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Subcutaneous glucose electrode

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US20080210557A1
US20080210557A1 US12039576 US3957608A US2008210557A1 US 20080210557 A1 US20080210557 A1 US 20080210557A1 US 12039576 US12039576 US 12039576 US 3957608 A US3957608 A US 3957608A US 2008210557 A1 US2008210557 A1 US 2008210557A1
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glucose
layer
electrode
sensor
electrodes
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Adam Heller
Michael V. Pishko
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Abbott Laboratories
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Abbott Laboratories
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    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12QMEASURING OR TESTING PROCESSES INVOLVING ENZYMES OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/001Enzyme electrodes
    • C12Q1/005Enzyme electrodes involving specific analytes or enzymes
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12QMEASURING OR TESTING PROCESSES INVOLVING ENZYMES OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/001Enzyme electrodes
    • C12Q1/002Electrode membranes
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00Chemistry: molecular biology and microbiology
    • Y10S435/817Enzyme or microbe electrode

Abstract

A small diameter flexible electrode designed for subcutaneous in vivo amperometric monitoring of glucose is described. The electrode is designed to allow “one-point” in vivo calibration, i.e., to have zero output current at zero glucose concentration, even in the presence of other electroreactive species of serum or blood. The electrode is preferably three or four-layered, with the layers serially deposited within a recess upon the tip of a polyamide insulated gold wire. A first glucose concentration-to-current transducing layer is overcoated with an electrically insulating and glucose flux limiting layer (second layer) on which, optionally, an immobilized interference-eliminating horseradish peroxidase based film is deposited (third layer). An outer (fourth) layer is biocompatible.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • [0001]
    This application is a Continuation of application Ser. No. 11/109,379, filed on Apr. 19, 2005, which is a Continuation application of Ser. No. 10/353,341, filed Jan. 28, 2003, now U.S. Pat. No. 6,881,551, which is a Continuation application of Ser. No. 09/997,808, filed Nov. 29, 2001, now U.S. Pat. No. 6,514,718, which is a Continuation application of Ser. No. 09/668,221, filed Sep. 22, 2000, now U.S. Pat. No. 6,329,161, which is a Continuation of application Ser. No. 09/477,053, filed Jan. 3, 2000, now U.S. Pat. No. 6,162,611, which is a Continuation of application Ser. No. 09/356,102, filed Jul. 16, 1999, now U.S. Pat. No. 6,121,009, which is a Continuation of application Ser. No. 08/767,110, filed Dec. 4, 1996, now U.S. Pat. No. 6,284,478, which is a continuation of application Ser. No. 08/299,526, filed Sep. 1, 1994, now U.S. Pat. No. 5,593,852, which is a continuation-in-part of application Ser. No. 08/161,682, filed Dec. 2, 1993, now U.S. Pat. No. 5,356,786, which is a continuation of application Ser. No. 07/664,054, filed Mar. 4, 1991, now abandoned, which applications are incorporated herein by reference.
  • STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
  • [0002]
    This work was supported in part by the National Institutes of Health (DK42015). Accordingly, the U.S. government may have rights in this invention.
  • FIELD OF THE INVENTION
  • [0003]
    The present invention relates to in vivo enzyme biosensors and more specifically to miniature glucose sensors for subcutaneous measurement of glucose with one-point calibration.
  • BACKGROUND
  • [0004]
    In response to the need for frequent or continuous in vivo monitoring of glucose in diabetics, particularly in brittle diabetes, a range of possible in vivo glucose electrodes have been studied. The desired characteristics of these electrodes include safety, clinical accuracy and reliability, feasibility of in vivo recalibration, stability for at least one hospital shift of eight hours, small size, ease of insertion and removal, and a sufficiently fast response to allow timely intervention. The in vivo recalibration should be based upon withdrawal of a single sample of body fluid, e.g., blood, and measuring its glucose concentration. This is termed “one point calibration”.
  • [0005]
    Keys to safety are absence of leachable components, biocompatibility, and limiting of the potentially hazardous foreign matter introduced into the body to an amount that is inconsequential in a worst case failure. The clinical accuracy must be such that even when the readings are least accurate, the clinical decisions based on these be still correct. Feasibility of prompt confirmation of proper functioning of the sensors and of periodic in vivo recalibration is of essence if a physician is to allow the treatment of a patient to depend on the readings of the sensor. This one-point calibration, relying on the signal at zero glucose concentration being zero and measuring the blood glucose concentration at one point in time, along with the signal, is of essence, but has heretofore been elusive. The sensitivity must be sufficiently stable for the frequency of required in vivo recalibration to not be excessive. The sensor must be small enough to be introduced and removed with minimal discomfort to the patient and for minimal tissue damage. It is preferred that the sensor be subcutaneous and that it be inserted and removed by the patient or by staff in a physician's office. Finally, its response time must be fast enough so that corrective measures, when needed, can be timely.
  • [0006]
    In response to some of these needs, needle type and other subcutaneous amperometric sensors were considered. The majority of these utilized platinum-iridium, or platinum black to electrooxidize H2O2 generated by the glucose oxidase (GOX) catalyzed reaction of glucose and oxygen. In these sensors, the GOX was usually in large excess and immobilized, often by crosslinking with albumin and glutaraldehyde. To exclude electrooxidizable interferants, membranes of cellulose acetate and sulfonated polymers including Nafion™ were used. Particular attention was paid to the exclusion of the most common electrooxidizable interferants: ascorbate, urate and acetaminophen. Also to cope with the interferants, two-electrode differential measurements were used, one electrode being sensitive to glucose and electrooxidizable interferants and the other only to interferants. One strategy for overcoming the problem of interferants, applicable also to the present invention, involves their preoxidation. Another strategy involves shifting, through chemical changes, the redox potential of the polymer in the sensing layer to more reducing potentials. When the redox potential of the polymer is in the region between about −0.15 V and +0.15 V versus the standard calomel electrode (SCE), and the electrodes are poised in their in vivo operation between about −0.10 and +0.25 V, the rate of electrooxidation of interferants such as ascorbate, urate, and acetaminophen is very slow relative to that of glucose through its physiological concentration range. Thus, also the currents from electrooxidation of interferants are small relative to those of glucose.
  • [0007]
    To make the electrodes more biocompatible, hydrophilic polyurethanes, poly(vinyl alcohol) and polyHEMA membranes have been used.
  • [0008]
    Several researchers tested GOX-based glucose sensors in vivo and obtained acceptable results in rats, rabbits, dogs, pigs, sheep and humans. These studies validated the subcutaneous tissue as an acceptable glucose sensing site. Good correlation was observed between intravascular and subcutaneous glucose concentrations. They also demonstrated the need for in vivo sensor calibration. Another approach to in vivo glucose monitoring was based on coupling subcutaneous microdialysis with electrochemical detection. To control and adjust the linear response range, electrodes have been made glucose-diffusion limited, usually through glucose transport limiting membranes.
  • [0009]
    Diffusional mediators, through which the O2 partial pressure dependence of the signals is reduced, are leached from sensors. Such leaching introduces an unwanted chemical into the body, and also leads to loss in sensitivity, particularly in small sensors. In microsensors, in which outward diffusion of the mediator is radial, the decline in sensitivity is rapid. This problem has been overcome in “wired” enzyme electrodes, i.e., electrodes made by connecting enzymes to electrodes through crosslinked electron-conducting redox hydrogels (“wires”). Glucose oxidase has been “wired” with polyelectrolytes having electron relaying [Os(bpy)2Cl]+/2+ redox centers in their backbones. Hydrogels were formed upon crosslinking the enzyme and its wire on electrodes. These electrodes had high current densities and operated at a potential of 0.3V vs. SCE. The electrooxidizable interferants are eliminated through peroxidase-catalyzed preoxidation in a second, nonwired, hydrogen peroxide generating layer on the “wired” enzyme electrode.
  • SUMMARY OF THE INVENTION
  • [0010]
    A small (e.g., 0.29 mm), recessed, non-corroding metal (e.g., gold, platinum, palladium) or carbon wire electrode for subcutaneous in vivo glucose monitoring, approaching in its performance all of the above listed requirements, including in vivo one-point calibration, has been produced. The electrode was constructed by depositing active polymer layers into a recess formed by etching away gold from an insulated gold wire.
  • [0011]
    The active polymer layers, including a sensing layer, a glucose flux-limiting layer, a biocompatable layer, and optionally a peroxidase-based interferant eliminating layer, were protected within the recess against mechanical damage. (The peroxidase-based interferant eliminating layer is not required when a lower redox potential polymer is used, as described above.) The recess and its polymer layers also reduced the transport of glucose to the wire electrode contacting sensing layer.
  • [0012]
    By limiting the glucose flux, the desired linear response range, spanning the clinically relevant glucose concentration range was obtained. The inventive biosensors are able to accurately measure, for example, approximately 2-30 mμ glucose and approximately 0.5-10 mμ lactate, in vivo. The sensor has no leachable components, and its four crosslinked polymer layers contain only about 5 μg of immobilized material, and only a few nanograms of polymer-bound osmium. Preoxidation of the interferants in one of the four layers makes possible one-point in vivo calibration of the sensor.
  • BRIEF DESCRIPTION OF THE FIGURES
  • [0013]
    FIG. 1 is a schematic drawing of an electrode of the present invention.
  • [0014]
    FIG. 2 is a graphical representation of data generated comparing current density of glucose electrooxidation on electrodes made with PVI5-Os (open triangles) with those made with PVI3-Os (filled triangles).
  • [0015]
    FIG. 3 is a graphical representation of data generated comparing dependency of current generated on the depth of the recess.
  • [0016]
    FIG. 4 is a graphical representation of data generated comparing dependency of the ratio of the current generated and the charge required to electroreduce or oxidize the polymer redox centers in the sensing layer on the thickness of the sensing layer.
  • [0017]
    FIG. 5 is a graphical representation of data generated comparing variation of current generated by electrodes having sensing layers of differing thickness and diffusion limiting layers of different compositions and thickness. Solid circles: 7.5 μm thick sensing layer of PVI5-Os (52%), rGOX (35%), PEGDGE (13%), coated with 4 μm PAL/PAZ (1:1 ratio). Open circles: 5.0 sensing layer. Solid triangles: 12.5 μm sensing layer and 7 μm PAL/PAZ (1:2 ratio). Open triangles: 7.5 μm sensing layer and 4.5 μm PAL/PAZ (1:2 ratio).
  • [0018]
    FIG. 6 is a graphical representation of data generated comparing dependency of current generated on the presence of ascorbate, in the absence and presence of lactate and glucose. The concentrations of ascorbate (A), lactate (L) and glucose (G) are shown. Ascorbate is an electrooxidizable interferant. Upon addition of lactate its electrooxidation current is suppressed while that of glucose is not suppressed.
  • [0019]
    FIG. 7 is a graphical representation of data showing current density and corresponding subcutaneous glucose concentration measured with the subcutaneously implanted electrodes of the present invention in a rat animal model. Large solid circles show blood glucose concentrations measured on withdrawn blood samples using a YSI analyzer.
  • [0020]
    FIG. 8 is a Clarke-type clinical grid analyzing the clinical relevance of the blood glucose measurements of FIG. 7.
  • [0021]
    FIG. 9 is a Clarke-type clinical grid of all possible correlations obtained when each of the 24 glucose analyses of FIG. 7 were used for single point calibration of either implanted electrode.
  • [0022]
    FIG. 10 is a Clarke-type clinical grid testing improvement of the single point calibration through redundant electrodes, the readings of which were within the standard deviation calculated for all differences between simultaneous readings by a pair of implanted electrodes.
  • DETAILED DESCRIPTION OF THE INVENTION
  • [0023]
    The present invention includes an insulated, non-corroding conducting metal (e.g., gold, platinum, palladium) or carbon wire-based small (e.g., 290 μm) O.D. subcutaneous glucose sensor, allowing one-point calibration in vivo. As shown in FIG. 1, its construction involves coating a small (e.g., 250 μm) diameter non-corroding metal or carbon wire 2 with an electrically insulating material 4, e.g., a polyimide, and, layering in a recess 6 formed by etching or removing a portion of the metal or carbon, the following active polymeric layers: an immobilized, “wired,” glucose oxidase layer 8; an electrically insulating and glucose diffusion limiting layer 10 formed, for example, by crosslinking a polyallylamine (PAL) with a polyaziridine (PAZ); optionally, an interference eliminating layer 12, e.g., of crosslinked horseradish-peroxidase and lactate oxidase; and a biocompatible film 14 e.g., of poly(ethylene oxide) (PEO) derivatized to allow its photo-crosslinking. The outside diameter a of the wire 2 is preferably about 0.25 mm or less, and the outside diameter b of the insulated wire is preferably about 0.3 mm or less. The recess 6 in the insulated electrode extends from the tip 16 of the electrode which is open to the surrounding environment, to the top 18 of the wire 2 in the insulating sheath, generally for a length c of less than about 0.150 mm, and preferably about 0.125 mm.
  • [0024]
    The electrodes have no leachable components. The total amount of polymers and enzymes is preferably about 5 μg. The glucose response through the physiologically relevant 2-20 mM concentration range is close to linear. The electrodes do not respond to ascorbate, urate or acetaminophenol for at least about 36 hours. Their 10-90% response time is about 90 seconds at 2 mM glucose and about 30 seconds at 20 mM glucose. Their sensitivity, after about 30 minutes equilibration, is stable for about 72 hours at 37° C. in 10 mM glucose, the current deviating from the average by less than .+−0.5%. The electrodes have substantially no signal output, e.g., current, charge, or potential, when the concentration of the analyte to be measured is zero.
  • [0025]
    Two electrodes implanted subcutaneously in a rat tracked blood glucose levels, and their absolute, uncorrected current output was proportional to the blood glucose concentration. Analysis of the correlation between the blood glucose levels in the tail vein and the current output of the sensors in the subcutaneous regions of the thorax and between the scapulae of the same rat showed that even when the probed sites and organs differed in the extreme, one point in vivo calibration was valid. The analysis also showed the value of implanting redundant sensors. Had clinical decisions been made based on individual sensor readings, calibrated at one point, 94% would have been clinically correct. By using redundant sensors and accepting only those pairs of readings that were within one standard deviation, the percentage of the clinically correct decisions was increased to 99%.
  • [0026]
    It is understood that one of skill in the art may substitute various components of the biosensor described above with known materials to obtain an modified biosensor using the principles outlined herein. For example, the following substitutions are contemplated:
  • [0027]
    Base electrode: The base electrode of the inventive sensor may be formed of a non-corroding metal or carbon wire, for example vitreous carbon, graphite, platinum, palladium, or gold. Gold is preferred, and is used in the following illustrative examples of the invention.
  • [0028]
    Insulator: The conductive metal or carbon wire is coated with an electrically insulating material, which also forms a wall about the recess which houses the active polymeric components. The insulating material may be, for example, polyurethane, teflon (fluorinated polymers), polyethyleneterephthalate (PET, Dacron) or polyimide. The insulating material is preferably a biocompatible polymer containing less than about 5% water when in equilibrium with physiological body fluids, e.g., subcutaneous tissue.
  • [0029]
    Recess: In general, the recess at the tip of the electrode is approximately 20 to 150 μm in length c, and preferably is approximately 50 to 125 μm.
  • [0030]
    Etching method: The method for etching metal from the tip of the electrode described herein may utilize chloride, bromide or iodide in the bath in lieu of cyanide as described. Bromide is preferred, because it is less toxic and, like Au(CN)2 , AuBr4 is a water soluble anion. Thus, in aqueous HBR, the metal, e.g., gold, an be etched by applying a sufficiently oxidizing potential where gold is electrolytically dissolved:
  • [0000]

    Au+4HBr→HAuBr4+(3/2)H2
  • [0031]
    Wired Enzyme Layer: In the sensing enzyme-containing layer, glucose oxidase may be substituted with other redox enzymes to measure other relevant clinical compounds. For example, lactate oxidase may be used for the in vivo detection of lactate, important in determining if an organ is receiving sufficient oxygen through the blood.
  • [0032]
    Useful redox polymers and methods for producing the sensing layer are described, for example, in U.S. Pat. Nos. 5,264,104; 5,356,786; 5,262,035, and 5,320,725. Additional redox polymers include, for example, poly(1-vinyl imidazole); poly(4-vinyl pyridine); or copolymers of 1-vinyl imidazole such as poly (acrylamide co-1-vinyl imidazole) where the imidazole or pyridine complexes with [Os(bpy)2Cl]+/2+; [Os(4,4′-dimethyl bipyridine)2Cl]+/2+; [Os(4,4′-dimethyl phenanthroline)2Cl—]+/2+; [Os(4,4′-dimethyoxy phenanthroline)2Cl]+/2+; and [Os(4,4′-dimethoxy bipyridine)2Cl]+/2+; to imidazole rings. The imidazole ring compounds are preferred because their complexes have more reducing redox potentials, i.e., closer to that of the SCE potential. At these more reducing potentials, the rate of electrooxidation of interferants and the current generated thereby.
  • [0033]
    Barrier Layer: The polymeric barrier layer is electrically insulating and limits diffusion of glucose through to the sensing layer. It may be formed, for example, by crosslinking a polyallylamine (PAL) with a polyaziridine (PAZ). Alternatively, PAL may be replaced wholly or in part with a zwitterionic polymer obtained by quaternizing poly(vinylpyridine) with bromoacetate and dialyzing against 0.15M NaCl or by a polyanion such as a polysulfonic acid.
  • [0034]
    The barrier layer may contain a polyanionic polymer, in which the rate of permeation of anionic interferants such as ascorbate and urate is slowed. This layer may also contain a polycation that enhances the retention of the polyanion by electrostatic bonds and improves wetting by the biocompatable layer.
  • [0035]
    Interference Eliminating Layer: As described above, this layer is optional, in that it is not required when a redox polymer having a more reducing potential is used, such as PVI15-dmeOs (Ohara et al., Analytical Chemistry, 1994, 64:2451-2457). At operating potentials of approximately −0.10 to +0.25 for the glucose biosensor, the rate of electrooxidation of interferants such as ascorbate, urate and acetaminophen is very slow relative to that of glucose through its physiological concentration range.
  • [0036]
    When a separate interferant eliminating layer is used, it preferably contains a peroxidase enzyme which may or may-not be preactivated. Such interferant eliminating layers are disclosed, for example, in U.S. Pat. No. 5,356,786, which discloses the structure and function of interferant eliminating biosensors. The glucose biosensor preferably contains lactate oxidase (LOX) in combination with peroxidase in the interferant eliminating layer. However, for biosensors used to detect lactate, glucose oxidase would be used with peroxidase. In a similar manner, the enzyme composition of the interferant eliminating layer may be altered for a specified function.
  • [0037]
    Biocompatable Layer: In general, the biocompatable layer is comprised of hydrogels, e.g., polymeric compositions which contain more than about 20% by weight of water when in equilibrium with a physiological environment such as living tissue or blood. An example is crosslinked poly(ethylene oxide), e.g., poly(ethylene oxide)tetraacrylate. The polymeric compositions must be non-toxic and compatible with living Systems.
  • [0038]
    Method for making multi-layered recessed biosensors: Insulated non-corroding metal or carbon wires that have been etched as described above to contain a recess at the tip, are placed in a block that serves as an X-Y positioner. The wires vertically traverse the block and are held in place, e.g., by pressure. The blocks with the wires can be formed of elements, each element having multiple half-cylinder grooves running vertically. The wires are placed in these grooves and the elements are assembled into the block using screws. For example, the block may be formed of aluminum having equally spaced holes, (900 for a 30×30 array of wires), each hole to contain one wire. The block is positioned under a fixed micronozzle that ejects a fluid in to the recess of the insulated wire.
  • [0039]
    To reduce the requirement of precision in the positioning of the block and the micronozzle, the nozzle is electrically charged, with the wire having an opposite charge, or the wire being grounded or at least having a potential such that there is a potential difference between the nozzle and the wire. Because the nozzle is charged, the microdroplets it ejects are also charged with the same type of charge (positive or negative) as the nozzle. The higher the potential on the nozzle (e.g., versus ground potential), the higher the charge on the ejected microdroplets. If the tip of the wire to be coated is at ground potential or has a charge of the opposite type, the charged microdroplets are guided into the recess to deposit on the electrode, even if the jet of microdroplets is not vertical, i.e., even if the micronozzle is not precisely aligned above the wire's tip.
  • [0040]
    Furthermore, the higher the electrical potential on the nozzle (relative to ground) the greater the charge on the ejected microdroplet. When the charge is high enough, the droplet breaks up into two or more smaller droplets because of electrostatic repulsion of charges on the droplet. Thus, the very small droplets all “drift” (drift meaning transport assisted by an electrical field) to the recessed electrode surface and are collected on it, even if they did not originate in a nozzle precisely aligned with the electrode.
  • [0041]
    This coating method is useful in making any small biosensor, not only those in recessed zones.
  • [0042]
    Clinical Use of the Recessed Biosensors:
  • [0043]
    The recessed biosensors of the present invention have sufficient sensitivity and stability to be used as very small, subcutaneous biosensors for the measurement of clinically relevant compounds such as glucose and lactate. The electrodes accurately measure glucose in the range of about 2-30 μM and lactate in the range of about 0.5-10 mM. One function of the implanted biosensor is to sound an alarm when, for example, a patient's glucose concentration is too low or too high. When pairs of implanted electrodes are used, there are three situations in which an alarm is triggered: low glucose concentration, high glucose concentration; sensor malfunction as determined by a discrepancy between paired readings of the two sensors. A discrepancy sufficient to trigger the alarm may be, for example more than two or three times the standard deviation persisting for a defined period, e.g., not less than ten minutes. Such a system may be useful in sleeping patients, and also in emergency and intensive care hospital rooms, where vital functions are continuously monitored.
  • [0044]
    Another function of the inventive biosensors in to assist diabetics in maintaining their blood glucose levels near normal. Many diabetics now maintain higher than normal blood glucose levels because of danger of coma and death in severe hypoglycemia. However, maintaining blood glucose levels substantially, e.g., approximately 40% or more above normal leads to retinopathy and blindness as well as to kidney failure. Use of the subcutaneous biosensors to frequently, if not continuously, monitor glucose concentrations is desirable so that glucose concentrations can be maintained closer to an optimum level.
  • [0045]
    The subcutaneous biosensors can be used to measure the rate of rise and decline of glucose concentrations after a meal or the administration of glucose (e.g., a glucose tolerance test). The sensors are also useful in feedback loops for automatic or manually controlled maintenance of glucose concentrations within a defined range. For example, when used in conjunction with an insulin pump, a specified amount of insulin is delivered from the pump if the sensor glucose reading is above a set value.
  • [0046]
    In all of these applications, the ability to promptly confirm that the implanted sensor reading is accurate is essential. Prompt confirmation and rapid recalibration are possible only when one-point calibration is valid. Generally, even if a sensor's response is linear through the relevant concentration range, calibration requires at least two blood or fluid samples, withdrawn from the patient at times when the glucose concentration differs. It usually takes several hours for the glucose concentration to change sufficiently to validate proper functioning by two-point calibration. The ability to confirm and recalibrate using only one point is thus a highly desirable feature of the present invention.
  • [0047]
    Redundant sensors (e.g., at least two) are preferred in the clinical application of the subcutaneous biosensors. Such redundancy permits signaling of failure of any one sensor by recognition of an increase in the discrepancy between the readings of the sensors at one time point, e.g., more than two standard deviations apart. The redundant sensors may be implanted near each other or at remote sites.
  • [0048]
    It is preferred that the biosensors be implanted in subcutaneous tissue so as to make the sensor relatively unobtrusive, and at a site where they would not be easily dislodged, e.g., with turning or movement. It is also preferred, when readings are not corrected for temperature (which they generally are) that the sensors be implanted where they are likely to be at body temperature, e.g., near 37° C., and preferably covered by clothing. Convenient sites include the abdomen, inner thigh, arm.
  • [0049]
    Although we describe here continuous current measurement for assaying glucose, the electrical measurement by which the glucose concentration is monitored can be continuous or pulsed. It can be a current measurement, a potential measurement or a measurement of charge. It can be a steady state measurement, where a current or potential that does not substantially change during the measurement is monitored, or it can be a dynamic measurement, e.g., one in which the rate of current or potential change in a given time period is monitored. These measurements require at least one electrode in addition to the sensing electrode. This second electrode can be placed on the skin or can be implanted, e.g., subcutaneously. When a current is measured it is useful to have a potentiostat in the circuit connecting the implanted sensing electrode and the second electrode, that can be a reference electrode, such as an Ag/AgCl electrode. When a current is measured the reference electrode may serve also as the counter electrode. The counter electrode can also be a separate, third electrode, such as a platinum, carbon, palladium or gold electrode.
  • [0050]
    In addition to implanting the sending electrode in the body, fluid from the body, particularly fluid from the subcutaneous region, can be routed to an external sensor. It is preferred in this case to implant in the subcutaneous region a microfiltration giver and pull fluid to an evacuated container, the fluid traversing a cell containing the sensing electrode. Preferably this cell also contains a second electrode, e.g., a reference electrode which may serve also as a counter electrode. Alternatively, the reference and counter electrodes may be separate electrodes. In coulometric measurements only two electrodes, the sensing electrode and the counter electrode are required. The flow of body fluid may be pulsed or continuous. Other than an implanted microfiltration fiber, also a microdialysis fiber may be used, preferably in conjunction with a pump.
  • [0051]
    Increased Stability of the Biosensors:
  • [0052]
    To increase the stability and useful life of the inventive biosensors, it is advantageous to use intrinsically more stable enzymes and redox polymers. However, even if the enzyme and redox polymer degrade in the glucose electrooxidation process by which the signal (current) is generated, it is possible to greatly extend the useful life of the implanted electrodes and reduce the frequency of their required recalibration after implantation.
  • [0053]
    A simple measure by which the life of the implanted electrodes can be extended and the frequency of their required recalibration reduced involves turning the electrodes “on” by applying a bias, i.e., a potential, only during the period of measurement, then turning the biasing potential off or reducing it, so that a lesser current will flow. It is generally sufficient to perform only one measurement every five or even ten minutes, or longer, because glucose concentrations do not change abruptly.
  • [0054]
    Another measure is to lower the glucose flux to the sensing layer much as possible, consistent with maintaining adequate sensitivity and detectivity. Reduction of the glucose flux to the sensing layer reduces the current. Therefore, even though this stabilizes the electrodes, i.e., slows the loss in sensitivity, the flux dependent current must not be excessively reduced. Usually a current of 3-5 nA at 2 mM glucose concentration is adequate. When the glucose flux is lowered by using one or more glucose-flux reducing polymer slayers, such as the PAL/PAZ layer, the lifetime of the sensor is increased.
  • EXAMPLES Example 1 Electrode Preparation
  • [0055]
    Electrodes were made of a polyamide-insulated 250 μm diameter gold wire, having an outer diameter (O.D.) of 290 μm (California Fine Wire Co., Grover City, Calif.). Heat shrinkable tubing (RNF 100 3/64″ BK and 1/16″ BK, Thermofit.RTM., Raychem, Menlo Park, Calif.) and a two component silver epoxy (Epo-tek H2OE; Epoxy Tech, Inc., Billerica, Mass.) were used for electrode preparation.
  • [0056]
    The glucose sensing layer was made by crosslinking a genetically engineered glucose oxidase (rGOX) (35% purity, Chiron Corp., Emeryville, Calif.) with a polymer derived of poly(vinylimidazole) (PVI), made by complexing part of the imidazoles to [Os(bpy)2Cl]+/2+. The resulting redox polymer, termed PVI-Os, was synthesized according to a previously published protocol. (Ohara et al., 1993, Anal. Chem., 65:24). Poly(ethylene glycol) diglycidyl ether 400 (PEDGE; Polysciences, Warrington, Pa.) was used as the crosslinker.
  • [0057]
    The barrier layer between the sensing and interference-eliminating layers was made of polyallylamine (PAL; Polysciences) crosslinked with a polyfunctional aziridine (PAZ) (XAMA-7; Virginia Chemicals, Portsmouth, Va.).
  • [0058]
    The interference-eliminating layer was prepared by co-immobilizing horseradish peroxidase (HRP) type VI (Cat. No. P-8375, 310 U/mg, denoted herein as HRP-VI, Sigma, St. Louis, Mo.) and HRP for immunological assay (No. 814407, min 1000 U/mg, denoted HRP-BM, Boehringer-Mannheim, Indianapolis, Ind.) with lactate oxidase from Pediococcus sp. (Cat. No. 1361, 40 U/mg denoted LOX, Genzyme, Cambridge, Mass.) and a recombinant microbial source (Cat. No. 1381 denoted rLOX, Genzyme). Co-immobilization was performed using sodium periodate (Cat. No. S-1147, Sigma) according to the methods described in Maidan and Heller, 1992, Anal. Chem. 64:2889-2896.
  • [0059]
    The biocompatible layer was made of 10% aqueous poly(ethylene oxide) tetraacrylate (PEO-TA). To form the photocrosslinkable polymer, PEO was acrylated by reaction with acryloyl chloride. The 18,500 g/mol PEO (Polysciences) is a tetrahydroxylated compound by virtue of two hydroxyl groups on a bisphenol A bisepoxide that linked two alpha., .omega.-hydroxy-terminated 9,000 g/mol PEO units. Acryloyl chloride (Aldrich, Milwaukee, Wis.) in a 2 to 5 molar excess was used to acrylate the polymer (10% w/v PEO in benzene). Triethylamine (Mallinkrodt, Paris, Ky.) was used as a proton acceptor equimolar with theacryloyl chloride.
  • [0060]
    Other chemicals used were bovine serum albumin (BSA) fraction V (Cat. No. A-2153), BSA, ascorbic acid, uric acid, 4-acetaminophenol, L(+)=lactic acid, and hydrogen peroxide 30%., all from Sigma. All chemicals were used as received. Solutions (if not otherwise specified) were made with distilled, deionized water. Glucose monitoring was performed in buffer, in bovine serum (Sigma, Cat. No. S-6648) containing antibiotic-antimycotic solution (Sigma, Cat. No. A-8909) at 37° C. and in rats.
  • [0061]
    Instrumentation
  • [0062]
    In making the recessed gold electrodes, a potentiostat/galvanostat (PAR Model 173, Princeton Applied Research, Princeton, N.J.) operated in a galvanostatic mode, and a sonicator (Fisher scientific, Pittsburgh, Pa.) were used. Cyclic voltammograms were recorded with a potentiostat (PAR Model 273A) and a conventional electrochemical cell having a Pt wire counter and a SCE reference electrode and were evaluated with PAR 270 software. Glucose signals were monitored with a bipotentiostat (Biometra EP 30) and a two channel strip-chart recorder. The recessed electrodes were coated under a microscope (Bausch & Lomb) using a micromanipulator (Narishige, Seacliff, N.Y.). The micropipettes were pulled with a micropipette puller (Narishige). Temperature was controlled with an isothermal circulator (Fisher Scientific).
  • [0063]
    Electrode Preparation:
  • [0064]
    Five cm lengths of polyamide insulated gold wire were cut with a sharp razor blade. Electrical contact was made at one end with silver epoxy to an insulated stainless steel wire and the junction was covered with insulating heat shrinkable tubing. The recess forming electrochemical etching process was carried out in 10 ml of 3M potassium cyanide, with the gold wire as the working electrode and a platinum or gold wire as the counter electrode. The wires were placed in contact with the bottom of the beaker, all electrodes being equidistant from the counter electrode. The beaker was sonicated during the etching procedure. The ends of the gold wires were bent upwards, so that agitation by the sonicator caused the oxygen bubbles formed during the etching process to rise and escape. The electrodes were then thoroughly washed and immersed in water for 30 minutes.
  • [0065]
    A recess 6, i.e., channel, in a polyamide insulated gold wire 2 is formed by electrochemical etching of the gold under galvanostatic control. By controlling the charge, the total amount of gold electrooxidized and dissolved as Au(CN)2 is defined.
  • [0066]
    When the conditions were set so that the CN— transport into the channel and the Au(CN)2— transport out of it are not rate limiting, (e.g., sonicated bath and high concentration of potassium cyanide, at least approximately 0.2M, and preferably 3M), a flat gold wire surface is produced at the bottom of channels with aspect ratios of 0.5 to 2.0. Thus, when the CN— concentration is high enough and the wires are ultrasonically vibrated, the tips of gold wires are flat. Passage of 1.5 coulombs per electrode at 8 mA current produced approximately 125 μm deep cavities or channels. At theoretical efficiency for one-electron oxidation, 3.08 mg of gold would have been etched. The amount of gold actually etched was only 0.076 mg, showing significant CN— or water oxidation.
  • [0067]
    Nevertheless, the process is reproducible, accurate and fast with 20 electrodes being processed in each batch in less than five minutes. The recess-forming procedure was highly reproducible, with a deviation of +−10 μm found (using an objective micrometer) for a batch of 30 recessed electrodes. Before coating, the electrodes were examined under a microscope for flatness of the gold surface and correct depth.
  • [0068]
    FIG. 1 shows a schematic side view in cross-section of an electrode of the present invention, showing the gold wire 2, insulating coating 4, and recess or channel 6. The recessed gold surfaces were coated by filling of the cavities or channels 6 with aqueous solutions containing the crosslinkable components of the different layers, and their crosslinkers. The solutions were introduced under a microscope with a micropipette (connected to a microsyringe by polyethylene tubing and shrink tubing), using a micromanipulator. After application of each of the individual layers, the electrodes were cured overnight at room temperature, in air.
  • [0069]
    Electrode Structure:
  • [0070]
    The electrodes were prepared by sequentially depositing four layers within the recess or channel 6. The layers were: the sensing layer 8, the insulating layer 10, the interference-eliminating layer 12 and the biocompatible layer 14. The sensing layer, containing “wired” redox enzyme is positioned adjacent to and in contact with the gold wire 2. The insulating layer 10 is positioned between the sensing layer 8 and the peroxidase-based interferant-eliminating layer 12. The biocompatible layer 14 fills the remaining space in the recess 6 and is in contact with the environment outside the electrode. The thin polymer layers are well protected by containment within the polyamide sleeve 4.
  • [0071]
    The sensing layer 8 was made by “wiring” rGOX to the gold electrode through a redox hydrogel to which the enzyme was covalently bound. The electrodes were prepared as follows: 10 mg/ml solutions were made from
  • [0072]
    1. the PVI-Os redox polymer in water,
  • [0073]
    2. the crosslinker, PEGDGE, in water, and
  • [0074]
    3. the enzyme, rGOX, in a 10 mM HEPES solution adjusted to pH 8.15.
  • [0075]
    A redox hydrogel was formed by mixing the three solutions so that the final composition (by weight) was 52% redox polymer, 35% enzyme and 13% crosslinker.
  • [0076]
    The insulating layer 10 prevented electrical contact between the redox hydrogel and the interference eliminating enzymes (HRP and LOX). PAL:PAZ was used as the insulating material. The film was deposited from a solution obtained by mixing in volume ratio of 1/1, ½ or ⅓, a PAL solution (4.5 mg in 100 mM HEPES buffer at pH 7.0) and a freshly prepared PAZ solution (30 mg/ml). The PAZ solution was used within 15 minutes of preparation.
  • [0077]
    The interference-eliminating layer 12 was prepared according to a previously published protocol, Maidan and Heller, 1992, Anal. Chem., 64:2889-2896. 50 μl of a 12 mg/ml freshly prepared sodium periodate solution was added to 100 μl of a solution containing 20 mg/ml HRP (HRP-VI or HRP-BM) and 100 mg/ml LOX (LOX or rLOX) in 0.1 M sodium bicarbonate and the mixture was incubated in the dark for two hours. Alternatively, the oxidation of HRP could be carried out prior to adding LOX and crosslinking.
  • [0078]
    The biocompatible layer 14 films were photocrosslinked by exposure to UV light (UVP, Inc., San Gabriel, Calif.; Blak-Ray; spectral peak at 360 nM UV irradiance at the sample 200 mW/cm2) for one minute. The initiator used was 2,2-dimethoxy-2-phenylacetophenone (Aldrich). A solution of 300 mg/ml of the initiator in 1-vinyl-2-pyrrolidinone (Aldrich) was added to the prepolymer mixtures. Approximately 30 μl of the initiator solution was added per ml of 10% w/w aqueous solution of the tetraacrylated PEO. The prepolymers were crosslinked in situ inside the recess of the electrode. The films were prepared by filling the recess with the prepolymer solution twice and exposing the electrode to the UV light source after each time the cavity was filled.
  • [0079]
    In vitro Testing of Electrodes:
  • [0080]
    In vitro experiments were carried out in batch fashion at 25° and 37° C., using a conventional three electrode electrochemical cell with the enzyme-modified gold wire as the working electrode, a platinum wire as the counter electrode and a saturated calomel reference electrode (SCE). The electrolyte was a 20 mM phosphate buffered-saline solution containing 0.15 M NaCl at pH 7.15. Experiments in serum were performed at 37° C., adding 100 μL antibiotic-antimycotic solution to 10 ml serum. Phosphate buffered-saline and serum were agitated during the experiments. The working potential was +0.3 V versus SCE for experiments with the PVI-Os polymers.
  • [0081]
    Structure and Performance: The depth c of the channel 6 and the thickness of the polymer layers in it controls the mass transport, i.e., flux of glucose, to the sensing layer. By controlling these parameters, the apparent Michaelis constant (Km) is adjusted to about 20-30 mM glucose. The polyimide wall 4 of the channel 6 also protects the four polymer and polymer/enzyme layers 8, 10, 12, 14 against mechanical damage and reduces the hazard of their loss in the body. Because the glucose electrooxidation current is limited by glucose mass transport through the recess 16 and its polymer films 8, 10, 12, 14, rather than by mass transport to the tissue-exposed tip 16, the current is practically insensitive to motion. Evidently, the electrooxidation rate of glucose in the recessed sensing layer 8 is slower than the rate of glucose diffusion to the channel's outer fluid contacting interface.
  • [0082]
    PVI5-Os is preferred as the “wire” of the sensing layer when an interference eliminating layer of HRP and LOX is used, but not in the absence of this layer, i.e., when redox polymers with more reducing redox potential are preferred. The subscript (5) is used to indicate that, on the average, every fifth vinylimidazole mer carries an electron-relaying osmium center. Use of electrodes formed with PVI5-Os and PVI3-Os (every third 1-vinylimidazole mer carrying an osmium center) are compared in FIG. 2, and show higher current density of glucose electrooxidation on electrodes made with PVI5-Os (open triangle) than on those made with PVI3-Os (filled triangles).
  • [0083]
    Depth of the recess and the sensing layer: Channels of 125, 250, and 500 μm depth, were investigated to assess the dependence of the current on the depth of the recess (FIG. 3), with the total amount of PVI5-Os and rGOX being kept constant. Much of the loss in current in the deeper cavities resulted not from reduced glucose mass transport, but from adsorptive retention of part of the enzyme and polymer on the polyamide wall when microdrops of the component solutions were introduced into the recess in the process of making the electrodes. Through repeated rinsing with water, some of the adsorbed polymer and enzyme on the walls were washed onto the electrode surface, increasing the current. The highest currents were seen after five washings. When the thickness of the sensing layer was increased through increasing the number of coatings (FIG. 4) the ratio of current to charge required to electroreduce or electrooxidize the redox polymer in the sensing layer reached a maximum, then dropped. For the preferred 125 μm recess, 10 coatings, producing an approximately 13 Am thick wired-rGOX sensing layer, yielded sensors that had the desired characteristics for in vivo use.
  • [0084]
    The insulating layer: This layer electrically insulates the redox enzymes of the interference eliminating layer (HRP and LOX) from the “wired” rGOX layer and limits the glucose flux to the sensing layer, thereby extending the useful life of the electrode. PAL crosslinked with PAZ, forming a polycationic network at pH 7.09 is preferred. The best results, i.e., best stability of current outputs, were obtained using 1:2 PAL:PAZ (FIG. 5), with three coatings applied to form an approximately 7 μm thick crosslinked film.
  • [0085]
    The interference eliminating layer: Interferants, particularly ascorbate, urate, and acetaminophenol, are oxidized in the third layer, containing LOX and HRP. In this layer, lactate, the typical concentration of which in blood is 1 mM, reacts with O2 to form H2O2 and pyruvate. H2O2, in the presence of HRP, oxidizes ascorbate, urate, and acetaminophenol, being reduced to water. The preferred coimmobilization process involved two separate steps: periodate oxidation of oligosaccharide functions of HRP to aldehydes, followed by mixing with LOX and formation of multiple Schiff bases between HRP-aldehydes and LOX amines (e.g. lysines) and between HRP aldehydes and amines. The thickness of the interference eliminating layer is approximately 85 μm and is made by applying successive coatings, e.g., about six coatings. FIG. 6 shows that electrooxidizable interferants were eliminated in the presence of lactate at physiological levels. LOX slowly lost its activity in the crosslinked HRP-LOX layer. This led to degradation of the ability of the layer to eliminate interferants. After 36 hours of operation at 37° C., a measurable current increment was noted when enough ascorbate was added to produce a 0.1 mM concentration.
  • [0086]
    The biocompatible layer: A preferred biocompatible layer consists, for example, of photocrosslinked tetraacrylated 18,500 Da poly(ethylene oxide) (Pathak et al., 1993, J. Am. Chem. Soc., 114:8311-8312). The thickness of this layer, made by sequential photo-crosslinking of two coatings, is about 20 μm. One minute UV exposure required for the photocrosslinking process reduced the sensitivity by 16+/−2%.
  • Example 2
  • [0087]
    In vivo Use of Sensor
  • [0088]
    The objective of this experiment was to establish the validity of a one-point in vivo calibration. Two sensors were simultaneously implanted subcutaneously in a rat, one on the thorax, the second between the scapulae. To make the difference between the blood sampled and the subcutaneous fluid proved with the sensors as extreme as possible, i.e., to probe whether the one-point calibration holds even if the organs sampled are different and the sampling sites are remote, blood was withdrawn from the tail vein. Blood glucose levels were periodically measured in withdrawn samples, while the absolute uncorrected sensor current output was continuously monitored.
  • [0089]
    In vivo experiments (6-10 hours) were carried out in 300 g male Sprague-Dawley rats. The rats were fasted overnight and prior to the experiment were anaesthetized with an intraperitoneal (i.p.) injection of sodium pentobarbital (65 mg/kg rat wt). An i.p. injection of atropine sulfate (166 mg/kg rat wt) was then administered to suppress respiratory depression. Once the rat was anaesthetized, a portion of the rat's abdomen was shaved, coated with a conductive gel, and an Ag/AgCl surface skin reference electrode was attached. This electrode served also as the counter electrode. Sensors were then implanted subcutaneously using a 22 gauge Per-Q-Cath Introducer (Gesco International, San Antonio, Tex.) on the rat's thorax, or subcutaneously in the intrascepular area through a small surgical incision. The sensors were taped to the skin to avoid sensor movement. The sensors, along with the reference electrode, were connected to an in-house built bipotentiostat. The operating potential of the sensors was 0.3 V vs. Ag/AgCl, with the Ag/AgCl electrode serving as both the reference counter electrode. Sensor readings were collected using a data logger (Rustrak Ranger, East Greenwich, R.I.) and at the end of the experiment were transferred to a computer. During the experiment, the rat's body temperature was maintained at 37° C. by a homeostatic blanket. The sensors were allowed to reach a basal signal level for at least one hour before blood sampling was started. Blood samples were obtained from the tail vein and all blood samples were analyzed using a glucose analyzer (YSI, Inc., Yellow Springs, Ohio; Model 23A).
  • [0090]
    Approximately thirty minutes after the start of blood sampling, an i.p. glucose infusion was started using a syringe pump (Harvard Apparatus, South Natick, Mass.) at a rate of 120 mg glucose/min kg rat wt. The glucose infusion was maintained for approximately one hour.
  • [0091]
    As seen in FIG. 7, at 410 min the current dropped precipitously. Such a drop was observed in other measurements with subcutaneously implanted electrodes between 400 and 600 min, but was never observed in electrodes operated in buffer at 37° C. When the failed electrodes were withdrawn and retested in buffer, most of their original sensitivity was found to be intact. The cause for this apparent deactivation was failure of the counter/reference Ag/AgCl electrode on the rat's skin to make good electrolytic contact, and was not due to any failure of the implanted sensor. Using an arbitrarily chosen point to calculate a calibration curve for each electrode, i.e., one blood glucose level determination and one current measurement to establish the scales, all the data from FIG. 7 were plotted in a Clarke-type, (Clarke et al., 1987, Diabetes Care, 5:622-627) clinical grid (FIG. 8), without further correction. In this analysis, points falling in region A of the grid are considered clinically accurate, while those in region B are considered clinically correct. Points falling in region C are not correct, but would not lead to improper treatment. Points in regions D and E are incorrect and if treatment would rely on these, it would be improper.
  • [0092]
    All of the points, from both electrodes, were in regions A and B, with 43 of the 48 points being in region A. The three points in region B near 100 mg/dl glucose, for the electrode implanted between the scapulae, were the last three points of the experiment, at about 410 min. Notwithstanding the failure mode at 400-600 min because of poor electrolytic contact of the counter/reference electrode with the skin and failure after 36 hours by deactivation of the lactate oxidase, resulting in loss of interference elimination, one-point calibration is shown here to be practical. After such calibration, the readings of the subcutaneous sensors provide, without any correction, clinically useful estimates of blood glucose levels.
  • [0093]
    FIG. 9 shows the distribution of all possible. correlations obtained when each of the 24 glucose analyses was used for single point calibration of either implanted electrode. There are 2×24×24=1152 points in the distribution. Of these, 78% are in region A, 15% are in region B, 1% in region C, 6% are in region D, and no points are in region E.
  • [0094]
    In FIG. 10, we tested for the improvement of the single point calibration through using redundant electrodes. First, the readings of electrode A were normalized with respect to those of electrode B by multiplying each reading by the average output of electrode B divided by the average output of electrode A. Next the standard deviation was calculated for the differences between the 24 sets of readings of implanted electrode B and corrected readings of implanted electrode A. Then, all those sets of readings that differed by more than the standard deviation were rejected. The number of sets was reduced thereby from 24 to 11; 82% of the points were in region A, 17% in region B, 1% in region D, and no points in regions C and E. The distribution demonstrates that the sensors can be calibrated through a single independent measurement of the glucose concentration in a withdrawn blood sample. They also demonstrate the improvement in clinical accuracy resulting from the use of redundant subcutaneous sensors. The selection of those data points that differed by less than the standard deviation for the entire set led to a sixfold reduction in the probability of clinically erring in a decision based on readings of the implanted sensors.
  • [0095]
    Stability and Other Characteristics:
  • [0096]
    In order to improve the stability, more thermostable recombinant GOX, (RGOX; Heller, 1992, J. Phys. Chem., 96:3579-3587) rather than GOX is used in the sensor and glucose transport is reduced to make the sensor current diffusion, not enzyme turnover, limited. The glucose flux is attenuated by the three outer layers and the sensing layer itself. Because the sensing layer contains a large excess of glucose oxidase, its activity greatly exceeds that needed for electrooxidizing the attenuated glucose flux, and the sensor's stability is improved.
  • [0097]
    The stability can be tested by methods known, for example, tested in the presence of 0.1 mM ascorbate in 10 mM glucose at 37° C. The current output of a typical optimized electrode was about 35 nA and the apparent Km, derived from an Eadie-Hofstee plot, was about 20 mM (Table 1). The 10-90% response time was approximately one minute.
  • [0098]
    As expected, and as can be seen in FIG. 5, with thinner films the glucose mass transport was increased, i.e., the current was higher, while for thicker films the stability was improved. Because of the high sensitivity of thin sensing film (approximately 1 μm) electrodes (less than 10−2 A cm−2 M−1), an order of magnitude decrease in sensitivity could be traded for stability, while the currents remained high enough to be easily measured.
  • [0099]
    As seen in FIG. 5, the sensitivity of the stabilized sensors does not change by more than +5% for 72 hours of operation at 37° C. After a small initial decrease in sensitivity, it increased to a maximum after 40 hours and the final 72 hour sensitivity was almost identical with the initial.
  • [0100]
    The characteristics of the electrodes of the present invention are summarized in Table 1. Each entry represents an average value for five tested electrodes. Baseline currents are typically less than 0.5 nA and the noise less than 10 pA. The currents observed throughout the physiological glucose concentration range (2-20 mM) exceed the noise equivalent current by at least a factor of 100. The apparent Km is 20 mM, and the 10% to 90% response time is, for aged electrodes, about 90 seconds at the lowest physiologically relevant glucose concentration (2 mM) and 20 seconds at the highest (20 mM).
  • [0101]
    The baseline of nil at 0 mM glucose is stable for 36 hours in the presence of 0.1 mM ascorbate. The stability observed and the existence of a valid zero-point in the presence of interferants suggest that the sensor can be used in vivo for 72 hours and tested/recalibrated in vivo through a single point calibration, i.e., by withdrawing only a single sample of blood for independent analysis.
  • [0000]
    TABLE 1
    SENSOR CHARACTERISTICS
    Current
    Km app(mM) Km app(mM) Variance
    i(nA) j(μA/cm2) EH LB tr(s) (%)
    33.9 69.1 18.5 33.4 30-90 5.0
    where:
    i is the current measured at 37° C. and at 10 mM glucose concentration
    j is the current density measured at 37° C. at 10 mM glucose concentration
    KM app is the apparent Michaelis-Menten coefficient determined from an electrochemical Eadie-Hoffstee (EH) or Lineweaver-Burk (LB) plot
    tr is the 10-90% risetime, 90s for 2 mM and 30 s for 20 mH glucose concentration.
    Current Variance is the maximum deviation from the mean value, measured during the 72 hour test, conducted in 10 mM glucose in the presence of interferants. The current was continuously monitored at 37° C.
  • [0102]
    The foregoing examples are designed to illustrate certain aspects of the present invention. The examples are not intended to be comprehensive of all features and all embodiments of the present invention, and should not be construed as limiting the claims presented herein.

Claims (35)

1. An electrochemical biosensor, comprising:
a substrate having a first surface and a second surface; and
at least one electrode formed on at least one of the surfaces of the substrate with a laser;
wherein the biosensor includes an end for connecting with a device.
2-20. (canceled)
21. A method for fabricating an analyte sensor configured for insertion into a host's soft tissue, the method comprising: forming a biointerface having a plurality of passageways and a solid portion on at least a sensing portion of a sensor, wherein the sensor is configured to measure an analyte in the host, and wherein the sensor has an architecture with at least one dimension less than about 1 mm.
22. The method of claim 21, wherein the step of forming a biointerface comprises a method selected from the group consisting of electrospinning, writing, lyophilizing, wrapping, weaving, and molding.
23. The method of claim 21, wherein the step of forming a biointerface comprises electrospinning the biointerface onto the sensor, writing the biointerface onto the sensor, lyophilizing the biointerface onto the sensor, wrapping the biointerface onto the sensor, weaving the biointerface onto the sensor, and molding the biointerface onto the sensor.
24. The method of claim 21, wherein the step of forming a biointerface comprises forming the biointerface directly on the sensor.
25. The method of claim 21, wherein the step of forming a biointerface comprises pre-forming the biointerface and then applying the preformed biointerface to the sensor.
26. The method of claim 21, wherein the step of forming a biointerface comprises pre-forming the biointerface and inserting the sensor into the preformed biointerface.
26. The method of claim 21, wherein the step of forming a biointerface comprises: forming a selectively removable porogen on the sensor, wherein the porogen comprises particles formed onto the sensor and solidified to form a solidified mass of continuously interconnected particles; filling the porogen with a material; substantially solidifying the material; and removing the mass of continuously interconnected particles from contact with the sensor and solidified material to thereby form a solid portion that defines a plurality of passageways of the biointerface.
27. The method of claim 21, wherein the biointerface comprises a material selected from the group consisting of silicone, polytetrafluoroethylene, expanded polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene, polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene, polyurethane homopolymer, polyurethane copolymer, polyurethane terpolymer, polypropylene, polyvinylchloride, polyvinylidene fluoride, polyvinyl alcohol, polybutylene terephthalate, polymethylmethacrylate, polyether ether ketone, polyamide, polyurethane, cellulosic polymer, poly(ethylene oxide), poly(propylene oxide), poly(propylene oxide) copolymer, polysulfone, polysulfone, block copolymers thereof, di-block copolymers thereof, tri-block copolymers thereof, alternating copolymers thereof, random copolymers thereof, graft copolymers thereof, mixtures thereof, and blends thereof.
28. The method of claim 21, wherein the step of forming a biointerface comprises forming an amorphous biointerface.
29. The method of claim 21, wherein the biointerface comprises pores of at least about 20 microns.
30. The method of claim 21, wherein the step of forming a biointerface comprises forming a fibrous biointerface.
31. The method of claim 31, wherein the biointerface comprises fibers less than about 6 microns in all but the longest dimension.
33. The method of claim 21, further comprising a step of incorporating a bioactive agent into the biointerface.
34. The method of claim 33, wherein the bioactive agent is selected from the group consisting of an anti-barrier cell agent, an anti-inflammatory agent, an anti-infective agent, a necrosing agent, an anesthetic, an inflammatory agent, a growth factor, an angiogenic factor, an adjuvant, an immunosuppressive agent, an antiplatelet agent, an anticoagulant, an ACE inhibitor, a cytotoxic agent, a vascularization compound, and an anti-sense molecule.
35. The method of claim 21, wherein the step of forming a biointerface comprises writing a biointerface onto the sensor using a computer-aided machine.
36. A method for fabricating an analyte sensor configured to be wholly implanted in a host's soft tissue, the method comprising: providing a sensor configured to measure an analyte in the host, wherein the sensor has an architecture with at least one dimension less than about 1 mm; and coating a biointerface onto the sensor, the biointerface comprising a plurality of cavities and a solid portion.
37. The method of claim 36, wherein the cavities are interconnected.
38. The method of claim 36, wherein the coating step comprises a method selected from the group consisting of electrospinning, writing, lyophilizing, wrapping, weaving, and molding.
39. The method of claim 36, further comprising a step of curing the biointerface.
40. The method of claim 36, wherein the coating step comprises: forming a selectively removable porogen onto the sensor, wherein the porogen comprises particles formed onto the sensor and solidified to form a solidified mass of continuously interconnected particles; filling the porogen with a material; substantially solidifying the material; and removing the mass of continuously interconnected particles from contact with the sensor and solidified material to thereby form a solid portion that defines a plurality of passageways of the biointerface.
41. The method of claim 36, wherein the biointerface comprises a material selected from the group consisting of silicone, polytetrafluoroethylene, expanded polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene, polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene, polyurethane homopolymer, polyurethane copolymer, polyurethane terpolymer, polypropylene, polyvinylchloride, polyvinylidene fluoride, polyvinyl alcohol, polybutylene terephthalate, polymethylmethacrylate, polyether ether ketone, polyamide, polyurethane, cellulosic polymer, poly(ethylene oxide), poly(propylene oxide), poly(propylene oxide) copolymer, polysulfone, polysulfone, block copolymers thereof, di-block copolymers thereof, tri-block copolymers thereof, alternating copolymers thereof, random copolymers thereof, graft copolymers thereof, mixtures thereof, and blends thereof.
42. The method of claim 36, wherein the biointerface is an amorphous biointerface.
43. The method of claim 42, wherein the amorphous biointerface is molded onto the sensor.
44. The method of claim 36, wherein the coating step comprises forming a fibrous biointerface.
45. The method of claim 44, wherein the biointerface comprises fibers less than about 6 microns in all but the longest dimension.
46. The method of claim 36, further comprising a step of incorporating a bioactive agent into the biointerface.
47. The method of claim 46, wherein the bioactive agent is selected from the group consisting of an anti-barrier cell agent, an anti-inflammatory agent, an anti-infective agent, a necrosing agent, an anesthetic, an inflammatory agent, a growth factor, an angiogenic factor, an adjuvant, a wound factor, an immunosuppressive agent, an antiplatelet agent, an anticoagulant, an ACE inhibitor, a cytotoxic agent, a vascularization compound, and an anti-sense molecule.
48. The method of claim 36, wherein the coating step comprises writing a biointerface onto the sensor using a computer-aided machine.
49. The method of claim 36, further comprising a step of curing the biointerface.
50. A method for making an analyte sensor configured for insertion into a host's soft tissue, the method comprising: providing a sensor configured to measure an analyte in a host, wherein the sensor has an architecture with at least one dimension less than about 1 mm; and directly writing a porous biointerface, wherein the porous biointerface is written based on a predefined pattern stored in a computer system.
51. The method of claim 50, further comprising a step of curing the biointerface during direct writing step or after the direct writing step.
52. The method of claim 50, wherein the porous biointerface is directly written onto the sensor.
53. The method of claim 50, wherein the porous biointerface is directly written onto a substrate and then applied to the sensor.
US12039576 1991-03-04 2008-02-28 Subcutaneous glucose electrode Abandoned US20080210557A1 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
US66405491 true 1991-03-04 1991-03-04
US08161682 US5356786A (en) 1991-03-04 1993-12-02 Interferant eliminating biosensor
US08299526 US5593852A (en) 1993-12-02 1994-09-01 Subcutaneous glucose electrode
US08767110 US6284478B1 (en) 1993-12-02 1996-12-04 Subcutaneous glucose electrode
US09356102 US6121009A (en) 1993-12-02 1999-07-16 Electrochemical analyte measurement system
US09477053 US6162611A (en) 1993-12-02 2000-01-03 Subcutaneous glucose electrode
US09668221 US6329161B1 (en) 1993-12-02 2000-09-22 Subcutaneous glucose electrode
US09997808 US6514718B2 (en) 1991-03-04 2001-11-29 Subcutaneous glucose electrode
US10353341 US6881551B2 (en) 1991-03-04 2003-01-28 Subcutaneous glucose electrode
US11109379 US20050287620A1 (en) 1991-03-04 2005-04-19 Method of determining analyte level using subcutaneous electrode
US11695612 US8741590B2 (en) 1991-03-04 2007-04-03 Subcutaneous glucose electrode
US12039576 US20080210557A1 (en) 1991-03-04 2008-02-28 Subcutaneous glucose electrode

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US12039576 US20080210557A1 (en) 1991-03-04 2008-02-28 Subcutaneous glucose electrode

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Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100099970A1 (en) * 1997-03-04 2010-04-22 Dexcom, Inc. Device and method for determining analyte levels
WO2010033724A3 (en) * 2008-09-19 2010-05-20 Dexcom, Inc. Particle-containing membrane and particulate electrode for analyte sensors
US7857760B2 (en) 2004-07-13 2010-12-28 Dexcom, Inc. Analyte sensor
US7901354B2 (en) 1997-03-04 2011-03-08 Dexcom, Inc. Low oxygen in vivo analyte sensor
US7905833B2 (en) 2004-07-13 2011-03-15 Dexcom, Inc. Transcutaneous analyte sensor
US7920906B2 (en) 2005-03-10 2011-04-05 Dexcom, Inc. System and methods for processing analyte sensor data for sensor calibration
US7927274B2 (en) 2003-11-19 2011-04-19 Dexcom, Inc. Integrated receiver for continuous analyte sensor
US7976492B2 (en) 2004-02-26 2011-07-12 Dexcom, Inc. Integrated delivery device for continuous glucose sensor
US8162829B2 (en) 1998-04-30 2012-04-24 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8255033B2 (en) 2003-07-25 2012-08-28 Dexcom, Inc. Oxygen enhancing membrane systems for implantable devices
US8277713B2 (en) 2004-05-03 2012-10-02 Dexcom, Inc. Implantable analyte sensor
US8287454B2 (en) 1998-04-30 2012-10-16 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
US8465425B2 (en) 1998-04-30 2013-06-18 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8483791B2 (en) 2004-07-13 2013-07-09 Dexcom, Inc. Transcutaneous analyte sensor
US8562558B2 (en) 2007-06-08 2013-10-22 Dexcom, Inc. Integrated medicament delivery device for use with continuous analyte sensor
US8612159B2 (en) 1998-04-30 2013-12-17 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8652043B2 (en) 2001-01-02 2014-02-18 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
US8744546B2 (en) 2005-05-05 2014-06-03 Dexcom, Inc. Cellulosic-based resistance domain for an analyte sensor
US8792955B2 (en) 2004-05-03 2014-07-29 Dexcom, Inc. Transcutaneous analyte sensor
US8808228B2 (en) 2004-02-26 2014-08-19 Dexcom, Inc. Integrated medicament delivery device for use with continuous analyte sensor
US8974386B2 (en) 1998-04-30 2015-03-10 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
US9439589B2 (en) 1997-03-04 2016-09-13 Dexcom, Inc. Device and method for determining analyte levels

Families Citing this family (388)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2050057A1 (en) 1991-03-04 1992-09-05 Adam Heller Interferant eliminating biosensors
US5593852A (en) * 1993-12-02 1997-01-14 Heller; Adam Subcutaneous glucose electrode
GB9215973D0 (en) * 1992-07-28 1992-09-09 Univ Manchester Sensor devices
KR970010981B1 (en) * 1993-11-04 1997-07-05 구자홍 Alcohol concentration measuring bio-sensor, manufacturing method and related apparatus
US5824473A (en) * 1993-12-10 1998-10-20 California Institute Of Technology Nucleic acid mediated electron transfer
US6071699A (en) 1996-06-07 2000-06-06 California Institute Of Technology Nucleic acid mediated electron transfer
US5620850A (en) * 1994-09-26 1997-04-15 President And Fellows Of Harvard College Molecular recognition at surfaces derivatized with self-assembled monolayers
US6329139B1 (en) 1995-04-25 2001-12-11 Discovery Partners International Automated sorting system for matrices with memory
US5611900A (en) * 1995-07-20 1997-03-18 Michigan State University Microbiosensor used in-situ
US5755953A (en) * 1995-12-18 1998-05-26 Abbott Laboratories Interference free biosensor
US5795453A (en) * 1996-01-23 1998-08-18 Gilmartin; Markas A. T. Electrodes and metallo isoindole ringed compounds
US5830341A (en) * 1996-01-23 1998-11-03 Gilmartin; Markas A. T. Electrodes and metallo isoindole ringed compounds
US7160678B1 (en) 1996-11-05 2007-01-09 Clinical Micro Sensors, Inc. Compositions for the electronic detection of analytes utilizing monolayers
US7393645B2 (en) * 1996-11-05 2008-07-01 Clinical Micro Sensors, Inc. Compositions for the electronic detection of analytes utilizing monolayers
US7014992B1 (en) 1996-11-05 2006-03-21 Clinical Micro Sensors, Inc. Conductive oligomers attached to electrodes and nucleoside analogs
US7045285B1 (en) 1996-11-05 2006-05-16 Clinical Micro Sensors, Inc. Electronic transfer moieties attached to peptide nucleic acids
US5956501A (en) * 1997-01-10 1999-09-21 Health Hero Network, Inc. Disease simulation system and method
JP3394262B2 (en) 1997-02-06 2003-04-07 イー.ヘラー アンド カンパニー Small volume in vitro analyte sensor
US6741877B1 (en) 1997-03-04 2004-05-25 Dexcom, Inc. Device and method for determining analyte levels
US20050033132A1 (en) 1997-03-04 2005-02-10 Shults Mark C. Analyte measuring device
US7381525B1 (en) 1997-03-07 2008-06-03 Clinical Micro Sensors, Inc. AC/DC voltage apparatus for detection of nucleic acids
US7806886B2 (en) 1999-06-03 2010-10-05 Medtronic Minimed, Inc. Apparatus and method for controlling insulin infusion with state variable feedback
DK0988534T3 (en) * 1997-06-12 2011-05-23 Clinical Micro Sensors Inc Electronic methods and apparatus for detecting analytes
US6013459A (en) 1997-06-12 2000-01-11 Clinical Micro Sensors, Inc. Detection of analytes using reorganization energy
US5922183A (en) * 1997-06-23 1999-07-13 Eic Laboratories, Inc. Metal oxide matrix biosensors
US6030827A (en) * 1998-01-23 2000-02-29 I-Stat Corporation Microfabricated aperture-based sensor
US6686150B1 (en) 1998-01-27 2004-02-03 Clinical Micro Sensors, Inc. Amplification of nucleic acids with electronic detection
CA2319170A1 (en) 1998-01-27 1999-07-29 Clinical Micro Sensors, Inc. Amplification of nucleic acids with electronic detection
US6479015B1 (en) 1998-03-03 2002-11-12 Pepex Biomedical, Llc Apparatus for monitoring a level of a chemical species in a body fluid
US6134461A (en) 1998-03-04 2000-10-17 E. Heller & Company Electrochemical analyte
US6103033A (en) 1998-03-04 2000-08-15 Therasense, Inc. Process for producing an electrochemical biosensor
US6085576A (en) * 1998-03-20 2000-07-11 Cyrano Sciences, Inc. Handheld sensing apparatus
US6600026B1 (en) 1998-05-06 2003-07-29 Clinical Micro Sensors, Inc. Electronic methods for the detection of analytes utilizing monolayers
US6294281B1 (en) * 1998-06-17 2001-09-25 Therasense, Inc. Biological fuel cell and method
US7087148B1 (en) 1998-06-23 2006-08-08 Clinical Micro Sensors, Inc. Binding acceleration techniques for the detection of analytes
US6761816B1 (en) 1998-06-23 2004-07-13 Clinical Micro Systems, Inc. Printed circuit boards with monolayers and capture ligands
US6281006B1 (en) 1998-08-24 2001-08-28 Therasense, Inc. Electrochemical affinity assay
US6638716B2 (en) 1998-08-24 2003-10-28 Therasense, Inc. Rapid amperometric verification of PCR amplification of DNA
US6251260B1 (en) 1998-08-24 2001-06-26 Therasense, Inc. Potentiometric sensors for analytic determination
US6740518B1 (en) * 1998-09-17 2004-05-25 Clinical Micro Sensors, Inc. Signal detection techniques for the detection of analytes
US6338790B1 (en) 1998-10-08 2002-01-15 Therasense, Inc. Small volume in vitro analyte sensor with diffusible or non-leachable redox mediator
JP4469504B2 (en) * 1998-10-08 2010-05-26 メドトロニック ミニメド インコーポレイテッド Remote plasma monitor system
US6541617B1 (en) * 1998-10-27 2003-04-01 Clinical Micro Sensors, Inc. Detection of target analytes using particles and electrodes
US7621893B2 (en) * 1998-10-29 2009-11-24 Medtronic Minimed, Inc. Methods and apparatuses for detecting occlusions in an ambulatory infusion pump
US7766873B2 (en) 1998-10-29 2010-08-03 Medtronic Minimed, Inc. Method and apparatus for detecting occlusions in an ambulatory infusion pump
US6128519A (en) 1998-12-16 2000-10-03 Pepex Biomedical, Llc System and method for measuring a bioanalyte such as lactate
US6833267B1 (en) * 1998-12-30 2004-12-21 Clinical Micro Sensors, Inc. Tissue collection devices containing biosensors
WO2000078992A3 (en) 1999-06-18 2001-07-19 Therasense Inc Mass transport limited in vivo analyte sensor
US20020177135A1 (en) 1999-07-27 2002-11-28 Doung Hau H. Devices and methods for biochip multiplexing
US6616819B1 (en) 1999-11-04 2003-09-09 Therasense, Inc. Small volume in vitro analyte sensor and methods
DE60011286T2 (en) 1999-11-15 2005-07-14 Therasense, Inc., Alameda Transition metal complex compounds with a bidentate ligands containing an imidazole ring
US8444834B2 (en) 1999-11-15 2013-05-21 Abbott Diabetes Care Inc. Redox polymers for use in analyte monitoring
US8268143B2 (en) * 1999-11-15 2012-09-18 Abbott Diabetes Care Inc. Oxygen-effect free analyte sensor
KR100360774B1 (en) 1999-12-27 2002-11-13 한국전자통신연구원 Enzyme electrode sensor and manufacturing method thereof
US7312087B2 (en) 2000-01-11 2007-12-25 Clinical Micro Sensors, Inc. Devices and methods for biochip multiplexing
US20030060765A1 (en) * 2000-02-16 2003-03-27 Arthur Campbell Infusion device menu structure and method of using the same
US6591125B1 (en) 2000-06-27 2003-07-08 Therasense, Inc. Small volume in vitro analyte sensor with diffusible or non-leachable redox mediator
JP4382265B2 (en) * 2000-07-12 2009-12-09 キヤノンアネルバ株式会社 Forming method and forming device of the silicon oxide film
WO2002078512A8 (en) 2001-04-02 2004-12-02 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
US7005273B2 (en) * 2001-05-16 2006-02-28 Therasense, Inc. Method for the determination of glycated hemoglobin
US20030136673A1 (en) * 2001-05-31 2003-07-24 Denis Pilloud Amperometric sensors using synthetic substrates based on modeled active-site chemistry
US20030032874A1 (en) 2001-07-27 2003-02-13 Dexcom, Inc. Sensor head for use with implantable devices
US6702857B2 (en) 2001-07-27 2004-03-09 Dexcom, Inc. Membrane 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
US6952604B2 (en) 2001-12-21 2005-10-04 Becton, Dickinson And Company Minimally-invasive system and method for monitoring analyte levels
US7368190B2 (en) * 2002-05-02 2008-05-06 Abbott Diabetes Care Inc. Miniature biological fuel cell that is operational under physiological conditions, and associated devices and methods
US7226978B2 (en) 2002-05-22 2007-06-05 Dexcom, Inc. Techniques to improve polyurethane membranes for implantable glucose sensors
US8260393B2 (en) 2003-07-25 2012-09-04 Dexcom, Inc. Systems and methods for replacing signal data artifacts in a glucose sensor data stream
US8423113B2 (en) 2003-07-25 2013-04-16 Dexcom, Inc. Systems and methods for processing sensor data
US7761130B2 (en) 2003-07-25 2010-07-20 Dexcom, Inc. Dual electrode system for a continuous analyte sensor
US20070100222A1 (en) * 2004-06-14 2007-05-03 Metronic Minimed, Inc. Analyte sensing apparatus for hospital use
US20040068230A1 (en) * 2002-07-24 2004-04-08 Medtronic Minimed, Inc. System for providing blood glucose measurements to an infusion device
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
CA2501825C (en) 2002-10-09 2009-12-01 Therasense, Inc. Fluid delivery device, system and method
US7993108B2 (en) 2002-10-09 2011-08-09 Abbott Diabetes Care Inc. Variable volume, shape memory actuated insulin dispensing pump
US7727181B2 (en) 2002-10-09 2010-06-01 Abbott Diabetes Care Inc. Fluid delivery device with autocalibration
US7501053B2 (en) * 2002-10-23 2009-03-10 Abbott Laboratories Biosensor having improved hematocrit and oxygen biases
US7670853B2 (en) * 2002-11-05 2010-03-02 Abbott Diabetes Care Inc. Assay device, system and method
US7381184B2 (en) 2002-11-05 2008-06-03 Abbott Diabetes Care Inc. Sensor inserter assembly
US7638228B2 (en) * 2002-11-27 2009-12-29 Saint Louis University Enzyme immobilization for use in biofuel cells and sensors
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
US7811231B2 (en) 2002-12-31 2010-10-12 Abbott Diabetes Care Inc. Continuous glucose monitoring system and methods of use
US7134999B2 (en) 2003-04-04 2006-11-14 Dexcom, Inc. Optimized sensor geometry for an implantable glucose sensor
US7679407B2 (en) 2003-04-28 2010-03-16 Abbott Diabetes Care Inc. Method and apparatus for providing peak detection circuitry for data communication systems
US7192450B2 (en) 2003-05-21 2007-03-20 Dexcom, Inc. Porous membranes for use with implantable devices
US7875293B2 (en) 2003-05-21 2011-01-25 Dexcom, Inc. Biointerface membranes incorporating bioactive agents
US8066639B2 (en) 2003-06-10 2011-11-29 Abbott Diabetes Care Inc. Glucose measuring device for use in personal area network
US8275437B2 (en) 2003-08-01 2012-09-25 Dexcom, Inc. Transcutaneous analyte sensor
US20100168542A1 (en) 2003-08-01 2010-07-01 Dexcom, Inc. System and methods for processing analyte sensor data
US8845536B2 (en) 2003-08-01 2014-09-30 Dexcom, Inc. Transcutaneous analyte sensor
US7774145B2 (en) 2003-08-01 2010-08-10 Dexcom, Inc. Transcutaneous analyte sensor
US8160669B2 (en) 2003-08-01 2012-04-17 Dexcom, Inc. Transcutaneous analyte sensor
US7778680B2 (en) 2003-08-01 2010-08-17 Dexcom, Inc. System and methods for processing analyte sensor data
US8233959B2 (en) 2003-08-22 2012-07-31 Dexcom, Inc. Systems and methods for processing analyte sensor data
US8010174B2 (en) 2003-08-22 2011-08-30 Dexcom, Inc. Systems and methods for replacing signal artifacts in a glucose sensor data stream
US9247901B2 (en) 2003-08-22 2016-02-02 Dexcom, Inc. Systems and methods for replacing signal artifacts in a glucose sensor data stream
WO2005040407A1 (en) 2003-10-24 2005-05-06 Bayer Healthcare Llc Enzymatic electrochemical biosensor
WO2005040404A1 (en) 2003-10-29 2005-05-06 Agency For Science, Technology And Research Biosensor
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
US8859151B2 (en) * 2003-11-05 2014-10-14 St. Louis University Immobilized enzymes in biocathodes
US8423114B2 (en) 2006-10-04 2013-04-16 Dexcom, Inc. Dual electrode system for a continuous analyte sensor
US7831287B2 (en) 2006-10-04 2010-11-09 Dexcom, Inc. Dual electrode system for a continuous analyte sensor
US7467003B2 (en) 2003-12-05 2008-12-16 Dexcom, Inc. Dual electrode system for a continuous analyte sensor
US7366556B2 (en) 2003-12-05 2008-04-29 Dexcom, Inc. Dual electrode system for a continuous analyte sensor
US7460898B2 (en) * 2003-12-05 2008-12-02 Dexcom, Inc. Dual electrode system for a continuous analyte sensor
US7424318B2 (en) 2003-12-05 2008-09-09 Dexcom, Inc. Dual electrode system for a continuous analyte sensor
EP2239567B1 (en) 2003-12-05 2015-09-02 DexCom, Inc. Calibration techniques for a continuous analyte sensor
US7081195B2 (en) * 2003-12-08 2006-07-25 Dexcom, Inc. Systems and methods for improving electrochemical analyte sensors
EP1711791B1 (en) 2003-12-09 2014-10-15 DexCom, Inc. Signal processing for continuous analyte sensor
JP2007523326A (en) 2004-02-06 2007-08-16 バイエル・ヘルスケア・エルエルシーBayer HealthCare LLC Species that may be oxidized as an internal standard for biosensors, and method of use
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
US8771183B2 (en) 2004-02-17 2014-07-08 Abbott Diabetes Care Inc. Method and system for providing data communication in continuous glucose monitoring and management system
US7709134B2 (en) * 2004-03-15 2010-05-04 St. Louis University Microfluidic biofuel cell
US9247900B2 (en) 2004-07-13 2016-02-02 Dexcom, Inc. Analyte sensor
US8452368B2 (en) 2004-07-13 2013-05-28 Dexcom, Inc. Transcutaneous analyte sensor
US8565848B2 (en) 2004-07-13 2013-10-22 Dexcom, Inc. Transcutaneous analyte sensor
US7783333B2 (en) 2004-07-13 2010-08-24 Dexcom, Inc. Transcutaneous medical device with variable stiffness
US7344500B2 (en) 2004-07-27 2008-03-18 Medtronic Minimed, Inc. Sensing system with auxiliary display
US7303543B1 (en) 2004-12-03 2007-12-04 Medtronic Minimed, Inc. Medication infusion set
US8571624B2 (en) 2004-12-29 2013-10-29 Abbott Diabetes Care Inc. Method and apparatus for mounting a data transmission device in a communication system
US7704229B2 (en) 2005-02-03 2010-04-27 Medtronic Minimed, Inc. Insertion device
US20060189926A1 (en) * 2005-02-14 2006-08-24 Hall W D Apparatus and methods for analyzing body fluid samples
US20060200070A1 (en) * 2005-02-14 2006-09-07 Callicoat David N Method and apparatus for calibrating an analyte detection system with a calibration sample
EP1863559A4 (en) 2005-03-21 2008-07-30 Abbott Diabetes Care Inc Method and system for providing integrated medication infusion and analyte monitoring system
US7651596B2 (en) 2005-04-08 2010-01-26 Dexcom, Inc. Cellulosic-based interference domain for an analyte sensor
US8112240B2 (en) 2005-04-29 2012-02-07 Abbott Diabetes Care Inc. Method and apparatus for providing leak detection in data monitoring and management systems
US7768408B2 (en) 2005-05-17 2010-08-03 Abbott Diabetes Care Inc. Method and system for providing data management in data monitoring system
US20070033074A1 (en) * 2005-06-03 2007-02-08 Medtronic Minimed, Inc. Therapy management system
US7620437B2 (en) 2005-06-03 2009-11-17 Abbott Diabetes Care Inc. Method and apparatus for providing rechargeable power in data monitoring and management systems
US20060272652A1 (en) * 2005-06-03 2006-12-07 Medtronic Minimed, Inc. Virtual patient software system for educating and treating individuals with diabetes
US20070016449A1 (en) * 2005-06-29 2007-01-18 Gary Cohen Flexible glucose analysis using varying time report deltas and configurable glucose target ranges
US20070066956A1 (en) * 2005-07-27 2007-03-22 Medtronic Minimed, Inc. Systems and methods for entering temporary basal rate pattern in an infusion device
US20070093786A1 (en) * 2005-08-16 2007-04-26 Medtronic Minimed, Inc. Watch controller for a medical 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
US7731657B2 (en) 2005-08-30 2010-06-08 Abbott Diabetes Care Inc. Analyte sensor introducer and methods of use
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
US8880138B2 (en) 2005-09-30 2014-11-04 Abbott Diabetes Care Inc. Device for channeling fluid and methods of use
US7756561B2 (en) 2005-09-30 2010-07-13 Abbott Diabetes Care Inc. Method and apparatus for providing rechargeable power in data monitoring and management systems
US8512243B2 (en) 2005-09-30 2013-08-20 Abbott Diabetes Care Inc. Integrated introducer and transmitter assembly and methods of use
US9398882B2 (en) 2005-09-30 2016-07-26 Abbott Diabetes Care Inc. Method and apparatus for providing analyte sensor and data processing device
US7883464B2 (en) 2005-09-30 2011-02-08 Abbott Diabetes Care Inc. Integrated transmitter unit and sensor introducer mechanism and methods of use
US9521968B2 (en) 2005-09-30 2016-12-20 Abbott Diabetes Care Inc. Analyte sensor retention mechanism and methods of use
US7583190B2 (en) 2005-10-31 2009-09-01 Abbott Diabetes Care Inc. Method and apparatus for providing data communication in data monitoring and management systems
CN101366137A (en) * 2005-11-02 2009-02-11 圣路易斯大学 Enzymes immobilized in hydrophobically modified polysaccharides
US8415059B2 (en) * 2005-11-02 2013-04-09 St. Louis University Direct electron transfer using enzymes in bioanodes, biocathodes, and biofuel cells
US7766829B2 (en) 2005-11-04 2010-08-03 Abbott Diabetes Care Inc. Method and system for providing basal profile modification in analyte monitoring and management systems
US20070179436A1 (en) * 2005-12-21 2007-08-02 Braig James R Analyte detection system with periodic sample draw and laboratory-grade analyzer
US8515518B2 (en) 2005-12-28 2013-08-20 Abbott Diabetes Care Inc. Analyte monitoring
US7697967B2 (en) 2005-12-28 2010-04-13 Abbott Diabetes Care Inc. Method and apparatus for providing analyte sensor insertion
CA2636034A1 (en) 2005-12-28 2007-10-25 Abbott Diabetes Care Inc. Medical device insertion
US8160670B2 (en) 2005-12-28 2012-04-17 Abbott Diabetes Care Inc. Analyte monitoring: stabilizer for subcutaneous glucose sensor with incorporated antiglycolytic agent
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
US20070169533A1 (en) 2005-12-30 2007-07-26 Medtronic Minimed, Inc. Methods and systems for detecting the hydration of sensors
US20070173712A1 (en) * 2005-12-30 2007-07-26 Medtronic Minimed, Inc. Method of and system for stabilization of sensors
US7774038B2 (en) * 2005-12-30 2010-08-10 Medtronic Minimed, Inc. Real-time self-calibrating sensor system and method
US8114268B2 (en) * 2005-12-30 2012-02-14 Medtronic Minimed, Inc. Method and system for remedying sensor malfunctions detected by electrochemical impedance spectroscopy
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
US7736310B2 (en) 2006-01-30 2010-06-15 Abbott Diabetes Care Inc. On-body medical device securement
US8344966B2 (en) 2006-01-31 2013-01-01 Abbott Diabetes Care Inc. Method and system for providing a fault tolerant display unit in an electronic device
US8029441B2 (en) 2006-02-28 2011-10-04 Abbott Diabetes Care Inc. Analyte sensor transmitter unit configuration for a data monitoring and management system
US7826879B2 (en) 2006-02-28 2010-11-02 Abbott Diabetes Care Inc. Analyte sensors and methods of use
US7885698B2 (en) 2006-02-28 2011-02-08 Abbott Diabetes Care Inc. Method and system for providing continuous calibration of implantable analyte sensors
US7620438B2 (en) 2006-03-31 2009-11-17 Abbott Diabetes Care Inc. Method and system for powering an electronic device
US7801582B2 (en) 2006-03-31 2010-09-21 Abbott Diabetes Care Inc. Analyte monitoring and management system and methods therefor
US8226891B2 (en) 2006-03-31 2012-07-24 Abbott Diabetes Care Inc. Analyte monitoring devices and methods therefor
US20100012049A1 (en) * 2006-04-12 2010-01-21 Jms Co., Ltd Cavitation heating system and method
US8073008B2 (en) 2006-04-28 2011-12-06 Medtronic Minimed, Inc. Subnetwork synchronization and variable transmit synchronization techniques for a wireless medical device network
US20070255125A1 (en) 2006-04-28 2007-11-01 Moberg Sheldon B Monitor devices for networked fluid infusion systems
US20080071157A1 (en) 2006-06-07 2008-03-20 Abbott Diabetes Care, Inc. Analyte monitoring system and method
US7699973B2 (en) * 2006-06-30 2010-04-20 Abbott Diabetes Care Inc. Rapid analyte measurement assay
GB0613500D0 (en) * 2006-07-07 2006-08-16 Lectus Therapeutics Ltd Apparatus and Methods
WO2008082694A3 (en) * 2006-07-14 2009-02-05 Akermin Inc Organelles in bioanodes, biocathodes, and biofuel cells
US7653425B2 (en) 2006-08-09 2010-01-26 Abbott Diabetes Care Inc. Method and system for providing calibration of an analyte sensor in an analyte monitoring system
US8333714B2 (en) 2006-09-10 2012-12-18 Abbott Diabetes Care Inc. Method and system for providing an integrated analyte sensor insertion device and data processing unit
CA2664186A1 (en) * 2006-09-22 2008-03-27 Bayer Healthcare Llc Biosensor system having enhanced stability and hematocrit performance
US7618369B2 (en) 2006-10-02 2009-11-17 Abbott Diabetes Care Inc. Method and system for dynamically updating calibration parameters for an analyte sensor
EP2129285B1 (en) 2007-03-26 2014-07-23 Dexcom, Inc. Analyte sensor
US8364231B2 (en) 2006-10-04 2013-01-29 Dexcom, Inc. Analyte sensor
US9259175B2 (en) 2006-10-23 2016-02-16 Abbott Diabetes Care, Inc. Flexible patch for fluid delivery and monitoring body analytes
US9788771B2 (en) 2006-10-23 2017-10-17 Abbott Diabetes Care Inc. Variable speed sensor insertion devices and methods of use
US7630748B2 (en) 2006-10-25 2009-12-08 Abbott Diabetes Care Inc. Method and system for providing analyte monitoring
JP2010508091A (en) 2006-10-26 2010-03-18 アボット ダイアベティス ケア インコーポレイテッドAbbott Diabetes Care Inc. The method for detecting a decrease sensitivity of the analyte sensor in real time systems, and computer program products
US20080119710A1 (en) * 2006-10-31 2008-05-22 Abbott Diabetes Care, Inc. Medical devices and methods of using the same
US20080119702A1 (en) * 2006-10-31 2008-05-22 Abbott Diabetes Care, Inc. Analyte meter having alert, alarm and test reminder capabilities and methods of use
US8579853B2 (en) 2006-10-31 2013-11-12 Abbott Diabetes Care Inc. Infusion devices and methods
US20110039164A1 (en) * 2006-11-06 2011-02-17 Akermin, Inc. Bioanode and biocathode stack assemblies
US8255034B2 (en) 2006-11-30 2012-08-28 Abbott Diabetes Care Inc. Lyotropic liquid crystal coated analyte monitoring device and methods of use
US20080139910A1 (en) * 2006-12-06 2008-06-12 Metronic Minimed, Inc. Analyte sensor and method of using the same
US20080214912A1 (en) * 2007-01-10 2008-09-04 Glucose Sensing Technologies, Llc Blood Glucose Monitoring System And Method
US8808515B2 (en) 2007-01-31 2014-08-19 Abbott Diabetes Care Inc. Heterocyclic nitrogen containing polymers coated analyte monitoring device and methods of use
US20080183060A1 (en) * 2007-01-31 2008-07-31 Steil Garry M Model predictive method and system for controlling and supervising insulin infusion
US8121857B2 (en) 2007-02-15 2012-02-21 Abbott Diabetes Care Inc. Device and method for automatic data acquisition and/or detection
US8930203B2 (en) 2007-02-18 2015-01-06 Abbott Diabetes Care Inc. Multi-function analyte test device and methods therefor
US8732188B2 (en) 2007-02-18 2014-05-20 Abbott Diabetes Care Inc. Method and system for providing contextual based medication dosage determination
US9636450B2 (en) 2007-02-19 2017-05-02 Udo Hoss Pump system modular components for delivering medication and analyte sensing at seperate insertion sites
ES2325226T3 (en) * 2007-02-28 2009-08-28 General Life Biotechnology Co., Ltd. Element sensor to detect total cholesterol in blood samples.
US8123686B2 (en) 2007-03-01 2012-02-28 Abbott Diabetes Care Inc. Method and apparatus for providing rolling data in communication systems
US9204827B2 (en) 2007-04-14 2015-12-08 Abbott Diabetes Care Inc. Method and apparatus for providing data processing and control in medical communication system
EP2137637A4 (en) 2007-04-14 2012-06-20 Abbott Diabetes Care Inc Method and apparatus for providing data processing and control in medical communication system
US9008743B2 (en) 2007-04-14 2015-04-14 Abbott Diabetes Care Inc. Method and apparatus for providing data processing and control in medical communication system
US7768387B2 (en) * 2007-04-14 2010-08-03 Abbott Diabetes Care Inc. Method and apparatus for providing dynamic multi-stage signal amplification in a medical device
CA2683959C (en) 2007-04-14 2017-08-29 Abbott Diabetes Care Inc. Method and apparatus for providing data processing and control in medical communication system
US20080269714A1 (en) 2007-04-25 2008-10-30 Medtronic Minimed, Inc. Closed loop/semi-closed loop therapy modification system
US8080385B2 (en) 2007-05-03 2011-12-20 Abbott Diabetes Care Inc. Crosslinked adduct of polyaniline and polymer acid containing redox enzyme for electrochemical sensor
US8456301B2 (en) 2007-05-08 2013-06-04 Abbott Diabetes Care Inc. Analyte monitoring system and methods
US8665091B2 (en) 2007-05-08 2014-03-04 Abbott Diabetes Care Inc. Method and device for determining elapsed sensor life
US8461985B2 (en) 2007-05-08 2013-06-11 Abbott Diabetes Care Inc. Analyte monitoring system and methods
US7928850B2 (en) 2007-05-08 2011-04-19 Abbott Diabetes Care Inc. Analyte monitoring system and methods
US8103471B2 (en) 2007-05-14 2012-01-24 Abbott Diabetes Care Inc. Method and apparatus for providing data processing and control in a medical communication system
US8260558B2 (en) 2007-05-14 2012-09-04 Abbott Diabetes Care Inc. Method and apparatus for providing data processing and control in a medical communication system
US8560038B2 (en) 2007-05-14 2013-10-15 Abbott Diabetes Care Inc. Method and apparatus for providing data processing and control in a medical communication system
US7996158B2 (en) 2007-05-14 2011-08-09 Abbott Diabetes Care Inc. Method and apparatus for providing data processing and control in a medical communication system
US8140312B2 (en) 2007-05-14 2012-03-20 Abbott Diabetes Care Inc. Method and system for determining analyte levels
US8600681B2 (en) 2007-05-14 2013-12-03 Abbott Diabetes Care Inc. Method and apparatus for providing data processing and control in a medical communication system
US9125548B2 (en) 2007-05-14 2015-09-08 Abbott Diabetes Care Inc. Method and apparatus for providing data processing and control in a medical communication system
US8444560B2 (en) 2007-05-14 2013-05-21 Abbott Diabetes Care Inc. Method and apparatus for providing data processing and control in a medical communication system
US8239166B2 (en) 2007-05-14 2012-08-07 Abbott Diabetes Care Inc. Method and apparatus for providing data processing and control in a medical communication system
WO2008150917A1 (en) 2007-05-31 2008-12-11 Abbott Diabetes Care, Inc. Insertion devices and methods
CA2690870C (en) 2007-06-21 2017-07-11 Abbott Diabetes Care Inc. Health monitor
US8597188B2 (en) 2007-06-21 2013-12-03 Abbott Diabetes Care Inc. Health management devices and methods
US8160900B2 (en) 2007-06-29 2012-04-17 Abbott Diabetes Care Inc. Analyte monitoring and management device and method to analyze the frequency of user interaction with the device
US8834366B2 (en) 2007-07-31 2014-09-16 Abbott Diabetes Care Inc. Method and apparatus for providing analyte sensor calibration
US7768386B2 (en) 2007-07-31 2010-08-03 Abbott Diabetes Care Inc. Method and apparatus for providing data processing and control in a medical communication system
US9044178B2 (en) 2007-08-30 2015-06-02 Pepex Biomedical, Llc Electrochemical sensor and method for manufacturing
WO2009032760A3 (en) 2007-08-30 2009-06-25 Pepex Biomedical Llc Electrochmical sensor and method for manufacturing
CA2699315A1 (en) * 2007-09-17 2009-03-26 Red Ivory Llc Self-actuating signal producing detection devices and methods
US8163146B2 (en) 2007-10-12 2012-04-24 Abbott Diabetes Care Inc. Mediator stabilized reagent compositions for use in biosensor electrodes
US8216138B1 (en) 2007-10-23 2012-07-10 Abbott Diabetes Care Inc. Correlation of alternative site blood and interstitial fluid glucose concentrations to venous glucose concentration
US8409093B2 (en) 2007-10-23 2013-04-02 Abbott Diabetes Care Inc. Assessing measures of glycemic variability
US8377031B2 (en) 2007-10-23 2013-02-19 Abbott Diabetes Care Inc. Closed loop control system with safety parameters and methods
US8374668B1 (en) 2007-10-23 2013-02-12 Abbott Diabetes Care Inc. Analyte sensor with lag compensation
RU2518310C2 (en) * 2007-12-10 2014-06-10 БАЙЕР ХЕЛТКЭА ЭлЭлСи Reagents and methods for detecting analytes
US8313467B2 (en) 2007-12-27 2012-11-20 Medtronic Minimed, Inc. Reservoir pressure equalization systems and methods
US8473022B2 (en) 2008-01-31 2013-06-25 Abbott Diabetes Care Inc. Analyte sensor with time lag compensation
US8431011B2 (en) 2008-01-31 2013-04-30 Abbott Diabetes Care Inc. Method for automatically and rapidly distinguishing between control and sample solutions in a biosensor strip
CA2715628A1 (en) 2008-02-21 2009-08-27 Dexcom, Inc. Systems and methods for processing, transmitting and displaying sensor data
US8583205B2 (en) 2008-03-28 2013-11-12 Abbott Diabetes Care Inc. Analyte sensor calibration management
US8346335B2 (en) 2008-03-28 2013-01-01 Abbott Diabetes Care Inc. Analyte sensor calibration management
EP2982383A1 (en) 2008-04-10 2016-02-10 Abbott Diabetes Care, Inc. Method for sterilizing an analyte sensor
US9295786B2 (en) * 2008-05-28 2016-03-29 Medtronic Minimed, Inc. Needle protective device for subcutaneous sensors
US8591410B2 (en) 2008-05-30 2013-11-26 Abbott Diabetes Care Inc. Method and apparatus for providing glycemic control
US7826382B2 (en) 2008-05-30 2010-11-02 Abbott Diabetes Care Inc. Close proximity communication device and methods
US8924159B2 (en) 2008-05-30 2014-12-30 Abbott Diabetes Care Inc. Method and apparatus for providing glycemic control
WO2010009172A1 (en) 2008-07-14 2010-01-21 Abbott Diabetes Care Inc. Closed loop control system interface and methods
US8734422B2 (en) 2008-08-31 2014-05-27 Abbott Diabetes Care Inc. Closed loop control with improved alarm functions
US9392969B2 (en) 2008-08-31 2016-07-19 Abbott Diabetes Care Inc. Closed loop control and signal attenuation detection
US8622988B2 (en) 2008-08-31 2014-01-07 Abbott Diabetes Care Inc. Variable rate closed loop control and methods
US20100057040A1 (en) 2008-08-31 2010-03-04 Abbott Diabetes Care, Inc. Robust Closed Loop Control And Methods
US8219173B2 (en) 2008-09-30 2012-07-10 Abbott Diabetes Care Inc. Optimizing analyte sensor calibration
US8986208B2 (en) 2008-09-30 2015-03-24 Abbott Diabetes Care Inc. Analyte sensor sensitivity attenuation mitigation
US8208973B2 (en) 2008-11-05 2012-06-26 Medtronic Minimed, Inc. System and method for variable beacon timing with wireless devices
US9326707B2 (en) 2008-11-10 2016-05-03 Abbott Diabetes Care Inc. Alarm characterization for analyte monitoring devices and systems
WO2010056878A3 (en) 2008-11-14 2010-08-26 Pepex Biomedical, Llc Electrochemical sensor module
EP2350629B1 (en) 2008-11-14 2013-12-18 Pepex Biomedical, LLC Electrochemical sensor module
US8951377B2 (en) 2008-11-14 2015-02-10 Pepex Biomedical, Inc. Manufacturing electrochemical sensor module
US8506740B2 (en) 2008-11-14 2013-08-13 Pepex Biomedical, Llc Manufacturing electrochemical sensor module
US20100160740A1 (en) * 2008-12-24 2010-06-24 Gary Cohen Use of Patterns in a Therapy Management System
US9330237B2 (en) * 2008-12-24 2016-05-03 Medtronic Minimed, Inc. Pattern recognition and filtering in a therapy management system
US8103456B2 (en) 2009-01-29 2012-01-24 Abbott Diabetes Care Inc. Method and device for early signal attenuation detection using blood glucose measurements
US8224415B2 (en) 2009-01-29 2012-07-17 Abbott Diabetes Care Inc. Method and device for providing offset model based calibration for analyte sensor
US8560082B2 (en) 2009-01-30 2013-10-15 Abbott Diabetes Care Inc. Computerized determination of insulin pump therapy parameters using real time and retrospective data processing
US20100198034A1 (en) 2009-02-03 2010-08-05 Abbott Diabetes Care Inc. Compact On-Body Physiological Monitoring Devices and Methods Thereof
US20100198188A1 (en) * 2009-02-05 2010-08-05 Abbott Diabetes Care Inc. Devices and Methods for Metering Insoluble Active Agent Particles
US20100213057A1 (en) 2009-02-26 2010-08-26 Benjamin Feldman Self-Powered Analyte Sensor
WO2010121084A1 (en) 2009-04-15 2010-10-21 Abbott Diabetes Care Inc. Analyte monitoring system having an alert
WO2010127050A1 (en) 2009-04-28 2010-11-04 Abbott Diabetes Care Inc. Error detection in critical repeating data in a wireless sensor system
US8758583B2 (en) 2009-04-28 2014-06-24 Abbott Diabetes Care Inc. Smart sensor ports and methods of using same
WO2010129375A1 (en) 2009-04-28 2010-11-11 Abbott Diabetes Care Inc. Closed loop blood glucose control algorithm analysis
US8368556B2 (en) 2009-04-29 2013-02-05 Abbott Diabetes Care Inc. Method and system for providing data communication in continuous glucose monitoring and management system
EP2425209A4 (en) 2009-04-29 2013-01-09 Abbott Diabetes Care Inc Method and system for providing real time analyte sensor calibration with retrospective backfill
WO2010141922A1 (en) 2009-06-04 2010-12-09 Abbott Diabetes Care Inc. Method and system for updating a medical device
US8613892B2 (en) 2009-06-30 2013-12-24 Abbott Diabetes Care Inc. Analyte meter with a moveable head and methods of using the same
US8298158B2 (en) * 2009-06-30 2012-10-30 Abbott Diabetes Care Inc. Integrated devices having extruded electrode structures and methods of using same
US8437827B2 (en) * 2009-06-30 2013-05-07 Abbott Diabetes Care Inc. Extruded analyte sensors and methods of using 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
EP2456351B1 (en) 2009-07-23 2016-10-12 Abbott Diabetes Care, Inc. Real time management of data relating to physiological control of glucose levels
CN104799866A (en) 2009-07-23 2015-07-29 雅培糖尿病护理公司 The analyte monitoring device
US8478557B2 (en) 2009-07-31 2013-07-02 Abbott Diabetes Care Inc. Method and apparatus for providing analyte monitoring system calibration accuracy
US9125603B2 (en) * 2009-08-11 2015-09-08 Abbott Diabetes Care Inc. Analyte sensor ports
EP2473099A4 (en) 2009-08-31 2015-01-14 Abbott Diabetes Care Inc Analyte monitoring system and methods for managing power and noise
US8514086B2 (en) 2009-08-31 2013-08-20 Abbott Diabetes Care Inc. Displays for a medical device
EP2473098A4 (en) 2009-08-31 2014-04-09 Abbott Diabetes Care Inc Analyte signal processing device and methods
US8357276B2 (en) 2009-08-31 2013-01-22 Abbott Diabetes Care Inc. Small volume test strips with large sample fill ports, supported test strips, and methods of making and using same
CA2765712A1 (en) 2009-08-31 2011-03-03 Abbott Diabetes Care Inc. Medical devices and methods
US8487758B2 (en) 2009-09-02 2013-07-16 Medtronic Minimed, Inc. Medical device having an intelligent alerting scheme, and related operating methods
EP2482720A4 (en) 2009-09-29 2014-04-23 Abbott Diabetes Care Inc Method and apparatus for providing notification function in analyte monitoring systems
US9351669B2 (en) 2009-09-30 2016-05-31 Abbott Diabetes Care Inc. Interconnect for on-body analyte monitoring device
WO2011053881A1 (en) 2009-10-30 2011-05-05 Abbott Diabetes Care Inc. Method and apparatus for detecting false hypoglycemic conditions
US8386042B2 (en) 2009-11-03 2013-02-26 Medtronic Minimed, Inc. Omnidirectional accelerometer device and medical device incorporating same
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
US8828330B2 (en) * 2010-01-28 2014-09-09 Abbott Diabetes Care Inc. Universal test strip port
US9326709B2 (en) 2010-03-10 2016-05-03 Abbott Diabetes Care Inc. Systems, devices and methods for managing glucose levels
CA2766693A1 (en) 2010-03-24 2011-09-29 Abbott Diabetes Care Inc. Medical device inserters and processes of inserting and using medical devices
WO2011133768A1 (en) 2010-04-22 2011-10-27 Abbott Diabetes Care Inc. Devices, systems, and methods related to analyte monitoring and management
JP5753720B2 (en) 2010-04-22 2015-07-22 アークレイ株式会社 Biosensor
US8726266B2 (en) 2010-05-24 2014-05-13 Abbott Diabetes Care Inc. Method and system for updating a medical device
US8635046B2 (en) 2010-06-23 2014-01-21 Abbott Diabetes Care Inc. Method and system for evaluating analyte sensor response characteristics
US9572534B2 (en) 2010-06-29 2017-02-21 Abbott Diabetes Care Inc. Devices, systems and methods for on-skin or on-body mounting of medical devices
CA2802867A1 (en) 2010-07-28 2012-02-02 Udo Hoss Analyte sensors having temperature independent membranes
US8603032B2 (en) 2010-10-15 2013-12-10 Medtronic Minimed, Inc. Medical device with membrane keypad sealing element, and related manufacturing method
US8603033B2 (en) 2010-10-15 2013-12-10 Medtronic Minimed, Inc. Medical device and related assembly having an offset element for a piezoelectric speaker
US8562565B2 (en) 2010-10-15 2013-10-22 Medtronic Minimed, Inc. Battery shock absorber for a portable medical device
US8479595B2 (en) 2010-10-20 2013-07-09 Medtronic Minimed, Inc. Sensor assembly and medical device incorporating same
US8495918B2 (en) 2010-10-20 2013-07-30 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
WO2012058237A1 (en) 2010-10-26 2012-05-03 Abbott Diabetes Care Inc. Analyte measurement devices and systems, and components and methods related thereto
US8702928B2 (en) 2010-11-22 2014-04-22 Abbott Diabetes Care Inc. Modular analyte measurement system with extendable strip port
US9713440B2 (en) 2010-12-08 2017-07-25 Abbott Diabetes Care Inc. Modular analyte measurement systems, modular components thereof and related methods
US8197444B1 (en) 2010-12-22 2012-06-12 Medtronic Minimed, Inc. Monitoring the seating status of a fluid reservoir in 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
US8690855B2 (en) * 2010-12-22 2014-04-08 Medtronic Minimed, Inc. Fluid reservoir seating procedure for a fluid infusion device
EP2661616B1 (en) 2011-01-06 2015-11-18 Pepex Biomedical, Inc. Sensor module with enhanced capillary flow
EP2661634A2 (en) 2011-01-06 2013-11-13 Pepex Biomedical, Inc. Sensor array mounted on flexible carrier
WO2012108936A1 (en) 2011-02-11 2012-08-16 Abbott Diabetes Care Inc. Data synchronization between two or more analyte detecting devices in a database
WO2013066362A1 (en) 2011-02-17 2013-05-10 Abbott Diabetes Care Inc. Analyte meter communication module
US8870829B2 (en) 2011-02-22 2014-10-28 Medtronic Minimed, Inc. Fluid infusion device and related sealing assembly for a needleless 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
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
CN107019515A (en) 2011-02-28 2017-08-08 雅培糖尿病护理公司 Devices, systems, and methods associated with analyte monitoring devices and devices incorporating the same
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
US9743862B2 (en) 2011-03-31 2017-08-29 Abbott Diabetes Care Inc. Systems and methods for transcutaneously implanting medical devices
WO2012145027A1 (en) 2011-04-20 2012-10-26 Abbott Diabetes Care Inc. Analyte monitoring devices and methods
US9585605B2 (en) 2011-05-19 2017-03-07 Pepex Biomedical, Inc. Fluid management and patient monitoring system
WO2012162151A3 (en) 2011-05-20 2013-02-14 Pepex Biomedical, Inc. Manufacturing electrochemical sensor modules
US9289164B2 (en) 2011-06-30 2016-03-22 Abbott Diabetes Care Inc. Methods for generating hybrid analyte level output, and devices and systems related thereto
US9622689B2 (en) 2011-09-28 2017-04-18 Abbott Diabetes Care Inc. Methods for analyte monitoring management and analyte measurement data management, and articles of manufacture related thereto
USD680454S1 (en) 2011-10-25 2013-04-23 Abbott Diabetes Care Inc. Analyte meter and strip port
WO2013066873A1 (en) 2011-10-31 2013-05-10 Abbott Diabetes Care Inc. Electronic devices having integrated reset systems and methods thereof
WO2013066849A1 (en) 2011-10-31 2013-05-10 Abbott Diabetes Care Inc. Model based variable risk false glucose threshold alarm prevention mechanism
US8710993B2 (en) 2011-11-23 2014-04-29 Abbott Diabetes Care Inc. Mitigating single point failure of devices in an analyte monitoring system and methods thereof
US9317656B2 (en) 2011-11-23 2016-04-19 Abbott Diabetes Care Inc. Compatibility mechanisms for devices in a continuous analyte monitoring system and methods thereof
US9339217B2 (en) 2011-11-25 2016-05-17 Abbott Diabetes Care Inc. Analyte monitoring system and methods of use
US8887911B2 (en) 2011-12-09 2014-11-18 Abbott Diabetes Care Inc. Packages and kits for analyte monitoring devices, and methods related thereto
EP2713879B1 (en) 2011-12-11 2017-07-26 Abbott Diabetes Care, Inc. Analyte sensor devices, connections, and methods
US9610401B2 (en) 2012-01-13 2017-04-04 Medtronic Minimed, Inc. Infusion set component with modular fluid channel element
US8603026B2 (en) 2012-03-20 2013-12-10 Medtronic Minimed, Inc. Dynamic pulse-width modulation motor control and medical device incorporating same
US8523803B1 (en) 2012-03-20 2013-09-03 Medtronic Minimed, Inc. Motor health monitoring and medical device incorporating same
US8603027B2 (en) 2012-03-20 2013-12-10 Medtronic Minimed, Inc. Occlusion detection using pulse-width modulation and medical device incorporating same
EP2840958A4 (en) 2012-04-24 2015-12-30 Abbott Diabetes Care Inc Methods of lag-compensation for analyte measurements, and devices related thereto
US9333292B2 (en) 2012-06-26 2016-05-10 Medtronic Minimed, Inc. Mechanically actuated fluid infusion device
US9535027B2 (en) 2012-07-25 2017-01-03 Abbott Diabetes Care Inc. Analyte sensors and methods of using same
US8808269B2 (en) 2012-08-21 2014-08-19 Medtronic Minimed, Inc. Reservoir plunger position monitoring and medical device incorporating same
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
US9662445B2 (en) 2012-08-30 2017-05-30 Medtronic Minimed, Inc. Regulating entry into a closed-loop operating mode of an 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
US9623179B2 (en) 2012-08-30 2017-04-18 Medtronic Minimed, Inc. Safeguarding techniques for a closed-loop insulin infusion system
US20140206966A1 (en) * 2012-09-17 2014-07-24 Google Inc. Sensor
US9675290B2 (en) 2012-10-30 2017-06-13 Abbott Diabetes Care Inc. Sensitivity calibration of in vivo sensors used to measure analyte concentration
US8870818B2 (en) 2012-11-15 2014-10-28 Medtronic Minimed, Inc. Systems and methods for alignment and detection of a consumable component
CN104918551A (en) 2012-12-03 2015-09-16 Pepex生物医药有限公司 Sensor module and method of using a sensor module
US9107994B2 (en) 2013-01-18 2015-08-18 Medtronic Minimed, Inc. Systems for fluid reservoir retention
US9522223B2 (en) 2013-01-18 2016-12-20 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
CA2902234A1 (en) 2013-03-15 2014-09-18 Abbott Diabetes Care Inc. Devices, systems, and methods associated with analyte monitoring devices and devices incorporating the same
US9474475B1 (en) 2013-03-15 2016-10-25 Abbott Diabetes Care Inc. Multi-rate analyte sensor data collection with sample rate configurable signal processing
US8920381B2 (en) 2013-04-12 2014-12-30 Medtronic Minimed, Inc. Infusion set with improved bore configuration
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
US9259528B2 (en) 2013-08-22 2016-02-16 Medtronic Minimed, Inc. Fluid infusion device with safety coupling
US9750877B2 (en) 2013-12-11 2017-09-05 Medtronic Minimed, Inc. Predicted time to assess and/or control a glycemic state
US9750878B2 (en) 2013-12-11 2017-09-05 Medtronic Minimed, Inc. Closed-loop control of glucose according to a predicted blood glucose trajectory
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
US9399096B2 (en) 2014-02-06 2016-07-26 Medtronic Minimed, Inc. Automatic closed-loop control adjustments and infusion systems incorporating same
US9861748B2 (en) 2014-02-06 2018-01-09 Medtronic Minimed, Inc. User-configurable closed-loop notifications and infusion systems incorporating same
US20150265768A1 (en) 2014-03-24 2015-09-24 Medtronic Minimed, Inc. Fluid infusion patch pump device with automatic fluid system priming feature
US9681828B2 (en) 2014-05-01 2017-06-20 Medtronic Minimed, Inc. Physiological characteristic sensors and methods for forming such sensors
CA2957676A1 (en) 2014-08-15 2016-02-18 Abbott Diabetes Care Inc. Temperature insensitive in vivo analyte devices, 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
US9833564B2 (en) 2014-11-25 2017-12-05 Medtronic Minimed, Inc. Fluid conduit assembly with air venting features
US9636453B2 (en) 2014-12-04 2017-05-02 Medtronic Minimed, Inc. Advance diagnosis of infusion device operating mode viability

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070045902A1 (en) * 2004-07-13 2007-03-01 Brauker James H Analyte sensor

Family Cites Families (254)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2059406A (en) * 1932-07-27 1936-11-03 George A Smith Fastenings and method of making the same
US3260656A (en) 1962-09-27 1966-07-12 Corning Glass Works Method and apparatus for electrolytically determining a species in a fluid
US3653841A (en) 1969-12-19 1972-04-04 Hoffmann La Roche Methods and compositions for determining glucose in blood
US3776832A (en) 1970-11-10 1973-12-04 Energetics Science Electrochemical detection cell
US3719564A (en) 1971-05-10 1973-03-06 Philip Morris Inc Method of determining a reducible gas concentration and sensor therefor
US3837339A (en) 1972-02-03 1974-09-24 Whittaker Corp Blood glucose level monitoring-alarm system and method therefor
US3908657A (en) 1973-01-15 1975-09-30 Univ Johns Hopkins System for continuous withdrawal of blood
US4100048A (en) 1973-09-20 1978-07-11 U.S. Philips Corporation Polarographic cell
US3926760A (en) 1973-09-28 1975-12-16 Du Pont Process for electrophoretic deposition of polymer
US3972320A (en) 1974-08-12 1976-08-03 Gabor Ujhelyi Kalman Patient monitoring system
US3979274A (en) 1975-09-24 1976-09-07 The Yellow Springs Instrument Company, Inc. Membrane for enzyme electrodes
US4016866A (en) 1975-12-18 1977-04-12 General Electric Company Implantable electrochemical sensor
US4055175A (en) 1976-05-07 1977-10-25 Miles Laboratories, Inc. Blood glucose control apparatus
DE2625834C3 (en) * 1976-06-09 1989-11-23 Boehringer Mannheim Gmbh, 6800 Mannheim, De
US4059406A (en) 1976-07-12 1977-11-22 E D T Supplies Limited Electrochemical detector system
US4076596A (en) 1976-10-07 1978-02-28 Leeds & Northrup Company Apparatus for electrolytically determining a species in a fluid and method of use
US4129128A (en) 1977-02-23 1978-12-12 Mcfarlane Richard H Securing device for catheter placement assembly
FR2387659B1 (en) 1977-04-21 1984-03-09 Armines
US4098574A (en) * 1977-08-01 1978-07-04 Eastman Kodak Company Glucose detection system free from fluoride-ion interference
US4178916A (en) 1977-09-26 1979-12-18 Mcnamara Elger W Diabetic insulin alarm system
JPS5912135B2 (en) 1977-09-28 1984-03-21 Matsushita Electric Ind Co Ltd
US4151845A (en) 1977-11-25 1979-05-01 Miles Laboratories, Inc. Blood glucose control apparatus
DK151000C (en) 1978-02-17 1988-06-13 Radiometer As Method and apparatus for determining a patient's in vivo plasma pH
US4172770A (en) 1978-03-27 1979-10-30 Technicon Instruments Corporation Flow-through electrochemical system analytical method
DE2817363C2 (en) 1978-04-20 1984-01-26 Siemens Ag, 1000 Berlin Und 8000 Muenchen, De
JPS5610457B2 (en) * 1978-06-16 1981-03-07
US4344438A (en) 1978-08-02 1982-08-17 The United States Of America As Represented By The Department Of Health, Education And Welfare Optical sensor of plasma constituents
DE2926647A1 (en) * 1978-09-08 1980-03-20 Radelkis Electrokemiai Industrial molekuelselektiver sensor and method of manufacturing the same
US4240438A (en) 1978-10-02 1980-12-23 Wisconsin Alumni Research Foundation Method for monitoring blood glucose levels and elements
US4247297A (en) * 1979-02-23 1981-01-27 Miles Laboratories, Inc. Test means and method for interference resistant determination of oxidizing substances
US4573994A (en) 1979-04-27 1986-03-04 The Johns Hopkins University Refillable medication infusion apparatus
US4365637A (en) 1979-07-05 1982-12-28 Dia-Med, Inc. Perspiration indicating alarm for diabetics
US4458686A (en) 1979-08-02 1984-07-10 Children's Hospital Medical Center Cutaneous methods of measuring body substances
US4401122A (en) 1979-08-02 1983-08-30 Children's Hospital Medical Center Cutaneous methods of measuring body substances
US4450842A (en) 1980-04-25 1984-05-29 Cordis Corporation Solid state reference electrode
US4340458A (en) 1980-06-02 1982-07-20 Joslin Diabetes Center, Inc. Glucose sensor
US4356074A (en) * 1980-08-25 1982-10-26 The Yellow Springs Instrument Company, Inc. Substrate specific galactose oxidase enzyme electrodes
US4404066A (en) 1980-08-25 1983-09-13 The Yellow Springs Instrument Company Method for quantitatively determining a particular substrate catalyzed by a multisubstrate enzyme
USRE32947E (en) 1980-09-30 1989-06-13 Baptist Medical Center Of Oklahoma, Inc. Magnetic transcutaneous mount for external device of an associated implant
US4352960A (en) 1980-09-30 1982-10-05 Baptist Medical Center Of Oklahoma, Inc. Magnetic transcutaneous mount for external device of an associated implant
US4425920A (en) 1980-10-24 1984-01-17 Purdue Research Foundation Apparatus and method for measurement and control of blood pressure
US4390621A (en) * 1980-12-15 1983-06-28 Miles Laboratories, Inc. Method and device for detecting glucose concentration
US4436094A (en) 1981-03-09 1984-03-13 Evreka, Inc. Monitor for continuous in vivo measurement of glucose concentration
DE3272121D1 (en) 1981-05-07 1986-08-28 Ottosensors Corp Mecidal trial
FR2508305B1 (en) 1981-06-25 1986-04-11 Slama Gerard Device to cause a small bite to collect a drop of blood
US4440175A (en) 1981-08-10 1984-04-03 University Patents, Inc. Membrane electrode for non-ionic species
DE3138194A1 (en) 1981-09-25 1983-04-14 Basf Ag Water-insoluble porous material protein whose production and use
DE3278334D1 (en) 1981-10-23 1988-05-19 Genetics Int Inc Sensor for components of a liquid mixture
US4431004A (en) 1981-10-27 1984-02-14 Bessman Samuel P Implantable glucose sensor
US4418148A (en) * 1981-11-05 1983-11-29 Miles Laboratories, Inc. Multilayer enzyme electrode membrane
US4494950A (en) 1982-01-19 1985-01-22 The Johns Hopkins University Plural module medication delivery system
JPS58153154A (en) 1982-03-09 1983-09-12 Ajinomoto Co Inc Qualified electrode
US4581336A (en) 1982-04-26 1986-04-08 Uop Inc. Surface-modified electrodes
DE3221339A1 (en) 1982-06-05 1983-12-08 Basf Ag A process for the electrochemical hydrogenation of nicotinamide adenine dinucleotide
US4427770A (en) * 1982-06-14 1984-01-24 Miles Laboratories, Inc. High glucose-determining analytical element
EP0098592A3 (en) 1982-07-06 1985-08-21 Fujisawa Pharmaceutical Co., Ltd. Portable artificial pancreas
DE3228551A1 (en) 1982-07-30 1984-02-02 Siemens Ag Method for determining the glucose concentration
US4534356A (en) 1982-07-30 1985-08-13 Diamond Shamrock Chemicals Company Solid state transcutaneous blood gas sensors
US4571292A (en) 1982-08-12 1986-02-18 Case Western Reserve University Apparatus for electrochemical measurements
US4552840A (en) 1982-12-02 1985-11-12 California And Hawaiian Sugar Company Enzyme electrode and method for dextran analysis
US4461691A (en) 1983-02-10 1984-07-24 The United States Of America As Represented By The United States Department Of Energy Organic conductive films for semiconductor electrodes
US4679562A (en) 1983-02-16 1987-07-14 Cardiac Pacemakers, Inc. Glucose sensor
US4633878A (en) 1983-04-18 1987-01-06 Guiseppe Bombardieri Device for the automatic insulin or glucose infusion in diabetic subjects, based on the continuous monitoring of the patient's glucose, obtained without blood withdrawal
CA1219040A (en) * 1983-05-05 1987-03-10 Elliot V. Plotkin Measurement of enzyme-catalysed reactions
CA1218704A (en) * 1983-05-05 1987-03-03 Graham Davis Assay systems using more than one enzyme
US4484987A (en) 1983-05-19 1984-11-27 The Regents Of The University Of California Method and membrane applicable to implantable sensor
US4650547A (en) 1983-05-19 1987-03-17 The Regents Of The University Of California Method and membrane applicable to implantable sensor
US5509410A (en) 1983-06-06 1996-04-23 Medisense, Inc. Strip electrode including screen printing of a single layer
US4524114A (en) 1983-07-05 1985-06-18 Allied Corporation Bifunctional air electrode
US4538616A (en) 1983-07-25 1985-09-03 Robert Rogoff Blood sugar level sensing and monitoring transducer
US4655880A (en) 1983-08-01 1987-04-07 Case Western Reserve University Apparatus and method for sensing species, substances and substrates using oxidase
US4543955A (en) 1983-08-01 1985-10-01 Cordis Corporation System for controlling body implantable action device
DE3475834D1 (en) 1983-10-18 1989-02-02 Leo Ab cuvette
US4560534A (en) 1983-11-02 1985-12-24 Miles Laboratories, Inc. Polymer catalyst transducers
US4522690A (en) 1983-12-01 1985-06-11 Honeywell Inc. Electrochemical sensing of carbon monoxide
US4840893A (en) 1983-12-16 1989-06-20 Medisense, Inc. Electrochemical assay for nucleic acids and nucleic acid probes
JPS61502402A (en) 1984-04-30 1986-10-23
US5141868A (en) 1984-06-13 1992-08-25 Internationale Octrooi Maatschappij "Octropa" Bv Device for use in chemical test procedures
DK8601218A (en) 1984-07-18 1986-03-17
DE3429596A1 (en) 1984-08-10 1986-02-20 Siemens Ag Device for the physiological frequency control of a stimulation electrode provided with a pacemaker
US4820399A (en) 1984-08-31 1989-04-11 Shimadzu Corporation Enzyme electrodes
CA1254091A (en) 1984-09-28 1989-05-16 Vladimir Feingold Implantable medication infusion system
US4717673A (en) 1984-11-23 1988-01-05 Massachusetts Institute Of Technology Microelectrochemical devices
US4721601A (en) 1984-11-23 1988-01-26 Massachusetts Institute Of Technology Molecule-based microelectronic devices
JPH0617889B2 (en) * 1984-11-27 1994-03-09 株式会社日立製作所 Biological and chemical sensors
DE3585915D1 (en) 1984-12-28 1992-10-15 Terumo Corp Ion sensor.
GB8500729D0 (en) 1985-01-11 1985-02-13 Hill H A O Surface-modified electrode
EP0200321A3 (en) 1985-03-20 1987-03-11 Erwin S. Hochmair Transcutaneous signal transmission system
US4627445A (en) 1985-04-08 1986-12-09 Garid, Inc. Glucose medical monitoring system
US5279294A (en) 1985-04-08 1994-01-18 Cascade Medical, Inc. Medical diagnostic system
US4781798A (en) 1985-04-19 1988-11-01 The Regents Of The University Of California Transparent multi-oxygen sensor array and method of using same
US4671288A (en) 1985-06-13 1987-06-09 The Regents Of The University Of California Electrochemical cell sensor for continuous short-term use in tissues and blood
EP0230472B2 (en) 1985-06-21 2000-12-13 Matsushita Electric Industrial Co., Ltd. Biosensor and method of manufacturing same
US4938860A (en) * 1985-06-28 1990-07-03 Miles Inc. Electrode for electrochemical sensors
US4796634A (en) 1985-08-09 1989-01-10 Lawrence Medical Systems, Inc. Methods and apparatus for monitoring cardiac output
US4805624A (en) 1985-09-09 1989-02-21 The Montefiore Hospital Association Of Western Pa Low-potential electrochemical redox sensors
US4680268A (en) 1985-09-18 1987-07-14 Children's Hospital Medical Center Implantable gas-containing biosensor and method for measuring an analyte such as glucose
US4890620A (en) 1985-09-20 1990-01-02 The Regents Of The University Of California Two-dimensional diffusion glucose substrate sensing electrode
US4627908A (en) 1985-10-24 1986-12-09 Chevron Research Company Process for stabilizing lube base stocks derived from bright stock
US4830959A (en) 1985-11-11 1989-05-16 Medisense, Inc. Electrochemical enzymic assay procedures
GB8529300D0 (en) 1985-11-28 1986-01-02 Ici Plc Membrane
US4776944A (en) * 1986-03-20 1988-10-11 Jiri Janata Chemical selective sensors utilizing admittance modulated membranes
US4685463A (en) 1986-04-03 1987-08-11 Williams R Bruce Device for continuous in vivo measurement of blood glucose concentrations
US4726378A (en) 1986-04-11 1988-02-23 Minnesota Mining And Manufacturing Company Adjustable magnetic supercutaneous device and transcutaneous coupling apparatus
US4994167A (en) 1986-04-15 1991-02-19 Markwell Medical Institute, Inc. Biological fluid measuring device
US4757022A (en) 1986-04-15 1988-07-12 Markwell Medical Institute, Inc. Biological fluid measuring device
US4909908A (en) 1986-04-24 1990-03-20 Pepi Ross Electrochemical cncentration detector method
DE3614821A1 (en) 1986-05-02 1987-11-05 Siemens Ag Implantable, can be calibrated measuring device for a koerpersubstanz and calibration procedures
US4703756A (en) 1986-05-06 1987-11-03 The Regents Of The University Of California Complete glucose monitoring system with an implantable, telemetered sensor module
US4731726A (en) 1986-05-19 1988-03-15 Healthware Corporation Patient-operated glucose monitor and diabetes management system
GB8612861D0 (en) 1986-05-27 1986-07-02 Cambridge Life Sciences Immobilised enzyme biosensors
US4969468A (en) 1986-06-17 1990-11-13 Alfred E. Mann Foundation For Scientific Research Electrode array for use in connection with a living body and method of manufacture
CA1283447C (en) 1986-06-20 1991-04-23 John W. Parce Zero volume electrochemical cell
US5001054A (en) 1986-06-26 1991-03-19 Becton, Dickinson And Company Method for monitoring glucose
JPH0419503B2 (en) * 1986-06-27 1992-03-30 Terumo Corp
US4764416A (en) 1986-07-01 1988-08-16 Mitsubishi Denki Kabushiki Kaisha Electric element circuit using oxidation-reduction substances
US4917800A (en) 1986-07-07 1990-04-17 Bend Research, Inc. Functional, photochemically active, and chemically asymmetric membranes by interfacial polymerization of derivatized multifunctional prepolymers
US4784736A (en) 1986-07-07 1988-11-15 Bend Research, Inc. Functional, photochemically active, and chemically asymmetric membranes by interfacial polymerization of derivatized multifunctional prepolymers
US4726716A (en) 1986-07-21 1988-02-23 Mcguire Thomas V Fastener for catheter
US4894137A (en) 1986-09-12 1990-01-16 Omron Tateisi Electronics Co. Enzyme electrode
US4897162A (en) 1986-11-14 1990-01-30 The Cleveland Clinic Foundation Pulse voltammetry
DE3700119A1 (en) 1987-01-03 1988-07-14 Inst Diabetestechnologie Gemei Implantable electrochemical sensor
US4934369A (en) 1987-01-30 1990-06-19 Minnesota Mining And Manufacturing Company Intravascular blood parameter measurement system
GB2201248B (en) 1987-02-24 1991-04-17 Ici Plc Enzyme electrode sensors
US4777953A (en) 1987-02-25 1988-10-18 Ash Medical Systems, Inc. Capillary filtration and collection method for long-term monitoring of blood constituents
US5002054A (en) 1987-02-25 1991-03-26 Ash Medical Systems, Inc. Interstitial filtration and collection device and method for long-term monitoring of physiological constituents of the body
US4854322A (en) 1987-02-25 1989-08-08 Ash Medical Systems, Inc. Capillary filtration and collection device for long-term monitoring of blood constituents
US4848351A (en) 1987-03-04 1989-07-18 Sentry Medical Products, Inc. Medical electrode assembly
US4923586A (en) 1987-03-31 1990-05-08 Daikin Industries, Ltd. Enzyme electrode unit
US4935345A (en) 1987-04-07 1990-06-19 Arizona Board Of Regents Implantable microelectronic biochemical sensor incorporating thin film thermopile
US4759828A (en) 1987-04-09 1988-07-26 Nova Biomedical Corporation Glucose electrode and method of determining glucose
US5352348A (en) 1987-04-09 1994-10-04 Nova Biomedical Corporation Method of using enzyme electrode
US4749985A (en) 1987-04-13 1988-06-07 United States Of America As Represented By The United States Department Of Energy Functional relationship-based alarm processing
EP0290683A3 (en) 1987-05-01 1988-12-14 Diva Medical Systems B.V. Diabetes management system and apparatus
US5286364A (en) 1987-06-08 1994-02-15 Rutgers University Surface-modified electochemical biosensor
US4822337A (en) 1987-06-22 1989-04-18 Stanley Newhouse Insulin delivery method and apparatus
JPH07122624B2 (en) 1987-07-06 1995-12-25 ダイキン工業株式会社 Biosensor
US4874500A (en) 1987-07-15 1989-10-17 Sri International Microelectrochemical sensor and sensor array
JPS6423155A (en) 1987-07-17 1989-01-25 Daikin Ind Ltd Electrode refreshing device for biosensor
GB8718430D0 (en) * 1987-08-04 1987-09-09 Ici Plc Sensor
WO1989001310A1 (en) 1987-08-11 1989-02-23 Terumo Kabushiki Kaisha Automatic sphygmomanometer
US4974929A (en) 1987-09-22 1990-12-04 Baxter International, Inc. Fiber optical probe connector for physiologic measurement devices
NL8702370A (en) 1987-10-05 1989-05-01 Groningen Science Park A method and system for determination of glucose and therefor useful meetcelsamenstel.
US4815469A (en) 1987-10-08 1989-03-28 Siemens-Pacesetter, Inc. Implantable blood oxygen sensor and method of use
GB8725936D0 (en) 1987-11-05 1987-12-09 Genetics Int Inc Sensing system
JPH01140054A (en) * 1987-11-26 1989-06-01 Nec Corp Glucose sensor
US4813424A (en) 1987-12-23 1989-03-21 University Of New Mexico Long-life membrane electrode for non-ionic species
DE68924026D1 (en) 1988-03-31 1995-10-05 Matsushita Electric Ind Co Ltd Biosensor and its production.
US5108564A (en) 1988-03-15 1992-04-28 Tall Oak Ventures Method and apparatus for amperometric diagnostic analysis
GB8817421D0 (en) 1988-07-21 1988-08-24 Medisense Inc Bioelectrochemical electrodes
US4925268A (en) 1988-07-25 1990-05-15 Abbott Laboratories Fiber-optic physiological probes
US4954129A (en) 1988-07-25 1990-09-04 Abbott Laboratories Hydrodynamic clot flushing
EP0353328A1 (en) 1988-08-03 1990-02-07 Dräger Nederland B.V. A polarographic-amperometric three-electrode sensor
US5340722A (en) 1988-08-24 1994-08-23 Avl Medical Instruments Ag Method for the determination of the concentration of an enzyme substrate and a sensor for carrying out the method
US5264106A (en) 1988-10-07 1993-11-23 Medisense, Inc. Enhanced amperometric sensor
US4995402A (en) 1988-10-12 1991-02-26 Thorne, Smith, Astill Technologies, Inc. Medical droplet whole blood and like monitoring
US5205920A (en) 1989-03-03 1993-04-27 Noboru Oyama Enzyme sensor and method of manufacturing the same
US5089112A (en) 1989-03-20 1992-02-18 Associated Universities, Inc. Electrochemical biosensor based on immobilized enzymes and redox polymers
US4953552A (en) 1989-04-21 1990-09-04 Demarzo Arthur P Blood glucose monitoring system
EP0396788A1 (en) 1989-05-08 1990-11-14 Dräger Nederland B.V. Process and sensor for measuring the glucose content of glucosecontaining fluids
US5198367A (en) 1989-06-09 1993-03-30 Masuo Aizawa Homogeneous amperometric immunoassay
FR2648353B1 (en) 1989-06-16 1992-03-27 Europhor Sa Microdialysis probe
DE59005357D1 (en) 1989-07-07 1994-05-19 Disetronic Holding Ag Burgdorf Glucose meter.
US4986271A (en) 1989-07-19 1991-01-22 The University Of New Mexico Vivo refillable glucose sensor
US5264105A (en) 1989-08-02 1993-11-23 Gregg Brian A Enzyme electrodes
US5320725A (en) 1989-08-02 1994-06-14 E. Heller & Company Electrode and method for the detection of hydrogen peroxide
US5264104A (en) 1989-08-02 1993-11-23 Gregg Brian A Enzyme electrodes
US5262035A (en) 1989-08-02 1993-11-16 E. Heller And Company Enzyme electrodes
US4944299A (en) 1989-08-08 1990-07-31 Siemens-Pacesetter, Inc. High speed digital telemetry system for implantable device
US5190041A (en) 1989-08-11 1993-03-02 Palti Yoram Prof System for monitoring and controlling blood glucose
US5101814A (en) 1989-08-11 1992-04-07 Palti Yoram Prof System for monitoring and controlling blood glucose
US5095904A (en) 1989-09-08 1992-03-17 Cochlear Pty. Ltd. Multi-peak speech procession
FR2652736A1 (en) 1989-10-06 1991-04-12 Neftel Frederic Device implantable evaluation of glucose levels.
EP0429076B1 (en) 1989-11-24 1996-01-31 Matsushita Electric Industrial Co., Ltd. Preparation of biosensor
US5082550A (en) 1989-12-11 1992-01-21 The United States Of America As Represented By The Department Of Energy Enzyme electrochemical sensor electrode and method of making it
US5342789A (en) 1989-12-14 1994-08-30 Sensor Technologies, Inc. Method and device for detecting and quantifying glucose in body fluids
KR0171222B1 (en) 1989-12-15 1999-02-18 스티브 올드함 Redox mediator reagent and biosensor
US5286362A (en) 1990-02-03 1994-02-15 Boehringer Mannheim Gmbh Method and sensor electrode system for the electrochemical determination of an analyte or an oxidoreductase as well as the use of suitable compounds therefor
US5109850A (en) 1990-02-09 1992-05-05 Massachusetts Institute Of Technology Automatic blood monitoring for medication delivery method and apparatus
US5161532A (en) 1990-04-19 1992-11-10 Teknekron Sensor Development Corporation Integral interstitial fluid sensor
US5165407A (en) 1990-04-19 1992-11-24 The University Of Kansas Implantable glucose sensor
US5288387A (en) * 1990-06-12 1994-02-22 Daikin Industries, Ltd. Apparatus for maintaining the activity of an enzyme electrode
US5250439A (en) 1990-07-19 1993-10-05 Miles Inc. Use of conductive sensors in diagnostic assays
US5202261A (en) 1990-07-19 1993-04-13 Miles Inc. Conductive sensors and their use in diagnostic assays
US5058592A (en) 1990-11-02 1991-10-22 Whisler G Douglas Adjustable mountable doppler ultrasound transducer device
FR2673289B1 (en) 1991-02-21 1994-06-17 Asulab Sa sensor for measuring the quantity of a solution component.
US5262305A (en) * 1991-03-04 1993-11-16 E. Heller & Company Interferant eliminating biosensors
US5593852A (en) 1993-12-02 1997-01-14 Heller; Adam Subcutaneous glucose electrode
CA2050057A1 (en) 1991-03-04 1992-09-05 Adam Heller Interferant eliminating biosensors
US5208154A (en) 1991-04-08 1993-05-04 The United States Of America As Represented By The Department Of Energy Reversibly immobilized biological materials in monolayer films on electrodes
US5192416A (en) 1991-04-09 1993-03-09 New Mexico State University Technology Transfer Corporation Method and apparatus for batch injection analysis
US5293546A (en) 1991-04-17 1994-03-08 Martin Marietta Corporation Oxide coated metal grid electrode structure in display devices
JP3118015B2 (en) 1991-05-17 2000-12-18 アークレイ株式会社 Biosensors and separation quantification method using the same
US5209229A (en) 1991-05-20 1993-05-11 Telectronics Pacing Systems, Inc. Apparatus and method employing plural electrode configurations for cardioversion of atrial fibrillation in an arrhythmia control system
JP2816262B2 (en) 1991-07-09 1998-10-27 三菱鉛筆株式会社 Carbon microelectrode sensor electrodes and a manufacturing method thereof
GB9120144D0 (en) 1991-09-20 1991-11-06 Imperial College A dialysis electrode device
US5322063A (en) 1991-10-04 1994-06-21 Eli Lilly And Company Hydrophilic polyurethane membranes for electrochemical glucose sensors
US5264103A (en) 1991-10-18 1993-11-23 Matsushita Electric Industrial Co., Ltd. Biosensor and a method for measuring a concentration of a substrate in a sample
US5217595A (en) 1991-10-25 1993-06-08 The Yellow Springs Instrument Company, Inc. Electrochemical gas sensor
US5415164A (en) 1991-11-04 1995-05-16 Biofield Corp. Apparatus and method for screening and diagnosing trauma or disease in body tissues
US5271815A (en) * 1991-12-26 1993-12-21 Via Medical Corporation Method for measuring glucose
US5285792A (en) 1992-01-10 1994-02-15 Physio-Control Corporation System for producing prioritized alarm messages in a medical instrument
US5246867A (en) 1992-01-17 1993-09-21 University Of Maryland At Baltimore Determination and quantification of saccharides by luminescence lifetimes and energy transfer
NL9200207A (en) 1992-02-05 1993-09-01 Nedap Nv Implantable biomedical sensor device, in particular for measurement of the glucose concentration.
GB9211402D0 (en) 1992-05-29 1992-07-15 Univ Manchester Sensor devices
US5421816A (en) 1992-10-14 1995-06-06 Endodermic Medical Technologies Company Ultrasonic transdermal drug delivery system
US5387327A (en) 1992-10-19 1995-02-07 Duquesne University Of The Holy Ghost Implantable non-enzymatic electrochemical glucose sensor
US5320098A (en) 1992-10-20 1994-06-14 Sun Microsystems, Inc. Optical transdermal link
WO1994010553A1 (en) 1992-10-23 1994-05-11 Optex Biomedical, Inc. Fibre-optic probe for the measurement of fluid parameters
US5899855A (en) 1992-11-17 1999-05-04 Health Hero Network, Inc. Modular microprocessor-based health monitoring system
CA2103325C (en) 1992-11-23 2004-07-20 Kirk W. Johnson Techniques to improve the performance of electrochemical sensors
DK148592D0 (en) 1992-12-10 1992-12-10 Novo Nordisk As Apparatus
FR2701117B1 (en) 1993-02-04 1995-03-10 Asulab Sa System of electrochemical measurement multizone sensor, and its application to glucose analysis.
DE4318519C2 (en) 1993-06-03 1996-11-28 Fraunhofer Ges Forschung An electrochemical sensor
DE4329898A1 (en) 1993-09-04 1995-04-06 Marcus Dr Besson Wireless medical diagnostic and monitoring equipment
US5582184A (en) 1993-10-13 1996-12-10 Integ Incorporated Interstitial fluid collection and constituent measurement
US5497772A (en) 1993-11-19 1996-03-12 Alfred E. Mann Foundation For Scientific Research Glucose monitoring system
US5791344A (en) 1993-11-19 1998-08-11 Alfred E. Mann Foundation For Scientific Research Patient monitoring system
US5589326A (en) 1993-12-30 1996-12-31 Boehringer Mannheim Corporation Osmium-containing redox mediator
US5437999A (en) 1994-02-22 1995-08-01 Boehringer Mannheim Corporation Electrochemical sensor
US5391250A (en) 1994-03-15 1995-02-21 Minimed Inc. Method of fabricating thin film sensors
US5390671A (en) 1994-03-15 1995-02-21 Minimed Inc. Transcutaneous sensor insertion set
JP3061351B2 (en) 1994-04-25 2000-07-10 松下電器産業株式会社 Determination and its apparatus of the specific compound
US5569186A (en) 1994-04-25 1996-10-29 Minimed Inc. Closed loop infusion pump system with removable glucose sensor
DE4415896A1 (en) 1994-05-05 1995-11-09 Boehringer Mannheim Gmbh Analysis system for monitoring the concentration of an analyte in the blood of a patient
US5545191A (en) 1994-05-06 1996-08-13 Alfred E. Mann Foundation For Scientific Research Method for optimally positioning and securing the external unit of a transcutaneous transducer of the skin of a living body
US5494562A (en) 1994-06-27 1996-02-27 Ciba Corning Diagnostics Corp. Electrochemical sensors
US5586553A (en) 1995-02-16 1996-12-24 Minimed Inc. Transcutaneous sensor insertion set
US5568806A (en) 1995-02-16 1996-10-29 Minimed Inc. Transcutaneous sensor insertion set
US5651869A (en) 1995-02-28 1997-07-29 Matsushita Electric Industrial Co., Ltd. Biosensor
US5596150A (en) 1995-03-08 1997-01-21 The United States Of America As Represented By The Administrator Of The National Aeronautics And Space Administration Capacitance probe for fluid flow and volume measurements
JPH08247987A (en) 1995-03-15 1996-09-27 Omron Corp Portable measuring instrument
US5582697A (en) 1995-03-17 1996-12-10 Matsushita Electric Industrial Co., Ltd. Biosensor, and a method and a device for quantifying a substrate in a sample liquid using the same
US5628310A (en) 1995-05-19 1997-05-13 Joseph R. Lakowicz Method and apparatus to perform trans-cutaneous analyte monitoring
JPH11506770A (en) 1995-06-07 1999-06-15 スーゲン,インコーポレーテッド Methods and compositions for inhibiting the adapter protein / tyrosine kinase interaction
US5567302A (en) 1995-06-07 1996-10-22 Molecular Devices Corporation Electrochemical system for rapid detection of biochemical agents that catalyze a redox potential change
US5995860A (en) 1995-07-06 1999-11-30 Thomas Jefferson University Implantable sensor and system for measurement and control of blood constituent levels
US5682233A (en) 1995-09-08 1997-10-28 Integ, Inc. Interstitial fluid sampler
US5628890A (en) 1995-09-27 1997-05-13 Medisense, Inc. Electrochemical sensor
US5741211A (en) 1995-10-26 1998-04-21 Medtronic, Inc. System and method for continuous monitoring of diabetes-related blood constituents
US5711861A (en) 1995-11-22 1998-01-27 Ward; W. Kenneth Device for monitoring changes in analyte concentration
US5708247A (en) 1996-02-14 1998-01-13 Selfcare, Inc. Disposable glucose test strips, and methods and compositions for making same
JP4012252B2 (en) 1996-06-18 2007-11-21 アルザ コーポレイション Apparatus for enhancing the transdermal delivery or sampling of an agent
US5964993A (en) 1996-12-19 1999-10-12 Implanted Biosystems Inc. Glucose sensor
US6093172A (en) 1997-02-05 2000-07-25 Minimed Inc. Injector for a subcutaneous insertion set
US6001067A (en) 1997-03-04 1999-12-14 Shults; Mark C. Device and method for determining analyte levels
US6579690B1 (en) 1997-12-05 2003-06-17 Therasense, Inc. Blood analyte monitoring through subcutaneous measurement
US6134461A (en) 1998-03-04 2000-10-17 E. Heller & Company Electrochemical analyte
US6175752B1 (en) 1998-04-30 2001-01-16 Therasense, Inc. Analyte monitoring device and methods of use
WO2000030532A1 (en) 1998-11-20 2000-06-02 University Of Connecticut Generic integrated implantable potentiostat telemetry unit for electrochemical sensors
US6360888B1 (en) 1999-02-25 2002-03-26 Minimed Inc. Glucose sensor package system
US6285897B1 (en) 1999-04-07 2001-09-04 Endonetics, Inc. Remote physiological monitoring system
US6669663B1 (en) 1999-04-30 2003-12-30 Medtronic, Inc. Closed loop medicament pump
US6873268B2 (en) 2000-01-21 2005-03-29 Medtronic Minimed, Inc. Microprocessor controlled ambulatory medical apparatus with hand held communication device

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070045902A1 (en) * 2004-07-13 2007-03-01 Brauker James H Analyte sensor

Cited By (104)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100099970A1 (en) * 1997-03-04 2010-04-22 Dexcom, Inc. Device and method for determining analyte levels
US9439589B2 (en) 1997-03-04 2016-09-13 Dexcom, Inc. Device and method for determining analyte levels
US7792562B2 (en) 1997-03-04 2010-09-07 Dexcom, Inc. Device and method for determining analyte levels
US9339223B2 (en) 1997-03-04 2016-05-17 Dexcom, Inc. Device and method for determining analyte levels
US7901354B2 (en) 1997-03-04 2011-03-08 Dexcom, Inc. Low oxygen in vivo analyte sensor
US8676288B2 (en) 1997-03-04 2014-03-18 Dexcom, Inc. Device and method for determining analyte levels
US8527025B1 (en) 1997-03-04 2013-09-03 Dexcom, Inc. Device and method for determining analyte levels
US8738109B2 (en) 1998-04-30 2014-05-27 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
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US8840553B2 (en) 1998-04-30 2014-09-23 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
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US8641619B2 (en) 1998-04-30 2014-02-04 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8649841B2 (en) 1998-04-30 2014-02-11 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8744545B2 (en) 1998-04-30 2014-06-03 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8660627B2 (en) 1998-04-30 2014-02-25 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8666469B2 (en) 1998-04-30 2014-03-04 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8734346B2 (en) 1998-04-30 2014-05-27 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8670815B2 (en) 1998-04-30 2014-03-11 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8672844B2 (en) 1998-04-30 2014-03-18 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US9326714B2 (en) 1998-04-30 2016-05-03 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
US8734348B2 (en) 1998-04-30 2014-05-27 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8226558B2 (en) 1998-04-30 2012-07-24 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US9011332B2 (en) 2001-01-02 2015-04-21 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8668645B2 (en) 2001-01-02 2014-03-11 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US9610034B2 (en) 2001-01-02 2017-04-04 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8652043B2 (en) 2001-01-02 2014-02-18 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US9498159B2 (en) 2001-01-02 2016-11-22 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US9597027B2 (en) 2003-07-25 2017-03-21 Dexcom, Inc. Oxygen enhancing membrane systems for implantable devices
US8255033B2 (en) 2003-07-25 2012-08-28 Dexcom, Inc. Oxygen enhancing membrane systems for implantable devices
US8909314B2 (en) 2003-07-25 2014-12-09 Dexcom, Inc. Oxygen enhancing membrane systems for implantable devices
US8255030B2 (en) 2003-07-25 2012-08-28 Dexcom, Inc. Oxygen enhancing membrane systems for implantable devices
US8282550B2 (en) 2003-11-19 2012-10-09 Dexcom, Inc. Integrated receiver for continuous analyte sensor
US7927274B2 (en) 2003-11-19 2011-04-19 Dexcom, Inc. Integrated receiver for continuous analyte sensor
US9155843B2 (en) 2004-02-26 2015-10-13 Dexcom, Inc. Integrated delivery device for continuous glucose sensor
US8808228B2 (en) 2004-02-26 2014-08-19 Dexcom, Inc. Integrated medicament delivery device for use with continuous analyte sensor
US9050413B2 (en) 2004-02-26 2015-06-09 Dexcom, Inc. Integrated delivery device for continuous glucose sensor
US8920401B2 (en) 2004-02-26 2014-12-30 Dexcom, Inc. Integrated delivery device for continuous glucose sensor
US8721585B2 (en) 2004-02-26 2014-05-13 Dex Com, Inc. Integrated delivery device for continuous glucose sensor
US7976492B2 (en) 2004-02-26 2011-07-12 Dexcom, Inc. Integrated delivery device for continuous glucose sensor
US8926585B2 (en) 2004-02-26 2015-01-06 Dexcom, Inc. Integrated delivery device for continuous glucose sensor
US8882741B2 (en) 2004-02-26 2014-11-11 Dexcom, Inc. Integrated delivery device for continuous glucose sensor
US8792955B2 (en) 2004-05-03 2014-07-29 Dexcom, Inc. Transcutaneous analyte sensor
US8277713B2 (en) 2004-05-03 2012-10-02 Dexcom, Inc. Implantable analyte sensor
US9833143B2 (en) 2004-05-03 2017-12-05 Dexcom, Inc. Transcutaneous analyte sensor
US9801572B2 (en) 2004-07-13 2017-10-31 Dexcom, Inc. Transcutaneous analyte sensor
US9060742B2 (en) 2004-07-13 2015-06-23 Dexcom, Inc. Transcutaneous analyte sensor
US8231531B2 (en) 2004-07-13 2012-07-31 Dexcom, Inc. Analyte sensor
US7857760B2 (en) 2004-07-13 2010-12-28 Dexcom, Inc. Analyte sensor
US9044199B2 (en) 2004-07-13 2015-06-02 Dexcom, Inc. Transcutaneous analyte sensor
US7905833B2 (en) 2004-07-13 2011-03-15 Dexcom, Inc. Transcutaneous analyte sensor
US8483791B2 (en) 2004-07-13 2013-07-09 Dexcom, Inc. Transcutaneous analyte sensor
US8792954B2 (en) 2004-07-13 2014-07-29 Dexcom, Inc. Transcutaneous analyte sensor
US9414777B2 (en) 2004-07-13 2016-08-16 Dexcom, Inc. Transcutaneous analyte sensor
US7920906B2 (en) 2005-03-10 2011-04-05 Dexcom, Inc. System and methods for processing analyte sensor data for sensor calibration
US8744546B2 (en) 2005-05-05 2014-06-03 Dexcom, Inc. Cellulosic-based resistance domain for an analyte sensor
US9078607B2 (en) 2005-11-01 2015-07-14 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8920319B2 (en) 2005-11-01 2014-12-30 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8915850B2 (en) 2005-11-01 2014-12-23 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US9326716B2 (en) 2005-11-01 2016-05-03 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8562558B2 (en) 2007-06-08 2013-10-22 Dexcom, Inc. Integrated medicament delivery device for use with continuous analyte sensor
US9741139B2 (en) 2007-06-08 2017-08-22 Dexcom, Inc. Integrated medicament delivery device for use with continuous analyte sensor
WO2010033724A3 (en) * 2008-09-19 2010-05-20 Dexcom, Inc. Particle-containing membrane and particulate electrode for analyte sensors
US9339222B2 (en) 2008-09-19 2016-05-17 Dexcom, Inc. Particle-containing membrane and particulate electrode for analyte sensors
US8560039B2 (en) 2008-09-19 2013-10-15 Dexcom, Inc. Particle-containing membrane and particulate electrode for analyte sensors

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US20110021895A1 (en) 2011-01-27 application
US8414750B2 (en) 2013-04-09 grant
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US20090137889A1 (en) 2009-05-28 application
US8414749B2 (en) 2013-04-09 grant

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