Patent Grant
11399745
The present invention relates generally to systems and methods for measuring an analyte concentration in a host.
Diabetes mellitus is a disorder in which the pancreas cannot create sufficient insulin (Type I or insulin dependent) and/or in which insulin is not effective (Type 2 or non-insulin dependent). In the diabetic state, the victim suffers from high blood sugar, which may cause an array of physiological derangements (for example, kidney failure, skin ulcers, or bleeding into the vitreous of the eye) associated with the deterioration of small blood vessels. A hypoglycemic reaction (low blood sugar) may be induced by an inadvertent overdose of insulin, or after a normal dose of insulin or glucose-lowering agent accompanied by extraordinary exercise or insufficient food intake.
Conventionally, a diabetic person carries a self-monitoring blood glucose (SMBG) monitor, which typically comprises uncomfortable finger pricking methods. Due to the lack of comfort and convenience, a diabetic will normally only measure his or her glucose level two to four times per day. Unfortunately, these time intervals are so far spread apart that the diabetic will likely find out too late, sometimes incurring dangerous side effects, of a hyper- or hypo-glycemic condition. In fact, it is not only unlikely that a diabetic will take a timely SMBG value, but the diabetic will not know if their blood glucose value is going up (higher) or down (lower) based on conventional methods, inhibiting their ability to make educated insulin therapy decisions.
A variety of continuous glucose sensors have been developed for detecting and/or quantifying glucose concentration in a host. These sensors have typically required one or more blood glucose measurements, or the like, from which to calibrate the continuous glucose sensor to calculate the relationship between the current output of the sensor and blood glucose measurements, to provide meaningful values to a patient or doctor. Unfortunately, continuous glucose sensors are conventionally also sensitive to non-glucose related changes in the baseline current and sensitivity over time, for example, due to changes in a host's metabolism, maturation of the tissue at the biointerface of the sensor, interfering species which cause a measurable increase or decrease in the signal, or the like. Therefore, in addition to initial calibration, continuous glucose sensors should be responsive to baseline and/or sensitivity changes over time, which requires recalibration of the sensor. Consequently, users of continuous glucose sensors have typically been required to obtain numerous blood glucose measurements daily and/or weekly in order to maintain calibration of the sensor over time.
In a first aspect, a continuous glucose sensor is provided, the sensor comprising a first working electrode comprising a first electroactive surface disposed beneath an active enzymatic portion of a sensor membrane, wherein the first working electrode is configured to generate a first signal having a first noise component related to a noise-causing species; and a second working electrode comprising a second electroactive surface disposed beneath an inactive-enzymatic or a non-enzymatic portion of the sensor membrane, wherein the second working electrode is configured to generate a second signal having a second noise component related to the noise-causing species; wherein the first electroactive surface and the second electroactive surface are each dimensioned to integrate at least one signal generated by a plurality of local point sources that produce the noise-causing species, such that the first noise component and the second noise component are substantially equivalent.
In an embodiment of the first aspect, at least one dimension of each of the first electroactive surface and second electroactive surface is greater than a sum of diameters of about 10 average human cells.
In an embodiment of the first aspect, at least one dimension of each of the first electroactive surface and second electroactive surface is greater than about 500 μm.
In an embodiment of the first aspect, each of the first electroactive surface and second electroactive surface is configured and arranged to integrate noise detected about a circumference of the sensor.
In an embodiment of the first aspect, the noise-causing species comprises at least one member selected from the group consisting of externally produced H2O2, urea, lactic acid, phosphates, citrates, peroxides, amino acids, amino acid precursors, amino acid break-down products, nitric oxide, NO-donors, NO-precursors, reactive oxygen species, compounds having electroactive acidic, amine or sulfhydryl groups, acetaminophen, ascorbic acid, dopamine, ephedrine, ibuprofen, L-dopa, methyldopa, salicylate, tetracycline, tolazamide, tolbutamide, and triglycerides.
In an embodiment of the first aspect, the noise-causing species is non-constant.
In an embodiment of the first aspect, the first electroactive surface and second electroactive surface are spaced at a distance that allows noise caused by a local point source that produces noise-causing species to be measured equivalently at the first electroactive surface and the second electroactive surface.
In an embodiment of the first aspect, the first electroactive surface and second electroactive surface are spaced at a distance less than a crosstalk diffusion distance of a measured species.
In an embodiment of the first aspect, the measured species comprises H2O2 produced in the active enzymatic portion of the sensor membrane.
In an embodiment of the first aspect, the sensor further comprises a physical diffusion barrier configured and arranged to physically block crosstalk from the active enzymatic portion of the sensor membrane to the second electroactive surface by at least 50%.
In an embodiment of the first aspect, the physical diffusion barrier is configured and arranged to physically block an amount of the measured species diffusing from the active enzymatic portion of the membrane to the second electroactive surface, such that there is substantially no signal associated with crosstalk measured at the second working electrode.
In an embodiment of the first aspect, the sensor further comprises a physical diffusion barrier comprising a discontinuous portion of a membrane disposed between the first electroactive surface and the second electroactive surface.
In an embodiment of the first aspect, the physical diffusion barrier comprises a first barrier layer formed on the first working electrode and a second barrier layer formed on the second working electrode, wherein the first barrier layer and the second barrier layer are each independently formed.
In an embodiment of the first aspect, the physical diffusion barrier comprises a first resistance domain formed on the first working electrode and a second resistance domain formed on the second working electrode, and the sensor membrane further comprises a third resistance domain disposed continuously over the first and second resistance domains, wherein the first resistance domain and the second resistance domain are configured and arranged to attenuate diffusion of the measurable species from the active enzymatic portion of the sensor to the second electroactive surface by at least 2-fold, and the third resistance domain is configured such that a sensitivity of each of the first signal and the second signal is substantially equivalent.
In an embodiment of the first aspect, the physical diffusion barrier is configured and arranged to attenuate the diffusion of the measured species by at least 10-fold.
In an embodiment of the first aspect, the sensitivities of the first signal and the second signals are within 20% of each other.
In a second aspect, a continuous glucose sensor configured for insertion into a host and for detecting glucose in the host is provided, the sensor comprising a first working electrode comprising a first electroactive surface disposed beneath an active enzymatic portion of a sensor membrane, wherein the first working electrode is configured to generate a first signal having a first noise component related to a noise-causing species; a second working electrode comprising a second electroactive surface disposed beneath an inactive-enzymatic or a non-enzymatic portion of the sensor membrane, wherein the second working electrode is configured to generate a second signal having a second noise component related to the noise-causing species; and a physical diffusion barrier; wherein the first electroactive surface and the second electroactive surface are spaced at a distance that allows noise caused by a local point source that produces noise-causing species to be measured substantially equivalently at the first electroactive surface and the second electroactive surface.
In an embodiment of the second aspect, the sensor membrane has a thickness, and wherein the distance between the first electroactive surface and the second electroactive surface is less than about twice the thickness of the sensor membrane.
In an embodiment of the second aspect, the thickness of the sensor membrane is less than about 80 microns.
In an embodiment of the second aspect, the distance between the first electroactive surface and the second electroactive surface is less than or equal to about a crosstalk diffusion distance of a measurable species.
In an embodiment of the second aspect, the measurable species comprises H2O2 produced in the active enzymatic portion of the sensor membrane.
In an embodiment of the second aspect, the noise-causing species comprises at least one member selected from the group consisting of externally produced H2O2, urea, lactic acid, phosphates, citrates, peroxides, amino acids, amino acid precursors, amino acid break-down products, nitric oxide, NO-donors, NO-precursors, reactive oxygen species, compounds having electroactive acidic, amine or sulfhydryl groups, acetaminophen, ascorbic acid, dopamine, ephedrine, ibuprofen, L-dopa, methyldopa, salicylate, tetracycline, tolazamide, tolbutamide, and triglycerides.
In an embodiment of the second aspect, the active enzymatic portion of the membrane is configured to produce a measurable species, and wherein the physical diffusion barrier is configured and arranged to physically block at least some diffusion of the measurable species from the active enzymatic portion of the membrane to the second electroactive surface.
In an embodiment of the second aspect, the physical diffusion barrier is configured and arranged to physically block at least 50% of the measurable species diffusing from the active enzymatic portion of the membrane to the second electroactive surface, such that there is substantially no signal associated with crosstalk measured at the second working electrode.
In an embodiment of the second aspect, the measurable species comprises H2O2 produced in the active enzymatic portion of the sensor membrane.
In an embodiment of the second aspect, the physical diffusion barrier comprises a discontinuous portion of the membrane disposed between the first electroactive surface and the second electroactive surface.
In an embodiment of the second aspect, the physical diffusion barrier comprises a first barrier layer formed on the first electrode and a second barrier layer formed on the second electrode, wherein each of the first barrier layer and the second barrier layer is independently formed.
In an embodiment of the second aspect, the physical diffusion barrier comprises a first resistance domain formed on the first electrode and a second resistance domain formed on the second electrode, and wherein the first resistance domain and the second resistance domain are configured and arranged to attenuate diffusion of the measurable species from the active enzymatic portion of the membrane to the second electroactive surface by at least 2-fold.
In an embodiment of the second aspect, the physical diffusion barrier is configured and arranged to attenuate the diffusion of the measurable species by at least 10-fold.
In an embodiment of the second aspect, the sensor membrane further comprises a third resistance domain disposed continuously over the first electroactive surface and the second electroactive surface, wherein the third resistance domain is configured such that a sensitivity of each of the first signal and the second signal is substantially equivalent.
In an embodiment of the second aspect, the sensor further comprises an insulator configured to insulate the first working electrode from the second working electrode, wherein the sensor membrane is the insulator.
In an embodiment of the second aspect, the first electroactive surface and the second electroactive surface are each dimensioned to integrate noise caused by a plurality of local point sources that produce noise-causing species in vivo.
In an embodiment of the second aspect, the first electroactive surface and the second electroactive surface are each sized in at least one dimension such that each of the first noise component and second noise component can be integrated across the dimension.
In an embodiment of the second aspect, the dimension is greater than a sum of diameters of about 10 average human cells.
In an embodiment of the second aspect, each of the first electroactive surface and the second electroactive surface is dimensioned such that each of the first noise component and the second noise component is substantially equivalent.
In a third aspect, a sensor configured and arranged for insertion into a host and for continuously detecting glucose in the host is provided, the sensor comprising a first working electrode configured to generate a first signal having a first noise component related to a noise-causing species, the first working electrode having a first electroactive surface having a first surface area; and a second working electrode configured to generate a second signal having a second noise component related to the noise-causing species, the second working electrode having a second electroactive surface having a second surface area; wherein the first working electrode and the second working electrode are configured and arranged to integrate the first noise component and the second noise component about a circumference of the sensor.
In an embodiment of the third aspect, the noise-causing species comprises at least one member selected from the group consisting of externally produced H2O2, urea, lactic acid, phosphates, citrates, peroxides, amino acids, amino acid precursors, amino acid break-down products, nitric oxide, NO-donors, NO-precursors, reactive oxygen species, compounds having electroactive acidic, amine or sulfhydryl groups, acetaminophen, ascorbic acid, dopamine, ephedrine, ibuprofen, L-dopa, methyldopa, salicylate, tetracycline, tolazamide, tolbutamide, and triglycerides.
In an embodiment of the third aspect, the noise-causing species is non-constant.
In an embodiment of the third aspect, the first surface area and the second surface area are each dimensioned to integrate noise caused by a plurality of local point sources that produce noise-causing species in vivo.
In an embodiment of the third aspect, the first surface area and the second surface area are each sized in at least one dimension such that each of the first noise component and the second noise component can be integrated across the dimension.
In an embodiment of the third aspect, the dimension is greater than a sum of diameters of about 10 average human cells.
In an embodiment of the third aspect, the dimension is greater than about 500 μm.
In an embodiment of the third aspect, the first surface area and the second surface area are each dimensioned such that each of the first noise component and the second noise component is substantially equivalent.
In an embodiment of the third aspect, the first surface area and the second surface area are each dimensioned such that each of the first noise component and the second noise component is equivalent to ±10%.
In an embodiment of the third aspect, the first electroactive surface and the second electroactive surface are spaced a distance that allows noise caused by a local point source that produces noise-causing species to be measured equivalently at the first electroactive surface and the second electroactive surface.
In an embodiment of the third aspect, the first electroactive surface is disposed beneath an active enzymatic portion of a sensor membrane and the second electroactive surface is disposed beneath at least one of an inactive enzymatic or a non-enzymatic portion of the sensor membrane, and wherein the first electroactive surface and the second electroactive surface are spaced a distance less than about a crosstalk distance of a measurable species produced in the active enzymatic portion of the sensor membrane.
In an embodiment of the third aspect, the measurable species comprises H2O2.
In an embodiment of the third aspect, the crosstalk distance comprises a maximum distance the measurable species can diffuse from the active enzymatic portion of the sensor membrane to the second electroactive surface, and thereby cause a measurable signal on the second working electrode.
In an embodiment of the third aspect, the sensor further comprises a physical diffusion barrier.
In an embodiment of the third aspect, the physical diffusion barrier comprises a first barrier layer formed on the first working electrode and a second barrier layer formed on the second working electrode, wherein each of the first barrier layer and the second barrier layer is independently formed.
In an embodiment of the third aspect, the physical diffusion barrier comprises a first resistance domain formed on the first working electrode and a second resistance domain formed on the second working electrode, and wherein the first resistance domain and the second resistance domain are configured and arranged to attenuate diffusion of the measurable species from the active enzymatic portion of the membrane to the second electroactive surface by at least 2-fold.
In an embodiment of the third aspect, the physical diffusion barrier is configured and arranged to attenuate the diffusion of the measurable species by at least 10-fold.
In an embodiment of the third aspect, the sensor membrane further comprises a third resistance domain disposed continuously over the first resistance domain and the second resistance domain, wherein the third resistance domain is configured such that a sensitivity of each of the first signal and the second signal is substantially equivalent.
In an embodiment of the third aspect, the sensor further comprises an insulator configured to insulate the first working electrode from the second working electrode, wherein the sensor membrane is the insulator.
In a fourth aspect, a continuous glucose sensor configured and arranged for insertion into a host and for detecting glucose in the host is provided, the sensor comprising a first working electrode comprising a first electroactive surface disposed beneath an active enzymatic portion of a sensor membrane, wherein the first electroactive surface is configured to measure a measurable species; a second working electrode comprising a second electroactive surface disposed beneath at least one of an inactive enzymatic portion of the sensor membrane and a non-enzymatic portion of the sensor membrane, wherein the second electroactive surface is configured to measure said measurable species, and wherein the first electroactive surface and the second electroactive surface are spaced within a crosstalk distance of the measurable species; and a physical diffusion barrier disposed between the first working electrode and the second working electrode, wherein the physical diffusion barrier is configured and arranged such that there is substantially no signal associated with crosstalk.
In an embodiment of the fourth aspect, the noise-causing species comprises at least one member selected from the group consisting of externally produced H2O2, urea, lactic acid, phosphates, citrates, peroxides, amino acids, amino acid precursors, amino acid break-down products, nitric oxide, NO-donors, NO-precursors, reactive oxygen species, compounds having electroactive acidic, amine or sulfhydryl groups, acetaminophen, ascorbic acid, dopamine, ephedrine, ibuprofen, L-dopa, methyldopa, salicylate, tetracycline, tolazamide, tolbutamide, and triglycerides.
In an embodiment of the fourth aspect, the noise-causing species is non-constant.
In an embodiment of the fourth aspect, the measurable species is H2O2 produced in an active enzymatic portion of a sensor membrane.
In an embodiment of the fourth aspect, the crosstalk distance is a maximum distance the measurable species can diffuse between the active enzymatic portion of the membrane and the second working electrode, and be detected as crosstalk.
In an embodiment of the fourth aspect, the first electroactive surface has a first area and the second electroactive surface has a second area; wherein the first area and the second area are dimensioned such that the first noise component and the second noise component are substantially equivalent.
In an embodiment of the fourth aspect, at least one dimension of each of the first area and the second area is greater than a sum of diameters of about 10 average human cells.
In an embodiment of the fourth aspect, at least one dimension of each of the first area and the second area is greater than about 500 μm.
In an embodiment of the fourth aspect, the first area and the second area are each configured and arranged to integrate noise caused by a plurality of local point sources that produce noise-causing species in vivo.
In an embodiment of the fourth aspect, the first area and the second area are each configured and arranged to integrate noise detected about a circumference of the sensor.
In an embodiment of the fourth aspect, the physical diffusion barrier comprises a discontinuous portion of the membrane disposed between the first electroactive surface and the second electroactive surface.
In an embodiment of the fourth aspect, the physical diffusion barrier comprises a first barrier layer formed on the first working electrode and a second barrier layer formed on the second working electrode, wherein the first barrier layer and the second barrier layer are independently formed.
In an embodiment of the fourth aspect, the physical diffusion barrier comprises a first resistance domain formed on the first working electrode and a second resistance domain formed on the second working electrode, and wherein the first resistance domain and the second resistance domain are configured and arranged to attenuate diffusion of the measurable species from the active enzymatic portion of the membrane to the second electroactive surface by at least 2-fold.
In an embodiment of the fourth aspect, the physical diffusion barrier is configured and arranged to attenuate the diffusion of the measurable species by at least 10-fold.
In an embodiment of the fourth aspect, the sensor membrane further comprises a third resistance domain disposed continuously over the first resistance domain and the second resistance domain, wherein the third resistance domain is configured such that a sensitivity of each of the first signal and the second signal is substantially equivalent.
In an embodiment of the fourth aspect, the sensor further comprises an insulator configured to insulate the first working electrode from the second working electrode, wherein the sensor membrane is the insulator.
In an embodiment of the fourth aspect, the first electroactive surface and the second electroactive surface are spaced a distance that allows noise caused by a local point source that produces noise-causing species to be measured equivalently at the first electroactive surface and the second electroactive surface.
In a fifth aspect, a continuous glucose sensor configured and arranged for insertion into a host for and detecting glucose in the host is provided, the sensor comprising a first working electrode comprising a first resistance domain, wherein the first working electrode is configured to generate a first signal having a first noise component related to a noise-causing species; a second working electrode comprising a second resistance domain, wherein the second working electrode is configured to generate a second signal having a second noise component related to the noise-causing species; and a third resistance domain disposed continuously over the first resistance domain and the second resistance domain.
In an embodiment of the fifth aspect, the noise-causing species comprises at least one member selected from the group consisting of externally produced H2O2, urea, lactic acid, phosphates, citrates, peroxides, amino acids, amino acid precursors, amino acid break-down products, nitric oxide, NO-donors, NO-precursors, reactive oxygen species, compounds having electroactive acidic, amine or sulfhydryl groups, acetaminophen, ascorbic acid, dopamine, ephedrine, ibuprofen, L-dopa, methyldopa, salicylate, tetracycline, tolazamide, tolbutamide, and triglycerides.
In an embodiment of the fifth aspect, the noise-causing species is non-constant.
In an embodiment of the fifth aspect, the first signal comprises a first sensitivity and the second signal comprises a second sensitivity, and wherein the third resistance domain is configured such that the first sensitivity and the second sensitivity are substantially equivalent.
In an embodiment of the fifth aspect, the first sensitivity and the second sensitivity are equivalent to ±10%.
In an embodiment of the fifth aspect, each of the first resistance domain and the second resistance domain is independently formed on the first working electrode and the second working electrode, respectively.
In an embodiment of the fifth aspect, the first working electrode comprises a first electroactive surface and a first membrane portion disposed thereon, the first membrane portion comprising an active enzymatic enzyme domain and the first resistance domain, and wherein the second working electrode comprises a second electroactive surface and a second membrane portion disposed thereon, the second membrane portion comprising at least one of an inactive enzymatic portion or a non-enzymatic portion and the second resistance domain.
In an embodiment of the fifth aspect, the active enzymatic enzyme domain is configured to generate a measurable species.
In an embodiment of the fifth aspect, the measurable species comprises H2O2 produced in the active enzymatic portion of the sensor membrane.
In an embodiment of the fifth aspect, the sensor further comprises a physical diffusion barrier, wherein physical diffusion barrier comprises the first resistance domain and the second resistance domain.
In an embodiment of the fifth aspect, the physical diffusion barrier is configured and arranged to attenuate diffusion of the measurable species from the active enzymatic enzyme domain to the second electroactive surface by at least 2-fold.
In an embodiment of the fifth aspect, the diffusion is attenuated by at least 10-fold.
In an embodiment of the fifth aspect, the physical diffusion barrier is configured and arranged to physically block some crosstalk from the active enzymatic enzyme domain to the second electroactive surface.
In an embodiment of the fifth aspect, the physical diffusion barrier is configured and arranged to physically block an amount of a measurable species diffusing from the active enzymatic enzyme domain to the second electroactive surface, such that there is substantially no signal associated with crosstalk measured at the second working electrode.
In an embodiment of the fifth aspect, the physical diffusion barrier comprises a first barrier layer formed on the first working electrode and a second barrier layer formed on the second working electrode, wherein each of the first barrier layer and the second barrier layer is independently formed.
In an embodiment of the fifth aspect, the first electroactive surface and the second electroactive surface are spaced closer together than a crosstalk distance.
In an embodiment of the fifth aspect, the crosstalk distance comprises a distance less than a maximum distance the measurable species can diffuse, and generate a signal associated with crosstalk.
In an embodiment of the fifth aspect, the first electroactive surface and the second electroactive surface are spaced a distance that allows noise caused by a local point source that produces noise-causing species to be measured equivalently at the first and second electroactive surfaces.
In an embodiment of the fifth aspect, each of the first electroactive surface and the second electroactive surface is configured and arranged to integrate the signal caused by a plurality of local point sources that produce noise-causing species in vivo, such that the first noise component and the second noise component are substantially equivalent.
In an embodiment of the fifth aspect, the first electroactive surface and the second electroactive surface are configured and arranged to integrate signals detected about a circumference of the sensor.
In an embodiment of the fifth aspect, the first electroactive surface and the second electroactive surface are each sized in at least one dimension such that the first noise component and the second noise component can be integrated across the dimension.
In an embodiment of the fifth aspect, the dimension of each of the first electroactive surface and the second electroactive surface is greater than a sum of diameters of about 10 average human cells.
In an embodiment of the fifth aspect, the dimension of each of the first electroactive surface and the second electroactive surface is greater than about 500 μm.
FIG. 7A1 is a schematic of one embodiment of a coaxial sensor having axis A-A.
FIG. 7A2 is a cross-section of the sensor shown in FIG. 7A1.
The following description and examples illustrate some exemplary embodiments of the disclosed invention in detail. Those of skill in the art will recognize that there are numerous variations and modifications of this invention that are encompassed by its scope. Accordingly, the description of a certain exemplary embodiment should not be deemed to limit the scope of the present invention.
In order to facilitate an understanding of the disclosed invention, a number of terms are defined below.
The term “analyte” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to a substance or chemical constituent in a biological fluid (for example, blood, interstitial fluid, cerebral spinal fluid, lymph fluid or urine) that can be analyzed. Analytes may include naturally occurring substances, artificial substances, metabolites, and/or reaction products. In some embodiments, the analyte for measurement by the sensor heads, devices, and methods disclosed herein is glucose. However, other analytes are contemplated as well, including but not limited to acarboxyprothrombin; acylcarnitine; adenine phosphoribosyl transferase; adenosine deaminase; albumin; alpha-fetoprotein; amino acid profiles (arginine (Krebs cycle), histidine/urocanic acid, homocysteine, phenylalanine/tyrosine, tryptophan); andrenostenedione; antipyrine; arabinitol enantiomers; arginase; benzoylecgonine (cocaine); biotinidase; biopterin; c-reactive protein; carnitine; carnosinase; CD4; ceruloplasmin; chenodeoxycholic acid; chloroquine; cholesterol; cholinesterase; conjugated 1-ß hydroxy-cholic acid; cortisol; creatine kinase; creatine kinase MM isoenzyme; cyclosporin A; d-penicillamine; de-ethylchloroquine; dehydroepiandrosterone sulfate; DNA (acetylator polymorphism, alcohol dehydrogenase, alpha 1-antitrypsin, cystic fibrosis, Duchenne/Becker muscular dystrophy, analyte-6-phosphate dehydrogenase, hemoglobinopathies, A,S,C,E, D-Punjab, beta-thalassemia, hepatitis B virus, HCMV, HIV-1, HTLV-1, Leber hereditary optic neuropathy, MCAD, RNA, PKU, Plasmodium vivax, sexual differentiation, 21-deoxycortisol); desbutylhalofantrine; dihydropteridine reductase; diptheria/tetanus antitoxin; erythrocyte arginase; erythrocyte protoporphyrin; esterase D; fatty acids/acylglycines; free ß-human chorionic gonadotropin; free erythrocyte porphyrin; free thyroxine (FT4); free tri-iodothyronine (FT3); fumarylacetoacetase; galactose/gal-1-phosphate; galactose-1-phosphate uridyltransferase; gentamicin; analyte-6-phosphate dehydrogenase; glutathione; glutathione perioxidase; glycocholic acid; glycosylated hemoglobin; halofantrine; hemoglobin variants; hexosaminidase A; human erythrocyte carbonic anhydrase I; 17 alpha-hydroxyprogesterone; hypoxanthine phosphoribosyl transferase; immunoreactive trypsin; lactate; lead; lipoproteins ((a), B/A-1, ß); lysozyme; mefloquine; netilmicin; phenobarbitone; phenytoin; phytanic/pristanic acid; progesterone; prolactin; prolidase; purine nucleoside phosphorylase; quinine; reverse tri-iodothyronine (rT3); selenium; serum pancreatic lipase; sissomicin; somatomedin C; specific antibodies (adenovirus, anti-nuclear antibody, anti-zeta antibody, arbovirus, Aujeszky's disease virus, dengue virus, Dracunculus medinensis, Echinococcus granulosus, Entamoeba histolytica, enterovirus, Giardia duodenalisa, Helicobacter pylori, hepatitis B virus, herpes virus, HIV-1, IgE (atopic disease), influenza virus, Leishmania donovani, leptospira, measles/mumps/rubella, Mycobacterium leprae, Mycoplasma pneumoniae, Myoglobin, Onchocerca volvulus, parainfluenza virus, Plasmodium falciparum, poliovirus, Pseudomonas aeruginosa, respiratory syncytial virus, rickettsia (scrub typhus), Schistosoma mansoni, Toxoplasma gondii, Trepenoma pallidium, Trypanosoma cruzi/rangeli, vesicular stomatis virus, Wuchereria bancrofti, yellow fever virus); specific antigens (hepatitis B virus, HIV-1); succinylacetone; sulfadoxine; theophylline; thyrotropin (TSH); thyroxine (T4); thyroxine-binding globulin; trace elements; transferrin; UDP-galactose-4-epimerase; urea; uroporphyrinogen I synthase; vitamin A; white blood cells; and zinc protoporphyrin. Salts, sugar, protein, fat, vitamins, and hormones naturally occurring in blood or interstitial fluids may also constitute analytes in certain embodiments. The analyte may be naturally present in the biological fluid, for example, a metabolic product, a hormone, an antigen, an antibody, and the like. Alternatively, the analyte may be introduced into the body, for example, a contrast agent for imaging, a radioisotope, a chemical agent, a fluorocarbon-based synthetic blood, or a drug or pharmaceutical composition, including but not limited to insulin; ethanol; cannabis (marijuana, tetrahydrocannabinol, hashish); inhalants (nitrous oxide, amyl nitrite, butyl nitrite, chlorohydrocarbons, hydrocarbons); cocaine (crack cocaine); stimulants (amphetamines, methamphetamines, Ritalin, Cylert, Preludin, Didrex, PreState, Voranil, Sandrex, Plegine); depressants (barbituates, methaqualone, tranquilizers such as Valium, Librium, Miltown, Serax, Equanil, Tranxene); hallucinogens (phencyclidine, lysergic acid, mescaline, peyote, psilocybin); narcotics (heroin, codeine, morphine, opium, meperidine, Percocet, Percodan, Tussionex, Fentanyl, Darvon, Talwin, Lomotil); designer drugs (analogs of fentanyl, meperidine, amphetamines, methamphetamines, and phencyclidine, for example, Ecstasy); anabolic steroids; and nicotine. The metabolic products of drugs and pharmaceutical compositions are also contemplated analytes. Analytes such as neurochemicals and other chemicals generated within the body may also be analyzed, such as, for example, ascorbic acid, uric acid, dopamine, noradrenaline, 3-methoxytyramine (3MT), 3,4-Dihydroxyphenylacetic acid (DOPAC), Homovanillic acid (HVA), 5-Hydroxytryptamine (5HT), and 5-Hydroxyindoleacetic acid (FHIAA).
The term “continuous glucose sensor” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to a device that continuously or continually measures glucose concentration, for example, at time intervals ranging from fractions of a second up to, for example, 1, 2, or 5 minutes, or longer. It should be understood that continuous glucose sensors can continually measure glucose concentration without requiring user initiation and/or interaction for each measurement, such as described with reference to U.S. Pat. No. 6,001,067, for example.
The phrase “continuous glucose sensing” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to the period in which monitoring of plasma glucose concentration is continuously or continually performed, for example, at time intervals ranging from fractions of a second up to, for example, 1, 2, or 5 minutes, or longer.
The term “biological sample” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to a sample of a host body, for example, blood, interstitial fluid, spinal fluid, saliva, urine, tears, sweat, tissue, and the like.
The term “host” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to plants or animals, for example humans.
The term “biointerface membrane” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to a permeable or semi-permeable membrane that can include one or more domains and is typically constructed of materials of a few microns thickness or more, which can be placed over the sensing region to keep host cells (for example, macrophages) from gaining proximity to, and thereby damaging the membrane system or forming a barrier cell layer and interfering with the transport of glucose across the tissue-device interface.
The term “membrane system” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to a permeable or semi-permeable membrane that can be comprised of one or more domains and is typically constructed of materials of a few microns thickness or more, which may be permeable to oxygen and are optionally permeable to glucose. In one example, the membrane system comprises an immobilized glucose oxidase enzyme, which enables an electrochemical reaction to occur to measure a concentration of glucose.
The term “domain” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to regions of a membrane that can be layers, uniform or non-uniform gradients (for example, anisotropic), functional aspects of a material, or provided as portions of the membrane.
The term “copolymer” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to polymers having two or more different repeat units and includes copolymers, terpolymers, tetrapolymers, and the like.
The term “sensing region” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to the region of a monitoring device responsible for the detection of a particular analyte. In one embodiment, the sensing region generally comprises a non-conductive body, at least one electrode, a reference electrode and a optionally a counter electrode passing through and secured within the body forming an electrochemically reactive surface at one location on the body and an electronic connection at another location on the body, and a membrane system affixed to the body and covering the electrochemically reactive surface. In another embodiment, the sensing region generally comprises a non-conductive body, a working electrode (anode), a reference electrode (optionally can be remote from the sensing region), an insulator disposed therebetween, and a multi-domain membrane affixed to the body and covering the electrochemically reactive surfaces of the working and optionally reference electrodes.
The term “electrochemically reactive surface” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to the surface of an electrode where an electrochemical reaction takes place. In one embodiment, a working electrode measures hydrogen peroxide creating a measurable electronic current.
The term “electrochemical cell” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to a device in which chemical energy is converted to electrical energy. Such a cell typically consists of two or more electrodes held apart from each other and in contact with an electrolyte solution. Connection of the electrodes to a source of direct electric current renders one of them negatively charged and the other positively charged. Positive ions in the electrolyte migrate to the negative electrode (cathode) and there combine with one or more electrons, losing part or all of their charge and becoming new ions having lower charge or neutral atoms or molecules; at the same time, negative ions migrate to the positive electrode (anode) and transfer one or more electrons to it, also becoming new ions or neutral particles. The overall effect of the two processes is the transfer of electrons from the negative ions to the positive ions, a chemical reaction.
The term “electrode” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to a conductor through which electricity enters or leaves something such as a battery or a piece of electrical equipment. In one embodiment, the electrodes are the metallic portions of a sensor (e.g., electrochemically reactive surfaces) that are exposed to the extracellular milieu, for detecting the analyte. In some embodiments, the term electrode includes the conductive wires or traces that electrically connect the electrochemically reactive surface to connectors (for connecting the sensor to electronics) or to the electronics.
The term “enzyme” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to a protein or protein-based molecule that speeds up a chemical reaction occurring in a living thing. Enzymes may act as catalysts for a single reaction, converting a reactant (also called an analyte herein) into a specific product. In one exemplary embodiment of a glucose oxidase-based glucose sensor, an enzyme, glucose oxidase (GOX) is provided to react with glucose (the analyte) and oxygen to form hydrogen peroxide.
The term “co-analyte” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to a molecule required in an enzymatic reaction to react with the analyte and the enzyme to form the specific product being measured. In one exemplary embodiment of a glucose sensor, an enzyme, glucose oxidase (GOX) is provided to react with glucose and oxygen (the co-analyte) to form hydrogen peroxide.
The term “constant analyte” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to an analyte that remains relatively constant over a time period, for example over an hour to a day as compared to other variable analytes. For example, in a person with diabetes, oxygen and urea may be relatively constant analytes in particular tissue compartments relative to glucose, which is known to oscillate between about 40 and 400 mg/dL during a 24-hour cycle. Although analytes such as oxygen and urea are known to oscillate to a lesser degree, for example due to physiological processes in a host, they are substantially constant, relative to glucose, and can be digitally filtered, for example low pass filtered, to minimize or eliminate any relatively low amplitude oscillations. Constant analytes other than oxygen and urea are also contemplated.
The term “proximal” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to near to a point of reference such as an origin or a point of attachment. For example, in some embodiments of a membrane system that covers an electrochemically reactive surface, the electrolyte domain is located more proximal to the electrochemically reactive surface than the resistance domain.
The term “distal” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to spaced relatively far from a point of reference, such as an origin or a point of attachment. For example, in some embodiments of a membrane system that covers an electrochemically reactive surface, a resistance domain is located more distal to the electrochemically reactive surfaces than the electrolyte domain.
The term “substantially” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to a sufficient amount that provides a desired function. For example, the interference domain of the preferred embodiments is configured to resist a sufficient amount of interfering species such that tracking of glucose levels can be achieved, which may include an amount greater than 50 percent, an amount greater than 60 percent, an amount greater than 70 percent, an amount greater than 80 percent, or an amount greater than 90 percent of interfering species.
The term “computer” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to machine that can be programmed to manipulate data.
The term “modem” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to an electronic device for converting between serial data from a computer and an audio signal suitable for transmission over a telecommunications connection to another modem.
The terms “processor module” and “microprocessor” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and they are not to be limited to a special or customized meaning), and refer without limitation to a computer system, state machine, processor, or the like designed to perform arithmetic and logic operations using logic circuitry that responds to and processes the basic instructions that drive a computer.
The term “ROM” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to read-only memory, which is a type of data storage device manufactured with fixed contents. ROM is broad enough to include EEPROM, for example, which is electrically erasable programmable read-only memory (ROM).
The term “RAM” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to a data storage device for which the order of access to different locations does not affect the speed of access. RAM is broad enough to include SRAM, for example, which is static random access memory that retains data bits in its memory as long as power is being supplied.
The term “A/D Converter” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to hardware and/or software that converts analog electrical signals into corresponding digital signals.
The term “RF transceiver” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to a radio frequency transmitter and/or receiver for transmitting and/or receiving signals.
The terms “raw data stream” and “data stream” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and they are not to be limited to a special or customized meaning), and refer without limitation to an analog or digital signal directly related to the analyte concentration measured by the analyte sensor. In one example, the raw data stream is digital data in “counts” converted by an A/D converter from an analog signal (for example, voltage or amps) representative of an analyte concentration. The terms broadly encompass a plurality of time spaced data points from a substantially continuous analyte sensor, which comprises individual measurements taken at time intervals ranging from fractions of a second up to, for example, 1, 2, or 5 minutes or longer. In some embodiments, raw data includes one or more values (e.g., digital value) representative of the current flow integrated over time (e.g., integrated value), for example, using a charge counting device, or the like.
The term “counts” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to a unit of measurement of a digital signal. In one example, a raw data stream measured in counts is directly related to a voltage (for example, converted by an A/D converter), which is directly related to current from a working electrode.
The term “electronic circuitry” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to the components (for example, hardware and/or software) of a device configured to process data. In the case of an analyte sensor, the data includes biological information obtained by a sensor regarding the concentration of the analyte in a biological fluid. U.S. Pat. Nos. 4,757,022, 5,497,772 and 4,787,398, which are hereby incorporated by reference in their entirety, describe suitable electronic circuits that can be utilized with devices of certain embodiments.
The term “potentiostat” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to an electrical system that applies a potential between the working and reference electrodes of a two- or three-electrode cell at a preset value and measures the current flow through the working electrode. Typically, the potentiostat forces whatever current is necessary to flow between the working and reference or counter electrodes to keep the desired potential, as long as the needed cell voltage and current do not exceed the compliance limits of the potentiostat.
The terms “operably connected” and “operably linked” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and they are not to be limited to a special or customized meaning), and refer without limitation to one or more components being linked to another component(s) in a manner that allows transmission of signals between the components. For example, one or more electrodes can be used to detect the amount of glucose in a sample and convert that information into a signal; the signal can then be transmitted to an electronic circuit. In this case, the electrode is “operably linked” to the electronic circuit. These terms are broad enough to include wired and wireless connectivity.
The term “smoothing” and “filtering” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and they are not to be limited to a special or customized meaning), and refer without limitation to modification of a set of data to make it smoother and more continuous and remove or diminish outlying points, for example, by performing a moving average of the raw data stream.
The term “algorithm” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to the computational processes (for example, programs) involved in transforming information from one state to another, for example using computer processing.
The term “regression” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to finding a line in which a set of data has a minimal measurement (for example, deviation) from that line. Regression can be linear, non-linear, first order, second order, and so forth. One example of regression is least squares regression.
The term “pulsed amperometric detection” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to an electrochemical flow cell and a controller, which applies the potentials and monitors current generated by the electrochemical reactions. The cell can include one or multiple working electrodes at different applied potentials. Multiple electrodes can be arranged so that they face the chromatographic flow independently (parallel configuration), or sequentially (series configuration).
The term “calibration” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to the relationship and/or the process of determining the relationship between the sensor data and corresponding reference data, which may be used to convert sensor data into meaningful values substantially equivalent to the reference. In some embodiments, namely in continuous analyte sensors, calibration may be updated or recalibrated over time if changes in the relationship between the sensor and reference data occur, for example due to changes in sensitivity, baseline, transport, metabolism, or the like.
The term “sensor analyte values” and “sensor data” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and they are not to be limited to a special or customized meaning), and refer without limitation to data received from a continuous analyte sensor, including one or more time-spaced sensor data points.
The term “reference analyte values” and “reference data” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and they are not to be limited to a special or customized meaning), and refer without limitation to data from a reference analyte monitor, such as a blood glucose meter, or the like, including one or more reference data points. In some embodiments, the reference glucose values are obtained from a self-monitored blood glucose (SMBG) test (for example, from a finger or forearm blood test) or an YSI (Yellow Springs Instruments) test, for example.
The term “matched data pairs” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to reference data (for example, one or more reference analyte data points) matched with substantially time corresponding sensor data (for example, one or more sensor data points).
The terms “interferants” and “interfering species” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and they are not to be limited to a special or customized meaning), and refer without limitation to effects and/or species that interfere with the measurement of an analyte of interest in a sensor to produce a signal that does not accurately represent the analyte measurement. In one example of an electrochemical sensor, interfering species are compounds with an oxidation potential that overlaps with the analyte to be measured, producing a false positive signal. In another example of an electrochemical sensor, interfering species are substantially non-constant compounds (e.g., the concentration of an interfering species fluctuates over time). In yet another example of an electrochemical sensor, an interferent is a “noise-causing species” that causes noise on the sensor. Interfering species include but are not limited to compounds with electroactive acidic, amine or sulfhydryl groups, urea, lactic acid, phosphates, citrates, peroxides, amino acids, amino acid precursors or break-down products, nitric oxide (NO), NO-donors, NO-precursors, acetaminophen, ascorbic acid, bilirubin, cholesterol, creatinine, dopamine, ephedrine, ibuprofen, L-dopa, methyl dopa, salicylate, tetracycline, tolazamide, tolbutamide, triglycerides, and uric acid electroactive species produced during cell metabolism and/or wound healing, electroactive species that arise during body pH changes and the like.
The term “bifunctional” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to having or serving two functions. For example, in a needle-type analyte sensor, a metal wire is bifunctional because it provides structural support and acts as an electrical conductor.
The term “function” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to an action or use for which something is suited or designed.
The term “electrical conductor” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning) and refers without limitation to materials that contain movable charges of electricity. When an electric potential difference is impressed across separate points on a conductor, the mobile charges within the conductor are forced to move, and an electric current between those points appears in accordance with Ohm's law.
Accordingly, the term “electrical conductance” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning) and refers without limitation to the propensity of a material to behave as an electrical conductor. In some embodiments, the term refers to a sufficient amount of electrical conductance (e.g., material property) to provide a necessary function (electrical conduction).
The terms “insulative properties,” “electrical insulator” and “insulator” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning) and refers without limitation to the tendency of materials that lack mobile charges to prevent movement of electrical charges between two points. In one exemplary embodiment, an electrically insulative material may be placed between two electrically conductive materials, to prevent movement of electricity between the two electrically conductive materials. In some embodiments, the terms refer to a sufficient amount of insulative property (e.g., of a material) to provide a necessary function (electrical insulation). The terms “insulator” and “non-conductive material” can be used interchangeably herein.
The term “structural support” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning) and refers without limitation to the tendency of a material to keep the sensor's structure stable or in place. For example, structural support can include “weight bearing” as well as the tendency to hold the parts or components of a whole structure together. A variety of materials can provide “structural support” to the sensor.
The term “diffusion barrier” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning) and refers without limitation to something that obstructs the random movement of compounds, species, atoms, molecules, or ions from one site in a medium to another. In some embodiments, a diffusion barrier is structural, such as a wall that separates two working electrodes and substantially prevents diffusion of a species from one electrode to the other. In some embodiments, a diffusion barrier is spatial, such as separating working electrodes by a distance sufficiently large enough to substantially prevent a species at a first electrode from affecting a second electrode. In other embodiments, a diffusion barrier can be temporal, such as by turning the first and second working electrodes on and off, such that a reaction at a first electrode will not substantially affect the function of the second electrode.
The terms “integral,” “integrally,” “integrally formed,” integrally incorporated,” “unitary” and “composite” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and they are not to be limited to a special or customized meaning), and refer without limitation to the condition of being composed of essential parts or elements that together make a whole. The parts are essential for completeness of the whole. In one exemplary embodiment, at least a portion (e.g., the in vivo portion) of the sensor is formed from at least one platinum wire at least partially covered with an insulative coating, which is at least partially helically wound with at least one additional wire, the exposed electroactive portions of which are covered by a membrane system (see description of
The term “coaxial” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to having a common axis, having coincident axes or mounted on concentric shafts.
The term “twisted” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to united by having one part or end turned in the opposite direction to the other, such as, but not limited to the twisted strands of fiber in a string, yarn, or cable.
The term “helix” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to a spiral or coil, or something in the form of a spiral or coil (e.g. a corkscrew or a coiled spring). In one example, a helix is a mathematical curve that lies on a cylinder or cone and makes a constant angle with the straight lines lying in the cylinder or cone. A “double helix” is a pair of parallel helices intertwined about a common axis, such as but not limited to that in the structure of DNA.
The term “in vivo portion” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to a portion of a device that is to be implanted or inserted into the host. In one exemplary embodiment, an in vivo portion of a transcutaneous sensor is a portion of the sensor that is inserted through the host's skin and resides within the host.
The terms “background,” “baseline,” and “noise” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refer without limitation to a component of an analyte sensor signal that is not related to the analyte concentration. In one example of a glucose sensor, the background is composed substantially of signal contribution due to factors other than glucose (for example, interfering species, non-reaction-related hydrogen peroxide, or other electroactive species with an oxidation potential that overlaps with hydrogen peroxide). In some embodiments wherein a calibration is defined by solving for the equation y=mx+b, the value of b represents the background of the signal. In general, the background (noise) comprises components related to constant and non-constant factors.
The term “constant noise” and “constant background” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refer without limitation to the component of the background signal that remains relatively constant over time. For example, certain electroactive compounds found in the human body are relatively constant factors (e.g., baseline of the host's physiology) and do not significantly adversely affect accuracy of the calibration of the glucose concentration (e.g., they can be relatively constantly eliminated using the equation y=mx+b). In some circumstances, constant background noise can slowly drift over time (e.g., increases or decreases), however this drift need not adversely affect the accuracy of a sensor, for example, because a sensor can be calibrated and re-calibrated and/or the drift measured and compensated for.
The term “non-constant noise” or non-constant background” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refer without limitation to a component of the background signal that is relatively non-constant, for example, transient and/or intermittent. For example, certain electroactive compounds, are relatively non-constant (e.g., intermittent interferents due to the host's ingestion, metabolism, wound healing, and other mechanical, chemical and/or biochemical factors), which create intermittent (e.g., non-constant) “noise” on the sensor signal that can be difficult to “calibrate out” using a standard calibration equations (e.g., because the background of the signal does not remain constant).
The terms “inactive enzyme” or “inactivated enzyme” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refer without limitation to an enzyme (e.g., glucose oxidase, GOx) that has been rendered inactive (e.g., “killed” or “dead”) and has no enzymatic activity. Enzymes can be inactivated using a variety of techniques known in the art, such as but not limited to heating, freeze-thaw, denaturing in organic solvent, acids or bases, cross-linking, genetically changing enzymatically critical amino acids, and the like. In some embodiments, a solution containing active enzyme can be applied to the sensor, and the applied enzyme subsequently inactivated by heating or treatment with an inactivating solvent.
The term “non-enzymatic” as used herein is a broad term, and is to be given their ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to a lack of enzyme activity. In some embodiments, a “non-enzymatic” membrane portion contains no enzyme; while in other embodiments, the “non-enzymatic” membrane portion contains inactive enzyme. In some embodiments, an enzyme solution containing inactive enzyme or no enzyme is applied. In one example of an electrochemical sensor, a non-enzymatic or inactive enzymatic portion of the membrane includes an enzyme domain formed of enzyme domain materials, as described elsewhere herein, and either inactivated enzyme or no enzyme.
The term “GOx” as used herein is a broad term, and is to be given their ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to the enzyme Glucose Oxidase (e.g., GOx is an abbreviation).
The term “equivalent,” as used herein is a broad term, and is to be given their ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to the state of being substantially equal or well matched; having the same or similar quantity, value, amplitude or measure as another. In some embodiments, equivalent amounts are within 20% of each other (e.g., a number plus or minus 10%). In some embodiments, equivalent amounts are within 10% of each other (e.g., a number plus or minus 5%).
The term “measured/measurable species,” as used herein is a broad term, and is to be given their ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to a compound that can be or is detected by an analyte sensor, the amount of which is indicative of the amount of analyte present. The identity of the measure/measurable species is dependent upon what substance (e.g., glucose, urea, creatinine, cholesterol, phosphate) the biosensor in question is configured to detect. In one example, in the case of a diffusion-based glucose biosensor including glucose oxidase (GOx), the measured/measurable species is H2O2, which is produced by the reaction of glucose with the GOx, and is subsequently detected/measured at a working electrode.
The term “crosstalk” as used herein is a broad term, and is to be given their ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to the presence of (e.g., detection of) an unwanted signal via an accidental coupling. In one exemplary circumstance, crosstalk can occur on a glucose sensor having two working electrodes when a measured species (e.g., H2O2) produced at one working electrode diffuses to and is detected by the other working electrode.
The term “crosstalk diffusion distance,” as used herein is a broad term, and is to be given their ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to, in a dual electrode biosensor, the maximum distance a measured species (e.g., H2O2 produced in the active enzymatic portion of the membrane) can diffuse from a first working electrode (e.g., having the active enzymatic portion of the membrane) toward/to a second working electrode (e.g., having the non-enzymatic/inactive enzymatic portion of the membrane) and cause a detectable signal on the second working electrode.
The term “physical diffusion barrier,” as used herein is a broad term, and is to be given their ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to a structure that physically (e.g., other than or in addition to spacing of the electrodes) attenuates diffusion (of a substance/compound/species/molecule) from one side of the barrier to the other. In one example of an electrochemical sensor, a physical diffusion barrier is configured and arranged to attenuate diffusion of H2O2 from a first portion of the sensor to a second portion of the sensor.
The term “comprising” as used herein is synonymous with “including,” “containing,” or “characterized by,” and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.
All numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.
Overview
The preferred embodiments provide a continuous analyte sensor that measures a concentration of the analyte of interest or a substance indicative of the concentration or presence of the analyte. In some embodiments, the analyte sensor is an invasive, minimally invasive, or non-invasive device, for example a subcutaneous, transdermal, or intravascular device. In some embodiments, the analyte sensor may analyze a plurality of intermittent biological samples. The analyte sensor may use any method of analyte-measurement, including enzymatic, chemical, physical, electrochemical, spectrophotometric, polarimetric, calorimetric, radiometric, or the like.
In general, analyte sensors provide at least one working electrode and at least one reference electrode, which are configured to measure a signal associated with a concentration of the analyte in the host, such as described in more detail below, and as appreciated by one skilled in the art. The output signal is typically a raw data stream that is used to provide a useful value of the measured analyte concentration in a host to the patient or doctor, for example. However, the analyte sensors of the preferred embodiments may further measure at least one additional signal. For example, in some embodiments, the additional signal is associated with the baseline and/or sensitivity of the analyte sensor, thereby enabling monitoring of baseline and/or sensitivity changes that may occur in a continuous analyte sensor over time.
In general, continuous analyte sensors define a relationship between sensor-generated measurements (for example, current in nA or digital counts after A/D conversion) and a reference measurement (for example, mg/dL or mmol/L) that are meaningful to a user (for example, patient or doctor). In the case of an implantable enzyme-based electrochemical glucose sensor, the sensing mechanism generally depends on phenomena that are linear with glucose concentration, for example: (1) diffusion of glucose through a membrane system (for example, biointerface membrane and membrane system) situated between implantation site and the electrode surface, (2) an enzymatic reaction within the membrane system (for example, membrane system), and (3) diffusion of the H2O2 to the sensor. Because of this linearity, calibration of the sensor can be understood by solving an equation:
y=Mx+b
where y represents the sensor signal (counts), x represents the estimated glucose concentration (mg/dL), m represents the sensor sensitivity to glucose (counts/mg/dL), and b represents the baseline signal (counts). Because both sensitivity m and baseline (background) b change over time in vivo, calibration has conventionally required at least two independent, matched data pairs (x1, y1; x2, y2) to solve for m and b and thus allow glucose estimation when only the sensor signal, y is available. Matched data pairs can be created by matching reference data (for example, one or more reference glucose data points from a blood glucose meter, or the like) with substantially time corresponding sensor data (for example, one or more glucose sensor data points) to provide one or more matched data pairs, such as described in co-pending U.S. Patent Publication No. US-2005-0027463-A1.
Accordingly, in some embodiments, the sensing region is configured to measure changes in sensitivity of the analyte sensor over time, which can be used to trigger calibration, update calibration, avoid inaccurate calibration (for example, calibration during unstable periods), and/or trigger filtering of the sensor data. Namely, the analyte sensor is configured to measure a signal associated with a non-analyte constant in the host. Preferably, the non-analyte constant signal is measured beneath the membrane system on the sensor. In one example of a glucose sensor, a non-glucose constant that can be measured is oxygen, wherein a measured change in oxygen transport is indicative of a change in the sensitivity of the glucose signal, which can be measured by switching the bias potential of the working electrode, an auxiliary oxygen-measuring electrode, an oxygen sensor, or the like, as described in more detail elsewhere herein.
Alternatively or additionally, in some embodiments, the sensing region is configured to measure changes in the amount of background noise (e.g., baseline) in the signal, which can be used to trigger calibration, update calibration, avoid inaccurate calibration (for example, calibration during unstable periods), and/or trigger filtering of the sensor data. In one example of a glucose sensor, the baseline is composed substantially of signal contribution due to factors other than glucose (for example, interfering species, non-reaction-related hydrogen peroxide, or other electroactive species with an oxidation potential that overlaps with hydrogen peroxide). Namely, the glucose sensor is configured to measure a signal associated with the baseline (all non-glucose related current generated) measured by sensor in the host. In some embodiments, an auxiliary electrode located beneath a non-enzymatic portion of the membrane system is used to measure the baseline signal. In some embodiments, the baseline signal is subtracted from the glucose signal (which includes the baseline) to obtain the signal contribution substantially only due to glucose. Subtraction may be accomplished electronically in the sensor using a differential amplifier, digitally in the receiver, and/or otherwise in the hardware or software of the sensor or receiver as is appreciated by one skilled in the art, and as described in more detail elsewhere herein.
One skilled in the art appreciates that the above-described sensitivity and baseline signal measurements can be combined to benefit from both measurements in a single analyte sensor.
Preferred Sensor Components
In general, sensors of the preferred embodiments describe a variety of sensor configurations, wherein each sensor generally comprises two or more working electrodes, a reference and/or counter electrode, an insulator, and a membrane system. In general, the sensors can be configured to continuously measure an analyte in a biological sample, for example, in subcutaneous tissue, in a host's blood flow, and the like. Although a variety of exemplary embodiments are shown, one skilled in the art appreciates that the concepts and examples here can be combined, reduced, substituted, or otherwise modified in accordance with the teachings of the preferred embodiments and/or the knowledge of one skilled in the art.
Preferably, each exemplary sensor design (e.g.,
Preferably, the working electrode is configured to measure the concentration of an analyte. In an enzymatic electrochemical sensor for detecting glucose, for example, the working electrode measures the hydrogen peroxide produced by an enzyme catalyzed reaction of the analyte being detected and creates a measurable electronic current. For example, in the detection of glucose wherein glucose oxidase produces hydrogen peroxide as a byproduct, hydrogen peroxide (H2O2) reacts with the surface of the working electrode producing two protons (2H+), two electrons (2e−) and one molecule of oxygen (O2), which produces the electronic current being detected.
Preferably, each exemplary sensor design (e.g.,
Preferably, each exemplary sensor design (e.g.,
Preferably, each exemplary sensor design (e.g.,
Preferably, each exemplary sensor design (e.g.,
Preferably, each exemplary sensor design (e.g.,
In general, the membrane system includes a plurality of domains, for example, one or more of an electrode domain 24, an optional interference domain 26, an enzyme domain 28 (for example, including glucose oxidase), and a resistance domain 30, as shown in
In some embodiments, one or more domains of the membrane systems are formed from materials such as silicone, polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene, polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene, homopolymers, copolymers, terpolymers of polyurethanes, polypropylene (PP), polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polybutylene terephthalate (PBT), polymethylmethacrylate (PMMA), polyether ether ketone (PEEK), polyurethanes, cellulosic polymers, polysulfones and block copolymers thereof including, for example, di-block, tri-block, alternating, random and graft copolymers. U.S. Patent Publication No. US-2005-0245799-A1 describes biointerface and membrane system configurations and materials that may be applied to the preferred embodiments.
Electrode Domain
In some embodiments, the membrane system comprises an optional electrode domain 24 (
In one embodiment, the electrode domain includes a flexible, water-swellable, hydrogel film having a “dry film” thickness of from about 0.05 micron or less to about 20 microns or more, more preferably from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and more preferably still from about 2, 2.5 or 3 microns to about 3.5, 4, 4.5, or 5 microns. “Dry film” thickness refers to the thickness of a cured film cast from a coating formulation by standard coating techniques.
In certain embodiments, the electrode domain is formed of a curable mixture of a urethane polymer and a hydrophilic polymer. Particularly preferred coatings are formed of a polyurethane polymer having carboxylate or hydroxyl functional groups and non-ionic hydrophilic polyether segments, wherein the polyurethane polymer is crosslinked with a water-soluble carbodiimide (e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)) in the presence of polyvinylpyrrolidone and cured at a moderate temperature of about 50° C.
In some preferred embodiments, the electrode domain is formed from a hydrophilic polymer such as polyvinylpyrrolidone (PVP). An electrode domain formed from PVP has been shown to reduce break-in time of analyte sensors; for example, a glucose sensor utilizing a cellulosic-based interference domain such as described in more detail below.
Preferably, the electrode domain is deposited by vapor deposition, spray coating, dip coating, or other thin film techniques on the electroactive surfaces of the sensor. In one preferred embodiment, the electrode domain is formed by dip-coating the electroactive surfaces in an electrode layer solution and curing the domain for a time of from about 15 minutes to about 30 minutes at a temperature of from about 40° C. to about 55° C. (and can be accomplished under vacuum (e.g., 20 to 30 mmHg)). In embodiments wherein dip-coating is used to deposit the electrode domain, a preferred insertion rate of from about 1 to about 3 inches per minute into the electrode layer solution, with a preferred dwell time of from about 0.5 to about 2 minutes in the electrode layer solution, and a preferred withdrawal rate of from about 0.25 to about 2 inches per minute from the electrode layer solution provide a functional coating. However, values outside of those set forth above can be acceptable or even desirable in certain embodiments, for example, depending upon solution viscosity and solution surface tension, as is appreciated by one skilled in the art. In one embodiment, the electroactive surfaces of the electrode system are dip-coated one time (one layer) and cured at 50° C. under vacuum for 20 minutes.
Although an independent electrode domain is described herein, in some embodiments sufficient hydrophilicity can be provided in the interference domain and/or enzyme domain (the domain adjacent to the electroactive surfaces) so as to provide for the full transport of ions in the aqueous environment (e.g. without a distinct electrode domain). In these embodiments, an electrode domain is not necessary.
Interference Domain
Interferents are molecules or other species that are reduced or oxidized at the electrochemically reactive surfaces of the sensor, either directly or via an electron transfer agent, to produce a false positive analyte signal. In preferred embodiments, an optional interference domain 26 is provided that substantially restricts, resists, or blocks the flow of one or more interfering species (
In one embodiment, the interference domain is formed from one or more cellulosic derivatives. In general, cellulosic derivatives include polymers such as cellulose acetate, cellulose acetate butyrate, 2-hydroxyethyl cellulose, cellulose acetate phthalate, cellulose acetate propionate, cellulose acetate trimellitate, and the like.
In one preferred embodiment, the interference domain is formed from cellulose acetate butyrate. Cellulose acetate butyrate with a molecular weight of about 10,000 daltons to about 75,000 daltons, preferably from about 15,000, 20,000, or 25,000 daltons to about 50,000, 55,000, 60,000, 65,000, or 70,000 daltons, and more preferably about 20,000 daltons is employed. In certain embodiments, however, higher or lower molecular weights can be preferred. Additionally, a casting solution or dispersion of cellulose acetate butyrate at a weight percent of about 15% to about 25%, preferably from about 15%, 16%, 17%, 18%, 19% to about 20%, 21%, 22%, 23%, 24% or 25%, and more preferably about 18% is preferred. Preferably, the casting solution includes a solvent or solvent system, for example an acetone:ethanol solvent system. Higher or lower concentrations can be preferred in certain embodiments. A plurality of layers of cellulose acetate butyrate can be advantageously combined to form the interference domain in some embodiments, for example, three layers can be employed. It can be desirable to employ a mixture of cellulose acetate butyrate components with different molecular weights in a single solution, or to deposit multiple layers of cellulose acetate butyrate from different solutions comprising cellulose acetate butyrate of different molecular weights, different concentrations, and/or different chemistries (e.g., functional groups). It can also be desirable to include additional substances in the casting solutions or dispersions, e.g., functionalizing agents, crosslinking agents, other polymeric substances, substances capable of modifying the hydrophilicity/hydrophobicity of the resulting layer, and the like.
In one alternative embodiment, the interference domain is formed from cellulose acetate. Cellulose acetate with a molecular weight of about 30,000 daltons or less to about 100,000 daltons or more, preferably from about 35,000, 40,000, or 45,000 daltons to about 55,000, 60,000, 65,000, 70,000, 75,000, 80,000, 85,000, 90,000, or 95,000 daltons, and more preferably about 50,000 daltons is preferred. Additionally, a casting solution or dispersion of cellulose acetate at a weight percent of about 3% to about 10%, preferably from about 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, or 6.5% to about 7.5%, 8.0%, 8.5%, 9.0%, or 9.5%, and more preferably about 8% is preferred. In certain embodiments, however, higher or lower molecular weights and/or cellulose acetate weight percentages can be preferred. It can be desirable to employ a mixture of cellulose acetates with molecular weights in a single solution, or to deposit multiple layers of cellulose acetate from different solutions comprising cellulose acetates of different molecular weights, different concentrations, or different chemistries (e.g., functional groups). It can also be desirable to include additional substances in the casting solutions or dispersions such as described in more detail above.
Layer(s) prepared from combinations of cellulose acetate and cellulose acetate butyrate, or combinations of layer(s) of cellulose acetate and layer(s) of cellulose acetate butyrate can also be employed to form the interference domain.
In some alternative embodiments, additional polymers, such as Nafion®, can be used in combination with cellulosic derivatives to provide equivalent and/or enhanced function of the interference domain. As one example, a 5 wt % Nafion® casting solution or dispersion can be used in combination with a 8 wt % cellulose acetate casting solution or dispersion, e.g., by dip coating at least one layer of cellulose acetate and subsequently dip coating at least one layer Nafion® onto a needle-type sensor such as described with reference to the preferred embodiments. Any number of coatings or layers formed in any order may be suitable for forming the interference domain of the preferred embodiments.
In some alternative embodiments, more than one cellulosic derivative can be used to form the interference domain of the preferred embodiments. In general, the formation of the interference domain on a surface utilizes a solvent or solvent system in order to solvate the cellulosic derivative (or other polymer) prior to film formation thereon. In preferred embodiments, acetone and ethanol are used as solvents for cellulose acetate; however one skilled in the art appreciates the numerous solvents that are suitable for use with cellulosic derivatives (and other polymers). Additionally, one skilled in the art appreciates that the preferred relative amounts of solvent can be dependent upon the cellulosic derivative (or other polymer) used, its molecular weight, its method of deposition, its desired thickness, and the like. However, a percent solute of from about 1% to about 25% is preferably used to form the interference domain solution so as to yield an interference domain having the desired properties. The cellulosic derivative (or other polymer) used, its molecular weight, method of deposition, and desired thickness can be adjusted, depending upon one or more other of the parameters, and can be varied accordingly as is appreciated by one skilled in the art.
In some alternative embodiments, other polymer types that can be utilized as a base material for the interference domain including polyurethanes, polymers having pendant ionic groups, and polymers having controlled pore size, for example. In one such alternative embodiment, the interference domain includes a thin, hydrophobic membrane that is non-swellable and restricts diffusion of low molecular weight species. The interference domain is permeable to relatively low molecular weight substances, such as hydrogen peroxide, but restricts the passage of higher molecular weight substances, including glucose and ascorbic acid. Other systems and methods for reducing or eliminating interference species that can be applied to the membrane system of the preferred embodiments are described in U.S. Patent Publication No. US-2005-0115832-A1, U.S. Patent Publication No. US-2005-0176136-A1, U.S. Patent Publication No. US-2005-0161346-A1, and U.S. Patent Publication No. US-2005-0143635-A1. In some alternative embodiments, a distinct interference domain is not included.
In preferred embodiments, the interference domain is deposited directly onto the electroactive surfaces of the sensor for a domain thickness of from about 0.05 micron or less to about 20 microns or more, more preferably from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and more preferably still from about 1, 1.5 or 2 microns to about 2.5 or 3 microns. Thicker membranes can also be desirable in certain embodiments, but thinner membranes are generally preferred because they have a lower impact on the rate of diffusion of hydrogen peroxide from the enzyme membrane to the electrodes.
In general, the membrane systems of the preferred embodiments can be formed and/or deposited on the exposed electroactive surfaces (e.g., one or more of the working and reference electrodes) using known thin film techniques (for example, casting, spray coating, drawing down, electro-depositing, dip coating, and the like), however casting or other known application techniques can also be utilized. Preferably, the interference domain is deposited by vapor deposition, spray coating, or dip coating. In one exemplary embodiment of a needle-type (transcutaneous) sensor such as described herein, the interference domain is formed by dip coating the sensor into an interference domain solution using an insertion rate of from about 20 inches/min to about 60 inches/min, preferably 40 inches/min, a dwell time of from about 0 minute to about 5 seconds, preferably 0 seconds, and a withdrawal rate of from about 20 inches/minute to about 60 inches/minute, preferably about 40 inches/minute, and curing (drying) the domain from about 1 minute to about 30 minutes, preferably from about 3 minutes to about 15 minutes (and can be accomplished at room temperature or under vacuum (e.g., 20 to 30 mmHg)). In one exemplary embodiment including cellulose acetate butyrate interference domain, a 3-minute cure (i.e., dry) time is preferred between each layer applied. In another exemplary embodiment employing a cellulose acetate interference domain, a 15-minute cure (i.e., dry) time is preferred between each layer applied.
The dip process can be repeated at least one time and up to 10 times or more. The preferred number of repeated dip processes depends upon the cellulosic derivative(s) used, their concentration, conditions during deposition (e.g., dipping) and the desired thickness (e.g., sufficient thickness to provide functional blocking of (or resistance to) certain interferents), and the like. In some embodiments, 1 to 3 microns may be preferred for the interference domain thickness; however, values outside of these can be acceptable or even desirable in certain embodiments, for example, depending upon viscosity and surface tension, as is appreciated by one skilled in the art. In one exemplary embodiment, an interference domain is formed from three layers of cellulose acetate butyrate. In another exemplary embodiment, an interference domain is formed from 10 layers of cellulose acetate. In another exemplary embodiment, an interference domain is formed of one relatively thicker layer of cellulose acetate butyrate. In yet another exemplary embodiment, an interference domain is formed of four relatively thinner layers of cellulose acetate butyrate. In alternative embodiments, the interference domain can be formed using any known method and combination of cellulose acetate and cellulose acetate butyrate, as will be appreciated by one skilled in the art.
In some embodiments, the electroactive surface can be cleaned prior to application of the interference domain. In some embodiments, the interference domain of the preferred embodiments can be useful as a bioprotective or biocompatible domain, namely, a domain that interfaces with host tissue when implanted in an animal (e.g., a human) due to its stability and biocompatibility.
Enzyme Domain
In preferred embodiments, the membrane system further includes an enzyme domain 28 disposed more distally from the electroactive surfaces than the interference domain; however other configurations can be desirable (
For an enzyme-based electrochemical glucose sensor to perform well, the sensor's response is preferably limited by neither enzyme activity nor co-reactant concentration. Because enzymes, including glucose oxidase (GOx), are subject to deactivation as a function of time even in ambient conditions, this behavior is compensated for in forming the enzyme domain. Preferably, the enzyme domain is constructed of aqueous dispersions of colloidal polyurethane polymers including the enzyme. However, in alternative embodiments the enzyme domain is constructed from an oxygen enhancing material, for example, silicone, or fluorocarbon, in order to provide a supply of excess oxygen during transient ischemia. Preferably, the enzyme is immobilized within the domain. See, e.g., U.S. Patent Publication No. US-2005-0054909-A1.
In preferred embodiments, the enzyme domain is deposited onto the interference domain for a domain thickness of from about 0.05 micron or less to about 20 microns or more, more preferably from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and more preferably still from about 2, 2.5 or 3 microns to about 3.5, 4, 4.5, or 5 microns. However in some embodiments, the enzyme domain can be deposited directly onto the electroactive surfaces. Preferably, the enzyme domain is deposited by spray or dip coating. In one embodiment of needle-type (transcutaneous) sensor such as described herein, the enzyme domain is formed by dip coating the interference domain coated sensor into an enzyme domain solution and curing the domain for from about 15 to about 30 minutes at a temperature of from about 40° C. to about 55° C. (and can be accomplished under vacuum (e.g., 20 to 30 mmHg)). In embodiments wherein dip coating is used to deposit the enzyme domain at room temperature, a preferred insertion rate of from about 0.25 inch per minute to about 3 inches per minute, with a preferred dwell time of from about 0.5 minutes to about 2 minutes, and a preferred withdrawal rate of from about 0.25 inch per minute to about 2 inches per minute provides a functional coating. However, values outside of those set forth above can be acceptable or even desirable in certain embodiments, for example, depending upon viscosity and surface tension, as is appreciated by one skilled in the art. In one embodiment, the enzyme domain is formed by dip coating two times (namely, forming two layers) in an enzyme domain solution and curing at 50° C. under vacuum for 20 minutes. However, in some embodiments, the enzyme domain can be formed by dip coating and/or spray coating one or more layers at a predetermined concentration of the coating solution, insertion rate, dwell time, withdrawal rate, and/or desired thickness.
Resistance Domain
In preferred embodiments, the membrane system includes a resistance domain 30 disposed more distal from the electroactive surfaces than the enzyme domain (
There exists a molar excess of glucose relative to the amount of oxygen in blood; that is, for every free oxygen molecule in extracellular fluid, there are typically more than 100 glucose molecules present (see Updike et al., Diabetes Care 5:207-21(1982)). However, an immobilized enzyme-based glucose sensor employing oxygen as co-reactant is preferably supplied with oxygen in non-rate-limiting excess in order for the sensor to respond linearly to changes in glucose concentration, while not responding to changes in oxygen concentration. Specifically, when a glucose-monitoring reaction is oxygen limited, linearity is not achieved above minimal concentrations of glucose. Without a semipermeable membrane situated over the enzyme domain to control the flux of glucose and oxygen, a linear response to glucose levels can be obtained only for glucose concentrations of up to about 40 mg/dL. However, in a clinical setting, a linear response to glucose levels is desirable up to at least about 400 mg/dL.
The resistance domain includes a semipermeable membrane that controls the flux of oxygen and glucose to the underlying enzyme domain, preferably rendering oxygen in a non-rate-limiting excess (e.g., by attenuating glucose flux). As a result, the upper limit of linearity of glucose measurement is extended to a much higher value than that which is achieved without the resistance domain. In one embodiment, the resistance domain exhibits an oxygen to glucose permeability ratio of from about 50:1 or less to about 400:1 or more, preferably about 200:1. As a result, one-dimensional reactant diffusion is adequate to provide excess oxygen at all reasonable glucose and oxygen concentrations found in the subcutaneous matrix (See Rhodes et al., Anal. Chem., 66:1520-1529 (1994)).
In alternative embodiments, a lower ratio of oxygen-to-glucose can be sufficient to provide excess oxygen by using a high oxygen solubility domain (for example, a silicone or fluorocarbon-based material or domain) to enhance the supply/transport of oxygen to the enzyme domain. If more oxygen is supplied to the enzyme, then more glucose can also be supplied to the enzyme without creating an oxygen rate-limiting excess. In alternative embodiments, the resistance domain is formed from a silicone composition, such as is described in U.S. Patent Publication No. US-2005-0090607-A1.
In a preferred embodiment, the resistance domain includes a polyurethane membrane with both hydrophilic and hydrophobic regions to control the diffusion of glucose and oxygen to an analyte sensor, the membrane being fabricated easily and reproducibly from commercially available materials. A suitable hydrophobic polymer component is a polyurethane, or polyetherurethaneurea. Polyurethane is a polymer produced by the condensation reaction of a diisocyanate and a difunctional hydroxyl-containing material. A polyurethaneurea is a polymer produced by the condensation reaction of a diisocyanate and a difunctional amine-containing material. Preferred diisocyanates include aliphatic diisocyanates containing from about 4 to about 8 methylene units. Diisocyanates containing cycloaliphatic moieties can also be useful in the preparation of the polymer and copolymer components of the membranes of preferred embodiments. The material that forms the basis of the hydrophobic matrix of the resistance domain can be any of those known in the art as appropriate for use as membranes in sensor devices and as having sufficient permeability to allow relevant compounds to pass through it, for example, to allow an oxygen molecule to pass through the membrane from the sample under examination in order to reach the active enzyme or electrochemical electrodes. Examples of materials which can be used to make non-polyurethane type membranes include vinyl polymers, polyethers, polyesters, polyamides, inorganic polymers such as polysiloxanes and polycarbosiloxanes, natural polymers such as cellulosic and protein based materials, and mixtures or combinations thereof.
In a preferred embodiment, the hydrophilic polymer component is polyethylene oxide. For example, one useful hydrophobic-hydrophilic copolymer component is a polyurethane polymer that includes about 20% hydrophilic polyethylene oxide. The polyethylene oxide portions of the copolymer are thermodynamically driven to separate from the hydrophobic portions of the copolymer and the hydrophobic polymer component. The 20% polyethylene oxide-based soft segment portion of the copolymer used to form the final blend affects the water pick-up and subsequent glucose permeability of the membrane.
In some embodiments, the resistance domain is formed from a silicone polymer modified to allow analyte (e.g., glucose) transport.
In some embodiments, the resistance domain is formed from a silicone polymer/hydrophobic-hydrophilic polymer blend. In one embodiment, The hydrophobic-hydrophilic polymer for use in the blend may be any suitable hydrophobic-hydrophilic polymer, including but not limited to components such as polyvinylpyrrolidone (PVP), polyhydroxyethyl methacrylate, polyvinylalcohol, polyacrylic acid, polyethers such as polyethylene glycol or polypropylene oxide, and copolymers thereof, including, for example, di-block, tri-block, alternating, random, comb, star, dendritic, and graft copolymers (block copolymers are discussed in U.S. Pat. Nos. 4,803,243 and 4,686,044, which are incorporated herein by reference). In one embodiment, the hydrophobic-hydrophilic polymer is a copolymer of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO). Suitable such polymers include, but are not limited to, PEO-PPO diblock copolymers, PPO-PEO-PPO triblock copolymers, PEO-PPO-PEO triblock copolymers, alternating block copolymers of PEO-PPO, random copolymers of ethylene oxide and propylene oxide, and blends thereof. In some embodiments, the copolymers may be optionally substituted with hydroxy substituents. Commercially available examples of PEO and PPO copolymers include the PLURONIC® brand of polymers available from BASF®. In one embodiment, PLURONIC® F-127 is used. Other PLURONIC® polymers include PPO-PEO-PPO triblock copolymers (e.g., PLURONIC® R products). Other suitable commercial polymers include, but are not limited to, SYNPERONICS® products available from UNIQEMA®.
In preferred embodiments, the resistance domain is deposited onto the enzyme domain to yield a domain thickness of from about 0.05 microns or less to about 20 microns or more, more preferably from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and more preferably still from about 2, 2.5 or 3 microns to about 3.5, 4, 4.5, or 5 microns. Preferably, the resistance domain is deposited onto the enzyme domain by vapor deposition, spray coating, or dip coating. In one preferred embodiment, spray coating is the preferred deposition technique. The spraying process atomizes and mists the solution, and therefore most or all of the solvent is evaporated prior to the coating material settling on the underlying domain, thereby minimizing contact of the solvent with the enzyme.
In a preferred embodiment, the resistance domain is deposited on the enzyme domain by spray coating a solution of from about 1 wt. % to about 5 wt. % polymer and from about 95 wt. % to about 99 wt. % solvent. In spraying a solution of resistance domain material, including a solvent, onto the enzyme domain, it is desirable to mitigate or substantially reduce any contact with enzyme of any solvent in the spray solution that can deactivate the underlying enzyme of the enzyme domain. Tetrahydrofuran (THF) is one solvent that minimally or negligibly affects the enzyme of the enzyme domain upon spraying. Other solvents can also be suitable for use, as is appreciated by one skilled in the art.
Preferably, each exemplary sensor design (e.g.,
In addition to the above-described advantages, the coaxial sensor design of the preferred embodiments enables the diameter of the connecting end of the sensor (proximal portion) to be substantially the same as that of the sensing end (distal portion) such that a needle is able to insert the sensor into the host and subsequently slide back over the sensor and release the sensor from the needle, without slots or other complex multi-component designs, as described in detail in U.S. Patent Publication No. US-2006-0063142-A1 and U.S. Patent Publication No. US-2007-0197889-A1 which are incorporated in their entirety herein by reference.
Exemplary Continuous Sensor Configurations
In some embodiments, the sensor is an enzyme-based electrochemical sensor, wherein the glucose-measuring working electrode 16 (e.g.,
Some alternative analyte sensors that can benefit from the systems and methods of the preferred embodiments include U.S. Pat. No. 5,711,861 to Ward et al., U.S. Pat. No. 6,642,015 to Vachon et al., U.S. Pat. No. 6,654,625 to Say et al., U.S. Pat. No. 6,565,509 to Say et al., U.S. Pat. No. 6,514,718 to Heller, U.S. Pat. No. 6,465,066 to Essenpreis et al., U.S. Pat. No. 6,214,185 to Offenbacher et al., U.S. Pat. No. 5,310,469 to Cunningham et al., and U.S. Pat. No. 5,683,562 to Shaffer et al., U.S. Pat. No. 6,579,690 to Bonnecaze et al., U.S. Pat. No. 6,484,046 to Say et al., U.S. Pat. No. 6,512,939 to Colvin et al., U.S. Pat. No. 6,424,847 to Mastrototaro et al., U.S. Pat. No. 6,424,847 to Mastrototaro et al, for example. All of the above patents are incorporated in their entirety herein by reference and are not inclusive of all applicable analyte sensors; in general, it should be understood that the disclosed embodiments are applicable to a variety of analyte sensor configurations.
Although some exemplary glucose sensor configurations are described in detail below, it should be understood that the systems and methods described herein can be applied to any device capable of continually or continuously detecting a concentration of analyte of interest and providing an output signal that represents the concentration of that analyte, for example oxygen, lactose, hormones, cholesterol, medicaments, viruses, or the like.
The body 12 of the sensor 10a can be formed from a variety of materials, including metals, ceramics, plastics, or composites thereof. In one embodiment, the sensor is formed from thermoset molded around the sensor electronics. U.S. Patent Publication No. US-2004-0199059-A1 discloses suitable configurations for the body, and is incorporated by reference in its entirety.
In some embodiments, the sensing region 14 includes a glucose-measuring working electrode 16, an optional auxiliary working electrode 18, a reference electrode 20, and a counter electrode 24. Generally, the sensing region 14 includes means to measure two different signals, 1) a first signal associated with glucose and non-glucose related electroactive compounds having a first oxidation potential, wherein the first signal is measured at the glucose-measuring working electrode disposed beneath an active enzymatic portion of a membrane system, and 2) a second signal associated with the baseline and/or sensitivity of the glucose sensor. In some embodiments, wherein the second signal measures sensitivity, the signal is associated with at least one non-glucose constant data point, for example, wherein the auxiliary working electrode 18 is configured to measure oxygen. In some embodiments, wherein the second signal measures baseline, the signal is associated with non-glucose related electroactive compounds having the first oxidation potential, wherein the second signal is measured at an auxiliary working electrode 18 and is disposed beneath a non-enzymatic portion of the membrane system, such as described in more detail elsewhere herein.
Preferably, a membrane system (see
The sensing region 14 comprises electroactive surfaces, which are in contact with an electrolyte phase (not shown), which is a free-flowing fluid phase disposed between the membrane system 22 and the electroactive surfaces. In this embodiment, the counter electrode is provided to balance the current generated by the species being measured at the working electrode. In the case of glucose oxidase based analyte sensors, the species being measured at the working electrode is H2O2. Glucose oxidase catalyzes the conversion of oxygen and glucose to hydrogen peroxide and gluconate according to the following reaction:
Glucose+O2→Gluconate+H2O2
The change in H2O2 can be monitored to determine glucose concentration because for each glucose molecule metabolized, there is a proportional change in the product H2O2 (see
One skilled in the art appreciates that the analyte sensor of
Preferably, each electrode is formed from a fine wire, with a diameter in the range of 0.001 to 0.010 inches, for example, and may be formed from plated wire or bulk material, however the electrodes may be deposited on a substrate or other known configurations as is appreciated by one skilled in the art.
In one embodiment, the glucose-measuring working electrode 16 comprises a wire formed from a conductive material, such as platinum, palladium, graphite, gold, carbon, conductive polymer, or the like. Alternatively, the glucose-measuring working electrode 16 can be formed of a non-conductive fiber or rod that is plated with a conductive material. The glucose-measuring working electrode 16 is configured and arranged to measure the concentration of glucose. The glucose-measuring working electrode 16 is covered with an insulating material, for example a non-conductive polymer. Dip-coating, spray-coating, or other coating or deposition techniques can be used to deposit the insulating material on the working electrode, for example. In one preferred embodiment, the insulating material comprises Parylene, which can be an advantageous conformal coating for its strength, lubricity, and electrical insulation properties, however, a variety of other insulating materials can be used, for example, fluorinated polymers, polyethyleneterephthalate, polyurethane, polyimide, or the like.
In this embodiment, the auxiliary working electrode 18 comprises a wire formed from a conductive material, such as described with reference to the glucose-measuring working electrode 16 above. Preferably, the reference electrode 20, which may function as a reference electrode alone, or as a dual reference and counter electrode, is formed from silver, Silver/Silver chloride, or the like.
Preferably, the electrodes are juxtapositioned and/or twisted with or around each other; however other configurations are also possible. In one example, the auxiliary working electrode 18 and reference electrode 20 may be helically wound around the glucose-measuring working electrode 16 as illustrated in
In some embodiments, the membrane system generally provides one or more of the following functions: 1) protection of the exposed electrode surface from the biological environment, 2) diffusion resistance (limitation) of the analyte, 3) a catalyst for enabling an enzymatic reaction, 4) optionally limitation or blocking of interfering species, and 5) hydrophilicity at the electrochemically reactive surfaces of the sensor interface, such as described in U.S. Patent Publication No. US-2005-0245799-A1. In some embodiments, the membrane system additionally includes a cell disruptive domain, a cell impermeable domain, and/or an oxygen domain (not shown), such as described in more detail in U.S. Patent Publication No. US-2005-0245799-A1. However, it is understood that a membrane system modified for other sensors, for example, by including fewer or additional domains is within the scope of the preferred embodiments.
One aspect of the preferred embodiments provides for a sensor (for transcutaneous, wholly implantable, or intravascular short-term or long-term use) having integrally formed parts, such as but not limited to a plurality of electrodes, a membrane system and an enzyme. For example, the parts may be coaxial, juxtapositioned, helical, bundled and/or twisted, plated and/or deposited thereon, extruded, molded, held together by another component, and the like. In another example, the components of the electrode system are integrally formed, (e.g., without additional support, such as a supporting substrate), such that substantially all parts of the system provide essential functions of the sensor (e.g., the sensing mechanism or “in vivo” portion). In a further example, a first electrode can be integrally formed directly on a second electrode (e.g., electrically isolated by an insulator), such as by vapor deposition of a conductive electrode material, screen printing a conductive electrode ink or twisting two electrode wires together in a coiled structure.
Some embodiments provide an analyte sensor that is configured for insertion into a host and for measuring an analyte in the host, wherein the sensor includes a first working electrode disposed beneath an active enzymatic portion of a membrane (e.g., membrane system) on the sensor and a second working electrode disposed beneath an inactive- or non-enzymatic portion of the membrane on the sensor. In these embodiments, the first and second working electrodes integrally form at least a portion of the sensor.
Exemplary Sensor Configurations
One skilled in the art will recognize that various electrode combinations are possible. For example, in one embodiment, the core 16 is a first working electrode and can be substantially straight. One of the coiled electrodes (18 or 20) is a second working electrode and the remaining coiled electrode is a reference or counter electrode. In a further embodiment, the reference electrode can be disposed remotely from the sensor, such as on the host's skin or on the exterior of the sensor, for example. Although this exemplary embodiment illustrates an integrally formed coaxial sensor, one skilled in the art appreciates a variety of alternative configurations. In one exemplary embodiment, the arrangement of electrodes is reversed, wherein the first working electrode is helically wound around the second working electrode core 16. In another exemplary embodiment, the reference electrode can form the central core 16 with the first and second working electrodes coiled there around. In some exemplary embodiments, the sensor can have additional working, reference and/or counter electrodes, depending upon the sensor's purpose. Generally, one or more of the electrode wires are coated with an insulating material, to prevent direct contact between the electrodes. Generally, a portion of the insulating material can be removed (e.g., etched, scraped or grit-blasted away) to expose an electroactive surface of the electrode. An enzyme solution can be applied to the exposed electroactive surface, as described herein.
The electrodes each have first and second ends. The electrodes can be of any geometric solid shape, such as but not limited to a cylinder having a circular or oval cross-section, a rectangle (e.g., extruded rectangle), a triangle (e.g., extruded triangle), an X-cross section, a Y-cross section, flower petal-cross sections, star-cross sections, melt-blown fibers loaded with conductive material (e.g., conductive polymers) and the like. The first ends (e.g., an in vivo portion, “front end”) of the electrodes are configured for insertion in the host and the second ends (e.g., an ex vivo portion, “back end”) are configured for electrical connection to sensor electronics. In some embodiments, the sensor includes sensor electronics that collect data from the sensor and provide the data to the host in various ways. Sensor electronics are discussed in detail elsewhere herein.
FIGS. 7A1 and 7A2 are schematics of an analyte sensor in another embodiment. FIG. 7A1 is a side view and FIG. 7A2 is a side-cutaway view. In some preferred embodiments, the sensor is configured to be integrally formed and coaxial, with an optional stepped end. In this exemplary embodiment, the sensor includes a plurality of electrodes E1, E2, E3 to En, wherein n equals any number of electrode layers. Layers of insulating material I (e.g., non-conductive material) separate the electrode layers. All of the electrode and insulating material layers share axis A-A. The layers can be applied by any technique known in the art, such as but not limited to spraying, dipping, spraying, etc. For example, a bulk metal wire electrode E1 can be dipped into a solution of insulating polymer that is vulcanized to form a layer of non-conductive, electrically insulating material I. A second electrode E2 can be plated (e.g., by electroplating or other plating technique used in the art) on the first insulating layer, followed by application of a second insulating layer I applied in the same manner as the first layer. Additional electrode layers (e.g., E3 to En) and insulating layers can be added to the construct, to create the desired number of electrodes and insulating layers. As an example, multiple sensors can be formed from a long wire (with insulating and electrode layers applied) that can be cut to yield a plurality of sensors of the desired length. After the sensor has been cut to size, it can be polished or otherwise treated to prepare the electrodes for use. In some embodiments, the various electrode and/or insulator layers can be applied by dipping, spraying, printing, vapor deposition, plating, spin coating or any other method known in the art. Although this exemplary embodiment illustrates an integrally formed coaxial sensor, one skilled in the art appreciates a variety of alternative configurations. For example, in some embodiments, the sensor can have two, three, four or more electrodes separated by insulating material I. In another embodiment, the analyte sensor has two or more electrodes, such as but not limited to a first working electrode, an auxiliary working electrode, a reference electrode and/or counter electrode.
In one exemplary embodiment, a diffusion barrier D (described in greater detail below) separates the working electrodes. The diffusion barrier can be spatial, physical, or temporal. For example, the distance around the reference electrode (e.g., from the first working electrode E1 to the second working electrode E2, around a portion of the circumference of the reference electrode R) acts as a spatial diffusion barrier. In one exemplary embodiment, the working electrodes are coated with a layer of insulating material I (e.g., non-conductive material or dielectric) to prevent direct contact between the working electrodes E1, E2 and the reference electrode R. A portion of the insulator I on an exterior surface of each working electrode is etched away, to expose the electrode's electroactive surface. In some embodiments, an enzyme solution (e.g., containing active GOx) is applied to the electroactive surfaces of both electrodes, and dried. Thereafter, the enzyme applied to one of the electroactive surfaces is inactivated. As is known in the art, enzymes can be inactivated by a variety of means, such as heat, treatment with inactivating (e.g., denaturing) solvents, proteolysis, laser irradiation or UV irradiation (e.g., at 254-320 nm). For example, the enzyme coating one of the electroactive surfaces can be inactivated by masking one of the electroactive surfaces/electrodes (e.g., E1, temporarily covered with a UV-blocking material); irradiating the sensor with UV light (e.g., 254-320 nm; a wavelength that inactivates the enzyme, such as by cross-linking amino acid residues) and removing the mask. Accordingly, the GOx on E2 is inactivated by the UV treatment, but the E1 GOx is still active due to the protective mask. In other embodiments, an enzyme solution containing active enzyme is applied to a first electroactive surface (e.g., E1) and an enzyme solution containing either inactivated enzyme or no enzyme is applied to the second electroactive surface (e.g., E2). Accordingly, the enzyme-coated first electroactive surface (e.g., E1) detects analyte-related signal and non-analyte-related signal; while the second electroactive surface (e.g., E2), which lacks active enzyme, detects non-analyte-related signal. As described herein, the sensor electronics can use the data collected from the two working electrodes to calculate the analyte-only signal.
Although this exemplary embodiment illustrates one embodiment of an integrally-formed sensor having a diffusion barrier D, one skilled in the art appreciates a variety of alternative configurations, such as but not limited to the embodiment shown in
The electrodes can be held in position by wrapping with wire or a non-conductive fiber, a non-conductive sheath, a biointerface membrane coating, or the like. The electroactive surfaces of the working electrodes are exposed. In some embodiments, the end of the sensor is cut off, to expose the ends of the wires. In other embodiments, the ends of the wires are coated with insulating material; and the electroactive surfaces are exposed by removing a portion of the insulating material (e.g., a window 802 cut into the side of the insulation coating the electrode). In some embodiments, the windows exposing the electroactive surfaces of the electrodes can be staggered (e.g., spaced such that one or more electrodes extends beyond the other one or more electrodes), symmetrically arranged or rotated to any degree; for example, to substantially prevent diffusion of electroactive species from one working electrode (e.g., 802a) to the other working electrode (e.g., 802b), as will be discussed in greater detail elsewhere herein. In various embodiments, the reference electrode is not coated with a nonconductive material. The reference electrode can have a surface area that is at least 6 times the surface area of the exposed working electrode electroactive surfaces. In some embodiments, the reference electrode R surface area is 7-10 times (or larger) than the surface area of the working electrode electroactive surfaces. In still other embodiments, the reference electrode can be only 1-5 times the surface area of working electrode electroactive surfaces (e.g., (E1+E2)×1=R or (E1+E2)×2=R, etc.).
The ex vivo end of the sensor is connected to the sensor electronics (not shown) by electrical connectors 804a, 804b, 804c. In some embodiments, the ex vivo end of the sensor is stepped. For example, the ex vivo end of the reference electrode R terminates within electrical connector 804a. The ex vivo end of the first working electrode E1 is exposed (e.g., nonconductive material removed therefrom) and terminates a small distance past the reference electrode R, within electrical connector 804b. Similarly, the ex vivo end of the second working electrode E2 is exposed (e.g., nonconductive material removed therefrom) and terminates a small distance past the termination of the first working electrode E1, within electrical connector 804c.
Although this exemplary embodiment illustrates one configuration of an integrally formed sensor, one skilled in the art appreciates a variety of alternative configurations. For example, in some embodiments, a portion of the in vivo portion of the sensor can be twisted and/or stepped. More working, reference, and/or counter electrodes, as well as insulators, can be included. The electrodes can be of relatively larger or smaller size, depending upon the sensor's intended function. In some embodiments, the electroactive surfaces can be staggered. In still other embodiments, the reference electrode can be disposed remotely from the sensor, as described elsewhere herein. For example, the reference electrode shown in
With reference to the ex vivo portion of the sensor, one skilled in the art appreciates additional alternative configurations. For example, in one embodiment, a portion of the ex vivo portion of the sensor can be twisted or coiled. In some embodiments, the working and reference electrodes can be of various lengths and configurations not shown in
Referring again to
In general, the windows 904a and 904b are separated or staggered by a distance D, which is selected to be sufficiently large that electroactive species (e.g., H2O2) do not substantially diffuse from one window to the other (e.g., from 904a to 904b). In an exemplary embodiment of a glucose-oxidase-based sensor, active enzyme is included in the membrane covering window 904a and inactive enzyme is included in the membrane covering window 904b. Distance D is configured to be large enough that H2O2 cannot diffuse from window 904a to window 904b, which lacks active enzyme (as discussed elsewhere herein). In some embodiments, the distance D is at least about 0.020 inches or less to about 0.120 inches or more. In some embodiments, D is at least about 0.030 to about 0.050 inches. In other embodiments, D is at least about 0.090 to about 0.095 inches. One skilled in the art appreciates alternative embodiments of the diffusion barrier D. Namely, the diffusion barrier D can be spatial (discussed herein with relation to
In various embodiments, one of the windows 904a or 904b comprises an enzyme system configured to detect the analyte of interest (e.g., glucose or oxygen). The other window comprises no active enzyme system (e.g., wherein the enzyme system lacks enzyme or wherein the enzyme has been de-activated). In some embodiments, wherein the “enzyme system lacks enzyme,” a layer may be applied, similar to an active enzyme layer, but without the actual enzyme included therein. In some embodiments, wherein “the enzyme has been de-activated” the enzyme can be inactivated (e.g., by heat or solvent) prior to addition to the enzyme system solution or the enzyme can be inactivated after application to the window.
In one exemplary embodiment, an enzyme is applied to both windows 904a and 904b followed by deactivation of the enzyme in one window. For example, one window can be masked (e.g., to protect the enzyme under the mask) and the sensor then irradiated (to deactivate the enzyme in the unmasked window). Alternatively, one of the enzyme-coated windows (e.g., the first window but not the second window) can be sprayed or dipped in an enzyme-deactivating solvent (e.g., treated with a protic acid solution such a hydrochloric acid or sulfuric acid). For example, a window coated with GOx can be dipped in dimethyl acetamide (DMAC), ethanol, or tetrahydrofuran (THF) to deactivate the GOx. In another example, the enzyme-coated window can be dipped into a hot liquid (e.g., water or saline) to deactivate the enzyme with heat.
In these embodiments, the design of the active and inactive enzyme window is at least partially dependent upon the sensor's intended use. In some embodiments, it is preferred to deactivate the enzyme coated on window 904a. In other embodiments, it is preferred to deactivate the enzyme coated on window 904b. For example, in the case of a sensor to be used in a host's blood stream, the choice depends upon whether the sensor will be inserted pointing upstream (e.g., against the blood flow) or pointing downstream (e.g., with the blood flow).
In one exemplary embodiment, an intravascular sensor is inserted into the host's vein pointing upstream (against the blood flow), an enzyme coating on electrode E1 (window 904a) is inactivated (e.g., by dipping in THF and rinsing) and an enzyme coating on electrode E2 (in window 904b) is not inactivated (e.g., by not dipping in THF). Because the enzyme on the first electrode E1 (e.g., in window 904a) is inactive, electroactive species (e.g., H2O2) will not be substantially generated at window 904a (e.g., the first electrode E1 generates substantially no H2O2 to effect the second electrode E2). In contrast, the active enzyme on the second electrode E2 (in window 904b) generates H2O2 which at least partially diffuses down stream (away from the windows) and thus has no effect on the first electrode E1, other features and advantages of spatial diffusion barriers are described in more detail elsewhere herein.
In another exemplary embodiment, an intravascular sensor is inserted into the host's vein pointing downstream (with the blood flow), the enzyme coating on electrode E1 (window 904a) is active and the enzyme coating on electrode E2 (in window 904b) is inactive. Because window 904a is located farther downstream than window 904b, the H2O2 produced by the enzyme in 904a diffuses downstream (away from window 904b), and therefore does not affect substantially electrode E2. In a preferred embodiment, the enzyme is GOx, and the sensor is configured to detect glucose. Accordingly, H2O2 produced by the GOx in window 904a does not affect electrode E2, because the sensor is pointing downstream and the blood flow carries away the H2O2 produced on electrode E1.
One skilled in the art recognizes a variety of alternative configurations for the embodiments described herein. For example, in any embodiment of an analyte sensor, the reference electrode (and optionally a counter electrode) can be disposed remotely from the working electrodes. For example, in FIGS. 7A1 through 9B and
As another example, in one embodiment of a sensor configured to measure a host's blood, such as described in co-pending U.S. patent application Ser. No. 11/543,396, entitled “ANALYTE SENSOR” and filed on even date herewith, and which is incorporated herein by reference in its entirety; one or more working electrodes can be inserted into the host's blood via a catheter and the reference and/or counter electrode can be placed within the a fluid connector (on the sensor) configured to be in fluid communication with the catheter; in such an example, the reference and/or counter electrode is in contact with fluid flowing through the fluid connector but not in direct contact with the host's blood. In still other embodiments, the reference and/or counter electrodes can be placed exterior to the sensor, in bodily contact for example.
With reference to the analyte sensor embodiments disclosed herein, the surface area of the electroactive portion of the reference (and/or counter) electrode is at least six times the surface area of one or more working electrodes. In other embodiments, the reference (and/or counter) electrode surface is 1, 2, 3, 4, 5, 7, 8, 9 or 10 times the surface area of the working electrodes. In other embodiments, the reference (and/or counter) electrode surface area is 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 times the surface area of the working electrodes. For example, in a needle-type glucose sensor, similar to the embodiment shown in
In various embodiments, the electrodes can be stacked or grouped similar to that of a leaf spring configuration, wherein layers of electrode and insulator (or individual insulated electrodes) are stacked in offset layers. The offset layers can be held together with bindings of non-conductive material, foil, or wire. As is appreciated by one skilled in the art, the strength, flexibility, and/or other material property of the leaf spring-configured or stacked sensor can be either modified (e.g., increased or decreased), by varying the amount of offset, the amount of binding, thickness of the layers, and/or materials selected and their thicknesses, for example.
In some embodiments, the sensor (e.g., a glucose sensor) is configured for implantation into the host. For example, the sensor may be wholly implanted into the host, such as but not limited to in the host's subcutaneous tissue (e.g., the embodiment shown in
In preferred embodiments, the analyte sensor substantially continuously measures the host's analyte concentration. In some embodiments, for example, the sensor can measure the analyte concentration every fraction of a second, about every fraction of a minute or every minute. In other exemplary embodiments, the sensor measures the analyte concentration about every 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes. In still other embodiments, the sensor measures the analyte concentration every fraction of an hour, such as but not limited to every 15, 30 or 45 minutes. Yet in other embodiments, the sensor measures the analyte concentration about every hour or longer. In some exemplary embodiments, the sensor measures the analyte concentration intermittently or periodically. In one preferred embodiment, the analyte sensor is a glucose sensor and measures the host's glucose concentration about every 4-6 minutes. In a further embodiment, the sensor measures the host's glucose concentration every 5 minutes.
In one exemplary embodiment, the analyte sensor is a glucose sensor having a first working electrode configured to generate a first signal associated with both glucose and non-glucose related electroactive compounds that have a first oxidation potential. Non-glucose related electroactive compounds can be any compound, in the sensor's local environment that has an oxidation potential substantially overlapping with the oxidation potential of H2O2, for example. While not wishing to be bound by theory, it is believed that the glucose-measuring electrode can measure both the signal directly related to the reaction of glucose with GOx (produces H2O2 that is oxidized at the working electrode) and signals from unknown compounds that are in the extracellular milieu surrounding the sensor. These unknown compounds can be constant or non-constant (e.g., intermittent or transient) in concentration and/or effect. In some circumstances, it is believed that some of these unknown compounds are related to the host's disease state. For example, it is know that blood chemistry changes dramatically during/after a heart attack (e.g., pH changes, changes in the concentration of various blood components/protein, and the like). Other compounds that can contribute to the non-glucose related signal are believed to be related to the wound healing process that is initiated by implantation/insertion of the sensor into the host, which is described in more detail with reference to co-pending U.S. patent application Ser. No. 11/503,367 filed Aug. 10, 2006 and entitled “ANALYTE SENSOR,” which is incorporated herein by reference in its entirety. For example, transcutaneously inserting a needle-type sensor initiates a cascade of events that includes the release of various reactive molecules by macrophages.
In some embodiments, the glucose sensor includes a second (e.g., auxiliary) working electrode that is configured to generate a second signal associated with non-glucose related electroactive compounds that have the same oxidation potential as the above-described first working electrode (e.g., para supra). In some embodiments, the non-glucose related electroactive species includes at least one of interfering species, non-reaction-related H2O2, and other electroactive species. For example, interfering species includes any compound that is not directly related to the electrochemical signal generated by the glucose-GOx reaction, such as but not limited to electroactive species in the local environment produces by other bodily processes (e.g., cellular metabolism, wound healing, a disease process, and the like). Non-reaction-related H2O2 includes H2O2 from sources other than the glucose-GOx reaction, such as but not limited to H2O2 released by nearby cells during the course of the cells' metabolism, H2O2 produced by other enzymatic reactions (e.g., extracellular enzymes around the sensor or such as can be released during the death of nearby cells or such as can be released by activated macrophages), and the like. Other electroactive species includes any compound that has an oxidation potential similar to or overlapping that of H2O2.
The non-analyte (e.g., non-glucose) signal produced by compounds other than the analyte (e.g., glucose) obscured the signal related to the analyte, contributes to sensor inaccuracy, and is considered background noise. As described in greater detail in the section entitled “Noise Reduction,” background noise includes both constant and non-constant components and must be removed to accurately calculate the analyte concentration. While not wishing to be bound by theory, it is believed that the sensor of the preferred embodiments are designed (e.g., with symmetry, coaxial design and/or integral formation) such that the first and second electrodes are influenced by substantially the same external/environmental factors, which enables substantially equivalent measurement of both the constant and non-constant species/noise. This advantageously allows the substantial elimination of noise (including transient biologically related noise that has been previously seen to affect accuracy of sensor signal due to it's transient and unpredictable behavior) on the sensor signal (using electronics described elsewhere herein) to substantially reduce or eliminate signal effects due to noise, including non-constant noise (e.g., unpredictable biological, biochemical species or the like) known to effect the accuracy of conventional continuous sensor signals. Preferably, the sensor includes electronics operably connected to the first and second working electrodes. The electronics are configured to provide the first and second signals that are used to generate glucose concentration data substantially without signal contribution due to non-glucose-related noise. Preferably, the electronics include at least a potentiostat that provides a bias to the electrodes. In some embodiments, sensor electronics are configured to measure the current (or voltage) to provide the first and second signals. The first and second signals are used to determine the glucose concentration substantially without signal contribution due to non-glucose-related noise such as by but not limited to subtraction of the second signal from the first signal or alternative data analysis techniques. In some embodiments, the sensor electronics include a transmitter that transmits the first and second signals to a receiver, where additional data analysis and/or calibration of glucose concentration can be processed. U.S. Patent Publication No. US-2005-0027463-A1, US-2005-0203360-A1 and U.S. Patent Publication No. US-2006-0036142-A1 describe systems and methods for processing sensor analyte data and are incorporated herein by reference in their entirety.
In preferred embodiments, the sensor electronics (e.g., electronic components) are operably connected to the first and second working electrodes. The electronics are configured to calculate at least one analyte sensor data point. For example, the electronics can include a potentiostat, A/D converter, RAM, ROM, transmitter, and the like. In some embodiments, the potentiostat converts the raw data (e.g., raw counts) collected from the sensor to a value familiar to the host and/or medical personnel. For example, the raw counts from a glucose sensor can be converted to milligrams of glucose per deciliter of glucose (e.g., mg/dl). In some embodiments, the electronics are operably connected to the first and second working electrodes and are configured to process the first and second signals to generate a glucose concentration substantially without signal contribution due to non-glucose noise artifacts. The sensor electronics determine the signals from glucose and non-glucose related signal with an overlapping measuring potential (e.g., from a first working electrode) and then non-glucose related signal with an overlapping measuring potential (e.g., from a second electrode). The sensor electronics then use these data to determine a substantially glucose-only concentration, such as but not limited to subtracting the second electrode's signal from the first electrode's signal, to give a signal (e.g., data) representative of substantially glucose-only concentration, for example. In general, the sensor electronics may perform additional operations, such as but not limited to data smoothing and noise analysis.
Bifunctionality
In some embodiments, the components of at least a portion (e.g., the in vivo portion or the sensing portion) of the sensor possess bifunctional properties (e.g., provide at least two functions to the sensor). These properties can include electrical conductance, insulative properties, structural support, and diffusion barrier properties.
In one exemplary embodiment, the analyte sensor is designed with two working electrodes, a membrane system and an insulating material disposed between the working electrodes. An active enzymatic membrane is disposed above the first working electrode, while an inactive- or non-enzymatic membrane is disposed above the second working electrode. Additionally, the working electrodes and the insulating material are configured provide at least two functions to the sensor, including but not limited to electrical conductance, insulative properties, structural support, and diffusion barrier. For example, in one embodiment of a glucose sensor, the two working electrodes support the sensor's structure and provide electrical conductance; the insulating material provides insulation between the two electrodes and provides additional structural support and/or a diffusional barrier.
In some embodiments, a component of the sensor is configured to provide both electrical conductance and structural support. In an exemplary embodiment, the working electrode(s) and reference electrode are generally manufactured of electrically conductive materials, such as but not limited silver or silver/silver chloride, copper, gold, platinum, iridium, platinum-iridium, palladium, graphite, carbon, conductive polymers, alloys, and the like. Accordingly, the electrodes are both conductive and they give the sensor its shape (e.g., are supportive).
Referring to
Similarly, the electrodes of
In some embodiments, the first and second working electrodes are configured to provide both electrical conductance and structural support. For example, in a needle-type sensor, the working electrodes are often manufactured of bulk metal wires (e.g., copper, gold, platinum, iridium, platinum-iridium, palladium, graphite, carbon, conductive polymers, alloys, and the like). The reference electrode, which can function as a reference electrode alone, or as a dual reference and counter electrode, are formed from silver or silver/silver chloride, or the like. The metal wires are conductive (e.g., can conduct electricity) and give the sensor its shape and/or structural support. For example, one electrode metal wire may be coiled around the other electrode metal wire (e.g.,
In some embodiments, the first and second working electrode and the insulating material are configured provide at least two functions, such as but not limited to electrical conductance, insulative properties, structural support, and diffusion barrier. As described elsewhere herein, the working electrodes are electrical conductors and also provide support for the sensor. The insulating material (e.g., I) acts as an insulator, to prevent electrical communication between certain parts of the various electrodes. The insulating material also provides structural support or substantially prevents diffusion of electroactive species from one working electrode to the other, which is discussed in greater detail elsewhere herein.
In preferred embodiments, the sensor has a diffusion barrier disposed between the first and second working electrodes. The diffusion barrier is configured to substantially block diffusion of the analyte or a co-analyte (e.g., H2O2) between the first and second working electrodes. For example, a sheet of a polymer through which H2O2 cannot diffuse can be interposed between the two working electrodes. Diffusion barriers are discussed in greater detail elsewhere herein.
In some embodiments of the preferred embodiments, the analyte sensor includes a reference electrode that is configured to provide electrical conductance and a diffusion barrier. Electrical conductance is an inherent property of the metal used to manufacture the reference electrode. However, the reference electrode can be configured to prevent species (e.g., H2O2) from diffusing from the first working electrode to the second working electrode. For example, a sufficiently large reference electrode can be placed between the two working electrodes. In some embodiments, the reference electrode projects farther than the two working electrodes. In other embodiments, the reference electrode is so broad that a substantial portion of the H2O2 produced at the first working electrode cannot diffuse to the second working electrode, and thereby significantly affect the second working electrode's function.
In a further embodiment, the reference electrode is configured to provide a diffusion barrier and structural support. As described elsewhere herein, the reference electrode can be constructed of a sufficient size and/or shape that a substantial portion of the H2O2 produced at a first working electrode cannot diffuse to the second working electrode and affect the second working electrode's function. Additionally, metal wires are generally resilient and hold their shape, the reference electrode can also provide structural support to the sensor (e.g., help the sensor to hold its shape).
In some embodiments of the analyte sensor described elsewhere herein, the insulating material is configured to provide both electrical insulative properties and structural support. In one exemplary embodiment, portions of the electrodes are coated with a non-conductive polymer. Inherently, the non-conductive polymer electrically insulates the coated electrodes from each other, and thus substantially prevents passage of electricity from one coated wire to another coated wire. Additionally, the non-conductive material (e.g., a non-conductive polymer or insulating material) can stiffen the electrodes and make them resistant to changes in shape (e.g., structural changes).
In some embodiments, a sensor component is configured to provide electrical insulative properties and a diffusion barrier. In one exemplary embodiment, the electrodes are coated with the non-conductive material that substantially prevents direct contact between the electrodes, such that electricity cannot be conducted directly from one electrode to another. Due to the non-conductive coatings on the electrodes, electrical current must travel from one electrode to another through the surrounding aqueous medium (e.g., extracellular fluid, blood, wound fluid, or the like). Any non-conductive material (e.g., insulator) known in the art can be used to insulate the electrodes from each other. In exemplary embodiments, the electrodes can be coated with non-conductive polymer materials (e.g., parylene, PTFE, ETFE, polyurethane, polyethylene, polyimide, silicone and the like) by dipping, painting, spraying, spin coating, or the like.
Non-conductive material (e.g., insulator, as discussed elsewhere herein) applied to or separating the electrodes can be configured to prevent diffusion of electroactive species (e.g., H2O2) from one working electrode to another working electrode. Diffusion of electroactive species from one working electrode to another can cause a false analyte signal. For example, electroactive species (e.g., H2O2) that are created at a first working electrode having active enzyme (e.g., GOx) can diffuse to a nearby working electrode (e.g., without active GOx). When the electroactive species arrives at the second working electrode, the second electrode registers a signal (e.g., as if the second working electrode comprised active GOx). The signal registered at the second working electrode due to the diffusion of the H2O2 is aberrant and can cause improper data processing in the sensor electronics. For example, if the second electrode is configured to measure a substantially non-analyte related signal (e.g., background) the sensor will record a higher non-analyte related signal than is appropriate, possibly resulting in the sensor reporting a lower analyte concentration than actually is present in the host. This is discussed in greater detail elsewhere herein.
In preferred embodiments, the non-conductive material is configured to provide a diffusion barrier and structural support to the sensor. Diffusion barriers are described elsewhere herein. Non-conductive materials can be configured to support the sensor's structure. In some, non-conductive materials with relatively more or less rigidity can be selected. For example, if the electrodes themselves are relatively flexible, it may be preferred to select a relatively rigid non-conductive material, to make the sensor stiffer (e.g., less flexible or bendable). In another example, if the electrodes are sufficiently resilient or rigid, a very flexible non-conductive material may be coated on the electrodes to bind the electrodes together (e.g., keep the electrodes together and thereby hold the sensor's shape).
Referring now to
In some embodiments, a component of the sensor is configured to provide both insulative properties and a diffusion barrier. Diffusion barriers are discussed elsewhere herein. In one exemplary embodiment, the working electrodes are separated by a non-conductive material/insulator that is configured such that electroactive species (e.g., H2O2) cannot diffuse around it (e.g., from a first electrode to a second electrode). For example, with reference to the embodiment shown in
In some preferred embodiments, in addition to two working electrodes and a non-conductive material/insulator, the sensor includes at least a reference or a counter electrode. In preferred embodiments, the reference and/or counter electrode, together with the first and second working electrodes, integrally form at least a portion of the sensor. In some embodiments, the reference and/or counter electrode is located remote from the first and second working electrodes. For example, in some embodiments, such as in the case of a transcutaneous sensor, the reference and/or counter electrodes can be located on the ex vivo portion of the sensor or reside on the host's skin, such as a portion of an adhesive patch. In other embodiments, such as in the case of an intravascular sensor, the reference and/or counter electrode can be located on the host's skin, within or on the fluid connector (e.g., coiled within the ex vivo portion of the device and in contact with fluid within the device, such as but not limited to saline) or on the exterior of the ex vivo portion of the device. In preferred embodiments, the surface area of the reference and/or counter electrode is as least six times the surface area of at least one of the first and second working electrodes. In a further embodiment, the surface area of the reference and/or counter electrode is at least ten times the surface area of at least one of the first and second electrodes.
In preferred embodiments, the sensor is configured for implantation into the host. The sensor can be configured for subcutaneous implantation in the host's tissue (e.g., transcutaneous or wholly implantable). Alternatively, the sensor can be configured for indwelling in the host's blood stream (e.g., inserted through an intravascular catheter or integrally formed on the exterior surface of an intravascular catheter that is inserted into the host's blood stream).
In some embodiments, the sensor is a glucose sensor that has a first working electrode configured to generate a first signal associated with glucose (e.g., the analyte) and non-glucose related electroactive compounds (e.g., physiological baseline, interferents, and non-constant noise) having a first oxidation potential. For example, glucose has a first oxidation potential. The interferents have an oxidation potential that is substantially the same as the glucose oxidation potential (e.g., the first oxidation potential). In a further embodiment, the glucose sensor has a second working electrode that is configured to generate a second signal associated with noise of the glucose sensor. The noise of the glucose sensor is signal contribution due to non-glucose related electroactive compounds (e.g., interferents) that have an oxidation potential that substantially overlaps with the first oxidation potential (e.g., the oxidation potential of glucose, the analyte). In various embodiments, the non-glucose related electroactive species include an interfering species, non-reaction-related hydrogen peroxide, and/or other electroactive species.
In preferred embodiments, the glucose sensor has electronics that are operably connected to the first and second working electrodes and are configured to provide the first and second signals to generate glucose concentration data substantially without signal contribution due to non-glucose-related noise. For example, the sensor electronics analyze the signals from the first and second working electrodes and calculate the portion of the first electrode signal that is due to glucose concentration only. The portion of the first electrode signal that is not due to the glucose concentration can be considered to be background, such as but not limited to noise.
In preferred embodiments, the glucose sensor has a non-conductive material (e.g., insulative material) positioned between the first and second working electrodes. The non-conductive material substantially prevents cross talk between the first and second working electrodes. For example, the electrical signal cannot pass directly from a first insulated electrode to a second insulated electrode. Accordingly, the second insulated electrode cannot aberrantly record an electrical signal due to electrical signal transfer from the first insulated electrode.
In preferred embodiments, the first and second working electrodes and the non-conductive material integrally form at least a portion of the sensor (e.g., a glucose sensor). The first and second working electrodes integrally form a substantial portion of the sensor configured for insertion in the host (e.g., the in vivo portion of the sensor). In a further embodiment, the sensor (e.g., a glucose sensor) includes a reference electrode that, in addition to the first and second working electrodes, integrally forms a substantial portion of the sensor configured for insertion in the host (e.g., the in vivo portion of the sensor). In yet a further embodiment, the sensor (e.g., a glucose sensor) has an insulator (e.g., non-conductive material), wherein the first and second working electrodes and the insulator integrally form a substantial portion of the sensor configured for insertion in the host (e.g., the in vivo portion of the sensor).
In preferred embodiments, the sensor (e.g., a glucose sensor) includes a diffusion barrier configured to substantially block diffusion of the analyte (e.g., glucose) or a co-analyte (e.g., H2O2) between the first and second working electrodes. For example, as described with reference to
With reference to
In additional embodiments, a component of the sensor is configured to provide both a diffusional barrier and a structural support, as discussed elsewhere herein. Namely, the diffusion barrier can be configured of a material that is sufficiently rigid to support the sensor's shape. In some embodiments, the diffusion barrier is an electrode, such as but not limited to the reference and counter electrodes (e.g.,
One preferred embodiment provides a glucose sensor configured for insertion into a host for measuring a glucose concentration in the host. The sensor includes a first working electrode configured to generate a first signal associated with glucose and non-glucose related electroactive compounds having a first oxidation potential. The sensor also includes a second working electrode configured to generate a second signal associated with noise of the glucose sensor comprising signal contribution due to non-glucose related electroactive compounds that have an oxidation potential that substantially overlaps with the first oxidation potential (e.g., the oxidation potential of H2O2). Additionally, the glucose sensor includes a non-conductive material located between the first and second working electrodes. Each of the first working electrode, the second working electrode, and the non-conductive material are configured to provide at least two functions selected from the group consisting of: electrical conductance, insulative properties, structural support, and diffusion barrier.
In some embodiments of the glucose sensor, each of the first working electrode and the second working electrode are configured to provide electrical conductance and structural support. For example, the metal plated wire of electrodes conducts electricity and helps maintain the sensor's shape. In a further embodiment, the glucose sensor includes a reference electrode that is configured to provide electrical conductance and structural support. For example, the silver/silver chloride reference electrode is both electrically conductive and supports the sensor's shape. In some embodiments of the glucose sensor includes a reference electrode that is configured to provide electrical conductance and a diffusion barrier. For example, the silver/silver chloride reference electrode can be configured as a large structure or protruding structure, which separates the working electrodes by the distance D (e.g.,
Noise Reduction
In another aspect, the sensor is configured to reduce noise, including non-constant non-analyte related noise with an overlapping measuring potential with the analyte. A variety of noise can occur when a sensor has been implanted in a host. Generally, implantable sensors measure a signal (e.g., counts) that generally comprises at least two components, the background signal (e.g., background noise) and the analyte signal. The background signal is composed substantially of signal contribution due to factors other than glucose (e.g., interfering species, non-reaction-related hydrogen peroxide, or other electroactive species with an oxidation potential that overlaps with the analyte or co-analyte). The analyte signal (e.g., glucose) is composed substantially of signal contribution due to the analyte. Consequently, because the signal includes these two components, a calibration is performed in order to determine the analyte (e.g., glucose) concentration by solving for the equation y=mx+b, where the value of b represents the background of the signal.
In some circumstances, the background is comprised of both constant (e.g., baseline) and non-constant (e.g., noise) factors. Generally, it is desirable to remove the background signal, to provide a more accurate analyte concentration to the host or health care professional.
The term “baseline” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a substantially constant signal derived from certain electroactive compounds found in the human body that are relatively constant (e.g., baseline of the host's physiology, non-analyte related). Therefore, baseline does not significantly adversely affect the accuracy of the calibration of the analyte concentration (e.g., baseline can be relatively constantly eliminated using the equation y=mx+b).
In contrast, “noise” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a substantially intermittent signal caused by relatively non-constant factors (e.g., the presence of intermittent noise-causing compounds that have an oxidation potential that substantially overlaps the oxidation potential of the analyte or co-analyte and arise due to the host's ingestion, metabolism, wound healing, and other mechanical, chemical and/or biochemical factors, also non-analyte related). Noise can be difficult to remove from the sensor signal by calibration using standard calibration equations (e.g., because the background of the signal does not remain constant). Noise can significantly adversely affect the accuracy of the calibration of the analyte signal. Additionally noise, as described herein, can occur in the signal of conventional sensors with electrode configurations that are not particularly designed to measure noise substantially equally at both active and inactive electrodes (e.g., wherein the electrodes are spaced and/or non symmetrical, noise may not be equally measured and therefore not easily removed using conventional dual electrode designs).
There are a variety of ways noise can be recognized and/or analyzed. In preferred embodiments, the sensor data stream is monitored, signal artifacts are detected, and data processing is based at least in part on whether or not a signal artifact has been detected, such as described in U.S. Patent Publication No. US-2005-0043598-A1 and co-pending U.S. application Ser. No. 11/503,367 filed Aug. 10, 2006 and entitled “ANALYTE SENSOR,” herein incorporated by reference in its entirety.
Accordingly, if a sensor is designed such that the signal contribution due to baseline and noise can be removed, then more accurate analyte concentration data can be provided to the host or a healthcare professional.
One embodiment provides an analyte sensor (e.g., glucose sensor) configured for insertion into a host for measuring an analyte (e.g., glucose) in the host. The sensor includes a first working electrode disposed beneath an active enzymatic portion of a membrane on the sensor; a second working electrode disposed beneath an inactive- or non-enzymatic portion of the membrane on the sensor; and electronics operably connected to the first and second working electrode and configured to process the first and second signals to generate an analyte (e.g., glucose) concentration substantially without signal contribution due to non-glucose related noise artifacts.
Referring now to
In one embodiment, the sensor is configured to substantially eliminate (e.g., subtract out) noise due to mechanical factors. Mechanical factors include macro-motion of the sensor, micro-motion of the sensor, pressure on the sensor, local tissue stress, and the like. Since both working electrodes are constructed substantially symmetrically and identically, and due to the sensor's small size, the working electrodes are substantially equally affected by mechanical factors impinging upon the sensor. For example, if a build-up of noise-causing compounds occurs (e.g., due to the host pressing upon and manipulating (e.g., fiddling with) the sensor, for example) both working electrodes will measure the resulting noise to substantially the same extend, while only one working electrode (the first working electrode, for example) will also measure signal due to the analyte concentration in the host's body. The sensor then calculates the analyte signal (e.g., glucose-only signal) by removing the noise that was measured by the second working electrode from the total signal that was measured by the first working electrode.
Non-analyte related noise can also be caused by biochemical and/or chemical factors (e.g., compounds with electroactive acidic, amine or sulfhydryl groups, urea, lactic acid, phosphates, citrates, peroxides, amino acids (e.g., L-arginine), amino acid precursors or break-down products, nitric oxide (NO), NO-donors, NO-precursors or other electroactive species or metabolites produced during cell metabolism and/or wound healing). As with noise due to mechanical factors, noise due to biochemical/chemical factors will impinge upon the two working electrodes of the preferred embodiments (e.g., with and without active GOx) about the same extent, because of the sensor's small size and symmetrical configuration. Accordingly, the sensor electronics can use these data to calculate the glucose-only signal, as described elsewhere herein.
In one exemplary embodiment, the analyte sensor is a glucose sensor that measures a first signal associated with both glucose and non-glucose related electroactive compounds having a first oxidation potential. For example, the oxidation potential of the non-glucose related electroactive compounds substantially overlaps with the oxidation potential of H2O2, which is produced according to the reaction of glucose with GOx and subsequently transfers electrons to the first working electrode (e.g., E1;
Diffusion Barrier
Another aspect of the sensor is a diffusion barrier, to prevent an undesired species, such as H2O2 or the analyte, from diffusing between active (with active enzyme) and inactive (without active enzyme) electrodes. In various embodiments, the sensor includes a diffusion barrier configured to be physical, spatial, and/or temporal.
Glucose and oxygen diffuse into the enzyme layer 1000, where they react with GOx, to produce gluconate and H2O2. At least a portion of the H2O2 diffuses to the first working electrode E1, where it is electrochemically oxidized to oxygen and transfers two electrons (e.g., 2e−) to the first working electrode E1, which results in a glucose signal that is recorded by the sensor electronics (not shown). The remaining H2O2 can diffuse to other locations in the enzyme layer or out of the enzyme layer (illustrated by the wavy arrows). Without a diffusion barrier D, a portion of the H2O2 can diffuse to the second working electrode E2, which results in an aberrant signal that can be recorded by the sensor electronics as a non-glucose related signal (e.g., background).
Preferred embodiments provide for a substantial diffusion barrier D between the first and second working electrodes (E1, E2) such that the H2O2 cannot substantially diffuse from the first working electrode E1 to the second working electrode E2. Accordingly, the possibility of an aberrant signal produced by H2O2 from the first working electrode E1 (at the second working electrode E2) is reduced or avoided.
In some alternative embodiments, the sensor is provided with a spatial diffusion barrier between electrodes (e.g., the working electrodes). For example, a spatial diffusion barrier can be created by separating the first and second working electrodes by a distance that is too great for the H2O2 to substantially diffuse between the working electrodes. In some embodiments, the spatial diffusion barrier is about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, or 0.08 inches to about 0.09, 0.10, 0.11, or 0.120 inches. In other embodiments, the spatial diffusion barrier is about 0.020 inches to about 0.050 inches. Still in other embodiments, the spatial diffusion barrier is about 0.055 inches to about 0.095 inches. A reference electrode R (e.g., a silver or silver/silver chloride electrode) or a non-conductive material I (e.g., a polymer structure or coating such as Parylene) can be configured to act as a spatial diffusion barrier.
In another embodiment, the sensor is an indwelling sensor, such as configured for insertion into the host's circulatory system via a vein or an artery. In some exemplary embodiments, an indwelling sensor includes at least two working electrodes that are inserted into the host's blood stream through a catheter. The sensor includes at least a reference electrode that can be disposed either with the working electrodes or remotely from the working electrodes. The sensor includes a spatial, a physical, or a temporal diffusion barrier. A spatial diffusion barrier can be configured as described elsewhere herein, with reference to
To configure a spatial diffusion barrier between the working electrodes, the location of the active enzyme (e.g., GOx) is dependent upon the orientation of the sensor after insertion into the host's artery or vein. For example, in an embodiment configured for insertion upstream in the host's blood flow (e.g., against the blood flow), active GOx would be applied to electroactive surface 904b and inactive GOX (or no GOx) would be applied to electroactive surface 904a (e.g., upstream from 904b, relative to the direction of blood flow). Due to this configuration, H2O2 produced at electroactive surface 904b would be carrier down stream (e.g., away from electroactive surface 904a) and thus not affect electrode E1.
Alternatively, the indwelling electrode can also be configured for insertion of the sensor into the host's vein or artery in the direction of the blood flow (e.g., pointing downstream). In this configuration, referred to as a spatial diffusion barrier, or as a flow path diffusion barrier, the active GOx can be advantageously applied to electroactive surface 904a on the first working electrode E1. The electroactive surface 904b on the second working electrode E2 has no active GOx. Accordingly, H2O2 produced at electroactive surface 904a is carried away by the blood flow, and has no substantial effect on the second working electrode E2.
In another embodiment of an indwelling analyte sensor, the reference electrode, which is generally configured of silver/silver chloride, can extend beyond the working electrodes, to provide a physical barrier around which the H2O2 generated at the electrode comprising active GOx cannot pass the other working electrode (that has active GOx). In some embodiments, the reference electrode has a surface area that is at least six times larger than the surface area of the working electrodes. In other embodiments, a 2-working electrode analyte sensor includes a counter electrode in addition to the reference electrode. As is generally know in the art, the inclusion of the counter electrode allows for a reduction in the reference electrode's surface area, and thereby allows for further miniaturization of the sensor (e.g., reduction in the sensor's diameter and/or length, etc.).
In some embodiments, a physical diffusion barrier is provided by a physical structure, such as an electrode, insulator, and/or membrane. For example, in the embodiments shown in
In other embodiments, a temporal diffusion barrier is provided (e.g., between the working electrodes). By temporal diffusion barrier is meant a period of time that substantially prevents an electroactive species (e.g., H2O2) from diffusing from a first working electrode to a second working electrode. For example, in some embodiments, the differential measurement can be obtained by switching the bias potential of each electrode between the measurement potential and a non-measurement potential. The bias potentials can be held at each respective setting (e.g., high and low bias settings) for as short as milliseconds to as long as minutes or hours. Pulsed amperometric detection (PED) is one method of quickly switching voltages, such as described in Bisenberger, M.; Brauchle, C.; Hampp, N. A triple-step potential waveform at enzyme multisensors with thick-film gold electrodes for detection of glucose and sucrose. Sensors and Actuators 1995, B, 181-189, which is incorporated herein by reference in its entirety. In some embodiments, bias potential settings are held long enough to allow equilibration.
One preferred embodiment provides a glucose sensor configured for insertion into a host for measuring glucose in the host. The sensor includes first and second working electrodes and an insulator located between the first and second working electrodes. The first working electrode is disposed beneath an active enzymatic portion of a membrane on the sensor and the second working electrode is disposed beneath an inactive- or non-enzymatic portion of the membrane on the sensor. The sensor also includes a diffusion barrier configured to substantially block (e.g., attenuate, restrict, suppress) diffusion of glucose or hydrogen peroxide between the first and second working electrodes.
In a further embodiment, the glucose sensor includes a reference electrode configured integrally with the first and second working electrodes. In some embodiments, the reference electrode can be located remotely from the sensor, as described elsewhere herein. In some embodiments, the surface area of the reference electrode is at least six times the surface area of the working electrodes. In some embodiments, the sensor includes a counter electrode that is integral to the sensor or is located remote from the sensor, as described elsewhere herein.
In a further embodiment, the glucose sensor detects a first signal associated with glucose and non-glucose related electroactive compounds having a first oxidation potential (e.g., the oxidation potential of H2O2). In some embodiments, the glucose sensor also detects a second signal is associated with background noise of the glucose sensor comprising signal contribution due to interfering species, non-reaction-related hydrogen peroxide, or other electroactive species with an oxidation potential that substantially overlaps with the oxidation potential of hydrogen peroxide; the first and second working electrodes integrally form at least a portion of the sensor; and each of the first working electrode, the second working electrode and the non-conductive material/insulator are configured provide at least two functions such as but not limited to electrical conductance, insulation, structural support, and a diffusion barrier
In further embodiments, the glucose sensor includes electronics operably connected to the first and second working electrodes. The electronics are configured to calculate at least one analyte sensor data point using the first and second signals described above. In still another further embodiment, the electronics are operably connected to the first and second working electrode and are configured to process the first and second signals to generate a glucose concentration substantially without signal contribution due to non-glucose noise artifacts.
Membrane Configurations
Reference is now made to
In some alternative embodiments, the membrane system is disposed on the surface of the electrode(s) using known deposition techniques. The electrode-exposed surfaces can be inset within the sensor body, planar with the sensor body, or extending from the sensor body. Although some examples of membrane systems have been provided above, the concepts described herein can be applied to numerous known architectures not described herein.
Sensor Configurations for Equivalent Measurement of Noise Signals at the Two Working Electrodes
In dual electrode biosensors (e.g., an analyte sensor having two working electrodes E1, E2), noise can be caused by a variety of sources, for example, located outside (e.g., by noise-causing species produced metabolically and/or consumed by the host) or within (e.g., crosstalk) the sensor. In some circumstances, biological and/or metabolic processes occurring in the host's body, such as in the locale of the implanted sensor, can cause noise. These metabolic processes, such as but not limited to wound healing, the body's response to illness and even daily cellular metabolic processes, can generate noise-causing metabolic species (e.g., compounds, substances) that impinge upon the sensor and cause noise on the signal. For example, some noise-causing species, the levels of which are relatively stable due to production during daily cellular metabolism, generally cause constant noise. In another example, some noise-causing species, the levels of which fluctuate due to production by intermittent metabolic process (e.g., wound healing or response to infection), generally cause non-constant noise. Noise-causing metabolic species include but are not limited to externally generated H2O2 (e.g., produced outside the sensor), compounds having electroactive acidic, amine or sulfhydryl groups, urea, lactic acid, phosphates, citrates, peroxides, amino acids (e.g., L-arginine), amino acid precursors or break-down products, nitric oxide (NO), NO-donors, NO-precursors, reactive oxygen species or other electroactive species or metabolites produced during cell metabolism and/or wound healing, for example. Noise-causing species, such as drugs, vitamins and the like, can also be consumed by the host. These noise causing species include but are not limited to acetaminophen, ascorbic acid, dopamine, ephedrine, ibuprofen, L-dopa, methyldopa, salicylate, tetracycline, tolazamide, tolbutamide and triglycerides. Further discussion of noise and its sources can be found in U.S. Patent Publication No. US-2007-0027370-A1 and co-pending U.S. patent application Ser. No. 11/750,907, filed on May 18, 2007 and entitled “ANALYTE SENSORS HAVING AN OPTIMIZED SIGNAL-TO-NOISE RATIO”, both of which are incorporated herein by reference in their entirety.
In dual-electrode sensors, noise can also be generated within the sensor, namely due to diffusion of a measured species (e.g., H2O2) from a first working electrode (e.g., the H2O2 is generated in an active enzymatic portion of the sensor membrane associated with the first working electrode) to a second working electrode and detection thereby (e.g., which is associated with a non-enzymatic portion of the sensor membrane). This type of noise is commonly referred to as “crosstalk.” Crosstalk is undesirable as it causes sensor error, which can result in inaccurate reporting of sensor data. In conventional sensors, a common solution to the problem of crosstalk is to space the two working electrodes far enough apart that a measured species diffusing from one working electrode cannot reach the other working electrode; unfortunately, such spacing does not enable substantially equivalent measurement of noise-cause species, as discussed in more detail elsewhere herein. Unlike conventional sensors, the sensors of the preferred embodiments ensure accurate subtraction of noise signal by ensuring substantially equivalent measurement of the noise (e.g., noise component, constant and/or non-constant noise components) detected by the two working electrodes.
Depending upon the scale (e.g., point) of reference, noise has a dual nature. On a larger scale, with respect to the in vivo portion of the sensor and the surrounding tissue, noise occurs randomly (e.g., is scattered, intermittent, dispersed, unevenly distributed) in the local of an implanted sensor. Yet, on a smaller scale, such as that of a few cells (e.g., 100-300 microns), noise is a localized phenomenon because it creates hot spots of noise-causing species generation whose effects extend about a thousandths of an inch (e.g., localized nature, character). A “hot spot” of noise generation is referred to herein as a “point source.” A point source (e.g., a localized hot spot for noise generation) can be a cell or a group of cells adjacent to the sensor membrane, or a noise-causing species (e.g., compound, substance, molecule) that diffused to the location of sensor implantation, such as by diffusion between cells (e.g., to the sensor). For example, in the circumstance of a single point source in contact with the sensor membrane's surface, noise is a local phenomenon, because the noise-causing species' ability to affect adjacent structures is limited by the maximum distance it can diffuse (e.g., through the membrane), which is generally very short (e.g., a few microns, such as between about 1-μm to about 500-μm). Due to the random yet localized nature of noise, the configuration of the electroactive surfaces (of the working electrodes) can substantially affect noise measurement. With respect to the configuration and arrangement (e.g., surface area) of the dual-electrode sensor's electroactive surfaces, the random yet localized nature of noise is discussed in greater detail below.
Random and/or unequally distributed noise can be generated in a variety of circumstances. For example, a peroxide-generating immune cell could be located adjacent to one electroactive surface but not the other. In general, a noise-causing species must be generated and/or occur close enough to the sensor membrane such that it can diffuse to (and through) the membrane, to the electroactive surfaces, and affect the sensor signal. If the noise-causing species is generated farther away from the membrane than the diffusion distance of the noise-causing species, then the noise-causing species may be unable to reach the electroactive surfaces, and therefore may have little effect on sensor signal. For example, H2O2 (produced by metabolic process when the sensor is implanted in a host) must be generated sufficiently close to the membrane for it to diffuse to the membrane and affect sensor function. The maximum distance that the noise-causing species can diffuse (e.g., from the cell to the membrane, from one working electrode to another working electrode) and still substantially affect sensor function is referred to herein as a “diffusion distance.”
The sensor electronics are configured to mathematically correct for noise on the sensor signal (e.g., such as by subtraction of the noise signal, applying a filter, averaging, or other calculations), such that a substantially analyte-only signal can be presented to the user. The inventors have discovered that successful mathematical correction of noise on the sensor signal can be substantially affected by the equivalence (e.g., similarity) of the noise signals detected by the two working electrodes. If the detected noise signals are substantially equivalent (e.g., similar amounts, amplitudes, levels, relatively equal), then the calculations will be produce a more accurate resultant analyte signal. If, on the other hand, the detected noise signals are not substantially equal (e.g., have very different amplitudes and/or wave forms), then the calculations will have a greater degree of error. While not wishing to be bound by theory, it is believed that presentation of more accurate sensor data (e.g., to the host) will improve the host's management of his diabetes, which will prevent the immediate risks of hypoglycemia (e.g., loss of consciousness and death) and postpone and/or prevent long term diabetes complications (blindness, loss of limb, kidney dysfunction, and the like). Additionally, the increased accuracy afforded by the sensors of the preferred embodiment increases the feasibility of insulin dosing and/or an artificial pancreas system based on a continuous glucose sensor.
In order to compensate for the unevenly distributed nature of noise (e.g., the point sources are randomly and/or non-equally and/or non-equivalently distributed relative to the in vivo portion of the sensor) and thereby render the noise components equivalent, a continuous dual electrode glucose sensor having sufficiently large electroactive surfaces, such that the noise components can be substantially equalized (e.g., made and/or become equivalent) by integration there across, is provided in one embodiment. The first working electrode includes a first electroactive surface (1004a,
Due to the random nature of noise, the configuration and/or arrangement of the first and second electroactive surfaces 1004a, 1004b can substantially affect the equivalence of the noise measured, the areas of the electroactive surfaces are dimensioned (e.g., sized, shaped) to be sufficiently large such that the noise detected at (e.g., across, along, and the like) each electroactive surface can be integrated. While not wishing to be bound by theory, it is believed that integration of noise across a sufficiently large area (e.g., surface area of an electroactive surface) ensures that, even though noise-causing species 1006 affect each electroactive surface unevenly (e.g., local hot spots 1000 for noise-causing species generation are intermittently distributed across the area of each electroactive surface), a sufficient amount of signal is detected at each electroactive surface, such that the first and second noise components caused by noise-causing species are substantially equivalent. Accordingly, in some embodiments, the first and second areas are each configured and arranged to integrate the signal caused by a plurality of local point sources 1000 that produce noise-causing species 1006, when the sensor is implanted in a host. In other words, each electroactive surface includes a sufficiently large area (e.g., in at least one dimension, such as but not limited to D2), such that the detected noise signals (e.g., noise components) can be integrated (e.g., averaged), such that the amount of the two noise components are substantially equivalent. In some embodiments, the areas are dimensioned such that noise signals integrated there across are equivalent by at least 40% (e.g., within plus or minus 20% of each other). In more preferred embodiment, the integrated signals are equivalent by at least 20% (e.g., within plus or minus 10% of each other). In a more preferred embodiment, the integrated signals are equivalent by at least 10% (e.g., within plus or minus 5% of each other).
In preferred embodiments, at least one dimension of each of the first and second areas is greater than the sum of the diameters of from about 10 to about 500 (or more) average human cells (e.g., the sum of the diameters of the cells). The diameter of an average human cell is about 20 μm to about 160 μm. Thus, in some embodiments, the at least one dimension (e.g., D2) of each of the first and second electroactive surface areas is greater than between about 200 μm to about 10,000 μm. In some embodiments, if an average human cell has a diameter of about 20 μm, the at least one dimension is greater than the sum of the diameters (e.g., total diameter) of about 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 average human cells, such as greater than about 300-μm, 400-μm, 500-μm, 600-μm, 700-μm, 800-μm, 900-μm, 1000-μm, 1200-μm, 1300-μm, 1400-μm, 1500-μm, 1600-μm, 1700-μm, 1800-μm, or 1900-μm in at least one dimension. In some embodiments, if an average human cell has a diameter of about 160 μm, the at least one dimension is greater than the sum of the diameters (e.g., total diameter) of about 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 average human cells, such as greater than about 2400-μm, 3200-μm, 4000-μm, 4800-μm, 5600-μm, 6400-μm, 7200-μm, 8000-μm, 8800-μm, 9600-μm, 10400-μm, 11200-μm, 12000-μm, 12800-μm, 13600-μm, or 14400-μm in at least one dimension. In some embodiments, the dimension is greater than the sum of the diameters of about 110 to 500 average human cells, or more.
In some embodiments, the first and second areas (e.g., of the electroactive surfaces) are also configured and arranged to integrate signals detected about a circumference of the sensor. For example, in some embodiments, the dual electrode sensor is fabricated of cylindrical wires, each of which includes a circumference. Accordingly, the electroactive surfaces can be disposed about a wire's circumference. In one exemplary embodiment, the two working electrodes can be twisted to share a common axis. As a result, in addition to extending along the sensor's length and/or width and/or about each wire's circumference, the electroactive surfaces extend around at least a portion of the sensor's circumference, and noise (e.g., from one or more point sources producing noise-causing species) can impinge upon the sensor about that circumference. Thus, noise impinging upon the sensor about a circumference can be integrated.
Referring now to
Depending upon the sensor's configuration, in some embodiments, D4 can be the distance between the outer edges of the electroactive surfaces, or D4 can be a distance equivalent to the maximum diameter of the bundles and/or twisted pair of working electrodes. For example,
As described above, dual electrode sensors can be affected by internally generated noise (e.g., generated by the sensor). The inventors have found that, in general, when D3 is sized to be sufficiently small such that the electroactive surfaces are equivalently affect by noise from an adjacent point source, the electroactive surfaces are also close enough together that crosstalk (an internally generated noise) can occur. In general, crosstalk is detection of an analyte signal generated at the plus-GOx working electrode (wherein the electrode includes the membrane portion thereon) by the minus-GOx working electrode (including the No GOx membrane portion thereon). For example, when the measured species is H2O2, crosstalk occurs when the H2O2 diffuses from the plus-GOx enzyme domain to the No GOx working electrode and is detected (e.g., a signal is generated on the No GOx electrode). In general, crosstalk is undesirable as it causes sensor error. However, in order for the two working electrodes to measure equivalent noise signals from a point source 1000, the electroactive surfaces must be spaced very close together. Accordingly, in preferred embodiments, this distance (D3) is less than a crosstalk diffusion distance of the measured species. In other words, D3 is shorter than the diffusion distance of H2O2 (e.g., the maximum distance H2O2 can diffuse from a first electrode to a second and still cause a signal on the second electrode).
In conventional dual-electrode sensors, spacing the electroactive surfaces within the crosstalk diffusion distance of the measured species is generally undesirable due to increased sensor error. However, in preferred embodiments, the sensor includes a physical diffusion barrier configured to attenuate crosstalk by physically blocking (e.g., suppressing, blocking, restricting) some of the crosstalk from the active enzymatic portion of the sensor membrane to the second electroactive surface. More preferably, the physical diffusion barrier is configured and arranged to attenuate and/or physically block a substantial amount of the measurable species (e.g., H2O2) diffusing from the active enzymatic portion of the membrane to the second electroactive surface, such that there is substantially no signal associated with crosstalk measured at the second working electrode.
In preferred embodiments, the physical diffusion barrier 1010 is disposed between the electroactive surfaces of working electrodes E1 and E2. In some embodiments, the physical diffusion barrier is formed of one or more membrane materials, such as those used in formation of an interference domain and/or a resistance domain. Such materials include but are not limited to silicones, polyurethanes, cellulose derivatives (cellulose butyrates and cellulose acetates, and the like) and combinations thereof, as described elsewhere herein. In some embodiments, the physical diffusion barrier includes one or more membrane domains. For example, in the exemplary embodiment of
In some embodiments, a dual electrode sensor having a physical barrier layer can be fabricated by initially preparing (e.g., fabricating, building) the first and second working electrodes E1, E2 independently (e.g., separately from each other), followed by joining and/or grouping and/or bundling the working electrodes and optionally applying one or more additional membrane domains fabrication. In this exemplary embodiment, to the first working electrode E1, an optional electrode domain 24, an enzyme domain 26 (e.g., plus-GOx), and at least one layer of the resistance domain material 28 (e.g., first resistance domain) are sequentially applied. Similarly, to the second working electrode E2, an optional electrode domain 24, an enzyme domain 26 (e.g., no-GOx), and at least one layer of the resistance domain material 28 (e.g., second resistance domain) are sequentially applied. The working electrodes are then held together, such as but not limited to by bundling and/or twisting them together, wrapping a material around them, or by any other method known in the art. In this embodiment, the physical diffusion barrier includes a discontinuous portion of a membrane (e.g., the initial layers of the resistance domain material applied independently to the two working electrodes) disposed between the first and second electroactive surfaces.
In an alternative exemplary sensor embodiment, the sensor includes working electrodes (including electroactive surfaces) disposed on a planar substrate and/or surface. The electroactive surfaces can be spaced a distance D3 that is sufficiently close together that the electroactive surfaces are equivalently affected by an adjacent noise hot spot (e.g., point source). In this configuration, D3 is also sufficiently small that crosstalk can occur between the Plus GOx working electrode (wherein the term “electrode” includes the membrane disposed thereon, for the purposes of this example) and the No GOx working electrode. However, in preferred embodiments, crosstalk is substantially attenuated by a physical diffusion barrier disposed between the working electrodes. Namely, the electrode domains (if present) and enzyme domains can be separately applied to the working electrodes and/or electroactive surfaces; followed by application of a continuous resistance domain applied thereon, such that a portion the resistance domain is deposited between the working electrodes. For example, a portion of resistance domain deposited on a planar substrate and between working electrodes can attenuate diffusion of the measured species (e.g., H2O2) from E1 to E2, such that the noise measured on E1 and E2 is equivalent.
In the context of glucose sensors, one skilled in the art recognizes that equivalent noise signals can have different amplitudes, but equivalent signal patterns (e.g., rises, falls, trends and the like) such that a noise component can be subtracted out (as described elsewhere herein) while compensating for any difference in signal amplitude (i.e., sensitivity of the first and second working electrodes), as described elsewhere herein. In some circumstances, the membrane portions associated with the working electrodes (e.g., of a dual electrode sensor) can possess different sensitivities (e.g., signal sensitivities), such that the amplitudes of the noise components measured by the working electrodes are not equivalent. In some circumstances, the areas of the electroactive surfaces may be different sizes, which can also result in non-equivalent signal amplitudes and/or sensitivities. While such differences in signal sensitivity can be corrected mathematically (e.g., by mathematical filters), mathematical correction of noise, in general, is improved when the signal sensitivities of the first and second working electrodes are closer. Accordingly, in a preferred embodiment, an additional resistance domain 28A (e.g., applied continuously over the discontinuous resistance domains 28 described elsewhere herein) is provided, such that the signal sensitivities are equivalent. In the exemplary embodiment shown in
In an alternative embodiment, the sensor electrodes can be disposed on a planar, cylindrical, pyramidal or otherwise shaped support. For example, the sensor's first and second working electrodes can be conductive traces deposited, such as by screen printing, sputtering or other thin film techniques known in the art, on a planar substrate. In this alternative embodiment, a physical diffusion barrier can be formed by layers of resistance domain material deposited separately (e.g., discontinuously) on each working electrode and/or between the electrodes, for example.
In the exemplary embodiments described above, diffusion of the H2O2 from the first working electrode E1 to the electroactive surface of the second working electrode E2 is first attenuated by the resistance domain 28 disposed over the first working electrode E1 (an independently formed first barrier layer), and then again by the resistance domain 28 disposed over the second working electrode E2 (an independently formed second barrier layer), such that only insubstantial amounts of H2O2 can reach the electroactive surface of the second working electrode. In preferred embodiments, the first and second resistance domains are configured and arranged to reduce diffusion of the measurable species (e.g., H2O2) from the first electroactive surface to the second electroactive surface by at least 2-fold. In more preferred embodiments, the physical diffusion barrier is configured and arranged to reduce diffusion of the measurable species by at least 10-fold. In some embodiments, the physical diffusion barrier is configured and arranged to reduce diffusion of the measurable species by at least 3-, 4-, 5-, 6-, 7-, 8-, or 9-fold. In some embodiments, the physical diffusion barrier is configured and arranged to reduce diffusion of the measurable species by at least 20-, 30-, 40- or 50-fold, or more. In some embodiments, the sensor's working electrodes E1, E2 are by an insulator I, which insulates the working electrodes from each other. In some embodiments, the insulator I is at least a portion of the sensor membrane.
In another exemplary embodiment, the membrane can be configured to function as an insulator I, and therefore block and/or attenuate crosstalk between the first and second working electrodes E1, E2. For example, as described herein in the section entitled “Exemplary Sensor Configurations,” a physical diffusion barrier can be formed by integrally forming the first and second working electrodes E1, E2 either on a reference electrode R or an insulator I, such that the reference electrode R and/or insulator I physically blocks diffusion from one working electrode to the other, such that substantially no crosstalk affects the sensor signal. For example, if the insulator I is a planar polymer sheet or support, the working electrodes E1, E2 can be integrally formed on opposite sides to the polymer sheet and/or support, such H2O2 produced in the active enzymatic portion of the sensor membrane (e.g., disposed over E1) cannot diffuse around the sheet and/or support (e.g., and impinge upon E2).
In yet another exemplary embodiment, if the working electrodes are integrally formed on a substrate (planar, cylindrical, pyramidal, and the like) an insulative material can be deposited between the working electrodes (e.g., onto the substrate) to form a physical diffusion barrier. For example, the physical diffusion barrier can project a sufficient distance away from the substrate (e.g., similar to a wall-like structure) such that the measurable species cannot diffuse around it. Such a physical diffusion barrier can be formed from a variety of insulative materials (e.g., materials through which only insubstantial amounts of the measurable species can diffuse) can be integrally formed and/or deposited on the substrate. Additionally, any thin film deposition technique known to one skilled in the art (e.g., printing, sputtering, spin coating, and the like) can be employed to form the physical diffusion barrier on the substrate.
In some embodiments, a continuous glucose sensor configured for insertion into a host and detecting glucose in the host is provided. In general, the sensor includes first and second working electrodes, wherein each working electrode includes an electroactive surface (each including an area) disposed beneath a sensor membrane. The first electroactive surface (e.g., of the first working electrode) is disposed beneath an active enzymatic portion (plus-GOx) of the membrane while the second electroactive surface (of the second working electrode) is disposed beneath a non-enzymatic (no-GOx) portion of the membrane. The non-enzymatic portion of the membrane can include inactivated enzyme and/or no enzyme. Additionally, each working electrode is configured to generate a signal having a noise component related to a noise-causing species. In some circumstances, the noise-causing species is non-constant and related to a biological process. Preferably, the first and second areas are sufficiently large such that the noise components (e.g., first and second noise components detected by the first and second working electrodes) are substantially equivalent. In some embodiments, the first and second areas are each greater than the sum of the diameters of about 10 average human cells, in at least one dimension. In some embodiments, the first and second areas are each greater than about 500 μm, in at least one dimension. Preferably, the first and second areas (e.g., of the electroactive surfaces) are configured and arranged such that the signals caused by a plurality of local point sources (that produce noise-causing species when implanted in a host) can be integrated along each area (e.g., each area independently from the other). In some further embodiments, the first and second areas are configured and arranged to integrate signals detected about a circumference of the sensor. Preferably, the first and second electroactive surfaces are spaced a distance that is less than a crosstalk diffusion distance of a measured species, such as H2O2 produced in the active enzymatic portion of the membrane. In some embodiments, the sensor includes a physical diffusion barrier configured and arranged to physically block some crosstalk from the active enzymatic portion of the membrane to the second electroactive surface. In some further embodiments, the physical diffusion barrier is configured and arranged to physically block a substantial amount of the measurable species diffusing from the active enzymatic portion of the membrane to the second electroactive surface (e.g., crosstalk), such that there is substantially no signal associated with crosstalk measured at the second working electrode. In some embodiments, the physical diffusion barrier is a discontinuous portion of the membrane disposed between the first and second electroactive surfaces. In some further embodiments, the physical diffusion barrier includes a first barrier layer formed on the first working electrode and a second barrier layer formed on the second working electrode, wherein the first and second barrier layers are independently formed (e.g., formed separately on the two electroactive surfaces). In some further embodiments, the physical diffusion barrier includes a first resistance domain formed on the first working electrode and a second resistance domain formed on the second working electrode, and wherein the first and second resistance domains are configured and arranged to reduce diffusion of the measurable species (e.g., crosstalk) from the active enzymatic portion of the sensor to the second electroactive surface by at least 2-fold. In a preferred embodiment, the physical diffusion barrier can reduce the diffusion of the measurable species (e.g., crosstalk) by at least 10-fold.
In some embodiments, the continuous glucose sensor includes first and second working electrodes, each working electrode including an electroactive surface (each including an area) disposed beneath a sensor membrane. As described elsewhere herein, the first electroactive surface is disposed beneath an active enzymatic portion of the membrane and the second electroactive surface is disposed beneath a non-enzymatic portion of the membrane. Preferably, the sensor includes a physical diffusion barrier, and the first and second electroactive surfaces are disposed sufficiently close together that the first and second noise components (detected by the first and second working electrodes) are substantially equivalent. In some embodiments, the distance between the first and second electroactive surfaces is less than about twice the thickness of the membrane. In some embodiments, the first and second electroactive surfaces are spaced a distance that is less than or equal to about a crosstalk diffusion distance of a measurable species, such as the H2O2 produced in the active enzymatic portion of the sensor membrane. In some embodiments, the physical diffusion barrier is configured and arranged to physically block some diffusion of the measurable species from the active enzymatic portion of the membrane to the second electroactive surface (e.g., crosstalk). In preferred embodiments, the physical diffusion barrier blocks a substantial amount of the measurable species, such that there is substantially no signal associated with crosstalk measured at the second working electrode. In some embodiments, the physical diffusion barrier is a discontinuous portion of the membrane disposed between the first and second electroactive surfaces. In some embodiments, the physical diffusion barrier is a first barrier layer formed on the first electrode and a second barrier layer formed on the second electrode, wherein the first and second barrier layers are independently formed. In some embodiments, the physical diffusion barrier includes a first resistance domain formed on the first electrode and a second resistance domain formed on the second electrode. Preferably, the first and second resistance domains reduce diffusion of the measurable species (e.g., crosstalk) by at least 2-fold. In more preferred embodiments, the diffusion of the measurable species is reduced by at least 10-fold. In some embodiments, the membrane is an insulator that insulates the first working electrode from the second working electrodes. In some further embodiments, the first and second areas are sufficiently large that the first and second noise components are substantially equivalent.
Sensor Electronics
In some embodiments, the sensing region may include reference and/or electrodes associated with the glucose-measuring working electrode and separate reference and/or counter electrodes associated with the optional auxiliary working electrode(s). In yet another embodiment, the sensing region may include a glucose-measuring working electrode, an auxiliary working electrode, two counter electrodes (one for each working electrode), and one shared reference electrode. In yet another embodiment, the sensing region may include a glucose-measuring working electrode, an auxiliary working electrode, two reference electrodes, and one shared counter electrode. However, a variety of electrode materials and configurations can be used with the implantable analyte sensor of the preferred embodiments.
In some alternative embodiments, the working electrodes are interdigitated. In some alternative embodiments, the working electrodes each comprise multiple exposed electrode surfaces; one advantage of these architectures is to distribute the measurements across a greater surface area to overcome localized problems that may occur in vivo, for example, with the host's immune response at the biointerface. Preferably, the glucose-measuring and auxiliary working electrodes are provided within the same local environment, such as described in more detail elsewhere herein.
A microprocessor 40, also referred to as the processor module, is the central control unit that houses EEPROM 42 and SRAM 44, and controls the processing of the sensor electronics. It is noted that certain alternative embodiments can utilize a computer system other than a microprocessor to process data as described herein. In other alternative embodiments, an application-specific integrated circuit (ASIC) can be used for some or all the sensor's central processing. The EEPROM 42 provides semi-permanent storage of data, for example, storing data such as sensor identifier (ID) and programming to process data streams (for example, such as described in U.S. Patent Publication No. US-2005-0027463-A1, which is incorporated by reference herein in its entirety. The SRAM 44 can be used for the system's cache memory, for example for temporarily storing recent sensor data. In some alternative embodiments, memory storage components comparable to EEPROM and SRAM may be used instead of or in addition to the preferred hardware, such as dynamic RAM, non-static RAM, rewritable ROMs, flash memory, or the like.
A battery 46 is operably connected to the microprocessor 40 and provides the necessary power for the sensor 10a. In one embodiment, the battery is a Lithium Manganese Dioxide battery, however any appropriately sized and powered battery can be used (for example, AAA, Nickel-cadmium, Zinc-carbon, Alkaline, Lithium, Nickel-metal hydride, Lithium-ion, Zinc-air, Zinc-mercury oxide, Silver-zinc, and/or hermetically-sealed). In some embodiments the battery is rechargeable. In some embodiments, a plurality of batteries can be used to power the system. In some embodiments, one or more capacitors can be used to power the system. A Quartz Crystal 48 may be operably connected to the microprocessor 40 to maintain system time for the computer system as a whole.
An RF Transceiver 50 may be operably connected to the microprocessor 40 to transmit the sensor data from the sensor 10 to a receiver (see
Receiver
A quartz crystal 60 may be operably connected to an RF transceiver 62 that together function to receive and synchronize data streams via an antenna 64 (for example, transmission 52 from the RF transceiver 50 shown in
The microprocessor 66, also referred to as the processor module, is the central control unit that provides the processing, such as storing data, calibrating sensor data, downloading data, controlling the user interface by providing prompts, messages, warnings and alarms, or the like. The EEPROM 68 may be operably connected to the microprocessor 66 and provides semi-permanent storage of data, storing data such as receiver ID and programming to process data streams (for example, programming for performing calibration and other algorithms described elsewhere herein). SRAM 70 may be used for the system's cache memory and is helpful in data processing. For example, the SRAM stores information from the continuous glucose sensor for later recall by the patient or a doctor; a patient or doctor can transcribe the stored information at a later time to determine compliance with the medical regimen or a comparison of glucose concentration to medication administration (for example, this can be accomplished by downloading the information through the pc com port 76). In addition, the SRAM 70 can also store updated program instructions and/or patient specific information. In some alternative embodiments, memory storage components comparable to EEPROM and SRAM can be used instead of or in addition to the preferred hardware, such as dynamic RAM, non-static RAM, rewritable ROMs, flash memory, or the like.
A battery 72 may be operably connected to the microprocessor 66 and provides power for the receiver. In one embodiment, the battery is a standard AAA alkaline battery, however any appropriately sized and powered battery can be used. In some embodiments, a plurality of batteries can be used to power the system. In some embodiments, a power port (not shown) is provided permit recharging of rechargeable batteries. A quartz crystal 84 may be operably connected to the microprocessor 66 and maintains system time for the system as a whole.
A PC communication (com) port 76 can be provided to enable communication with systems, for example, a serial communications port, allows for communicating with another computer system (for example, PC, PDA, server, or the like). In one exemplary embodiment, the receiver is able to download historical data to a physician's PC for retrospective analysis by the physician. The PC communication port 76 can also be used to interface with other medical devices, for example pacemakers, implanted analyte sensor patches, infusion devices, telemetry devices, or the like.
A user interface 78 comprises a keypad 80, speaker 82, vibrator 84, backlight 86, liquid crystal display (LCD) 88, and one or more buttons 90. The components that comprise the user interface 78 provide controls to interact with the user. The keypad 80 can allow, for example, input of user information about himself/herself, such as mealtime, exercise, insulin administration, and reference glucose values. The speaker 82 can provide, for example, audible signals or alerts for conditions such as present and/or predicted hyper- and hypoglycemic conditions. The vibrator 84 can provide, for example, tactile signals or alerts for reasons such as described with reference to the speaker, above. The backlight 94 can be provided, for example, to aid the user in reading the LCD in low light conditions. The LCD 88 can be provided, for example, to provide the user with visual data output. In some embodiments, the LCD is a touch-activated screen. The buttons 90 can provide for toggle, menu selection, option selection, mode selection, and reset, for example. In some alternative embodiments, a microphone can be provided to allow for voice-activated control.
The user interface 78, which is operably connected to the microprocessor 70, serves to provide data input and output for the continuous analyte sensor. In some embodiments, prompts can be displayed to inform the user about necessary maintenance procedures, such as “Calibrate Sensor” or “Replace Battery.” In some embodiments, prompts or messages can be displayed on the user interface to convey information to the user, such as malfunction, outlier values, missed data transmissions, or the like. Additionally, prompts can be displayed to guide the user through calibration of the continuous glucose sensor, for example when to obtain a reference glucose value.
Keypad, buttons, touch-screen, and microphone are all examples of mechanisms by which a user can input data directly into the receiver. A server, personal computer, personal digital assistant, insulin pump, and insulin pen are examples of external devices that can be connected to the receiver via PC com port 76 to provide useful information to the receiver. Other devices internal or external to the sensor that measure other aspects of a patient's body (for example, temperature sensor, accelerometer, heart rate monitor, oxygen monitor, or the like) can be used to provide input helpful in data processing. In one embodiment, the user interface can prompt the patient to select an activity most closely related to their present activity, which can be helpful in linking to an individual's physiological patterns, or other data processing. In another embodiment, a temperature sensor and/or heart rate monitor can provide information helpful in linking activity, metabolism, and glucose excursions of an individual. While a few examples of data input have been provided here, a variety of information can be input and can be helpful in data processing as will be understood by one skilled in the art.
Calibration Systems and Methods
As described above in the Overview Section, continuous analyte sensors define a relationship between sensor-generated measurements and a reference measurement that is meaningful to a user (for example, blood glucose in mg/dL). This defined relationship must be monitored to ensure that the continuous analyte sensor maintains a substantially accurate calibration and thereby continually provides meaningful values to a user. Unfortunately, both sensitivity m and baseline b of the calibration are subject to changes that occur in vivo over time (for example, hours to months), requiring updates to the calibration. Generally, any physical property that influences diffusion or transport of molecules through the membrane can alter the sensitivity (and/or baseline) of the calibration. Physical properties that can alter the transport of molecules include, but are not limited to, blockage of surface area due to foreign body giant cells and other barrier cells at the biointerface, distance of capillaries from the membrane, foreign body response/capsule, disease, tissue ingrowth, thickness of membrane system, or the like.
In one example of a change in transport of molecules, an implantable glucose sensor is implanted in the subcutaneous space of a human, which is at least partially covered with a biointerface membrane, such as described in U.S. Patent Publication No. US-2005-0112169-A1, which is incorporated by reference herein in its entirety. Although the body's natural response to a foreign object is to encapsulate the sensor, the architecture of this biointerface membrane encourages tissue ingrowth and neo-vascularization over time, providing transport of solutes (for example, glucose and oxygen) close to the membrane that covers the electrodes. While not wishing to be bound by theory, it is believed that ingrowth of vascularized tissue matures (changes) over time, beginning with a short period of high solute transport during the first few days after implantation, continuing through a time period of significant tissue ingrowth a few days to a week or more after implantation during which low solute transport to the membrane has been observed, and into a mature state of vascularized tissue during which the bed of vascularized tissue provides moderate to high solute transport, which can last for months and even longer after implantation. In some embodiments, this maturation process accounts for a substantial portion of the change in sensitivity and/or baseline of the calibration over time due to changes in solute transport to the membrane.
Accordingly, in one aspect of the preferred embodiments, systems and methods are provided for measuring changes in sensitivity, also referred to as changes in solute transport or biointerface changes, of an analyte sensor 10 implanted in a host over a time period. Preferably, the sensitivity measurement is a signal obtained by measuring a constant analyte other than the analyte being measured by the analyte sensor. For example, in a glucose sensor, a non-glucose constant analyte is measured, wherein the signal is measured beneath the membrane system 22 on the glucose sensor 10. While not wishing to be bound by theory, it is believed that by monitoring the sensitivity over a time period, a change associated with solute transport through the membrane system 22 can be measured and used as an indication of a sensitivity change in the analyte measurement. In other words, a biointerface monitor is provided, which is capable of monitoring changes in the biointerface surrounding an implantable device, thereby enabling the measurement of sensitivity changes of an analyte sensor over time.
In some embodiments, the analyte sensor 10 is provided with an auxiliary electrode 18 configured as a transport-measuring electrode disposed beneath the membrane system 22. The transport-measuring electrode can be configured to measure any of a number of substantially constant analytes or factors, such that a change measured by the transport-measuring electrode can be used to indicate a change in solute (for example, glucose) transport to the membrane system 22. Some examples of substantially constant analytes or factors that can be measured include, but are not limited to, oxygen, carboxylic acids (such as urea), amino acids, hydrogen, pH, chloride, baseline, or the like. Thus, the transport-measuring electrode provides an independent measure of changes in solute transport to the membrane, and thus sensitivity changes over time.
In some embodiments, the transport-measuring electrode measures analytes similar to the analyte being measured by the analyte sensor. For example, in some embodiments of a glucose sensor, water soluble analytes are believed to better represent the changes in sensitivity to glucose over time than non-water soluble analytes (due to the water-solubility of glucose), however relevant information may be ascertained from a variety of molecules. Although some specific examples are described herein, one skilled in the art appreciates a variety of implementations of sensitivity measurements that can be used as to qualify or quantify solute transport through the biointerface of the analyte sensor.
In one embodiment of a glucose sensor, the transport-measuring electrode is configured to measure urea, which is a water-soluble constant analyte that is known to react directly or indirectly at a hydrogen peroxide sensing electrode (similar to the working electrode of the glucose sensor example described in more detail above). In one exemplary implementation wherein urea is directly measured by the transport-measuring electrode, the glucose sensor comprises a membrane system as described in more detail above, however, does not include an active interference domain or active enzyme directly above the transport-measuring electrode, thereby allowing the urea to pass through the membrane system to the electroactive surface for measurement thereon. In one alternative exemplary implementation wherein urea is indirectly measured by the transport-measuring electrode, the glucose sensor comprises a membrane system as described in more detail above, and further includes an active uricase oxidase domain located directly above the transport-measuring electrode, thereby allowing the urea to react at the enzyme and produce hydrogen peroxide, which can be measured at the electroactive surface thereon.
In some embodiments, the change in sensitivity is measured by measuring a change in oxygen concentration, which can be used to provide an independent measurement of the maturation of the biointerface, and to indicate when recalibration of the system may be advantageous. In one alternative embodiment, oxygen is measured using pulsed amperometric detection on the glucose-measuring working electrode 16 (eliminating the need for a separate auxiliary electrode). In another embodiment, the auxiliary electrode is configured as an oxygen-measuring electrode. In another embodiment, an oxygen sensor (not shown) is added to the glucose sensor, as is appreciated by one skilled in the art, eliminating the need for an auxiliary electrode.
In some embodiments, a stability module is provided; wherein the sensitivity measurement changes can be quantified such that a co-analyte concentration threshold is determined. A co-analyte threshold is generally defined as a minimum amount of co-analyte required to fully react with the analyte in an enzyme-based analyte sensor in a non-limiting manner. The minimum co-analyte threshold is preferably expressed as a ratio (for example, a glucose-to-oxygen ratio) that defines a concentration of co-analyte required based on a concentration of analyte available to ensure that the enzyme reaction is limited only by the analyte. While not wishing to be bound by theory, it is believed that by determining a stability of the analyte sensor based on a co-analyte threshold, the processor module can be configured to compensate for instabilities in the glucose sensor accordingly, for example by filtering the unstable data, suspending calibration or display, or the like.
In one such embodiment, a data stream from an analyte signal is monitored and a co-analyte threshold set, whereby the co-analyte threshold is determined based on a signal-to-noise ratio exceeding a predetermined threshold. In one embodiment, the signal-to-noise threshold is based on measurements of variability and the sensor signal over a time period, however one skilled in the art appreciates the variety of systems and methods available for measuring signal-to-noise ratios. Accordingly, the stability module can be configured to set determine the stability of the analyte sensor based on the co-analyte threshold, or the like.
In some embodiments, the stability module is configured to prohibit calibration of the sensor responsive to the stability (or instability) of the sensor. In some embodiments, the stability module can be configured to trigger filtering of the glucose signal responsive to a stability (or instability) of the sensor.
In some embodiments, sensitivity changes can be used to trigger a request for one or more new reference glucose values from the host, which can be used to recalibrate the sensor. In some embodiments, the sensor is re-calibrated responsive to a sensitivity change exceeding a preselected threshold value. In some embodiments, the sensor is calibrated repeatedly at a frequency responsive to the measured sensitivity change. Using these techniques, patient inconvenience can be minimized because reference glucose values are generally only requested when timely and appropriate (namely, when a sensitivity or baseline shift is diagnosed).
In some alternative embodiments, sensitivity changes can be used to update calibration. For example, the measured change in transport can be used to update the sensitivity m in the calibration equation. While not wishing to be bound by theory, it is believed that in some embodiments, the sensitivity m of the calibration of the glucose sensor is substantially proportional to the change in solute transport measured by the transport-measuring electrode.
It should be appreciated by one skilled in the art that in some embodiments, the implementation of sensitivity measurements of the preferred embodiments typically necessitate an addition to, or modification of, the existing electronics (for example, potentiostat configuration or settings) of the glucose sensor and/or receiver.
In some embodiments, the signal from the oxygen measuring electrode may be digitally low-pass filtered (for example, with a passband of 0-10−5 Hz, dc-24 hour cycle lengths) to remove transient fluctuations in oxygen, due to local ischemia, postural effects, periods of apnea, or the like. Since oxygen delivery to tissues is held in tight homeostatic control, this filtered oxygen signal should oscillate about a relatively constant. In the interstitial fluid, it is thought that the levels are about equivalent with venous blood (40 mmHg). Once implanted, changes in the mean of the oxygen signal (for example, >5%) may be indicative of change in transport through the biointerface (change in sensor sensitivity and/or baseline due to changes in solute transport) and the need for system recalibration.
The oxygen signal may also be used in its unfiltered or a minimally filtered form to detect or predict oxygen deprivation-induced artifact in the glucose signal, and to control display of data to the user, or the method of smoothing, digital filtering, or otherwise replacement of glucose signal artifact. In some embodiments, the oxygen sensor may be implemented in conjunction with any signal artifact detection or prediction that may be performed on the counter electrode or working electrode voltage signals of the electrode system. U.S. Patent Publication No. US-2005-0043598-A1, which is incorporated by reference in its entirety herein, describes some methods of signal artifact detection and replacement that may be useful such as described herein.
Preferably, the transport-measuring electrode is located within the same local environment as the electrode system associated with the measurement of glucose, such that the transport properties at the transport-measuring electrode are substantially similar to the transport properties at the glucose-measuring electrode.
In a second aspect the preferred embodiments, systems and methods are provided for measuring changes baseline, namely non-glucose related electroactive compounds in the host. Preferably the auxiliary working electrode is configured to measure the baseline of the analyte sensor over time. In some embodiments, the glucose-measuring working electrode 16 is a hydrogen peroxide sensor coupled to a membrane system 22 containing an active enzyme 32 located above the electrode (such as described in more detail with reference to
Signalglucose only=Signalglucose-measuring working electrode−Signalbaseline-measuring working electrode
In some embodiments, electronic subtraction of the baseline signal from the glucose signal can be performed in the hardware of the sensor, for example using a differential amplifier. In some alternative embodiments, digital subtraction of the baseline signal from the glucose signal can be performed in the software or hardware of the sensor or an associated receiver, for example in the microprocessor.
One aspect the preferred embodiments provides for a simplified calibration technique, wherein the variability of the baseline has been eliminated (namely, subtracted). Namely, calibration of the resultant differential signal (Signalglucose only) can be performed with a single matched data pair by solving the following equation:
y=mx
While not wishing to be bound by theory, it is believed that by calibrating using this simplified technique, the sensor is made less dependent on the range of values of the matched data pairs, which can be sensitive to human error in manual blood glucose measurements, for example. Additionally, by subtracting the baseline at the sensor (rather than solving for the baseline b as in conventional calibration schemes), accuracy of the sensor may increase by altering control of this variable (baseline b) from the user to the sensor. It is additionally believed that variability introduced by sensor calibration may be reduced.
In some embodiments, the glucose-measuring working electrode 16 is a hydrogen peroxide sensor coupled to a membrane system 22 containing an active enzyme 32 located above the electrode, such as described in more detail above; however the baseline signal is not subtracted from the glucose signal for calibration of the sensor. Rather, multiple matched data pairs are obtained in order to calibrate the sensor (for example using y=mx+b) in a conventional manner, and the auxiliary working electrode 18 is used as an indicator of baseline shifts in the sensor signal. Namely, the auxiliary working electrode 18 is monitored for changes above a certain threshold. When a significant change is detected, the system can trigger a request (for example, from the patient or caregiver) for a new reference glucose value (for example, SMBG), which can be used to recalibrate the sensor. By using the auxiliary working electrode signal as an indicator of baseline shifts, recalibration requiring user interaction (namely, new reference glucose values) can be minimized due to timeliness and appropriateness of the requests. In some embodiments, the sensor is re-calibrated responsive to a baseline shifts exceeding a preselected threshold value. In some embodiments, the sensor is calibrated repeatedly at a frequency responsive to the rate-of-change of the baseline.
In yet another alternative embodiment, the electrode system of the preferred embodiments is employed as described above, including determining the differential signal of glucose less baseline current in order to calibrate using the simplified equation (y=mx), and the auxiliary working electrode 18 is further utilized as an indicator of baseline shifts in the sensor signal. While not wishing to be bound by theory, it is believed that shifts in baseline may also correlate and/or be related to changes in the sensitivity m of the glucose signal. Consequently, a shift in baseline may be indicative of a change in sensitivity m. Therefore, the auxiliary working electrode 18 is monitored for changes above a certain threshold. When a significant change is detected, the system can trigger a request (for example, from the patient or caregiver) for a new reference glucose value (for example, SMBG), which can be used to recalibrate the sensor. By using the auxiliary signal as an indicator of possible sensitivity changes, recalibration requiring user interaction (new reference glucose values) can be minimized due to timeliness and appropriateness of the requests.
It is noted that infrequent new matching data pairs may be useful over time to recalibrate the sensor because the sensitivity m of the sensor may change over time (for example, due to maturation of the biointerface that may increase or decrease the glucose and/or oxygen availability to the sensor). However, the baseline shifts that have conventionally required numerous and/or regular blood glucose reference measurements for updating calibration (for example, due to interfering species, metabolism changes, or the like) can be consistently and accurately eliminated using the systems and methods of the preferred embodiments, allowing reduced interaction from the patient (for example, requesting less frequent reference glucose values such as daily or even as infrequently as monthly).
An additional advantage of the sensor of the preferred embodiments includes providing a method of eliminating signal effects of interfering species, which have conventionally been problematic in electrochemical glucose sensors. Namely, electrochemical sensors are subject to electrochemical reaction not only with the hydrogen peroxide (or other analyte to be measured), but additionally may react with other electroactive species that are not intentionally being measured (for example, interfering species), which cause an increase in signal strength due to this interference. In other words, interfering species are compounds with an oxidation potential that overlap with the analyte being measured. Interfering species such as acetaminophen, ascorbate, and urate, are notorious in the art of glucose sensors for producing inaccurate signal strength when they are not properly controlled. Some glucose sensors utilize a membrane system that blocks at least some interfering species, such as ascorbate and urate. Unfortunately, it is difficult to find membranes that are satisfactory or reliable in use, especially in vivo, which effectively block all interferants and/or interfering species (for example, see U.S. Pat. Nos. 4,776,944, 5,356,786, 5,593,852, 5,776,324B1, and U.S. Pat. No. 6,356,776).
The preferred embodiments are particularly advantageous in their inherent ability to eliminate the erroneous transient and non-transient signal effects normally caused by interfering species. For example, if an interferant such as acetaminophen is ingested by a host implanted with a conventional implantable electrochemical glucose sensor (namely, one without means for eliminating acetaminophen), a transient non-glucose related increase in signal output would occur. However, by utilizing the electrode system of the preferred embodiments, both working electrodes respond with substantially equivalent increased current generation due to oxidation of the acetaminophen, which would be eliminated by subtraction of the auxiliary electrode signal from the glucose-measuring electrode signal.
In summary, the system and methods of the preferred embodiments simplify the computation processes of calibration, decreases the susceptibility introduced by user error in calibration, and eliminates the effects of interfering species. Accordingly, the sensor requires less interaction by the patient (for example, less frequent calibration), increases patient convenience (for example, few reference glucose values), and improves accuracy (via simple and reliable calibration).
In another aspect of the preferred embodiments, the analyte sensor is configured to measure any combination of changes in baseline and/or in sensitivity, simultaneously and/or iteratively, using any of the above-described systems and methods. While not wishing to be bound by theory, the preferred embodiments provide for improved calibration of the sensor, increased patient convenience through less frequent patient interaction with the sensor, less dependence on the values/range of the paired measurements, less sensitivity to error normally found in manual reference glucose measurements, adaptation to the maturation of the biointerface over time, elimination of erroneous signal due to non-constant analyte-related signal so interfering species, and/or self-diagnosis of the calibration for more intelligent recalibration of the sensor.
Dual-electrode sensors (having a configuration similar to the embodiment shown in
This sensor was constructed similarly to the sensor of Example 1, except that the configuration was similar to the embodiment shown in
A dual-electrode sensor was assembled similarly to the sensor of Example 1, with a bundled configuration similar to that shown in
The sensor was challenged with increasing concentrations of hydrogen peroxide in PBS. As expected, both the “Enzyme” and “No Enzyme” electrodes responded substantially the same with increases in signal corresponding increased in H2O2 concentration (˜50 μM, 100 μM and 250 μM H2O2). When the “No Enzyme” signal was subtracted from the “Enzyme” signal, the graph indicated that the signal was not related to glucose concentration.
The sensor was challenged with increasing concentrations of glucose (˜20 mg/dl, 200 mg/dl, 400 mg/dl) in PBS. As glucose concentration increased, the “Enzyme” electrode registered a corresponding increase in signal. In contrast, the “No Enzyme” electrode did not record an increase in signal. Subtracting the “No Enzyme” signal from the “Enzyme” signal shows a step-wise increase in signal related to only glucose concentration.
The sensor was challenged with the addition of acetaminophen (˜0.22 mM) to the highest glucose concentration. Acetaminophen is known to be an interferent (e.g., produces non-constant noise) of the sensors built as described above, e.g., due to a lack of acetaminophen-blocking membrane and/or mechanism formed thereon or provided therewith. Both the “Enzyme” and “No Enzyme” electrodes showed a substantial increase in signal. The “Enzyme minus No Enzyme” graph substantially shows the portion of the signal that was related to glucose concentration.
From these data, it is believed that a dual-electrode system can be used to determine the analyte-only portion of the signal.
An intravascular dual-electrode sensor was built substantially as described in co-pending U.S. patent application Ser. No. 11/543,396 filed on even date herewith and entitled “ANALYTE SENSOR.” Namely, the sensor was built by providing two platinum wires (e.g., dual working electrodes) and vapor-depositing the platinum wires with Parylene to form an insulating coating. A portion of the insulation on each wire was removed to expose the electroactive surfaces (e.g., 904a and 904b). The wires were bundled such that the windows were offset to provide a diffusion barrier, as described herein, cut to the desired length, to form an “assembly.” A silver/silver chloride reference electrode was disposed remotely from the working electrodes (e.g., coiled inside the sensor's fluid connector).
An electrode domain was formed over the electroactive surface areas of the working electrodes by dip coating the assembly in an electrode solution (comprising BAYHYDROL® 123 with PVP and added EDC)) and drying.
An enzyme domain was formed over the electrode domain by subsequently dip coating the assembly in an enzyme domain solution (BAYHYDROL 140AQ mixed with glucose oxidase and glutaraldehyde) and drying. This dip coating process was repeated once more to form an enzyme domain having two layers and subsequently drying. Next an enzyme solution containing active GOx was applied to one window; and an enzyme solution without enzyme (e.g., No GOx) was applied to the other window.
A resistance domain was formed over the enzyme domain by subsequently spray coating the assembly with a resistance domain solution (Chronothane H and Chronothane 1020) and drying.
After the sensor was constructed, it was placed in a protective sheath and then threaded through and attached to a fluid coupler, as described in co-pending U.S. patent application Ser. No. 11/543,396 filed on even date herewith and entitled “ANALYTE SENSOR.” Prior to use, the sensors were sterilized using electron beam radiation.
The forelimb of an anesthetized dog (2 years old, ˜40 pounds) was cut down to the femoral artery and vein. An arterio-venous shunt was placed from the femoral artery to the femoral vein using 14 gauge catheters and ⅛-inch IV tubing. A pressurized arterial fluid line was connected to the sensor systems at all times. The test sensor system included a 20 gauge×1.25-inch catheter and took measurements every 30 seconds. The catheter was aseptically inserted into the shunt, followed by insertion of the sensor into the catheter. As controls, the dog's glucose was checked with an SMBG, as well as removing blood samples and measuring the glucose concentration with a Hemocue.
The term “Plus GOx” refers to the signal from the electrode coated with active GOx, which represents signal due to both the glucose concentration and non-glucose-related electroactive compounds as described elsewhere herein (e.g., glucose signal and background signal, which includes both constant and non-constant noise). “No GOx” is signal from the electrode lacking GOx, which represents non-glucose related signal (e.g., background signal, which includes both constant and non-constant noise). The “Glucose Only” signal (e.g., related only to glucose concentration) is determined during data analysis (e.g., by sensor electronics). In this experiment, the “Glucose Only” signal was determined by a subtraction of the “No GOx” signal from the “Plus GOx” signal.
During the experiment, the “No GOx” signal (thin line) substantially paralleled the “Plus GOx” signal (medium line). The “Glucose Only” signal substantially paralleled the control tests (SMBG/Hemocue).
Acetaminophen is known to be an interferent (e.g., produces non-constant noise) of the sensors built as described above, e.g., due to a lack of acetaminophen-blocking membrane and/or mechanism formed thereon or provided therewith. The SMBG or Hemocue devices utilized in this experiment, however, do include mechanisms that substantially block acetaminophen from the signal (see
From these experimental results, the inventors believe that an indwelling, dual-electrode glucose sensor system (as described herein) in contact with the circulatory system can provide substantially continuous glucose data that can be used to calculate a glucose concentration that is free from background components (e.g., constant and non-constant noise), in a clinical setting.
In general, crosstalk in dual electrode sensors can be examined by recording the signal detected at each working electrode while placing them in a series of analyte solutions. This example describes one exemplary in vitro test for crosstalk on a dual electrode analyte sensor. A variety of dual electrode analyte sensors can be tested for crosstalk, using this method.
First, the sensor to be tested is placed in a phosphate buffered saline (PBS) for several minutes, such as until a stable signal is detected from both working electrodes. Next, the sensor is challenged with glucose solutions and optionally with one or more known noise-causing substances. For example, sensor can be placed sequentially in a series of glucose solutions (e.g., 40-mg/dl, 200-mg/dl and 400-mg/dl glucose in PBS) and the signals from the two working electrodes graphed.
If there is no crosstalk between the working electrodes, then, as the sensor is placed in solutions of increasingly higher glucose concentration, the graphed signal of the Plus GOx electrode should show corresponding signal increases, while the No GOx electrode signal should exhibit little or no change in signal. However, when the sensor is placed in a solution of a known noise-causing species (e.g., acetaminophen, ibuprofen, vitamin C, urea, and the like), both working electrodes (Plus GOx and No GOx) should exhibit an increase in signal. In some circumstances, this increase in signal is a dramatic spike in signal.
If there is crosstalk, then the signals from both electrodes should increase as the sensor is moved to solutions of increased glucose concentration. Similarly, when the sensor is placed in a solution of a known noise-causing species, both working electrodes should exhibit an increase in signal.
The effect of size of the electroactive surfaces (of the working electrodes) on noise measurement was examined in non-diabetic human hosts. Sensors having electroactive surfaces of different sizes, and lacking GOx in the enzyme layer were constructed as follows. Clean, insulated Pt/Ir wires were separated into two groups. For Group 1, 0.029″ of the insulation was removed from each wire (e.g., about its entire circumference), to expose electroactive surfaces. For Group 2, the same procedure was performed, except that two sequential 0.029″ portions of the insulation were removed; effectively doubling the size of the Group 2 electroactive surfaces relative to those of Group 1. After exposure of the electroactive surfaces, the two groups of wires were treated identically. On each wire, a portion of the sensor's membrane was fabricated by the sequential application (and curing thereof) of electrode domain, enzyme domain and resistance domain materials. The enzyme domain material contained no active GOx, so that the sensors would be able to detect only noise (no analyte). Next, pairs of wires (e.g., two Group 1 wires or two Group 2 wires) were aligned such that the electroactive surfaces were parallel to each other, and then twisted together. An Ag/AgCl ribbon was wrapped around a portion of the twisted wires (to form the reference electrode), and then additional resistance domain material was applied to the assembly. Each host consumed 1,000-mg of acetaminophen near the end of the trial, so that the affect of a known interferent could be examined.
From these data, the inventors concluded that the electroactive surfaces of a dual electrode glucose sensor must be sufficiently large in order for the two electrodes to detect substantially equal noise signal components. For example, in this experiment, the electroactive surfaces of the Group 1 working electrodes, which did not measure noise equivalently, were 0.029″ (e.g., along the electrode's length); while electroactive surfaces of the Group 2 working electrodes, which did measure noise substantially equivalently, were two times as large (e.g., 2×0.029″=0.058″ along the electrode's length) as those of the Group 1 working electrodes.
The effect of the spacing of the electroactive surfaces (of the working electrodes) on noise measurement was examined in non-diabetic human hosts. Sensors having two different configurations were built and tested. Sensors of Configuration 1 (Config. 1) included Plus GOx and No GOx working electrodes with non-aligned (e.g., miss-aligned, skewed) electroactive surfaces. In other words, the electroactive surfaces were spaced such that, in the completed sensor, one electroactive surface would be more proximal to the sensor's tip than then other. Sensors of Configuration 2 (Config. 2) also included Plus GOx and No GOx working electrodes, except that the electroactive surfaces were closely aligned (e.g., parallel). In Config. 2, the membrane was the insulator between the two working electrodes, enabling the very close spacing (i.e., the thickness of the membrane determined the spacing between the two working electrodes, between about 0.001 inches to about 0.003 inches between the two working electrodes.)
Config. 1 sensors were fabricated as follow. For each sensor, two clean, insulated Pt/Ir wires were wound together (and an Ag/AgCl ribbon twisted there around), followed by removal of a portion of the insulating material from each wire to create the electroactive surfaces. The electroactive surfaces were offset (e.g., not next to each other) relative to the sensor's tip. The twisted wire pairs were then dipped in enzyme domain solution (including GOx) just far enough such that only the electroactive surface closest to the tip of the sensor was coated with the enzyme domain material (e.g., E1, Plus GOx). The electroactive surface farthest from the sensor tip was not coated with the enzyme domain material (e.g., E2, No GOx). After curing, resistance domain material was applied to the twisted pairs of wires.
Config. 2 sensors were fabricated as follow. Clean, insulated Pt/Ir wires were divided into two groups. Electrode and enzyme (Plus GOx) domain materials were sequentially applied to the E1, Plus GOx working electrode wires. Electrode and enzyme (No GOx) domain materials were sequentially applied to the E2, No GOx working electrode wires. Resistance domain material was applied to all wires individually (e.g., to form independent/discontinuous first and second resistance domains). After the resistance domain material was cured, one each of the E1, Plus GOx and E2, No GOx were placed together such that the wires' electroactive surfaces were aligned, and then twisted together to form a twisted pair. An Ag/AgCl ribbon was wrapped around each twisted pair (but not covering the electroactive surfaces), followed by application of a continuous resistance domain (e.g., a third resistance domain) over the sensor. The resulting sensors included a configuration similar to the example illustrated in
From these data, the inventors concluded that the electroactive surfaces of a dual electrode glucose sensor must be sufficiently close together in order for the two electrodes to detect substantially equivalent noise signal components. Additionally, the inventors concluded that for a dual electrode sensor including the combination of a continuous resistance domain disposed over discontinuous resistance domains (e.g., applied independently to the two working electrodes) the detected signal amplitudes more closely correspond to each other. This improves mathematical noise correction by enabling better noise signal subtraction.
Methods and devices that are suitable for use in conjunction with aspects of the preferred embodiments are disclosed in U.S. Pat. Nos. 4,994,167; 4,757,022; 6,001,067; 6,741,877; 6,702,857; 6,558,321; 6,931,327; 6,862,465; 7,074,307; 7,081,195; 7,108,778; 7,110,803; 7,192,450; 7,226,978; 7,236,890.
Methods and devices that are suitable for use in conjunction with aspects of the preferred embodiments are disclosed in U.S. Patent Publication No. US-2005-0176136-A1; U.S. Patent Publication No. US-2005-0251083-A1; U.S. Patent Publication No. US-2005-0143635-A1; U.S. Patent Publication No. US-2005-0181012-A1; U.S. Patent Publication No. US-2005-0177036-A1; U.S. Patent Publication No. US-2005-0124873-A1; U.S. Patent Publication No. US-2005-0115832-A1; U.S. Patent Publication No. US-2005-0245799-A1; U.S. Patent Publication No. US-2005-0245795-A1; U.S. Patent Publication No. US-2005-0242479-A1; U.S. Patent Publication No. US-2005-0182451-A1; U.S. Patent Publication No. US-2005-0056552-A1; U.S. Patent Publication No. US-2005-0192557-A1; U.S. Patent Publication No. US-2005-0154271-A1; U.S. Patent Publication No. US-2004-0199059-A1; U.S. Patent Publication No. US-2005-0054909-A1; U.S. Patent Publication No. US-2005-0051427-A1; U.S. Patent Publication No. US-2003-0032874-A1; U.S. Patent Publication No. US-2005-0103625-A1; U.S. Patent Publication No. US-2005-0203360-A1; U.S. Patent Publication No. US-2005-0090607-A1; U.S. Patent Publication No. US-2005-0187720-A1; U.S. Patent Publication No. US-2005-0161346-A1; U.S. Patent Publication No. US-2006-0015020-A1; U.S. Patent Publication No. US-2005-0043598-A1; U.S. Patent Publication No. US-2005-0033132-A1; U.S. Patent Publication No. US-2005-0031689-A1; U.S. Patent Publication No. US-2004-0186362-A1; U.S. Patent Publication No. US-2005-0027463-A1; U.S. Patent Publication No. US-2005-0027181-A1; U.S. Patent Publication No. US-2005-0027180-A1; U.S. Patent Publication No. US-2006-0020187-A1; U.S. Patent Publication No. US-2006-0036142-A1; U.S. Patent Publication No. US-2006-0020192-A1; U.S. Patent Publication No. US-2006-0036143-A1; U.S. Patent Publication No. US-2006-0036140-A1; U.S. Patent Publication No. US-2006-0019327-A1; U.S. Patent Publication No. US-2006-0020186-A1; U.S. Patent Publication No. US-2006-0020189-A1; U.S. Patent Publication No. US-2006-0036139-A1; U.S. Patent Publication No. US-2006-0020191-A1; U.S. Patent Publication No. US-2006-0020188-A1; U.S. Patent Publication No. US-2006-0036141-A1; U.S. Patent Publication No. US-2006-0020190-A1; U.S. Patent Publication No. US-2006-0036145-A1; U.S. Patent Publication No. US-2006-0036144-A1; U.S. Patent Publication No. US-2006-0016700-A1; U.S. Patent Publication No. US-2006-0142651-A1; U.S. Patent Publication No. US-2006-0086624-A1; U.S. Patent Publication No. US-2006-0068208-A1; U.S. Patent Publication No. US-2006-0040402-A1; U.S. Patent Publication No. US-2006-0036142-A1; U.S. Patent Publication No. US-2006-0036141-A1; U.S. Patent Publication No. US-2006-0036143-A1; U.S. Patent Publication No. US-2006-0036140-A1; U.S. Patent Publication No. US-2006-0036139-A1; U.S. Patent Publication No. US-2006-0142651-A1; U.S. Patent Publication No. US-2006-0036145-A1; U.S. Patent Publication No. US-2006-0036144-A1; U.S. Patent Publication No. US-2006-0200022-A1; U.S. Patent Publication No. US-2006-0198864-A1; U.S. Patent Publication No. US-2006-0200019-A1; U.S. Patent Publication No. US-2006-0189856-A1; U.S. Patent Publication No. US-2006-0200020-A1; U.S. Patent Publication No. US-2006-0200970-A1; U.S. Patent Publication No. US-2006-0183984-A1; U.S. Patent Publication No. US-2006-0183985-A1; U.S. Patent Publication No. US-2006-0195029-A1; U.S. Patent Publication No. US-2006-0229512-A1; U.S. Patent Publication No. US-2007-0032706-A1; U.S. Patent Publication No. US-2007-0016381-A1; U.S. Patent Publication No. US-2007-0027370-A1; U.S. Patent Publication No. US-2007-0027384-A1; U.S. Patent Publication No. US-2007-0032717-A1; U.S. Patent Publication No. US-2007-0032718 A1; U.S. Patent Publication No. US-2007-0059196-A1; U.S. Patent Publication No. US-2007-0066873-A1; U.S. Patent Publication No. US-2007-0093704-A1; U.S. Patent Publication No. US-2007-0197890-A1; U.S. Patent Publication No. US-2007-0173709-A1; U.S. Patent Publication No. US-2007-0173710-A1; U.S. Patent Publication No. US-2007-0197889-A1; U.S. Patent Publication No. US-2007-0163880-A1; U.S. Patent Publication No. US-2007-0203966-A1; U.S. Patent Publication No. US-2007-0208245-A1; U.S. Patent Publication No. US-2007-0208246-A1; U.S. Patent Publication No. US-2007-0208244-A1; and U.S. Patent Publication No. US-2007-0173708 A1.
Methods and devices that are suitable for use in conjunction with aspects of the preferred embodiments are disclosed in U.S. patent application Ser. No. 09/447,227 filed Nov. 22, 1999 and entitled “DEVICE AND METHOD FOR DETERMINING ANALYTE LEVELS”; U.S. patent application Ser. No. 11/675,063 filed Feb. 14, 2007 and entitled “ANALYTE SENSOR”; U.S. patent application Ser. No. 11/543,396 filed Oct. 4, 2006 and entitled “ANALYTE SENSOR”; U.S. patent application Ser. No. 11/543,490 filed Oct. 4, 2006 and entitled “ANALYTE SENSOR”; U.S. patent application Ser. No. 11/543,404 filed Oct. 4, 2006 and entitled “ANALYTE SENSOR”; U.S. patent application Ser. No. 11/691,426 filed Mar. 26, 2007 and entitled “ANALYTE SENSOR”; U.S. patent application Ser. No. 11/691,432 filed Mar. 26, 2007 and entitled “ANALYTE SENSOR”; U.S. patent application Ser. No. 11/691,424 filed Mar. 26, 2007 and entitled “ANALYTE SENSOR”; U.S. patent application Ser. No. 11/691,466 filed Mar. 26, 2007 and entitled “ANALYTE SENSOR”; U.S. patent application Ser. No. 11/692,154 filed Mar. 27, 2007 and entitled “DUAL ELECTRODE SYSTEM FOR A CONTINUOUS ANALYTE SENSOR”; U.S. patent application Ser. No. 11/797,520 filed May 3, 2007 and entitled “TRANSCUTANEOUS ANALYTE SENSOR”; U.S. patent application Ser. No. 11/797,521 filed May 3, 2007 and entitled “TRANSCUTANEOUS ANALYTE SENSOR”; and U.S. patent application Ser. No. 11/750,907 filed May 18, 2007 and entitled “ANALYTE SENSORS HAVING A SIGNAL-TO-NOISE RATIO SUBSTANTIALLY UNAFFECTED BY NON-CONSTANT NOISE”; U.S. patent application Ser. No. 11/762,638 filed Jun. 13, 2007 and entitled “SYSTEMS AND METHODS FOR REPLACING SIGNAL DATA ARTIFACTS IN A GLUCOSE SENSOR DATA STREAM”; U.S. patent application Ser. No. 11/763,215 filed Jun. 14, 2007 and entitled “SILICONE COMPOSITION FOR BIOCOMPATIBLE MEMBRANE”; U.S. patent application Ser. No. 11/842,148 filed Aug. 21, 2007 and entitled “TRANSCUTANEOUS ANALYTE SENSOR”; U.S. patent application Ser. No. 11/842,142 filed Aug. 21, 2007 and entitled “TRANSCUTANEOUS ANALYTE SENSOR”; U.S. patent application Ser. No. 11/842,154 filed Aug. 21, 2007 and entitled “TRANSCUTANEOUS ANALYTE SENSOR”; U.S. patent application Ser. No. 11/842,146 filed Aug. 21, 2007 and entitled “ANALYTE SENSOR”; U.S. patent application Ser. No. 11/842,151 filed Aug. 21, 2007 and entitled “ANALYTE SENSOR”; U.S. patent application Ser. No. 11/842,156 filed Aug. 21, 2007 and entitled “ANALYTE SENSORS HAVING A SIGNAL-TO-NOISE RATIO SUBSTANTIALLY UNAFFECTED BY NON-CONSTANT NOISE”; U.S. patent application Ser. No. 11/842,157 filed Aug. 21, 2007 and entitled “ANALYTE SENSOR”; U.S. patent application Ser. No. 11/842,143 filed Aug. 21, 2007 and entitled “TRANSCUTANEOUS ANALYTE SENSOR”; U.S. patent application Ser. No. 11/842,149 filed Aug. 21, 2007 and entitled “TRANSCUTANEOUS ANALYTE SENSOR”; and U.S. patent application Ser. No. 11/855,101 filed Sep. 13, 2007 and entitled “TRANSCUTANEOUS ANALYTE SENSOR”.
All references cited herein, including but not limited to published and unpublished applications, patents, and literature references, are incorporated herein by reference in their entirety and are hereby made a part of this specification. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material.
All numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of any claims in any application claiming priority to the present application, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.
The term “comprising” as used herein is synonymous with “including,” “containing,” or “characterized by,” and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.
The above description discloses several methods and materials of the present invention. This invention is susceptible to modifications in the methods and materials, as well as alterations in the fabrication methods and equipment. Such modifications will become apparent to those skilled in the art from a consideration of this disclosure or practice of the invention disclosed herein. Consequently, it is not intended that this invention be limited to the specific embodiments disclosed herein, but that it cover all modifications and alternatives coming within the true scope and spirit of the invention.
Any and all priority claims identified in the Application Data Sheet, or any correction thereto, are hereby incorporated by reference under 37 CFR 1.57. This application is a continuation of U.S. application Ser. No. 15/356,134 filed Nov. 18, 2016, which is a continuation of U.S. application Ser. No. 13/863,204, filed Apr. 15, 2013, now U.S. Pat. No. 9,504,413, which is a divisional of U.S. application Ser. No. 11/865,572 filed Oct. 1, 2007, now U.S. Pat. No. 8,423,114, which is a continuation-in-part of U.S. application Ser. No. 11/543,683 filed Oct. 4, 2006, now U.S. Pat. No. 7,366,556. Each of the aforementioned applications is incorporated by reference herein in its entirety, and each is hereby expressly made a part of this specification.
| Number | Name | Date | Kind |
|---|---|---|---|
| 1564641 | St. James | Dec 1925 | A |
| 2130578 | Baker et al. | Sep 1938 | A |
| 2402306 | Turkel | Jun 1946 | A |
| 2719797 | Rosenblatt et al. | Oct 1955 | A |
| 3210578 | Sherer | Oct 1965 | A |
| 3219533 | Mullins | Nov 1965 | A |
| 3381371 | Russell et al. | May 1968 | A |
| 3506032 | Eveleigh et al. | Apr 1970 | A |
| 3539455 | Clark | Nov 1970 | A |
| 3556950 | Dahms et al. | Jan 1971 | A |
| 3652475 | Wada et al. | Mar 1972 | A |
| 3775182 | Patton et al. | Nov 1973 | A |
| 3780727 | King | Dec 1973 | A |
| 3791871 | Rowley | Feb 1974 | A |
| 382624 | Salcman et al. | Jul 1974 | A |
| 3838033 | Mindt et al. | Sep 1974 | A |
| 3838682 | Clark et al. | Oct 1974 | A |
| 3874850 | Sorensen et al. | Apr 1975 | A |
| 3898984 | Mandel et al. | Aug 1975 | A |
| 3910256 | Clark et al. | Oct 1975 | A |
| 3926760 | Allen et al. | Dec 1975 | A |
| 3929971 | Roy et al. | Dec 1975 | A |
| 3933593 | Sternberg | Jan 1976 | A |
| 3943918 | Lewis | Mar 1976 | A |
| 3957613 | Macur | May 1976 | A |
| 3964974 | Banauch et al. | Jun 1976 | A |
| 3966580 | Janata et al. | Jun 1976 | A |
| 3979274 | Newman | Sep 1976 | A |
| 3982530 | Storch | Sep 1976 | A |
| 4008717 | Kowarski et al. | Feb 1977 | A |
| 4016866 | Lawton et al. | Apr 1977 | A |
| 4024312 | Korpman et al. | May 1977 | A |
| 4036749 | Anderson | Jul 1977 | A |
| 4037563 | Pflueger et al. | Jul 1977 | A |
| 4040908 | Clark, Jr. et al. | Aug 1977 | A |
| 4052754 | Homsy | Oct 1977 | A |
| 4055175 | Clemens et al. | Oct 1977 | A |
| 4067322 | Johnson | Jan 1978 | A |
| 4073713 | Newman | Feb 1978 | A |
| 4076656 | White et al. | Feb 1978 | A |
| 4109505 | Clark et al. | Aug 1978 | A |
| 4119406 | Clemens et al. | Oct 1978 | A |
| 4151845 | Clemens | May 1979 | A |
| 4172770 | Semersky et al. | Oct 1979 | A |
| 4176659 | Rolfe | Dec 1979 | A |
| 4180470 | Tokosh et al. | Dec 1979 | A |
| 4197840 | Beck et al. | Apr 1980 | A |
| 4197852 | Schindler et al. | Apr 1980 | A |
| 4206755 | Klein | Jun 1980 | A |
| 4215703 | Willson | Aug 1980 | A |
| 4225410 | Pace et al. | Sep 1980 | A |
| 4240438 | Shults et al. | Dec 1980 | A |
| 4240889 | Yoda et al. | Dec 1980 | A |
| 4253469 | Asian | Mar 1981 | A |
| 4255500 | Hooke | Mar 1981 | A |
| 4259540 | Sabia et al. | Mar 1981 | A |
| 4265249 | Schindler et al. | May 1981 | A |
| 4319578 | Enger et al. | Mar 1982 | A |
| 4324257 | Albarda et al. | Apr 1982 | A |
| 4327725 | Cortese et al. | May 1982 | A |
| 4331004 | Schmidt | May 1982 | A |
| 4340457 | Kater et al. | Jul 1982 | A |
| 4353368 | Slovak et al. | Oct 1982 | A |
| 4353888 | Sefton et al. | Oct 1982 | A |
| 4366040 | Marsoner et al. | Dec 1982 | A |
| 4369785 | Rehkopf et al. | Jan 1983 | A |
| 4374013 | Enfors | Feb 1983 | A |
| 4378016 | Loeb | Mar 1983 | A |
| 4388166 | Suzuki et al. | Jun 1983 | A |
| 4402694 | Ash et al. | Sep 1983 | A |
| 4403847 | Chrestensen | Sep 1983 | A |
| 4403984 | Ash et al. | Sep 1983 | A |
| 4415666 | D'Orazio et al. | Nov 1983 | A |
| 4418148 | Oberhardt | Nov 1983 | A |
| 4419535 | O'hara | Dec 1983 | A |
| 4420564 | Tsuji et al. | Dec 1983 | A |
| 4431507 | Nankai et al. | Feb 1984 | A |
| 4432366 | Margules | Feb 1984 | A |
| 4436094 | Cerami | Mar 1984 | A |
| 4442841 | Uehara et al. | Apr 1984 | A |
| 4454295 | Wittmann et al. | Jun 1984 | A |
| 4457339 | Juan et al. | Jul 1984 | A |
| 4477314 | Richter et al. | Oct 1984 | A |
| 4478222 | Koning et al. | Oct 1984 | A |
| 4484987 | Gough | Nov 1984 | A |
| 4486290 | Cahalan et al. | Dec 1984 | A |
| 4492575 | Mabille | Jan 1985 | A |
| 4494950 | Fischell | Jan 1985 | A |
| 4506680 | Stokes | Mar 1985 | A |
| 4519973 | Cahalan et al. | May 1985 | A |
| RE31916 | Oswin et al. | Jun 1985 | E |
| 4526569 | Bernardi | Jul 1985 | A |
| 4534825 | Koning et al. | Aug 1985 | A |
| 4535786 | Kater | Aug 1985 | A |
| 4538616 | Rogoff | Sep 1985 | A |
| 4545382 | Higgins et al. | Oct 1985 | A |
| 4554927 | Fussell | Nov 1985 | A |
| 4561963 | Owen et al. | Dec 1985 | A |
| 4565665 | Fogt | Jan 1986 | A |
| 4565666 | Cahalan et al. | Jan 1986 | A |
| 4568444 | Nakamura et al. | Feb 1986 | A |
| 4571292 | Liu et al. | Feb 1986 | A |
| 4573968 | Parker | Mar 1986 | A |
| 4577642 | Stokes | Mar 1986 | A |
| 4578215 | Bradley | Mar 1986 | A |
| 4579120 | MacGregor | Apr 1986 | A |
| 4583976 | Ferguson | Apr 1986 | A |
| 4592824 | Smith et al. | Jun 1986 | A |
| 4600495 | Fogt | Jul 1986 | A |
| 4603152 | Laurin et al. | Jul 1986 | A |
| 4614514 | Carr et al. | Sep 1986 | A |
| 4619793 | Lee | Oct 1986 | A |
| 4626104 | Pointon et al. | Dec 1986 | A |
| RE32361 | Duggan | Feb 1987 | E |
| 4650547 | Gough | Mar 1987 | A |
| 4655880 | Liu | Apr 1987 | A |
| 4663824 | Kenmochi | May 1987 | A |
| 4671288 | Gough | Jun 1987 | A |
| 4672970 | Uchida et al. | Jun 1987 | A |
| 4675346 | Lin et al. | Jun 1987 | A |
| 4680268 | Clark, Jr. | Jul 1987 | A |
| 4685463 | Williams | Aug 1987 | A |
| 4694861 | Goodale et al. | Sep 1987 | A |
| 4703756 | Gough et al. | Nov 1987 | A |
| 4705503 | Dorman et al. | Nov 1987 | A |
| 4711245 | Higgins et al. | Dec 1987 | A |
| 4711251 | Stokes | Dec 1987 | A |
| 4721677 | Clark, Jr. | Jan 1988 | A |
| 4726381 | Jones | Feb 1988 | A |
| 4731726 | Aller | Mar 1988 | A |
| 4736748 | Nakamura et al. | Apr 1988 | A |
| 4747822 | Peabody | May 1988 | A |
| 4750496 | Reinhart et al. | Jun 1988 | A |
| 4752935 | Beck | Jun 1988 | A |
| 4753652 | Langer et al. | Jun 1988 | A |
| 4755168 | Romanelli et al. | Jul 1988 | A |
| 4757022 | Shults et al. | Jul 1988 | A |
| 4759828 | Young et al. | Jul 1988 | A |
| 4763648 | Wyatt | Aug 1988 | A |
| 4763658 | Jones | Aug 1988 | A |
| 4776944 | Janata et al. | Oct 1988 | A |
| 4777953 | Ash et al. | Oct 1988 | A |
| 4781798 | Gough | Nov 1988 | A |
| 4783250 | Pons et al. | Nov 1988 | A |
| 4784157 | Halls et al. | Nov 1988 | A |
| 4786394 | Enzer et al. | Nov 1988 | A |
| 4786657 | Hammar et al. | Nov 1988 | A |
| 4787398 | Garcia et al. | Nov 1988 | A |
| 4789467 | Lindsay et al. | Dec 1988 | A |
| 4791932 | Margules | Dec 1988 | A |
| 4795435 | Steer | Jan 1989 | A |
| 4795542 | Ross et al. | Jan 1989 | A |
| 4803243 | Fujimoto et al. | Feb 1989 | A |
| 4805624 | Yao et al. | Feb 1989 | A |
| 4805625 | Wyler | Feb 1989 | A |
| 4808089 | Buchholtz et al. | Feb 1989 | A |
| 4808292 | Kessler et al. | Feb 1989 | A |
| 4809704 | Sogawa et al. | Mar 1989 | A |
| 4810243 | Howson | Mar 1989 | A |
| 4813424 | Wilkins | Mar 1989 | A |
| 4815471 | Stobie | Mar 1989 | A |
| 4820281 | Lawler, Jr. | Apr 1989 | A |
| 4822336 | Ditraglia | Apr 1989 | A |
| 4828544 | Lane et al. | May 1989 | A |
| 4830013 | Maxwell | May 1989 | A |
| 4831070 | McInally et al. | May 1989 | A |
| 4832005 | Takamiya et al. | May 1989 | A |
| 4832034 | Pizziconi et al. | May 1989 | A |
| 4834101 | Collison et al. | May 1989 | A |
| 4838281 | Rogers et al. | Jun 1989 | A |
| 4841974 | Gumbrecht et al. | Jun 1989 | A |
| 4849458 | Reed et al. | Jul 1989 | A |
| 4852573 | Kennedy | Aug 1989 | A |
| 4854322 | Ash et al. | Aug 1989 | A |
| 4858615 | Meinema | Aug 1989 | A |
| 4861454 | Ushizawa et al. | Aug 1989 | A |
| 4861830 | Ward, Jr. | Aug 1989 | A |
| 4867741 | Portnoy | Sep 1989 | A |
| 4871440 | Nagata et al. | Oct 1989 | A |
| 4874363 | Abell | Oct 1989 | A |
| 4883057 | Broderick | Nov 1989 | A |
| 4883467 | Franetzki et al. | Nov 1989 | A |
| 4886740 | Vadgama | Dec 1989 | A |
| 4889528 | Nadai et al. | Dec 1989 | A |
| 4889744 | Quaid | Dec 1989 | A |
| 4890620 | Gough | Jan 1990 | A |
| 4890621 | Hakky | Jan 1990 | A |
| 4900305 | Smith et al. | Feb 1990 | A |
| 4902294 | Gosserez | Feb 1990 | A |
| 4907857 | Giuliani et al. | Mar 1990 | A |
| 4909786 | Gijselhart et al. | Mar 1990 | A |
| 4909908 | Ross et al. | Mar 1990 | A |
| 4919141 | Zier et al. | Apr 1990 | A |
| 4919649 | Timothy et al. | Apr 1990 | A |
| 4921477 | Davis | May 1990 | A |
| 4921480 | Sealfon | May 1990 | A |
| 4925444 | Orkin et al. | May 1990 | A |
| 4927407 | Dorman | May 1990 | A |
| 4927516 | Yamaguchi et al. | May 1990 | A |
| 4928694 | Maxwell | May 1990 | A |
| 4934369 | Maxwell | Jun 1990 | A |
| 4934375 | Cole et al. | Jun 1990 | A |
| 4944299 | Silvian | Jul 1990 | A |
| 4946439 | Eggers | Aug 1990 | A |
| 4951669 | Maxwell et al. | Aug 1990 | A |
| 4953552 | DeMarzo | Sep 1990 | A |
| 4955861 | Enegren et al. | Sep 1990 | A |
| 4957483 | Gonser et al. | Sep 1990 | A |
| 4958148 | Olson | Sep 1990 | A |
| 4963595 | Ward et al. | Oct 1990 | A |
| 4966579 | Polaschegg | Oct 1990 | A |
| 4967940 | Blette et al. | Nov 1990 | A |
| 4970145 | Bennetto et al. | Nov 1990 | A |
| 4973320 | Brenner et al. | Nov 1990 | A |
| 4974592 | Branco | Dec 1990 | A |
| 4974929 | Curry | Dec 1990 | A |
| 4975175 | Karube et al. | Dec 1990 | A |
| 4975636 | Desautels | Dec 1990 | A |
| 4976687 | Martin | Dec 1990 | A |
| 4979509 | Hakky | Dec 1990 | A |
| 4984929 | Roeck et al. | Jan 1991 | A |
| 4986271 | Wilkins | Jan 1991 | A |
| 4986671 | Sun et al. | Jan 1991 | A |
| 4988341 | Columbus et al. | Jan 1991 | A |
| 4988758 | Fukuda et al. | Jan 1991 | A |
| 4992794 | Brouwers | Feb 1991 | A |
| 4994026 | Fecondini | Feb 1991 | A |
| 4994167 | Shults et al. | Feb 1991 | A |
| 4997627 | Bergkuist et al. | Mar 1991 | A |
| 5002055 | Merki et al. | Mar 1991 | A |
| 5002572 | Picha | Mar 1991 | A |
| 5006050 | Cooke et al. | Apr 1991 | A |
| 5006111 | Inokuchi et al. | Apr 1991 | A |
| 5007929 | Quaid | Apr 1991 | A |
| 5009251 | Pike et al. | Apr 1991 | A |
| 5019096 | Fox, Jr. et al. | May 1991 | A |
| 5026348 | Venegas | Jun 1991 | A |
| 5030199 | Barwick et al. | Jul 1991 | A |
| 5030333 | Clark, Jr. | Jul 1991 | A |
| 5034112 | Murase et al. | Jul 1991 | A |
| 5041092 | Barwick | Aug 1991 | A |
| 5045057 | Van Driessche et al. | Sep 1991 | A |
| 5046496 | Betts et al. | Sep 1991 | A |
| 5048525 | Maxwell | Sep 1991 | A |
| 5050612 | Matsumura | Sep 1991 | A |
| 5055171 | Peck | Oct 1991 | A |
| 5055198 | Shettigar | Oct 1991 | A |
| 5059654 | Hou et al. | Oct 1991 | A |
| 5063081 | Cozzette et al. | Nov 1991 | A |
| 5067491 | Taylor, II et al. | Nov 1991 | A |
| 5068536 | Rosenthal | Nov 1991 | A |
| 5077476 | Rosenthal | Dec 1991 | A |
| 5082550 | Rishpon et al. | Jan 1992 | A |
| 5088981 | Howson et al. | Feb 1992 | A |
| 5089112 | Skotheim et al. | Feb 1992 | A |
| 5089421 | Dieffenbach | Feb 1992 | A |
| 5096669 | Lauks et al. | Mar 1992 | A |
| 5097834 | Skrabal | Mar 1992 | A |
| 5098377 | Borsanyi et al. | Mar 1992 | A |
| 5101814 | Palti | Apr 1992 | A |
| 5108819 | Heller et al. | Apr 1992 | A |
| 5109850 | Blanco et al. | May 1992 | A |
| 5112301 | Fenton, Jr. et al. | May 1992 | A |
| 5116313 | McGregor | May 1992 | A |
| 5130231 | Kennedy et al. | Jul 1992 | A |
| 5137928 | Nishimura | Aug 1992 | A |
| 5140985 | Schroeder et al. | Aug 1992 | A |
| 5145565 | Kater et al. | Sep 1992 | A |
| 5152746 | Atkinson et al. | Oct 1992 | A |
| 5155149 | Atwater et al. | Oct 1992 | A |
| 5160418 | Mullen | Nov 1992 | A |
| 5161532 | Joseph | Nov 1992 | A |
| 5165406 | Wong | Nov 1992 | A |
| 5165407 | Wilson et al. | Nov 1992 | A |
| 5171689 | Kawaguri et al. | Dec 1992 | A |
| 5174291 | Schoonen et al. | Dec 1992 | A |
| 5176632 | Bernardi | Jan 1993 | A |
| 5176658 | Ranford | Jan 1993 | A |
| 5178142 | Harjunmaa et al. | Jan 1993 | A |
| 5182004 | Kohno | Jan 1993 | A |
| 5183549 | Joseph et al. | Feb 1993 | A |
| 5188591 | Dorsey, III | Feb 1993 | A |
| 5190041 | Palti | Mar 1993 | A |
| 5195963 | Yafuso et al. | Mar 1993 | A |
| 5198771 | Fidler et al. | Mar 1993 | A |
| 5200051 | Cozzette et al. | Apr 1993 | A |
| 5202261 | Musho et al. | Apr 1993 | A |
| 5208147 | Kagenow et al. | May 1993 | A |
| 5212050 | Mier et al. | May 1993 | A |
| 5220917 | Cammilli et al. | Jun 1993 | A |
| 5220920 | Gharib | Jun 1993 | A |
| 5222980 | Gealow | Jun 1993 | A |
| 5224929 | Remiszewski | Jul 1993 | A |
| 5225063 | Gumbrecht et al. | Jul 1993 | A |
| 5232434 | Inagaki et al. | Aug 1993 | A |
| 5235003 | Ward et al. | Aug 1993 | A |
| 5242835 | Jensen | Sep 1993 | A |
| 5243696 | Carr et al. | Sep 1993 | A |
| 5243982 | Moestl et al. | Sep 1993 | A |
| 5243983 | Tarr et al. | Sep 1993 | A |
| 5249576 | Goldberger et al. | Oct 1993 | A |
| 5250439 | Musho et al. | Oct 1993 | A |
| 5254102 | Ogawa | Oct 1993 | A |
| 5262305 | Heller et al. | Nov 1993 | A |
| 5264103 | Yoshioka et al. | Nov 1993 | A |
| 5264104 | Gregg et al. | Nov 1993 | A |
| 5265173 | Nankai et al. | Nov 1993 | A |
| 5265594 | Olsson et al. | Nov 1993 | A |
| 5269891 | Colin | Dec 1993 | A |
| 5271736 | Picha | Dec 1993 | A |
| 5271815 | Wong | Dec 1993 | A |
| 5279294 | Anderson et al. | Jan 1994 | A |
| 5281319 | Kaneko et al. | Jan 1994 | A |
| 5282848 | Schmitt | Feb 1994 | A |
| 5284140 | Allen et al. | Feb 1994 | A |
| 5284570 | Savage et al. | Feb 1994 | A |
| 5285513 | Kaufman et al. | Feb 1994 | A |
| 5286364 | Yacynych et al. | Feb 1994 | A |
| 5287753 | Routh et al. | Feb 1994 | A |
| 5298022 | Bernardi | Mar 1994 | A |
| 5298144 | Spokane | Mar 1994 | A |
| 5299571 | Mastrototaro | Apr 1994 | A |
| 5302093 | Owens et al. | Apr 1994 | A |
| 5304468 | Phillips et al. | Apr 1994 | A |
| 5307263 | Brown | Apr 1994 | A |
| 5310469 | Cunningham et al. | May 1994 | A |
| 5311908 | Barone et al. | May 1994 | A |
| 5312361 | Zadini et al. | May 1994 | A |
| 5314471 | Brauker et al. | May 1994 | A |
| 5316008 | Suga et al. | May 1994 | A |
| 5316452 | Bogen et al. | May 1994 | A |
| 5318511 | Riquier et al. | Jun 1994 | A |
| 5322063 | Allen et al. | Jun 1994 | A |
| 5324322 | Grill et al. | Jun 1994 | A |
| 5326356 | Della Valle et al. | Jul 1994 | A |
| 5326449 | Cunningham | Jul 1994 | A |
| 5328451 | Davis et al. | Jul 1994 | A |
| 5330521 | Cohen | Jul 1994 | A |
| 5330634 | Wong et al. | Jul 1994 | A |
| 5331555 | Hashimoto et al. | Jul 1994 | A |
| 5335658 | Bedingham | Aug 1994 | A |
| 5337747 | Neftel | Aug 1994 | A |
| 5342409 | Mullett | Aug 1994 | A |
| 5342789 | Chick et al. | Aug 1994 | A |
| 5343869 | Pross et al. | Sep 1994 | A |
| 5344454 | Clarke et al. | Sep 1994 | A |
| 5345932 | Yafuso et al. | Sep 1994 | A |
| 5348788 | White | Sep 1994 | A |
| 5352348 | Young et al. | Oct 1994 | A |
| 5352351 | White et al. | Oct 1994 | A |
| 5354272 | Swendson et al. | Oct 1994 | A |
| 5354449 | Band et al. | Oct 1994 | A |
| 5356375 | Higley | Oct 1994 | A |
| 5356378 | Doan | Oct 1994 | A |
| 5356786 | Heller et al. | Oct 1994 | A |
| 5368028 | Palti | Nov 1994 | A |
| 5368224 | Richardson et al. | Nov 1994 | A |
| 5368562 | Blomquist et al. | Nov 1994 | A |
| 5372133 | Hogen Esch | Dec 1994 | A |
| 5372135 | Mendelson et al. | Dec 1994 | A |
| 5372709 | Hood | Dec 1994 | A |
| 5372719 | Afeyan et al. | Dec 1994 | A |
| 5376070 | Purvis et al. | Dec 1994 | A |
| 5378229 | Layer et al. | Jan 1995 | A |
| 5380268 | Wheeler | Jan 1995 | A |
| 5380422 | Negishi et al. | Jan 1995 | A |
| 5380491 | Carver, Jr. et al. | Jan 1995 | A |
| 5380536 | Hubbell et al. | Jan 1995 | A |
| 5380665 | Cusack et al. | Jan 1995 | A |
| 5382514 | Passaniti et al. | Jan 1995 | A |
| 5384028 | Ito | Jan 1995 | A |
| 5387327 | Khan | Feb 1995 | A |
| 5390671 | Lord et al. | Feb 1995 | A |
| 5391250 | Cheney, II et al. | Feb 1995 | A |
| 5397848 | Yang et al. | Mar 1995 | A |
| 5411052 | Murray | May 1995 | A |
| 5411551 | Winston et al. | May 1995 | A |
| 5411647 | Johnson et al. | May 1995 | A |
| 5411866 | Luong | May 1995 | A |
| 5417206 | Kaneyoshi | May 1995 | A |
| 5421328 | Bedingham | Jun 1995 | A |
| 5423738 | Robinson et al. | Jun 1995 | A |
| 5423749 | Merte et al. | Jun 1995 | A |
| 5425717 | Mohiuddin | Jun 1995 | A |
| 5426032 | Phillips et al. | Jun 1995 | A |
| 5428123 | Ward et al. | Jun 1995 | A |
| 5429129 | Lovejoy et al. | Jul 1995 | A |
| 5429485 | Dodge | Jul 1995 | A |
| 5429602 | Hauser | Jul 1995 | A |
| 5429735 | Johnson et al. | Jul 1995 | A |
| 5431160 | Wilkins | Jul 1995 | A |
| 5431174 | Knute | Jul 1995 | A |
| 5431921 | Thombre | Jul 1995 | A |
| 5434412 | Sodickson et al. | Jul 1995 | A |
| 5437635 | Fields et al. | Aug 1995 | A |
| 5438984 | Schoendorfer | Aug 1995 | A |
| 5445610 | Evert | Aug 1995 | A |
| 5448992 | Kupershmidt | Sep 1995 | A |
| 5451260 | Versteeg et al. | Sep 1995 | A |
| 5453199 | Afeyan et al. | Sep 1995 | A |
| 5453278 | Chan et al. | Sep 1995 | A |
| 5458631 | Xavier | Oct 1995 | A |
| 5462051 | Oka et al. | Oct 1995 | A |
| 5462064 | D'Angelo et al. | Oct 1995 | A |
| 5462645 | Albery et al. | Oct 1995 | A |
| 5466356 | Schneider et al. | Nov 1995 | A |
| 5466575 | Cozzette et al. | Nov 1995 | A |
| 5469846 | Khan | Nov 1995 | A |
| 5474552 | Palti | Dec 1995 | A |
| 5476094 | Allen et al. | Dec 1995 | A |
| 5476776 | Wilkins | Dec 1995 | A |
| 5482008 | Stafford et al. | Jan 1996 | A |
| 5482446 | Williamson et al. | Jan 1996 | A |
| 5482473 | Lord et al. | Jan 1996 | A |
| 5484404 | Schulman et al. | Jan 1996 | A |
| 5486776 | Wilkins | Jan 1996 | A |
| 5491474 | Suni et al. | Feb 1996 | A |
| 5494562 | Maley et al. | Feb 1996 | A |
| 5496453 | Uenoyama et al. | Mar 1996 | A |
| 5497772 | Schulman et al. | Mar 1996 | A |
| 5502396 | Desarzens et al. | Mar 1996 | A |
| 5505828 | Wong et al. | Apr 1996 | A |
| 5507288 | Booker et al. | Apr 1996 | A |
| 5508203 | Fuller et al. | Apr 1996 | A |
| 5508509 | Yafuso et al. | Apr 1996 | A |
| 5509888 | Miller | Apr 1996 | A |
| 5512046 | Pusinelli et al. | Apr 1996 | A |
| 5512248 | Van | Apr 1996 | A |
| 5513636 | Palti | May 1996 | A |
| 5514253 | Davis et al. | May 1996 | A |
| 5515851 | Goldstein | May 1996 | A |
| 5518601 | Foos et al. | May 1996 | A |
| 5529066 | Palti | Jun 1996 | A |
| 5529676 | Maley et al. | Jun 1996 | A |
| 5531679 | Schulman et al. | Jul 1996 | A |
| 5531878 | Vadgama et al. | Jul 1996 | A |
| 5540828 | Yacynych | Jul 1996 | A |
| 5545220 | Andrews et al. | Aug 1996 | A |
| 5545223 | Neuenfeldt et al. | Aug 1996 | A |
| 5549547 | Cohen et al. | Aug 1996 | A |
| 5549548 | Larsson | Aug 1996 | A |
| 5549569 | Lynn et al. | Aug 1996 | A |
| 5549651 | Lynn | Aug 1996 | A |
| 5549675 | Neuenfeldt et al. | Aug 1996 | A |
| 5551850 | Williamson et al. | Sep 1996 | A |
| 5553616 | Ham et al. | Sep 1996 | A |
| 5562614 | O'Donnell | Oct 1996 | A |
| 5562615 | Nassif | Oct 1996 | A |
| 5564439 | Picha | Oct 1996 | A |
| 5568806 | Cheney, II et al. | Oct 1996 | A |
| 5569186 | Lord et al. | Oct 1996 | A |
| 5569188 | Mackool | Oct 1996 | A |
| 5569219 | Hakki et al. | Oct 1996 | A |
| 5569462 | Martinson et al. | Oct 1996 | A |
| 5571395 | Park et al. | Nov 1996 | A |
| 5575293 | Miller et al. | Nov 1996 | A |
| 5575930 | Tietje-Girault et al. | Nov 1996 | A |
| 5577499 | Teves | Nov 1996 | A |
| 5582184 | Ericson et al. | Dec 1996 | A |
| 5582593 | Hultman | Dec 1996 | A |
| 5582696 | Sheehan | Dec 1996 | A |
| 5582697 | Ikeda | Dec 1996 | A |
| 5584813 | Livingston et al. | Dec 1996 | A |
| 5584876 | Bruchman et al. | Dec 1996 | A |
| 5586553 | Halili et al. | Dec 1996 | A |
| 5587273 | Yan et al. | Dec 1996 | A |
| 5588560 | Benedict et al. | Dec 1996 | A |
| 5589133 | Suzuki | Dec 1996 | A |
| 5589563 | Ward et al. | Dec 1996 | A |
| 5590651 | Shaffer et al. | Jan 1997 | A |
| 5593440 | Brauker et al. | Jan 1997 | A |
| 5593852 | Heller et al. | Jan 1997 | A |
| 5605152 | Slate et al. | Feb 1997 | A |
| 5607565 | Azarnia et al. | Mar 1997 | A |
| 5609572 | Lang | Mar 1997 | A |
| 5611900 | Worden | Mar 1997 | A |
| 5624409 | Seale | Apr 1997 | A |
| 5624537 | Turner et al. | Apr 1997 | A |
| 5626563 | Dodge et al. | May 1997 | A |
| 5628619 | Wilson | May 1997 | A |
| 5628890 | Carter et al. | May 1997 | A |
| 5637083 | Bertrand et al. | Jun 1997 | A |
| 5640470 | Iyer et al. | Jun 1997 | A |
| 5640954 | Pfeiffer et al. | Jun 1997 | A |
| 5643195 | Drevet et al. | Jul 1997 | A |
| 5651767 | Schulman et al. | Jul 1997 | A |
| 5653756 | Clarke et al. | Aug 1997 | A |
| 5653863 | Genshaw et al. | Aug 1997 | A |
| 5658250 | Blomquist et al. | Aug 1997 | A |
| 5658330 | Carlisle et al. | Aug 1997 | A |
| 5660163 | Schulman et al. | Aug 1997 | A |
| 5665061 | Antwiler | Sep 1997 | A |
| 5665065 | Colman et al. | Sep 1997 | A |
| 5665222 | Heller et al. | Sep 1997 | A |
| 5667504 | Baumann et al. | Sep 1997 | A |
| 5676651 | Larson, Jr. et al. | Oct 1997 | A |
| 5676820 | Wang et al. | Oct 1997 | A |
| 5682884 | Hill | Nov 1997 | A |
| 5683562 | Schaffar et al. | Nov 1997 | A |
| 5686829 | Girault | Nov 1997 | A |
| 5688239 | Walker | Nov 1997 | A |
| 5688244 | Lang | Nov 1997 | A |
| 5695623 | Michel et al. | Dec 1997 | A |
| 5696314 | McCaffrey et al. | Dec 1997 | A |
| 5697366 | Kimball et al. | Dec 1997 | A |
| 5697899 | Hillman et al. | Dec 1997 | A |
| 5703359 | Wampler, III | Dec 1997 | A |
| 5704354 | Preidel et al. | Jan 1998 | A |
| 5706807 | Picha | Jan 1998 | A |
| 5707502 | McCaffrey et al. | Jan 1998 | A |
| 5711801 | Ward et al. | Jan 1998 | A |
| 5711861 | Ward et al. | Jan 1998 | A |
| 5713888 | Neuenfeldt et al. | Feb 1998 | A |
| 5714123 | Sohrab | Feb 1998 | A |
| 5730654 | Brown | Mar 1998 | A |
| 5733336 | Neuenfeldt et al. | Mar 1998 | A |
| 5735273 | Kurnik et al. | Apr 1998 | A |
| 5741330 | Brauker et al. | Apr 1998 | A |
| 5741634 | Nozoe et al. | Apr 1998 | A |
| 5743262 | Lepper, Jr. et al. | Apr 1998 | A |
| 5746898 | Preidel | May 1998 | A |
| 5749832 | Vadgama et al. | May 1998 | A |
| 5749907 | Mann | May 1998 | A |
| 5755692 | Manicom | May 1998 | A |
| 5756632 | Ward et al. | May 1998 | A |
| 5758643 | Wong et al. | Jun 1998 | A |
| 5763760 | Gumbrecht et al. | Jun 1998 | A |
| 5766151 | Valley et al. | Jun 1998 | A |
| 5771890 | Tamada | Jun 1998 | A |
| 5776324 | Usala | Jul 1998 | A |
| 5777060 | Van Antwerp | Jul 1998 | A |
| 5781455 | Hyodo | Jul 1998 | A |
| 5782912 | Brauker et al. | Jul 1998 | A |
| 5787900 | Butler et al. | Aug 1998 | A |
| 5791344 | Schulman et al. | Aug 1998 | A |
| 5791880 | Wilson | Aug 1998 | A |
| 5795453 | Gilmartin | Aug 1998 | A |
| 5795774 | Matsumoto et al. | Aug 1998 | A |
| 5798065 | Picha | Aug 1998 | A |
| 5800383 | Chandler et al. | Sep 1998 | A |
| 5800420 | Gross | Sep 1998 | A |
| 5800529 | Brauker et al. | Sep 1998 | A |
| 5804048 | Wong et al. | Sep 1998 | A |
| 5806517 | Gerhardt et al. | Sep 1998 | A |
| 5807274 | Henning et al. | Sep 1998 | A |
| 5807312 | Dzwonkiewicz | Sep 1998 | A |
| 5807375 | Gross et al. | Sep 1998 | A |
| 5807406 | Brauker et al. | Sep 1998 | A |
| 5810770 | Chin et al. | Sep 1998 | A |
| 5811487 | Schulz, Jr. et al. | Sep 1998 | A |
| 5814599 | Mitragotri et al. | Sep 1998 | A |
| 5820589 | Torgerson et al. | Oct 1998 | A |
| 5820622 | Gross et al. | Oct 1998 | A |
| 5822715 | Worthington. et al. | Oct 1998 | A |
| 5823802 | Bartley | Oct 1998 | A |
| 5833603 | Kovacs et al. | Nov 1998 | A |
| 5836887 | Oka et al. | Nov 1998 | A |
| 5836989 | Shelton | Nov 1998 | A |
| 5837454 | Cozzette et al. | Nov 1998 | A |
| 5837728 | Purcell | Nov 1998 | A |
| 5840026 | Uber, III et al. | Nov 1998 | A |
| 5840148 | Campbell et al. | Nov 1998 | A |
| 5840240 | Stenoien et al. | Nov 1998 | A |
| 5851197 | Marano et al. | Dec 1998 | A |
| 5858365 | Faller | Jan 1999 | A |
| 5861019 | Sun et al. | Jan 1999 | A |
| 5863400 | Drummond et al. | Jan 1999 | A |
| 5871499 | Hahn et al. | Feb 1999 | A |
| 5871514 | Wiklund et al. | Feb 1999 | A |
| 5873862 | Lopez | Feb 1999 | A |
| 5879373 | Roper et al. | Mar 1999 | A |
| 5882494 | Van Antwerp | Mar 1999 | A |
| 5895235 | Droz | Apr 1999 | A |
| 5897525 | Dey et al. | Apr 1999 | A |
| 5897578 | Wiklund et al. | Apr 1999 | A |
| 5899855 | Brown | May 1999 | A |
| 5904666 | Dedecker et al. | May 1999 | A |
| 5904708 | Goedeke | May 1999 | A |
| 5911219 | Aylsworth et al. | Jun 1999 | A |
| 5913998 | Butler et al. | Jun 1999 | A |
| 5914026 | Blubaugh, Jr. et al. | Jun 1999 | A |
| 5916445 | Hjerten et al. | Jun 1999 | A |
| 5917346 | Gord | Jun 1999 | A |
| 5919215 | Wiklund et al. | Jul 1999 | A |
| 5921951 | Morris | Jul 1999 | A |
| 5928130 | Schmidt | Jul 1999 | A |
| 5928155 | Eggers et al. | Jul 1999 | A |
| 5928182 | Kraus et al. | Jul 1999 | A |
| 5928189 | Phillips et al. | Jul 1999 | A |
| 5928195 | Malamud et al. | Jul 1999 | A |
| 5931814 | Alex et al. | Aug 1999 | A |
| 5932175 | Knute et al. | Aug 1999 | A |
| 5933136 | Brown | Aug 1999 | A |
| 5935785 | Reber et al. | Aug 1999 | A |
| 5938636 | Kramer et al. | Aug 1999 | A |
| 5944661 | Swette et al. | Aug 1999 | A |
| 5947911 | Wong et al. | Sep 1999 | A |
| 5954643 | Van Antwerp et al. | Sep 1999 | A |
| 5954954 | Houck et al. | Sep 1999 | A |
| 5957854 | Besson et al. | Sep 1999 | A |
| 5957903 | Mirzaee et al. | Sep 1999 | A |
| 5959050 | Mosbach et al. | Sep 1999 | A |
| 5961451 | Reber et al. | Oct 1999 | A |
| 5963132 | Yoakum | Oct 1999 | A |
| 5964804 | Brauker et al. | Oct 1999 | A |
| 5964993 | Blubaugh et al. | Oct 1999 | A |
| 5965125 | Mineau-Hanschke | Oct 1999 | A |
| 5965380 | Heller et al. | Oct 1999 | A |
| 5971922 | Arita et al. | Oct 1999 | A |
| 5972199 | Haller et al. | Oct 1999 | A |
| 5976085 | Kimball et al. | Nov 1999 | A |
| 5985129 | Gough et al. | Nov 1999 | A |
| 5989409 | Kurnik et al. | Nov 1999 | A |
| 5995208 | Sarge et al. | Nov 1999 | A |
| 5995860 | Sun et al. | Nov 1999 | A |
| 5999848 | Gord et al. | Dec 1999 | A |
| 6001067 | Shults et al. | Dec 1999 | A |
| 6001471 | Bries et al. | Dec 1999 | A |
| 6011984 | Van Antwerp et al. | Jan 2000 | A |
| 6013113 | Mika | Jan 2000 | A |
| 6014577 | Henning et al. | Jan 2000 | A |
| 6016448 | Busacker et al. | Jan 2000 | A |
| 6017435 | Hassard et al. | Jan 2000 | A |
| 6023629 | Tamada | Feb 2000 | A |
| 6024720 | Chandler et al. | Feb 2000 | A |
| 6027445 | Von Bahr | Feb 2000 | A |
| 6027479 | Alei et al. | Feb 2000 | A |
| 6030827 | Davis et al. | Feb 2000 | A |
| 6032059 | Henning et al. | Feb 2000 | A |
| 6032667 | Heinonen | Mar 2000 | A |
| 6036924 | Simons et al. | Mar 2000 | A |
| 6048691 | Maracas | Apr 2000 | A |
| 6049727 | Crothall | Apr 2000 | A |
| 6051372 | Bayerl et al. | Apr 2000 | A |
| 6051389 | Ahl et al. | Apr 2000 | A |
| 6057377 | Sasaki et al. | May 2000 | A |
| 6059946 | Yukawa et al. | May 2000 | A |
| 6063637 | Arnold et al. | May 2000 | A |
| 6065154 | Hulings et al. | May 2000 | A |
| 6066083 | Slater et al. | May 2000 | A |
| 6066088 | Davis | May 2000 | A |
| 6066448 | Wohlstadter et al. | May 2000 | A |
| 6071391 | Gotoh et al. | Jun 2000 | A |
| 6074775 | Gartstein et al. | Jun 2000 | A |
| 6077299 | Adelberg et al. | Jun 2000 | A |
| 6080583 | Von Bahr | Jun 2000 | A |
| 6081735 | Diab et al. | Jun 2000 | A |
| 6081736 | Colvin et al. | Jun 2000 | A |
| 6083523 | Dionne et al. | Jul 2000 | A |
| 6083710 | Heller et al. | Jul 2000 | A |
| 6088608 | Schulman et al. | Jul 2000 | A |
| 6090087 | Tsukada et al. | Jul 2000 | A |
| 6091975 | Daddona et al. | Jul 2000 | A |
| 6093156 | Cunningham et al. | Jul 2000 | A |
| 6093172 | Funderburk et al. | Jul 2000 | A |
| 6099511 | Devos et al. | Aug 2000 | A |
| 6103033 | Say et al. | Aug 2000 | A |
| 6104940 | Watanabe et al. | Aug 2000 | A |
| 6107083 | Collins et al. | Aug 2000 | A |
| 6115634 | Donders et al. | Sep 2000 | A |
| 6117290 | Say | Sep 2000 | A |
| 6119628 | Schulman et al. | Sep 2000 | A |
| 6120676 | Heller et al. | Sep 2000 | A |
| 6121009 | Heller et al. | Sep 2000 | A |
| 6122536 | Sun et al. | Sep 2000 | A |
| 6123827 | Wong et al. | Sep 2000 | A |
| 6127154 | Mosbach et al. | Oct 2000 | A |
| 6128519 | Say | Oct 2000 | A |
| 6134461 | Say et al. | Oct 2000 | A |
| 6135978 | Houben et al. | Oct 2000 | A |
| 6142939 | Eppstein et al. | Nov 2000 | A |
| 6144869 | Berner et al. | Nov 2000 | A |
| 6144871 | Saito et al. | Nov 2000 | A |
| 6159186 | Wickham et al. | Dec 2000 | A |
| 6162201 | Cohen et al. | Dec 2000 | A |
| 6162611 | Heller et al. | Dec 2000 | A |
| 6164921 | Moubayed et al. | Dec 2000 | A |
| 6165154 | Gray et al. | Dec 2000 | A |
| 6167614 | Tuttle et al. | Jan 2001 | B1 |
| 6168568 | Gavriely | Jan 2001 | B1 |
| 6169155 | Alvarez et al. | Jan 2001 | B1 |
| 6171276 | Lippe et al. | Jan 2001 | B1 |
| 6175752 | Say et al. | Jan 2001 | B1 |
| 6175753 | Menkes et al. | Jan 2001 | B1 |
| 6180416 | Kurnik et al. | Jan 2001 | B1 |
| 6183437 | Walker | Feb 2001 | B1 |
| 6187062 | Oweis et al. | Feb 2001 | B1 |
| 6189536 | Martinez et al. | Feb 2001 | B1 |
| 6191860 | Klinger et al. | Feb 2001 | B1 |
| 6201980 | Darrow et al. | Mar 2001 | B1 |
| 6201993 | Kruse et al. | Mar 2001 | B1 |
| 6206856 | Mahurkar | Mar 2001 | B1 |
| 6208894 | Schulman et al. | Mar 2001 | B1 |
| 6212416 | Ward et al. | Apr 2001 | B1 |
| 6212417 | Ikeda et al. | Apr 2001 | B1 |
| 6212424 | Robinson | Apr 2001 | B1 |
| 6213739 | Phallen et al. | Apr 2001 | B1 |
| 6214185 | Offenbacher et al. | Apr 2001 | B1 |
| 6219574 | Cormier et al. | Apr 2001 | B1 |
| 6223083 | Rosar | Apr 2001 | B1 |
| 6230059 | Duffin | May 2001 | B1 |
| 6231879 | Li et al. | May 2001 | B1 |
| 6232783 | Merrill | May 2001 | B1 |
| 6233080 | Brenner et al. | May 2001 | B1 |
| 6233471 | Berner et al. | May 2001 | B1 |
| 6241863 | Monbouquette | Jun 2001 | B1 |
| 6248067 | Causey, III et al. | Jun 2001 | B1 |
| 6248077 | Elson et al. | Jun 2001 | B1 |
| 6248093 | Moberg | Jun 2001 | B1 |
| 6251280 | Dai et al. | Jun 2001 | B1 |
| 6254586 | Mann et al. | Jul 2001 | B1 |
| 6256522 | Schultz | Jul 2001 | B1 |
| 6259937 | Schulman et al. | Jul 2001 | B1 |
| 6263222 | Diab et al. | Jul 2001 | B1 |
| 6264825 | Blackburn et al. | Jul 2001 | B1 |
| 6268161 | Han et al. | Jul 2001 | B1 |
| 6270478 | Mernoee | Aug 2001 | B1 |
| 6272364 | Kurnik | Aug 2001 | B1 |
| 6272480 | Tresp et al. | Aug 2001 | B1 |
| 6274285 | Gries et al. | Aug 2001 | B1 |
| 6274686 | Mosbach et al. | Aug 2001 | B1 |
| 6275717 | Gross et al. | Aug 2001 | B1 |
| 6280408 | Sipin | Aug 2001 | B1 |
| 6284478 | Heller et al. | Sep 2001 | B1 |
| 6285897 | Kilcoyne et al. | Sep 2001 | B1 |
| 6293925 | Safabash et al. | Sep 2001 | B1 |
| 6294281 | Heller | Sep 2001 | B1 |
| 6298254 | Tamada | Oct 2001 | B2 |
| 6299578 | Kurnik et al. | Oct 2001 | B1 |
| 6299583 | Eggers et al. | Oct 2001 | B1 |
| 6300002 | Webb et al. | Oct 2001 | B1 |
| 6302855 | Lav et al. | Oct 2001 | B1 |
| 6309351 | Kurnik et al. | Oct 2001 | B1 |
| 6309384 | Harrington et al. | Oct 2001 | B1 |
| 6309526 | Fujiwara et al. | Oct 2001 | B1 |
| 6309884 | Cooper et al. | Oct 2001 | B1 |
| 6310110 | Markowitz et al. | Oct 2001 | B1 |
| 6315738 | Nishikawa et al. | Nov 2001 | B1 |
| 6319566 | Polanyi et al. | Nov 2001 | B1 |
| 6325978 | Labuda et al. | Dec 2001 | B1 |
| 6325979 | Hahn et al. | Dec 2001 | B1 |
| 6326160 | Dunn et al. | Dec 2001 | B1 |
| 6329161 | Heller et al. | Dec 2001 | B1 |
| 6329929 | Weijand et al. | Dec 2001 | B1 |
| 6330464 | Colvin, Jr. et al. | Dec 2001 | B1 |
| 6343225 | Clark, Jr. | Jan 2002 | B1 |
| 6356776 | Berner et al. | Mar 2002 | B1 |
| 6358225 | Butterfield | Mar 2002 | B1 |
| 6360888 | McIver et al. | Mar 2002 | B1 |
| 6365670 | Fry | Apr 2002 | B1 |
| 6366794 | Moussy et al. | Apr 2002 | B1 |
| 6368141 | VanAntwerp et al. | Apr 2002 | B1 |
| 6368274 | Van Antwerp et al. | Apr 2002 | B1 |
| 6370941 | Nakamura et al. | Apr 2002 | B2 |
| 6379301 | Worthington et al. | Apr 2002 | B1 |
| 6379317 | Kintzig et al. | Apr 2002 | B1 |
| 6387709 | Mason et al. | May 2002 | B1 |
| 6391019 | Ito | May 2002 | B1 |
| 6400974 | Lesho | Jun 2002 | B1 |
| 6402703 | Kensey et al. | Jun 2002 | B1 |
| 6403944 | Mackenzie et al. | Jun 2002 | B1 |
| 6406066 | Uegane | Jun 2002 | B1 |
| 6406426 | Reuss et al. | Jun 2002 | B1 |
| 6407195 | Sherman et al. | Jun 2002 | B2 |
| 6409674 | Brockway et al. | Jun 2002 | B1 |
| 6413393 | Van Antwerp et al. | Jul 2002 | B1 |
| 6413396 | Yang et al. | Jul 2002 | B1 |
| 6416651 | Millar | Jul 2002 | B1 |
| 6418332 | Mastrototaro et al. | Jul 2002 | B1 |
| 6424847 | Mastrototaro et al. | Jul 2002 | B1 |
| 6424861 | Meredith | Jul 2002 | B2 |
| 6430437 | Marro | Aug 2002 | B1 |
| 6442413 | Silver | Aug 2002 | B1 |
| 6447448 | Ishikawa et al. | Sep 2002 | B1 |
| 6447542 | Weadock | Sep 2002 | B1 |
| 6454710 | Ballerstadt et al. | Sep 2002 | B1 |
| 6459917 | Gowda et al. | Oct 2002 | B1 |
| 6461496 | Feldman et al. | Oct 2002 | B1 |
| 6464849 | Say et al. | Oct 2002 | B1 |
| 6465066 | Rule et al. | Oct 2002 | B1 |
| 6466810 | Ward et al. | Oct 2002 | B1 |
| 6467480 | Meier et al. | Oct 2002 | B1 |
| 6468287 | Baugh | Oct 2002 | B1 |
| 6471689 | Joseph et al. | Oct 2002 | B1 |
| 6434045 | Holker et al. | Nov 2002 | B2 |
| 6434046 | Say et al. | Nov 2002 | B2 |
| 6474360 | Ito | Nov 2002 | B1 |
| 6475372 | Ohara et al. | Nov 2002 | B1 |
| 6475750 | Han et al. | Nov 2002 | B1 |
| 6477392 | Honigs et al. | Nov 2002 | B1 |
| 6477395 | Schulman et al. | Nov 2002 | B2 |
| 6481440 | Gielen et al. | Nov 2002 | B2 |
| 6485449 | Ito | Nov 2002 | B2 |
| 6488652 | Weijand et al. | Dec 2002 | B1 |
| 6494830 | Wessel | Dec 2002 | B1 |
| 6494879 | Lennox et al. | Dec 2002 | B2 |
| 6498043 | Schulman et al. | Dec 2002 | B1 |
| 6498941 | Jackson | Dec 2002 | B1 |
| 6501976 | Sohrab | Dec 2002 | B1 |
| 6510329 | Heckel | Jan 2003 | B2 |
| 6512939 | Colvin et al. | Jan 2003 | B1 |
| 6514718 | Heller et al. | Feb 2003 | B2 |
| 6520326 | McIvor et al. | Feb 2003 | B2 |
| 6520477 | Trimmer | Feb 2003 | B2 |
| 6520937 | Hart et al. | Feb 2003 | B2 |
| 6520997 | Pekkarinen et al. | Feb 2003 | B1 |
| 6526298 | Khalil et al. | Feb 2003 | B1 |
| 6527729 | Turcott | Mar 2003 | B1 |
| 6534711 | Pollack | Mar 2003 | B1 |
| 6536433 | Cewers | Mar 2003 | B1 |
| 6537318 | Ita et al. | Mar 2003 | B1 |
| 6541107 | Zhong et al. | Apr 2003 | B1 |
| 6541266 | Modzelewski et al. | Apr 2003 | B2 |
| 6542765 | Guy et al. | Apr 2003 | B1 |
| 6544212 | Galley et al. | Apr 2003 | B2 |
| 6545085 | Kilgour et al. | Apr 2003 | B2 |
| 6546268 | Ishikawa et al. | Apr 2003 | B1 |
| 6546269 | Kurnik | Apr 2003 | B1 |
| 6551494 | Heller et al. | Apr 2003 | B1 |
| 6551496 | Moles et al. | Apr 2003 | B1 |
| 6553241 | Mannheimer et al. | Apr 2003 | B2 |
| 6553244 | Lesho et al. | Apr 2003 | B2 |
| 6554805 | Hiejima | Apr 2003 | B2 |
| 6554822 | Holschneider et al. | Apr 2003 | B1 |
| 6647839 | Zhang et al. | Apr 2003 | B2 |
| 6558320 | Causey | May 2003 | B1 |
| 6558321 | Burd et al. | May 2003 | B1 |
| 6558347 | Jhuboo et al. | May 2003 | B1 |
| 6558351 | Steil et al. | May 2003 | B1 |
| 6560471 | Heller et al. | May 2003 | B1 |
| 6561978 | Conn et al. | May 2003 | B1 |
| 6565509 | Say et al. | May 2003 | B1 |
| 6565535 | Zaias et al. | May 2003 | B2 |
| 6565807 | Patterson et al. | May 2003 | B1 |
| 6569309 | Otsuka et al. | May 2003 | B2 |
| 6569521 | Sheridan et al. | May 2003 | B1 |
| 6572545 | Knobbe et al. | Jun 2003 | B2 |
| 6572579 | Raghavan et al. | Jun 2003 | B1 |
| 6574490 | Abbink et al. | Jun 2003 | B2 |
| 6575905 | Knobbe et al. | Jun 2003 | B2 |
| 6579257 | Elgas et al. | Jun 2003 | B1 |
| 6579498 | Eglise | Jun 2003 | B1 |
| 6579890 | Bonnecaze et al. | Jun 2003 | B1 |
| 6584335 | Haar et al. | Jun 2003 | B1 |
| 6585644 | Lebel et al. | Jul 2003 | B2 |
| 6585675 | O'Mahony et al. | Jul 2003 | B1 |
| 6585763 | Kellman et al. | Jul 2003 | B1 |
| 6587705 | Kim et al. | Jul 2003 | B1 |
| 6589229 | Connelly et al. | Jul 2003 | B1 |
| 6591125 | Buse et al. | Jul 2003 | B1 |
| 6594514 | Berner et al. | Jul 2003 | B2 |
| 6595756 | Gray et al. | Jul 2003 | B2 |
| 6595919 | Berner et al. | Jul 2003 | B2 |
| 6602221 | Saravia et al. | Aug 2003 | B1 |
| 6605072 | Struys et al. | Aug 2003 | B2 |
| 6607509 | Bobroff et al. | Aug 2003 | B2 |
| 6607658 | Heller et al. | Aug 2003 | B1 |
| 6609071 | Shapiro et al. | Aug 2003 | B2 |
| 6612984 | Kerr | Sep 2003 | B1 |
| 6613379 | Ward et al. | Sep 2003 | B2 |
| 6615078 | Burson et al. | Sep 2003 | B1 |
| 6618603 | Varalli et al. | Sep 2003 | B2 |
| 6618934 | Feldman et al. | Sep 2003 | B1 |
| 6633772 | Ford et al. | Oct 2003 | B2 |
| 6641533 | Causey, III et al. | Nov 2003 | B2 |
| 6642015 | Vachon et al. | Nov 2003 | B2 |
| 6645181 | Lavi et al. | Nov 2003 | B1 |
| 6648821 | Lebel et al. | Nov 2003 | B2 |
| 6653091 | Dunn et al. | Nov 2003 | B1 |
| 6654625 | Say et al. | Nov 2003 | B1 |
| 6656157 | Duchon et al. | Dec 2003 | B1 |
| 6673022 | Bobo et al. | Jan 2004 | B1 |
| 6673596 | Sayler et al. | Jan 2004 | B1 |
| 6679865 | Shekalim | Jan 2004 | B2 |
| 6679872 | Turovskiy et al. | Jan 2004 | B2 |
| 6683535 | Utke | Jan 2004 | B1 |
| 6684904 | Ito | Feb 2004 | B2 |
| 6685668 | Cho et al. | Feb 2004 | B1 |
| 6687522 | Tamada | Feb 2004 | B2 |
| 6689089 | Tiedtke et al. | Feb 2004 | B1 |
| 6689265 | Heller et al. | Feb 2004 | B2 |
| 6694191 | Starkweather et al. | Feb 2004 | B2 |
| 6695860 | Ward et al. | Feb 2004 | B1 |
| 6695958 | Adam et al. | Feb 2004 | B1 |
| 6699188 | Wessel | Mar 2004 | B2 |
| 6699218 | Flaherty et al. | Mar 2004 | B2 |
| 6699383 | Lemire et al. | Mar 2004 | B2 |
| 6702249 | Ito | Mar 2004 | B2 |
| 6702857 | Brauker et al. | Mar 2004 | B2 |
| 6702972 | Markle | Mar 2004 | B1 |
| 6705833 | Tam et al. | Mar 2004 | B2 |
| 6711424 | Fine et al. | Mar 2004 | B1 |
| 6712796 | Fentis et al. | Mar 2004 | B2 |
| 6721587 | Gough | Apr 2004 | B2 |
| 6723086 | Bassuk et al. | Apr 2004 | B2 |
| 6730200 | Stewart et al. | May 2004 | B1 |
| 6731976 | Penn et al. | May 2004 | B2 |
| 6733655 | Davies et al. | May 2004 | B1 |
| 6736783 | Blake et al. | May 2004 | B2 |
| 6737158 | Thompson | May 2004 | B1 |
| 6740075 | Lebel et al. | May 2004 | B2 |
| 6741877 | Shults et al. | May 2004 | B1 |
| 6742635 | Hirshberg | Jun 2004 | B2 |
| 6743635 | Neel et al. | Jun 2004 | B2 |
| 6749587 | Flaherty | Jun 2004 | B2 |
| 6770030 | Schaupp et al. | Aug 2004 | B1 |
| 6770067 | Lorenzen et al. | Aug 2004 | B2 |
| 6773565 | Kunimoto et al. | Aug 2004 | B2 |
| 6780297 | Matsumoto et al. | Aug 2004 | B2 |
| 6784274 | Van Antwerp et al. | Aug 2004 | B2 |
| 6793632 | Sohrab | Sep 2004 | B2 |
| 6793802 | Lee et al. | Sep 2004 | B2 |
| 6801041 | Karinka et al. | Oct 2004 | B2 |
| 6802957 | Jung et al. | Oct 2004 | B2 |
| 6804002 | Fine et al. | Oct 2004 | B2 |
| 6804544 | Van Antwerp et al. | Oct 2004 | B2 |
| 6805693 | Gray et al. | Oct 2004 | B2 |
| 6809507 | Morgan et al. | Oct 2004 | B2 |
| 6809653 | Mann et al. | Oct 2004 | B1 |
| 6810290 | Lebel et al. | Oct 2004 | B2 |
| 6811548 | Jeffrey | Nov 2004 | B2 |
| 6815186 | Clark, Jr. | Nov 2004 | B2 |
| 6850790 | Berner et al. | Feb 2005 | B2 |
| 6858020 | Rusnak | Feb 2005 | B2 |
| 6862465 | Shults et al. | Mar 2005 | B2 |
| 6869413 | Langley et al. | Mar 2005 | B2 |
| 6881551 | Heller et al. | Apr 2005 | B2 |
| 6887228 | McKay | May 2005 | B2 |
| 6891317 | Pei et al. | May 2005 | B2 |
| 6891552 | Bush | May 2005 | B1 |
| 6892085 | McIvor et al. | May 2005 | B2 |
| 6893552 | Wang et al. | May 2005 | B1 |
| 6895263 | Shin et al. | May 2005 | B2 |
| 6895265 | Silver | May 2005 | B2 |
| 6902544 | Ludin et al. | Jun 2005 | B2 |
| 6925393 | Kalatz et al. | Aug 2005 | B1 |
| 6926691 | Miethke | Aug 2005 | B2 |
| 6931327 | Goode et al. | Aug 2005 | B2 |
| 6932584 | Gray et al. | Aug 2005 | B2 |
| 6932894 | Mao et al. | Aug 2005 | B2 |
| 6936006 | Sabra | Aug 2005 | B2 |
| 6945965 | Whiting | Sep 2005 | B2 |
| 6948492 | Wermeling et al. | Sep 2005 | B2 |
| 6952604 | DeNuzzio et al. | Oct 2005 | B2 |
| 6954662 | Freger et al. | Oct 2005 | B2 |
| 6960192 | Flaherty et al. | Nov 2005 | B1 |
| 6965791 | Hitchcock et al. | Nov 2005 | B1 |
| 6966325 | Erickson | Nov 2005 | B2 |
| 6972080 | Tomioka et al. | Dec 2005 | B1 |
| 6975893 | Say et al. | Dec 2005 | B2 |
| 6979315 | Rogers et al. | Dec 2005 | B2 |
| 6989891 | Braig et al. | Jan 2006 | B2 |
| 6997921 | Gray et al. | Feb 2006 | B2 |
| 6998247 | Monfre et al. | Feb 2006 | B2 |
| 7003336 | Holker et al. | Feb 2006 | B2 |
| 7003341 | Say et al. | Feb 2006 | B2 |
| 7008979 | Schottman et al. | Mar 2006 | B2 |
| 7011630 | Desai et al. | Mar 2006 | B2 |
| 7016713 | Gardner et al. | Mar 2006 | B2 |
| 7022072 | Fox et al. | Apr 2006 | B2 |
| 7022219 | Mansouri et al. | Apr 2006 | B2 |
| 7025727 | Brockway et al. | Apr 2006 | B2 |
| 7025743 | Mann et al. | Apr 2006 | B2 |
| 7027848 | Robinson et al. | Apr 2006 | B2 |
| 7029444 | Shin et al. | Apr 2006 | B2 |
| 7033322 | Silver | Apr 2006 | B2 |
| 7048727 | Moss | May 2006 | B1 |
| 7058437 | Buse et al. | Jun 2006 | B2 |
| 7060059 | Keith et al. | Jun 2006 | B2 |
| 7061593 | Braig et al. | Jun 2006 | B2 |
| 7063086 | Shahbazpour et al. | Jun 2006 | B2 |
| 7066884 | Custer et al. | Jun 2006 | B2 |
| 7070577 | Haller et al. | Jul 2006 | B1 |
| 7070580 | Nielsen | Jul 2006 | B2 |
| 7074307 | Simpson et al. | Jul 2006 | B2 |
| 7078582 | Stebbings et al. | Jul 2006 | B2 |
| 7081195 | Simpson et al. | Jul 2006 | B2 |
| 7097775 | Greenberg et al. | Aug 2006 | B2 |
| 7098803 | Mann et al. | Aug 2006 | B2 |
| 7100628 | Izenson et al. | Sep 2006 | B1 |
| 7108778 | Simpson et al. | Sep 2006 | B2 |
| 7110803 | Shults et al. | Sep 2006 | B2 |
| 7115884 | Walt et al. | Oct 2006 | B1 |
| 7120483 | Russell et al. | Oct 2006 | B2 |
| 7131967 | Gray et al. | Nov 2006 | B2 |
| 7134999 | Brauker et al. | Nov 2006 | B2 |
| 7136689 | Shults et al. | Nov 2006 | B2 |
| 7146202 | Ward et al. | Dec 2006 | B2 |
| 7150741 | Erickson et al. | Dec 2006 | B2 |
| 7153265 | Vachon | Dec 2006 | B2 |
| 7162290 | Levin | Jan 2007 | B1 |
| 7166074 | Reghabi et al. | Jan 2007 | B2 |
| 7168597 | Jones et al. | Jan 2007 | B1 |
| 7169289 | Schuelein et al. | Jan 2007 | B2 |
| 7171252 | Scarantino et al. | Jan 2007 | B1 |
| 7183102 | Monfre et al. | Feb 2007 | B2 |
| 7184810 | Caduff et al. | Feb 2007 | B2 |
| 7190988 | Say et al. | Mar 2007 | B2 |
| 7192450 | Brauker et al. | Mar 2007 | B2 |
| 7207968 | Harcinske | Apr 2007 | B1 |
| 7207974 | Safabash et al. | Apr 2007 | B2 |
| 7211074 | Sansoucy | May 2007 | B2 |
| 7221970 | Parker | May 2007 | B2 |
| 7223253 | Hogendijk | May 2007 | B2 |
| 7225535 | Feldman et al. | Jun 2007 | B2 |
| 7228162 | Ward et al. | Jun 2007 | B2 |
| 7229288 | Stuart et al. | Jun 2007 | B2 |
| 7238165 | Vincent et al. | Jul 2007 | B2 |
| 7247138 | Reghabi et al. | Jul 2007 | B2 |
| 7248906 | Dirac et al. | Jul 2007 | B2 |
| 7254450 | Christopherson et al. | Aug 2007 | B2 |
| 7255690 | Gray et al. | Aug 2007 | B2 |
| 7258681 | Houde | Aug 2007 | B2 |
| 7261690 | Teller et al. | Aug 2007 | B2 |
| 7266400 | Fine et al. | Sep 2007 | B2 |
| 7267665 | Steil et al. | Sep 2007 | B2 |
| 7276029 | Goode et al. | Oct 2007 | B2 |
| 7278983 | Ireland et al. | Oct 2007 | B2 |
| 7279174 | Pacetti et al. | Oct 2007 | B2 |
| 7288085 | Olsen | Oct 2007 | B2 |
| 7295867 | Berner et al. | Nov 2007 | B2 |
| 7299082 | Feldman et al. | Nov 2007 | B2 |
| 7302153 | Thom | Nov 2007 | B2 |
| 7310544 | Brister et al. | Dec 2007 | B2 |
| 7311690 | Burnett | Dec 2007 | B2 |
| 7313425 | Finarov et al. | Dec 2007 | B2 |
| 7314452 | Madonia | Jan 2008 | B2 |
| 7315767 | Caduff et al. | Jan 2008 | B2 |
| 7316662 | Delnevo et al. | Jan 2008 | B2 |
| 7317939 | Fine et al. | Jan 2008 | B2 |
| 7318814 | Levine et al. | Jan 2008 | B2 |
| 7327273 | Hung et al. | Feb 2008 | B2 |
| 7329234 | Sansoucy | Feb 2008 | B2 |
| 7329239 | Safabash et al. | Feb 2008 | B2 |
| 7334594 | Ludin | Feb 2008 | B2 |
| 7335179 | Burnett | Feb 2008 | B2 |
| 7335195 | Mehier | Feb 2008 | B2 |
| 7335286 | Abel et al. | Feb 2008 | B2 |
| 7336984 | Gough et al. | Feb 2008 | B2 |
| 7338464 | Blischak et al. | Mar 2008 | B2 |
| 7344499 | Prausnitz et al. | Mar 2008 | B1 |
| 7354420 | Steil et al. | Apr 2008 | B2 |
| 7357793 | Pacetti | Apr 2008 | B2 |
| 7359723 | Jones | Apr 2008 | B2 |
| 7361155 | Sage, Jr. et al. | Apr 2008 | B2 |
| 7364562 | Braig et al. | Apr 2008 | B2 |
| 7366556 | Brister et al. | Apr 2008 | B2 |
| 7366566 | Henry et al. | Apr 2008 | B2 |
| 7367942 | Grage et al. | May 2008 | B2 |
| 7379765 | Petisce et al. | May 2008 | B2 |
| 7381184 | Funderburk et al. | Jun 2008 | B2 |
| 7396353 | Lorenzen et al. | Jul 2008 | B2 |
| 7399277 | Saidara et al. | Jul 2008 | B2 |
| 7402153 | Steil et al. | Jul 2008 | B2 |
| 7417164 | Suri | Aug 2008 | B2 |
| 7424318 | Brister et al. | Sep 2008 | B2 |
| 7426408 | DeNuzzio et al. | Sep 2008 | B2 |
| 7433727 | Ward et al. | Oct 2008 | B2 |
| 7460898 | Brister et al. | Dec 2008 | B2 |
| 7467003 | Brister et al. | Dec 2008 | B2 |
| 7471972 | Rhodes et al. | Dec 2008 | B2 |
| 7494465 | Brister et al. | Feb 2009 | B2 |
| 7497827 | Brister et al. | Mar 2009 | B2 |
| 7519408 | Rasdal et al. | Apr 2009 | B2 |
| 7519478 | Bartkowiak et al. | Apr 2009 | B2 |
| 7523004 | Bartkowiak et al. | Apr 2009 | B2 |
| 7525298 | Morgan et al. | Apr 2009 | B2 |
| 7583990 | Goode, Jr. et al. | Sep 2009 | B2 |
| 7587287 | Connolly et al. | Sep 2009 | B2 |
| 7591801 | Brauker et al. | Sep 2009 | B2 |
| 7599726 | Goode, Jr. et al. | Oct 2009 | B2 |
| 7604593 | Parris et al. | Oct 2009 | B2 |
| 7618368 | Brown | Nov 2009 | B2 |
| 7618369 | Hayter et al. | Nov 2009 | B2 |
| 7624028 | Brown | Nov 2009 | B1 |
| 7636602 | Baru Fassio et al. | Dec 2009 | B2 |
| 7637868 | Saint et al. | Dec 2009 | B2 |
| 7640032 | Jones | Dec 2009 | B2 |
| 7640048 | Dobbles et al. | Dec 2009 | B2 |
| 7647237 | Malave et al. | Jan 2010 | B2 |
| 7654956 | Brister et al. | Feb 2010 | B2 |
| 7657297 | Simpson et al. | Feb 2010 | B2 |
| 7695434 | Malecha | Apr 2010 | B2 |
| 7711402 | Shults et al. | May 2010 | B2 |
| 7715893 | Kamath et al. | May 2010 | B2 |
| 7731659 | Malecha | Jun 2010 | B2 |
| 7761126 | Gardner et al. | Jul 2010 | B2 |
| 7761130 | Simpson et al. | Jul 2010 | B2 |
| 7766830 | Fox et al. | Aug 2010 | B2 |
| 7771352 | Shults et al. | Aug 2010 | B2 |
| 7774145 | Brauker et al. | Aug 2010 | B2 |
| 7792562 | Shults et al. | Sep 2010 | B2 |
| 7831287 | Brister et al. | Nov 2010 | B2 |
| 7896809 | Simpson et al. | Mar 2011 | B2 |
| 7905833 | Brister et al. | Mar 2011 | B2 |
| 7927274 | Rasdal et al. | Apr 2011 | B2 |
| 7917186 | Kamath et al. | Aug 2011 | B2 |
| 8005524 | Brauker et al. | Aug 2011 | B2 |
| 8005525 | Goode, Jr. et al. | Aug 2011 | B2 |
| 8010174 | Goode, Jr. et al. | Aug 2011 | B2 |
| RE43039 | Brister et al. | Dec 2011 | E |
| 8160671 | Kamath et al. | Apr 2012 | B2 |
| 8249684 | Kamath et al. | Aug 2012 | B2 |
| 8287453 | Li et al. | Oct 2012 | B2 |
| 8386004 | Kamath et al. | Feb 2013 | B2 |
| 8423114 | Simpson et al. | Apr 2013 | B2 |
| 8428678 | Kamath et al. | Apr 2013 | B2 |
| 8483793 | Simpson et al. | Jul 2013 | B2 |
| RE44695 | Simpson et al. | Jan 2014 | E |
| 8650687 | Klerer et al. | Feb 2014 | B2 |
| 8850687 | Shah et al. | Oct 2014 | B2 |
| 8850688 | Shah et al. | Oct 2014 | B2 |
| 8911369 | Brister et al. | Dec 2014 | B2 |
| 8929968 | Brister et al. | Jan 2015 | B2 |
| 9504413 | Simpson | Nov 2016 | B2 |
| 9579053 | Brister et al. | Feb 2017 | B2 |
| 10136844 | Simpson | Nov 2018 | B2 |
| 10188333 | Kamath et al. | Jan 2019 | B2 |
| 10299712 | Brister et al. | May 2019 | B2 |
| 20010016682 | Berner et al. | Aug 2001 | A1 |
| 20010020546 | Eldridge et al. | Sep 2001 | A1 |
| 20010041830 | Varalli et al. | Nov 2001 | A1 |
| 20010051768 | Schulman et al. | Dec 2001 | A1 |
| 20020016535 | Martin et al. | Feb 2002 | A1 |
| 20020019022 | Dunn et al. | Feb 2002 | A1 |
| 20020019330 | Murray et al. | Feb 2002 | A1 |
| 20020022883 | Burg | Feb 2002 | A1 |
| 20020023852 | McIvor et al. | Feb 2002 | A1 |
| 20020026110 | Parris et al. | Feb 2002 | A1 |
| 20020026111 | Ackerman | Feb 2002 | A1 |
| 20020042090 | Heller et al. | Apr 2002 | A1 |
| 20020042561 | Schulman et al. | Apr 2002 | A1 |
| 20020043471 | Ikeda et al. | Apr 2002 | A1 |
| 20020045808 | Ford et al. | Apr 2002 | A1 |
| 20020055673 | Van Antwerp et al. | May 2002 | A1 |
| 20020065453 | Lesho et al. | May 2002 | A1 |
| 20020068860 | Clark, Jr. | Jun 2002 | A1 |
| 20020084196 | Liamos et al. | Jul 2002 | A1 |
| 20020099282 | Knobbe et al. | Jul 2002 | A1 |
| 20020099997 | Pi ret | Jul 2002 | A1 |
| 20020111547 | Knobbe et al. | Aug 2002 | A1 |
| 20020119711 | Van Antwerp et al. | Aug 2002 | A1 |
| 20020123048 | Gau | Sep 2002 | A1 |
| 20020151796 | Koulik | Oct 2002 | A1 |
| 20020151816 | Rich et al. | Oct 2002 | A1 |
| 20020155615 | Novikov et al. | Oct 2002 | A1 |
| 20020160722 | Terranova et al. | Oct 2002 | A1 |
| 20020161288 | Shin et al. | Oct 2002 | A1 |
| 20020169369 | Ward et al. | Nov 2002 | A1 |
| 20020177763 | Burns et al. | Nov 2002 | A1 |
| 20020177764 | Sohrab et al. | Nov 2002 | A1 |
| 20020182241 | Borenstein et al. | Dec 2002 | A1 |
| 20020188185 | Sohrab | Dec 2002 | A1 |
| 20020188216 | Kayyali et al. | Dec 2002 | A1 |
| 20020193885 | Legeay et al. | Dec 2002 | A1 |
| 20020198513 | Lebel et al. | Dec 2002 | A1 |
| 20030003524 | Taniike et al. | Jan 2003 | A1 |
| 20030004432 | Assenheimer | Jan 2003 | A1 |
| 20030004457 | Andersson | Jan 2003 | A1 |
| 20030006669 | Pei et al. | Jan 2003 | A1 |
| 20030009093 | Silver | Jan 2003 | A1 |
| 20030023171 | Sato et al. | Jan 2003 | A1 |
| 20030023317 | Brauker et al. | Jan 2003 | A1 |
| 20030028089 | Galley et al. | Feb 2003 | A1 |
| 20030032874 | Rhodes et al. | Feb 2003 | A1 |
| 20030036773 | Whitehurst et al. | Feb 2003 | A1 |
| 20030050537 | Wessel | Mar 2003 | A1 |
| 20030050546 | Desai et al. | Mar 2003 | A1 |
| 20030054428 | Monfre et al. | Mar 2003 | A1 |
| 20030060765 | Campbell et al. | Mar 2003 | A1 |
| 20030065254 | Schulman et al. | Apr 2003 | A1 |
| 20030070548 | Clausen | Apr 2003 | A1 |
| 20030076082 | Morgan et al. | Apr 2003 | A1 |
| 20030078481 | McIvor et al. | Apr 2003 | A1 |
| 20030078560 | Miller et al. | Apr 2003 | A1 |
| 20030088166 | Say et al. | May 2003 | A1 |
| 20030097082 | Purdy et al. | May 2003 | A1 |
| 20030100040 | Bonnecaze | May 2003 | A1 |
| 20030100821 | Heller et al. | May 2003 | A1 |
| 20030114735 | Silver et al. | Jun 2003 | A1 |
| 20030114836 | Estes et al. | Jun 2003 | A1 |
| 20030117296 | Seely | Jun 2003 | A1 |
| 20030119208 | Yoon et al. | Jun 2003 | A1 |
| 20030120152 | Omiya | Jun 2003 | A1 |
| 20030125612 | Fox et al. | Jul 2003 | A1 |
| 20030125613 | Enegren et al. | Jul 2003 | A1 |
| 20030130616 | Steil et al. | Jul 2003 | A1 |
| 20030134347 | Heller et al. | Jul 2003 | A1 |
| 20030138674 | Zeikus et al. | Jul 2003 | A1 |
| 20030153821 | Berner et al. | Aug 2003 | A1 |
| 20030176183 | Drucker et al. | Sep 2003 | A1 |
| 20030181794 | Rini et al. | Sep 2003 | A1 |
| 20030187338 | Say et al. | Oct 2003 | A1 |
| 20030188427 | Say et al. | Oct 2003 | A1 |
| 20030199744 | Buse et al. | Oct 2003 | A1 |
| 20030199745 | Burson et al. | Oct 2003 | A1 |
| 20030203498 | Neel et al. | Oct 2003 | A1 |
| 20030208113 | Mault et al. | Nov 2003 | A1 |
| 20030211050 | Majeti et al. | Nov 2003 | A1 |
| 20030211625 | Cohan | Nov 2003 | A1 |
| 20030212317 | Kovatchev et al. | Nov 2003 | A1 |
| 20030212346 | Yuzhakov et al. | Nov 2003 | A1 |
| 20030212347 | Sohrab | Nov 2003 | A1 |
| 20030225324 | Anderson et al. | Dec 2003 | A1 |
| 20030225437 | Ferguson | Dec 2003 | A1 |
| 20030228681 | Ritts et al. | Dec 2003 | A1 |
| 20030235817 | Bartkowiak et al. | Dec 2003 | A1 |
| 20040006263 | Anderson et al. | Jan 2004 | A1 |
| 20040008761 | Kelliher et al. | Jan 2004 | A1 |
| 20040011671 | Shults et al. | Jan 2004 | A1 |
| 20040015063 | DeNuzzio et al. | Jan 2004 | A1 |
| 20040015134 | Lavi et al. | Jan 2004 | A1 |
| 20040018486 | Dunn et al. | Jan 2004 | A1 |
| 20040023253 | Kunwar et al. | Feb 2004 | A1 |
| 20040023317 | Motamedi et al. | Feb 2004 | A1 |
| 20040024327 | Brodnick | Feb 2004 | A1 |
| 20040030285 | Lavi et al. | Feb 2004 | A1 |
| 20040039298 | Abreu | Feb 2004 | A1 |
| 20040040840 | Mao et al. | Mar 2004 | A1 |
| 20040045879 | Shults et al. | Mar 2004 | A1 |
| 20040054352 | Adams et al. | Mar 2004 | A1 |
| 20040063167 | Kaastrup et al. | Apr 2004 | A1 |
| 20040068230 | Estes et al. | Apr 2004 | A1 |
| 20040074785 | Holker | Apr 2004 | A1 |
| 20040078219 | Kaylor | Apr 2004 | A1 |
| 20040087671 | Tamada et al. | May 2004 | A1 |
| 20040106857 | Gough | Jun 2004 | A1 |
| 20040106859 | Say et al. | Jun 2004 | A1 |
| 20040111017 | Say et al. | Jun 2004 | A1 |
| 20040133131 | Kuhn et al. | Jul 2004 | A1 |
| 20040133164 | Funderburk et al. | Jul 2004 | A1 |
| 20040138543 | Russell et al. | Jul 2004 | A1 |
| 20040143173 | Reghabi et al. | Jul 2004 | A1 |
| 20040146909 | Duong et al. | Jul 2004 | A1 |
| 20040152187 | Haight et al. | Aug 2004 | A1 |
| 20040152622 | Keith et al. | Aug 2004 | A1 |
| 20040158138 | Kilcoyne et al. | Aug 2004 | A1 |
| 20040167801 | Say et al. | Aug 2004 | A1 |
| 20040173472 | Jung et al. | Sep 2004 | A1 |
| 20040176672 | Silver et al. | Sep 2004 | A1 |
| 20040180391 | Gratzl et al. | Sep 2004 | A1 |
| 20040186362 | Brauker et al. | Sep 2004 | A1 |
| 20040186365 | Jin et al. | Sep 2004 | A1 |
| 20040193025 | Steil et al. | Sep 2004 | A1 |
| 20040199059 | Brauker et al. | Oct 2004 | A1 |
| 20040204687 | Mogensen | Oct 2004 | A1 |
| 20040219664 | Heller et al. | Nov 2004 | A1 |
| 20040220517 | Starkweather et al. | Nov 2004 | A1 |
| 20040224001 | Pacetti et al. | Nov 2004 | A1 |
| 20040234575 | Horres et al. | Nov 2004 | A1 |
| 20040236200 | Say et al. | Nov 2004 | A1 |
| 20040236251 | Roe et al. | Nov 2004 | A1 |
| 20040242982 | Sakata et al. | Dec 2004 | A1 |
| 20040248282 | Sobha et al. | Dec 2004 | A1 |
| 20040254433 | Bandis | Dec 2004 | A1 |
| 20050006122 | Burnette | Jan 2005 | A1 |
| 20050008671 | Van Antwerp | Jan 2005 | A1 |
| 20050010265 | Baru Fassio et al. | Jan 2005 | A1 |
| 20050026689 | Marks | Feb 2005 | A1 |
| 20050027180 | Goode et al. | Feb 2005 | A1 |
| 20050027181 | Goode et al. | Feb 2005 | A1 |
| 20050027182 | Siddiqui et al. | Feb 2005 | A1 |
| 20050027462 | Goode et al. | Feb 2005 | A1 |
| 20050027463 | Goode et al. | Feb 2005 | A1 |
| 20050031689 | Shults et al. | Feb 2005 | A1 |
| 20050033132 | Shults et al. | Feb 2005 | A1 |
| 20050038332 | Saidara et al. | Feb 2005 | A1 |
| 20050043598 | Goode et al. | Feb 2005 | A1 |
| 20050051427 | Brauker et al. | Mar 2005 | A1 |
| 20050051440 | Simpson et al. | Mar 2005 | A1 |
| 20050054909 | Petisce et al. | Mar 2005 | A1 |
| 20050056551 | White et al. | Mar 2005 | A1 |
| 20050056552 | Simpson et al. | Mar 2005 | A1 |
| 20050059871 | Gough et al. | Mar 2005 | A1 |
| 20050065464 | Talbot et al. | Mar 2005 | A1 |
| 20050070770 | Dirac et al. | Mar 2005 | A1 |
| 20050077584 | Uhland et al. | Apr 2005 | A1 |
| 20050079200 | Rathenow et al. | Apr 2005 | A1 |
| 20050090607 | Tapsak et al. | Apr 2005 | A1 |
| 20050096519 | DeNuzzio et al. | May 2005 | A1 |
| 20050101847 | Routt et al. | May 2005 | A1 |
| 20050103625 | Rhodes et al. | May 2005 | A1 |
| 20050107677 | Ward et al. | May 2005 | A1 |
| 20050112169 | Brauker et al. | May 2005 | A1 |
| 20050113653 | Fox et al. | May 2005 | A1 |
| 20050115832 | Simpson et al. | Jun 2005 | A1 |
| 20050118344 | Pacetti | Jun 2005 | A1 |
| 20050119720 | Gale et al. | Jun 2005 | A1 |
| 20050121322 | Say | Jun 2005 | A1 |
| 20050131305 | Danielson et al. | Jun 2005 | A1 |
| 20050133368 | Davies et al. | Jun 2005 | A1 |
| 20050139489 | Davies et al. | Jun 2005 | A1 |
| 20050143635 | Kamath et al. | Jun 2005 | A1 |
| 20050143675 | Neel et al. | Jun 2005 | A1 |
| 20050154271 | Rasdal et al. | Jul 2005 | A1 |
| 20050154272 | Dirac et al. | Jul 2005 | A1 |
| 20050176136 | Burd et al. | Aug 2005 | A1 |
| 20050176678 | Horres et al. | Aug 2005 | A1 |
| 20050177036 | Shults et al. | Aug 2005 | A1 |
| 20050177398 | Watanabe et al. | Aug 2005 | A1 |
| 20050181012 | Saint et al. | Aug 2005 | A1 |
| 20050182451 | Griffin et al. | Aug 2005 | A1 |
| 20050183954 | Hitchcock et al. | Aug 2005 | A1 |
| 20050187720 | Goode et al. | Aug 2005 | A1 |
| 20050192557 | Brauker et al. | Sep 2005 | A1 |
| 20050195930 | Spital et al. | Sep 2005 | A1 |
| 20050197554 | Polcha | Sep 2005 | A1 |
| 20050203360 | Brauker et al. | Sep 2005 | A1 |
| 20050211571 | Schulein et al. | Sep 2005 | A1 |
| 20050215871 | Feldman et al. | Sep 2005 | A1 |
| 20050215872 | Berner et al. | Sep 2005 | A1 |
| 20050239154 | Feldman et al. | Oct 2005 | A1 |
| 20050242479 | Petisce et al. | Nov 2005 | A1 |
| 20050245795 | Goode et al. | Nov 2005 | A1 |
| 20050245799 | Brauker et al. | Nov 2005 | A1 |
| 20050258037 | Hajizadeh et al. | Nov 2005 | A1 |
| 20050261563 | Zhou et al. | Nov 2005 | A1 |
| 20050271546 | Gerber et al. | Dec 2005 | A1 |
| 20050272989 | Shah et al. | Dec 2005 | A1 |
| 20050288596 | Eigler et al. | Dec 2005 | A1 |
| 20060003398 | Heller et al. | Jan 2006 | A1 |
| 20060015020 | Neale et al. | Jan 2006 | A1 |
| 20060015024 | Brister et al. | Jan 2006 | A1 |
| 20060016700 | Brister et al. | Jan 2006 | A1 |
| 20060019327 | Brister et al. | Jan 2006 | A1 |
| 20060020186 | Brister et al. | Jan 2006 | A1 |
| 20060020187 | Brister et al. | Jan 2006 | A1 |
| 20060020188 | Kamath et al. | Jan 2006 | A1 |
| 20060020189 | Brister et al. | Jan 2006 | A1 |
| 20060020190 | Kamath et al. | Jan 2006 | A1 |
| 20060020191 | Brister et al. | Jan 2006 | A1 |
| 20060020192 | Brister et al. | Jan 2006 | A1 |
| 20060036139 | Brister et al. | Feb 2006 | A1 |
| 20060036140 | Brister et al. | Feb 2006 | A1 |
| 20060036141 | Kamath et al. | Feb 2006 | A1 |
| 20060036142 | Brister et al. | Feb 2006 | A1 |
| 20060036143 | Brister et al. | Feb 2006 | A1 |
| 20060036144 | Brister et al. | Feb 2006 | A1 |
| 20060036145 | Brister et al. | Feb 2006 | A1 |
| 20060040402 | Brauker et al. | Feb 2006 | A1 |
| 20060047095 | Pacetti | Mar 2006 | A1 |
| 20060047215 | Newman et al. | Mar 2006 | A1 |
| 20060052745 | Van Antwerp et al. | Mar 2006 | A1 |
| 20060067908 | Ding | Mar 2006 | A1 |
| 20060078908 | Pitner et al. | Apr 2006 | A1 |
| 20060079740 | Silver et al. | Apr 2006 | A1 |
| 20060079809 | Goldberger et al. | Apr 2006 | A1 |
| 20060094946 | Kellogg et al. | May 2006 | A1 |
| 20060100588 | Brunnberg et al. | May 2006 | A1 |
| 20060134165 | Pacetti | Jun 2006 | A1 |
| 20060142651 | Brister et al. | Jun 2006 | A1 |
| 20060155180 | Brister et al. | Jul 2006 | A1 |
| 20060171980 | Helmus et al. | Aug 2006 | A1 |
| 20060173444 | Choy et al. | Aug 2006 | A1 |
| 20060177379 | Asgari | Aug 2006 | A1 |
| 20060183871 | Ward et al. | Aug 2006 | A1 |
| 20060183984 | Dobbles et al. | Aug 2006 | A1 |
| 20060183985 | Brister et al. | Aug 2006 | A1 |
| 20060189856 | Petisce et al. | Aug 2006 | A1 |
| 20060189863 | Peyser et al. | Aug 2006 | A1 |
| 20060195029 | Shults et al. | Aug 2006 | A1 |
| 20060198864 | Shults et al. | Sep 2006 | A1 |
| 20060200019 | Petisce et al. | Sep 2006 | A1 |
| 20060200020 | Brister et al. | Sep 2006 | A1 |
| 20060200022 | Brauker et al. | Sep 2006 | A1 |
| 20060200970 | Brister et al. | Sep 2006 | A1 |
| 20060204536 | Shults et al. | Sep 2006 | A1 |
| 20060211921 | Brauker et al. | Sep 2006 | A1 |
| 20060222566 | Brauker et al. | Oct 2006 | A1 |
| 20060224108 | Brauker et al. | Oct 2006 | A1 |
| 20060224141 | Rush et al. | Oct 2006 | A1 |
| 20060229512 | Petisce et al. | Oct 2006 | A1 |
| 20060235285 | Brister et al. | Oct 2006 | A1 |
| 20060253085 | Geismar et al. | Nov 2006 | A1 |
| 20060258761 | Boock et al. | Nov 2006 | A1 |
| 20060258929 | Goode et al. | Nov 2006 | A1 |
| 20060263839 | Ward et al. | Nov 2006 | A1 |
| 20060269586 | Pacetti | Nov 2006 | A1 |
| 20060270922 | Brauker et al. | Nov 2006 | A1 |
| 20060270923 | Brauker et al. | Nov 2006 | A1 |
| 20060275857 | Kjaer et al. | Dec 2006 | A1 |
| 20060275859 | Kjaer | Dec 2006 | A1 |
| 20060281985 | Ward et al. | Dec 2006 | A1 |
| 20060289307 | Yu et al. | Dec 2006 | A1 |
| 20060293487 | Gaymans et al. | Dec 2006 | A1 |
| 20070007133 | Mang et al. | Jan 2007 | A1 |
| 20070016381 | Kamath et al. | Jan 2007 | A1 |
| 20070017805 | Hodges et al. | Jan 2007 | A1 |
| 20070027384 | Brister et al. | Feb 2007 | A1 |
| 20070027385 | Brister et al. | Feb 2007 | A1 |
| 20070032706 | Kamath et al. | Feb 2007 | A1 |
| 20070032717 | Brister et al. | Feb 2007 | A1 |
| 20070032718 | Shults et al. | Feb 2007 | A1 |
| 20070038044 | Dobbles et al. | Feb 2007 | A1 |
| 20070045902 | Brauker et al. | Mar 2007 | A1 |
| 20070049873 | Hansen et al. | Mar 2007 | A1 |
| 20070066873 | Kamath et al. | Mar 2007 | A1 |
| 20070073129 | Shah et al. | Mar 2007 | A1 |
| 20070085995 | Pesach et al. | Apr 2007 | A1 |
| 20070088208 | Yasuzawa et al. | Apr 2007 | A1 |
| 20070093704 | Brister et al. | Apr 2007 | A1 |
| 20070129524 | Sunkara | Jun 2007 | A1 |
| 20070129619 | Ward et al. | Jun 2007 | A1 |
| 20070129621 | Kellogg et al. | Jun 2007 | A1 |
| 20070135698 | Shah et al. | Jun 2007 | A1 |
| 20070163880 | Woo et al. | Jul 2007 | A1 |
| 20070173709 | Petisce et al. | Jul 2007 | A1 |
| 20070173710 | Petisce et al. | Jul 2007 | A1 |
| 20070173711 | Shah et al. | Jul 2007 | A1 |
| 20070197889 | Brister et al. | Aug 2007 | A1 |
| 20070200254 | Curry | Aug 2007 | A1 |
| 20070200267 | Tsai | Aug 2007 | A1 |
| 20070202672 | Curry | Aug 2007 | A1 |
| 20070203407 | Hoss et al. | Aug 2007 | A1 |
| 20070203410 | Say et al. | Aug 2007 | A1 |
| 20070203966 | Brauker et al. | Aug 2007 | A1 |
| 20070208244 | Brauker et al. | Sep 2007 | A1 |
| 20070208245 | Brauker et al. | Sep 2007 | A1 |
| 20070208246 | Brauker et al. | Sep 2007 | A1 |
| 20070213610 | Say et al. | Sep 2007 | A1 |
| 20070213611 | Simpson | Sep 2007 | A1 |
| 20070215491 | Heller et al. | Sep 2007 | A1 |
| 20070218097 | Heller et al. | Sep 2007 | A1 |
| 20070227907 | Shah et al. | Oct 2007 | A1 |
| 20070232876 | Otto et al. | Oct 2007 | A1 |
| 20070232879 | Brister et al. | Oct 2007 | A1 |
| 20070233013 | Schoenberg | Oct 2007 | A1 |
| 20070235331 | Simpson et al. | Oct 2007 | A1 |
| 20070259217 | Logan | Nov 2007 | A1 |
| 20070275193 | Desimone et al. | Nov 2007 | A1 |
| 20070299385 | Santini, Jr. et al. | Dec 2007 | A1 |
| 20070299409 | Whitbourne et al. | Dec 2007 | A1 |
| 20080021008 | Pacetti et al. | Jan 2008 | A1 |
| 20080021666 | Goode et al. | Jan 2008 | A1 |
| 20080027301 | Ward et al. | Jan 2008 | A1 |
| 20080033254 | Kamath et al. | Feb 2008 | A1 |
| 20080033269 | Zhang | Feb 2008 | A1 |
| 20080034972 | Gough et al. | Feb 2008 | A1 |
| 20080045824 | Tapsak et al. | Feb 2008 | A1 |
| 20080071157 | McGarraugh et al. | Mar 2008 | A1 |
| 20080071158 | McGarraugh et al. | Mar 2008 | A1 |
| 20080072663 | Keenan et al. | Mar 2008 | A1 |
| 20080154101 | Jain et al. | Jun 2008 | A1 |
| 20080183061 | Goode et al. | Jul 2008 | A1 |
| 20080183399 | Goode et al. | Jul 2008 | A1 |
| 20080187655 | Markle et al. | Aug 2008 | A1 |
| 20080188722 | Markle et al. | Aug 2008 | A1 |
| 20080188725 | Markle et al. | Aug 2008 | A1 |
| 20080188731 | Brister et al. | Aug 2008 | A1 |
| 20080189051 | Goode et al. | Aug 2008 | A1 |
| 20080193936 | Squirrell | Aug 2008 | A1 |
| 20080194935 | Brister et al. | Aug 2008 | A1 |
| 20080194936 | Goode et al. | Aug 2008 | A1 |
| 20080194937 | Goode et al. | Aug 2008 | A1 |
| 20080194938 | Brister et al. | Aug 2008 | A1 |
| 20080195967 | Goode et al. | Aug 2008 | A1 |
| 20080208025 | Shults et al. | Aug 2008 | A1 |
| 20080214915 | Brister et al. | Sep 2008 | A1 |
| 20080214918 | Brister et al. | Sep 2008 | A1 |
| 20080242961 | Brister et al. | Oct 2008 | A1 |
| 20080262334 | Dunn et al. | Oct 2008 | A1 |
| 20080262469 | Brister et al. | Oct 2008 | A1 |
| 20080275313 | Brister et al. | Nov 2008 | A1 |
| 20080287764 | Rasdal et al. | Nov 2008 | A1 |
| 20080287765 | Rasdal et al. | Nov 2008 | A1 |
| 20080287766 | Rasdal et al. | Nov 2008 | A1 |
| 20080296155 | Shults et al. | Dec 2008 | A1 |
| 20080305009 | Gamsey et al. | Dec 2008 | A1 |
| 20080305506 | Suri | Dec 2008 | A1 |
| 20080306368 | Goode, Jr. et al. | Dec 2008 | A1 |
| 20080306433 | Cesaroni | Dec 2008 | A1 |
| 20080306434 | Dobbles et al. | Dec 2008 | A1 |
| 20080306435 | Kamath et al. | Dec 2008 | A1 |
| 20080306444 | Brister et al. | Dec 2008 | A1 |
| 20090005666 | Shin et al. | Jan 2009 | A1 |
| 20090012379 | Goode, Jr. et al. | Jan 2009 | A1 |
| 20090018418 | Markle et al. | Jan 2009 | A1 |
| 20090018426 | Markle et al. | Jan 2009 | A1 |
| 20090030297 | Miller et al. | Jan 2009 | A1 |
| 20090036758 | Brauker et al. | Feb 2009 | A1 |
| 20090043181 | Brauker et al. | Feb 2009 | A1 |
| 20090043182 | Brauker et al. | Feb 2009 | A1 |
| 20090043525 | Brauker et al. | Feb 2009 | A1 |
| 20090043541 | Brauker et al. | Feb 2009 | A1 |
| 20090043542 | Brauker et al. | Feb 2009 | A1 |
| 20090045055 | Rhodes et al. | Feb 2009 | A1 |
| 20090061528 | Suri | Mar 2009 | A1 |
| 20090062633 | Brauker et al. | Mar 2009 | A1 |
| 20090062635 | Brauker et al. | Mar 2009 | A1 |
| 20090062645 | Fehre et al. | Mar 2009 | A1 |
| 20090069658 | Say et al. | Mar 2009 | A1 |
| 20090076356 | Simpson | Mar 2009 | A1 |
| 20090076360 | Brister et al. | Mar 2009 | A1 |
| 20090076361 | Kamath et al. | Mar 2009 | A1 |
| 20090081803 | Gamsey et al. | Mar 2009 | A1 |
| 20090099434 | Liu et al. | Apr 2009 | A1 |
| 20090099436 | Brister et al. | Apr 2009 | A1 |
| 20090124877 | Goode, Jr. et al. | May 2009 | A1 |
| 20090124878 | Goode, Jr. et al. | May 2009 | A1 |
| 20090124879 | Brister et al. | May 2009 | A1 |
| 20090143660 | Brister et al. | Jun 2009 | A1 |
| 20090156924 | Shariati et al. | Jun 2009 | A1 |
| 20090177143 | Markle et al. | Jul 2009 | A1 |
| 20090182217 | Li et al. | Jul 2009 | A1 |
| 20090192366 | Mensinger et al. | Jul 2009 | A1 |
| 20090192380 | Shariati et al. | Jul 2009 | A1 |
| 20090192722 | Shariati et al. | Jul 2009 | A1 |
| 20090192724 | Brauker et al. | Jul 2009 | A1 |
| 20090192745 | Kamath et al. | Jul 2009 | A1 |
| 20090192751 | Kamath et al. | Jul 2009 | A1 |
| 20090203981 | Brauker et al. | Aug 2009 | A1 |
| 20090204341 | Brauker et al. | Aug 2009 | A1 |
| 20090216103 | Brister et al. | Aug 2009 | A1 |
| 20090240120 | Mensinger et al. | Sep 2009 | A1 |
| 20090240128 | Mensinger et al. | Sep 2009 | A1 |
| 20090240193 | Mensinger et al. | Sep 2009 | A1 |
| 20090242399 | Kamath et al. | Oct 2009 | A1 |
| 20090242425 | Kamath et al. | Oct 2009 | A1 |
| 20090247857 | Harper et al. | Oct 2009 | A1 |
| 20090264719 | Markle et al. | Oct 2009 | A1 |
| 20090264856 | Lebel et al. | Oct 2009 | A1 |
| 20090287074 | Shults et al. | Nov 2009 | A1 |
| 20090299162 | Brauker et al. | Dec 2009 | A1 |
| 20090299276 | Brauker et al. | Dec 2009 | A1 |
| 20100010324 | Brauker et al. | Jan 2010 | A1 |
| 20100010331 | Brauker et al. | Jan 2010 | A1 |
| 20100010332 | Brauker et al. | Jan 2010 | A1 |
| 20100016687 | Brauker et al. | Jan 2010 | A1 |
| 20100022855 | Brauker et al. | Jan 2010 | A1 |
| 20100030053 | Goode, Jr. et al. | Feb 2010 | A1 |
| 20100030484 | Brauker et al. | Feb 2010 | A1 |
| 20100030485 | Brauker et al. | Feb 2010 | A1 |
| 20100036215 | Goode, Jr. et al. | Feb 2010 | A1 |
| 20100036216 | Goode, Jr. et al. | Feb 2010 | A1 |
| 20100036222 | Goode, Jr. et al. | Feb 2010 | A1 |
| 20100036223 | Goode, Jr. et al. | Feb 2010 | A1 |
| 20100036224 | Goode, Jr. et al. | Feb 2010 | A1 |
| 20100036225 | Goode, Jr. et al. | Feb 2010 | A1 |
| 20100041971 | Goode, Jr. et al. | Feb 2010 | A1 |
| 20100045465 | Brauker et al. | Feb 2010 | A1 |
| 20100049024 | Saint et al. | Feb 2010 | A1 |
| 20100081908 | Dobbles et al. | Apr 2010 | A1 |
| 20100161269 | Kamath et al. | Jun 2010 | A1 |
| 20100174158 | Kamath et al. | Jul 2010 | A1 |
| 20100174167 | Kamath et al. | Jul 2010 | A1 |
| 20100174168 | Goode, Jr. et al. | Jul 2010 | A1 |
| 20100179399 | Goode, Jr. et al. | Jul 2010 | A1 |
| 20100179401 | Rasdal et al. | Jul 2010 | A1 |
| 20100179405 | Goode, Jr. et al. | Jul 2010 | A1 |
| 20100179406 | Goode, Jr. et al. | Jul 2010 | A1 |
| 20100179407 | Goode, Jr. et al. | Jul 2010 | A1 |
| 20100179408 | Kamath et al. | Jul 2010 | A1 |
| 20100179409 | Kamath et al. | Jul 2010 | A1 |
| 20100185065 | Goode, Jr. et al. | Jul 2010 | A1 |
| 20100185070 | Brister et al. | Jul 2010 | A1 |
| 20100185071 | Simpson et al. | Jul 2010 | A1 |
| 20100185072 | Goode, Jr. et al. | Jul 2010 | A1 |
| 20100185073 | Goode, Jr. et al. | Jul 2010 | A1 |
| 20100185074 | Goode, Jr. et al. | Jul 2010 | A1 |
| 20100198035 | Kamath et al. | Aug 2010 | A1 |
| 20100198036 | Kamath et al. | Aug 2010 | A1 |
| 20100204555 | Shults et al. | Aug 2010 | A1 |
| 20100214104 | Goode, Jr. et al. | Aug 2010 | A1 |
| 20100217106 | Goode, Jr. et al. | Aug 2010 | A1 |
| 20100217555 | Kamath et al. | Aug 2010 | A1 |
| 20100234707 | Goode, Jr. et al. | Sep 2010 | A1 |
| 20100234796 | Kamath et al. | Sep 2010 | A1 |
| 20100235106 | Kamath et al. | Sep 2010 | A1 |
| 20100240975 | Goode, Jr. et al. | Sep 2010 | A1 |
| 20100240976 | Goode, Jr. et al. | Sep 2010 | A1 |
| 20100286496 | Simpson et al. | Nov 2010 | A1 |
| 20100331648 | Kamath et al. | Dec 2010 | A1 |
| 20100331655 | Kamath et al. | Dec 2010 | A1 |
| 20110046467 | Simpson et al. | Feb 2011 | A1 |
| 20110118579 | Goode, Jr. et al. | May 2011 | A1 |
| 20110124997 | Goode, Jr. et al. | May 2011 | A1 |
| 20110130970 | Goode, Jr. et al. | Jun 2011 | A1 |
| 20110137601 | Goode, Jr. et al. | Jun 2011 | A1 |
| 20110218414 | Kamath et al. | Sep 2011 | A1 |
| 20110231140 | Goode, Jr. et al. | Sep 2011 | A1 |
| 20110231141 | Goode, Jr. et al. | Sep 2011 | A1 |
| 20110231142 | Goode, Jr. et al. | Sep 2011 | A1 |
| 20110319739 | Kamath et al. | Dec 2011 | A1 |
| 20120226121 | Kamath et al. | Sep 2012 | A1 |
| 20140114159 | Brister et al. | Apr 2014 | A1 |
| 20140128702 | Brister et al. | May 2014 | A1 |
| 20160235348 | Kamath et al. | Aug 2016 | A1 |
| 20170135618 | Brister et al. | May 2017 | A1 |
| 20190110724 | Kamath et al. | Apr 2019 | A1 |
| 20190261907 | Brister et al. | Aug 2019 | A1 |
| 20200029876 | Brister et al. | Jan 2020 | A1 |
| Number | Date | Country |
|---|---|---|
| 2127172 | Jul 1998 | CA |
| 26 58 734 | Jun 1978 | DE |
| 4221848 | Jan 1994 | DE |
| 0 098 592 | Jan 1984 | EP |
| 0107634 | May 1984 | EP |
| 0 127 958 | Dec 1984 | EP |
| 0 284 518 | Sep 1988 | EP |
| 0 286 118 | Oct 1988 | EP |
| 0288793 | Nov 1988 | EP |
| 0 320 109 | Jun 1989 | EP |
| 0352610 | Jan 1990 | EP |
| 0352631 | Jan 1990 | EP |
| 0 353 328 | Feb 1990 | EP |
| 0 390 390 | Oct 1990 | EP |
| 0396788 | Nov 1990 | EP |
| 0406473 | Jan 1991 | EP |
| 0440044 | Aug 1991 | EP |
| 0441252 | Aug 1991 | EP |
| 0441394 | Aug 1991 | EP |
| 0467078 | Jan 1992 | EP |
| 0 476 980 | Mar 1992 | EP |
| 0534074 | Mar 1993 | EP |
| 0539625 | May 1993 | EP |
| 0 563 795 | Oct 1993 | EP |
| 0563796 | Oct 1993 | EP |
| 0323605 | Jan 1994 | EP |
| 0561966 | Oct 1994 | EP |
| 0286118 | Jan 1995 | EP |
| 0647849 | Apr 1995 | EP |
| 0 690 134 | Jan 1996 | EP |
| 0424633 | Jan 1996 | EP |
| 0776628 | Jun 1997 | EP |
| 0817809 | Jan 1998 | EP |
| 0 838 230 | Apr 1998 | EP |
| 0880936 | Dec 1998 | EP |
| 0885932 | Dec 1998 | EP |
| 0967788 | Dec 1999 | EP |
| 1 077 634 | Feb 2001 | EP |
| 1078258 | Feb 2001 | EP |
| 1153571 | Nov 2001 | EP |
| 0817809 | Jul 2002 | EP |
| 0 958 495 | Nov 2002 | EP |
| 1266607 | Dec 2002 | EP |
| 1 785 085 | May 2007 | EP |
| 2223710 | Sep 2010 | EP |
| 2226086 | Sep 2010 | EP |
| 2656423 | Jun 1991 | FR |
| 2760962 | Sep 1998 | FR |
| 1442303 | Jul 1976 | GB |
| 1 556 969 | Dec 1979 | GB |
| 2149918 | Jun 1985 | GB |
| S6258154 | Mar 1987 | JP |
| S6283649 | Apr 1987 | JP |
| S6283849 | Apr 1987 | JP |
| S6367560 | Mar 1988 | JP |
| 02602913 | Jan 1990 | JP |
| 3-293556 | Dec 1991 | JP |
| 2000060826 | Feb 2000 | JP |
| 2002513602 | May 2002 | JP |
| 2002189015 | Jul 2002 | JP |
| 2003108679 | Apr 2003 | JP |
| WO 1987-063242 | Oct 1987 | WO |
| WO 1989-002720 | Apr 1989 | WO |
| WO-9000738 | Jan 1990 | WO |
| WO-9010861 | Sep 1990 | WO |
| WO-9013021 | Nov 1990 | WO |
| WO 1991-009302 | Jun 1991 | WO |
| WO-9207525 | May 1992 | WO |
| WO-9210584 | Jun 1992 | WO |
| WO 1992-013271 | Aug 1992 | WO |
| WO 1993-005701 | Apr 1993 | WO |
| WO 1993-014693 | Aug 1993 | WO |
| WO-9319701 | Oct 1993 | WO |
| WO 1993-023744 | Nov 1993 | WO |
| WO 1993-025898 | Dec 1993 | WO |
| WO 1994-022367 | Oct 1994 | WO |
| WO 1995-002357 | Jan 1995 | WO |
| WO-9507109 | Mar 1995 | WO |
| WO-9601611 | Jan 1996 | WO |
| WO 1996-014026 | May 1996 | WO |
| WO 1996-025089 | Aug 1996 | WO |
| WO-9630431 | Oct 1996 | WO |
| WO-9632076 | Oct 1996 | WO |
| WO-9636296 | Nov 1996 | WO |
| WO 1997-001986 | Jan 1997 | WO |
| WO 1997-006727 | Feb 1997 | WO |
| WO 1997-017884 | May 1997 | WO |
| WO-9728737 | Aug 1997 | WO |
| WO-9743633 | Nov 1997 | WO |
| WO 1998-019159 | May 1998 | WO |
| WO 1998-024358 | Aug 1998 | WO |
| WO 1998-038906 | Sep 1998 | WO |
| WO 1999-056613 | Apr 1999 | WO |
| WO-9948419 | Sep 1999 | WO |
| WO 1999-058051 | Nov 1999 | WO |
| WO 1999-058709 | Nov 1999 | WO |
| WO-9958973 | Nov 1999 | WO |
| WO-9959657 | Nov 1999 | WO |
| WO-0012720 | Mar 2000 | WO |
| WO-0013002 | Mar 2000 | WO |
| WO-0013003 | Mar 2000 | WO |
| WO 2000-019887 | Apr 2000 | WO |
| WO 2000-032098 | Jun 2000 | WO |
| WO 2000-033065 | Jun 2000 | WO |
| WO 2000-049940 | Aug 2000 | WO |
| WO 2000-059373 | Oct 2000 | WO |
| WO 2000-074753 | Dec 2000 | WO |
| WO 2000-079258 | Dec 2000 | WO |
| WO-0078210 | Dec 2000 | WO |
| WO-0112158 | Feb 2001 | WO |
| WO 2001-020019 | Mar 2001 | WO |
| WO-0116579 | Mar 2001 | WO |
| WO-0120334 | Mar 2001 | WO |
| WO-0134243 | May 2001 | WO |
| WO-0143660 | Jun 2001 | WO |
| WO-0152727 | Jul 2001 | WO |
| WO 2001-058348 | Aug 2001 | WO |
| WO-0168901 | Sep 2001 | WO |
| WO-0169222 | Sep 2001 | WO |
| WO 2001-073109 | Oct 2001 | WO |
| WO 2001-088524 | Nov 2001 | WO |
| WO 2001-088534 | Nov 2001 | WO |
| WO-0205702 | Jan 2002 | WO |
| WO-0224065 | Mar 2002 | WO |
| WO-02082989 | Oct 2002 | WO |
| WO-02089666 | Nov 2002 | WO |
| WO-02097414 | Dec 2002 | WO |
| WO-02100266 | Dec 2002 | WO |
| WO 2003-000127 | Jan 2003 | WO |
| WO 2003-012422 | Feb 2003 | WO |
| WO 2003-032411 | Apr 2003 | WO |
| WO 2003-082091 | Sep 2003 | WO |
| WO-03094714 | Nov 2003 | WO |
| WO-03101862 | Dec 2003 | WO |
| WO-2004110256 | Dec 2004 | WO |
| WO 2005-012873 | Feb 2005 | WO |
| WO-2005011489 | Feb 2005 | WO |
| WO 2005-026689 | Mar 2005 | WO |
| WO-2005032400 | Apr 2005 | WO |
| WO 2005-045414 | May 2005 | WO |
| WO-2005044088 | May 2005 | WO |
| WO 2005-057168 | Jun 2005 | WO |
| WO-2005057173 | Jun 2005 | WO |
| WO-2005057175 | Jun 2005 | WO |
| WO-2005078424 | Aug 2005 | WO |
| WO-2005026689 | Oct 2005 | WO |
| WO 2005-122296 | Dec 2005 | WO |
| WO 2006-017358 | Feb 2006 | WO |
| WO-2006050405 | May 2006 | WO |
| WO 2006-105146 | Oct 2006 | WO |
| WO 2006-127694 | Nov 2006 | WO |
| WO-2006118713 | Nov 2006 | WO |
| WO-2006131288 | Dec 2006 | WO |
| WO-2007002209 | Jan 2007 | WO |
| WO-2007002579 | Jan 2007 | WO |
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| WO-2007114943 | Oct 2007 | WO |
| WO-2007127606 | Nov 2007 | WO |
| WO-2007143225 | Dec 2007 | WO |
| WO-2008076868 | Jun 2008 | WO |
| WO 2003-011131 | Feb 2013 | WO |
| Entry |
|---|
| US 7,530,950 B2, 05/2009, Brister et al. (withdrawn) |
| Extended European Search Report for Application No. 06816228.8 dated Oct. 11, 2012, 12 pages. |
| Extended European Search Report for Application No. 14165505.0 dated Jul. 21, 2014, 7 pages. |
| File History of U.S. Appl. No. 12/109,049, filed Apr. 24, 2008, 531 pages. |
| File History of U.S. Appl. No. 12/210,122, filed Sep. 12, 2008, 223 pages. |
| International Search Report and Written Opinion for Application No. PCT/US2006/034284 dated Aug. 17, 2007, 8 pages. |
| Invitation to Pay Additional Fees for for Application No. PCT/US07/080228, dated May 14, 2008, 8 pages. |
| “Raya Systems Pioneers Healthy Video Games,” PlayRight, Nov. 1993, pp. 14-15. |
| Adilman, et al., “Videogames: Knowing The Score, Creative Computing,” Dec. 1983, Dialog: File 148; IAC Trade & Industry Database, vol. 9, p. 224(5) (9 pages). |
| Asberg P., et al., “Hydrogels of a Conducting Conjugated Polymer as 3-D Enzyme Electrode,” Biosensors Bioelectronics, 2003, vol. 19, pp. 199-207. |
| Baker D.A., et al., “Dynamic Concentration Challenges for Biosensor Characterization,” Biosensors & Bioelectronics, vol. 8, 1993, pp. 433-441. |
| Baker D.A., et al., “Dynamic Delay and Maximal Dynamic Error in Continuous Biosensors,” Analytical Chemistry, vol. 68 (8), Apr. 15, 1996, pp. 1292-1297. |
| Bindra D.S., et al., “Pulsed Amperometric Detection of Glucose in Biological Fluids at a Surface-Modified Gold Electrode,” Analytical Chemistry, vol. 61 (22), Nov. 15, 1989, pp. 2566-2570. |
| Bland J.M., et al., “Statistical Methods for Assessing Agreement Between Two Methods of Clinical Measurement,” The Lancet, Feb. 8, 1986, pp. 307-310. |
| Bolinder J., et al., “Microdialysis Measurement of the Absolute Glucose Concentration in Subcutaneous Adipose Tissue Allowing Glucose Monitoring in Diabetic Patients,” Rapid Communication, Diabetologia, vol. 35, 1992, pp. 1177-1180. |
| Bolinder J., et al., “Self-Monitoring of Blood Glucose in Type I Diabetic Patients: Comparison with Continuous Microdialysis Measurements of Glucose in Subcutaneous Adipose Tissue during Ordinary Life Conditions,” Diabetes Care, vol. 20 (1), Jan. 1997, pp. 64-70. |
| Bott A.W., “A Comparison of Cyclic Voltammetry and Cyclic Staircase Voltammetry,” Current Separations, vol. 16 (1), 1997, pp. 23-26. |
| Bott A.W., “Electrochemical Methods for the Determination of Glucose,” Current Separations, vol. 17 (1), 1998, pp. 25-31. |
| Boustead I. (PlasticsEurope), “Tolylene diisocyanate (TDI),” Mar. 2005, 20 pages. |
| Brauker J H., et al., “Neovascularization of Synthetic Membranes Directed by Membrane Microarchitecture,” Journal of Biomedical Material Research, 1995, vol. 29, pp. 1517-1524. |
| Brauker J., “Unraveling Mysteries at the Biointerface: Molecular Mediator of Inhibition of Blood Vessel Formation in the Foreign Body Capsule Revealed,” SurFACTS in Biomaterials, vol. 6 (3), 2001, 2 pages. |
| Brauker, et al., “Sustained Expression of High Levels of Human Factor IX from Human Cells Implanted within an Immunoisolation Device into Athymic Rodents,” Human Gene Therapy, Apr. 10, 1998, vol. 9, pp. 879-888. |
| Bremer T., et al., “Is Blood Glucose Predictable from Previous Values? A Solicitation for Data,” Perspectives in Diabetes, vol. 48, Mar. 1999, pp. 445-451. |
| Brunner G.A., et al., “Validation of Home Blood Glucose Meters with Respect to Clinical and Analytical Approaches,” Diabetes Care, vol. 21(4), Apr. 1998, pp. 585-590. |
| Brunstein E., et al., “Preparation and Validation of Implantable Electrodes for the Measurement of Oxygen and Glucose,” Biomed Biochim. Acta, vol. 48 (11/12), 1989, pp. 911-917. |
| Cameron T., et al., “Micromodular Implants to Provide Electrical Stimulation of Paralyzed Muscles and Limbs,” IEEE Transactions on Biomedical Engineering, vol. 44 (9), Sep. 1997, pp. 781-790. |
| Chatterjee G., et al., “Poly(ether urethane) and Poly(ether urethane urea) Membranes with High H2S/CH4 Selectivity,” Journal of Membrane Science, vol. 135, 1997, pp. 99-106. |
| Chen C., et al., “A Noninterference Polypyrrole Glucose Biosensor,” Biosensors and Bioelectronics, vol. 22, 2006, pp. 639-643. |
| Chen T., et al., “Defining the Period of Recovery of the Glucose Concentration after its Local Perturbation by the Implantation of a Miniature Sensor,” Clinical Chemistry and Laboratory Medicine, vol. 40 (8), 2002, pp. 786-789. |
| Clarke W.L., et al., “Evaluating Clinical Accuracy of Systems for Self Monitoring of Blood Glucose,” Technical Articles, Diabetes Care, vol. 10 (5), Sep.-Oct. 1987, pp. 622-628. |
| Csoregi E., et al., “Amperometric Microbiosensors for Detection of Hydrogen Peroxide and Glucose Based on Peroxidase-Modified Carbon Fibers,” Electroanalysis, vol. 6, 1994, pp. 925-933. |
| Currie J.F., et al., “Novel Non-lntrusive Trans-Dermal Remote Wireless Micro-Fluidic Monitoring System Applied to Continuous Glucose and Lactate Assays for Casualty Care and Combat Readiness Assessment,” RTO HFM Symposium, RTO-MP-HFM-109, Aug. 16-18, 2004, pp. 24-1-24-18. |
| Dai W.S., et al., “Hydrogel Membranes with Mesh Size Asymmetry based on the Gradient Crosslinking of Poly(Vinyl Alcohol),” Journal of Membrane Science, 1999, vol. 156, pp. 67-79. |
| D'Arrigo, et al., “Porous-Si Based Bio Reactors for Glucose Monitoring and Drugs Production,” Proceedings of SPIE, 2003, vol. 4982, pp. 178-184. |
| Deutsch T., et al., “Time Series Analysis and Control of Blood Glucose Levels in Diabetic Patients,” Computer Methods and Programs in Biomedicine, Elsevier Scientific Publishers, vol. 41, 1994, pp. 167-182. |
| Extended European Search Report for Application No. 10163675.1 dated Aug. 3, 2010, 10 pages. |
| Extended European Search Report for Application No. 98908875.2 dated Apr. 29, 2004, 5 pages. |
| Fabietti P.G., et al., “Clinical Validation of a New Control-Oriented Model of Insulin and Glucose Dynamics in Subjects with Type 1 Diabetes,” Diabetes Technology & Therapeutics, vol. 9 (4), 2007, pp. 327-338. |
| File History of U.S. Appl. No. 09/447,227, filed Nov. 22, 1999, 1184 pages. |
| File History of U.S. Appl. No. 10/838,658, filed May 3, 2004, 748 pages. |
| File History of U.S. Appl. No. 10/838,909, filed May 3, 2004, 356 pages. |
| File History of U.S. Appl. No. 10/838,912, filed May 3, 2004, 1288 pages. |
| File History of U.S. Appl. No. 10/885,476, filed Jul. 6, 2004, 226 pages. |
| File History of U.S. Appl. No. 10/896,312, filed Jul. 20, 2004, 237 pages. |
| File History of U.S. Appl. No. 11/004,561, filed Dec. 3, 2004, 390 pages. |
| File History of U.S. Appl. No. 11/157,365, filed Jun. 21, 2005, 977 pages. |
| File History of U.S. Appl. No. 11/543,539, filed Oct. 4, 2006, 368 pages. |
| File History of U.S. Appl. No. 11/543,683, filed Oct. 4, 2006, 368 pages. |
| File History of U.S. Appl. No. 11/543,707, filed Oct. 4, 2006, 380 pages. |
| File History of U.S. Appl. No. 11/543,734, filed Oct. 4, 2008, 412 pages. |
| File History of U.S. Appl. No. 11/692,154, filed Mar. 27, 2007, 528 pages. |
| File History of U.S. Appl. No. 12/098,353, filed Apr. 4, 2008, 526 pages. |
| File History of U.S. Appl. No. 12/111,062, filed Apr. 28, 2008, 553 pages. |
| File History of U.S. Appl. No. 12/133,738, filed Jun. 5, 2008, 630 pages. |
| File History of U.S. Appl. No. 12/133,761, filed Jun. 5, 2008, 658 pages. |
| File History of U.S. Appl. No. 12/133,786, filed Jun. 5, 2008, 890 pages. |
| File History of U.S. Appl. No. 12/264,160, filed Nov. 3, 2008, 630 pages. |
| File History of U.S. Appl. No. 12/335,403, filed Dec. 15, 2008, 742 pages. |
| File History of U.S. Appl. No. 12/536,852, filed Aug. 6, 2009, 532 pages. |
| File History of U.S. Appl. No. 12/579,385, filed Oct. 14, 2009, 558 pages. |
| File History of U.S. Appl. No. 12/619,502, filed Nov. 16, 2009, 293 pages. |
| Freiberger P., “Video Game Takes on Diabetes Superhero ‘Captain Novolin’ Offers Treatment Tips,” Fourth Edition, Jun. 26, 1992, Business Section, 2 pages. |
| Gao S., et al., “Determination of Interfacial Parameters of Cellulose Acetate Membrane Materials by HPLC,” Journal of Liquid Chromatography, 1989, vol. 12(11), pp. 2083-2092. |
| Garg S.K., et al., “Correlation of Fingerstick Blood Glucose Measurements With GlucoWatch Biographer Glucose Results in Young Subjects With Type 1 Diabetes,” Emerging Treatments and Technologies, Diabetes Care, vol. 22 (10), Oct. 1999, pp. 1708-1714. |
| Geller R.I., et al., “Use of an Immunoisolation Device for Cell Transplantation and Tumor Immunotherapy,” Annals of the New York Academy of Science, 1997, vol. 831, pp. 438-451. |
| Gerritsen M., et al., “Influence of Inflammatory Cells and Serum on the Performance of Implantable Glucose Sensors,” Journal of Biomedical Material Research, 2001, vol. 54, pp. 69-75. |
| Gough D.A., “The implantable Glucose Sensor: An Example of Bioengineering Design,” Introduction to Bioengineering, 2001, Chapter 3, pp. 57-66. |
| Gregg B A., et al., “Cross-Linked Redox Gels Containing Glucose Oxidase for Amperometric Biosensor Applications,” Anal Chem, 1990, vol. 62, pp. 258-263. |
| Guo M., et al., “Modification of Cellulose Acetate Ultrafiltration Membrane by Gamma Ray Radiation,” Shuichuli Jishi Bianji Weiyuanhui, 1998, vol. 23(6), pp. 315-318. (Abstract only). |
| Heise T., et al., “Hypoglycemia warning signal and glucose sensors: Requirements and concepts,” Diabetes Technology & Therapeutics, vol. 5, No. 4, 2003, pp. 563-571. |
| International Preliminary Examination Report on for Application No. PCT/US2001/023850 dated Jun. 4, 2003, 3 pages. |
| International Preliminary Report on Patentability for Application No. PCT/US2004/024263 dated Feb. 6, 2006, 5 pages. |
| International Preliminary Report on Patentability for Application No. PCT/US2004/041095 dated Jun. 12, 2006, 4 pages. |
| International Preliminary Report on Patentability for Application No. PCT/US2004/38724 dated Feb. 24, 2009, 4 pages. |
| International Preliminary Report on Patentability for Application No. PCT/US2005/024993 dated Jan. 16, 2007, 7 pages. |
| International Preliminary Report on Patentability for Application No. PCT/US2006/024132 dated Dec. 24, 2007, 6 pages. |
| International Preliminary Report on Patentability for Application No. PCT/US2006/034284 dated Sep. 9, 2008, 6 pages. |
| International Preliminary Report on Patentability for Application No. PCT/US2007/080228 dated Apr. 7, 2009, 11 pages. |
| International Preliminary Report on Patentability for Application No. PCT/US2008/058158 dated Sep. 29, 2009, 9 pages. |
| International Preliminary Report on Patentability for Application No. PCT/US2008/066600 dated Dec. 17, 2009, 6 pages. |
| International Search Report and Written Opinion for Application No. PCT/US2004/024263, dated Nov. 29, 2004, 6 pages. |
| International Search Report and Written Opinion for Application No. PCT/US2004/038724, dated Jan. 9, 2006, 4 pages. |
| International Search Report and Written Opinion for Application No. PCT/US2004/041095, dated Jun. 1, 2005, 5 pages. |
| International Search Report and Written Opinion for Application No. PCT/US2005/024993, dated Nov. 4, 2005, 12 pages. |
| International Search Report and Written Opinion for Application No. PCT/US2006/019889 dated Feb. 20, 2007, 6 pages. |
| International Search Report and Written Opinion for Application No. PCT/US2006/024132 dated Jul. 20, 2007, 6 pages. |
| International Search Report and Written Opinion for Application No. PCT/US2006/031496 dated Sep. 20, 2007, 9 pages. |
| International Search Report and Written Opinion for Application No. PCT/US2007/079220 dated Jul. 1, 2008, 16 pages. |
| International Search Report and Written Opinion for Application No. PCT/US2008/058158 dated Aug. 8, 2008, 10 pages. |
| International Search Report and Written Opinion for Application No. PCT/US2008/066600 dated Oct. 7, 2008, 6 pages. |
| International Search Report for Application No. PCT/US2001/023850 dated Jan. 16, 2002, 3 pages. |
| International Preliminary Report on Patentability for Application No. PCT/US2007/007512, dated Nov. 27, 2008, 15 pages. |
| Invitation to Pay Additional Fees for Application No. PCT/US2007/079220, dated Apr. 25, 2008, 7 pages. |
| Jablecki M., et al., “Simulations of the Frequency Response of Implantable Glucose Sensors,” Analytical Chemistry, vol. 72, 2000, 1853-1859. |
| Jaremko J., et al., “Advances Toward the Implantable Artificial Pancreas for Treatment of Diabetes,” Diabetes Care, vol. 21 (3), Mar. 1998, pp. 444-450. |
| Jeutter D.C., et al., “Design of a Radio-Linked Implantable Cochlear Prosthesis Using Surface Acoustic Wave Devices,” IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control, vol. 40 (5), Sep. 1993, pp. 469-477. |
| Johnson R C., et al., “Abstract: Neovascularization of Cell Transplantation Devices: Role of Membrane Architecture and Encapsulated Tissue,” Abstracts of Papers, American Chemical Society, Sep. 7-11, 1997, 214th ACS National Meeting, Part 2, 305-PMSE, 2 pages. |
| Joung G.B., et al., “An Energy Transmission System for an Artificial Heart Using Leakage Inductance Compensation of Transcutaneous Transformer,” IEEE Transactions on Power Electronics, vol. 13 (6), Nov. 1998, pp. 1013-1022. |
| Kargol M., et al., “Studies on the Structural Properties of Porous Membranes: Measurement of Linear Dimensions of Solutes,” Biophysical Chemistry, 2001, vol. 91, pp. 263-271. |
| Karube I., et al., “Microbiosensors for Acetylcholine and Glucose,” Biosensors & Bioelectronics, 1993, vol. 8, pp. 219-228. |
| Kerner W., “Implantable Glucose Sensors: Present Status and Future Developments,” Experimental and Clinical Endocrinol Diabetes, vol. 109 (2), 2001, pp. S341-S346. |
| Kiechle F.L., “The Impact of Continuous Glucose Monitoring on Hospital Point-of-Care Testing Programs,” Diabetes Technology and Therapeutics, vol. 3 (4), 2001, pp. 647-650. |
| Kovatchev B.P., et al., “Evaluating the Accuracy of Continuous Glucose-Monitoring Sensors: Continuous Glucose-Error Grid Analysis Illustrated by TheraSense Freestyle Navigator Data,” Diabetes Care, vol. 27 (8), Aug. 2004, pp. 1922-1928. |
| Krouwer J.S., “Setting Performance Goals and Evaluating Total Analytical Error for Diagnostic Assays,” Clinical Chemistry, vol. 48 (6), 2002, pp. 919-927. |
| Kurnik R.T., et al., “Application of the Mixtures of Experts Algorithm for Signal Processing in a Noninvasive Glucose Monitoring System,” Sensors and Actuators B, vol. 60, 1999, pp. 19-26. |
| Lacourse W.R., et al., “Optimization of Waveforms for Pulsed Amperometric Detection of Carbohydrates Based on Pulsed Voltammetry,” Analytical Chemistry, vol. 65, 1993, pp. 50-52. |
| Lee E., et al., “Effects of Pore Size, Void Volume and Pore Connectivity on Tissue Responses to Porous Silicone Implants,” Society for Biomaterials, 25th Annual Meeting, 1999, p. 171. |
| Loffler P., et al., “Separation and Determination of Traces of Ammonia in Air by Means of Chromatomembrane Cells,” Fresenius Journal of Analytical Chemistry, 1995, vol. 352, pp. 613-614. |
| Lohn A., et al., “A Knowledge-Based System for Real-Time Validation of Calibrations and Measurements,” Chemometrics and Intelligent Laboratory Systems, vol. 46, 1999, pp. 57-66. |
| Lynch S.M., et al., “Estimation-Based Model Predictive Control of Blood Glucose in Type I Diabetics: A Simulation Study,” Proceedings of the IEEE 27th Annual Northeast Bioengineering Conference, 2001, pp. 79-80. |
| Lynn P.A., “Recursive Digital Filters for Biological Signals,” Med. & Biol. Engineering, vol. 9, 1971, pp. 37-43. |
| Mancy K.H., et al., “A Galvanic Cell Oxygen Analyzer,” Journal of Electroanalytical Chemistry, vol. 4, 1962, pp. 65-92. |
| Martin R.F., “General Deming Regression for Estimating Systematic Bias and its Confidence Interval in Method-Comparison Studies,” Clinical Chemistry, vol. 46 (1), 2000, pp. 100-104. |
| Matsuki H., “Energy Transfer System Utilizing Amorphous Wires For Implantable Medical Devices,” IEEE Transactions on Magnetics, vol. 31 (2), 1994, pp. 1276-1282. |
| Mazzola F., et al., “Video Diabetes: A Teaching Tool for Children with Insulin-Dependent Diabetes,” IEEE, Proceedings 7th Annual Symposium on Computer Applications in Medical Care, Oct. 1983, 1 page Abstract. |
| Merriam-Webster Online Dictionary, Definition of “Nominal” retrieved from http://www.merriam-webster.com/dictionary/nominal, Apr. 23, 2007, 1 page. |
| Metzger M., et al., “Reproducibility of Glucose Measurements using the Glucose Sensor,” Diabetes Care, vol. 25 (6), Jul. 2002, pp. 1185-1191. |
| Miller J.A., et al., “Development of an Autotuned Transcutaneous Energy Transfer System,” ASAIO Journal, vol. 39, 1993, pp. M706-M710. |
| Miller K.M., et al., “Generation of IL-1 like Activity in Response to Biomedical Polymer Implants: a Comparison of in Vitro and in Vivo Models,” Journal of Biomedical Materials Research, vol. 23(9), 1989, pp. 1007-1026. |
| Miller K.M., et al., “Human monocyte/macrophage activation and interleukin 1 generation by biomedical polymers,” Journal of Biomedical Materials Research, vol. 22 (8), 1988, pp. 713-731. |
| Miller K.M., et al., “In Vitro Stimulation of Fibroblast Activity by Factors Generated from Human Monocytes Activated by Biomedical Polymers,” Journal of Biomedical Materials Research, vol. 23(8), 1989, pp. 911-930. |
| Monsod T.P., et al., “Do Sensor Glucose Levels Accurately Predict Plasma Glucose Concentrations During Hypoglycemia And Hyperinsulinemia?,” Diabetes Care, vol. 25 (5), 2002, pp. 889-893. |
| Moussy F., et al., “A Miniaturized Nafion-Based Glucose Sensor: In Vitro and In Vivo Evaluation in Dogs,” International Journals of Artificial Organs, vol. 17 (2), 1994, pp. 88-94. |
| Mowery K.A., et al., “Preparation and Characterization by Hydrophobic Polymeric Films that are Thromboresistant via Nitric Oxide Release,” Biomaterials, 2000, pp. 9-21. |
| Nam Y.S., et al., “A Novel Fabrication Method of Macroporous Biodegradable Polymer Scaffolds Using Gas Foaming Salt as a Porogen Additive,” J Biomed Mater Res, 2000, vol. 53, pp. 1-7. |
| Neuburger G.G., et al., “Pulsed Amperometric Detection of Carbohydrates at Gold Electrodes with a Two-Step Potential Waveform,” Anal. Chern., vol. 59, 1987, pp. 150-154. |
| Nintendo Healthcare, Wired, Dec. 1993, 1 page. |
| Novo Nordisk Pharmaceuticals Inc., “Diabetes Educational Video Game Recognized by Software Publishers Association,” Press Release, Mar. 14, 1994, 4 pages. |
| Office Action for European Application No. 06816228.8, dated Oct. 30, 2013, 3 pages. |
| Office Action for European Application No. 10163675.1, dated Mar. 17, 2011, 5 pages. |
| Office Action for Japanese Application No. 10-538680, dated Nov. 20, 2007, 13 pages. |
| Office Action for Japanese Application No. 2006-522016, dated Jun. 28, 2011, 3 pages. |
| Office Action for U.S. Appl. No. 08/811,473, dated Dec. 7, 1998, 5 pages. |
| Office Action for U.S. Appl. No. 09/489,588, dated Aug. 14, 2001, 4 pages. |
| Office Action for U.S. Appl. No. 09/489,588, dated Feb. 27, 2002, 5 pages. |
| Office Action for U.S. Appl. No. 09/489,588, dated Jun. 12, 2003, 6 pages. |
| Office Action for U.S. Appl. No. 09/636,369, dated Sep. 30, 2002, 4 pages. |
| Office Action for U.S. Appl. No. 09/916,386, dated Apr. 9, 2003, 8 pages. |
| Office Action for U.S. Appl. No. 09/916,711, dated Dec. 23, 2004, 9 pages. |
| Office Action for U.S. Appl. No. 09/916,711, dated Feb. 11, 2004, 5 pages. |
| Office Action for U.S. Appl. No. 09/916,711, dated Feb. 14, 2006, 6 pages. |
| Office Action for U.S. Appl. No. 09/916,711, dated Jul. 1, 2005, 8 pages. |
| Office Action for U.S. Appl. No. 09/916,711, dated Jul. 23, 2004, 6 pages. |
| Office Action for U.S. Appl. No. 09/916,711, dated Sep. 5, 2006, 6 pages. |
| Office Action for U.S. Appl. No. 09/916,711, dated Sep. 24, 2003, 7 pages. |
| Office Action for U.S. Appl. No. 09/916,858, dated Mar. 22, 2004, 11 pages. |
| Office Action for U.S. Appl. No. 09/916,858, dated Sep. 21, 2004, 8 pages. |
| Office Action for U.S. Appl. No. 10/632,537, dated Dec. 21, 2004, 7 pages. |
| Office Action for U.S. Appl. No. 10/632,537, dated Oct. 20, 2004, 7 pages. |
| Office Action for U.S. Appl. No. 10/633,329, dated Apr. 27, 2010, 5 pages. |
| Office Action for U.S. Appl. No. 10/633,329, dated Dec. 18, 2008, 9 pages. |
| Office Action for U.S. Appl. No. 10/633,329, dated Feb. 4, 2008, 7 pages. |
| Office Action for U.S. Appl. No. 10/633,329, dated Jul. 30, 2007, 9 pages. |
| Office Action for U.S. Appl. No. 10/633,329, dated Jun. 11, 2009, 8 pages. |
| Office Action for U.S. Appl. No. 10/633,329, dated Jun. 12, 2008, 7 pages. |
| Office Action for U.S. Appl. No. 10/633,329, dated Mar. 26, 2007, 05 pages. |
| Office Action for U.S. Appl. No. 10/633,329, dated Oct. 5, 2006, 6 pages. |
| Office Action for U.S. Appl. No. 10/633,367, dated Jul. 15, 2008, 8 pages. |
| Office Action for U.S. Appl. No. 10/633,367, dated Jun. 11, 2009, 7 pages. |
| Office Action for U.S. Appl. No. 10/633,404, dated Feb. 12, 2007, 14 pages. |
| Office Action for U.S. Appl. No. 10/646,333, dated Feb. 24, 2006, 6 pages. |
| Office Action for U.S. Appl. No. 10/646,333, dated Jun. 6, 2005, 17 pages. |
| Office Action for U.S. Appl. No. 10/646,333, dated Sep. 22, 2004, 10 pages. |
| Office Action for U.S. Appl. No. 10/647,065, dated Oct. 16, 2006, 6 pages. |
| Office Action for U.S. Appl. No. 10/648,849, dated Jun. 23, 2009, 10 pages. |
| Office Action for U.S. Appl. No. 10/657,843, dated Sep. 21, 2004, 8 pages. |
| Office Action for U.S. Appl. No. 10/789,359, dated Mar. 20, 2008, 7 pages. |
| Office Action for U.S. Appl. No. 10/789,359, dated Nov. 27, 2006, 10 pages. |
| Office Action for U.S. Appl. No. 10/789,359, dated Oct. 3, 2008, 7 pages. |
| Office Action for U.S. Appl. No. 10/842,716, dated Jul. 9, 2010, 8 pages. |
| Office Action for U.S. Appl. No. 10/842,716, dated May 21, 2007, 18 pages. |
| Office Action for U.S. Appl. No. 10/842,716, dated Nov. 17, 2006, 16 pages. |
| Office Action for U.S. Appl. No. 10/896,637, dated Jul. 20, 2009, 14 pages. |
| Office Action for U.S. Appl. No. 10/896,637, dated Mar. 5, 2009, 10 pages. |
| Office Action for U.S. Appl. No. 10/896,637, dated Oct. 8, 2008, 17 pages. |
| Office Action for U.S. Appl. No. 10/896,772, dated Dec. 14, 2005, 10 pages. |
| Office Action for U.S. Appl. No. 10/896,772, dated Jan. 11, 2005, 16 pages. |
| Office Action for U.S. Appl. No. 10/896,772, dated Jul. 19, 2005, 17 pages. |
| Office Action for U.S. Appl. No. 10/896,772, dated May 22, 2006, 31 pages. |
| Office Action for U.S. Appl. No. 10/897,312, dated Feb. 9, 2006, 31 pages. |
| Office Action for U.S. Appl. No. 10/897,377, dated May 11, 2006, 20 pages. |
| Office Action for U.S. Appl. No. 10/897,377, dated Oct. 18, 2005, 27 pages. |
| Office Action for U.S. Appl. No. 10/991,353 dated Mar. 4, 2009, 7 pages. |
| Office Action for U.S. Appl. No. 10/991,353 dated Sep. 12, 2008, 9 pages. |
| Office Action for U.S. Appl. No. 10/991,966, dated Jul. 22, 2008, 12 pages. |
| Office Action for U.S. Appl. No. 10/991,966, dated Nov. 28, 2007, 13 pages. |
| Office Action for U.S. Appl. No. 11/007,635, dated Jan. 27, 2006, 9 pages. |
| Office Action for U.S. Appl. No. 11/007,920, dated Jun. 24, 2008, 10 pages. |
| Office Action for U.S. Appl. No. 11/021,046, dated Aug. 19, 2009, 6 pages. |
| Office Action for U.S. Appl. No. 11/021,046, dated Dec. 26, 2007, 6 pages. |
| Office Action for U.S. Appl. No. 11/021,046, dated Feb. 4, 2009, 7 pages. |
| Office Action for U.S. Appl. No. 11/021,046, dated Jun. 23, 2008, 6 pages. |
| Office Action for U.S. Appl. No. 11/021,162, dated Jun. 19, 2008, 8 pages. |
| Office Action for U.S. Appl. No. 11/034,343, dated Dec. 30, 2008, 4 pages. |
| Office Action for U.S. Appl. No. 11/034,343, dated Jul. 10, 2008, 6 pages. |
| Office Action for U.S. Appl. No. 11/034,343, dated Nov. 1, 2007, 5 pages. |
| Office Action for U.S. Appl. No. 11/034,344, dated Jan. 15, 2008, 5 pages. |
| Office Action for U.S. Appl. No. 11/038,340, dated Feb. 2, 2010, 18 pages. |
| Office Action for U.S. Appl. No. 11/038,340, dated Jan. 5, 2009, 13 pages. |
| Office Action for U.S. Appl. No. 11/038,340, dated Jun. 7, 2010, 18 pages. |
| Office Action for U.S. Appl. No. 11/038,340, dated Jun. 17, 2008, 11 pages. |
| Office Action for U.S. Appl. No. 11/038,340, dated May 19, 2009, 14 pages. |
| Office Action for U.S. Appl. No. 11/038,340, dated Nov. 9, 2009, 16 pages. |
| Office Action for U.S. Appl. No. 11/039,269, dated Aug. 14, 2006, 9 pages. |
| Office Action for U.S. Appl. No. 11/039,269, dated Feb. 24, 2006, 7 pages. |
| Office Action for U.S. Appl. No. 11/039,269, dated May 4, 2005, 06 pages. |
| Office Action for U.S. Appl. No. 11/039,269, dated Nov. 2, 2005, 5 pages. |
| Office Action for U.S. Appl. No. 11/055,779, dated May 23, 2007, 13 pages. |
| Office Action for U.S. Appl. No. 11/055,779, dated Oct. 24, 2007, 15 pages. |
| Office Action for U.S. Appl. No. 11/077,643, dated Apr. 21, 2008, 15 pages. |
| Office Action for U.S. Appl. No. 11/077,643, dated Mar. 11, 2009, 7 pages. |
| Office Action for U.S. Appl. No. 11/077,643, dated Oct. 1, 2008, 13 pages. |
| Office Action for U.S. Appl. No. 11/077,714, dated Apr. 10, 2007, 16 pages. |
| Office Action for U.S. Appl. No. 11/077,714, dated Apr. 16, 2009, 12 pages. |
| Office Action for U.S. Appl. No. 11/077,714, dated Dec. 31, 2009, 8 pages. |
| Office Action for U.S. Appl. No. 11/077,714, dated Jan. 10, 2008, 18 pages. |
| Office Action for U.S. Appl. No. 11/077,714, dated Jan. 27, 2010, 9 pages. |
| Office Action for U.S. Appl. No. 11/077,714, dated Jul. 27, 2007, 13 pages. |
| Office Action for U.S. Appl. No. 11/077,714, dated Oct. 11, 2006, 9 pages. |
| Office Action for U.S. Appl. No. 11/077,714, dated Sep. 16, 2008, 16 pages. |
| Office Action for U.S. Appl. No. 11/077,715, dated Apr. 10, 2007, 14 pages. |
| Office Action for U.S. Appl. No. 11/077,715, dated Jan. 28, 2008, 12 pages. |
| Office Action for U.S. Appl. No. 11/077,715, dated Jul. 26, 2007, 9 pages. |
| Office Action for U.S. Appl. No. 11/077,715, dated May 12, 2008, 13 pages. |
| Office Action for U.S. Appl. No. 11/077,715, dated Nov. 12, 2008, 15 pages. |
| Office Action for U.S. Appl. No. 11/077,715, dated Oct. 31, 2006, 12 pages. |
| Office Action for U.S. Appl. No. 11/077,739, dated Dec. 29, 2009, 9 pages. |
| Office Action for U.S. Appl. No. 11/077,739, dated Jul. 21, 2009, 8 pages. |
| Office Action for U.S. Appl. No. 11/077,739, dated Mar. 1, 2010, 9 pages. |
| Office Action for U.S. Appl. No. 11/077,740, dated Apr. 28, 2009, 27 pages. |
| Office Action for U.S. Appl. No. 11/077,740, dated Feb. 7, 2008, 16 pages. |
| Office Action for U.S. Appl. No. 11/077,740, dated Jul. 25, 2008, 24 pages. |
| Office Action for U.S. Appl. No. 11/077,740, dated Jun. 1, 2007, 14 pages. |
| Office Action for U.S. Appl. No. 11/077,740, dated Nov. 1, 2007, 13 pages. |
| Office Action for U.S. Appl. No. 11/077,759, dated Jul. 10, 2008, 10 pages. |
| Office Action for U.S. Appl. No. 11/077,759, dated Mar. 31, 2008, 16 pages. |
| Office Action for U.S. Appl. No. 11/077,759, dated May 17, 2007, 13 pages. |
| Office Action for U.S. Appl. No. 11/077,759, dated May 26, 2009, 8 pages. |
| Office Action for U.S. Appl. No. 11/077,763, dated Jan. 30, 2007, 12 pages. |
| Office Action for U.S. Appl. No. 11/077,765, dated Dec. 31, 2007, 10 pages. |
| Office Action for U.S. Appl. No. 11/077,765, dated Feb. 3, 2010, 10 pages. |
| Office Action for U.S. Appl. No. 11/077,765, dated Jan. 23, 2009, 11 pages. |
| Office Action for U.S. Appl. No. 11/077,765, dated May 16, 2008, 9 pages. |
| Office Action for U.S. Appl. No. 11/077,765, dated Sep. 19, 2008, 9 pages. |
| Office Action for U.S. Appl. No. 11/077,883, dated Apr. 6, 2009, 10 pages. |
| Office Action for U.S. Appl. No. 11/077,883, dated Jun. 24, 2008, 28 pages. |
| Office Action for U.S. Appl. No. 11/077,883, dated Nov. 12, 2009, 8 pages. |
| Office Action for U.S. Appl. No. 11/077,883, dated Oct. 9, 2007, 16 pages. |
| Office Action for U.S. Appl. No. 11/077,883, dated Sep. 18, 2008, 23 pages. |
| Office Action for U.S. Appl. No. 11/078,072, dated Feb. 18, 2010, 6 pages. |
| Office Action for U.S. Appl. No. 11/078,072, dated Sep. 2, 2009, 13 pages. |
| Office Action for U.S. Appl. No. 11/078,230, dated Jan. 26, 2009, 7 pages. |
| Office Action for U.S. Appl. No. 11/078,230, dated Jun. 30, 2008, 9 pages. |
| Office Action for U.S. Appl. No. 11/078,230, dated Sep. 5, 2008, 7 pages. |
| Office Action for U.S. Appl. No. 11/078,230, dated Sep. 18, 2007, 9 pages. |
| Office Action for U.S. Appl. No. 11/078,232, dated Jan. 5, 2010, 15 pages. |
| Office Action for U.S. Appl. No. 11/078,232, dated Jul. 21, 2009, 13 pages. |
| Office Action for U.S. Appl. No. 11/078,232, dated Mar. 5, 2009, 14 pages. |
| Office Action for U.S. Appl. No. 11/078,232, dated May 5, 2008, 21 pages. |
| Office Action for U.S. Appl. No. 11/078,232, dated Nov. 12, 2008, 28 pages. |
| Office Action for U.S. Appl. No. 11/157,746, dated Jan. 3, 2008, 9 pages. |
| Office Action for U.S. Appl. No. 11/157,746, dated May 1, 2008, 8 pages. |
| Office Action for U.S. Appl. No. 11/280,672, dated Oct. 29, 2009, 19 pages. |
| Office Action for U.S. Appl. No. 11/333,837, dated Jun. 29, 2009, 13 pages. |
| Office Action for U.S. Appl. No. 11/333,837, dated Nov. 28, 2008, 11 pages. |
| Office Action for U.S. Appl. No. 11/334,876, dated Aug. 25, 2009, 18 pages. |
| Office Action for U.S. Appl. No. 11/334,876, dated Aug. 26, 2008, 8 pages. |
| Office Action for U.S. Appl. No. 11/334,876, dated May 2, 2008, 18 pages. |
| Office Action for U.S. Appl. No. 11/334,876, dated Oct. 4, 2006, 9 pages. |
| Office Action for U.S. Appl. No. 11/334,876, dated Sep. 25, 2007, 14 pages. |
| Office Action for U.S. Appl. No. 11/360,250, dated Jun. 15, 2009, 11 pages. |
| Office Action for U.S. Appl. No. 11/360,250, dated Mar. 5, 2010, 9 pages. |
| Office Action for U.S. Appl. No. 11/360,250, dated Nov. 20, 2009, 10 pages. |
| Office Action for U.S. Appl. No. 11/360,250, dated Nov. 28, 2008, 8 pages. |
| Office Action for U.S. Appl. No. 11/360,252, dated Jan. 29, 2009, 15 pages. |
| Office Action for U.S. Appl. No. 11/360,252, dated Jul. 23, 2009, 10 pages. |
| Office Action for U.S. Appl. No. 11/360,252, dated Jun. 30, 2008, 10 pages. |
| Office Action for U.S. Appl. No. 11/360,299, dated Aug. 21, 2009, 18 pages. |
| Office Action for U.S. Appl. No. 11/360,819, dated Apr. 7, 2010, 10 pages. |
| Office Action for U.S. Appl. No. 11/360,819, dated Aug. 11, 2008, 10 pages. |
| Office Action for U.S. Appl. No. 11/360,819, dated Dec. 26, 2008, 12 pages. |
| Office Action for U.S. Appl. No. 11/360,819, dated Oct. 29, 2009, 15 pages. |
| Office Action for U.S. Appl. No. 11/360,819, dated Sep. 2, 2010, 8 pages. |
| Office Action for U.S. Appl. No. 11/373,628, dated Aug. 10, 2010, 10 pages. |
| Office Action for U.S. Appl. No. 11/439,630, dated Feb. 23, 2009, 13 pages. |
| Office Action for U.S. Appl. No. 11/439,630, dated Jan. 22, 2010, 10 pages. |
| Office Action for U.S. Appl. No. 11/439,630, dated Sep. 2, 2009, 15 pages. |
| Office Action for U.S. Appl. No. 11/439,630, dated Sep. 18, 2008, 15 pages. |
| Office Action for U.S. Appl. No. 11/691,424, dated Sep. 25, 2008, 15 pages. |
| Office Action for U.S. Appl. No. 11/691,432, dated Sep. 19, 2008, 11 pages. |
| Office Action for U.S. Appl. No. 11/691,466, dated Oct. 3, 2008, 15 pages. |
| Office Action for U.S. Appl. No. 12/055,098, dated Oct. 5, 2010, 12 pages. |
| Office Action for U.S. Appl. No. 12/098,359, dated Jul. 7, 2010, 18 pages. |
| Office Action for U.S. Appl. No. 12/102,654, dated Jul. 30, 2009, 9 pages. |
| Office Action for U.S. Appl. No. 12/102,654, dated Mar. 10, 2010, 6 pages. |
| Office Action for U.S. Appl. No. 12/102,729, dated Jul. 7, 2009, 7 pages. |
| Office Action for U.S. Appl. No. 12/102,745, dated Dec. 23, 2008, 4 pages. |
| Office Action for U.S. Appl. No. 12/113,508, dated Feb. 23, 2010, 9 pages. |
| Office Action for U.S. Appl. No. 12/139,305, dated Jan. 13, 2010, 12 pages. |
| Office Action for U.S. Appl. No. 12/182,008, dated Aug. 24, 2010, 15 pages. |
| Office Action for U.S. Appl. No. 12/182,073, dated Jun. 28, 2010, 20 pages. |
| Office Action for U.S. Appl. No. 12/182,083, dated Jun. 24, 2010, 8 pages. |
| Office Action for U.S. Appl. No. 12/353,787, dated Aug. 6, 2010, 6 pages. |
| Office Action for U.S. Appl. No. 12/353,799, dated Aug. 6, 2010, 8 pages. |
| Office Action for U.S. Appl. No. 12/364,786, dated Jul. 29, 2010, 6 pages. |
| Office Action for U.S. Appl. No. 95/001,038, dated Jun. 17, 2008, 32 pages. |
| Office Action for U.S. Appl. No. 95/001,038, dated May 28, 2010, 32 pages. |
| Office Action for U.S. Appl. No. 95/001,039, dated May 29, 2008, 21 pages. |
| Office Action from European Patent Application No. 05771646.6, dated Aug. 16, 2011, 3 pages. |
| Office Action from European Patent Application No. 05771646.6, dated Aug. 19, 2009, 4 pages. |
| Office Action from European Patent Application No. 05771646.6, dated Jun. 2, 2010, 5 pages. |
| Office Action from Japanese Patent Application No. 2006-522016 dated Aug. 31, 2010, 6 pages. |
| Oxford English Dictionary Online, Definition of “Impending,” http://www.askoxford.com/results/?view=devdict&field-12668446_Impending&branch=, Jan. 11, 2010, 1 page. |
| Panetti T.S., “Differential Effects of Sphingosine 1-Phosphate and Lysophosphatidic Acid on Endothelial Cells,” Biochimica et Biophysica Acta, vol. 1582, 2002, pp. 190-196. |
| Panteleon A.E., et al., “The Role of the Independent Variable to Glucose Sensor Calibration,” Diabetes Technology & Therapeutics, vol. 5 (3), 2003, pp. 401-410. |
| Parker R.S., et al., “A Model-Based Algorithm for Blood Glucose Control In Type I Diabetic Patients,” IEEE Trans Biomed Engg (BME), vol. 46(2), 1999, pp. 148-157. |
| Phillips R.P., “A High Capacity Transcutaneous Energy Transmission System,” ASIAO Journal, vol. 41, 1995, pp. M259-M262. |
| Pickup J.C., et al., “Responses and Calibration of Amperometric Glucose Sensors Implanted in the Subcutaneous Tissue of Man,” ACTA Diabetol, vol. 30, 1993, pp. 143-148. |
| Pineda L.M., et al., “Bone Regeneration with Resorbable Polymeric Membranes. III. Effect of Poly(L-lactide) Membrane Pore Size on the Bone Healing Process in Large Defects,” Journal of Biomedical Materials Research, vol. 31, 1996, pp. 385-394. |
| Poirier J.Y., et al., “Clinical and Statistical Evaluation of Self-Monitoring Blood Glucose Meters,” Diabetes Care, vol. 21 (11), Nov. 1998, pp. 1919-1924. |
| Ratner B.D., “Reducing Capsular Thickness and Enhancing Angiogenesis around Implant Drug Release Systems,” Journal of Controlled Release, vol. 78, 2002, pp. 211-218. |
| Rebrin K., et al., “Subcutaneous Glucose Predicts Plasma Glucose Independent of Insulin: Implications for Continuous Monitoring,” The American Physiological Society, vol. 277, 1999, pp. E561-E571. |
| Rinken T., et al., “Calibration of Glucose Biosensors By Using Pre-Steady State Kinetic Data,” Biosensors & Bioelectronics, vol. 13, 1998, pp. 801-807. |
| Roche Diagnostics GmbH Grounds of Opposition dated Apr. 14, 2011 against EP 1711802 (04813255.9), issued Jul. 14, 2010. |
| San Diego Plastics Inc, “Polyethylene,” Datasheet, Retrieved from http://www.sdplastics.com/polyeth.html on Aug. 19, 2009, 7 pages. |
| Schmidt F.J., et al., “Calibration of a Wearable Glucose Sensor,” The International Journal of Artificial Organs, vol. 15 (1), 1992, pp. 55-61. |
| Schmidtke D.W., et al., “Accuracy of the One-Point in Vivo Calibration of “Wired” Glucose Oxidase Electrodes Implanted in Jugular Veins of Rats in Periods of Rapid Rise and Decline of the Glucose Concentration,” Analytical Chemistry, vol. 70 (10), May 15, 1998, pp. 2149-2155. |
| Sieminski, et al., “Biomaterial-Microvasculature Interactions,” Biomaterials, 2000, vol. 21, pp. 2233-2241. |
| Sigma-Aldrich Corp “Nation® 117 Solution Product Description, Product No. 70160,” retrieved from https//:www.sigmaaldrich.com/cgi-bin/hsrun/Suite7/Suite/HAHTpage/Suite.HsExternalProd on Apr. 7, 2005, 1 page. |
| Sigma-Aldrich Corp., “Cellulose Acetate,” Product Description, Product No. 419028, St. Louis, MO, 2005, 1 page. |
| Smith B., et al., “An Externally Powered, Multichannel, Implantable Stimulator-Telemeter for Control of Paralyzed Muscle,” IEEE Transactions on Biomedical Engineering, vol. 45 (4), Apr. 1998, pp. 463-475. |
| Sokolov S., et al., “Metrological Opportunities of the Dynamic Mode of Operating an Enzyme Amperometric Biosensor,” Medical Engineering & Physics, vol. 17 (6), 1995, pp. 471-476. |
| Sparacino G., et al., “Continuous Glucose Monitoring Time Series and Hypo-Hyperglycemia Prevention: Requirements, Methods, Open Problems,” Current Diabetes Reviews, vol. 4 (3), 2008, pp. 181-192. |
| Sproule B.A., et al., “Fuzzy Pharmacology: Theory and Applications,” Trends in Pharmacological Sciences, vol. 23 (9), Sep. 2002, pp. 412-417. |
| Sternberg F., et al., “Does Fall in Tissue Glucose Precede Fall in Blood Glucose?,” Diabetologia, vol. 39, 1996, pp. 609-612. |
| Street J.O., et al., “A Note on Computing Robust Regression Estimates Via Iteratively Reweighted Least Squares,” The American Statistician, vol. 42 (2), May 1988, pp. 152-154. |
| Supplementary European Search Report for Application No. 04812899.5 dated May 29, 2008, 3 pages. |
| Tamura T., et al., “Preliminary Study of Continuous Glucose Monitoring with a Microdialysis Technique and a Null Method—A Numerical Analysis,” Frontiers of Medical & Biological Engineering, vol. 10 (2), 2000, pp. 147-156. |
| Tang, et al., “Fibrin(ogen) Mediates Acute Inflammatory Responses to Biomaterials,” J.Exp.Med, 1993, vol. 178, pp. 2147-2156. |
| Tang, et al., “Inflammatory Responses to Biomaterials,” Am J Clin Pathol, 1995, vol. 103, pp. 466-471. |
| Tang, et al., “Mast Cells Mediate Acute Inflammatory Responses to Implanted Biomaterials,” Proceedings of the National Academy of Sciences of the USA, 1998, vol. 95, pp. 8841-8846. |
| Tang, et al., “Molecular Determinants of Acute Inflammatory Responses to Biomaterials,” J Clin Invest, 1996, vol. 97, pp. 1329-1334. |
| Thijssen P.C.,“A Kalman Filter for Calibration, Evaluation of Unknown Samples and Quality Control in Drifting Systems,” Part 2,Optimal Designs, Analytica chimica Acta, vol. 162, 1984, pp. 253-262. |
| Thijssen, et al., “A Kalman Filter for Calibration, Evaluation of Unknown Samples and Quality Control in Drifting Systems,” Part 1,Theory and Simulations, Analytica chimica Acta, 1984, vol. 156, pp. 87-101. |
| Thijssen, et al., “A Kalman Filter for Calibration, Evaluation of Unknown Samples and Quality Control in Drifting Systems,” Part 3,Variance Reduction ,Analytica chimica Acta, 1985, vol. 173, pp. 265-272. |
| Thijssen, et al., “A Kalman Filter for Calibration, Evaluation of Unknown Samples and Quality Control in Drifting Systems,” Part 4,Flow Injection Analysis, Analytica chimica Acta, 1985, vol. 174, pp. 27-40. |
| Tibell, et al., “Survival of Macroencapsulated Allogeneic Parathyroid Tissue One Year after Transplantation in Nonimmunosuppressed Humans,” Cell Transplantation, 2001, vol. 10, pp. 591-599. |
| Tilbury J.B., et al., “Receiver Operating Characteristic Analysis for Intelligent Medical Systems—A New Approach for Finding Confidence Intervals,” IEEE Transactions on Biomedical Engineering, vol. 47 (7), Jul. 2000, pp. 952-963. |
| Trajanoski Z., et al., “Neural Predictive Controller For Insulin Delivery Using The Subcutaneous Route,” IEEE Transactions on Biomedical Engineering, vol. 45(9), 1998, pp. 1122-1134. |
| Valdes T.I., et al., “In Vitro and In Vivo Degradation of Glucose Oxidase Enzyme used for an Implantable Glucose Biosensor,” Diabetes Technology & Therapeutics, vol. 2 (3), 2000, pp. 367-376. |
| Wade L.G., “Reactions of Aromatic Compounds,” Organic Chemistry, Chapter 17, 5th edition, 2003, pp. 762-763. |
| Wilkins E., et al., “Glucose Monitoring: State of the Art and Future Possibilities,” Med. Eng. Phys., vol. 18 (4), 1996, pp. 273-288. |
| Zavalkoff S.R., et al., “Evaluation Of Conventional Blood Glucose Monitoring as An Indicator of Integrated Glucose Values Using a Continuous Subcutaneous Sensor,” Diabetes Care, vol. 25(9), 2002, pp. 1603-1606. |
| Zhu, et al., “Planar Amperometric Glucose Sensor Based on Glucose Oxidase Immobilized by Chitosan Film on Prussian blue Layer,” Sensors, 2002, vol. 2, pp. 127-136. |
| Ziaie, et al., “A Single-Channel Implantable Microstimulator for Functional Neuromuscular Stimulation,” IEEE Transactions on Biomedical Engineering, 1997, vol. 44(10), pp. 909-920. |
| Aalders et al. 1991. Development of a wearable glucose sensor; studies in healthy volunteers and in diabetic patients. The International Journal of Artificial Organs 14(2):102-108. |
| Abe et al. 1992. Characterization of glucose microsensors for intracellular measurements. Analytical Chemistry 64(18):2160-2163. |
| Abel et al. 1984. Experience with an implantable glucose sensor as a prerequisite of an artificial beta cell. Biomed Biochim Acta 43(5):577-584. |
| Abel et al. 2002. Biosensors for in vivo glucose measurement: can we cross the experimental stage. Biosensors & Bioelectronics 17:1059-1070. |
| Alcock & Turner,1994. Continuous Analyte Monitoring to Aid Clinical Practice. IEEE Engineering in Med & Biol Mag 13:319-325. |
| American Heritage Dictionary, 4th Edition. 2000. Houghton Mifflin Company, p. 82. |
| Amin et al. 2003. Hypoglycemia prevalence in prepubertal children with type 1 diabetes on standard insulin regimen: Use of continuous glucose monitoring system. Diabetes Care 26(3):662-667. |
| Answers.com. “xenogenic.” The American Heritage Stedman's Medical Dictionary. Houghton Mifflin Company, 2002. Answers.com Nov. 7, 2006 http://www.Answers.com/topic/xenogenic. |
| Armour et al., Dec. 1990. Application of Chronic Intravascular Blood Glucose Sensor in Dogs. Diabetes 39:1519-1526. |
| Assolant-Vinet et al. 1986. New Immohlized Enzyme Membranes for Tailor-Made Biosensors. Anal Letters 19(7&8): 875-885.. |
| Atanasov et al. 1997. Implantation of a refillable glucose monitoring-telemetry device. Biosensors & Bioelectronics 12:669-680. |
| Atanasov et al. 1994. Biosensor for continuous glucose monitoring. Biotechnology and Bioengineering 43:262-266. |
| Aussedat et al. 1997. A user-friendly method for calibrating a subcutaneous glucose sensor-based hypoglycaemic alarm. Biosensors & Bioelectronics 12( 11):1061-1071. |
| Bailey et al. 2007. Reduction in hemoglobin A1c with real-time continuous glucose monitoring: results from a 12-week observational study. Diabetes Technology & Therapeutics 9(3):203-210. |
| Bani Amer, M. M. 2002. An accurate amperometric glucose sensor based glucometer with eliminated cross-sensitivity. J Med Eng Technol 26(5):208-213. |
| Bard et al. (Eds.) 1980. Electrochemical Methods: Fundamentals and Applications. John Wiley & Sons, New York, New York, pp. 173-175. |
| Bardeletti et al. 1986. A Reliable L-Lactate Electrode with a New Membrane for Enzyme Immobilization for Amperometric Assay of Lactate. Anal Chimica Acta 187:47-54. |
| Beach et al. 1999. Subminiature implantable potentiostat and modified commercial telemetry device for remote glucose monitoring. IEEE Trans Instrumentation and Measurement 48(6):1239-1245. |
| Bellucci et al. Jan. 1986. Electrochemical behaviour of graphite-epoxy composite materials (GECM) in aqueous salt solutions. J Applied Electrochemistry 16(1):15-22. |
| Bertrand et al. 1981. Multipurpose Electrode with Different Enzyme Systems Bound to Collagen Films. Anal Chimica Acta 126: 23-34. |
| Bessman et al. 1973. Progress toward a glucose sensor for the artificial pancreas. Proceedings of a Workshop on Ion-Selective Microelectrodes, Jun. 4-5, 1973, Boston, MA, pp. 189-197. |
| Biermann et al. 2008. would patients behave if they were continually informed of their blood glucose levels? A simulation study using a “virtual” patient. Diabetes Technology & Therapeutics 10:178-187. |
| Bindra et al. 1991. Design and In Vitro Studies of a Needle-Type Glucose Sensor for Subcutaneous Monitoring. Analytical Chemistry 63:1692-1696. |
| Bisenberger et al. 1995. A triple-step potential waveform at enzyme multisensors with thick-film gold electrodes for detection of glucose and sucrose. Sensors and Actuators B 28:181-189. |
| Bland et al. 1990. A note on the use of the intraclass correlation coefficient in the evaluation of agreement between two methods of measurement. Comput Biol Med 20(5):337-340. |
| Bobbioni-Harsch et al. 1993. Lifespan of subcutaneous glucose sensors and their performances during dynamic glycaemia changes in rats. J Biomed Eng 15:457-463. |
| Bode et al. 1999. Continuous glucose monitoring used to adjust diabetes therapy improves glycosylated hemoglobin: A pilot study. Diabetes Research and Clinical Practice 46:183-190. |
| Bode et al. 2000. U sing the continuous glucose monitoring system to improve the management of type 1 diabetes. Diabetes Technology & Therapeutics 2(Suppl 1):S43-S48. |
| Bode, B. W. 2000. Clinical utility of the continuous glucose monitoring system, Diabetes Technology & Therapeutics 2(Suppl 1):S35-S41. |
| Boedeker Plastics, Inc. 2009. Polyethylene Specifications Data Sheet, http://www.boedeker.com/polye_p.htm [Aug. 19, 2009 3:36:33 PM]. |
| Boland et al. 2001. Limitations of conventional methods of self-monitoring of blood glucose. Diabetes Care 24(11):1858-1862. |
| Bowman, L.; Meindl, J. D., 1986. The packaging of implantable integrated sensors. IEEE Trans Biomed Eng (BME) 33(2):248-255. |
| Brauker et al., Jun. 27, 1996. Local Inflammatory Response Around Diffusion Chambers Containing Xenografts. Transplantation 61(12):1671-1677. |
| Braunwald, 2008. Biomarkers in heart failure. NEJM 368:2148-2159. |
| Bremer et al. 2001. Benchmark data from the literature for evaluation of new glucose sensing technologies. Diabetes Technology & Therapeutics 3(3):409-418. |
| Brooks, et al. 1987/88. Development of an on-line glucose sensor for fermentation monitoring. Biosensors 3:45-56. |
| Bruckel et al. 1989. In vivo measurement of subcutaneous glucose concentrations with an enzymatic glucose sensor and a wick method. Kiln Wochenschr 67:491-495. |
| Burmeister et al. 2001. Self-Referencing Ceramic-Based Multisite Microelectrodes for the Detection and Elimination of Interferences from the Measurement of L-Glutamate and Other Analytes. Analytical Chemistry 73:1037-1042. |
| Cai et al. 2004. A wireless, remote query glucose biosensor based on a pH-sensitive polymer. Analytical Chemistry 76(4):4038-4043. |
| Campanella et al. 1993. Biosensor for direct determination of glucose and lactate in undiluted biological fluids. Biosensors & Bioelectronics 8:307-314. |
| Candas et al 1994. An adaptive plasma glucose controller based on a nonlinear insulin/glucose model. IEEE Trans Biomed Eng (BME) 41(2):116-124. |
| Cass et al. 1984. Ferrocene-mediated enzyme electrodes for amperometric determination of glucose. Analytical Chemistry 36:667-671. |
| Cassidy et al., Apr. 1993. Novel electrochemical device for the detection of cholesterol or glucose. Analyst 118:415-418. |
| Chase et al. 2001. Continuous subcutaneous glucose monitoring in children with type 1 diabetes. Pediatrics 107:222-226. |
| Chia et al. 2004. Glucose sensors: toward closed loop insulin delivery. Endocrinol Metab Clin North Am 33:175-196. |
| Choleau, et al. 2002. Calibration of a subcutaneous amperometric glucose sensor implanted for 7 days in diabetic patients. Part 1. Effect of measurement uncertainties on the determination of sensor sensitivity and background current. Biosensors & Bioelectronics 17:641-646. |
| Choleau, et al. 2002, Calibration of a subcutaneous amperometric glucose sensor implanted for 7 days in diabetic patients. Part 2. Superiority of the one-point calibration method. Biosensors & Bioelectronics 17:647-654. |
| Ciba Specialty Chemicals, Inc. 1998. Ciba® Irgacure® 2959 Photoinitiator, Product Description. Apr. 2, 1998. Basel, Switzerland (3 pages). |
| Claremont et al. 1986. Subcutaneous implantation of a ferrocene-medlated glucose sensor in pigs. Diabetologie 29:817-821. |
| Claremont et al. Jul. 1986. Potentially-implntable, ferrocene-mediated glucose sensor. J Biomed Eng 8:272-274. |
| Clark et al. 1981. One-minute electrochemical enzymic assay for cholesterol in biological materials. Clinical Chemistry 27(12): 1978-1982. |
| Clark et al. 1987. Configurational cyclic voltammetry: increasing the specificity and reliability of implanted electrodes. IEEE/Ninth Annual Conference of the Engineering in Medicine and Biology Society, pp. 0782-0783. |
| Clark et al. 1988. Long-term stability of electroenzymatic glucose sensors implanted in mice. Trans Am Soc Artif Intern Organs 34:259-265. |
| CLSI 2008. Performance metrics for continuous interstitial glucose monitoring; approved guideline, CLSI document POCT05-A, Wayne, PA: Clinical and Laboratory Standards Institute 2008 28(33), 72 pp. |
| Colangelo et al. 1967. Corrosion rate measurements in vivo. J Biomed Matls Res 1:405-414. |
| Colowick et al. 1976. Methods in Enzymology, vol. XLIV, Immobilized Enzymes. New York: Academic Press. |
| Coulet et al. 1981. Enzymes immobilized on collagen membranes: A tool for fundamental research and enzyme engineering. J Chromatography 215:65-72. |
| Coulet, P.R. 1992. Polymeric membranes and coupled enzymes in the design of biosensors. J Membrane Science 68:217-228. |
| Cox et al. 1985. Accuracy of perceiving blood glucose in IDDM. Diabetes Care 8(6):529-536. |
| Csoregi et al. 1994. Design, characterization, and one-point in vivo calibration of a subcutaneously implanted glucose electrode. Analytical Chemistry 66(19):3131-3138. |
| Dade International Chemistry Systems 1998, DuPont1 Dimension AR®, 1998. The chemistry analyzer that makes the most of your time, money and effort (Catalog) Newark, DE (18 pages). |
| Danielsson et al. 1988. Enzyme thermistors. Methods in Enzymology 137:181-197. |
| Dassau et al. 2009. In silico evaluation platform for artificial pancreatic (3-cell development—a dynamic simulator for closed loop control with hardware-in-the-loop. Diabetes Technology & Therapeutics 11 (3):1-8. |
| Davies et al. 1992. Polymer membranes in clinical sensor applications. I. An overview of membrane function. Biomaterials 13(14):971-978. |
| Davis et al. 1983. Bioelectrochemical fuel ceil and sensor based on a quinoprotein, alcohol dehydrogenase. Enzyme Microb Technol 5:383-388. |
| Dixon et al. 2002. Characterization in vitro and in vivo of the oxygen dependence of an enzyme/polymer biosensor for monitoring brain glucose. Journal of Neuroscience Methods 119:135-142. |
| Durliat et al. 1976. Spectrophotometric and electrochemical determinations of L(+)-lactate in blood by use of lactate dehydrogenase from yeast. Clinical Chemistry 22(11):1802-1805. |
| Edwards Lifesciences, 2000. Accuracy for you and your patients (marketing materials, 4 pages). |
| El Degheidy et al. 1986. Optimization of an implantable coated wire glucose sensor. J Biomed Eng. 8:121-129. |
| Electronic File History of Reissue U.S. Appl. No. 12/839,260, filed Jul. 19, 2010 containing Office Action(s) dated Aug. 9, 2010, dated Feb. 28, 2011 and Applicant Response(s) filed Jul. 19, 2010, Apr. 1, 2011 as of Jun. 2, 2011. |
| El-Khatib et al. 2007. Adaptive closed-loop control provides blood-glucose regulation using dual subcutaneous Insulin and glucagon infusion in diabetic swine. J Diab Sci & Tech 1(2):181-192. |
| El-Sa'ad et al. 1990. Moisture Absorption by Epoxy Resins: the Reverse Thermal Effect. Matis Science 25:3577-3582. |
| Ernst, et al. 2002. Reliable glucose monitoring through the use of microsystem technology. Analytical Bioanalytical Chemistry 373:758-761. |
| Fahy et al. 2008. An analysis: hyperglycemic intensive care patients need continuous glucose monitoring—easier said than done. J Diabetes Sci & Tech 2(2):201-204. |
| Fare et al. 1998. Functional characterization of a conducting polymer-based immunoassay system. Biosensors 8 Bioelectronics 13(3-4):459-470. |
| Feldman et al. 2003. A continuous glucose sensor based on wired enzyme technology—results from a 3-day trial in patients with type 1 diabetes. Diabetes Technology & Therapeutics 5(5):769-779. |
| Fischer et al. 1987. Assessment of subcutaneous glucose concentration: validation of the wick technique as a reference for implanted electrochemical sensors in normal and diabetic dogs. Diabetologia 30:940-945. |
| Fischer et al. 1989. Oxygen Tension at the Subcutaneous Implantation Site of Glucose Sensors. Biomed Biochem 11/12:965-972. |
| Fischer et al. 1995. Hypoglycaemia-warning by means of subcutaneous electrochemical glucose sensors: an animal study. Horm Metab Res 27:53. |
| Freedman et al. 1991. Statistics, Second Edition, W.W. Norton & Company, p. 74. |
| Frohnauer et al. 2001. Graphical human insulin time-activity profiles using standardized definitions. Diabetes Technology & Therapeutics 3(3):419-429. |
| Frost et al. 2002. Implantable chemical sensors for real-time clinical monitoring: Progress and challenges. Current Opinion in Chemical Biology 6:633-641. |
| Gabbay et al. 2008. Optical coherence tomography-based continuous noninvasive glucose monitoring in patients with diabetes. Diabetes Technology & Therapeutics 10:188-193. |
| Ganesan et al. 2005. Gold layer-based dual crosslinking procedure of glucose oxidase with ferrocene monocarboxylic acid provides a stable biosensor. Analytical Biochemistry 343:188-191. |
| Ganesh et al. 2008. Evaluation of the VIA® blood chemistry monitor for glucose in healthy and diabetic volunteers. J Diabetes Sci & Tech 2(2):182-193. |
| Garg et al. 2004. Improved Glucose Excursions Using an Implantable Real-Time continuous Glucose Sensor in Adults with Type I Diabetes. Diabetes Care 27:734-738. |
| Gerritsen et al. 1999. Performance of subcutaneously implanted glucose sensors for continuous monitoring. The Netherlands Journal of Medicine 54:167-179. |
| Gerritsen, M. 2000. Problems associated with subcutaneously implanted glucose sensors. Diabetes Care 23(2): 143-145. |
| Gilligan et al. 2004. Feasibility of continuous long-term glucose monitoring from a subcutaneous glucose sensor in humans. Diabetes Technology & Therapeutics 6:378-386. |
| Gilligan, et al. 1994. Evaluation of a subcutaneous glucose sensor out to 3 months in a dog model. Diabetes Care 17(8):882-887. |
| Godsland, et al. 2001. Maximizing the Success Rate of Minimal Model Insulin Sensitivity Measurement in Humans: The Importance of Basal Glucose Levels. Clinical Science 101:1-9. |
| Gouda et al., Jul. 4, 2003. Thermal inactivation of glucose oxidase. J of Biological Chemistry 278(27):24324-24333. |
| Gough et al. 2000. Immobilized glucose oxidase in implantable glucose sensor technology. Diabetes Technology & Therapeutics 2(3):377-380. |
| Gough et al. 2003. Frequency characterization of blood glucose dynamics. Annals of Biomedical Engineering 31:91-97. |
| Gross et al. 2000. Efficacy and reliability of the continuous glucose monitoring system. Diabetes Technology & Therapeutics, 2(Suppl 1):S19-S26. |
| Gross et al. 2000. Performance evaluation of the MiniMed® continuous glucose monitoring system during patient home use. Diabetes Technology & Therapeutics 2(1):49-56. |
| Guerci et al. 2003. Clinical performance of CGMS in type 1 diabetic patients treated by continuous subcutaneous insulin infusion using insulin analogs. Diabetes Care 26:582-589, 2003. |
| Hall et al. 1998. Electrochemical oxidation of hydrogen peroxide at platinum electrodes. Part I: An adsorption-controlled mechanism. Electrochimica Acta 43(5-6):579-588. |
| Hall et al. 1998. Electrochemical oxidation of hydrogen peroxide at platinum electrodes. Part II: Effect of potential. Electrochimica Acta 43(14-15):2015-2024. |
| Hall et al. 1999. Electrochemical oxidation of hydrogen peroxide at platinum electrodes. Part III: Effect of temperature. Electrochimica Acta 44:2455-2462. |
| Hall et al. 1999. Electrochemical oxidation of hydrogen peroxide at platinum electrodes. Part IV: Phosphate buffer dependence. Electrochimica Acta 44:4573-4582. |
| Hall et al. 2009. Electrochemical oxidation of hydrogen peroxide at platinum electrodes. Part V: Inhibition by chloride. Electrochimica Acta 45:3573-3579. |
| Hamilton Syringe Selection Guide. 2006. Syringe Selection, www.hamiltoncompany.com. |
| Harrison, et al. 1988. Characterization of perfluorosulfonic acid polymer coated enzyme electrodes and a miniaturized integrated potentiostat for glucose analysis in whole blood. Analytical Chemistry 60:2002-2007. |
| Hashiguchi et al. 1994. Development of a miniaturized glucose monitoring system by combining a needle-type glucose sensor with microdialysis sampling method: Long-term subcutaneous tissue glucose monitoring in ambulatory diabetic patients. Diabetes Care 17(5): 387-396. |
| Heller 1990. Electrical wiring of redox enzymes. Acc. Chem. Res. 23:128-134. |
| Heller, A. 1992. Electrical Connection of Enzyme Redox Centers to Electrodes. J Phys Chem 96:3579-3587. |
| Heller. A. 1999. Implanted electrochemical glucose sensors for the management of diabetes. Annu Rev Biomed Eng 1:153-175. |
| Heller, A. 2003. Plugging metal connectors into enzymes. Nature Biotechnology 21:632-632. |
| Hicks 1985. In Situ Monitoring. Clinical Chemistry 31(12):1931-1935. |
| Hitchman, M. L. 1978. Measurement of Dissolved Oxygen. In Elving et al. (Eds.),. Chemical Analysis, vol. 49, Chap. 3, pp. 34-49, 59-123. New York: John Wiley & Sons. |
| Hoel, Paul G. 1976. Elementary Statistics, Fourth Edition. John Wiley & Sons, Inc., pp. 113-114. |
| Hrapovic et al. 2003. Picoamperometric detection of glucose at ultrasmall platinum-based biosensors: preparation and characterization. Analytical Chemistry 75:3308-3315. |
| Merrian Webster On-Line Dictionary 3008. http://www.merriam-webster.com/dictionary, definition for “aberrant,” Aug. 19, 2008, p. 1. |
| Hu et al. 1993. A needle-type enzyme-based lactate sensor for in vivo monitoring, Analytica Chimica Acta 281:503-511. |
| Huang et al. Aug. 1975. Electrochemical Generation of Oxygen. 1: The Effects of Anions and Cations on Hydrogen Chemisorption and Anodic Oxide Film Formation on Platinum Electrode. 2: The Effects of Anions and Cations on Oxygen Generation on Platinum Electrode. U.S. Department of Commerce/NTIS, pp. 1-116. |
| Huang et al. Sep. 1997. A 0.5mW Passive Telemetry IC for Biomedical Applications, Proceedings of the 23rd European Solid-State Circuits Conference (ESSCIRC '97), pp. 172-175, Southampton, UK. |
| Hunter et al. Mar. 31, 2000. Minimally Invasive Glucose Sensor and Insulin Delivery System. MIT Home Automation and Healthcare Consortium. Progress Report No. 2-5.17 pages. |
| Ishikawa et al. 1998. Initial evaluation of a 290-mm diameter subcutaneous glucose sensor; Glucose monitoring with a biocompatible, flexible-wire, enzyme-based amperometric microsensor in diabetic and nondiabetic humans. J Diabetes and Its Complications 12:295-301. |
| Jaffari et al. 1995. Recent advances in amperometric glucose biosensors for in vivo monitoring. Physiol Meas 16:1-15. |
| Jensen et al. 1997. Fast wave forms for pulsed electrochemical detection of glucose by incorporation of reductive desorption of oxidation products. Analytical Chemistry 69(9):1776-1781. |
| Jeong, et al. 2003. In vivo calibration of the subcutaneous amperometric glucose sensors using a non-enzyme electrode. Biosensors and Bioelectronics 19:313-319. |
| Jeutter, D. C. 1982. A transcutaneous implanted battery recharging and biotelemeter power switching system. IEEE Trans Biomed Eng (BME) 29:314-321. |
| Jobst et al. 1996. Thin-Film Microbiosensors for Glucose-Lactate Monitoring. Analytical Chemistry 68(18):3173-3179. |
| Johnson 1991. Reproducible electrodeposition of biomolecules for the fabrication of miniature electroenzymatic biosensors. Sensors and Actuators B 5:85-89. |
| Johnson et al. 1992. In vivo evaluation of an electroenzymatic glucose sensor implanted in subcutaneous tissue. Biosensors & Bioelectronics 7:709-714. |
| Jovanovic, L. 2000. The role of continuous glucose monitoring in gestationai diabetes mellitus. Diabetes Technology & Therapeutics 2(Suppl 1):S67-S71. |
| Kacaniklic May-Jun. 1994. Amperometric Biosensors for Detection of L- and D-Amino Acids Based on Coimmobilized Peroxidase and L- and D-Amino Oxidases in Carbon Paste Electrodes. Electroanalysis 6(5-6):381-390. |
| Kamath et al. 2008. (Abstract.) Calibration of a continuous glucose monitor: effect of glucose rate of change. Eighth Annual Diabetes Technology Meeting, Nov. 13-15, 2008, p. A88. |
| Kang et al. 2003. In vitro and short-term in vivo characteristics of a Kel-F thin film modified glucose sensor. Anal Sci 19:1481-1486. |
| Kaufman et al. 2001. A pilot study of the continuous glucose monitoring system. Diabetes Care 24(12):2030-2034. |
| Kaufman. 2000. Role of the continuous glucose monitoring system in pediatric patients. Diabetes Technology & Therapeutics 2(Suppl 1):S49-S52. |
| Kawagoe et al. 1991. Enzyme-modified organic conducting salt microelectrode. Analytical Chemistry 63:2961-2965. |
| Keedy et al. 1991. Determination of urate in undiluted whole blood by enzyme electrode. Biosensors & Bioelectronics 6:491-499. |
| Kerner et al. 1988. A potentially implantable enzyme electrode for amperometric measurement of glucose. Horm Metab Res Suppl. 20:8-13. |
| Kerner, et al. 1993. The function of a hydrogen peroxide-detecting electroenzymatic glucose electrode is markedly impaired in human sub-cutaneous tissue and plasma. Biosensors & Bioelectronics 8:473-482. |
| Klueh et al. 2003. Use of Vascular Endothelia Ceil Growth Factor Gene Transfer To Enhance Implantable Sensor Function in Vivo, Biosensor Function and Vegf-Gene Transfer, J Biomed Matis Res 67A:1072-1086. |
| Kondo et al. 1982. A miniature glucose sensor, implantable in the blood stream. Diabetes Care 5(3):218-221. |
| Koschinsky et al. 2001. Sensors for glucose monitoring: Technical and clinical aspects. Diabetes Metab Res Rev 17:113-123. |
| Koschinsky, et al. 1998. New approach to technical and clinical evaluation of devices for self-monitoring of blood glucose. Diabetes Care 11(8):619-619. |
| Kost et al. 1985. Glucose-sensitive membranes containing glucose oxidase: activity, swelling, and permeability studies. J Biomed Matis Res 19:1117-1133. |
| Koudelka et al. 1989. In vivo response of microfabricated glucose sensors to glycemia changes in normal rats. Biomed Biochim Acta 48(11-12):953-956. |
| Koudelka et al. 1991. In-vivo behaviour of hypodermically implanted microfabricated glucose sensors. Biosensors & Bioelectronics 6:31-36. |
| Kraver et al. 2001. A mixed-signal sensor interface microinstrument. Sensors and Actuators A 91:266-277. |
| Kruger et al. 2000. Psychological motivation and patient education: A role for continuous glucose monitoring. Diabetes Technology & Therapeutics 2(Suppl1):S93-S97. |
| Kulys et al., 1994. Carbon-paste biosensors array for long-term glucose measurement, Biosensors & Beioelectronics 9:491-500. |
| Kunjan et al. 2008, Automated blood sampling and glocuse sensing in critical care settings. J Diabetes Sci & Technology 2(3):194-200. |
| Kurtz et al. 2005. Recommendations for blood pressure measurement in humans and experimental animals, Part 2: Blood pressure measurement in experimental animals, A statement for professionals from the subcommittee of professional and public education of the American Heart Association Council on High Blood Pressure Research. Hypertension 45:299-310. |
| Ladd et al. 1996. Structure Determination by X-ray Crystallography, 3rd ed. Plenum, Ch. 1, pp. xxi-xxiv and pp. 1-58. |
| Lehmann et al. May 1994. Retrospective validation of a physiological model of glucose-insulin interaction in type 1 diabetes mellitus. Med Eng Phys 16:193-202. |
| Lerner et al. 1984. An implantable electrochemical glucose sensor. Annais NY Acad Sci 428:263-278. |
| Lewandowski et al. 1988. Evaluation of a miniature blood glucose sensor. Trans Am Soc Artif Intern Organs 34:255-258. |
| Leypoldt et al. 1984. Model of a two-substrate enzyme electrode for glucose. Analytical Chemistry 56:2896-2904. |
| Linke et al. 1994. Amperometric biosensor for in vivo glucose sensing based on glucose oxidase immobilized in a redox hydrogel. Biosensors & Bioelectronics 9:151-158. |
| Lowe, 1984. Biosensors. Trends in Biotechnology 2(3):59-65. |
| Luong et al. 2004. Solubilization of Multiwall Carbon Nanotubes by 3-Aminopropyltriethoxysiiane Towards the Fabrication of Electrochemical Biosensors with Promoted Electron Transfer. Electroanalysis 16(1-2):132-139. |
| Lyandres et al. 2008. Progress toward an in vivo surface-enhanced raman spectroscopy glucose sensor. Diabetes Technology & Therapeutics 10(4):257-265. |
| Maidan et al. 1992. Elimination of Electrooxidizable Interfront-Produced Currents in Amperometric Biosensors. Analytical Chemistry 64:2889-2896. |
| Makale et al. 2003. Tissue window chamber system for validation of implanted oxygen sensors. Am J Physiol Heart Circ Physiol 284:H2288-H2294. |
| Malin et al. 1999. Noninvasive Prediction of Glucose by Near-Infrared Diffuse Reflectance Spectroscopy. Clinical Chemistry 45(9):1651-1658. |
| Maran et al. 2002. Continuous subcutaneous glucose monitoring in diabetic patients: A multicenter analysis. Diabetes Care 25(2):347-352. |
| March, W. F. 2002. Dealing with the delay. Diabetes Technology & Therapeutics 4(1):49-50. |
| Marena et al. 1993. The artificial endocrine pancreas in clinical practice and research. Panminerva Medico 35(2):67-74. |
| Markwell Medical 1990. Direct 30/30® Blood Glucose Sensor (Catalog) © 1990, ELCO Diagnostics Company. 1 page. |
| Mascini et al. 1989. Glucose electrochemical probe with extended linearity for whole blood. J Pharm Biomed Anal 7(12):1507-1512. |
| Mastrototaro et al. 1991. An electroenzymatlo glucose sensor fabricated on a flexible substrate. Sensors and Actuators B 5:139-144. |
| Matsumoto et al. 1998. A micro-planar amperometeric glucose sensor unsusceptible to Interference species. Sensors and Actuators B 49:68-72. |
| Matsumoto, et al. 2001. A long-term lifetime amperometric glucose sensor with a perfluorocarbon polymer coating. Biosensors & Bioelectronics 16:271-276. |
| McGrath et al. 1995. The use of differential measurements with a glucose biosensor for interference compensation during glucose determinations by flow injection analysis. Biosensors & Bioelectronics 10:937-943. |
| McKean, et al. Jul. 7, 1988. A Telemetry Instrumentation System for Chronically Implanted Glucose and Oxygon Sensors. IEEE Trans Biomed Eng (BME) 35:526-532. |
| Memoli et al. 2002. A comparison between different immobilised glucoseoxidase-based electrodes. J Pharm Biomed Anal 29:1045-1052. |
| Moatti-Sirat et al. 1992. Evaluating in vitro and in vivo the interference of ascorbate and acetaminophen on glucose detection by a needle-type glucose sensor. Biosensors & Bioelectronics 7:345-352. |
| Moatti-Sirat et al. 1992. Towards continuous glucose monitoring: in vivo evaluation of a miniaturized glucose sensor implanted for several days in rat subcutaneous tissue. Diabetologia 35:224-230. |
| Moatti-Sirat et al. 1994. Reduction of acetaminophen interference in glucose sensors by a composite Nation membrane: demonstration in rats and man. Diabetologia 37(6):610-616. |
| Morff et al. 1990. Microfabrication of reproducible, economical, electroenzymatic glucose sensor. Annual International Conference of the IEEE Engineering in Medicine and Biology Society 12(2):0483-0484. |
| Moussy et al. 1993. Performance of subcutaneously implanted needle-type glucose sensors employing a novel trilayer coating. Analytical Chemistry 85:2072-2077. |
| Moussy, Francis, Nov. 2002. Implantable Glucose Sensor: Progress and Problems. Sensors 1:270-273. |
| Murphy et al. 1992. Polymer membranes in clincial sensor applications. II. The design and fabrication of permselective hydrogels for electrochemical devices. Biomaterials 13(14):979-990. |
| Ohara et al. 1994. “Wired” enzyme electrodes for amperometric determination of glucose or lactate in the presence of interfering substances. Analytical Chemistry 66:2451-2457. |
| Ohara et al. Dec. 1993. Glucose electrodes based on cross-linked bis(2,2′-bipyridine)chloroosmium(+/2+) complexed poly(l-vinylimidazole) films. Analytical Chemistry 65:3512-3517. |
| Palmisano, et al. 2000. Simultaneous monitoring of glucose and lactate by an interference and crosstalk free dual electrode amperometric biosensor based on electropolymerized thin films. Biosensors & Bioelectronics 15:531-539. |
| Peguin et al. 1983. Pyruvate Oxidase and Oxaloacetate Decarbozylase Enzyme Electrodes—Simultaneous Determination of Transaminases with a Two-electrode-based Analyzer. Anal Chimoca Acta 222:83-93. |
| Pickup et al. 1987/88. Implantable glucose sensors: choosing the appropriate sensor strategy. Biosensors 3:335-346. |
| Pickup et al. 1989. In vivo molecular sensing in diabetes mellitus: an implantable glucose sensor with direct electron transfer. Diabetologia 32:213-217. |
| Pishko et al. 1991. Amperometric glucose microelectrodes prepared through immobilization of glucose oxidase in redox hydrogels. Analytical Chemistry 63:2268-2272. |
| Poitout, et al. 1991. In Vitro and In Vivo Evaluation in Dogs of a Miniaturized Glucose Sensor. ASAIO Transactions 37:M298-M300. |
| Postlethwaite et al. 1996. Interdigitated array electrode as an alternative to the rotated ring-disk electrode for determination of the reaction products of dioxygen reduction. Analytical Chemistry 68:2951-2958. |
| Reach et al. 1992. Can continuous glucose monitoring be used for the treatment of dlabetes? Analytical Chemistry 64(5):381-386. |
| Rebrin, et al. 1989. Automated feedback control of subcutaneous glucose concentration in diabetic dogs. Diabetologia 32:573-576. |
| Rhodes et al. 1994. Prediction of pocket-portable and implantable glucose enzyme electrode performance from combined species permeability and digital simulation analysis. Analytical Chemistry 66(9):1520-1529. |
| Sakakida et al. 1993. Ferrocene-Mediated Needle Type Glucose Sensor Covered with Newly Designed Biocompatible Membrane. Sensors and Actuators B 13-14:319-322. |
| Samuels, M.P. 2004. The effects of flight and aititude. Arch Dis Child 89:448-455. |
| Schaffar, Bernhard P.H., Dec. 2001. Thick film biosensors for metabolites in undiluted whole blood and plasma samples. Analytical & Bioanalytical Chemistry 372:254-260. |
| Shaw, et al. 1991. In vitro testing of a simply constructed, highly stable glucose sensor suitable for implantation in diabetic patients. Biosensors & Bioelectronics 6:401-406. |
| Shichiri et al. 1983. Glycaemic Control in Pancreatectomized Dogs with a Wearable Artificial Endocrine Pancreas. Diabetologia 24:179-184. |
| Shichiri et al. 1985. Needle-type Glucose Sensor for Wearable Artificial Endocrine Pancreas in Implantable Sensors. Chapter 15, pp. 197-210 in Ko, Wen H. (Ed.), Implantabie Sensors for Closed-Loop Prosthetic Systems, Futura Pub. Co., Inc., Mt. Kisco, NY. |
| Shichiri et al. 1986. Telemetry Glucose Monitoring Device with Needle-Type Glucose Sensor: A Useful Tool for Blood Glucose Monitoring in Diabetic Individuals. Diabetes Care 9(3):298-301. |
| Shichiri et al. 1989. Membrane Design For Extending the Long-Life of an Implantable Glucose Sensor. Diab Nut Metab 2:309-313. |
| Shults et al. 1994. A telemetry-instrumentation system for monitoring multiple subcutaneously implanted glucose sensors. IEEE Trans Biomed Eng (BME) 41(10):937-942. |
| Sokol et al. 1980. Immobilized-enzyme rate-determination method for glucose analysis. Clinical Chemistry 26(1):89-92. |
| Sternberg et al. 1988. Study and Development of Multilayer Needle-type Enzyme-based Glucose Microsensors. Biosensors 4:27-40. |
| Takatsuetal. 1987. Solid State Biosensors Using Thln-Film Electrodes. Sensors & Actuators 11:309-317. |
| Thome et al. 1995. Can the decrease in subcutaneous glucose concentration precede the decrease in blood glucose level? Proposition for a push-pull kinetics hypothesis. Horm Metab Res Res. 27:53. |
| Thome-Duret et al. 1996. Modification of the sensitivity of glucose sensor implanted into subcutaneous tissue. Diabetes Metabolism 22:174-178. |
| Thompson et al. 1986. In Vivo Probes: Problems and Perspectives, Department of Chemistry, University of Toronto, Canada, pp. 255-261. |
| Tierney et al. 2000. Effect of acetaminophen on the accuracy of glucose measurements obtained with the GlucoWatch biographer. Diabetes Technology & Therapeutics 2(2):199-207. |
| Turner and Pickup 1985. Diabetes mellitus: biosensors for research and management. Biosensors 1:85-115. |
| Turner, A.P.F. 1988. Amperometric biosensor basead on mediator-modified electrodes. Methods in Enzymology 137:90-103. |
| Updike et al. 1979. Continuous glucose monitor based on an immobilized enzyme electrode detector. J Lab Clin Med 93(4):518-527. |
| Updike et al. 1997. Principles of long-term fully implanted sensors with emphasis on radiotelemetric monitoring of blood glucose form inside a subcutaneous foreign body capsule (FBC). In Fraser, ed., Biosensors in the Body. New York. John Wiley & Sons, pp. 117-137. |
| Updike, et al. 1982. Implanting the glucose enzyme electrode: Problems, progress, and alternative solutions. Diabetes Care 5(3):207-212. |
| Velho et al. 1989. Strategies for calibrating a subcutaneous glucose sensor. Biomed Biochim Acta 48(11/12):957-964. |
| Von Woedtke et al. 1989. In situ calibration of implanted electrochemical glucose sensors. Biomed Biochim Acta 48(11/12):943-952. |
| Wagner et al. 1998. Continuous amperometric monitoring of glucose in a brittle diabetic chimpanzee with a miniature subcutaneous electrode. PNAS USA 95:6379-6382. |
| Ward et al. 1999. Assessment of chronically implanted subcutaneous glucose sensors in dogs: The effect of surrounding fluid masses. ASAIO Journal 45:555-561. |
| Ward et al. 2000. Rise in background current overtime in a subcutaneous glucose sensor in the rabbit: Relevance to calibration and accuracy. Biosensors & Bioelectronics 15:53-61. |
| Ward et al. 2000. Understanding Spontaneous Output Fluctuations of an Amperometric Glucose Sensor: Effect of Inhalation Anesthesia and e of a Nonezyme Containing Electrode. ASAIO Journal 46:540-546. |
| Ward et al. 2004. A wire-based dual-analyte sensor for Glucose and Lactate: In Vitro and In Vivo Evaluation Diabetes Technology & Therapeutics 6(3):389-401. |
| Wilkins et al. 1994. Integrated implantable device for long-term glucose monitoring. Biosensors & Bioelectronics 10:485-494. |
| Wilson, et al. 1992. Progress toward the development of an implantable sensor for glucose. Clinical Chemistry 38(9):1613-1617. |
| Yang et al. 1996. A glucose biosensor based on an oxygen electrode: In-vitro performances in a model buffer solution and in blood plasma. Biomedical Instrumentation & Technology 30:55-61. |
| Yang et al. 1995. Glucose Biosensors with enzyme entrapped in polymer coating. Biorned Instrum Technol 29(2):125-133. |
| Zhang et al. 1993. Electrochemical oxidation of H202 on Pt and Pt + Ir electrodes in physiological buffer and its applicability to H202-based biosensors. J Electroanalytical Chemistry 345:253-271. |
| Zhang, et al. 1994. Elimination of the acetaminophen interference in an implantable/ glucose sensor. Analytical Chemistry 66(7):1183-1188. |
| Zhu et al. 1994. Fabrication and characterization of glucose sensors based on a microarray H202 electrode. Biosensors & Bioelectronics 9: 295-300. |
| PCT/US2004/040476, filed Dec. 3, 2004: International Preliminary Report on Patentability. |
| EP 04812899.5: EPO Examination Report dated May 5, 2009. |
| EP 04812899.5: EPO Examination Report dated Oct. 8, 2008. |
| EP 04812899.5: Supplemental EP Search Report dated May 8, 2008. |
| EP 07853741.2: EPO Communication dated Oct. 8, 2010. |
| EP 10168368.8: EPO Communication dated Oct. 14, 2010. |
| EP 10168369.6: EPO Communication dated Oct. 13, 2010. |
| EP 10168371.2: EPO Communication dated Oct. 14, 2010. |
| EP 1711790: Abbott Diabetes Care Inc. Grounds of Opposition dated Mar. 30, 2011. |
| EP 1711790: EPO Notice of Opposition dated May 11, 2011. |
| EP 1711790: EPO Notice of Opposition dated Jun. 20, 2011. |
| EP 1711790: Roche Diagnostics GmbH Grounds of Opposition dated Jun. 6, 2011. |
| PCT/US2004/040476, filed Dec. 3, 2004: International Search Report and Written Opinion. |
| PCT/US2006/038820, filed Oct. 4, 2008: International Search Report and Written Opinion dated Jun. 20, 2007. |
| PCT/US2006/038820, filed Oct. 4, 2008: International Preliminary Report on Patentabilty. |
| PCT/US2007/007612, filed Mar. 27, 2007 International Preliminary Report on Patentability dated Oct. 23, 2008. |
| PCT/US2007/007612, filed Mar. 27, 2007: International Search Report and Written Opinion dated Aug. 8, 2008. |
| PCT/US2007/080228, filed Oct. 2, 2007: International Search Report and Written Opinion. |
| US Reexamination Control No. 90/011,671, filed May 5, 2011: Partial Electronic File History, including Office Action dated May 13, 2011 and 3rd Party Submission dated May 5, 2011. |
| Bessman et al. 1973. Progress toward a glucose sensor for the artificial pancreas. In Berman et al. (eds.), Ion-Selective Microelectrodes. Advances in Experimental Medicine & Biology 50:1819-197. Springer Publishing Co., Boston, MA. |
| ELCO Diagnostics Company 1990. Direct 30/30 Blood Glucose Sensor (1 page). |
| Mastrototaro 2000. The MiniMed Continuous Glucose Monitoring System. Diabetes Technology & Therapeutics 2(Suppl. 1):S13-S18. |
| Mastrototaro et al. 2003. Reproducibility of the continuous glucose monitoring system matches previous reports and the intended use of the product. Diabetes Care 26(1):256-257. |
| Matthews et al. 1988. An amperometric needle-type glucose sensor testing in rats and man. Diabetic Medicine 5:248-252. |
| Mazze et al. 2008. Characterizing glucose exposure for individuals with normal glucose tolerance using continuous glucose monitoring and ambulatory glucose profile analysis. Diabetes Technology & Therapeutcs 10(3):149-159. |
| McCartney et al. 2001. Near-infrared fluorescence lifetime assay for serum glucose based on allophycocyanin-labeled concanavalin A. Analytical Biochemistry 292:216-221. |
| Merriam-Webster on-line dictionary, 2010. Definition of “acceleration”, http://www.merriam-webster.com/dictionary/acceleration, downloaded Jan. 11, 2010. |
| Merriam-Webster on-line dictionary, 2010. Definition of “system”, http://www.merriam-webster.com/dictionary/system, downloaded Jan. 11, 2010. |
| Meyerhoff et al. 1992. On-line continuous monitoring of subcutaneous tissue glucose in men by combining portable glucosensor with microdialysis. Diabetologia 35:1087-1092. |
| Mosbach et al. 1975. Determination of heat changes in the proximity of immobilized enzymes with an enzyme thermistor and its use for the assay of metabolites. Biochimica et Biophysica Acta 403:256-265. |
| Motonaka et al. 1993. Determination of cholesterol and cholesterol ester with novel enzyme microsensors. Analytical Chemistry 65:3258-3261. |
| Muslu 1991. Trickling filter performance. Applied Biochemistry and Biotechnology 37:211-224. |
| Okuda et al. 1971. Mutarotase effect on micro determinations of D-glucose and its anomers with beta-D-glucose oxidase. Analytical Biochemistry 43:312-315. |
| Patel et al. 2003. Amperometric glucose sensors based on ferrocene containing polymeric electron transfer systems—a preliminary report. Biosensors & Bioelectronics 18:1073-1076. |
| Peacock et al. 2008. Cardiac troponin and outcome in acute heart failure. NEJM 358:2117-2126. |
| Pfeiffer et al. 1990. The glucose sensor: the missing link in diabetes therapy. Horm Metab Res Suppl 24:154-164. |
| Pfeiffer et al. 1993. On-line continuous monitoring of subcutaneous tissue glucose is feasible by combining portable glucosensor with microdialysis. Horm Metab Res 25:121-124. |
| Pichert et al. 2000. Issues for the coming age of continuous glucose monitoring. Diabetes Educator 26(6):969-980. |
| Pickup et al. 1989. Potentially-implantable, amperometric glucose sensors with mediated electron transfer: improving the operating stability. Biosensors 4:109-119. |
| Pickup et al. 1993. Developing glucose sensors for in vivo use. TIBTECH 11:285-291. |
| Pinner et al. 1959. Cross-linking of cellulose acetate by ionizing radiation. Nature 184:1303-1304. |
| Pitzer et al. 2001. Detection of hypoglycemia with the GlucoWatch biographer. Diabetes Care 24(5):881-885. |
| Poitout 1993. A glucose monitoring system for on line estimation in man of blood glucose concentration using a miniaturized glucose sensor implanted in the subcutaneous tissues and a wearable control unit. Diabetologia 36:658-663. |
| Poitout 1994. Development of a glucose sensor for glucose monitoring in man: the disposable implant concept. Clinical materials 15:241-246. |
| Pabhu el al. 1981. Electrochemical studies of hydrogen peroxide at a platinum disc electrode. Electrochimica Acta 26(6):725-729. |
| Quinn et al. 1995. Kinetics of glucose delivery to subcutaneous tissues in rates measured with 0.3.mm amperometric microsensors. Am J Physiol 269(1 Pt 1):E155-E161. |
| Quinn et al. 1997. Biocompatible glucose-permeable hydrogen for in situ coating of implantable biosensors. Biomaterials 18:1665-1670. |
| Rabah et al. 1991. Electrochemical wear of graphite anodes during electrolysis of brine. Carbon 29(2):165-171. |
| Reach et al. 1986. A method for evaluating in vivo the functional characteristics of glucose sensors. Biosensors 2:211-220. |
| Reach 2001. Letters to the Editor re Diabetes Technology & Therapeitucs 2000, 2:49-56. Diabetes Technology & Therapeutics 3(1):129-130. |
| Reach 2001. Which threshold to detect hypoglycemia? Value of receiver-operator curve analysis to find a compromise4 between sensitivity and specificity. Diabetes Care 24(5):803-804. |
| Rebrin et al. 1992. Subcutaneous glucose monitoring by means of electrochemical sensors: Fiction or reality? J Biomed Engineering 14:33-40. |
| Reusch 2004. Chemical Reactivity, Organometallic Compounds. Virtual Textbook of Organic Chemistry, pp. 1-16, http://www.cern.msu.edu/.about.reusch/VirtualText/orgmetal.htm. |
| Rigla et al. 2008. Real-time continuous glucose monitoring together with telemedical assistance improves glycemic control and glucose stability in pump-treated patients. Diabetes Technology & Therapeutics 10(3):194-199. |
| Rivers et al. 2001. Central venous oxygen saturation monitoring in the critically ill patient. Curr Opin Critical Care 7:204-211. |
| Sakakida et al. 1992. Development Of ferrocene-mediated neelde-type glucose sensor as a measure of true subcutaneous tissue glucose concentrations. Artif Organs Today 2(2):145-158. |
| Salardi et al. 2002. The glucose area under the profiles obtained with continuous glucose monitoring system relationships with HbA1C in pediatric Type 1 diabetic patients. Diabetes Care 25(10):1840-1844. |
| Sansen et al. 1985. Glucose sensor with telemetry system, Chapter 12, pp. 167-175 in Ko, W.H. (Ed.), Implantable Sensors for Closed Loop Prosthetic Systems, Futura Publishing Company, Mount Kiscco NY. |
| Sansen et al. 1990. A smart sensor for the voltammetric measurement of oxygen or glucose concentrations. Sensors and Actuators B 1:298-302. |
| Schaffar 2002. Thick film biosensors for metabolites in undiluted whole blood and plasma samples. Analytical Bioanalytical Chemistry 372:254-260. |
| Schmidt et al. 1993, Glucose concentration in subcutaneous extracellular space. Diabetes Care 16(6):696-700. |
| Schmidtke et al. 1998. Measurement and modeling of the transient difference between blood and subcutaneous glucose concentration in the rate after injection of insulin. PNAS-USA 95:294-299. |
| Schoemaker et al. 2003. The SCGM1 system: subcutaneous continuous glucose monitoring based on microdialysis technique. Diabetes Technology & Therapeutics 5(4):599-608. |
| Schoonen et al. 1990. Development Of a potentially wearable glucose sensor for patients with diabetes mellitus: design and in-vitro evaluation. Biosensors & Bioelectronics 5:37-46. |
| Service et al. 1970. Mean amplitude of glycemic excursions, a measure of diabetic instability. Diabetes 19:644-655. |
| Service et al. 1987. Measurements of glucose control. Diabetes Care 10:225-237. |
| Service 2002. Can sensors make a home in the body? Science 297:962-963. |
| Sharkawy et al. 1996. Engineering the tissue which encapsulates subcutaneous implants. I. Diffusion properties. J Biomed Matis Res 37:401-412. |
| Shichiri et al. 1982. Wearable artificial endocrine pancrease with needle-type glucose sensor. Lancet 2:1129-1131. |
| Skyler 2000. The economic burden of diabetes and the benefits of improved glycemic control: the potential role of a continuous glucose monitoring system. Diabetes Technology & Therapeutics 2(10):S7-S12. |
| Slater-MacLean et al. 2008. Accuracy of glycemic measurements in the critically ill, Diabetes Technology & Therapeutics 10:169-177. |
| Sriyudthsak et al. 1996. Enzyme-epoxy membrane based glucose analyzing system and medical applications. Biosensors Bioelectronics 11:735-742. |
| Stell et al. 2003. Determination of plasma glucose during rapid glucose excursions with a subcutaneous glucose sensor. Diabetes Technology & Therapeutics 5(1):27-31. |
| Stern et al. 1957. Electrochemical polarization: 1. A theoretical analysi8s of the shape of polarization curves. J Electrochemical Society 104(1):56-63. |
| Sumino et all. 1998. Preliminary study of calibration-free continuous glucose monitoring with microdialysis technique. Proc of IEEE Eng Med Biol Soc 20(40):1775-1778. |
| Takegami et al. 1992. Pervaporation of ethanol water mixtures using novel hydrophobic membranes containing polydimethylsiloxane. J Membrane Science 74:93-105. |
| Tannenberg et al. 2000. Continuous glucose monitoring system: a new approach to the diagnosis of diabetic gastroparesis. Diabetes Technology & Therapeutics 2(Suppl 1):S73-S78. |
| Tatsuma et al. 1991. Oxidase/peroxidase bilayer-modified electrodes as sensors for lactate, pyruvate, cholesterol and uric acid. Analytica Chimica Acta 242:85-89. |
| Thome-Duret et al. 1996. Use of a subcutaneous glucose sensor to detect decreases in glucose concentration prior to observation blood. Analytical Chemistry 68:3822-3826. |
| Thome-Duret et al. 1998. Continuous glucose monitoring in the free-moving rat. Metabolism 47:799-803. |
| Tierney et al. 2000. The GlucoWatch® biographer: a frequent automatic and noninvesive glucose monitor. Ann. Med 32:632-641. |
| Torjman et al. 2008. Glucose monitoring in acute care: technologies on the horizon. J Diabetes Sci Technology 2(2):178-181. |
| Trecroci 2002. A glimpse into the future—continuous monitoring of glucose with a microfiber. Diabetes Interview 42-43. |
| Tse & Gough 1987. Time-dependent inactivation of immobilized glucose oxidase and catalase. Biotech Bioengineering 29:705-713. |
| Turner et al. 1984. Carbon monoxide; Acceptor oxidoreductase from Pseudomonas thermocaroxydovorans strain C2 and its use in a carbon monoxide sensor. Analytical Chimica Acta 163:161-174. |
| Unger et al. 2004. Glucose controlin the hospitalized patient. Emerg Med 36(9):12-18. |
| Updike et al. 1967. The enzyme electrode. Nature 214:986-988. |
| Updike 35 al. 1988. Laboratory evaluation of new reusable blood glucose sensor. Diabetes Care 11:801-807. |
| Updike et al. 1994. Enzymatic glucose sensor: improved long-term performance in vitro and in vivo. ASAIO J 40(2):157-163. |
| Updike et al. 2000. A subcutaneous glucose sensor with improved longevity, dynamic range, and stability of calibration. Diabetes Care 23(2):208-214. |
| Utah Medical products, Inc. 2003. Blood Pressure Transducers. Product Specifications (6 pages). |
| Vadgama 1981. Enzyme electrodes as practical biosensors. J Med Eng Technology 5(6):293-298. |
| Vadgama 1988. Diffusion limited enzyme electrodes. NATO ASI Series: Series C, Math and Phys Sci 226:359-377. |
| Van den Berghe 2004. Tight blood glucose contro9! with Insulin in “real-life” intensive care, Mayo Clin Proc 79(8):977-978. |
| Velho et al. 1989. In vitro and in vivo stability of electrode potential sin needle-type glucose sensors. Influence of needle material. Diabetes 38:164-171. |
| Wang et al. 1994. Highly selective membrane-free, mediator-free glucose biosensor, Analytical Chemistry 66:3600-3603. |
| Wang et al. 1997. Improved ruggedness for membrane-based amperometric sensors using a pulsed amperometric method. Analytical Chemistry 569:4482-4489. |
| Ward et al. 2002. A new amperometric glucose microsensor: in vitro and short-term in vivo evaluation. Biosensors Bloelectronics 17:181-189. |
| Wientjes 2000. Development of a glucose sensor for diabetic patients (Ph.D. Thesis). |
| Wikipedia 2006. “Intravenous tnerapy.” http://en.wikipedia.org/wiki/intravenous.sub.--therapy, downloaded Aug. 15, 2006 (6 pages). |
| Wiley Electrical and Electronics Dictionary 2004. John Wiley & Sons, Inc., pp. 141, 142, 548, 549. |
| Wilkins et al. 1988. The coated wire electrode glucose sensor. Horm Metab Res Suppl 20:50-55. |
| Wilson et al. 2000. Enzyme-based biosensors for in vivo measurements. Chemical Rev 100:2693-2704. |
| Wood et al. 1990. Hermetic Sealing with Epoxy. Mechanical Engineering 1-3. |
| Woodward 1982. How fibroblasts and giant cells encapsulate implants: considerations in design of glucose sensor. Diabetes Care 5:278-281. |
| Worsley et al. 2008. Measurement of glucose in blood with a phenylboronic acid optical sensor. J Diabetes Sci Technology 2(2):213-220. |
| Wright et al. 1999. Bioelectrochemical dehalogenations via direct electrochemistry of poly(ethylene oxide)-modifled myoglobin. Electrochemistry Comm 1:603-611. |
| Wu et al. 1999. In situ electrochemical oxygen generation with ah immunoisolation device. Ann NY Acad Sci 875:105-125. |
| Yamasaki 1984. The development of a needle-type glucose sensor for wearable artificial endocrine pancreas. Med J Osaka University 35(1-2):25-34. |
| Yamasaki et al. 1989. Direct measurement of whole blood glucose by a needle-type sensor. Clinica Chimica Acta 93:93-98. |
| Yang et al. 1998. Development of needle-type glucose sensor with nigh selectivity. Science and Actuators B 45:249-255. |
| Yang et al. 2004. A comparison of physical properties and fuel cell performance of Nafion and zirconium phosphate/Nafion composite membranes. J Membrane Sci 237:145-161. |
| Ye et al. 1993. High current density “wired” quinoprotein glucose dehydrogenase electrode. Analytical Chemistry 65:238-241. |
| Zamzoe et al. 1990. Development and evaluation of a wearable blood glucose monitor. ASAIO Transactions 3693):M588-M591. |
| Zethelius et al. 2008. Use of multiple biomarkers to improve the prediction of death from cardiovascular causes. NEJM 358:2107-2116. |
| Zhang et al. 1993. In vitro and in vivo evaluation of oxygen effects on a glucose oxidase based implantable glucose sensor. Analytica Chimica Acta 281:513-520. |
| Zhu et al. 1994. Fabrication and characterization of glucose sensors based on a microarray H2O2 electrode. Biosensors and Bloelectronics 9:295-300. |
| EP 1711790: Abbott Diabetes Care Grounds of Opposition dated Mar. 30, 2011. |
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