically situated in close proximity to one another. Other embodiments may also include a reference electrode.
Still other embodiments may utilize an separate reference not formed on the sensor. The exposed electrodes and/or contact pads can also undergo secondary processing through the apertures 108, such as additional plating processing, to prepare the surfaces and/or strengthen the conductive regions.
A dvn sensor chemistry layer 110 is typically disposed on one or more of the exposed electzodes of the conductive layer 104 through the apertures 108.
Preferably, the sensor chemistry layer 110 is an enzyme layer. Most preferably, the sensor chemistry layer 110 comprises the enzyme glucose oxidase. In such embodiments, the sensor chemistry layer 110 reacts with glucose to produce hydrogen peroxide which modulates a current to the electrode which can be monitored to measure an amount of glucose present. The sensor chemistry layer 110 can be applied over portions of the sensor layer or over the entire region of the sensor layer, including the protective layer 106 as shown in FIG. 1. Preferably the sensor chemistry layer 110 is disposed on portions of a working electrode and a counter electrode that comprise the sensor layer. Preferred methods fox generating the thin sensor chemistry layer 110 include spin coating processes, dip and dry processes, low shear spraying processes, ink-jet printing processes, silk screen processes and the like. Most preferably the thin sensor chemistry layer 110 is applied using a spin coating process.
Typically, the thin sensor chemistry layer 110 is coated with one or more cover layers. In preferred embodiments of the invention, the cover layer comprises a membrane which can regulate the aanount of analyte that can contact the enzyme of the sensor layer. Fox example, the cover layer can comprise a glucose limiting membrane, which regulates the amount of glucose that contacts the glucose oxidase enzyme layer on an electrode. Such glucose limiting membranes can be made from a wide variety of materials known to be suitable for such purposes, e.g., silicone, polyurethane, polyurea r cellulose acetate, Nafion, polyester sulfonic acid (Kodak AQ), hydxogels or any other membrane known to those skilled in the art.
In preferred embodiments of the invention, the cover layer is a glucose limiting membrane layer 112 which is disposed above the sensor chemistry layer 110 to regulate S glucose contact with the sensor chemistry layer 110. In some embodiments of ; the invention, an adhesion promoter layer 114 is disposed between the membrane layer 112 and the sensor chemistry layer 110 as shown 'vl FIG. 1 iii order to facilitate their contact and/or adhesion. The adhesion promoter layer 114 can be made from any one of a wide variety of materials known in the art to Facilitate the bonding between such layers.
Preferably, the adhesion promoter layer 114 comprises a silane compound. In alternative embodiments, protein or like molecules in the sensor chemistry layer 110 can be sufficiently crosslinked or otherwise prepared to allow the membrane layer 112 to be disposed in direct contact with the sensor chemistry layer 110 in the absence of an adhesion promoter layer 114.
The sensors of the invention can have any desired configuration, fox example planar or cyftndxical. The base layer 102 can be self supportive, such as a rigid polymeric layer, or non-self supportive, such as a flexible film. The latter embodiment is desirable in that it permits continuous manufacture of sensors using, for example, a roll of a polymeric film which is continuously unwound and upon which sensor elements, cover layers and functional coating layers are continuously applied.
As noted above, embodiments of the invention typically include a sensor layer having one or more sensor elements. According to the present invention, useful sensor elements (referred to herein as conductive elements) include thin film conductors ox other electrically conductive elements that produce detectable electrical signals.
Preferably, such conductive elements axe electrodes. Preferably, an enzyme, such as glucose oxidase, is disposed in the aperture 108 defined above the sensor element.
According to a specific preferred embodiment, the sensor element is an electrically conductive sensor element. However, sensor elements of the present invention are not lirxiited to conductive elements. Other useful sensor elements can be formed from any material that is capable of producing a detectable signal after interacting with a preselected analyte whose presence is to be detected (referred to herein as reactive elements). The detectable signal can be, for example, an optically detectable change, such as a color change or a visible accumulation of the desired analyte (e.g., cells).
Exemplary materials include polymers that bind specific types of cells; single-strand DNA; antigens; antibodies and reactive fragments thereof; etc. Sensor elements can also be formed from materials that are essentially non-reactive (i.e., controls).
The foregoing alternative sensor elements are beneficially included, for example, in sensors for use in cell-sorting assays and assays for the presence of pathogenic organisms, such as viruses (HIV, hepatitis-C, etc.), bacteria, protozoa and the like.
Embodiments of the present invention can include one or more functional coating layers. As used herein, the term "functional coating layer" denotes a layer that coats at least a portion of at least one surface of a sensor, more preferably substantially all of a surface of the sensor, and that is capable of interacting with one or more analytes, such as chemical compounds, cells and fragments thereof, etc., in the environment in which the sensor is disposed. Non-limiting examples of functional coating layers include sensor chemistry layers (e.g., enzyme layers), analyte limiting layers, biocompatible layers; layers that increase the slipperiness of the sensor; layers that promote cellular attachment to the sensor; layers that reduce cellular attachment to the sensor; and the like.
Typically analyte limiting layers operate to prevent or restrict the diffusion of one or more analytes, such as glucose, through the layers. Optionally such layers can be formed to prevent or restrict the diffusion of one type of molecule through the layer (e.g.
glucose), while at the same time allowing or even facilitating the diffusion of other types of molecules through the layer (e.g. Oz). An illustrative functional coating layer is a hydrogel such as those disclosed in U.S. Patent Nos. 5,786,439 and 5,391,250, the disclosures of each being incorporated herein by reference. The hydrogels described therein are particularly useful with a variety of implantable devices for which it is advantageous to provide a surrounding water layer.
The sensor embodiments disclosed herein can include layers having UV-absorbing polymers. In accordance with one aspect of the present invention, there is provided a sensor including at least one functional coating layer including a UV-absorbing polymer. In preferred embodiments, the UV-absorbing polymer is a polyurethane, a polyuxea ox a polyuxethane/polyurea copolymer. More preferably, the selected UV-absorbing polymer is formed from a reaction mixture including a diisocyanate, at least one diol, diainine or mixture thereof, and a polyfunctional UV
absorbing monomer.
UV-absorbing polymers are used with advantage in a variety of sensor fabrication methods, such as those described in U.S. Pat. No. 5,390,671, to Lord et al., entitled "Transcutaneous Sensor Insertion Set"; No. 5,165,407, to Wilson et al., entitled "Implantable Glucose Sensor"; and U.S. Pat. No. 4,890,620, to Gough, entitled "Two-Dimensional Diffusion Glucose Substrate Sensing Electrode", which are incorporated herein in their entireties by reference. However, any sensor production method which includes the step of forming a UV-absorbing polymer layer above ox below a sensor element is considered to be within the scope of the present invention. In particular, the inventive methods axe not limited to thin-film fabrication methods, and can work with other sensor fabrication methods that utilize UV-laser cutting. Embodiments can work with tlvck-film, planar ox cylindrical sensors and the like, and other sensor shapes requiring laser cutting.
As disclosed herein, the sensors of the present invention are particularly designed for use as subcutaneous ox txanscutaneous glucose sensors for monitoring blood glucose levels in a diabetic patient. Typically each sensor comprises a plurality of sensor elements, for example electrically conductive elements such as elongated thin film conductors, formed between an underlying insulative thin film base layer and an overlying insulative thin film cover layer.
If desired, a plurality of different sensor elements can be included in a single sensor. For example, both conductive and reactive sensor elements can be combined in one sensor, optionally with each sensor element being disposed on a different portion of the base layer. One or more control elements can also be provided. In such embodiments, the sensor can have defined in its cover layer a plurality of openings ox apertures. One or more openings can also be defined in the cover layer directly over a portion of the base layer, in order to provide for interaction of the base layer with one or more analytes in the environment in which the sensor is disposed. The base and cover layers can be comprised of a vaxiety of materials, typically polymers. In more specific embodiments the base and cover layers are comprised of an insulative material such as a polyicoide. Openings are typically formed in the cover layer to expose distal end electrodes and proximal end contact pads. In a glucose monitoring application, for example, the sensor is placed transcutaneously so that the distal end electrodes are in contact with patient blood or extracellular fluid, and the contact pads axe disposed externally for convenient connection to a monitoring device.
An illustrative embodiment of the invention is a sensor designed for implantation within a body that comprises a base layer, a sensor layer disposed upon the base layer which includes a plurality of sensor elements, an enzyme layer (preferably less than 2 microns in thickness) disposed upon the sensor layer which coats all of the plurality of sensing elements on the sensor layer, and a cover layer. Typically the enzyme layer comprises glucose oxidase, preferably in a substantially fixed ratio with a carrier protein.
In a specific embodiment, the glucose oxidase and the carrier protein are distributed in a substantially uniform manner throughout the disposed enzyme layer. Typically the carrier protein comprises albumin, preferably in an amount of about 5% by weight. As used herein, "albumin" refers to those albumin proteins typically used by artisans to stabilize polypeptide compositions such as human senun albumin, bovine serum albumin and the like. In highly preferred embodiments of the invention, the cover layer is an analyte contacting layer which is disposed on the sensor so as to regulate the amount of analyte that can contact the enzyme-layer. In further highly preferred embodiments, the sensor includes an adhesion promoter layer disposed between the enzyme layer and the analyte contacting layer and the enzyme layer is less than 1, 0.5, 0.25 or 0.1 microns in thickness.
A related embodiment of the invention is an electrochemical analyte sensor which includes a base layer, a sensor layer disposed upon the base layer that includes at least one working electrode and at least one counter electrode, an enzyme layer disposed upon the sensor layer, wherein the enzyme layer is less than 2 microns in thickness; and an analyte contacting layer that regulates the amount of analyte that contacts the enzyme layer. In a specific embodiment of the invention, the working electrode and/or the coated surface of the working electrode is larger than counter electrode and/or the coated surface of the counter electrode. In preferred embodiments, the enzyme layer comprises glucose oxidase stabilized by coating it on the working electrode and the counter electrode in combination with a carrier protein in a fixed ratio. In a highly preferred embodiment, the enzyme layer substantially covers the sensor layer.
Embodiments where the glucose oxidase enzyme layer is disposed in a uniform coating over the whole sensor layer are preferred because they may avoid problems associated with sensors having multiple different coatings on a single layer such as the selective delamination of different coatings having different material properties.
Optionally, the sensor includes an adhesion promoting layer disposed between the enzyme layer and the analyte contacting layer.
A related embodiment of the invention is an electrochemical analyte sensor which includes a base layer, a sensor layer disposed upon the base layer that includes at least one working electrode, at least one reference electrode and at least one counter electrode, an enzyme layer disposed upon the sensor layer, and an analyte contacting cover layer that regulates the amount of analyte that contacts the enzyme layer. In preferred embodiments, the enzyme layer is less than 2 microns in thickness and is coated on at least a portion of the working electrode, the reference electrode and the counter electrode. In a highly preferred embodiment, the enzyme layer substantially covers the working electrode, the reference electrode and the counter electrode.
Optionally, the enzyme layer comprises glucose oxidase in combination with a carrier protein (e.g, albumin) in a fixed ratio. Typically, the sensor includes an adhesion promoting layer disposed between the enzyme layer and the analyte contacting layer.
Yet another embodiment of the invention comprises a glucose sensor for implantation within a body which includes a base layer, a sensor layer disposed upon the base layer, a glucose oxidase layer disposed upon the sensor layer, wherein the glucose oxidase is stabilized by combining it with albumin in a defined ratio and further wherein the glucose oxidase and the albumin are distributed in a substantially uniform manner throughout the disposed layer, and a glucose limiting layer that regulates the amount of glucose that contacts the glucose oxidase layer. In preferred embodiments, the sensor layer includes a plurality of sensor elements including at least one working electrode and at least one counter electrode. In such sensor embodiments, the glucose oxidase layer is preferably less than 2, 1, 0.5, 0.25 or 0.1 microns in thickness and the albl»'!'m?n in the layer is present in an amount of about 5% albumin by weight. Preferably the sensor includes an adhesion promoting layer disposed between the glucose oxidase layer and the glucose )uniting layer.
A highly preferred embodiment of the invention is an electrochemical glucose sensor having hydrogen peroxide recycling capabilities. Typically such sensors include a , base layer, a sensor layer disposed upon the base layer, wherein the sensor layer includes at least one working electrode and at least one counter electrode, a glucose oxidase layer disposed upon the sensor layer, wherein the glucose oxidase layer coats at least a portion of the working electrode and at least a portion of the counter electrode in a manner such that the working electrode oxidizes hydrogen peroxide that is produced by glucose oxidase upon reaction with glucose, and a glucose limiting layer disposed on the sensor so as to regulate the amount of glucose that can contact the glucose oxidase layer and to inhibit die diffusion of hydrogen peroxide into the environment in which the sensor is placed. Typically such sensors include an adhesion promoting layer disposed between the glucose oxidase layer and the glucose limiting layer. In addition such sensors usually include an insulation layer between the base layer and the glucose oxidase layer. The embodiments of the invention relating to electrochemical glucose sensors having hydrogen peroxide recycling capabilities are particularly preferred because the recycling of this molecule reduces the amount of hydrogen peroxide that can escape from the sensor into the environment in which it is placed. In this context, implantable sensors that are designed to reduce the release of tissue irritants such as hydrogen peroxide will have improved biocompatibility profiles. Consequently, yet another embodiment of the invention is a method of improving the biocompatibility of a glucose oxidase sensor by designing the sensor to incorporate the hydrogen peroxide recycling elements disclosed herein.
In certain embodiments of the invention disclosed herein (e.g., those having hydrogen peroxide recycling capabilities) the sensor layer has a plurality of electzodes including a working electrode and a counter electrode, both of which are coated with a layer of glucose oxidase. Such sensor designs have surprising properties including an enhanced sensitivity. Without being bound by a specific theory, these properties may result from the enhanced oxidation of hydrogen peroxide at the surface of the electrode which produces additional oxygen that can be utilized in the glucose sensing reaction (see, e.g., FIG. 2). Therefore this recycling effect may reduce the oxygen dependent limitations of such sensors. Moreover, this design may result in a sensor having a counter electrode that can readily reduce available hydrogen peroxide and consequently has a lower electrode potential. Sensors designed to function with lower electrode potentials are preferred embodiments of the invention because high electrode potentials in sensors of this type can result in a gas producing hydrolysis reaction which can destabilize the sensors (due to the disruption of sensor layers from gas bubbles produced by hydrolysis reactions). In addition, in sensor embodiments designed so that the counter electrode is coated with a very thin layer of glucose oxidase, the hydrogen peroxide generated when glucose reacts with glucose oxidase is very close to the reactive surface of the counter electrode. This can increase the overall efficiency of the sensor in a manner that allows for the production of compact sensor designs which include for example, counter electrodes with smaller reactive surfaces.
A variety of art-accepted methods and materials can be utilized to generate such sensors. For example, while a variety adhesion promoting compounds axe known in the art, typically this layer comprises a silane compound. In preferred embodiments of the invention, the base layer comprises a polyixnmide, the insulation layer comprises a polyimmide, an electrode comprises platinum black and the glucose limiting layer comprises a hydroplvlic polymer. Preferably, the glucose oxidase layer is vapor crosslinked on the sensor layer.
C. METHODS FOR PRODUCING ANALYTE SENSORS OF THE INVENTION
The disclosure provided herein teaches methods for applying very thin enzyme coatings to these types of sensors as well as sensors produced by such processes. In this context, preferred embodiments of the invention include methods for making such sensors on a substrate according to art accepted processes. In certain embodiments, the substrate comprises a rigid and flat structure suitable for use in photolithogxaphic mask and etch processes. In this regard, the substrate typically defines an upper surface having a high degs:ee of uniform flatness. A polished glass plate may be used to define the smooth upper surface. Alternative substrate materials include, for example, stainless steel, aluminum, and plastic materials such as delrin, etc. In other embodiments, the substrate is non-rigid and can be another layer of filth or insulation that is used as a substrate, fox example plastics such as polyi~nides and the like.
An W itial step in the methods of the invention t~rpically includes the formation of a base layer of the sensor. The base layer can be disposed on the substrate by any desired means, fox example by controlled spin coating. In addition, an adhesive may be used if there is not sufficient adhesion between the substrate layer and the base layer. A base layer of insulative material is formed on the substrate, typically by applying the base layer material onto the substrate in liquid form and thereafter spinning the substrate to yield fine base layer of thin, substantially uniform thickness. These steps are repeated to build up the base layer of sufficient thickness, followed by a sequence of photolithogxaphic and jor chemical mask and etch steps to form the conductors discussed below.
In a preferred form, the base layer comprises a thin film sheet of insulative material, such as polyicoide having a filin thickness on the order of about 0.003 inch.
The methods of the invention further include the generation of a. sensor layer having one or more sensor elements. Typically these sensor elements are electrodes that are formed by one of the variety of methods known in the art such as photoresist, etching and rinsing to define the geometry of the active electrodes. The electrodes can then be made electrochemically active, for example by elect~odeposition of Pt 'black for the working and counter electrode, and silver followed by silver chloride on the reference electrode. The enzyme layer is then disposed on the sensor layer by a method other than electrochemical deposition, followed by vapor cxosslinking, for example with a dialdehyde (glutaraldehyde) ox a carbodi-imide.
In an exemplary embodiment of the invention, the base layer is initially coated I
with a thin film conductive layer by electrode deposition, surface sputtering, or other suitable process step. In the preferred form, this conductive layer may be provided as a plurality of thin film conductive layers, such as an initial chrome-based layer suitable for chemical adhesion to a polyicoide base layer followed by subsequent formation of thin film gold-based and chrome-based layers in sequence. In alternative embodiments, other electrode layer conformations or materials can be used. The conductive layer is then covered,-in accordance with conventional photolithographic techniques, with a selected photoxesist coating, and a contact mask can be applied over the photoresist coating fox suitable photoimaging. The contact mask typically includes one ox more conductor trace patterns for appropriate exposure of the photoresist coating, followed by an etch step resulting in a plurality of conductive sensor traces remaining on the base layer. In an illustrative sensor construction designed for use as a subcutaneous glucose sensor, each sensor trace can include three parallel sensor elements corresponding with three separate electrodes such as a working electrode, a counter electrode and a reference electrode.
Portions of the conductive sensors axe typically covered by a insulative layer, preferably of a material such as a polyicoide. The insulative layer can be applied in any desired manner. In an exemplary procedure, the insulative layer is applied in a liquid layer over the sensor traces, after which the substrate is spun to distribute the liquid material as a thin film overlying the sensor traces and extending beyond the marginal edges of the sensor traces in sealed contact with the base layer. This liquid material can then be subjected to one or more suitable radiation and/or chemical and/or heat curing steps as axe known in the art. In alternative embodiments, the liquid material can be applied using spray techniques ox any other desired means of application.
Various insulative layer materials may be used such as photoixnagable epoxyacrylate, with a preferred material comprising a photoimagable polyicoide available from OCG, Inc. of West Patexson, N.J., under the product number 7020.
Appropriate electrode chemistries defining the distal end electrodes can be applied to the sensor tips, optionally subsequent to exposure of the sensor tips through the openings. In an illustrative sensor embodiment having three electrodes for use as a glucose sensor, an enzyme (preferably glucose oxidase) is provided within one of the openings, thus coating one of the sensor tips to define a working electrode.
One ox both of die other electrodes can be provided with d1e same coating as the working electrode.
Alternatively, the other two electrodes can be provided with other suitable chemistries, such as other enzymes, left uncoated, or provided with chemistries to define a reference electrode and a counter electrode for the electrochemical sensor.
A significant aspect of the present invention involves processes for making sensors having extremely thin coatings for electrode chemistries (e.g., enzyme coatings of less than 2 microns in thickness) with enhanced material properties. Methods for producing the extremely thin enzyme coatings of the invention include spin coating processes, dip and dry processes, low shear spraying processes, ink-jet printing processes, silk screen processes and the like. As artisans can readily determine the thickness of an enzyme coat applied by process of the art, they can readily identify those methods capable of generating the extremely thin coatings of the invention. Typically, such coatings are vapor cxosslinked subsequent to their application. Surprisingly, sensors produced by these processes have material properties that exceed those of sensors having coatings produced by electrodeposition including enhanced longevity, linearity, regularity as well as improved signal to noise ratios. In addition, embodiments of the invention that utilize glucose oxidase coatings formed by such processes are designed to recycle hydrogen peroxide and improve the biocompatibility profiles of such sensors.
~Xlhile not being bound by a specific scientific theory, it is believed that the surprising properties of sensors produced by such processes have enhanced characteristics as compared to those generated by electrodeposition because electrodeposition produces 3-5 micron thick enzyme layers in which only a fraction of the reactive enzyme is able to access the analyte to be sensed. Moreover, in sensors utilizing glucose oxidase, the thick coatings produced by electrodeposition may hinder the ability of hydrogen peroxide generated at the reactive interface to reach the sensor surface and thereby generate a signal. Moreover, hydrogen peroxide that is unable to reach a sensor surface due to such thick coatings typically diffuses away from the sensor into the environment in which the sensor is placed, thereby decreasing the biocompatibility of such sensors. In addition, as glucose oxidase and albumin have different isoelectric points, electrodeposition processes can result in a surface coating in which an optimally determined ratio of enzyme to carrier protein is detrimentally altered and further wherein the glucose oxidase and the carrier protein are not distributed in a substantially uniform manner throughout the disposed enzyme layer. The thin coating processes utilized to produce the sensors disclosed herein avoid these problems associated with electrodeposition.
Sensors generated by processes such as spin coating processes also avoid other problems associated with electrodeposition, such as those pertaining to the material stresses placed on the sensor during the electrodeposition process. In particular, the process of electrodeposition is observed to produce mechanical stresses on the sensor, for example mechanical stresses that result from tensile andjor compression forces. In certain contexts, such mechanical stresses may result in sensors having coatings with some tendency to crack or delaminate. Tllis is not observed in coatings disposed on sensor via spin coating or other low-stress processes. Consequently, yet another embodiment of the invention is a method of avoiding the electrodeposition influenced cracking and ox delamination of a coating on a sensor comprising applying the coating via a spin coating process.
Subsequent to treatment of the sensor elements, one or more additional functional coating or cover layers can then be applied by any one of a wide variety of methods known in the art, such as spraying, dipping, etc. In preferred embodiments of the invention, the sensor is made by methods which apply a cover layer that comprises a hydrophilic membrane coating which can regulate the amount of analyte that can contact the enzyme of the sensor layer. For example, the cover layer that is added to the glucose sensors of the invention can comprise a glucose limiting membrane, which regulates the amount of glucose that contacts glucose oxidase enzyme layer on an electrode.
Such glucose linvting membranes can be made from a wide variety of materials known to be suitable for such purposes, e.g., silicone, polyurethane, cellulose acetate, Nafion, polyester sulfonic acid (Kodak AQ), hydrogels or any other membrane known to those skilled in the art. In certain embodiments of the invention pertaining to sensors having hydrogen peroxide recycling capabilities, the membrane layer is disposed on the glucose oxidase enzyme layer to inhibit the release of hydrogen peroxide into the environment in which the sensor is placed and to facilitate the contact between the hydrogen peroxide molecules and the electrode sensing elements.
In some embodunents of the methods of invention, an adhesion promoter layer is disposed between the cover layer and the sensor chemistry layer in order to facilitate their contact. The adhesion promoter layer can be made from any one of a wide variety of materials known in the art to facilitate the bonding between such layers and can be applied by any one of a wide variety of methods known in the art. Preferably, the adhesion promoter layer comprises a silane compound. Like certain other coating layers of the sensor, the adhesion promoter layer can then be subjected to one or more suitable radiation andf ox chemical and/or heat curing steps as are known in the art.
In alternative embodiments, the enzyme layer can be sufficiently crosslinked or otherwise prepared to allow the membrane cover layer to be disposed in direct contact with the sensor chemistry layer in the absence of an adhesion promoter layer.
A preferred embodiment of the invention is a method of making a sensor by providing a base layer, forming a sensor layer on the base layer, spin coating an enzyme layer on the sensor layer and then foxmixig an analyte contacting layer on the sensor, wherein the analyte contacting layer regulates the amount of analyte that can contact the enzyme layer. In preferred methods, the enzyme layer is vapor cxosslinked on the sensor layer. In a typical embodiment of the invention, the sensor layer is formed to include at least one working electrode and at least one counter electrode. In highly preferred embodiments, the enzyme layer is formed on at least a portion of the working electrode and at least a portion of the counter electrode. Typically, the enzyme layer that is formed on the sensor layer is less than 2, 1, 0.5, 0.25 or 0.1 microns in thickness.
Preferably, the enzyme layer comprises glucose oxidase, glucose dehydrogenase, lactose oxidase, hexokinase or lactose dehydxogenase. In a specific method, the enzyme layer comprises glucose oxidase that is stabilized by coating it on the sensor layer in combination with a carrier protein in a ~txed ratio. Typically the carrier protein is albumin.
Preferably such methods include the step of forming an adhesion promoter layer disposed between the glucose oxidase layer and the analyte contacting layer. Optionally, the adhesion promoter layer is subjected to a curing process prior to the formation of the analyte contacting layer.
,A related embodiment of the invention is a method of making a glucose sensor by providing a base layer, forming a sensor layer on the base layer that includes at least S one working electrode and at least one counter electrode, forming a glucose oxidase layer on the sensor layer by a spin coating process (a layer which is preferably stabilized by combining the glucose oxidase with albumin in a fixed ratio), wherein the glucose oxidase layer coats at least a portion of the working electrode and at least a portion of the counter electrode, and then forming an glucose limiting layer on the glucose sensor so as to regulate the amount of glucose that can contact the glucose oxidase layer.
In such processes, the glucose oxidase layer that is formed on the sensor layer is preferably less than 2, 1, 0.5, 0.25 or 0.1 microns in thickness. Typically, the glucose oxidase coating is vapor crosslinked on the sensor layer. Optionally, the glucose oxidase coating covers the entire sensor layer. In highly preferred embodiments of the invention, an adhesion promoter layer disposed between the glucose oxidase layer and the analyte contacting layer The finished sensors produced by such processes are typically quickly and easily removed from a supporting substrate (if one is used), for example, by cutting along a line surrounding each sensor on the substrate. The cutting step can use methods typically used in this art such as those that include a W laser cutting device that is used to cut through the base and cover layers and the functional coating layers along a line surrounding or circumscribing each sensor, typically in at least slight outward spaced relation from the conductive elements so that the sufficient interconnected base and cover layer material remains to seal the side edges of the finished sensor.
Since the base layer is typically not physically attached or only minimally adhered directly to the underlying supporting substrate, the sensors can be lifted quickly and easily from the supporting substrate, without significant further processing steps or potential damage due to stresses incurred by physically pulling or peeling attached sensors from the supporting substrate. The supporting substrate can thereafter be cleaned and reused, or otherwise discarded. Alternatively, the functional coating layers) can be applied after the sensor including base layer, sensor elements and cover layer is removed from the supporting substrate by cutting.
D. KITS AND SENSOR SETS OF THE INVENTION
In another embodiment of the invention, a kit and/or sensor set, useful for the sensing an analyte as is described above, is provided. The kit and/or sensor set typically comprises a container, a label and a sensor having an extremely thin enzyme coating as described above. Suitable containers include, for example, an easy to open package made from a material such as a metal foil, bottles, vials, syringes, and test tubes. The containers may be formed from a variety of materials such as metals (e.g.
foils) paper products, glass or plastic. The container preferably holds a glucose sensor coated with a layer of glucose oxidase that is less than 2 microns in thickness. The label on, or associated with, the container indicates that the sensor is used for assaying the analyte of choice. The kit and/or sensor set may further include other materials desirable from a commercial and user standpoint, including elements or devices designed to facilitate the introduction of the sensor into the analyte environment, other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.
Various citations are referenced throughout the specification. In addition, certain text from related art is reproduced herein to more clearly delineate the various embodiments of the invention. The disclosures of all citations in the specification are expressly incorporated herein by reference.
Claims (50)
1. A sensor for implantation within a body, the sensor comprising:
a base layer;
a sensor layer disposed upon the base layer wherein the sensor layer includes a plurality of sensor elements;
an enzyme layer disposed upon the sensor layer, wherein the enzyme layer is less than 2 microns in thickness and further wherein the enzyme layer coats all of the plurality of sensing elements on the sensor layer; and a cover layer.
a base layer;
a sensor layer disposed upon the base layer wherein the sensor layer includes a plurality of sensor elements;
an enzyme layer disposed upon the sensor layer, wherein the enzyme layer is less than 2 microns in thickness and further wherein the enzyme layer coats all of the plurality of sensing elements on the sensor layer; and a cover layer.
2. The sensor of claim 1, wherein the enzyme layer comprises glucose oxidase.
3. The sensor of claim 2, wherein the enzyme layer further comprises a carrier protein in a substantially fixed ratio with the glucose oxidase.
4. The sensor of claim 3, wherein the glucose oxidase and the carrier protein are distributed in a substantially uniform manner throughout the disposed enzyme layer.
5. The sensor of claim 3, wherein the carrier protein comprises albumin.
6. The sensor of claim 5, wherein the albumin is present in an amount of about 5%
albumin by weight.
albumin by weight.
7. The sensor of claim 1, wherein the cover layer is a analyte contacting layer;
wherein the analyte contacting layer is disposed on the sensor so as to regulate the amount of analyte that can contact the enzyme layer.
wherein the analyte contacting layer is disposed on the sensor so as to regulate the amount of analyte that can contact the enzyme layer.
8. The sensor of claim 1, wherein the enzyme layer is a thickness selected from the group consisting of less than 1, 0.5, 0.25 and 0.1 microns.
9. The sensor of claim 7, further comprising an adhesion promoter layer disposed between the enzyme layer and the analyte contacting layer.
10. An electrochemical analyte sensor, the sensor comprising:
a base layer;
a sensor layer disposed upon the base layer wherein the sensor layer includes at least one working electrode, at least one counter electrode, and at least one reference electrode;
an enzyme layer disposed upon the sensor layer, wherein the enzyme layer is less than 2 microns in thickness; and an analyte contacting layer; wherein the analyte contacting layer regulates the amount of analyte that contacts the enzyme layer.
a base layer;
a sensor layer disposed upon the base layer wherein the sensor layer includes at least one working electrode, at least one counter electrode, and at least one reference electrode;
an enzyme layer disposed upon the sensor layer, wherein the enzyme layer is less than 2 microns in thickness; and an analyte contacting layer; wherein the analyte contacting layer regulates the amount of analyte that contacts the enzyme layer.
11. The sensor of claim 10, wherein the coated surface of the working electrode is larger than the coated surface of the counter electrode.
12. The sensor of claim 11, wherein the enzyme layer comprises glucose oxidase and further wherein the glucose oxidase is stabilized by coating it on the working electrode, the counter electrode and the reference electrode in combination with a carrier protein in a fixed ratio.
13. The sensor of claim 10, wherein the enzyme layer substantially covers the sensor layer.
14. The sensor of claim 10, further comprising an adhesion promoter layer disposed between the enzyme layer and the analyte contacting layer.
15. A glucose sensor for implantation within a body, the sensor comprising:
a base layer;
a sensor layer disposed upon the base layer, a glucose oxidase layer disposed upon the sensor layer, wherein the glucose oxidase is stabilized by combining it with albumin in a defined ratio and further wherein the glucose oxidase and the albumin are distributed in a substantially uniform manner throughout the disposed layer; and a glucose limiting layer; wherein the glucose limiting layer regulates the amount of glucose that contacts the glucose oxidase layer.
a base layer;
a sensor layer disposed upon the base layer, a glucose oxidase layer disposed upon the sensor layer, wherein the glucose oxidase is stabilized by combining it with albumin in a defined ratio and further wherein the glucose oxidase and the albumin are distributed in a substantially uniform manner throughout the disposed layer; and a glucose limiting layer; wherein the glucose limiting layer regulates the amount of glucose that contacts the glucose oxidase layer.
16. The sensor of claim 15, wherein the sensor layer includes a plurality of sensor elements including at least one working electrode and at least one counter electrode.
17. The sensor of claim 15, wherein the glucose oxidase layer is a thickness selected from the group consisting of less than 1, 0.5, 0.25 and 0.1 microns.
18. The sensor of claim 15, wherein the albumin is present in an amount of about 5% albumin by weight.
19. The sensor of claim 15, further comprising an adhesion promoter layer disposed between the glucose oxidase layer and the glucose limiting layer.
20. An electrochemical glucose sensor having hydrogen peroxide recycling capabilities, the sensor comprising:
a base layer;
a sensor layer disposed upon the base layer wherein the sensor layer includes at least one working electrode and at least one counter electrode;
a glucose oxidase layer disposed upon the sensor layer, wherein the glucose oxidase layer coats at least a portion of the working electrode and at least a portion of the counter electrode in a manner such that the working electrode oxidizes hydrogen peroxide that is produced by glucose oxidase upon reaction with glucose; and a glucose limiting layer; wherein the glucose limiting layer is disposed on the sensor so as to regulate the amount of glucose that can contact the glucose oxidase layer and further wherein the glucose limiting layer is disposed on the sensor so as to inhibit the diffusion of hydrogen peroxide into the environment in which the sensor is placed.
a base layer;
a sensor layer disposed upon the base layer wherein the sensor layer includes at least one working electrode and at least one counter electrode;
a glucose oxidase layer disposed upon the sensor layer, wherein the glucose oxidase layer coats at least a portion of the working electrode and at least a portion of the counter electrode in a manner such that the working electrode oxidizes hydrogen peroxide that is produced by glucose oxidase upon reaction with glucose; and a glucose limiting layer; wherein the glucose limiting layer is disposed on the sensor so as to regulate the amount of glucose that can contact the glucose oxidase layer and further wherein the glucose limiting layer is disposed on the sensor so as to inhibit the diffusion of hydrogen peroxide into the environment in which the sensor is placed.
21. The sensor of claim 20, further comprising an adhesion promoter layer disposed between the glucose oxidase layer and the glucose limiting layer.
22. The sensor of claim 21, wherein the adhesion promoter layer comprises a silane compound.
23. The sensor of claim 20, wherein the sensor further includes an insulation layer between the base layer and the glucose oxidase layer.
24. The sensor of claim 20, wherein the insulation layer comprises a polyimmide.
25. The sensor of claim 20, wherein an electrode comprises platinum black.
26. The sensor of claim 20, wherein the glucose oxidase layer is vapor crosslinked on the sensor layer.
27. The sensor of claim 20, wherein the glucose oxidase layer is stabilized by coating it on the sensor layer in combination with a carrier protein in a fixed ratio.
28. The sensor of claim 20, wherein the base layer comprises a polyimmide.
29. The sensor of claim 20, wherein the glucose limiting layer comprises a hydrophilic polymer.
30. A method of making a sensor comprising the steps of:
a providing a base layer;
forming a sensor layer on the base layer;
spin coating an enzyme layer on the sensor layer; and forming an analyte contacting layer on the sensor, wherein the analyte contacting layer regulates the amount of analyte that can contact the enzyme layer.
a providing a base layer;
forming a sensor layer on the base layer;
spin coating an enzyme layer on the sensor layer; and forming an analyte contacting layer on the sensor, wherein the analyte contacting layer regulates the amount of analyte that can contact the enzyme layer.
31. The method of claim 30, further comprising vapor crosslinking the enzyme layer.
32. The method of claim 30, further wherein the sensor layer includes at least one working electrode and at least one counter electrode.
33. The method of claim 32, wherein the enzyme layer is formed on at least a portion of the working electrode and at least a portion of the counter electrode.
34. The sensor of claim 30, wherein the enzyme layer that is formed on the sensor layer is a thickness selected from the group consisting of less than 1, 0.5, 0.25 and 0.1 microns.
35. The method of claim 30, wherein the enzyme layer comprises glucose oxidase, glucose dehydrogenase, lactose oxidase, hexokinase or lactose dehydrogenase.
36. The method of claim 35, wherein the enzyme layer comprises glucose oxidase and further wherein the glucose oxidase is stabilized by coating it on the sensor layer in combination with a carrier protein in a fixed ratio.
37. The method of claim 36, wherein the wherein the carrier protein is albumin and further wherein the glucose oxidase and the albumin are distributed in a substantially uniform manner throughout the disposed enzyme layer.
38. The method of claim 30, further comprising forming an adhesion promoter layer disposed between the glucose oxidase layer and the analyte contacting layer.
39. The method of claim 38, wherein the adhesion promoter layer is subjected to a curing process prior to the formation of the analyte contacting layer.
40. A method of making a glucose sensor comprising the steps of:
a providing a base layer;
forming a sensor layer on the base, wherein the sensor layer includes at least one working electrode and at least one counter electrode;
forming a glucose oxidase layer on the sensor layer by a spin coating process, wherein the glucose oxidase layer coats at least a portion of the working electrode and at least a portion of the counter electrode; and forming an glucose limiting layer on the glucose sensor so as to regulate the amount of glucose that can contact the glucose oxidase layer.
a providing a base layer;
forming a sensor layer on the base, wherein the sensor layer includes at least one working electrode and at least one counter electrode;
forming a glucose oxidase layer on the sensor layer by a spin coating process, wherein the glucose oxidase layer coats at least a portion of the working electrode and at least a portion of the counter electrode; and forming an glucose limiting layer on the glucose sensor so as to regulate the amount of glucose that can contact the glucose oxidase layer.
41. The method of claim 40, wherein the wherein the glucose oxidase layer that is formed on the sensor layer is a thickness selected from the group consisting of less than 1, 0.5, 0.25 and 0.1 microns.
42. The method of claim 40, further comprising vapor crosslinking the glucose oxidase layer.
43. The method of claim 40, wherein the glucose oxidase layer is stabilized by combining the glucose oxidase with albumin in a fixed ratio.
44. The method of claim 40, further comprising forming an adhesion promoter layer disposed between the glucose oxidase layer and the analyte contacting layer.
45. A method of making a less than about 2 micron coating of stabilized glucose oxidase on the surface of at least one electrode comprising combining glucose oxidase with albumin in a ratio of about 20,000 units of glucose oxidase and about 5%
albumin by weight and applying the glucose oxidase and albumin mixture to the surface of an electrode by a process selected from the group consisting of a spin coating process, a dip and dry process, a microdeposition process, a jet printer deposition process, a screen printing process or a doctor blading process.
albumin by weight and applying the glucose oxidase and albumin mixture to the surface of an electrode by a process selected from the group consisting of a spin coating process, a dip and dry process, a microdeposition process, a jet printer deposition process, a screen printing process or a doctor blading process.
46. The methods of claim 45, wherein the stabilized glucose oxidase coating is applied to the surface of the electrode by a spin coating process.
47. The method of claim 45, wherein the stabilized glucose oxidase coating is formed on the on the surface of at least two electrodes.
48. The method of claim 45, wherein the albumin is present in an amount of about 5% albumin by weight.
49. The method of claim 45, wherein the wherein the stabilized glucose oxidase layer that is formed on the sensor layer is a thickness selected from the group consisting of less than 1, 0.5, 0.25 and 0.1 microns.
50. A stabilized glucose oxidase layer for coating the surface of an electrode wherein:
the glucose oxidase is mixed with a carrier protein in a fixed ratio within the layer;
the glucose oxidase and the carrier protein are distributed in a substantially uniform manner throughout the layer; and the layer is less than 2 microns in thickness.
the glucose oxidase is mixed with a carrier protein in a fixed ratio within the layer;
the glucose oxidase and the carrier protein are distributed in a substantially uniform manner throughout the layer; and the layer is less than 2 microns in thickness.
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Families Citing this family (285)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE9700384D0 (en) * | 1997-02-04 | 1997-02-04 | Biacore Ab | Analytical method and apparatus |
US8527026B2 (en) | 1997-03-04 | 2013-09-03 | Dexcom, Inc. | Device and method for determining analyte levels |
US6001067A (en) | 1997-03-04 | 1999-12-14 | Shults; Mark C. | Device and method for determining analyte levels |
US7899511B2 (en) | 2004-07-13 | 2011-03-01 | Dexcom, Inc. | Low oxygen in vivo analyte sensor |
US7657297B2 (en) | 2004-05-03 | 2010-02-02 | Dexcom, Inc. | Implantable analyte sensor |
US9155496B2 (en) | 1997-03-04 | 2015-10-13 | Dexcom, Inc. | Low oxygen in vivo analyte sensor |
US6175752B1 (en) | 1998-04-30 | 2001-01-16 | Therasense, 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 |
US8480580B2 (en) | 1998-04-30 | 2013-07-09 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
US8974386B2 (en) | 1998-04-30 | 2015-03-10 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
US8346337B2 (en) | 1998-04-30 | 2013-01-01 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
US9066695B2 (en) | 1998-04-30 | 2015-06-30 | 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 |
US8688188B2 (en) | 1998-04-30 | 2014-04-01 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
US6338790B1 (en) | 1998-10-08 | 2002-01-15 | Therasense, Inc. | Small volume in vitro analyte sensor with diffusible or non-leachable redox mediator |
EP1119285A1 (en) * | 1998-10-08 | 2001-08-01 | Minimed Inc. | Telemetered characteristic monitor system |
US7766873B2 (en) | 1998-10-29 | 2010-08-03 | Medtronic Minimed, Inc. | Method and apparatus for detecting occlusions in an ambulatory infusion pump |
US7621893B2 (en) * | 1998-10-29 | 2009-11-24 | Medtronic Minimed, Inc. | Methods and apparatuses for detecting occlusions in an ambulatory infusion pump |
US7806886B2 (en) | 1999-06-03 | 2010-10-05 | Medtronic Minimed, Inc. | Apparatus and method for controlling insulin infusion with state variable feedback |
US20030060765A1 (en) * | 2000-02-16 | 2003-03-27 | Arthur Campbell | Infusion device menu structure and method of using the same |
US6560471B1 (en) | 2001-01-02 | 2003-05-06 | Therasense, Inc. | Analyte monitoring device and methods of use |
WO2002078512A2 (en) | 2001-04-02 | 2002-10-10 | Therasense, Inc. | Blood glucose tracking apparatus and methods |
US8070934B2 (en) | 2001-05-11 | 2011-12-06 | Abbott Diabetes Care Inc. | Transition metal complexes with (pyridyl)imidazole ligands |
US8226814B2 (en) * | 2001-05-11 | 2012-07-24 | Abbott Diabetes Care Inc. | Transition metal complexes with pyridyl-imidazole ligands |
US6676816B2 (en) * | 2001-05-11 | 2004-01-13 | Therasense, Inc. | Transition metal complexes with (pyridyl)imidazole ligands and sensors using said complexes |
US6932894B2 (en) * | 2001-05-15 | 2005-08-23 | Therasense, Inc. | Biosensor membranes composed of polymers containing heterocyclic nitrogens |
US20030032874A1 (en) | 2001-07-27 | 2003-02-13 | Dexcom, Inc. | Sensor head for use with implantable devices |
US6827702B2 (en) | 2001-09-07 | 2004-12-07 | Medtronic Minimed, Inc. | Safety limits for closed-loop infusion pump control |
US7052591B2 (en) | 2001-09-21 | 2006-05-30 | Therasense, Inc. | Electrodeposition of redox polymers and co-electrodeposition of enzymes by coordinative crosslinking |
US8010174B2 (en) | 2003-08-22 | 2011-08-30 | Dexcom, Inc. | Systems and methods for replacing signal artifacts in a glucose sensor data stream |
US7613491B2 (en) | 2002-05-22 | 2009-11-03 | Dexcom, Inc. | Silicone based membranes for use in implantable glucose sensors |
US9247901B2 (en) | 2003-08-22 | 2016-02-02 | Dexcom, Inc. | Systems and methods for replacing signal artifacts in a glucose sensor data stream |
US8364229B2 (en) | 2003-07-25 | 2013-01-29 | Dexcom, Inc. | Analyte sensors having a signal-to-noise ratio substantially unaffected by non-constant noise |
US8260393B2 (en) | 2003-07-25 | 2012-09-04 | Dexcom, Inc. | Systems and methods for replacing signal data artifacts in a glucose sensor data stream |
US7828728B2 (en) | 2003-07-25 | 2010-11-09 | Dexcom, Inc. | Analyte sensor |
US20070227907A1 (en) * | 2006-04-04 | 2007-10-04 | Rajiv Shah | Methods and materials for controlling the electrochemistry of analyte sensors |
US9492111B2 (en) * | 2002-04-22 | 2016-11-15 | Medtronic Minimed, Inc. | Methods and materials for stabilizing analyte sensors |
US7813780B2 (en) * | 2005-12-13 | 2010-10-12 | Medtronic Minimed, Inc. | Biosensors and methods for making and using them |
US8512276B2 (en) | 2002-07-24 | 2013-08-20 | Medtronic Minimed, Inc. | System for providing blood glucose measurements to an infusion device |
US7278983B2 (en) | 2002-07-24 | 2007-10-09 | Medtronic Minimed, Inc. | Physiological monitoring device for controlling a medication infusion device |
US20040068230A1 (en) * | 2002-07-24 | 2004-04-08 | Medtronic Minimed, Inc. | System for providing blood glucose measurements to an infusion device |
US20050272989A1 (en) * | 2004-06-04 | 2005-12-08 | Medtronic Minimed, Inc. | Analyte sensors and methods for making and using them |
US9237865B2 (en) * | 2002-10-18 | 2016-01-19 | Medtronic Minimed, Inc. | Analyte sensors and methods for making and using them |
US20040122353A1 (en) * | 2002-12-19 | 2004-06-24 | Medtronic Minimed, Inc. | Relay device for transferring information between a sensor system and a fluid delivery system |
MXPA05012307A (en) * | 2003-05-16 | 2006-07-03 | Acorda Therapeutics Inc | Proteoglycan degrading mutants for treatment of cns. |
US9763609B2 (en) | 2003-07-25 | 2017-09-19 | Dexcom, Inc. | Analyte sensors having a signal-to-noise ratio substantially unaffected by non-constant noise |
WO2007120442A2 (en) | 2003-07-25 | 2007-10-25 | Dexcom, Inc. | Dual electrode system for a continuous analyte sensor |
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 |
US7074307B2 (en) | 2003-07-25 | 2006-07-11 | Dexcom, Inc. | Electrode systems for electrochemical sensors |
US7774145B2 (en) * | 2003-08-01 | 2010-08-10 | Dexcom, Inc. | Transcutaneous analyte sensor |
US8060173B2 (en) | 2003-08-01 | 2011-11-15 | Dexcom, Inc. | System and methods for processing analyte sensor data |
US8160669B2 (en) | 2003-08-01 | 2012-04-17 | Dexcom, Inc. | Transcutaneous analyte sensor |
US8275437B2 (en) | 2003-08-01 | 2012-09-25 | Dexcom, Inc. | Transcutaneous analyte sensor |
US7591801B2 (en) | 2004-02-26 | 2009-09-22 | Dexcom, Inc. | Integrated delivery device for continuous glucose sensor |
US20190357827A1 (en) | 2003-08-01 | 2019-11-28 | Dexcom, Inc. | Analyte sensor |
US7519408B2 (en) | 2003-11-19 | 2009-04-14 | Dexcom, Inc. | Integrated receiver for continuous analyte sensor |
US9135402B2 (en) | 2007-12-17 | 2015-09-15 | Dexcom, Inc. | Systems and methods for processing sensor data |
US20080119703A1 (en) | 2006-10-04 | 2008-05-22 | Mark Brister | Analyte sensor |
US8622905B2 (en) | 2003-08-01 | 2014-01-07 | Dexcom, Inc. | System and methods for processing analyte sensor data |
US7920906B2 (en) | 2005-03-10 | 2011-04-05 | Dexcom, Inc. | System and methods for processing analyte sensor data for sensor calibration |
US20140121989A1 (en) | 2003-08-22 | 2014-05-01 | Dexcom, Inc. | Systems and methods for processing analyte sensor data |
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 |
EP1691679B1 (en) * | 2003-11-13 | 2010-08-11 | Medtronic MiniMed, Inc. | Long term analyte sensor array |
US8414489B2 (en) * | 2003-11-13 | 2013-04-09 | Medtronic Minimed, Inc. | Fabrication of multi-sensor arrays |
US9247900B2 (en) | 2004-07-13 | 2016-02-02 | Dexcom, Inc. | Analyte sensor |
US8615282B2 (en) | 2004-07-13 | 2013-12-24 | Dexcom, Inc. | Analyte 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 |
US11633133B2 (en) | 2003-12-05 | 2023-04-25 | Dexcom, Inc. | Dual electrode system for a continuous analyte sensor |
EP1711790B1 (en) | 2003-12-05 | 2010-09-08 | DexCom, Inc. | Calibration techniques for a continuous analyte sensor |
US7637868B2 (en) * | 2004-01-12 | 2009-12-29 | Dexcom, Inc. | Composite material for implantable device |
US20050182451A1 (en) * | 2004-01-12 | 2005-08-18 | Adam Griffin | Implantable device with improved radio frequency capabilities |
US8165651B2 (en) * | 2004-02-09 | 2012-04-24 | Abbott Diabetes Care Inc. | Analyte sensor, and associated system and method employing a catalytic agent |
US7699964B2 (en) | 2004-02-09 | 2010-04-20 | Abbott Diabetes Care Inc. | Membrane suitable for use in an analyte sensor, analyte sensor, and associated method |
US8808228B2 (en) | 2004-02-26 | 2014-08-19 | Dexcom, Inc. | Integrated medicament delivery device for use with continuous analyte sensor |
US8277713B2 (en) | 2004-05-03 | 2012-10-02 | Dexcom, Inc. | Implantable analyte sensor |
US8792955B2 (en) | 2004-05-03 | 2014-07-29 | Dexcom, Inc. | Transcutaneous analyte sensor |
US20070100222A1 (en) * | 2004-06-14 | 2007-05-03 | Metronic Minimed, Inc. | Analyte sensing apparatus for hospital use |
US20060015020A1 (en) * | 2004-07-06 | 2006-01-19 | Dexcom, Inc. | Systems and methods for manufacture of an analyte-measuring device including a membrane system |
WO2006127694A2 (en) * | 2004-07-13 | 2006-11-30 | Dexcom, Inc. | 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 |
US8565848B2 (en) | 2004-07-13 | 2013-10-22 | Dexcom, Inc. | Transcutaneous analyte sensor |
US7654956B2 (en) | 2004-07-13 | 2010-02-02 | Dexcom, Inc. | Transcutaneous analyte sensor |
US20060016700A1 (en) | 2004-07-13 | 2006-01-26 | Dexcom, Inc. | Transcutaneous analyte sensor |
US7344500B2 (en) * | 2004-07-27 | 2008-03-18 | Medtronic Minimed, Inc. | Sensing system with auxiliary display |
US7146939B2 (en) * | 2004-09-14 | 2006-12-12 | Federal-Mogul Worldwide, Inc. | Anti-cavitation diesel cylinder liner |
JP4643222B2 (en) * | 2004-10-27 | 2011-03-02 | 日機装株式会社 | Biosensor and manufacturing method thereof |
US7303543B1 (en) * | 2004-12-03 | 2007-12-04 | Medtronic Minimed, Inc. | Medication infusion set |
RU2430264C2 (en) * | 2004-12-16 | 2011-09-27 | Индепендент Нэчурэл Ресорсиз, Инк. | Power system built around float-type pump |
ATE497166T1 (en) | 2005-01-26 | 2011-02-15 | Univ Ramot | BIOLOGICALLY ACTIVE SILVER-COATED PROTEINS |
US7704229B2 (en) * | 2005-02-03 | 2010-04-27 | Medtronic Minimed, Inc. | Insertion device |
US20060184104A1 (en) * | 2005-02-15 | 2006-08-17 | Medtronic Minimed, Inc. | Needle guard |
US7241586B2 (en) | 2005-02-17 | 2007-07-10 | Medtronic Minimed, Inc. | Polypeptide formulations and methods for making, using and characterizing them |
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 |
US8744546B2 (en) * | 2005-05-05 | 2014-06-03 | Dexcom, Inc. | Cellulosic-based resistance domain for an analyte sensor |
US20090127112A1 (en) * | 2005-05-18 | 2009-05-21 | Ramot At Tel Aviv University Ltd. | Biologically active metal-coated proteins |
US20070033074A1 (en) * | 2005-06-03 | 2007-02-08 | Medtronic Minimed, Inc. | Therapy management system |
US20060272652A1 (en) * | 2005-06-03 | 2006-12-07 | Medtronic Minimed, Inc. | Virtual patient software system for educating and treating individuals with diabetes |
WO2006132250A1 (en) * | 2005-06-06 | 2006-12-14 | Nikkiso Co., Ltd. | Biosensor and biosensor cell |
US20070016449A1 (en) * | 2005-06-29 | 2007-01-18 | Gary Cohen | Flexible glucose analysis using varying time report deltas and configurable glucose target ranges |
EP1901646B1 (en) | 2005-07-14 | 2017-04-05 | Abbott Point of Care Inc. | Photoformed silicone sensor membrane |
US20070066956A1 (en) * | 2005-07-27 | 2007-03-22 | Medtronic Minimed, Inc. | Systems and methods for entering temporary basal rate pattern in an infusion device |
US20090227855A1 (en) * | 2005-08-16 | 2009-09-10 | Medtronic Minimed, Inc. | Controller device for an infusion pump |
US7737581B2 (en) | 2005-08-16 | 2010-06-15 | Medtronic Minimed, Inc. | Method and apparatus for predicting end of battery life |
US20070093786A1 (en) * | 2005-08-16 | 2007-04-26 | Medtronic Minimed, Inc. | Watch controller for a medical device |
US20070060870A1 (en) * | 2005-08-16 | 2007-03-15 | Tolle Mike Charles V | Controller device for an infusion pump |
US20070060869A1 (en) * | 2005-08-16 | 2007-03-15 | Tolle Mike C V | Controller device for an infusion pump |
US7713240B2 (en) | 2005-09-13 | 2010-05-11 | Medtronic Minimed, Inc. | Modular external infusion device |
US7725148B2 (en) | 2005-09-23 | 2010-05-25 | Medtronic Minimed, Inc. | Sensor with layered electrodes |
US9072476B2 (en) | 2005-09-23 | 2015-07-07 | Medtronic Minimed, Inc. | Flexible sensor apparatus |
TW200718785A (en) * | 2005-11-10 | 2007-05-16 | Toyo Boseki | A process for improving the thermal stability of a composition containing a soluble coenzyme conjugated glucose dehydrogenase (GDH) |
EP1797817A1 (en) * | 2005-12-19 | 2007-06-20 | F.Hoffmann-La Roche Ag | Sandwich sensor for determining the concentration of an analyte |
EP1962668B1 (en) * | 2005-12-19 | 2009-06-17 | F. Hoffmann-La Roche AG | Sandwich sensor for the determination of an analyte concentration |
US8114268B2 (en) | 2005-12-30 | 2012-02-14 | Medtronic Minimed, Inc. | Method and system for remedying sensor malfunctions detected by electrochemical impedance spectroscopy |
US20070169533A1 (en) * | 2005-12-30 | 2007-07-26 | Medtronic Minimed, Inc. | Methods and systems for detecting the hydration of sensors |
US8114269B2 (en) | 2005-12-30 | 2012-02-14 | Medtronic Minimed, Inc. | System and method for determining the point of hydration and proper time to apply potential to a glucose sensor |
US7774038B2 (en) * | 2005-12-30 | 2010-08-10 | Medtronic Minimed, Inc. | Real-time self-calibrating sensor system and method |
US7985330B2 (en) * | 2005-12-30 | 2011-07-26 | Medtronic Minimed, Inc. | Method and system for detecting age, hydration, and functional states of sensors using electrochemical impedance spectroscopy |
US20070173712A1 (en) * | 2005-12-30 | 2007-07-26 | Medtronic Minimed, Inc. | Method of and system for stabilization of sensors |
US9757061B2 (en) | 2006-01-17 | 2017-09-12 | Dexcom, Inc. | Low oxygen in vivo analyte sensor |
US7885698B2 (en) | 2006-02-28 | 2011-02-08 | Abbott Diabetes Care Inc. | Method and system for providing continuous calibration of implantable analyte sensors |
US8073008B2 (en) * | 2006-04-28 | 2011-12-06 | Medtronic Minimed, Inc. | Subnetwork synchronization and variable transmit synchronization techniques for a wireless medical device network |
US20070254593A1 (en) * | 2006-04-28 | 2007-11-01 | Medtronic Minimed, Inc. | Wireless data communication for a medical device network that supports a plurality of data communication modes |
US7942844B2 (en) | 2006-04-28 | 2011-05-17 | Medtronic Minimed, Inc. | Remote monitoring for networked fluid infusion systems |
US20070253380A1 (en) * | 2006-04-28 | 2007-11-01 | James Jollota | Data translation device with nonvolatile memory for a networked medical device system |
US20070255126A1 (en) * | 2006-04-28 | 2007-11-01 | Moberg Sheldon B | Data communication in networked fluid infusion systems |
US7920907B2 (en) | 2006-06-07 | 2011-04-05 | Abbott Diabetes Care Inc. | Analyte monitoring system and method |
WO2008038274A1 (en) | 2006-09-29 | 2008-04-03 | Medingo Ltd. | Fluid delivery system with electrochemical sensing of analyte concentration levels |
US7831287B2 (en) | 2006-10-04 | 2010-11-09 | Dexcom, Inc. | Dual electrode system for a continuous analyte sensor |
US20080139910A1 (en) * | 2006-12-06 | 2008-06-12 | Metronic Minimed, Inc. | Analyte sensor and method of using the same |
US10154804B2 (en) | 2007-01-31 | 2018-12-18 | Medtronic Minimed, Inc. | Model predictive method and system for controlling and supervising insulin infusion |
US20080269714A1 (en) | 2007-04-25 | 2008-10-30 | Medtronic Minimed, Inc. | Closed loop/semi-closed loop therapy modification system |
US20200037874A1 (en) | 2007-05-18 | 2020-02-06 | Dexcom, Inc. | Analyte sensors having a signal-to-noise ratio substantially unaffected by non-constant noise |
US20080300572A1 (en) * | 2007-06-01 | 2008-12-04 | Medtronic Minimed, Inc. | Wireless monitor for a personal medical device system |
US20080306434A1 (en) | 2007-06-08 | 2008-12-11 | Dexcom, Inc. | Integrated medicament delivery device for use with continuous analyte sensor |
US20090024015A1 (en) * | 2007-07-17 | 2009-01-22 | Edwards Lifesciences Corporation | Sensing element having an adhesive backing |
US9968742B2 (en) | 2007-08-29 | 2018-05-15 | Medtronic Minimed, Inc. | Combined sensor and infusion set using separated sites |
US9452258B2 (en) | 2007-10-09 | 2016-09-27 | Dexcom, Inc. | Integrated insulin delivery system with continuous glucose sensor |
US8417312B2 (en) | 2007-10-25 | 2013-04-09 | Dexcom, Inc. | Systems and methods for processing sensor data |
US20090112626A1 (en) * | 2007-10-30 | 2009-04-30 | Cary Talbot | Remote wireless monitoring, processing, and communication of patient data |
US8512731B2 (en) * | 2007-11-13 | 2013-08-20 | Medtronic Minimed, Inc. | Antimicrobial coatings for medical devices and methods for making and using them |
US8290559B2 (en) | 2007-12-17 | 2012-10-16 | Dexcom, Inc. | Systems and methods for processing sensor data |
US8313467B2 (en) | 2007-12-27 | 2012-11-20 | Medtronic Minimed, Inc. | Reservoir pressure equalization systems and methods |
CA2715628A1 (en) | 2008-02-21 | 2009-08-27 | Dexcom, Inc. | Systems and methods for processing, transmitting and displaying sensor data |
US8396528B2 (en) | 2008-03-25 | 2013-03-12 | Dexcom, Inc. | Analyte sensor |
US8583204B2 (en) | 2008-03-28 | 2013-11-12 | Dexcom, Inc. | Polymer membranes for continuous analyte sensors |
US8682408B2 (en) | 2008-03-28 | 2014-03-25 | Dexcom, Inc. | Polymer membranes for continuous analyte sensors |
US20090247856A1 (en) * | 2008-03-28 | 2009-10-01 | Dexcom, Inc. | Polymer membranes for continuous analyte sensors |
US11730407B2 (en) | 2008-03-28 | 2023-08-22 | Dexcom, Inc. | Polymer membranes for continuous analyte sensors |
US9295786B2 (en) | 2008-05-28 | 2016-03-29 | Medtronic Minimed, Inc. | Needle protective device for subcutaneous sensors |
US8700114B2 (en) | 2008-07-31 | 2014-04-15 | Medtronic Minmed, Inc. | Analyte sensor apparatuses comprising multiple implantable sensor elements and methods for making and using them |
US20100025238A1 (en) * | 2008-07-31 | 2010-02-04 | Medtronic Minimed, Inc. | Analyte sensor apparatuses having improved electrode configurations and methods for making and using them |
WO2010033724A2 (en) | 2008-09-19 | 2010-03-25 | Dexcom, Inc. | Particle-containing membrane and particulate electrode for analyte sensors |
US8208973B2 (en) * | 2008-11-05 | 2012-06-26 | Medtronic Minimed, Inc. | System and method for variable beacon timing with wireless devices |
US9330237B2 (en) | 2008-12-24 | 2016-05-03 | Medtronic Minimed, Inc. | Pattern recognition and filtering in a therapy management system |
US9351677B2 (en) * | 2009-07-02 | 2016-05-31 | Dexcom, Inc. | Analyte sensor with increased reference capacity |
EP3970610A3 (en) * | 2009-07-02 | 2022-05-18 | Dexcom, Inc. | Analyte sensors and methods of manufacturing same |
US8344847B2 (en) | 2009-07-09 | 2013-01-01 | Medtronic Minimed, Inc. | Coordination of control commands in a medical device system having at least one therapy delivery device and at least one wireless controller device |
US20110006880A1 (en) * | 2009-07-09 | 2011-01-13 | Medtronic Minimed, Inc. | Fingerprint-linked control of a portable medical device |
US20110009813A1 (en) * | 2009-07-09 | 2011-01-13 | Medtronic Minimed, Inc. | Panning a display of a portable medical device |
EP2724739B1 (en) | 2009-07-30 | 2015-07-01 | Tandem Diabetes Care, Inc. | Portable infusion pump system |
US8487758B2 (en) * | 2009-09-02 | 2013-07-16 | Medtronic Minimed, Inc. | Medical device having an intelligent alerting scheme, and related operating methods |
US8386042B2 (en) * | 2009-11-03 | 2013-02-26 | Medtronic Minimed, Inc. | Omnidirectional accelerometer device and medical device incorporating same |
US8660628B2 (en) * | 2009-12-21 | 2014-02-25 | Medtronic Minimed, Inc. | Analyte sensors comprising blended membrane compositions and methods for making and using them |
US8574201B2 (en) | 2009-12-22 | 2013-11-05 | Medtronic Minimed, Inc. | Syringe piston with check valve seal |
US8755269B2 (en) * | 2009-12-23 | 2014-06-17 | Medtronic Minimed, Inc. | Ranking and switching of wireless channels in a body area network of medical devices |
US20110152970A1 (en) * | 2009-12-23 | 2011-06-23 | Medtronic Minimed, Inc. | Location-based ranking and switching of wireless channels in a body area network of medical devices |
DK2544582T3 (en) * | 2010-03-11 | 2017-03-27 | Hoffmann La Roche | Method for electrochemical measurement of an analyte concentration in vivo and fuel cell for this purpose |
US8603033B2 (en) | 2010-10-15 | 2013-12-10 | Medtronic Minimed, Inc. | Medical device and related assembly having an offset element for a piezoelectric speaker |
US8603032B2 (en) | 2010-10-15 | 2013-12-10 | Medtronic Minimed, Inc. | Medical device with membrane keypad sealing element, and related manufacturing method |
US8562565B2 (en) | 2010-10-15 | 2013-10-22 | Medtronic Minimed, Inc. | Battery shock absorber for a portable medical device |
US8495918B2 (en) | 2010-10-20 | 2013-07-30 | Medtronic Minimed, Inc. | Sensor assembly and medical device incorporating same |
US8479595B2 (en) | 2010-10-20 | 2013-07-09 | Medtronic Minimed, Inc. | Sensor assembly and medical device incorporating same |
US8474332B2 (en) | 2010-10-20 | 2013-07-02 | Medtronic Minimed, Inc. | Sensor assembly and medical device incorporating same |
US8690855B2 (en) * | 2010-12-22 | 2014-04-08 | Medtronic Minimed, Inc. | Fluid reservoir seating procedure for a fluid infusion device |
US8469942B2 (en) | 2010-12-22 | 2013-06-25 | Medtronic Minimed, Inc. | Occlusion detection for a fluid infusion device |
US8628510B2 (en) | 2010-12-22 | 2014-01-14 | Medtronic Minimed, Inc. | Monitoring the operating health of a force sensor in a fluid infusion device |
US8197444B1 (en) | 2010-12-22 | 2012-06-12 | Medtronic Minimed, Inc. | Monitoring the seating status of a fluid reservoir in a fluid infusion device |
US8900206B2 (en) | 2011-02-22 | 2014-12-02 | Medtronic Minimed, Inc. | Pressure vented fluid reservoir for a fluid infusion device |
US9393399B2 (en) | 2011-02-22 | 2016-07-19 | Medtronic Minimed, Inc. | Sealing assembly for a fluid reservoir of a fluid infusion device |
US9463309B2 (en) | 2011-02-22 | 2016-10-11 | Medtronic Minimed, Inc. | Sealing assembly and structure for a fluid infusion device having a needled fluid reservoir |
US9283318B2 (en) | 2011-02-22 | 2016-03-15 | Medtronic Minimed, Inc. | Flanged sealing element and needle guide pin assembly for a fluid infusion device having a needled fluid reservoir |
US8614596B2 (en) | 2011-02-28 | 2013-12-24 | Medtronic Minimed, Inc. | Systems and methods for initializing a voltage bus and medical devices incorporating same |
US9101305B2 (en) | 2011-03-09 | 2015-08-11 | Medtronic Minimed, Inc. | Glucose sensor product and related manufacturing and packaging methods |
US9018893B2 (en) | 2011-03-18 | 2015-04-28 | Medtronic Minimed, Inc. | Power control techniques for an electronic device |
US8564447B2 (en) | 2011-03-18 | 2013-10-22 | Medtronic Minimed, Inc. | Battery life indication techniques for an electronic device |
ES2847578T3 (en) | 2011-04-15 | 2021-08-03 | Dexcom Inc | Advanced analyte sensor calibration and error detection |
JP5592440B2 (en) * | 2011-10-05 | 2014-09-17 | 池田食研株式会社 | Glucose dehydrogenase |
US9610401B2 (en) | 2012-01-13 | 2017-04-04 | Medtronic Minimed, Inc. | Infusion set component with modular fluid channel element |
US8603027B2 (en) | 2012-03-20 | 2013-12-10 | Medtronic Minimed, Inc. | Occlusion detection using pulse-width modulation and medical device incorporating same |
US8523803B1 (en) | 2012-03-20 | 2013-09-03 | Medtronic Minimed, Inc. | Motor health monitoring and medical device incorporating same |
US8603026B2 (en) | 2012-03-20 | 2013-12-10 | Medtronic Minimed, Inc. | Dynamic pulse-width modulation motor control and medical device incorporating same |
US9180242B2 (en) | 2012-05-17 | 2015-11-10 | Tandem Diabetes Care, Inc. | Methods and devices for multiple fluid transfer |
US20130338630A1 (en) | 2012-06-07 | 2013-12-19 | Medtronic Minimed, Inc. | Diabetes therapy management system for recommending adjustments to an insulin infusion device |
US9333292B2 (en) | 2012-06-26 | 2016-05-10 | Medtronic Minimed, Inc. | Mechanically actuated fluid infusion device |
US8808269B2 (en) | 2012-08-21 | 2014-08-19 | Medtronic Minimed, Inc. | Reservoir plunger position monitoring and medical device incorporating same |
US10496797B2 (en) | 2012-08-30 | 2019-12-03 | Medtronic Minimed, Inc. | Blood glucose validation for a closed-loop operating mode of an insulin infusion system |
US9662445B2 (en) | 2012-08-30 | 2017-05-30 | Medtronic Minimed, Inc. | Regulating entry into a closed-loop operating mode of an insulin infusion system |
US9878096B2 (en) | 2012-08-30 | 2018-01-30 | Medtronic Minimed, Inc. | Generation of target glucose values for a closed-loop operating mode of an insulin infusion system |
US9623179B2 (en) | 2012-08-30 | 2017-04-18 | Medtronic Minimed, Inc. | Safeguarding techniques for a closed-loop insulin infusion system |
US10130767B2 (en) | 2012-08-30 | 2018-11-20 | Medtronic Minimed, Inc. | Sensor model supervisor for a closed-loop insulin infusion system |
US9364609B2 (en) | 2012-08-30 | 2016-06-14 | Medtronic Minimed, Inc. | Insulin on board compensation for a closed-loop insulin infusion system |
US9849239B2 (en) | 2012-08-30 | 2017-12-26 | Medtronic Minimed, Inc. | Generation and application of an insulin limit for a closed-loop operating mode of an insulin infusion system |
US8870818B2 (en) | 2012-11-15 | 2014-10-28 | Medtronic Minimed, Inc. | Systems and methods for alignment and detection of a consumable component |
US9522223B2 (en) | 2013-01-18 | 2016-12-20 | Medtronic Minimed, Inc. | Systems for fluid reservoir retention |
US9107994B2 (en) | 2013-01-18 | 2015-08-18 | Medtronic Minimed, Inc. | Systems for fluid reservoir retention |
US9033924B2 (en) | 2013-01-18 | 2015-05-19 | Medtronic Minimed, Inc. | Systems for fluid reservoir retention |
US9308321B2 (en) | 2013-02-18 | 2016-04-12 | Medtronic Minimed, Inc. | Infusion device having gear assembly initialization |
US9173998B2 (en) | 2013-03-14 | 2015-11-03 | Tandem Diabetes Care, Inc. | System and method for detecting occlusions in an infusion pump |
US8920381B2 (en) | 2013-04-12 | 2014-12-30 | Medtronic Minimed, Inc. | Infusion set with improved bore configuration |
ITMI20131096A1 (en) * | 2013-06-28 | 2014-12-29 | St Microelectronics Srl | INTEGRATED GAS SENSOR DEVICE, IN PARTICULAR FOR THE DETECTION OF CARBON MONOXIDE (CO) |
US9433731B2 (en) | 2013-07-19 | 2016-09-06 | Medtronic Minimed, Inc. | Detecting unintentional motor motion and infusion device incorporating same |
US9402949B2 (en) | 2013-08-13 | 2016-08-02 | Medtronic Minimed, Inc. | Detecting conditions associated with medical device operations using matched filters |
US9889257B2 (en) | 2013-08-21 | 2018-02-13 | Medtronic Minimed, Inc. | Systems and methods for updating medical devices |
US9880528B2 (en) | 2013-08-21 | 2018-01-30 | Medtronic Minimed, Inc. | Medical devices and related updating methods and systems |
US9259528B2 (en) | 2013-08-22 | 2016-02-16 | Medtronic Minimed, Inc. | Fluid infusion device with safety coupling |
CN103462615B (en) * | 2013-09-13 | 2015-12-16 | 上海移宇科技有限公司 | Micrometer-scale glucose sensor microelectrode |
US9750878B2 (en) | 2013-12-11 | 2017-09-05 | Medtronic Minimed, Inc. | Closed-loop control of glucose according to a predicted blood glucose trajectory |
US9750877B2 (en) | 2013-12-11 | 2017-09-05 | Medtronic Minimed, Inc. | Predicted time to assess and/or control a glycemic state |
US10105488B2 (en) | 2013-12-12 | 2018-10-23 | Medtronic Minimed, Inc. | Predictive infusion device operations and related methods and systems |
US9849240B2 (en) | 2013-12-12 | 2017-12-26 | Medtronic Minimed, Inc. | Data modification for predictive operations and devices incorporating same |
US9694132B2 (en) | 2013-12-19 | 2017-07-04 | Medtronic Minimed, Inc. | Insertion device for insertion set |
WO2015102745A1 (en) | 2013-12-31 | 2015-07-09 | Abbott Diabetes Care Inc. | Self-powered analyte sensor and devices using the same |
US9861748B2 (en) | 2014-02-06 | 2018-01-09 | Medtronic Minimed, Inc. | User-configurable closed-loop notifications and infusion systems incorporating same |
US9399096B2 (en) | 2014-02-06 | 2016-07-26 | Medtronic Minimed, Inc. | Automatic closed-loop control adjustments and infusion systems incorporating same |
CN104849317B (en) | 2014-02-18 | 2018-09-18 | 元太科技工业股份有限公司 | Semiconductor sensing device and manufacturing method thereof |
US9987422B2 (en) | 2014-03-24 | 2018-06-05 | Medtronic Minimed, Inc. | Fluid infusion patch pump device with automatic startup feature |
US10001450B2 (en) | 2014-04-18 | 2018-06-19 | Medtronic Minimed, Inc. | Nonlinear mapping technique for a physiological characteristic sensor |
US10232113B2 (en) | 2014-04-24 | 2019-03-19 | Medtronic Minimed, Inc. | Infusion devices and related methods and systems for regulating insulin on board |
US10275572B2 (en) | 2014-05-01 | 2019-04-30 | Medtronic Minimed, Inc. | Detecting blockage of a reservoir cavity during a seating operation of a fluid infusion device |
US9681828B2 (en) | 2014-05-01 | 2017-06-20 | Medtronic Minimed, Inc. | Physiological characteristic sensors and methods for forming such sensors |
US10274349B2 (en) | 2014-05-19 | 2019-04-30 | Medtronic Minimed, Inc. | Calibration factor adjustments for infusion devices and related methods and systems |
US10152049B2 (en) | 2014-05-19 | 2018-12-11 | Medtronic Minimed, Inc. | Glucose sensor health monitoring and related methods and systems |
US10007765B2 (en) | 2014-05-19 | 2018-06-26 | Medtronic Minimed, Inc. | Adaptive signal processing for infusion devices and related methods and systems |
US9839753B2 (en) | 2014-09-26 | 2017-12-12 | Medtronic Minimed, Inc. | Systems for managing reservoir chamber pressure |
US9833563B2 (en) | 2014-09-26 | 2017-12-05 | Medtronic Minimed, Inc. | Systems for managing reservoir chamber pressure |
US10279126B2 (en) | 2014-10-07 | 2019-05-07 | Medtronic Minimed, Inc. | Fluid conduit assembly with gas trapping filter in the fluid flow path |
US9833564B2 (en) | 2014-11-25 | 2017-12-05 | Medtronic Minimed, Inc. | Fluid conduit assembly with air venting features |
US10195341B2 (en) | 2014-11-26 | 2019-02-05 | Medtronic Minimed, Inc. | Systems and methods for fluid infusion device with automatic reservoir fill |
US9987420B2 (en) | 2014-11-26 | 2018-06-05 | Medtronic Minimed, Inc. | Systems and methods for fluid infusion device with automatic reservoir fill |
US9636453B2 (en) | 2014-12-04 | 2017-05-02 | Medtronic Minimed, Inc. | Advance diagnosis of infusion device operating mode viability |
US9943645B2 (en) | 2014-12-04 | 2018-04-17 | Medtronic Minimed, Inc. | Methods for operating mode transitions and related infusion devices and systems |
US9937292B2 (en) | 2014-12-09 | 2018-04-10 | Medtronic Minimed, Inc. | Systems for filling a fluid infusion device reservoir |
US10307535B2 (en) | 2014-12-19 | 2019-06-04 | Medtronic Minimed, Inc. | Infusion devices and related methods and systems for preemptive alerting |
US10265031B2 (en) | 2014-12-19 | 2019-04-23 | Medtronic Minimed, Inc. | Infusion devices and related methods and systems for automatic alert clearing |
US10307528B2 (en) | 2015-03-09 | 2019-06-04 | Medtronic Minimed, Inc. | Extensible infusion devices and related methods |
US10449298B2 (en) | 2015-03-26 | 2019-10-22 | Medtronic Minimed, Inc. | Fluid injection devices and related methods |
US9999721B2 (en) | 2015-05-26 | 2018-06-19 | Medtronic Minimed, Inc. | Error handling in infusion devices with distributed motor control and related operating methods |
US10137243B2 (en) | 2015-05-26 | 2018-11-27 | Medtronic Minimed, Inc. | Infusion devices with distributed motor control and related operating methods |
US10575767B2 (en) | 2015-05-29 | 2020-03-03 | Medtronic Minimed, Inc. | Method for monitoring an analyte, analyte sensor and analyte monitoring apparatus |
US9993594B2 (en) | 2015-06-22 | 2018-06-12 | Medtronic Minimed, Inc. | Occlusion detection techniques for a fluid infusion device having a rotary pump mechanism and rotor position sensors |
US9878095B2 (en) | 2015-06-22 | 2018-01-30 | Medtronic Minimed, Inc. | Occlusion detection techniques for a fluid infusion device having a rotary pump mechanism and multiple sensor contact elements |
US9987425B2 (en) | 2015-06-22 | 2018-06-05 | Medtronic Minimed, Inc. | Occlusion detection techniques for a fluid infusion device having a rotary pump mechanism and sensor contact elements |
US9879668B2 (en) | 2015-06-22 | 2018-01-30 | Medtronic Minimed, Inc. | Occlusion detection techniques for a fluid infusion device having a rotary pump mechanism and an optical sensor |
US10010668B2 (en) | 2015-06-22 | 2018-07-03 | Medtronic Minimed, Inc. | Occlusion detection techniques for a fluid infusion device having a rotary pump mechanism and a force sensor |
US10543314B2 (en) | 2015-08-21 | 2020-01-28 | Medtronic Minimed, Inc. | Personalized parameter modeling with signal calibration based on historical data |
US10201657B2 (en) | 2015-08-21 | 2019-02-12 | Medtronic Minimed, Inc. | Methods for providing sensor site rotation feedback and related infusion devices and systems |
US10463297B2 (en) | 2015-08-21 | 2019-11-05 | Medtronic Minimed, Inc. | Personalized event detection methods and related devices and systems |
US10293108B2 (en) | 2015-08-21 | 2019-05-21 | Medtronic Minimed, Inc. | Infusion devices and related patient ratio adjustment methods |
US20170053552A1 (en) | 2015-08-21 | 2017-02-23 | Medtronic Minimed, Inc. | Management and prioritization of the delivery of glycemic insight messages |
US10117992B2 (en) | 2015-09-29 | 2018-11-06 | Medtronic Minimed, Inc. | Infusion devices and related rescue detection methods |
US11501867B2 (en) | 2015-10-19 | 2022-11-15 | Medtronic Minimed, Inc. | Medical devices and related event pattern presentation methods |
US11666702B2 (en) | 2015-10-19 | 2023-06-06 | Medtronic Minimed, Inc. | Medical devices and related event pattern treatment recommendation methods |
US10146911B2 (en) | 2015-10-23 | 2018-12-04 | Medtronic Minimed, Inc. | Medical devices and related methods and systems for data transfer |
US10037722B2 (en) | 2015-11-03 | 2018-07-31 | Medtronic Minimed, Inc. | Detecting breakage in a display element |
US10449306B2 (en) | 2015-11-25 | 2019-10-22 | Medtronics Minimed, Inc. | Systems for fluid delivery with wicking membrane |
US10589038B2 (en) | 2016-04-27 | 2020-03-17 | Medtronic Minimed, Inc. | Set connector systems for venting a fluid reservoir |
US11097051B2 (en) | 2016-11-04 | 2021-08-24 | Medtronic Minimed, Inc. | Methods and apparatus for detecting and reacting to insufficient hypoglycemia response |
US10238030B2 (en) | 2016-12-06 | 2019-03-26 | Medtronic Minimed, Inc. | Wireless medical device with a complementary split ring resonator arrangement for suppression of electromagnetic interference |
US10272201B2 (en) | 2016-12-22 | 2019-04-30 | Medtronic Minimed, Inc. | Insertion site monitoring methods and related infusion devices and systems |
US10532165B2 (en) | 2017-01-30 | 2020-01-14 | Medtronic Minimed, Inc. | Fluid reservoir and systems for filling a fluid reservoir of a fluid infusion device |
US10500135B2 (en) | 2017-01-30 | 2019-12-10 | Medtronic Minimed, Inc. | Fluid reservoir and systems for filling a fluid reservoir of a fluid infusion device |
US10552580B2 (en) | 2017-02-07 | 2020-02-04 | Medtronic Minimed, Inc. | Infusion system consumables and related calibration methods |
US10363365B2 (en) | 2017-02-07 | 2019-07-30 | Medtronic Minimed, Inc. | Infusion devices and related consumable calibration methods |
US10646649B2 (en) | 2017-02-21 | 2020-05-12 | Medtronic Minimed, Inc. | Infusion devices and fluid identification apparatuses and methods |
US11207463B2 (en) | 2017-02-21 | 2021-12-28 | Medtronic Minimed, Inc. | Apparatuses, systems, and methods for identifying an infusate in a reservoir of an infusion device |
US11512384B2 (en) * | 2017-05-11 | 2022-11-29 | Medtronic Minimed, Inc. | Analyte sensors and methods for fabricating analyte sensors |
CN107727723A (en) * | 2017-09-29 | 2018-02-23 | 清华大学 | Ultrathin flexible glucose measuring sensor of one species skin and preparation method thereof |
US11331022B2 (en) | 2017-10-24 | 2022-05-17 | Dexcom, Inc. | Pre-connected analyte sensors |
CN111246797A (en) | 2017-10-24 | 2020-06-05 | 德克斯康公司 | Pre-attached analyte sensors |
CN111272850B (en) * | 2019-08-20 | 2024-02-13 | 深圳硅基传感科技有限公司 | Working electrode of glucose sensor |
CN114660140B (en) * | 2020-12-23 | 2024-02-23 | 北京京东方技术开发有限公司 | Biological detection device, biological chip, microelectrode structure and preparation method thereof |
Family Cites Families (75)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2899658A (en) * | 1959-08-11 | Leaf-type electrical resistance strain gage | ||
US2402950A (en) * | 1943-04-13 | 1946-07-02 | Merlyn M Culver | Molded part and method of forming same |
US2519541A (en) * | 1947-11-08 | 1950-08-22 | Fluid Control Engineering Co | Valve construction |
US4034959A (en) * | 1975-12-24 | 1977-07-12 | Acf Industries, Incorporated | Valve seal retaining means |
US4104099A (en) * | 1977-01-27 | 1978-08-01 | International Telephone And Telegraph Corporation | Method and apparatus for lapping or polishing materials |
US4163544A (en) * | 1977-11-10 | 1979-08-07 | Acf Industries, Incorporated | Two piece composite valve seal ring construction |
US4573994A (en) * | 1979-04-27 | 1986-03-04 | The Johns Hopkins University | Refillable medication infusion apparatus |
US4373527B1 (en) * | 1979-04-27 | 1995-06-27 | Univ Johns Hopkins | Implantable programmable medication infusion system |
US4783441A (en) * | 1979-04-30 | 1988-11-08 | Hoechst Aktiengesellschaft | Aqueous protein solutions stable to denaturation |
US4356074A (en) * | 1980-08-25 | 1982-10-26 | The Yellow Springs Instrument Company, Inc. | Substrate specific galactose oxidase enzyme electrodes |
US4373009A (en) * | 1981-05-18 | 1983-02-08 | International Silicone Corporation | Method of forming a hydrophilic coating on a substrate |
US4714234A (en) * | 1982-09-07 | 1987-12-22 | Greatbatch Enterprises, Inc. | Low power electromagnetic valve |
US4568250A (en) * | 1982-09-07 | 1986-02-04 | Greatbatch Enterprises, Inc. | Low power electromagnetic pump |
US4569641A (en) * | 1982-09-07 | 1986-02-11 | Greatbatch Enterprises, Inc. | Low power electromagnetic pump |
US4769013A (en) * | 1982-09-13 | 1988-09-06 | Hydromer, Inc. | Bio-effecting medical material and device |
US4636150A (en) * | 1983-05-23 | 1987-01-13 | Greatbatch Enterprises, Inc. | Low power electromagnetic pump |
US4560375A (en) * | 1983-06-30 | 1985-12-24 | Pudenz-Schulte Medical Research Corp. | Flow control valve |
US4626244A (en) * | 1985-02-01 | 1986-12-02 | Consolidated Controls Corporation | Implantable medication infusion device |
DE3610316A1 (en) * | 1985-03-29 | 1986-10-30 | Four Brain K.K., Hiroshima | BIT BASE WITH A RUBBER-LIKE ELASTIC LINING OR INSERT LAYER AND METHOD FOR THE PRODUCTION THEREOF |
US4897173A (en) * | 1985-06-21 | 1990-01-30 | Matsushita Electric Industrial Co., Ltd. | Biosensor and method for making the same |
US4890620A (en) * | 1985-09-20 | 1990-01-02 | The Regents Of The University Of California | Two-dimensional diffusion glucose substrate sensing electrode |
US5019260A (en) * | 1986-12-23 | 1991-05-28 | Pall Corporation | Filtration media with low protein adsorbability |
US4759828A (en) * | 1987-04-09 | 1988-07-26 | Nova Biomedical Corporation | Glucose electrode and method of determining glucose |
US5001009A (en) * | 1987-09-02 | 1991-03-19 | Sterilization Technical Services, Inc. | Lubricious hydrophilic composite coated on substrates |
US4950256A (en) * | 1988-04-07 | 1990-08-21 | Luther Medical Products, Inc. | Non-thrombogenic intravascular time release catheter |
US5196088A (en) * | 1988-08-05 | 1993-03-23 | Tru Vue, Inc. | Process and apparatus for producing non-glare glass by etching |
US5200051A (en) * | 1988-11-14 | 1993-04-06 | I-Stat Corporation | Wholly microfabricated biosensors and process for the manufacture and use thereof |
US5212050A (en) * | 1988-11-14 | 1993-05-18 | Mier Randall M | Method of forming a permselective layer |
US5077210A (en) * | 1989-01-13 | 1991-12-31 | Eigler Frances S | Immobilization of active agents on substrates with a silane and heterobifunctional crosslinking agent |
US5128170A (en) * | 1989-05-11 | 1992-07-07 | Kanegafunchi Kagaku Kogyo Kabushiki Kaisha | Method for manufacturing medical device having a highly biocompatible surface |
US4958661A (en) * | 1989-08-08 | 1990-09-25 | The Lee Company | Check valve |
US5330911A (en) * | 1989-09-28 | 1994-07-19 | Board Of Regents, The University Of Texas System | Surfaces having desirable cell adhesive effects |
CA2069946C (en) * | 1989-12-15 | 1999-01-26 | Klaus H. Pollmann | Redox mediator reagent and biosensor |
DE58904449D1 (en) * | 1989-12-21 | 1993-06-24 | Siemens Ag | ARRANGEMENT FOR TRANSCUTANALLY FILLING OR REFILLING LIQUID MEDICINES IN AN IMPLANTABLE MEDICINE DOSING DEVICE. |
US5108819A (en) * | 1990-02-14 | 1992-04-28 | Eli Lilly And Company | Thin film electrical component |
US5165407A (en) * | 1990-04-19 | 1992-11-24 | The University Of Kansas | Implantable glucose sensor |
US5166063A (en) * | 1990-06-29 | 1992-11-24 | Eli Lilly And Company | Immobolization of biomolecules by enhanced electrophoretic precipitation |
JP3017816B2 (en) * | 1991-02-20 | 2000-03-13 | 清原 まさ子 | Fluid controller |
EP0593561B1 (en) * | 1991-07-05 | 2000-03-22 | Biocompatibles Limited | Polymeric surface coatings |
US5168104A (en) * | 1991-09-13 | 1992-12-01 | Chembiomed, Ltd. | Macroporous particles as biocompatible chromatographic supports |
US5322063A (en) * | 1991-10-04 | 1994-06-21 | Eli Lilly And Company | Hydrophilic polyurethane membranes for electrochemical glucose sensors |
ZA938555B (en) * | 1992-11-23 | 1994-08-02 | Lilly Co Eli | Technique to improve the performance of electrochemical sensors |
US5229172A (en) * | 1993-01-19 | 1993-07-20 | Medtronic, Inc. | Modification of polymeric surface by graft polymerization |
US5308641A (en) * | 1993-01-19 | 1994-05-03 | Medtronic, Inc. | Biocompatibility of solid surfaces |
US5299571A (en) * | 1993-01-22 | 1994-04-05 | Eli Lilly And Company | Apparatus and method for implantation of sensors |
US5433710A (en) * | 1993-03-16 | 1995-07-18 | Minimed, Inc. | Medication infusion pump with fluoropolymer valve seat |
US5328954A (en) * | 1993-04-16 | 1994-07-12 | Icet, Inc. | Encrusting and bacterial resistant coatings for medical applications |
US5390691A (en) * | 1994-01-27 | 1995-02-21 | Sproule; Ronald | Bleed valve for water supply for camping vehicle |
US5390671A (en) * | 1994-03-15 | 1995-02-21 | Minimed Inc. | Transcutaneous sensor insertion set |
US5391250A (en) * | 1994-03-15 | 1995-02-21 | Minimed Inc. | Method of fabricating thin film sensors |
EP0755272B1 (en) * | 1994-04-15 | 2001-07-11 | Cobe Cardiovascular, Inc. | Biocompatible coated article |
US5482473A (en) * | 1994-05-09 | 1996-01-09 | Minimed Inc. | Flex circuit connector |
US5662960A (en) * | 1995-02-01 | 1997-09-02 | Schneider (Usa) Inc. | Process for producing slippery, tenaciously adhering hydrogel coatings containing a polyurethane-urea polymer hydrogel commingled with a poly (n-vinylpyrrolidone) polymer hydrogel |
US5568806A (en) * | 1995-02-16 | 1996-10-29 | Minimed Inc. | Transcutaneous sensor insertion set |
US5702754A (en) * | 1995-02-22 | 1997-12-30 | Meadox Medicals, Inc. | Method of providing a substrate with a hydrophilic coating and substrates, particularly medical devices, provided with such coatings |
AU5363596A (en) * | 1995-03-17 | 1996-10-08 | Regents Of The University Of Minnesota | Biocompatible materials |
US5786439A (en) * | 1996-10-24 | 1998-07-28 | Minimed Inc. | Hydrophilic, swellable coatings for biosensors |
US5882494A (en) * | 1995-03-27 | 1999-03-16 | Minimed, Inc. | Polyurethane/polyurea compositions containing silicone for biosensor membranes |
US5620738A (en) * | 1995-06-07 | 1997-04-15 | Union Carbide Chemicals & Plastics Technology Corporation | Non-reactive lubicious coating process |
US5609629A (en) * | 1995-06-07 | 1997-03-11 | Med Institute, Inc. | Coated implantable medical device |
US5607475A (en) * | 1995-08-22 | 1997-03-04 | Medtronic, Inc. | Biocompatible medical article and method |
US5672638A (en) * | 1995-08-22 | 1997-09-30 | Medtronic, Inc. | Biocompatability for solid surfaces |
US5711861A (en) * | 1995-11-22 | 1998-01-27 | Ward; W. Kenneth | Device for monitoring changes in analyte concentration |
JPH09264870A (en) * | 1996-03-28 | 1997-10-07 | Casio Comput Co Ltd | Biosensor |
US5696314A (en) * | 1996-07-12 | 1997-12-09 | Chiron Diagnostics Corporation | Multilayer enzyme electrode membranes and methods of making same |
US6013855A (en) * | 1996-08-06 | 2000-01-11 | United States Surgical | Grafting of biocompatible hydrophilic polymers onto inorganic and metal surfaces |
US5804048A (en) * | 1996-08-15 | 1998-09-08 | Via Medical Corporation | Electrode assembly for assaying glucose |
US5964993A (en) * | 1996-12-19 | 1999-10-12 | Implanted Biosystems Inc. | Glucose sensor |
FR2762054B1 (en) * | 1997-04-09 | 1999-05-21 | Pont A Mousson | METAL SLOTTED JUNC FOR LOCKED JOINT BETWEEN PIPE ELEMENTS, AND CORRESPONDING LOCKED JOINT |
US5939208A (en) * | 1997-11-07 | 1999-08-17 | Biomimetics, Inc. | Method for creation of biomimetic surfaces |
US6103033A (en) * | 1998-03-04 | 2000-08-15 | Therasense, Inc. | Process for producing an electrochemical biosensor |
US6475750B1 (en) * | 1999-05-11 | 2002-11-05 | M-Biotech, Inc. | Glucose biosensor |
US6368274B1 (en) * | 1999-07-01 | 2002-04-09 | Medtronic Minimed, Inc. | Reusable analyte sensor site and method of using the same |
US6413393B1 (en) * | 1999-07-07 | 2002-07-02 | Minimed, Inc. | Sensor including UV-absorbing polymer and method of manufacture |
US6340421B1 (en) * | 2000-05-16 | 2002-01-22 | Minimed Inc. | Microelectrogravimetric method for plating a biosensor |
-
2002
- 2002-10-18 US US10/273,767 patent/US20040074785A1/en not_active Abandoned
-
2003
- 2003-10-17 AU AU2003286473A patent/AU2003286473A1/en not_active Abandoned
- 2003-10-17 WO PCT/US2003/033065 patent/WO2004036183A2/en active Application Filing
- 2003-10-17 JP JP2004545498A patent/JP2006502810A/en active Pending
- 2003-10-17 CA CA002502277A patent/CA2502277A1/en not_active Abandoned
- 2003-10-17 EP EP03777673A patent/EP1554567A4/en not_active Withdrawn
Also Published As
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WO2004036183A2 (en) | 2004-04-29 |
AU2003286473A8 (en) | 2004-05-04 |
JP2006502810A (en) | 2006-01-26 |
AU2003286473A1 (en) | 2004-05-04 |
WO2004036183A3 (en) | 2005-03-24 |
EP1554567A2 (en) | 2005-07-20 |
WO2004036183A8 (en) | 2004-07-01 |
US20040074785A1 (en) | 2004-04-22 |
EP1554567A4 (en) | 2009-04-15 |
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