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WO2009120240A1 - Détecteur de substances à analyser - Google Patents

Détecteur de substances à analyser Download PDF

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Publication number
WO2009120240A1
WO2009120240A1 PCT/US2008/082905 US2008082905W WO2009120240A1 WO 2009120240 A1 WO2009120240 A1 WO 2009120240A1 US 2008082905 W US2008082905 W US 2008082905W WO 2009120240 A1 WO2009120240 A1 WO 2009120240A1
Authority
WO
WIPO (PCT)
Prior art keywords
sensor
analyte
analyte sensor
biological sample
catheter
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2008/082905
Other languages
English (en)
Inventor
Apurv U. Kamath
Jacob S. Leach
Michael J. Estes
Mohammad Ali Shariati
Paul V. Neale
Peter C. Simpson
Richard C. Yang
Robert Boock
Ying Li
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dexcom Inc
Original Assignee
Dexcom Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US12/055,078 external-priority patent/US20080197024A1/en
Priority claimed from US12/055,149 external-priority patent/US20080200788A1/en
Priority claimed from US12/055,203 external-priority patent/US8425416B2/en
Priority claimed from US12/055,114 external-priority patent/US8364231B2/en
Priority claimed from US12/055,227 external-priority patent/US8364230B2/en
Priority claimed from US12/258,345 external-priority patent/US9135402B2/en
Application filed by Dexcom Inc filed Critical Dexcom Inc
Publication of WO2009120240A1 publication Critical patent/WO2009120240A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/1455—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using optical sensors, e.g. spectral photometrical oximeters
    • A61B5/1459—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using optical sensors, e.g. spectral photometrical oximeters invasive, e.g. introduced into the body by a catheter
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/14546—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue for measuring analytes not otherwise provided for, e.g. ions, cytochromes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/1468—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means
    • A61B5/1486—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means using enzyme electrodes, e.g. with immobilised oxidase
    • A61B5/14865—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means using enzyme electrodes, e.g. with immobilised oxidase invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/1495—Calibrating or testing of in-vivo probes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/41—Detecting, measuring or recording for evaluating the immune or lymphatic systems
    • A61B5/412—Detecting or monitoring sepsis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M39/00—Tubes, tube connectors, tube couplings, valves, access sites or the like, specially adapted for medical use
    • A61M39/10—Tube connectors; Tube couplings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/14539—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue for measuring pH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/72—Signal processing specially adapted for physiological signals or for diagnostic purposes
    • A61B5/7271—Specific aspects of physiological measurement analysis
    • A61B5/7275—Determining trends in physiological measurement data; Predicting development of a medical condition based on physiological measurements, e.g. determining a risk factor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M39/00—Tubes, tube connectors, tube couplings, valves, access sites or the like, specially adapted for medical use
    • A61M39/10—Tube connectors; Tube couplings
    • A61M2039/1077—Adapters, e.g. couplings adapting a connector to one or several other connectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/33—Controlling, regulating or measuring
    • A61M2205/3303—Using a biosensor

Definitions

  • the preferred embodiments relate generally to systems and methods for measuring an analyte in a host.
  • analyte levels in patient biological samples are routinely measured during the process of diagnosing, monitoring and/or prognosticating a patient's medical status.
  • a basic metabolic panel e.g., BMP or chem.-7 measures sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), creatinine and glucose.
  • BMP or chem.-7 measures sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), creatinine and glucose.
  • Bodily sample analyte tests are routinely conducted in a variety of medical settings (e.g., doctor's office, clinic, hospital, by medical personnel) and in the home by the host and/or a caretaker. For example, some medical conditions require frequent testing of blood analyte levels.
  • diabetes mellitus 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)
  • bodily fluid samples e.g., blood, interstitial fluid
  • the victim surfers from high blood sugar, which can cause an array of physiological derangements associated with the deterioration of small blood vessels, for example, kidney failure, skin ulcers, or bleeding into the vitreous of the eye.
  • a hypoglycemic reaction low blood sugar
  • a variety of sensors are known that use an electrochemical cell to provide output signals by which the presence or absence of an analyte, such as glucose, in a sample can be determined.
  • an analyte or a species derived from it
  • an enzyme is provided that reacts with the analyte to be measured, and the byproduct of the reaction is qualified or quantified at the electrode.
  • An enzyme has the advantage that it can be very specific to an analyte and also, when the analyte itself is not sufficiently electro-active, can be used to interact with the analyte to generate another species which is electro-active and to which the sensor can produce a desired output.
  • immobilized glucose oxidase catalyses the oxidation of glucose to form hydrogen peroxide, which is then quantified by amperometric measurement (for example, change in electrical current) through a polarized electrode.
  • an integrated sensor system for measuring an analyte in a sample of a host and for fluid infusion into the host, comprising: an analyte sensor configured and arranged for measuring an analyte concentration in a biological sample of a circulatory system of a host; a vascular access device; tubing assembly comprising tubing; and a flow control device configured to regulate exposure of the analyte sensor to a biological sample and to a reference solution according to a flow profile, wherein the flow control device comprises a valve, and wherein the valve is configured and arranged with a gravity flow position and a controlled flow position.
  • the system is configured such that the analyte sensor is flushed by the reference solution when the valve is in the gravity flow position.
  • the gravity flow position comprises a first flow rate of the solution
  • the controlled flow position comprises a second flow rate of the solution
  • a ratio of the first flow rate to the second flow rate is at least about 10: 1.
  • the gravity flow position has a flow rate of at least about 600 ml/hr.
  • the controlled flow position has a flow rate of from about 0.5ml/hr to about 4.0 ml/hour.
  • the valve is configured and arranged to receive the tubing in a substantially linear configuration.
  • valve and the tubing assembly are configured and arranged such that the tubing is in a stretched state after installation of the tubing in the valve
  • valve is configured and arranged such that the tubing is substantially linear in the gravity flow position and the tubing is substantially non-linear in the controlled flow position.
  • the valve is configured and arranged to preclude tubing installation when the valve is in the controlled flow position.
  • the valve is configured and arranged to receive the tubing assembly in only one orientation.
  • valve and tubing assembly are configured and arranged to releasably interlock such that a portion of the valve mechanically interlocks with a portion of the tubing assembly.
  • the vascular access device and the tubing assembly are configured and arranged to substantially preclude rotational movement between the vascular access device and the tubing assembly when engaged.
  • system further comprises a free-flow mitigation device.
  • the free-flow mitigation device comprises a spring clip occluder located on the tubing assembly.
  • system is configured for electronic control of the free-flow mitigation device.
  • system further comprises an electronic solenoid associated with the flow control device, wherein the electronic solenoid provides electronic control of the free-flow mitigation device.
  • the system is configured and arranged such that the free-flow mitigation device precludes flow responsive to at least one of power removal, loss to the system, and loss to the flow control device.
  • system is configured and arranged such that the free-flow mitigation device is controlled at least in part by the flow profile.
  • the system further comprises an intravenous bag containing a reference solution, wherein the reference solution has a known analyte concentration.
  • the analyte sensor is configured to measure at least one analyte selected from the group consisting of albumin, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit, lactate, lactate dehydrogenase, magnesium, oxygen, pH, phosphorus, potassium, sodium, total protein, uric acid, a metabolic marker and a drug.
  • analyte selected from the group consisting of albumin, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit, lactate, lactate dehydrogenase
  • a system configured to measure at least one analyte in a host
  • the system comprising: a vascular access device comprising a first portion configured for insertion into a host and a second portion configured to remain outside the host after insertion of the first portion; at least one analyte sensor located within the second portion of the vascular access device, such that the at least one analyte sensor is exposed to a biological sample when the biological sample is drawn back by a distance of about 40 mm or less into the vascular access device, when the vascular access device is in fluid communication with a circulatory system of the host; and a flow control device configured to regulate exposure of the at least one analyte sensor to a biological sample and to a reference solution according to a flow profile.
  • the at least one analyte sensor is exposed to the biological sample when a volume of about 300 ⁇ l or less of the biological sample is drawn back.
  • the at least one analyte sensor is exposed to the biological sample when a volume of about 200 ⁇ l or less of the biological sample is drawn back.
  • the vascular access device comprises a catheter.
  • the second portion comprises a connecting end* ⁇ f the catheter, wherein the connecting end is configured for connection to tubing.
  • the vascular access device is a catheter, and wherein the catheter is 22 gauge or smaller.
  • the second portion comprises a fluid coupler, wherein the fluid coupler is configured to releasably mate with the catheter.
  • the at least one sensor is incorporated into the second portion.
  • the at least one sensor is located on an inner surface of the second portion.
  • the at least one sensor is disposed within a lumen of the second portion.
  • At least a portion of the at least one sensor is disposed in an orientation substantially parallel to a longitudinal axis of the second portion.
  • At least a portion of the at least one sensor is disposed in an orientation substantially perpendicular to a longitudinal axis of the second portion.
  • the at least one sensor comprises an exposed electroactive surface area with a dimension substantially equal to a width of a lumen of the second portion
  • the exposed electroactive surface area intersects the lumen of the second portion.
  • the second portion is configured to provide identification information associated with the flow profile.
  • system is configured to program the flow profile of the flow control device in response to an automatic receipt of the identification information.
  • the identification information is provided -by a mechanical structure of the second portion.
  • the identification information is provided by electronics of the second portion.
  • the vascular access device comprises at least two lumens, and wherein the system is configured and arranged to infuse a fluid into a first lumen of the vascular access device, and wherein the system is configured and arranged to draw back a biological sample into a second lumen of the vascular access device.
  • the at least one analyte sensor is configured to measure an analyte selected from the group consisting of albumin, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit, lactate, lactate dehydrogenase, magnesium, oxygen, pH, phosphorus, potassium, sodium, total protein, uric acid, a metabolic marker and a drug.
  • an analyte selected from the group consisting of albumin, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit, lactate, lactate dehydrogena
  • the system comprises at least three analyte sensors located within the second portion of the vascular access device, wherein the three sensors in combination are configured to measure at least three analytes selected from the group consisting of albumin, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit, lactate, lactate dehydrogenase, magnesium, oxygen, pH, phosphorus, potassium, sodium, total protein, uric acid, a metabolic marker and a drug.
  • albumin alkaline phosphatase
  • alanine transaminase aspartate aminotransferase
  • bilirubin blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit, lac
  • the system comprises at least eight analyte sensors located within the second portion of the vascular access device, wherein the three sensors in combination are configured to measure at least eight analytes selected from the group consisting of albumin, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit, lactate, lactate dehydrogenase, magnesium, oxygen, pH, phosphorus, potassium, sodium, total protein, uric acid, a metabolic marker and a drug.
  • analyte sensors located within the second portion of the vascular access device, wherein the three sensors in combination are configured to measure at least eight analytes selected from the group consisting of albumin, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirub
  • a lumen of the second portion is wider than a lumen of the first portion.
  • a system configured to measure at least one analyte in a host
  • the system comprising: a catheter comprising a first portion configured for insertion into a host and a second portion configured to remain outside the host after insertion of the first portion; and at least one analyte sensor located within the second portion of the catheter, such that the at least one analyte sensor is exposed to a biological sample when the biological sample is drawn baek into the catheter to a distance of about 40 mm or less, when the catheter is in fluid communication with a circulatory system of the host.
  • the at least one analyte sensor is exposed to the biological sample when a volume of about 300 ⁇ l or less of the biological sample is drawn back.
  • the at least one analyte sensor is exposed to the biological sample when a volume of about 200 ⁇ l or less of the biological sample is drawn back.
  • the catheter is 22 gauge or smaller.
  • the second portion comprises a fluid coupler, wherein the fluid coupler is configured to releasably mate with the catheter.
  • the at least one sensor is incorporated into the second portion.
  • the at least one sensor is located on an inner surface of the second portion.
  • the at least one sensor is disposed within a lumen of the second portion.
  • At least a portion of the at least one sensor is disposed in an orientation substantially parallel to a longitudinal axis of the second portion.
  • At least a portion of the at least one sensor is disposed in an orientation substantially perpendicular to a longitudinal axis of the second portion.
  • the at least one sensor comprises an exposed electroactive surface area with a dimension substantially equal to a width of a lumen of the second portion.
  • the exposed electroactive surface area intersects the lumen of the second portion.
  • the second portion is configured to provide identification information associated with a flow profile.
  • system is configured to program the flow profile of the flow control device in response to an automatic receipt of the identification information
  • identification information is provided by- a mechanical structure of the catheter.
  • the identification information is provided by electronics associated with the catheter.
  • the catheter comprises at least two lumens, and wherein the system is configured and arranged to infuse a fluid into a first lumen of the catheter, and wherein the system is configured and arranged draw back a biological sample into a second lumen of the catheter.
  • the at least one analyte sensor is configured to measure an analyte selected from the group consisting of albumin, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit, lactate, lactate dehydrogenase, magnesium, oxygen, pH, phosphorus, potassium, sodium, total protein, uric acid, a metabolic marker and a drug.
  • an analyte selected from the group consisting of albumin, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit, lactate, lactate dehydrogena
  • the system comprises at least three analyte sensors located within the second portion of the catheter, wherein the three sensors in combination are configured to measure at least three analytes selected from the group consisting of albumin, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit, lactate, lactate dehydrogenase, magnesium, oxygen, pH, phosphorus, potassium, sodium, total protein, uric acid, a metabolic marker and a drug.
  • albumin alkaline phosphatase
  • alanine transaminase aspartate aminotransferase
  • bilirubin blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit
  • lactate lac
  • the system comprises at least eight analyte sensors located within the second portion of the catheter, wherein the eight sensors in combination are configured to measure at least eight analytes selected from the group consisting of albumin, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit, lactate, lactate dehydrogenase, magnesium, oxygen, pH, phosphorus, potassium, sodium, total protein, uric acid, a metabolic marker and a drug.
  • the system further comprises a flow control deviee configured to regulate exposure of the at least one sensor to a biological sample and to a solution according to a flow profile.
  • a lumen of the second portion is wider than a lumen of the first portion.
  • a system configured to measure at least one analyte in a biological sample of the host, the system comprising: a fluid coupler comprising a first end and a second end, wherein the first end is configured to releasably mate with a connecting end of a catheter, and wherein the second end is configured to releasably mate with a tubing assembly; and at least one analyte sensor located within the fluid coupler such that when the fluid coupler is mated to a catheter inserted into a circulatory system of a host, the at least one analyte sensor is exposed to a biological sample when the biological sample is drawn back into the catheter to a distance of about 40 mm or less.
  • the at least one analyte sensor is exposed to the biological sample when a volume of about 300 ⁇ l or less of the biological sample is drawn back.
  • the at least one analyte sensor is exposed to the biological sample when a volume of about 200 ⁇ l or less of the biological sample is drawn back.
  • the at least one analyte sensor is incorporated into the fluid coupler.
  • the at least one analyte sensor is located on an inner surface of the fluid coupler.
  • the at least one analyte sensor is disposed within a lumen of the fluid coupler.
  • At least a portion of the at least one sensor is disposed in an orientation substantially parallel to a longitudinal axis of the fluid coupler.
  • At least a portion of the at least one sensor is disposed in an orientation substantially perpendicular to a longitudinal axis of the fluid couple?.
  • the at least one sensor comprises an exposed electroactive surface area with a dimension substantially equal to a width of a lumen of the fluid coupler. In an embodiment of the fourth aspect, the exposed electroactive surface area interseets the lumen of the fluid coupler
  • the fluid coupler is configured to provide identification information associated with a flow profile.
  • system is configured to program the flow profile of the flow control device in response to an automatic receipt of the identification information.
  • the identification information is provided by a mechanical structure of the fluid coupler.
  • the identification information is provided by electronics associated with the fluid coupler.
  • the fluid coupler comprises at least two lumens, and wherein the system is configured and arranged to infuse a fluid into a first lumen of the fluid coupler, and wherein the system is configured and arranged draw back a biological sample into a second lumen of the fluid coupler.
  • the at least one analyte sensor is configured to measure an analyte selected from the group consisting of albumin, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit, lactate, lactate dehydrogenase, magnesium, oxygen, pH, phosphorus, potassium, sodium, total protein, uric acid, a metabolic marker and a drug.
  • an analyte selected from the group consisting of albumin, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit, lactate, lactate dehydrogena
  • the system comprises at least three analyte sensors located within the fluid coupler, wherein the three sensors in combination are configured to measure at least three analytes selected from the group consisting of albumin, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit, lactate, lactate dehydrogenase, magnesium, oxygen, pH, phosphorus, potassium, sodium, total protein, uric acid, a metabolic marker and a drug.
  • albumin alkaline phosphatase
  • alanine transaminase aspartate aminotransferase
  • bilirubin blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit
  • lactate lactate de
  • the system comprises at least eight analyte sensors located within the fluid coupler, wherein the three sensors in combination are configured to measure at least eight analytes selected from the group consisting of albumin, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit, lactate, lactate dehydrogenase, magnesium, oxygen, pH, phosphorus, potassium, sodium, total protein, uric acid, a metabolic marker and a drug.
  • analyte sensors located within the fluid coupler, wherein the three sensors in combination are configured to measure at least eight analytes selected from the group consisting of albumin, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium,
  • the system further comprises a catheter.
  • system further comprises a flow control device configured to regulate exposure of the at least one sensor to a biological sample and to a solution according to a flow profile.
  • a method for evaluating a change in a sensitivity of an analyte sensor over a predetermined time period comprising, receiving sensor data from an analyte sensor, wherein the sensor data comprises one or more sensor analyte values measured in a biological sample of a host; intermittently calculating a sensitivity of the analyte sensor based at least in part on reference analyte data; and evaluating a change in sensitivity by evaluating a plurality of time-spaced sensitivity calculations over a predetermined time period.
  • the predetermined time period is less than or equal to about 30 minutes.
  • the predetermined time period is less than or equal to about 20 minutes.
  • the predetermined time period is less than or equal to about 10 minutes.
  • the step of evaluating a change in sensitivity comprises evaluating at least two sensitivity measurements during the predetermined time period.
  • the method further comprises averaging and/or filtering the at least two sensitivity measurements prior to the step of evaluating the at least two sensitivity measurements.
  • the step of evaluating a change in sensitivity comprises comparing the change in sensitivity with one or more criteria. In an embodiment of the fifth aspect, the method farther comprises using a most recent sensitivity calculation evaluated to calibrate the analyte sensor when the change in sensitivity meets one or more criteria.
  • the method further comprises not using a most recent sensitivity calculation evaluated to calibrate the analyte sensor when the change in sensitivity does not meet one or more criteria.
  • the step of intermittently calculating a sensitivity of the analyte sensor comprises intermittently receiving a reference analyte value.
  • the step of intermittently receiving a reference analyte value comprises periodically receiving a measured analyte concentration from a reference analyte solution.
  • the step of intermittently receiving a reference analyte value comprises receiving a reference analyte value obtained from an in vitro analyte monitor.
  • the step of evaluating a sensitivity is iteratively performed on the plurality of time-spaced sensitivity calculations over the predetermined time period.
  • the predetermined time period is at least about 30 minutes.
  • the predetermined time period is at least about 60 minutes.
  • the predetermined time period is at least about 120 minutes.
  • the step of evaluating a sensitivity is iteratively performed on the plurality of time-spaced sensitivity calculations over the predetermined time period.
  • the step of evaluating a sensitivity comprises evaluating all sensitivity calculations over a sensor session.
  • the step of evaluating a sensitivity is based at least in part on a priori sensitivity information.
  • the a priori sensitivity information is an expected profile.
  • the a priori sensitivity information defines a range of acceptable change in sensitivity.
  • the analyte sensor comprises a first working electrode and a second working electrode, wherein the first working electrode is configured to provide a first signal comprising an analyte component and a baseline component and wherein the second working electrode is configured to provide a second signal comprising a baseline component without an analyte component.
  • the step of intermittently calculating a sensitivity of lhe analyte sensor is based at least in part on the first signal.
  • the step of intermittently calculating a sensitivity of the analyte sensor is based at least in part on the second signal.
  • the method further comprises subtracting the second signal from the first signal to obtain a subtracted signal, wherein the step of intermittently calculating a sensitivity of the analyte sensor is based at least in part on the subtracted signal.
  • the analyte sensor is intermittently exposed to a biological sample and to a reference solution.
  • the step of intermittently calculating a sensitivity of the analyte sensor is based at least in part on a signal obtained when the analyte sensor is exposed to a biological sample.
  • the step of intermittently calculating a sensitivity of the analyte sensor is based at least in part on a signal obtained when the analyte sensor is exposed to a reference solution.
  • the step of intermittently calculating a sensitivity of the analyte sensor is based at least in part on a signal obtained when the analyte sensor is exposed to a biological sample and a signal obtained when the analyte sensor is exposed to a reference solution.
  • a system for evaluating a change in a sensitivity of an analyte sensor over a predetermined time period comprising: an analyte sensor; and a computer system, wherein the computer system comprises: an input module configured to receive sensor analyte data and reference analyte data, wherein the sensor data comprises one or more sensor analyte values measured in a biological sample of a host and wherein the reference data comprises one or more reference analyte values; and a processor module configured to intermittently calculate a sensitivity of the analyte sensor based at least in part on the reference analyte data and to evaluate a change in sensitivity by evaluating a plurality of time-spaced sensitivity calculations over a predetermined time period.
  • the predetermined time period is less than or equal to about 30 minutes.
  • the predetermined time period is less than or equal to about 20 minutes.
  • the predetermined time period is less than or equal to about 10 minutes.
  • the processor module is configured to evaluate the change in sensitivity at least in part by evaluating at least two sensitivity measurements during the predetermined time period.
  • the processor module is further configured to average and/or filter the at least two sensitivity measurements prior to evaluating the at least two sensitivity measurements.
  • the processor module is further configured to compare the change in sensitivity with one or more criteria.
  • the processor module is further configured to use a most recent sensitivity calculation evaluated to calibrate the analyte sensor when the change in sensitivity meets one or more criteria.
  • the processor module is further configured to not use a most recent sensitivity calculation evaluated to calibrate the analyte sensor when the change in sensitivity does not meet one or more criteria.
  • the predetermined time period is at least about 30 minutes. In an embodiment of the sixth aspect, the predetermined time period is at least about €0 minutes.
  • the predetermined time period is at least about 120 minutes.
  • the processor module is configured to iteratively evaluate a sensitivity of the plurality of time-spaced sensitivity calculations over the predetermined time period.
  • the processor module is configured to evaluate all sensitivity calculations over a sensor session.
  • the processor module is configured to evaluate a sensitivity based at least in part on a priori sensitivity information.
  • the a priori sensitivity information is an expected profile.
  • the a priori sensitivity information defines a range of acceptable change in sensitivity.
  • the analyte sensor data comprises a first signal comprising an analyte component and a baseline component and a second signal comprising a baseline component without an analyte component.
  • the processor module is configured to calculate a sensitivity of the analyte sensor based at least in part on the first signal.
  • the processor module is configured to calculate a sensitivity of the analyte sensor based at least in part on the second signal.
  • the processor module is further configured to calculate a sensitivity of the analyte sensor based at least in part on a subtracted signal, wherein the subtracted signal comprises the second signal subtracted from the first signal.
  • system further comprises a flow control device configured to intermittently expose the sensor to the biological sample and to a reference solution.
  • the processor module is configured to intermittently calculate a sensitivity of the analyte sensor based at least in part on a signal obtained when the analyte sensor is exposed to the biological sample. In an embodiment of the sixth aspect, the processor module is configured to intermittently calculate a sensitivity of the analyte sensor based at least in part on a signal obtained when the analyte sensor is exposed to the reference solution.
  • the processor module is configured to intermittently calculate a sensitivity of the analyte sensor based on a signal obtained when the analyte sensor is exposed to the biological sample and a signal obtained when the analyte sensor is exposed to the reference solution.
  • a method for performing a diagnostic of an analyte sensor system comprising: providing a sensor system comprising an analyte sensor and a flow control device configured to intermittently expose the analyte sensor to a biological sample and an infusion solution, wherein the analyte sensor comprises: a first working electrode configured to provide a first signal comprising an analyte component and a baseline component; and a second working electrode configured to provide a second signal comprising a baseline component substantially without an analyte component; and evaluating the sensor system based at least in part on the second signal.
  • the second signal comprises a signal waveform
  • the step of evaluating the sensor system comprises evaluating the signal waveform for at least one of an expected shape and a pattern when the analyte sensor is exposed to at least one of the biological sample and the infusion solution.
  • the step of evaluating the signal waveform comprises evaluating at least one of a similarity and a correlation between the signal waveform and a waveform template.
  • the waveform template is based at least in part on a priori information.
  • the waveform template is based at least in part on a signal waveform measured by the sensor system.
  • the step of evaluating at least one of a similarity and a correlation of the signal waveform to a waveform template comprises performing a correlation waveform analysis.
  • the method farther comprises updating Ae waveform template when at least one of the similarity and the correlation between the signal waveform and the waveform template meets one or more criteria.
  • the method farther comprises detecting a level of interferent in the biological sample, wherein the waveform template is updated when the level of interferent meets one or more criteria.
  • the step of evaluating the signal waveform comprises evaluating a monotonicity of the signal waveform.
  • the step of evaluating a monotonicity of the signal waveform comprises performing a correlation waveform analysis of the signal waveform with the waveform template.
  • the step of evaluating a monotonicity of the signal waveform comprises performing a time-series analysis.
  • the step of evaluating the sensor system comprises detecting an interferent by evaluating at least one of an amplitude, a change in amplitude, a signal waveform, and a change in a signal waveform of the second signal when the sensor is exposed to the biological sample.
  • the step of detecting an interferent is farther based at least in part on a calibrated analyte value.
  • the method farther comprises controlling a display of the sensor system based at least in part on a level of interferent detected on the second signal.
  • the method farther comprises processing the first signal and the second signal to obtain a subtracted signal, wherein the step of processing is based at least in part a level of interferent of the sensor system.
  • the method farther comprises determining a level of reliability of the sensor system by comparing at least one of an amplitude, a change in amplitude, a signal waveform, and a change in a signal waveform of the second signal to one or more criteria. In an embodiment of the seventh aspect, the method further comprises controlling- a display of the sensor system based at least in part on the level of reliability of the sensor system.
  • the step of evaluating comprises determining a success of a biological sample draw-back from a host's circulatory system to the analyte sensor.
  • the method further comprises displaying an analyte value measured during the biological sample draw-back in response to a determination of a successful biological sample draw-back.
  • the step of evaluating comprises determining a success of infusing the infusion solution such that the biological sample is washed from the sensor.
  • the step of determining a success of infusing comprises displaying an analyte value measured in the biological sample after infusing the infusion solution in response to a determination of a successful infusion.
  • a system for performing a diagnostic of an analyte sensor system comprising- an analyte sensor system comprising a sensor, wherein the analyte sensor comprises a first working electrode configured to provide a first signal comprising an analyte component and a baseline component and a second working electrode configured to provide a second signal comprising a baseline component substantially without an analyte component; a flow control device configured to intermittently expose the analyte sensor to a biological sample and an infusion solution, and a processor module configured to evaluate the analyte sensor system based at least in part on the second signal.
  • the second signal comprises a signal waveform
  • the processor module is configured to evaluate the signal waveform for at least one of an expected shape and a pattern when the analyte sensor is exposed to at least one of the biological sample and the infusion solution.
  • the processor module is configured to evaluate the signal waveform by evaluating at least one of a similarity and a correlation between the signal waveform and a waveform template.
  • the waveform template is based at least in part on a priori information. In an embodiment of the eighth aspect, the waveform template is based at least in part « ⁇ n a signal waveform measured by the analyte sensor system.
  • the processor module is configured to evaluate at least one of a similarity and a correlation between the signal waveform and the waveform template by performing a correlation waveform analysis.
  • the processor module is further configured to update the waveform template when at least one of a similarity and a correlation between the signal waveform and the waveform template meets one or more criteria.
  • the processor module is configured to detect a level of an interferent in the biological sample, and wherein the processor module is further configured to update the waveform template when the level of the interferent meets one or more criteria.
  • the processor module is configured to evaluate the signal waveform by evaluating a monotonicity of the signal waveform.
  • the processor module is configured to evaluate a monotonicity at least in part by performing a correlation waveform analysis of the signal waveform with a waveform template.
  • the processor module is configured evaluate a monotonicity at least in part by performing a time-series analysis.
  • the processor module is configured to detect an interferent at least in part by evaluating at least one of an amplitude, a change in amplitude, a signal waveform, and a change in a signal waveform of the second signal when the sensor is exposed to a biological sample.
  • the processor module is configured to detect an interferent at least in part by evaluating a calibrated analyte value with one or more criteria.
  • the one or more criteria are based on physiological feasibility.
  • the processor module is configured to control a display of the analyte sensor system based at least in part on a level of an interferent detected on the second signal. In an embodiment of the eighth aspect, the processor module is further configured *4o process the first signal and the second signal to obtain a subtracted signal based at least in part on a level of an interferent of the sensor system.
  • the processor module is configured evaluate a level of reliability of the sensor system at least in part by comparing at least one of an amplitude, a change in amplitude, a signal waveform, and a change in a signal waveform of the second signal to one or more criteria.
  • the processor module is configured to control a display of the sensor system based at least in part on a level of reliability of the sensor system.
  • processor module is further configured determine a success of drawing-back of a biological sample from a host's circulatory system to the analyte sensor, based at least in part on the evaluation of the analyte sensor system.
  • the processor module is configured to display an analyte value measured during the biological sample draw-back, in response to a determination of a successful draw-back of the biological sample.
  • the processor module is further configured to determine a success of infusing the infusion solution such that the biological sample is washed from the sensor.
  • the processor module is configured to display an analyte value measured in the biological sample after infusing the infusion solution, in response to a determination of a successful infusion.
  • a method for determining a stability of an analyte sensor comprising: exposing an analyte sensor to a biological sample, wherein the analyte sensor comprises a first working electrode that measures an analyte component and a baseline component and a second working electrode that measures a baseline component substantially without an analyte component; receiving sensor data from the analyte sensor, wherein the sensor data comprises first sensor data associated with the first working electrode and second sensor data associated with the second working electrode; and determining a stability of the analyte sensor based at least in part on the second sensor data.
  • the second sensor data comprises a plurality of time spaced data points
  • the step of determining a stability of the analyte sensor comprises evaluating a change in amplitude of two or more of the plurality of time spaced data points.
  • the step of exposing the analyte sensor to a biological sample comprises intermittently exposing the analyte sensor to a biological sample and to an infusion solution.
  • the step of evaluating comprises comparing a plurality of time spaced points measured when the analyte sensor is exposed to the biological sample.
  • the step of evaluating comprises comparing a first point measured when the analyte sensor is exposed to the biological sample to a second point measured when the analyte sensor is exposed to the infusion solution.
  • the step of evaluating comprises evaluating transient information of the second sensor data during a step change from exposure of the sensor to the infusion solution to exposure of the sensor to the biological sample.
  • the method further comprises determining a predetermined level of stability when a change in an amplitude of the second sensor data meets one or more criteria.
  • the method further comprises controlling a display associated with the analyte sensor system in response to the determination of the predetermined level of stability.
  • the step of controlling a display comprises providing at least one of a numeric estimated analyte value, a directional trend of analyte concentration, and a graphical representation of a plurality of estimated analyte values.
  • the step of controlling a display comprises requesting reference analyte data.
  • the step of determining a stability of the arralyte sensor is performed during a predetermined time period.
  • the step of determining a stability of the analyte sensor is performed after a predetermined time period. In an embodiment of the ninth aspect, the method further comprises repeating the step'-of determining a stability, wherein the step is conducted after a system re-start.
  • the analyte sensor is a glucose sensor.
  • a system for determining a stability of an analyte sensor comprising: an analyte sensor; and a computer system, the computer system comprising: an input module operatively connected to the analyte sensor and configured to receive sensor data from an analyte sensor, wherein the analyte sensor comprises a first working electrode configured to provide first sensor data comprising an analyte component and a baseline component and a second working electrode configured to provide second sensor data comprising a baseline component substantially without an analyte component; and a processor module configured to determine a stability of the analyte sensor based at least in part on the second sensor data.
  • the processor module is configured to determine a stability of the analyte sensor at least in part by evaluating a change in amplitude of a plurality of time spaced points from the second sensor data.
  • the system further comprises a flow control device configured and arranged to intermittently expose the analyte sensor to a biological sample and to an infusion solution.
  • the processor module is configured to evaluate the change in amplitude at least in part by comparing a plurality of time spaced points from the second sensor data measured when the analyte sensor is exposed to the biological sample.
  • the processor module is configured to evaluate the change in amplitude at least in part by comparing a first point measured when the analyte sensor is exposed to the biological sample to a second point measured when the analyte sensor is exposed to the infusion solution.
  • the processor module is configured to evaluate the change in amplitude at least in part by evaluating transient information of the second sensor data during a step change from exposure of the sensor to the infusion solution to exposure of the sensor to the biological sample. In an embodiment of the tenth aspect, the processor module is configured to determine- a level of stability when a change in amplitude of a plurality of time spaced points from the second sensor data meets one or more criteria.
  • the processor module is configured to control a display of calibrated sensor based at least in part on the level of stability.
  • the calibrated sensor data comprises at least one of a numeric estimated analyte value, a directional trend of analyte concentration, and a graphical representation of a plurality of estimated analyte values.
  • the processor module is configured to request reference analyte data based at least in part on the level of stability
  • the processor module is further configured to determine a stability of the analyte sensor during a predetermined time period.
  • processor module is further configured to determine a stability of the analyte sensor after a predetermined time period.
  • the analyte sensor is a glucose sensor.
  • Fig. IA is a perspective view of one embodiment of an analyte sensor system, including a vascular access device (e.g., a catheter), a sensor, a fluid connector, and a protective sheath.
  • a vascular access device e.g., a catheter
  • a sensor e.g., a sensor
  • a fluid connector e.g., a catheter
  • a protective sheath e.g., a sheath
  • Fig IB is a side view of the analyte sensor system of Fig. IA, showing the protective sheath removed.
  • Fig. ICi is a close-up cut away view of a portion of the analyte sensor system of Fig. IA.
  • Fig. IC 2 is a close-up cut away view of a portion of the analyte sensor system of Fig. IA.
  • Fig. ID is a close-up cut away view of a portion of the analyte sensor system of Fig. IA.
  • Fig. IE is a close-up cut away view of a portion of the analyte sensor system of Fig. IA.
  • Fig. IF is a schematic an analyte sensor system in another embodiment, including a vascular access device, a sensor, a fluid connector, and a protective sheath.
  • Fig. 1 G is an exploded view of the analyte sensor system of Fig. IF.
  • Fig. IH is a cut-away view of the analyte sensor system of Fig. IF.
  • Fig. U is a magnified view of the encircled portion of the analyte sensor system of Fig. IH.
  • Fig. 1 K is a cut-away view of an analyte sensor system in another embodiment. ⁇ *-
  • Fig. IL is a cut-away view of an analyte sensor system in another embodiment.
  • IM is a cut-away view of an analyte sensor system in another embodiment.
  • Fig. 2A is a perspective view of another embodiment of the analyte sensor system, including a catheter with a sensor integrally formed thereon.
  • Fig. 2B is a perspective view of the analyte sensor system of Fig. 2A.
  • Fig. 2C is a close-up view of a portion of the analyte sensor system of Fig. 2A in an alternative configuration of an embodiment having three electrodes disposed on the catheter.
  • Fig. 2D is a close-up view of a portion of the analyte sensor system of Fig. 2A in an alternative configuration of an embodiment having three electrodes disposed on the catheter.
  • Fig. 2E is a close-up view of a portion of the analyte sensor system of Fig. 2A in an alternative embodiment having two electrodes disposed on the catheter.
  • Fig. 2F is a close-up view of a portion of the analyte sensor system of Fig. 2A in an alternative embodiment having one electrode disposed on the catheter.
  • Fig. 2G is a cross-section of analyte sensor system in one embodiment, including a plurality of analyte sensors disposed within the connector of a catheter.
  • Fig. 2H is a cross-section of analyte sensor system in one embodiment, including a plurality of analyte sensors disposed within a fluid coupler, such as but not limited to a connector, a valve, and a Leur lock.
  • a fluid coupler such as but not limited to a connector, a valve, and a Leur lock.
  • Fig. 21 is a cross-section of analyte sensor system of Fig. 2H, taken along line 21 - 21.
  • Fig. 2 J is a cross-section of analyte sensor system of Fig. 2H, taken along line 21 - 21.
  • Fig. 2K is a cross-section of analyte sensor system of Fig. 2H, taken along line 21 - 21.
  • Fig. 2L is a cross-section of analyte sensor system of Fig. 2H, taken along line 21 - 21.
  • Fig. 2M is a side view schematic of an analyte sensor system in another embodiment, including a plurality of electrodes disposed in a fluid coupler.
  • Fig. 2N is a schematic of an analyte sensor system in yet another embodiment, including a fluid coupler having a plurality of lumens, each of which includes an analyte sensor
  • Fig. 20 is a schematic illustrating a method of manufacturing the analyte sensor system of Fig. 2M, in one embodiment.
  • Fig. 2P is a schematic illustrating a method of manufacturing the analyte sensor system* ⁇ f Fig. 2M, in another embodiment.
  • Fig. 2Q is a side view schematic of an analyte sensor system, including a fluid coupler including a plurality of sensor electrodes disposed therein, in one embodiment.
  • Fig. 2R is a cross-sectional schematic of an analyte sensor system, including a fluid coupler including a plurality of sensor electrodes disposed therein, in another embodiment.
  • Fig. 2 S is a side view schematic of an analyte sensor system, including a fluid coupler including a plurality of sensor electrodes disposed therein, in still another embodiment.
  • Fig. 3 A is a perspective view of a first portion of one embodiment of an analyte sensor.
  • Fig. 3B is a perspective view of a second portion of the analyte sensor of Fig. 3 A.
  • Fig. 3C is a cross section of the analyte sensor of Fig. 3B, taken on line C - C.
  • Fig. 3D is a cross-sectional schematic view of a sensing region of a dual-electrode continuous analyte sensor in one embodiment wherein an active enzyme of an enzyme domain is positioned over the first working electrode but not over the second working electrode.
  • Fig. 3E is a perspective view of a dual-electrode continuous analyte sensor in one embodiment.
  • Fig. 3F is a schematic illustrating metabolism of glucose by Glucose Oxidase (GOx) and one embodiment of a diffusion barrier D that substantially prevents the diffusion of H 2 O 2 produced on a first side of the sensor (e.g., from a first working electrode that has active GOx) to a second side of the sensor (e.g., to the second working electrode that lacks active GOx).
  • a diffusion barrier D that substantially prevents the diffusion of H 2 O 2 produced on a first side of the sensor (e.g., from a first working electrode that has active GOx) to a second side of the sensor (e.g., to the second working electrode that lacks active GOx).
  • Fig. 3G is a two-dimensional schematic of a dual-electrode sensor in one embodiment, illustrating the sensor's first and second electroactive surfaces (of the first and second working electrodes, respectively) beneath a sensor membrane, wherein noise-causing species produced by a plurality of point sources can impinge upon an electroactive surface.
  • Fig. 3H is a two-dimensional schematic of a dual-electrode sensor in one embodiment, illustrating the sensor's first and second electroactive surfaces (of the first and second working electrodes, respectively) beneath a sensor membrane, wherein noise from a single point source (e.g., a cell) can impinge upon both electroactive surfaces.
  • a single point source e.g., a cell
  • Fig. 31 is a cross-sectional schematic illustrating a dual-electrode sensor, in one embodiment, including a physical diffusion barrier.
  • Fig. 3J is a graph illustrating signal response of the electrodes of a dual-electrode sensor, in one embodiment.
  • Fig. 3K is a graph illustrating signal response of the electrodes of a dual-electrode sensor, in one embodiment.
  • Fig. 4 is a graph illustrating in vivo function of an analyte sensor system of the embodiment shown in Fig. IA.
  • Fig. 5 is a graph illustrating in vivo function of an analyte sensor system of the embodiment shown in Fig. IA.
  • Fig. 6 is a schematic of an integrated sensor system.
  • Fig. 7 is a block diagram of an integrated sensor system
  • Figs. 8A through 8C are schematic illustrations of a flow control device in one exemplary embodiment, including is relative movement/positions and the consequential effect on the flow of fluids through the sensor/catheter inserted in a host.
  • Fig. 9 is a cut-away illustration of one exemplary embodiment of a catheter implanted in a host's vessel.
  • Fig. 1 OA is a schematic illustrating one exemplary embodiment of a flow control device and tubing assembly.
  • Fig. 1OB is a schematic illustrating another exemplary embodiment of a flow control device and tubing assembly.
  • Fig. 1OC is a schematic illustrating another exemplary embodiment of a flow control device with installed tubing assembly, wherein the valve is in a gravity flow position.
  • Fig. 1OD is a schematic illustrating another exemplary embodiment of a flow control device with installed tubing assembly, wherein the valve is in a controlled-flow position.
  • Fig. 1OE is a graph illustrating an exemplary flow profile, in one embodiment.
  • Fig. 11 is a graph that schematically illustrates a signal produced during exposure of the sensor to a step change in analyte concentration, in one exemplary embodiment.
  • Fig. 12 is a graph that schematically illustrates a derivative of the step response shown in Fig. 9.
  • Fig. 13 is a graph that illustrates level vs. rate for a plurality of time-spaced signals associated with exposure of the sensor to biological samples of unknown or uncalibrated analyte concentration.
  • Fig. 14 is a flow chart illustrating sensor sensitivity evaluation, in one embodiment.
  • Fig. 15 is a flow chart illustrating sensor stability evaluation, in one embodiment.
  • Fig. 16 is a flow chart illustrating system diagnostics, in one embodiment.
  • Fig. 17 is a graphical representation showing exemplary glucose sensor data and corresponding blood glucose values over time in a pig.
  • Fig. 18 is a graphical representation showing exemplary calibrated glucose sensor data (test) and corresponding blood glucose values (YSl control) over time in a human.
  • Fig. 19A is a graph that illustrates an in vivo signal (counts) detected from a dual- electrode sensor, in one embodiment, implanted in a non-diabetic human host.
  • Fig. 19B is a graph that illustrates an in vivo signal (counts) detected from a dual- electrode, in another embodiment, implanted in a non-diabetic human host.
  • Fig. 2OA is a graph that illustrates an in vivo signal (counts) detected from a dual- electrode, in one embodiment, implanted in a non-diabetic human host.
  • Fig. 2OB is a graph that illustrates an in vivo signal (counts) detected from a dual- electrode, in another embodiment, implanted in a non-diabetic human host.
  • Fig. 21 A is a graph that illustrates an in vivo glucose values detected from a dual- electrode, in another embodiment, implanted in a non-diabetic porcine host.
  • Fig. 21B is a Clark Error Grid graph of the data of Fig. 21A.
  • Fig. 22 is a graph of a signal waveform generated during a successful infusion of the reference solution into the host versus the adaptive calibration waveform template.
  • Fig. 23 is a graph of a signal waveform generated during an unsuccessful infusion of the reference solution into the host versus the adaptive calibration waveform template.
  • Fig. 24 is a graph of the signals generated from the plus-enzyme working electrode and from the no-enzyme working electrode illustrating sensor stabilization.
  • Fig. 25 is a graph illustrating sensor sensitivity over time. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT - ⁇
  • 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 is not to be limited to a special or customized meaning), and refers without limitation to a substance or chemical constituent in a biological sample (e.g., bodily fluids, including, blood, serum, plasma, interstitial fluid, cerebral spinal fluid, lymph fluid, ocular fluid, saliva, oral fluid, urine, excretions or exudates).
  • a biological sample e.g., bodily fluids, including, blood, serum, plasma, interstitial fluid, cerebral spinal fluid, lymph fluid, ocular fluid, saliva, oral fluid, urine, excretions or exudates.
  • Analytes can include naturally occurring substances, artificial substances, metabolites, and/or reaction products.
  • the analyte for measurement by the sensing regions, devices, and methods is albumin, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, CO2, chloride, creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit, lactate, lactate dehydrogenase, magnesium, oxygen, pH, phosphorus, potassium, sodium, total protein, uric acid, metabolic markers, and drugs.
  • analytes are contemplated as well, including but not limited to acetaminophen, dopamine, ephedrine, terbutaline, ascorbate, uric acid, oxygen, d-amino acid oxidase, plasma amine oxidase, xanthine oxidase, NADPH oxidase, alcohol oxidase, alcohol dehydrogenase, pyruvate dehydrogenase, diols, Ros, NO, bilirubin, cholesterol, triglycerides, gentisic acid, ibuprophen, L- Dopa, methyl dopa, salicylates, tetracycline, tolazamide, tolbutamide, acarboxyprothrombin; acylcarnitine; adenine phosphoribosyl transferase; adenosine deaminase; albumin; alpha- fetoprotein; amino acid
  • Salts, sugar, protein, fat, vitamins, and hormones naturally occurring in blood or interstitial fluids can also constitute analytes in certain embodiments.
  • the analyte can be naturally present in the biological fluid, for example, a metabolic product, a hormone, an antigen, an antibody, and the like.
  • the analyte can 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, p
  • Analytes such as neurochemicals and other chemicals generated within the body can 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), histamine, Advanced Glycation End Products (AGEs) and 5-hydroxyindoleacetic acid (FHIAA).
  • ascorbic acid uric acid
  • dopamine dopamine
  • noradrenaline 3-methoxytyramine (3MT)
  • 3-methoxytyramine (3MT) 3,4-dihydroxyphenylacetic acid
  • DOPAC 3,4-dihydroxyphenylacetic acid
  • HVA homovanillic acid
  • 5HT 5-hydroxytryptamine
  • histamine histamine
  • AGEs Advanced Glycation End Products
  • FHIAA 5-hydroxyindoleacetic acid
  • 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/reduction potential that overlaps with hydrogen peroxide).
  • a calibration is defined by solving for tfee equation y-mx+ b, the value of b represents the baseline, or background, of the signal.
  • baseline and/or sensitivity shift is broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to a change in the baseline and/or sensitivity of the sensor signal over time. While the term “shift” generally refers to a substantially distinct change over a relatively short time period, and the term “drift” generally refers to a substantially gradual change over a relatively longer time period, the terms can be used interchangeably and can also be generally referred to as "change” in baseline and/or sensitivity.
  • biological sample 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, serum, plasma, interstitial fluid, cerebral spinal fluid, lymph fluid, ocular fluid, saliva, oral fluid, urine, sweat, excretions, exudates, and the like.
  • blood chemistry analysis device is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refers without limitation to a device that measures a variety of blood components, characteristics or analytes therein.
  • a blood chemistry analysis device periodically withdraws an aliquot of blood from the host, measures glucose, O 2; CO 2 , PCO 2 , PO 2 , potassium, sodium, pH, lactate, urea, bilirubin, creatinine, hematocrit, various minerals, and/or various metabolites, and the like, and returns the blood to the host's circulatory system.
  • a blood pressure monitor is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refers without limitation to an instrument for monitoring the blood pressure of a human or other animal.
  • a blood pressure monitor can be an invasive blood pressure monitor, which periodically monitors the host's blood pressure via a peripheral artery, using a blood pressure transducer, such as but not limited to a disposable blo ⁇ d pressure transducer.
  • a blood pressure transducer such as but not limited to a disposable blo ⁇ d pressure transducer.
  • Utah Medical Products Inc. (Midvale, Utah, USA) produces a variety of DELTRAN® Brand disposable blood pressure transducers that are suitable for use with various embodiments disclosed herein.
  • calibration 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 relationship and/or process of determining the relationship between the sensor data and the corresponding reference data, which can be used to convert sensor data into values substantially equivalent to the reference data.
  • calibration can be updated or recalibrated over time if changes in the relationship between the sensor data and reference data occur, for example, due to changes in sensitivity, baseline, transport, metabolism, and the like.
  • casting 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 process where a fluid material is applied to a surface or surfaces and allowed to cure or dry.
  • the term is broad enough to encompass a variety of coating techniques, for example, using a draw-down machine (i.e., drawing-down), dip coating, spray coating, spin coating, and the like.
  • catheter 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 are not to be limited to a special or customized meaning), and refers without limitation to a tube that can be inserted into a host's body (e.g., cavity, duct or vessel). In some circumstances, catheters allow drainage or injection of fluids or access by medical instruments or devices.
  • a catheter is a thin, flexible tube (e.g., a "soft” catheter). In alternative embodiments, the catheter can be a larger, solid tube (e.g., a "hard” catheter).
  • cannula is interchangeable with the term “catheter” herein.
  • coaxial 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.
  • 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.
  • 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.
  • 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.
  • constant noise and constant background 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.
  • 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).
  • 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.
  • continuous and “continuously” as used herein are broad terms, and are to be given their ordinary and customary meanings to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to the condition of being marked by substantially uninterrupted extension in space, time or sequence.
  • an analyte concentration is measured continuously or continually, for example at time intervals ranging from fractions of a second up to, for example, about 1, 2, 5, 10, 15, 20, 30, 40, 50 or 60 minutes, or longer.
  • continuous glucose sensors generally continually measure glucose concentration without required user initiation and/or interaction for each measurement, such as described with reference to U.S. Pat. N. 6,001,067, -for example. These terms include situations wherein data gaps can exist (e.g , when a continuous glucose sensor is temporarily not providing data).
  • continuous (or continual) analyte sensing 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 period in which monitoring of analyte concentration is continuously, continually, and or intermittently (regularly or irregularly) performed, for example, about every 5 to 10 minutes.
  • count 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 unit of measurement of a digital signal.
  • a raw data stream or raw data signal measured in counts is directly related to a voltage (for example, converted by an A/D converter), which is directly related to current from the working electrode.
  • the terms can refer to data that has been integrated or averaged over a time period (e.g., 5 minutes).
  • Coupled and "operatively coupling” as used herein are broad terms, and are to be given their ordinary and customary meanings to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to a joining or linking together of two or more things, such as two parts of a device or two devices, such that the things can function together.
  • two containers can be operatively coupled by tubing, such that fluid can flow from one container to another. Coupling does not imply a physical connection.
  • a transmitter and a receiver can be operatively coupled by radio frequency (RF) transmission/communication
  • RF radio frequency
  • 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.
  • 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.
  • 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.
  • dip coating 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 coating, which involves dipping an object or material into a liquid coating substance.
  • distal to 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 spatial relationship between various elements in comparison to a particular point of reference. In general, the term indicates an element is located relatively far from the reference point than another element.
  • domain 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 region of the membrane system that can be a layer, a uniform or non-uniform gradient (for example, an anisotropic region of a membrane), or a portion of a membrane.
  • electrochemical break-in 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 time, after in vitro and/or in vivo settling of the current output from the sensor following the application of the potential to the sensor.
  • electrochemically reactive surface 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 surface where an electrochemical reaction takes place.
  • a working electrode measures hydrogen peroxide produced by the enzyme-catalyzed reaction of the analyte detected, which reacts to create an electric current.
  • Glucose analyte can be detected utilizing glucose oxidase, which produces H 2 O 2 as a byproduct.
  • H 2 O 2 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.
  • Electrode connection is 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 any connection between two electrical conductors known to those in the art.
  • electrodes are in electrical connection with the electronic circuitry of a device.
  • the terms “electronics” and “sensor electronics” 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 are not to be limited to a special or customized meaning), and refer without limitation to electronics operatively coupled to the sensor and configured to measure, process, receive, and/or transmit data associated with a sensor.
  • the electronics include at least a potentiostat that provides a bias to the electrodes and measures a current to provide the raw data signal.
  • the electronics are configured to calculate at least one analyte sensor data point.
  • the electronics can include a potentiostat, A/D converter, RAM, ROM, and/or transmitter.
  • the potentiostat converts the raw data (e.g., raw counts) collected from the sensor and converts it to a value familiar to the host and/or medical personnel.
  • the raw counts from a glucose sensor can be converted to milligrams of glucose per deciliter of blood (e.g., mg/dl).
  • the sensor electronics include a transmitter that transmits the signals from the potentiostat to a receiver (e.g., a remote analyzer, such as but not limited to a remote analyzer unit), where additional data analysis and glucose concentration determination can occur.
  • ex vivo portion 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 portion of a device (for example, a sensor) adapted to remain and/or exist outside of a living body of a host.
  • fluid communication is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refers without limitation to two or more components (e.g., things such as parts of a body or parts of a device) functionally linked such that fluid can move from one component to another. These terms do not imply directionality.
  • GOx 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).
  • 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).
  • 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.
  • 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 is not to be limited to a special or customized meaning), and refers without limitation to animals or plants, for example humans.
  • hyperglycemia is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refers without limitation to a condition in which an excessive or high amount of glucose exists in a host.
  • Hyperglycemia is one of the classic symptoms of diabetes mellitus. Non-diabetic hyperglycemia is associated with obesity and certain eating disorders, such as bulimia nervosa. Hyperglycemia is also associated with other diseases (or medications) affecting pancreatic function, such as pancreatic cancer. Hyperglycemia is also associated with poor medical outcomes in a variety of clinical settings, such as intensive or critical care settings.
  • hypoglycemia is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refers without limitation to a condition in which a limited or low amount of glucose exists in a host.
  • Hypoglycemia can produce a variety of symptoms and effects but the principal problems arise from an inadequate supply of glucose as fuel to the brain, resulting in impairment of function (neuroglycopenia). Derangements of function can range fr ⁇ m vaguely "feeling bad” to coma, and (rarely) permanent brain damage or death.
  • 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.
  • 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.
  • indwell is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refers without limitation to reside within a host's body.
  • Some medical devices can indwell within a host's body for various lengths of time, depending upon the purpose of the medical device, such as but not limited to a few hours, days, or weeks, to months, years, or even the host's entire lifetime.
  • an arterial catheter may indwell within the host's artery for a few hours, days, a week, or longer, such as but not limited to the host's perioperative period (e.g., from the time the host is admitted to the hospital to the time he is discharged).
  • insulative properties 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.
  • an electrically insulative material may be placed between two electrically conductive materials, to prevent movement of electricity between the two electrically conductive materials.
  • the terms refer to a sufficient amount of insulative property (e.g., of a material) to provide a necessary function (electrical insulation).
  • insulator and “non-conductive material” can be used interchangeably herein.
  • integral integral
  • integrally integrally incorporated
  • unitary integrally incorporated
  • composite refers 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.
  • 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 Fig. IB or 9B); in this exemplary embodiment, each element of the sensor is formed as an integral part of the sensor (e.g., both functionally and structurally).
  • 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.
  • interfering species are compounds with an oxidation/reduction potential that overlaps with the analyte to be measured, producing a false positive signal.
  • interfering species are substantially non-constant compounds (e.g., the concentration of an interfering species fluctuates over time).
  • 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.
  • NO nitric oxide
  • NO-donors NO-precursors
  • acetaminophen ascorbic acid
  • bilirubin cholesterol
  • creatinine dopamine
  • viv ⁇ portion 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 portion of a device (for example ⁇ a sensor) adapted for insertion into and/or existence within a living body of a host.
  • medical device 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 are not to be limited to a special or customized meaning), and refers without limitation to an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or intended to affect the structure or any function of the body of man or other animals.
  • Medical devices that can be used in conjunction with various embodiments of the analyte sensor system include any monitoring device requiring placement in a human vessel, duct or body cavity, a dialysis machine, a heart-lung bypass machine, blood collection equipment, a blood pressure monitor, an automated blood chemistry analysis device and the like.
  • membrane and “membrane system” 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 are not to be limited to a special or customized meaning), and refer 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 one or more microns in thickness, which is permeable to oxygen and to an analyte, e.g., glucose or another analyte.
  • the membrane system includes an immobilized glucose oxidase enzyme, which enables a reaction to occur between glucose and oxygen whereby a concentration of glucose can be measured.
  • membrane break-in 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 equilibration of the membrane to its surrounding environment (e.g., physiological environment in vivo).
  • needle 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 slender hollow instrument for introducing material into or removing material from the body.
  • 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.
  • 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).
  • intermittent interferents due to the host's ingestion, metabolism, wound healing, and other mechanical, chemical and/or biochemical factors
  • 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.
  • a "non-enzymatic" membrane portion contains no enzyme; while in other embodiments, the "non-enzymatic" membrane portion contains inactive enzyme.
  • an enzyme solution containing inactive enzyme or no enzyme is applied.
  • operatively connected is broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to one or more components linked to one or more other components.
  • the terms can refer to a mechanical connection, an electrical connection, or any connection that allows transmission of signals between the components.
  • one or more electrodes can be used to detect the amount of analyte in a sample and to convert that information into a signal; the signal can then be transmitted to a circuit.
  • the electrode is "operably linked" to the electronic circuitry.
  • the terms include wired and wireless connections.
  • 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 is not to be limited to a special or customized meaning), and refers without limitation to an electronic instrument that controls the electrical potential between the working and reference electrodes at one or more preset values.
  • a potentiostat works to keep the potential constant by noticing changes in the resistance of the system and compensating inversely with a change in the current As a result, a change to ⁇ a higher resistance would cause the current to decrease to keep the voltage constant in the system.
  • a potentiostat forces whatever current is necessary to flow between the working and 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.
  • pressure transducer 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 are not to be limited to a special or customized meaning), and refers without limitation to a component of an intraarterial blood pressure monitor that measures the host's blood pressure.
  • 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 are not to be limited to a special or customized meaning), and refer without limitation to a computer system, state machine, processor, and the like designed to perform arithmetic or logic operations using logic circuitry that responds to and processes the basic instructions that drive a computer.
  • proximal to 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 spatial relationship between various elements in comparison to a particular point of reference. In general, the term indicates an element is located relatively near to the reference point than another element.
  • pump 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 are not to be limited to a special or customized meaning), and refers without limitation to a device used to move liquids, or slurries. In general, a pump moves liquids from lower pressure to higher pressure, and overcomes this difference in pressure by adding energy to the system (such as a water system).
  • sensor break-in 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 time (after implantation) during which the sensor's signal is becoming substantially representative of the analyte (e.g., glucose) concentration (e.g., where the current output from the sensor is stable relative to the glucose level).
  • the signal may not be 'flat' when the sensor has broken-in, but in general, variation in the signal level at that point is due to a change in the analyte (e.g., glucose) concentration.
  • sensor break-in occurs prior to obtaining a meaningful calibration of the sensor output.
  • sensor break-in generally includes both electrochemical break-in and membrane break-in.
  • small diameter sensor small structured sensor
  • micro-sensor refers without limitation to sensing mechanisms that are less than about 2 mm in at least one dimension, and more preferably less than about 1 mm in at least one dimension.
  • the sensing mechanism is less than about 0.95, 0.9, 0.85, 0.8, 0.75, 0.7, 0.65, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 mm.
  • the sensing mechanism is a needle-type sensor, wherein the diameter is less than about 1 mm (see, for example, U.S. Patent No. 6,613,379 and U.S. Patent Publication No. US-2006-0020187-A1 , each of which is incorporated herein by reference in its entirety).
  • the sensing mechanism includes electrodes deposited on a planar substrate, wherein the thickness of the implantable portion is less than about 1 mm, see, for example U.S. Patent No. 6,175,752 and U.S. Patent No. 5,779,665, both of which are incorporated herein by reference in their entirety.
  • raw data is broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to an analog or digital signal from the analyte sensor directly related to the measured analyte.
  • 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 can include a plurality of time spaced data points from a substantially continuous analyte sensor, each of which includes 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, the terms can refer to data that has been integrated or averaged over a time period (e.g., 5 minutes).
  • the term "regulator” or ''flow control device,” as used herein are broad terms, and arcto be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to a device that regulates the flow of a fluid or gas, for example, a valve or a pump.
  • grade is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refers without limitation to orientation (e.g., of a catheter) against the direction of blood flow.
  • sensing region 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 region of a monitoring device responsible for the detection of a particular analyte.
  • sensitivity and “slope” 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 are not to be limited to a special or customized meaning), and refer without limitation to an amount of electrical current produced by a predetermined amount (unit) of the measured analyte.
  • a glucose sensor has a sensitivity (or slope) of from about 1 to about 25 picoAmps of current for every 1 mg/dL of glucose.
  • sensor and “sensor system” 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 are not to be limited to a special or customized meaning), and refer without limitation to a device, component, or region of a device by which an analyte can be quantified.
  • sheath 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 are not to be limited to a special or customized meaning), and refers without limitation to a covering or supporting structure that fits closely around something, for example, in the way that a sheath covers a blade.
  • a sheath is a slender, flexible, polymer tube that covers and supports a wire4ype sensor prior to and during insertion of the sensor into a catheter.
  • single point glucose monitor 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 device that can be used*to measure a glucose concentration within a host at a single point in time, for example, some embodiments utilize a small volume in vitro glucose monitor that includes an enzyme membrane such as described with reference to U.S. Patent No. 4,994,167 and U.S. Patent No. 4,757,022. It should be understood that single point glucose monitors can measure multiple samples (for example, blood, or interstitial fluid); however only one sample is measured at a time and typically requires some user initiation and/or interaction.
  • slot is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refers without limitation to a relatively narrow opening.
  • solvent and “solvent system” 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 are not to be limited to a special or customized meaning), and refer without limitation to substances (e.g., liquids) capable of dissolving or dispersing one or more other substances.
  • Solvents and solvent systems can include compounds and/or solutions that include components in addition to the solvent itself.
  • specific gravity 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 ratio of density of a material (e.g., a liquid or a solid) to the density of distilled water.
  • spin coating 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 coating process in which a thin film is created by dropping a raw material solution onto a substrate while it is rotating.
  • spray coating 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 coating, which involves spraying a liquid coating substance onto an object or material.
  • 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.
  • valve 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 are not to be limited to a special or customized meaning), and refers without limitation to a device that regulates the flow of substances (either gases, fluidized solids, slurries, or liquids), for example, by opening, closing, or partially obstructing a passageway through which the substance flows.
  • a valve allows no flow, free flow and/or gravity flow and/or metered flow through movement of the valve between one or more discreet positions.
  • vascular access device 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 are not to be limited to a special or customized meaning), and refers without limitation to any device that is in communication with the vascular system of a host.
  • Vascular access devices include but are not limited to catheters, shunts, blood withdrawal devices, connectors, valves, tubing and the like. Overview
  • Intensive care medicine or critical care medicine is concerned with providing greater than ordinary medical care and/or observation to people in a critical or unstable condition.
  • People requiring intensive care include those recovering after major surgery, with severe head trauma, life- threatening acute illness, respiratory insufficiency, coma, hemodynamic insufficiency, severe -fluid imbalance or with the failure of one or more of the major organ systems (life-critical systems or others).
  • ICUs intensive care units
  • CCUs critical care units
  • Intensive medical care requires frequent testing and/or monitoring of a variety of analytes, such as but not limited to albumin, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, CO2, chloride, creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit, lactate, lactate dehydrogenase, magnesium, oxygen, pH, phosphorus, potassium, sodium, total piotein, uric acid, a metabolic marker and a drug.
  • Some embodiments disclosed herein are suitable for use in an intensive care or critical care unit of a medical care facility for substantially continuously measuring the concentration of one or more analytes in the host.
  • diabetes is one medical condition requiring frequent testing of the host's analyte levels (e.g., blood glucose levels), in hospital settings.
  • Hosts having diabetes are at risk of developing hyperglycemia, a medical condition in which an excessive amount of glucose circulates in a host.
  • Perioperative hyperglycemia is associated with increased rates and severity of myocardial infarction (MI) and stroke, while tight glucose control with intravenous (IV) insulin therapy is linked to a 30% reduction in mortality one year after admission for acute MI.
  • MI myocardial infarction
  • IV intravenous
  • strict in-hospital glucose control is associated with 40% reductions of morbidity, mortality, sepsis, dialysis, blood transfusions, as well as reduced length of stay, reduced costs and the like.
  • diabetic hosts are also susceptible to hypoglycemia (e.g., excessively low circulating blood glucose), which can cause shock and death (immediate problems), which the clinical staff rigorously avoids, often by maintaining the host at elevated blood glucose concentrations (which can degrade the clinical outcome in the long run) and causes the problems of hyperglycemia discussed above.
  • hypoglycemia e.g., excessively low circulating blood glucose
  • the clinical staff rigorously avoids, often by maintaining the host at elevated blood glucose concentrations (which can degrade the clinical outcome in the long run) and causes the problems of hyperglycemia discussed above.
  • tight glucose control requires frequent monitoring of the host by the clinical staff, IV insulin or injections, and on-time feeding. Frequent monitoring typically requires a nurse or other staff member to measure the host's glucose concentration using a lancet (to obtain a blood sample) and a hand held glucose monitor. The nurse can perform this task many times a day (erg., every hour or more frequently).
  • Some embodiments disclose systems and methods to reduce and/or minimize the interaction required to regularly (e.g., continuously) measure the host's glucose concentration. Additional and/or alternative analytes can also be continuously monitored using the devices and methods of the preferred embodiments.
  • the preferred embodiments describe systems and methods for providing continuous analyte monitoring while providing alarms or alerts that aid in avoiding adverse events.
  • the in vivo continuous analyte monitoring system of the preferred embodiments can be used in clinical settings, such as in the hospital, the doctor's office, long-term nursing facilities, or even in the home.
  • the present device can be used in any setting in which frequent or continuous analyte monitoring is desirable.
  • hosts are often recovering from serious illness, disease, or surgery, and control of host glucose levels is important for host recovery.
  • use of a continuous glucose sensor as described in the some embodiments allows tight control of host glucose concentration and improved host care, while reducing hypoglycemic episodes and reducing the ICU staff work load.
  • the system can be used for the entire hospital stay or for only a part of the hospital stay.
  • the continuous glucose monitor of the preferred embodiments can be used in medical settings wherein the host is unable to communicate with the medical staff, such as an ER setting.
  • the host is unable to communicate with the medical staff, such as an ER setting.
  • a host may be unconscious and therefore unable to communicate with the staff.
  • a very young, non-verbal host may also be unable to communicate with the staff regarding his or her condition.
  • a host undergoing surgery is unable to communicate with the anesthesiologist, due to certain drugs being delivered.
  • Routine use of a continuous analyte monitors e.g., glucose, calcium, sodium, potassium, CO 2 , chloride, blood urea nitrogen, creatinine, pH, oxygen, albumin, total protein, alkaline phosphatase, alanine amino transferase, aspartate amino transferase, bilirubin, phosphate, electrolytes, hematocrit and/or drugs
  • a continuous analyte monitors e.g., glucose, calcium, sodium, potassium, CO 2 , chloride, blood urea nitrogen, creatinine, pH, oxygen, albumin, total protein, alkaline phosphatase, alanine amino transferase, aspartate amino transferase, bilirubin, phosphate, electrolytes, hematocrit and/or drugs
  • a continuous analyte monitors e.g., glucose, calcium, sodium, potassium, CO 2 , chloride, blood urea nitrogen, creatinine, pH
  • a continuous analyte monitor can be used in the general hospital population to monitor host analyte concentrations, for various lengths of time, such as during the entire hospital stay or for a portion of the hospital stay (e.g., only during surgery).
  • a diabetic host's glucose concentration can be monitored during his or her entire stay.
  • a cardiac host's glucose can be monitored during surgery and while in the ICU, but not after being moved to the general host population.
  • a jaundiced newborn infant can have his or her bilirubin concentration continuously monitored by an in-dwelling continuous analyte monitor until the condition has receded.
  • the analyte sensor of the preferred embodiments can be used in other body locations.
  • the sensor is used subcutaneously.
  • the sensor can be used intracranially.
  • the sensor can be used within the spinal compartment, such as but not limited to the epidural space.
  • the sensor of the preferred embodiments can be used with or without a catheter.
  • One aspect of the preferred embodiments provides a system for in vivo continuous analyte monitoring (e.g., albumin, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, CO 2 , chloride, creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit, lactate, lactate dehydrogenase, magnesium, oxygen, pH, phosphorus, potassium, sodium, total protein, uric acid, a metabolic marker, a drug, various minerals, various metabolites, and the like) that can be operatively coupled to a catheter to measure analyte concentration within the host's blood stream.
  • analyte monitoring e.g., albumin, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, CO
  • the system includes an analyte sensor that extends a short distance into the blood stream (e.g., out of the catheter) without substantially occluding the catheter or the host's blood stream.
  • the catheter can be fluidly coupled to additional IV and diagnostic devices, such as a saline bag, an automated blood pressure monitor, or a blood chemistry monitor device.
  • blood samples can be removed from the host via the sensor system, as described elsewhere herein.
  • the sensor is a glucose sensor, and the medical staff monitors the host's gluc ⁇ e level.
  • the analyte sensor is disposed within or on the catheter itself, such as the in vivo portion of the catheter.
  • the analyte sensor is disposed entirely within and/or on the fluid coupler, which is in turn fluidly coupled to a catheter or other vascular access device, as described elsewhere herein.
  • Figs. IA to IJ illustrate two embodiments of an exemplary analyte sensor system 10 for measuring an analyte, as described elsewhere herein, that includes a catheter 12 configured to be inserted or pre-inserted into a host's blood stream.
  • catheters are often inserted into hosts to allow direct access to the circulatory system without frequent needle insertion (e.g., venipuncture).
  • Suitable catheters can be sized as is known and appreciated by one skilled in the art, such as but not limited to from about 1 French (0.33mm) or less to about 30 French (10mm) or more; and can be, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, or 20 French (3 French is equivalent to about 1 mm) and/or from about 33 gauge or less to about 16 gauge or more, for example, 33, 32, 31 , 30, 29, 28, 27, 26, 25, 24, 23, 22, 21 , 20, 19, 18, 17, or 16 gauge. Additionally, the catheter can be shorter or longer, for example 0.75, 1.0, 1.25, 1.5, 1.75, 2.0 inches in length or longer. In some embodiments, the catheter is a venous catheter.
  • the catheter is configured for insertion into a peripheral or a central artery.
  • the catheter is configured to extend from a peripheral artery to a central portion of the host's circulatory system, such as but not limited to the heart.
  • the catheter is configured for insertion into neonatal or other pediatric hosts (e.g., 22-24 gauge or smaller).
  • the catheter can be manufactured of any medical grade material known in the art, such as but not limited to polymers and glass as described herein.
  • a catheter can include a single lumen or multiple lumens.
  • a catheter can include one or more perforations, to allow the passage of host fluid through the lumen of the catheter.
  • inserted or "pre-inserted” 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 are not to be limited to a special or customized meaning), and refer without limitation to insertion of one thing into another thing.
  • a catheter can be inserted into a host's blood stream.
  • a catheter is "pre-inserted,” meaning inserted before another action is taken (e.g., insertion of a catheter into a host's blood stream prior to insertion of a sensor into the catheter).
  • a sensor is coupled to a pre-inserted catheter, namely, one tf*at has been previously inserted (or pre-inserted) into the host's circulatory system.
  • the sensor and the catheter can be configured to be inserted together and/or the sensor can be integrally formed with the catheter.
  • the catheter 12 is a thin, flexible tube having a lumen 12a, such as is known in the art
  • the catheter can be rigid; in other embodiments, the catheter can be custom manufactured to desired specifications (e.g., rigidity, dimensions, etc).
  • the catheter can be a single-lumen catheter or a multi-lumen catheter
  • the catheter is a peripheral catheter configured and arranged for insertion into a peripheral vessel (e.g., vein and/or artery) in a host's arm and/or leg.
  • the catheter is a central catheter, configured and arranged for insertion into a host's central vessel (e.g., internal jugular vein, subclavian vein, femoral vein and/or pulmonary artery).
  • a host's central vessel e.g., internal jugular vein, subclavian vein, femoral vein and/or pulmonary artery.
  • a small orifice 12b for fluid connection of the catheter to the blood stream
  • a connector 18 such as a Leur connector or other fluid connector known in the art.
  • Figs. IA to IJ show two exemplary embodiments of the connector 18 including a flange 18a and a duct 18b.
  • the flange 18a is configured to enable connection of the catheter to other medical equipment (e.g., saline bag, pressure transducer, blood chemistry device, and the like) or capping (e.g., with a bung and the like).
  • other medical equipment e.g., saline bag, pressure transducer, blood chemistry device, and the like
  • capping e.g., with a bung and the like.
  • the duct 18b is in fluid communication with the catheter lumen and terminates in a connector orifice 18c.
  • the catheter is inserted into the host's blood stream, such as into a vein or artery by any useful method known in the art.
  • the catheter is supported by a hollow needle or trochar (not shown)
  • the supported catheter can be inserted into a peripheral vein or artery, such as in the host's arm, leg, hand, or foot.
  • the supporting needle is removed (e.g., pulled out of the connector) and the catheter is connected (e.g., via the connector 18) to IV tubing and a saline drip, for example.
  • the catheter is configured to operatively couple to medical equipment, such as but not limited to a sensor system of the preferred embodiments.
  • the catheter can be configured to operatively couple to another medreal device, such as a pressure transducer, for measurement of the host's blood pressure.
  • the catheter and the analyte sensor are configured to indwell within the host's blood stream in vivo.
  • An indwelling medical device such as a catheter or implant, is disposed within a portion of the body for a period of time, from a few minutes or hours to a few days, months, or even years.
  • An indwelling catheter is typically inserted within a host's vein or artery for a period of time, often 2 or more days, a month, or even a few months.
  • the catheter can indwell in a host's artery or vein for the length of a perioperative period (e.g., the entire hospital stay) or for shorter or longer periods.
  • an indwelling catheter permits continuous access of an analyte sensor to a blood stream while simultaneously allowing continuous access to the host's blood stream for other purposes, for example, the administration of therapeutics (e.g., fluids, drugs, etc.), measurement of physiologic properties (e.g., blood pressure), fluid removal, and the like.
  • therapeutics e.g., fluids, drugs, etc.
  • measurement of physiologic properties e.g., blood pressure
  • fluid removal e.g., and the like.
  • the system 10 also includes an analyte sensor 14 configured to extend through the catheter lumen 12a (see Fig. IE), out of the catheter orifice 12b and into the host's blood stream by about 0.010 inches to about 1 inch, or shorter or longer lengths.
  • the sensor may not extend out of the catheter, for example, can reside just inside the catheter tip.
  • the sensor can extend through the catheter in any functional manner.
  • the sensor is configured to be held (e.g., located, disposed) on an inner surface (e.g., the lumenal surface) or outer surface of the catheter.
  • the sensor is deposited (e.g., formed) on a surface of the catheter.
  • a sensor is attached to a surface of the catheter, such as by an adhesive and/or welding. In some other embodiments, the sensor is configured to "free float" within the lumen of the catheter. In some embodiments, the sensor resides within the fluid coupler.
  • the senor 14 is configured to measure the concentration of an analyte (e.g., albumin, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, CO 2 , chloride, creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit, lactate, lactate dehydrogenase, magnesium, oxygen, pH, phosphorus, potassium, sodium, total protein, uric acid, a metabolic marker, various drugs, various minerals, various metabolites, and the like) within the host's blood stream.
  • an analyte e.g., albumin, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, CO 2 , chloride, creatinine, glucose, gamma-glutamyl transpeptida
  • the senor includes at least one electrode (see, e g , Fig. 3B), for example a working electrode; however any combination of working electrode(s), reference electrode(s), and/or counter electrode(s) can be implemented as is appreciated by one skilled in the art.
  • the sensor includes at least two working electrodes, as is described with reference to Figs. 3D through 31.
  • two or more analyte sensors are in fluid communication with the vascular access device (e.g., disposed within the vascular access device), such that two or more analytes can be monitored simultaneously, and/or sequentially, continuously and/or intermittently, and the like.
  • the senor 14 includes at least one exposed electroactive area (e g , working electrode), a membrane system (e g , including an enzyme), a reference electrode (proximal to or remote from the working electrode), and an insulator material.
  • a membrane system e g , including an enzyme
  • a reference electrode proximal to or remote from the working electrode
  • an insulator material e.g , a senor material.
  • the senor is a needle-type continuous analyte sensor, configured as disclosed in U S. Patent Publication No. US-2006-0020192-A1 and U S. Patent Publication No. US-2006-0036143-A1, both of which are inco ⁇ orated herein by reference in their entirety.
  • the sensor is disposed on a planar substrate, configured as disclosed in U.S.
  • the senor is configured to measure glucose concentration. Exemplary sensor configurations are discussed in more detail, elsewhere herein.
  • the senor has a proximal end 14a and a distal end 14b. At its distal end 14b, the sensor 14 is associated with (e.g., connected to, held by, extends through, and the like) a fluid coupler 20 having first and second sides (20a and 20b, respectively). The fluid coupler is configured to mate (via its first side 20a) to the catheter connector 18.
  • a skirt 20c is located at the fluid coupler's first side and includes an interior surface 2Od with threads 2Oe (see Figs. ID and IE).
  • the fluid coupler is configured to mate with the connector flange 18a, which is screwed into the fluid coupler via the screw threads.
  • the fluid coupler is configured to mate with the connector using any known mating configuration, for example, a snap-fit, a press-fit, an interference-fit, and the like, and can include a locking mechanism to prevent separation of the connector and fluid coupler.
  • the fluid coupler 20 includes a lumen 2Of extending from a first orifice 2Oh on its first side 20a to a second orifice 2Oi located on the flmd coupler's second side 20b (Figs. ICl to IE). When the catheter connector is mated with the fluid coupler, the catheter's lumen 12a is in fluid communication with the fluid coupler's lumen 2Of via orifices 18c and 2Oh.
  • Figs. IA to ID show one embodiment of a fluid coupler 20, namely, a Y-coupler; however, any known coupler configuration can be used, including but not limited to a straight coupler, a T-coupler, a cross-coupler, a custom configured coupler, and the like.
  • the fluid coupler includes at least one valve (e.g., a septum, a 3-way valve, a stopcock valve), which can be used for a variety of purposes (e g , injection of drugs).
  • Figs. IF-U illustrate a fluid coupler configured for connection of the sensor to sensor electronics via a female socket 2On configured to releasably mate with a male plug on an electronic cable.
  • the fluid coupler can be made of any convenient material, such as but not limited to plastic, glass, metal or combinations thereof and can be configured to withstand known sterilization techniques.
  • the second side 20b of the fluid coupler 20 is configured to be operably connected to IV equipment, another medical device or to be capped, and can use any known mating configuration, for example, a snap-fit, a press-fit, an interference-fit, and the like.
  • the second side 20b is configured to mate with a saline drip, for delivery of saline to the host.
  • the saline flows from an elevated bag of sterile saline via tubing, through the fluid coupler, through the catheter and into the host's blood system (e.g., vein or artery).
  • a syringe can be mated to the fluid coupler, for example, to withdraw blood from the host, via the catheter.
  • Additional connection devices e.g., a three- way valve
  • a blood pressure transducer can be operably connected to the fluid coupler, to support additional functionality and connection of various devices, such as but not limited to a blood pressure transducer.
  • the senor 14 passes through the fluid coupler 20 (e.g., the fluid coupler lumen 20f) and is operatively connected to sensor electronics (not shown) via a hardwire 24.
  • the sensor electronics can be disposed in part or in whole with the fluid coupler (e.g., integrally with or proximal to) or can be disposed in part or in whole remotely from the fluid coupler (e.g., on a stand or at the bed side). Connections between the sensor and sensor electronics (in part or in whole) can be accomplished using known wired or wireless technology.
  • the senor is hardwired to the electronics located substantially wholly remote from the fluid coupler (e.g., disposed on a stand or near the bedside); one advantage of remote electronics includes enabling a smaller sized fluid coupler design.
  • a portion of the sensor electronics, such as a potentiostat is disposed on the fluid coupler and the remaining electronics (e.g., electronics for receiving, data processing, printing, connection to a nurses' station, etc.) are disposed remotely from the fluid coupler (e.g., on a stand or near the bedside).
  • One advantage of this design can include more reliable electrical connection with the sensor in some circumstances.
  • the potentiostat can be hardwired directly to the remaining electronics or a transmitter can be disposed on or proximal to the fluid coupler, for remotely connecting the potentiostat to the remaining electronics (e.g., by radio frequency (RF)).
  • RF radio frequency
  • all of the sensor electronics can be disposed on the fluid coupler.
  • the sensor electronics disposed on the fluid coupler include a potentiostat.
  • a protective sheath 26 is configured to cover at least a portion of the sensor 14 during insertion, and includes hub 28 and slot 30.
  • the protective sheath protects and supports the sensor prior to and during insertion into the catheter 12 via the connector 18.
  • the protective sheath can be made of biocompatible polymers known in the art, such as but not limited to polyethylene (PE), polyurethane (PE), polyvinyl chloride (PVC), polycarbonate (PC), nylon, polyamides, polyimide, polytetrafluoroethylene (PTFE), Teflon, nylon and the like.
  • the protective sheath includes a hub 28, for grasping the sheath (e.g., while maintaining sterilization of the sheath).
  • the hub additionally provides for mating with the second side 20b of the fluid coupler 20, prior to and during sensor insertion into the catheter.
  • the slot of the protective sheath is configured to facilitate release of the sensor therefrom.
  • the hub is grasped and pulled from the second side of the fluid coupler. This action peels the protective sheath from the sensor (e.g., the sensor slides through the slot as the sheath is removed), leaving the sensor within the catheter.
  • the second side of the fluid coupler can be connected to other medical devices (e.g., a blood pressure monitor) or an IV drip (e.g., a saline drip), or capped.
  • the sheath can fold (e g , fold back or concertinas) or retract (e.g., telescope) during insertion, to expose the sensor.
  • the sheath can be configured to tear away from the sensor before, during, or after insertion of the sensor.
  • the sheath can include an outlet hole 30a, to allow protrusion of the sensor from the back end of the sheath (e.g., near the hub 28).
  • additional configurations can be used, to separate the sensor 14 from the sheath 26.
  • the senor includes at least two working electrodes 14, which can be twisted and/or bundled, such as in a helical and/or coaxial configuration.
  • the two working electrodes are twisted into a "twisted pair," which can be configured to be inserted into and to extend within a vascular access device, such as a catheter 12 or cannula implanted in a host's vein or artery, as is described in more detail in the section entitled "Integrated Sensor System.”
  • the twisted pair is configured to reside within the lumen 12a of the catheter 12; while in other embodiments, the twisted pair is configured to protrude from the catheter's proximal orifice 12b. In still other embodiments, the twisted pair is configured to intermittently protrude from the catheter's proximal orifice 12b.
  • the sheath 26 can be optional, depending upon the sensor design.
  • the sensor can be inserted into a catheter or other vascular access device with or without the use of a protective sheath).
  • the sensor can be disposed on the outer surface of a catheter (as described elsewhere herein) or on the inner surface of a catheter; and no sheath is provided.
  • a multi-lumen catheter can be provided with a sensor already disposed within one of the lumens; wherein the catheter is inserted into the host's vein or artery with the sensor already disposed in one of the lumens.
  • the system includes a catheter having multiple lumens, and is configured and arranged to infuse a fluid in a first lumen of the catheter and to draw back a biological sample into a second lumen of the catheter.
  • an analyte sensor is located in the second lumen of the catheter.
  • the system is configured to infuse a fluid into the second lumen, such as to reinfuse a drawn back sample into the host and/or to wash the sensor.
  • a flow control device is configured and arranged for infusion of at least two solutions, such as via a multi-lumen catheter, and includes at least two valves, such as described with reference to Figs 8A through 10D.
  • an analyte sensor is integrally formed on a catheter.
  • the catheter can be placed into a host's vein or artery in the usual way a catheter is inserted, as is known by one skilled in the art, and the host's analyte concentration measured substantially continuously.
  • the sensor system can be coupled to one or more additional devices, such as a saline bag, an automated blood pressure monitor, a blood chemistry monitor device, and the like
  • the integrally formed analyte sensor is a glucose sensor.
  • Figs. IF through IJ illustrate another embodiment of the sensor system, wherein the fluid coupler 20 includes a housing 2Oj configured and arranged for electrical connection of the analyte sensor 14 to at least some system electronics, such as an electronic cable (not shown).
  • the housing 2Oj includes a housing cover 20k and an electrical connector 2On. While a female socket 2On (e g., configured to releasably mate with a male plug) is shown, any electrical connection known in the art can be used, as is appreciate by one skilled in the art
  • Figs. 1G-1H are exploded and cut-away views, respectively, of the embodiment shown in Fig. IF.
  • the encircled portion of Fig. IH is shown in Fig. IJ and illustrates the configuration of the distal portion of the analyte sensor 14 within the housing 2Oj, in this embodiment.
  • the analyte sensor can be configured and arranged to detect one or more analytes, as described elsewhere herein.
  • the proximal portion (ex vivo portion) of the analyte sensor 14 is configured and arranged for electrical connection with the sensor electronics via one or more elastomeric contacts and/or connectors 20s and a printed circuit board (PCB) 2Ot disposed within the housing.
  • PCB printed circuit board
  • connection is a solderless connection.
  • electrical connection of the electrodes to the electronics can be made by other means, for example, wires, contact pads, pogo pins, domed metallic contacts, cantilevered fingers, metallic springs, soldering and/or conductive adhesive.
  • an elastomeric contact and/or connector 20s which can be manufactured of an conductive elastomeric material such as a carbon black elastomer, makes an electrical connection between each of the sensor's electrodes (e.g., working (plus or minus enzyme), counter and/or reference electrodes) and the PCB
  • working (plus or minus enzyme), counter and/or reference electrodes) e.g., working (plus or minus enzyme), counter and/or reference electrodes
  • the electrodes make contact with the elastomeric contacts, and the elastomeric contacts make contact with the PCB.
  • the PCB is configured and arranged to make an electrical connection with at least some of the system electronics, such as but not limited to by socket 2On.
  • Conductive elastomers are advantageously employed because their resilient properties create a natural compression against mutually engaging contacts, forming a secure press fit therewith.
  • conductive elastomers can be molded in such a way that pressing the elastomer against an adjacent contact performs a wiping action on the surface of the contact, thereby creating a cleaning action during initial connection.
  • the sensor 14 extends through the contacts 20s wherein the sensor is electrically and mechanically secured by the relaxation of elastomer around the sensor.
  • a conductive, stiff plastic forms the contacts, which are shaped to comply upon application of pressure (for example, a leaf-spring shape).
  • Contacts of such a configuration can be used instead of a metallic spring, for example, and advantageously avoid the need for crimping or soldering through compliant materials; additionally, a wiping action can be incorporated into the design to remove contaminants from the surfaces during connection.
  • Non-metallic contacts can be advantageous because of their seamless manufacturability, robustness to thermal compression, non-corrosive surfaces, and native resistance to electrostatic discharge (ESD) damage due to their higher-than-metal resistance.
  • each electrode While in this embodiment (e.g., shown in Figs. IH and IJ), the proximal portion (e.g., part of the ex vivo portion, also referred to herein as the first portion) of each electrode physically contacts the bottom of (e.g., beneath) an elastomeric connector, the electrodes can make an electrical connection with elastomeric contacts by a variety of other ways. For example, in some embodiments, one or more of the electrodes can contact the top and/or side of the elastomeric contacts (e.g., above and/or beside). Tn still other embodiments, an electrode can intersect an elastomeric contact (e.g., pass through at least a portion of the elastomeric contact).
  • the proximal portion of an electrode can be wrapped around an elastomeric contact.
  • Additional configurations are considered in the preferred embodiments.
  • the different configurations can be combined, such as for example, with one electrode touching the bottom of a first elastomeric contact, a second electrode touching the top of a second elastomeric contact, and a third electrode passing through yet another elastomer contact.
  • the interior of the housing is configured to guide placement of the electrodes for contact with the elastomeric contacts, which can simplify manufacturing and ensure formation of a good electrical contact between each electrode and its corresponding elastomeric contact.
  • pathways e.g., recessed
  • wells or cups are provided to receive the elastomeric contacts.
  • the proximal portion of each of the sensor's electrodes are received into one of the three pathways provided, an elastomeric contact 20s is placed in each of the three wells, and then the PCB 2Ot is placed on top of the elastomeric contacts.
  • the housing cover 20k which, in some embodiments, includes a connector 2On, is applied to close the housing.
  • Fig. IK illustrates another embodiment of the analyte sensor 14 is incorporated into a fluid coupler 20.
  • the sensor is configured such that it extends at least a portion of the length of the lumen 2Of of the fluid coupler, but does not extend out of the fluid coupler itself (e g , past the fluid coupler's first orifice 2Oh)
  • the first side 20a of the fluid coupler releasably mates with the catheter hub 18, such that a portion of the fluid coupler's first orifice 2Oh is located within a portion of the catheter hub's duct or lumen (e.g., 18b, see Figs. ID-IE).
  • the sensor tip 14a can be located within the catheter hub's duct or lumen.
  • this embodiment simplifies device installation as no insertion of the sensor into a catheter is required. Additionally, sensor performance is maintained because the sensor is protected by the fluid coupler's hard structure during connection of the fluid coupler to the catheter (e.g., the sensor cannot be accidentally touched, bent or flexed during installation).
  • function of an enzymatic analyte sensor is dependent upon the kinetics of the enzyme comprised in the sensor.
  • the function of a glucose sensor is dependent upon the kinetics of the glucose oxidase contained in the sensor's membrane.
  • enzyme kinetics are influenced by the availability of the reactants. When all required reactants are freely available, the enzyme will react at its maximum rate, given the prevailing temperature and pH conditions. If, on the other hand, the concentration of one of the reactants is low (e.g., limiting), the enzyme reaction will proceed at a slower rate, which is associated with the concentration of the limited reactant.
  • a particular reactant e.g., the analyte
  • that reactant should be present in limiting amounts.
  • the other reactants e.g., a co-reactant
  • the reactants should be present in excess (e.g., non-limiting amounts).
  • glucose and oxygen are the reactants of some GO££- containing glucose sensors. Since the analyte is glucose, oxygen (e.g., the co-reactant) should be present in excess (e.g., non-limiting), so that the reaction rate is dependent upon the glucose concentration. In some circumstances, however, the co-reactant is limiting.
  • the senor is configured to compensate for a limiting reactant, such as but not limited to oxygen.
  • the membrane can be configured and arranged to restrict the amount of excess reactant that diffuses therethrough (e.g., see the section entitled "Resistance Domain ”) Tn other embodiments, the sensor can be configured to increase the level of limiting reactant (e.g., co- reactant).
  • the membrane can include a domain configured to increase the concentration of oxygen.
  • the vascular access device such as the ex vivo portion of a catheter or a fluid coupler can be configured to increase the amount of oxygen (e.g., co-reactant) available to the enzyme.
  • the fluid coupler 20 of Fig. IK includes an enrichment body 2Op configured and arranged to increase the oxygen concentration at the sensor 14.
  • An enrichment body 2Op can be provided in many forms.
  • the enrichment body includes an "oxygen port" including a membrane, plug or filter located in a side of the fluid coupler.
  • the oxygen port intersects the fluid coupler wall, such that oxygen can diffuse from the exterior of the fluid coupler to the lumen 2Of.
  • the oxygen port includes a plug and/or membrane formed of silicone, ePTFE or other polymer known to increase oxygen diffusion.
  • the enrichment body 2Op includes an "oxygen capacitor" configured to absorb oxygen when the oxygen concentration (e.g., around the sensor) is high, and to release the absorbed (e.g., stored) oxygen when the oxygen concentration is low.
  • the infusion solution is oxygenated, such that as the infusion solution flows through the fluid coupler and/or catheter and contacts the oxygen capacitor, the capacitor absorbs at least some of the oxygen present in the solution.
  • the oxygen capacitor is an oxygen-absorbing and oxygen- releasing polymer applied to the lumenal surface of the fluid coupler and/or catheter.
  • the oxygen capacitor is a membrane or plug attached to the lumenal surface of the catheter and/or fluid coupler.
  • the enrichment body is inserted into the lumen of the fluid coupler and/or catheter hub.
  • Fig. IL illustrated an embodiment similar to that of Fig. IK, except that at least a portion of the sensor 14 extends toward the fluid coupler's 20 second side 20b.
  • the sensor tip extends to the fluid coupler's second orifice 20i, but not there past.
  • the sensor is configured to extend into connected tubing. Accordingly, in this embodiment, the sensor's electroactive surface(s) can be located at any point along the length of the fluid coupler's lumen 2Of.
  • Fig. IM illustrates yet another embodiment of an analyte sensor incorporated into a fluid coupler 20.
  • at least one analyte sensor 14 is located on a support 2Oq that is located on the lumenal surface of the fluid coupler
  • the support including the at least one analyte sensor located thereon, is inserted into the fluid coupler via an orifice (e.g., 2Oi).
  • the fluid coupler includes a port (e.g., an orifice, hole or opening, not shown) configured and arranged to receive the support (e.g., the port and the support are configured to mate with each other), such as via insertion through the wall of the fluid coupler.
  • the at least one analyte sensor comprises two or more analyte sensors, wherein the analyte sensors are configured to detect one or more analytes. In some embodiments, the at least one analyte sensor comprises 3, 4, 5, 6, 7, 8, 9, 10 or more analytes sensors. In some embodiments, the at least one analyte sensor comprises a plurality of micro- fabricated sensors, such as but not limited to a sensor array. The sensor(s) can be applied to and/or deposited on the support using any method known in the art, such as but not limited to thin and/or thin film techniques, printing, plating, and the like.
  • an analyte sensor is configured to intersect the support, such as described with reference to Figs. 2M-2Q.
  • the sensor e.g., working electrode
  • the sensor is substantially flush with the support, similar to the manner of some glucose test strips that have electrodes printed on a planar support using thin and/or thick film techniques.
  • the sensor e.g., working electrode
  • the support is manufactured from a polymer.
  • the polymer is configured for malleability during manufacture but also provides sufficient strength to function as a side of the fluid coupler.
  • the support is formed from a metal, a ceramic or glass.
  • the support can have any shape, such as a planar or non-planar shape.
  • the support has a planar lumenal surface (e.g., the surface of the support that faces the lumen of the fluid coupler).
  • the support's lumenal surface is curved.
  • the support e.g., with sensor(s) applied thereto
  • the support is received into a port.
  • the support makes a friction fit into the port.
  • the support and port are configured for a snap fit of the support into the port.
  • the support can be secured into the port with an adhesive, hooks, pins, and/or via welding.
  • the support (including one or more analyte sensors) is inserted into the lumen of the fluid coupler.
  • the fluid coupler does not include a port; rather the support (e.g., including sensors) is inserted through one of the fluid coupler's orifices, such that the support is located adjacent to and/or on the fluid coupler's lumenal surface.
  • the support is configured to conform to the lumenal surface of the fluid coupler.
  • the support is attached to the lumenal surface of the fluid coupler, such as with adhesive or welding.
  • a catheter hub includes a port configured for receipt of the support.
  • manufacturing the sensor(s) on a support and then integrating them with the fluid coupler simplify manufacturing and reduce costs by enabling high through put, automated manufacturing methods.
  • a wider array of sensors and custom-order sensors can be easily manufactured (e.g., as "panels" of sensors that test a panel of analytes) and subsequently integrated into the fluid couplers and/or catheter hubs.
  • cassettes of sensors are manufactured in an automated reel-to-reel process wherein sensor panels (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19 or 20 or more sensors) are applied to a continuous roll of polymer material (e.g., the support), wherein the individual sensor cassettes are subsequently cut out of the roll, such as using a die.
  • sensor panels e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19 or 20 or more sensors
  • the individual sensor cassettes are subsequently cut out of the roll, such as using a die.
  • the completed sensor cassettes are installed into the ports of separately manufactured fluid couplers.
  • Sensor electronics such as a PCB and electronic connectors are applied in yet another automated process.
  • each type of sensor cassette includes a different panel of analyte sensors
  • can be manufactured e.g., simultaneously on separate manufacturing lines or on a single line at different times
  • each configuration includes a port configured to receive a single size and/or shape of sensor cassette, wherein the size and/or shape of the cassette is associated with a fluid coupler or catheter configuration.
  • each type of sensor cassette (e.g., analyte panel) includes a unique shape, such that it must be received by a port configured to mate with it, similar to an interlocking lock and key, such that certain cassettes are used with certain fluid couplers and/or catheters.
  • certain interlocking cassette and port configurations are associated with a particular panel of analytes and/or a client.
  • the sensor cassettes are configured to be replaceable prior-to and/or during use.
  • the fluid coupler is provided with two or more types of cassettes (e.g., different panels), such that the user inserts a selected cassette into the fluid coupler's port prior to use.
  • the fluid coupler can be provided with two or more cassettes of the same type, such that the cassette can be changed out during use. For example, if a sensor on a first cassette fails, the cassette can be replaced with a second cassette of the same type.
  • Analyte sensors and manufacturing methods suitable for use with these embodiments can be found in U.S. Patent No. 5,108,819, U.S. Patent No. 5, 178,957, U.S. Patent No. 5,879,828, U.S. Patent No. 6,175,752, U.S. Patent No. 6,284,478, U.S Patent No. 6,329,161, U.S. Patent No. 6,565,509, U.S. Patent No. 6,990,366, U.S. Patent No.
  • Figs. 2A to 2B illustrate one exemplary embodiment of an analyte sensor integrally formed on a catheter.
  • the system 210 is configured to measure an analyte and generally includes a catheter 212 configured for insertion into a host's blood stream (e.g., via a vein or artery) and a sensor at least partially integrally formed on the catheter's exterior surface 232.
  • the sensor 214 includes at least one exposed electroactive area 240 (e.g., a working electrode), a membrane system (e.g., including an enzyme), a reference electrode (proximal to or remote from the working electrode), and an insulator.
  • the catheter includes a lumen 212a and an orifice 212b at its proximal end, for providing fluid connection from the catheter's lumen to the host's blood stream (see Fig. 2A).
  • the catheter is inserted into a vein, as described elsewhere herein. In other embodiments, the catheter is inserted into an artery, as described elsewhere herein.
  • the catheter can be any type of venous or arterial catheter commonly used in the art (e.g., peripheral catheter, central catheter, Swan-Gantz catheter, etc.).
  • the catheter can be made of any useful medical grade material (e.g., polymers and/or glass) and can be of any size, such as but not limited to from about 1 French (0.33mm) or less to about 30 French (10mm) or more; for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 French (3 French is equivalent to about 1 mm).
  • the catheter is configured and arranged for insertion into neonatal or other pediatric hosts (e.g., 22-24 gauge or smaller).
  • the catheter can be a single lumen catheter or a multi-lumen catheter.
  • the catheter can include one or more perforations, to allow the passage of host fluid through the lumen of the catheter.
  • the catheter is a dual-lumen catheter wherein a first lumen is configured to receive an analyte sensor and a second lumen is configured for fluid infusion.
  • the catheter is configured such that the orifice of the first lumen is sufficiently proximal to connector (of the catheter) relative to the orifice of the second lumen, that samples drawn back into the first lumen (e.g., to be tested by the analyte sensor) are substantially undiluted by the infused fluid.
  • the catheter 212 includes (e.g., in fluid communication) a connector 218.
  • the connector can be of any known type, such as a Leur lock, a T-connector, a Y- connector, a cross-connector or a custom configuration, for example.
  • the connector includes at least one valve.
  • the connector 218 can be operatively connected to a saline system (e.g., saline bag and tubing), other medical devices (e.g., automatic blood chemistry machine, dialysis machine, a blood bag for collecting donated blood, etc.), or capped.
  • a saline system e.g., saline bag and tubing
  • other medical devices e.g., automatic blood chemistry machine, dialysis machine, a blood bag for collecting donated blood, etc.
  • the system 210 includes sensor electronics (not shown) operatively connected to the analyte sensor, wherein the sensor electronics are generally configured to measure and/or process the sensor data as described in more detail elsewhere herein.
  • the sensor electronics can be partially or wholly disposed with (e.g., integral with, disposed on, or proximal to) the connector 218 at the distal end of the catheter or partially or wholly remote from the catheter (e.g., on a stand or on the bedside).
  • the sensor electronics disposed with the connector include a potentiostat.
  • the sensor electronics are configured to measure the host's analyte concentration substantially continuously. For example, the sensor can measure the analyte concentration continuously or at time intervals ranging from fractions of a second up to, for example, 1 , 2, or 5 minutes or longer.
  • Figs. 2C to 2F illustrate additional embodiments of the sensor shown in Figs. 2A to 2B.
  • the catheter 212 is shown with an integral sensor 214 having at least one electrode 240 formed on its exterior surface 232 (e.g., Fig. 2F).
  • the sensor can be designed with 1, 2, 3, 4 or more electrodes and can be connected by traces (or the like) to electrical contacts 218d (or the like) at the second end of the connector 218 (e.g., Figs. 2A to 2F).
  • the sensor is hard-wired to the sensor electronics; alternatively, any operable connection can be used.
  • the sensor includes at least one working electrode and at least one reference or counter electrode.
  • the reference electrode is located proximal to the at least one working electrode (e.g., adjacent to or near to the working electrode). In some alternative embodiments, the reference electrode is located remotely from the working electrode (e.g., away from the working electrode, such as but not limited to within the lumen of the catheter 212 (or connector 218), on the exterior of the sensor system, in contact with the patient (e.g., on the skin), or the like). In some embodiments, the reference electrode is located proximal to or within the fluid connector, such as but not limited to, coiled about the catheter adjacent to the fluid connector or coiled within the fluid connector and in contact with fluid flowing through the fluid coupler, such as saline or blood.
  • the senor can also include one or more additional working electrodes (e.g., for measuring baseline, for measuring a second analyte, or for measuring a substantially non-analyte related signal, and the like, such as described in more detail in U.S. Patent Publication No. US-2005-0143635-A1 and U.S. Patent Publication No. US- 2007-0027385-A1, which are incorporated herein by reference in their entirety.
  • one or more counter electrodes can be provided on a surface of the catheter or within or on the fluid connector.
  • the catheter is designed to indwell within a host's blood flow (e.g., a peripheral vein or artery) and remain in the blood flow for a period of time (e.g., the catheter is not immediately removed).
  • a host's blood flow e.g., a peripheral vein or artery
  • the indwelling catheter can be inserted into the blood flow for example, for a few minutes or more, or from about 1 to 24 hours, or from about 1 to 10 days, or even longer.
  • the catheter can indwell in the host's blood stream during an entire perioperative period (e.g., from host admittance, through an operation, and to release from the hospital).
  • the catheter is configured as an intravenous catheter (e.g., configured to be inserted into a vein).
  • the catheter can be inserted into any commonly used vein, such as in a peripheral vein (e.g., one of the metacarpal veins of the arm); in some embodiments (e.g., such as described with reference to Figs. IA to IE) the analyte sensor inserted into a catheter.
  • the sensor is integrally formed on a catheter such as described in more detail with reference to Figs. 2A to 2F, for example.
  • Other veins such as leg or foot veins, hand veins, or even scalp or umbilical veins, can also be used.
  • the intravenous catheter can be used for delivery of fluids and/or drugs to the host's circulatory system.
  • the catheter can be configured to be coupled to other medical devices or functions, for example, saline, blood products, total parenteral feeding or medications can be given to the host via the indwelling intravenous catheter.
  • the catheter can be operatively connected to a pump, such as an infusion pump, to facilitate flow of the fluids into the host and a desired rate.
  • a pump such as an infusion pump
  • an infusion pump can pump saline into the host at a rate of Ice per minute, or at higher or lower rates.
  • the rate of infusion can be changed (increased or decreased).
  • an infusion can be temporarily stopped, to permit injection of pain medication into the IV system, followed by increasing the infusion rate (e.g., for 5 minutes) to rapidly deliver the pain medication to the host's circulatory system.
  • the catheter is configured as an arterial catheter (e.g., configured to be inserted into an arterial line or as part of an arterial line).
  • an arterial catheter is inserted in the wrist (radial artery), armpit (axillary artery), groin (femoral artery), or foot (pedal artery).
  • arterial catheters provide access to the host's blood stream (arterial side) for removal of blood samples and/or application of test devices, such as but not limited to a pressure transducer (for measuring blood pressure automatically), however, arterial catheters can also ⁇ be used for delivery of fluids or medications.
  • a catheter is inserted into an arterial line and the sensor inserted into the catheter (e.g., functionally coupled) as described elsewhere herein Saline filled non-compressible tubing is then coupled to the sensor, followed by a pressure transducer.
  • An automatic flushing system e.g., saline
  • Electronics are generally operatively coupled to the pressure transducer for calculating and displaying a variety of parameters including blood pressure.
  • Other medical devices can also be connected to the arterial catheter, to measure various blood components, such as but not limited to Cb, CO2, PCO2, PO2, potassium, sodium, pH, lactate, urea, bilirubin, creatinine, hematocrit, various minerals, various metabolites, and the like.
  • various blood components such as but not limited to Cb, CO2, PCO2, PO2, potassium, sodium, pH, lactate, urea, bilirubin, creatinine, hematocrit, various minerals, various metabolites, and the like.
  • a blood pressure measurement system is inserted into the host and can be used as is known in the art.
  • the analyte sensor e.g., glucose sensor
  • the pre-inserted catheter e.g., already in-dwelling catheter
  • the pressure transducer is temporarily disabled by disconnecting from the pre-inserted catheter.
  • a cap covers the protective slotted sheath and can be removed so as to enable the sensor to be grasped at the fluid coupler.
  • the sheath which is generally more rigid than the sensor but less flexible than a needle, is then threaded through the pre-inserted catheter so as to extend beyond the catheter into the blood stream (e.g., by about 0.001 inches to about 1 inches).
  • the sheath is then removed by sliding the sensor through a small outlet hole and/or slot in the sheath.
  • the sensor remains within the pre-inserted catheter and the fluid coupler, which supports the distal portion of the sensor, is coupled to the catheter itself.
  • Saline filled non-compressible tubing is then coupled to the second side (e.g., back end) of the fluid coupler.
  • the sensor electronics are then operatively connected (e.g., wired or wirelessly) to the sensor to initiate sensor function.
  • a portion of the sensor system can be configured to allow removal of blood samples from the host's blood stream (e.g., artery or vein).
  • Sample removal can be done using any systems and methods known in the art, for example, as is practiced for removing a blood sample from an arterial catheter (e.g., and arterial line).
  • any tubing or equipment coupled to the second side of the fluid coupler is disconnected A syringe is then be coupled to the second side aftd blood removed via the catheter by pulling back on the syringe plunger.
  • saline can be flushed through the fluid coupler and catheter.
  • the fluid coupler can be configured with a side valve, to allow coupling of a syringe, for removal of blood samples or delivery of fluids, such as medications, without disconnecting attached tubing of equipment, and the like.
  • a valve or diaphragm for access to the system by a syringe, can be coupled into the tubing at a short distance from the fluid coupler.
  • the sensor is integrally formed on the arterial catheter, such as the embodiment shown in Figs. 2A-2B, and tubing can be disconnected from the connector, a syringe operably associated with the connector, and blood removed with the syringe. After blood collection, the syringe is removed and the tubing reconnected to the connector.
  • the analyte sensor can be functionally coupled to an extraco ⁇ oreal blood flow device.
  • a variety of devices exist for testing various blood properties and/or analytes at the bedside such as but not limited to the blood gas and chemistry devices manufactured by Via Medical, Austin, Texas, USA. These devices generally withdraw a blood sample from the host, test the blood sample, and then return it to the host.
  • Such a device can be connected in series to the arterial catheter, with the sensor in-between, and using systems and methods known in the art.
  • a sensor such as the embodiment shown in Figs.
  • the extraco ⁇ oreal blood flow device is connected to the second side of the fluid coupler.
  • the sensor is integrally formed on the arterial catheter, such as the embodiment shown in Figs. 2A-2F, and the extraco ⁇ oreal blood flow device is functionally connected to the connector 218.
  • Other devices such as but not limited to dialysis machines, heart-lung bypass machines or blood collection bags, or other vascular access devices, can be functionally coupled to the analyte sensor.
  • the analyte sensor system of the preferred embodiments can be designed with a variety of alternative configurations.
  • the sensor is connected to a fluid connection device.
  • the fluid connection device in these embodiments can be any standard fluid connection device known in the art, such as a fluid coupler, or a fluid coupler custom manufactured to preferred specifications
  • the fluid coupler is configured to couple to an existing catheter or cannula (as described with reference to Figs. IA-IE)
  • the catheter (or cannula) ⁇ is typically inserted into a vascular access device and/or into a hospital host during a hospital stay.
  • the catheter can be inserted into an arterial line (e.g., for removing blood samples or for measuring blood pressure using a pressure transducer) or a venous line (e.g., for intravenous delivery of drugs and other fluids).
  • the catheter is inserted into the host's blood vessel, for example, and maintained there for a period of time during the host's hospital stay, such as part of the stay or during the entire stay (e.g., perioperatively).
  • another vascular access device e.g., other than a catheter
  • the sensor system of the preferred embodiments can be inserted into a vascular access device (e.g., rather than the vascular system directly).
  • vascular access devices include but are not limited to, catheters, shunts, automated blood withdrawal devices and the like.
  • the system 10 is configured such that the sensor is inserted into a vascular access device, such as but not limited to a catheter 12 (e.g., a catheter that has been inserted into the host's blood stream prior to sensor insertion).
  • a catheter 12 e.g., a catheter that has been inserted into the host's blood stream prior to sensor insertion.
  • catheters are small, flexible tubes (e.g., soft catheter) but they can also be larger, rigid tubes.
  • Catheters are inserted into a host's body cavity, vessel, or duct to provide access for fluid removal or insertion, or for access to medical equipment.
  • Catheters can also be inserted into extracorporeal devices, such as but not limed to an arterio-venous shunt for the transfer of blood from an artery to a vein.
  • Some catheters are used to direct access to the circulatory system (e.g., venous or arterial catheters, Swan Gantz catheters) to allow removal of blood samples, the infusion of fluids (e g , saline, medications, blood or total parenteral feeding) or access by medical devices (e.g., stents, extracorporeal blood chemistry analysis devices, invasive blood pressure monitors, etc.).
  • venous or arterial catheters e.g venous or arterial catheters, Swan Gantz catheters
  • fluids e.g , saline, medications, blood or total parenteral feeding
  • medical devices e.g., stents, extracorporeal blood chemistry analysis devices, invasive blood pressure monitors, etc.
  • the senor is designed to include a protective cap, as illustrated in Figs. 1A-1E.
  • Fig. IA and IB illustrates the catheter (the catheter cap having been removed prior to insertion), well known to those skilled in the art, which can be inserted into the host's blood vessel using standard methods.
  • the sensor 14 is configured for measurement of an analyte (e.g., glucose) in the host's body, and is in fluid connection within the catheter lumen, which is in fluid connection with the fluid coupler 20 of the sensor.
  • the first side 20a of the fluid coupler 20 of the sensor is designed to couple to the catheter, e.g., by screwing or snapping thereon, and can also couple (on its second side 20b) with other medical devices.
  • One advantage of the fluid coupler is that it provides for a small amount of bleed back, to prevent air bubbles in the host's blood stream.
  • the exemplary sensor system 10 of Fig. IA and IB further includes a slotted protective sheath 26 that supports and protects the sensor during sensor insertion, for example, the sheath increases the sensor visibility (e.g., the sensor is so thin that it can be difficult for some people to see without the protective sheath) and provides for ease of sliding the sensor into the catheter.
  • the slotted protective sheath is configured to fit within the fluid coupler and houses the sensor during insertion of the sensor into the catheter (e.g., an indwelling catheter within the host's blood flow).
  • the protective sheath is substantially more rigid than the sensor and at the same time substantially more flexible that a standard syringe needle, however other designs are possible.
  • a slot 30 is provided with an optional outlet hole 30a, which is described in more detail with reference to Fig. 1C, and a hub 28.
  • the user e.g., health care professional
  • a cap is provided, to cover the protective sheath, for example, to keep the sheath and sensor sterile, and to prevent damage to the components during shipping and/or handling.
  • the sensor system is configured with a potentiostat and/or sensor electronics that are operatively coupled to the sensor.
  • a portion of the sensor electronics such as the potentiostat, can be disposed directly on the fluid coupler.
  • some or all of the sensor electronics can be disposed remotely from the fluid coupler (e.g., on the bedside or on a stand) and can be functionally coupled (e.g., wired or wireless), as is generally known to those skilled in the art.
  • Figs. ICl and 1C2 are cross-sectional views (not to scale) of the fluid coupler, including a protective sheath 26, a sensor 14, and a cap 32 (cap to be removed prior to insertion) in one embodiment.
  • the protective sheath 26 extends through the fluid coupler and houses the sensor, for sensor insertion into a catheter.
  • the protective sheath includes an optional outlet hole 30a, through which the sensor extends and a slot 30 along a length of the protective sheath that communicates with the outlet hole and enables the protective sheath to be removed after the sensor has been inserted into the host's body
  • the protective sheath includes a hub 28 for handling.
  • the glucose sensor is utilized in combination with another medical device (e.g., a medical device or access port that is already coupled to, applied to, or connected to the host) in a hospital or similar clinical setting.
  • a catheter can be inserted into the host's vein or artery, wherein the catheter can is connected to additional medical equipment.
  • the catheter is placed in the host to provide quick access to the host's circulatory system (in the event of a need arising) and is simply capped.
  • a dialysis machine can be connected to the host's circulatory system.
  • a central line can be connected to the host, for insertion of medical equipment at the heart (e.g., the medical equipment reaches the heart through the vascular system, from a peripheral location such as a leg or arm pit).
  • the access port is opened
  • the cap is removed and the sensor inserted into the catheter.
  • the back end of the sensor system can be capped or attached to additional medical equipment (e.g., saline drip, blood pressure transducer, dialysis machine, blood chemistry analysis device, etc.).
  • additional medical equipment e.g., saline drip, blood pressure transducer, dialysis machine, blood chemistry analysis device, etc.
  • medical equipment e g , saline drip, blood pressure transducer, dialysis machine, blood chemistry analysis device, etc.
  • the medical equipment is disconnected from the catheter, the sensor inserted into (and coupled to) the catheter and then the medical equipment reconnected (e.g., coupled to the back end of the sensor system).
  • the senor is inserted directly into the host's circulatory system without a catheter or other medical device.
  • the sheath covering the sensor is relatively rigid and supports the sensor during insertion. After the sensor has been inserted into the host's vein or artery, the supportive sheath is removed, leaving the exposed sensor in the host's vein or artery.
  • the sensor is inserted into a vascular access device (e.g., with or without a catheter) and the sheath removed, to leave the sensor in the host's vein or artery (e.g., through the vascular access device).
  • the cap 32 over the protective sheath is removed as the health care professional holds the glucose sensor by the fluid coupler 20.
  • the protective sheath 26 which is generally more rigid than the sensor but more flexible than-a needle, is then threaded through the catheter so as to extend beyond the catheter into the blood flow (e.g., by about 0.010 inches to about 1 inches).
  • the protective sheath is then removed by sliding the sensor through the (optional) outlet hole 30a and slotted portion 30 of the sheath (e.g., by withdrawing the protective sheath by pulling the hub 28).
  • the sensor remains within the catheter; and the fluid coupler 20, which holds the sensor 14, is coupled to the catheter itself (via its connector 18).
  • the sensor electronics e.g., adjacent to the fluid coupler or otherwise coupled to the fluid coupler
  • the sensor electronics are then operatively connected (e.g., wired or wirelessly) to the sensor for proper sensor function as is known in the art.
  • the catheter 12 includes a plurality of perforations (e.g., holes) that allow the host's fluid (e.g., blood) to flow through the lumen 12a of the catheter.
  • the fluid flowing through the catheter can make contact with a sensor 14 inserted therein.
  • the sensor does not protrude out of the catheter's tip 12b and the host's blood flowing through the perforated catheter's lumen contacts the sensor's electroactive surfaces.
  • the catheter 12 includes at least a first lumen and a second lumen.
  • the sensor 14 is configured for insertion into the catheter's first lumen.
  • the second lumen can be used for infusions into the host's circulatory system or sample removal without disturbing the sensor within the first lumen.
  • Figs. 2A-2F are schematic views of a sensor integrally formed (integrally incorporated) onto a surface of a catheter, in some exemplary embodiments.
  • the sensor can be integrally formed on an exterior surface 232 of the catheter.
  • the sensor can be integrally formed on an interior surface of the catheter (e.g., on a lumenal surface).
  • the sensor can be integrally formed on the sensor's tip (e.g., as indicated by 214a).
  • the sensor can be integrally incorporated with the catheter, for example by bonding a sensor of the type described in Figs. 3A to 3C into an inner or outer surface of the catheter.
  • one or more of the electrodes is deposited on the in vivo portion of the catheter 212, such as via screen-printing and/or electrospinning.
  • at least one of the electrodes 240 such as but not limited to a counter and/or a reference electrode is deposited within the ex vivo portion of the catheter (e.g., within the connector/hub).
  • two working electrodes 240 are disposed on the exterior surface 232 of the catheter's in vivo portion. The first working electrode is configured to generate a signal associated with the analyte and with non-analyte-related species that have an oxidation/reduction potential that overlaps with that of the analyte.
  • the second working electrode is configured to generate a signal associated with non-analyte-related species that have an oxidation/reduction potential that overlaps with that of the analyte.
  • the signals of the first and second working electrodes can be processed to provide a substantially analyte-only signal.
  • Continuous analyte sensors including two working electrodes are described in greater detail elsewhere herein, in U.S. Patent Publication No. US-2007-0027385-A1, U.S. Patent Publication No. US-2007-0213611-A1, U.S. Patent Publication No. US-2007-0027284-A1, U.S. Patent Publication No. US-2007-0032717-A1, U.S. Patent Publication No. US-2007-0093704- Al, and U.S. Patent Publication No. US-2008-0083617-AJ, each of which is incorporated herein by reference in its entirety.
  • one or more analyte sensors are disposed (e.g., deposited, formed) on the exterior surface of the in vivo portion of the catheter.
  • Each sensor can include one, two or more working electrodes. The electrodes can be configured as described elsewhere therein.
  • the catheter 12 is configured with two or more analyte sensors, wherein each of the sensors is configured to detect a different analyte and/or a property of the sample, as described elsewhere herein.
  • the sensors are configured to detect at least two analytes such as but not limited to albumin, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, COa, chloride, creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit, lactate, lactate dehydrogenase, magnesium, oxygen, pH, phosphorus, potassium, sodium, total protein, uric acid, a metabolic marker, various drugs, various minerals, various metabolites, and the like.
  • analytes such as but not limited to albumin, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, COa, chloride, creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit, lactate, lactate dehydrogena
  • At least one of the sensors is configured to detect a property of the host's blood, such as but not limited to pH, oxygen tension, PCO 2 , PO 2 , temperature, hematocrit, and the like.
  • one or more of the plurality of analyte sensor can be configured as a backup or redundant sensor to a first sensor, such as to confirm the correct functioning of the first sensor
  • two glucose sensors could be disposed within the connector, such that Ae second glucose sensor provides a confirmation of the first glucose sensor's measurements.
  • the sensor system is provided with a cap 32 that covers the catheter and the in vivo portion of the integral sensor (e.g., see Fig. IC2).
  • a needle or trochar that runs the length of the catheter supports the device during insertion into the host's blood stream.
  • medical caregiver holds the device by the fluid connector 218 and removes the cap to expose the in vivo portion of the device (e.g., the catheter).
  • the caregiver inserts the in vivo portion of the device into one of the host's veins or arteries (depending upon whether the catheter is an intravenous catheter or an arterial catheter) After insertion, the needle is withdrawn from the device.
  • the device is then capped or connected to other medical equipment (e.g., saline bag, pressure transducer, blood collection bag, total parenteral feeding, dialysis equipment, automated blood chemistry equipment, etc.).
  • other medical equipment e.g., saline bag, pressure transducer, blood collection bag, total parenteral feeding, dialysis equipment, automated blood chemistry equipment, etc.
  • the sensor-integrated catheter can be in communication (e.g., fluid communication) with the host's vascular system through a vascular access device.
  • an analyte sensor system includes a sensing mechanism substantially similar to that described in U.S. Patent Publication No. US-2006-0020187-A1, which is incorporated herein by reference in its entirety; for example, with platinum working electrode and silver reference electrode coiled there around.
  • the reference electrode can be located remote from the working electrode so as not to be inserted into the host, and can be located, for example, within the fluid coupler 20, thereby allowing a smaller footprint in the portion of the sensor adapted for insertion into the body (e.g., blood stream); for example, without a coiled or otherwise configured reference electrode proximal to the working electrode.
  • the reference electrode can be located away from the working electrode (e.g., the electroactive portion) at any location and with any configuration so as to maintain bodily and/or in fluid communication therewith as is appreciated by one skilled in the art.
  • the sensor tip 14a includes an enlarged, atraumatic area, for example a dull or bulbous portion about two times the diameter of the sensor or larger.
  • the enlarged portion is created by heating, welding, crushing or bonding a substantially rounded structure onto the tip of the sensor (e.g., polymer or metal)
  • the tip of the sensor is heated (e.g., arc welded or flash-butt resistance welded) to cause the tip to enlarge (e.g., by melting).
  • the enlarged portion can be of any atraumatic shape, such as but not limited to oval, round, cone-shaped, cylindrical, teardrop, etc.
  • an atraumatic or enlarged area enables enhanced stability of a small diameter sensor in the blood flow and ensures that the sensor remains within the blood flow (e.g., to avoid piercing a vessel wall and/or becoming inserted subluminally.)
  • one or more additional working electrodes can be provided on the sensor for measuring baseline, and thereby subtracting the baseline from the first working electrode to obtain a glucose-only signal and/or to measure additional analytes, as disclosed in copending U.S. Patent Publication No. US-2005-0143635-A1, U.S. Patent Publication No. US- 2007-0027385-A1, U.S. Patent Publication No. US-2007-021361 1-A1, and U.S. Patent Publication No. US-2008-0083617-A1, all of which are herein incorporated by reference in their entirety.
  • some embodiments of the analyte sensor system include a catheter 212 adapted for inserting into a host in a hospital or clinical setting, wherein the analyte sensor 214 is built integrally with the catheter 212.
  • a glucose sensor can be integrally formed on the catheter itself.
  • Figs 2A-2B illustrate one embodiment, wherein the catheter 212 is configured both for insertion into a host, and can be configured to couple to other medical devices on its ex vivo end. However, coupling to other medical devices is not necessary.
  • the catheter includes a connector 218 configured for connection to tubing or other medical devices, as described herein. The embodiment shown in Figs.
  • the catheter 2A-2B includes two or three electrodes 240 on the outer surface of the in vivo portion of the catheter 212
  • the catheter is perforated (as described elsewhere herein) and at least one electrode is disposed within the lumen (not shown) of the perforated catheter.
  • the catheter includes a single lumen. In other embodiment, the catheter includes two or more lumens.
  • At least one working electrode 240 is disposed on the exterior surface of the in vivo portion of the catheter.
  • the at least one working electrode can be disposed on an interior surface of the catheter, on the tip of the catheter, extend from the catheter, and the like.
  • the preferred embodiments can be designed with any number of electrodes, including one or more counter electrodes, one or more reference electrodes, and/or one or more auxiliary working electrodes.
  • the electrodes can be of relatively larger or smaller surface area, depending upon their uses.
  • a sensor includes a working electrode and a reference electrode that has a larger surface area (relative to the surface area of the working electrode) on the surface of the catheter.
  • a sensor in another example, includes a working electrode, a counter electrode, and a reference electrode sized to have an increased surface area as compared to the working and/or counter electrode.
  • the reference electrode is disposed at a location remote from the working electrode, such as within the connector (e.g., coiled within the connector). In some embodiments, the reference electrode is located on the host's body (e.g., in body contact).
  • the electrodes 240 can be deposited on the catheter using any suitable techniques known in the art, for example, thick or thin film deposition techniques.
  • the electrodes can be formed of any advantageous electrode materials known in the art (e.g., platinum, platinum-iridium, palladium, graphite, gold, carbon, silver, silver-silver chloride, conductive polymer, alloys, combinations thereof, and the like).
  • one or more of the electrodes is formed from an electrically conductive material (e g , wire or foil comprising platinum, platinum- iridium, palladium, graphite, gold, carbon, silver, silver-silver chloride, conductive polymer, alloys, combinations thereof, and the like) applied to the exterior surface of the catheter, such as but not limited twisting, coiling, rolling or adhering.
  • an electrically conductive material e g , wire or foil comprising platinum, platinum- iridium, palladium, graphite, gold, carbon, silver, silver-silver chloride, conductive polymer, alloys, combinations thereof, and the like
  • the catheter is (wired or wirelessly) connected to sensor electronics (not shown, disposed on the catheter's connector and/or remote from the catheter) so as to electrically connect the electrodes on the catheter with the sensor electronics.
  • sensor electronics not shown, disposed on the catheter's connector and/or remote from the catheter
  • the inserted catheter can be utilized by other medical devices for a variety of functions (e.g., blood pressure monitor, drug delivery, etc).
  • a plurality of analyte sensors 240 are disposed within a widened portion of the catheter, such as but not limited to a flared portion and/or a connector portion 212, or within the interior of a connector 250, such as but not limited to a Leur lock, a Y-connector, a T-connector, an X-connector, and a valve, wherein a first side/end of the connector is configured to be coupled and/or connected to another vascular access device, such as a catheter or cannula, and a second side (e.g., end) of the connector is configured to be coupled/connected to other IV equipment, such as another connector, a valve, IV tubing, and the like.
  • a connector 250 such as but not limited to a Leur lock, a Y-connector, a T-connector, an X-connector, and a valve
  • a first side/end of the connector is configured to be coupled and/or connected to another vascular access device, such as
  • Fig. 2G is a cross section of a vascular access device including a plurality of analyte sensors 240 in one embodiment.
  • the vascular access device such as a catheter includes an in vivo portion configured for insertion into a circulatory system of the host, including a lumen 212a, and a connector 218 having a wall 260 defining a duct 218b.
  • an inner diameter of the connector is greater than an inner diameter of the in vivo portion.
  • the vascular access device is a 20-guage or smaller catheter.
  • the in vivo portion of the catheter is configured and arranged for insertion into a circulatory system of a pediatric host, such as but not limited to a neonatal host.
  • the vascular access device is configured and arranged for receipt of a sample of a bodily fluid of a host (e.g., blood after catheter insertion).
  • the vascular access device includes a catheter 212 having a lumen 212a and a small orifice 212b.
  • the vascular access device includes a connector 218, also referred to herein as the "hub.”
  • the hub includes an orifice 218c, which is configured for connection (e.g., fluid communication) with other IV equipment, such as via one or more flanges 218a.
  • the connector 218 also includes a duct 218b, also referred to a widened portion (as compared to lumen 212a, which may be referred to as the connector's lumen.
  • a plurality of analyte sensors 240 is disposed within the duct 218b.
  • the device includes an analyte sensor 240, wherein at least a portion of the analyte sensor is located in the lumen or duct, such that the analyte sensor is located within about 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, 4, 3, 2, or l-mm or less from a source of the biological sample.
  • the electroactive surfaces are within about 40-mm or less of the blood prior to drawing the blood back into the hub of an implanted catheter or into a fluid coupler connected to an implanted catheter.
  • the analyte sensor is located within about 30"-mm or less from a source of the sample.
  • the device is configured such that the analyte sensor is bathed in the sample when (no more than) about 1000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 50, 25, 15, 10, or 5- ⁇ l or less of the bodily fluid (e.g., blood) is drawn back.
  • the bodily fluid e.g., blood
  • one or more of the analyte sensors 240 is deposited and/or formed on a surface of the duct 218b, such as by screen printing or other useful deposition techniques. In some embodiments, one or more of the analyte sensors 240 is applied to the duct's surface, such as by adhering or micro welding a previously formed sensor to the duct's surface.
  • analyte sensors 240 can be configured to detect one or more analytes using any means known in the art, such as but not limited to electrochemical detection, enzymatic detection, chemical detection, physical detection, immunochemical detection, optical detection, radiometric detection, and combinations thereof.
  • electrochemical detection enzymatic detection
  • chemical detection physical detection
  • immunochemical detection enzymatic detection
  • optical detection e.g., optical senorization
  • radiometric detection e.g., radiometric detection, and combinations thereof.
  • a first sensor 240 is configured to detect glucose electrochemically
  • a second sensor 240 is configured to detect oxygen optically
  • the third sensor 240 is configured to detect bilirubin immunochemically.
  • a system configured to measure one or more analytes in a host, wherein the system includes a vascular access device including a first portion configured for insertion into a host and a second portion configured to remain outside the host after insertion of the first portion; at least one analyte sensor 240 located within the second portion of the vascular access device, such that the at least one analyte sensor is exposed to a biological sample when the biological sample is drawn back about 40-mm or less, when the vascular access device is in fluid communication with a circulatory system of the host; and a flow control device configured to regulate exposure of the at least one sensor to a biological sample and to a reference solution according to a flow profile.
  • the system is configured such that the at least one analyte sensor is exposed to the biological sample when about 300- ⁇ l or less of the biological sample is drawn back. In another embodiment, the system is configured such that the at least one analyte sensor is exposed to the biological sample when about 200- ⁇ l or less of the biological sample is drawn back.
  • the vascular access device includes a catheter.
  • the catheter is 22-gauge or smaller.
  • a lumen of the second portion is wider than a lumen of the first portion.
  • the lumen (e.g., duct) of a catheter hub is wider than the lumen of the** « vivo portion of the catheter, in exemplary embodiments.
  • the second portion includes a connecting end on the catheter.
  • the second end of the catheter e.g., the hub
  • tubing e.g., IV tubing, the tubing assembly.
  • the second portion includes a fluid coupler, wherein the fluid coupler is configured to releasably mate with a catheter
  • the at least one sensor is incorporated into the second portion (e.g., the ex vivo portion of the catheter), such as on an inner surface of the second portion.
  • At least a portion of the at least one sensor is disposed in an orientation substantially parallel to a longitudinal axis of the second portion In some embodiments, at least a portion of the at least one sensor is disposed in an orientation substantially perpendicular to a longitudinal axis of the second portion In some embodiments, the at least one sensor includes an exposed electroactive surface area with a dimension substantially equal to a width of a lumen of the second portion. In some embodiments, the exposed electroactive surface area intersects the lumen of the second portion. In some embodiments, the at least one analyte sensor includes at least three analyte sensors located within the second portion of the catheter.
  • the at least one analyte sensor includes at least eight analyte sensors located within the second portion of the catheter.
  • the second portion is configured to provide identification information associated with a flow profile, such as described elsewhere herein.
  • the system is configured to program the flow profile (of a flow control device) in response to automatic receipt of the identification information.
  • the identification information is provided by a mechanical structure of the second portion (e.g., the catheter).
  • the identification information is provided by electronics of the second portion (e.g., the catheter).
  • a system configured to measure one or more analytes in a host, wherein the system includes a fluid coupler including a first end and a second end, wherein the first end is configured to releasably mate with a connecting end of a catheter, and wherein the second end is configured to releasably mate with a tubing assembly; and at least one analyte sensor located within the fluid coupler such that when the fluid coupler is mated to a catheter inserted into a circulatory system of a host, the at least one analyte sensor is exposed to a biological sample when the biological sample is drawn back about 40-mm or less.
  • the at least one sensor is located on an inner surface of the fluid coupler. *4 ⁇ i some embodiments, the at least one sensor is incorporated into the fluid coupler. In a further embodiment, the at least one sensor is disposed within a lumen of the fluid coupler (e.g., the second portion). In some embodiments, the system is configured such that the at least one analyte sensor is exposed to the biological sample when about 300- ⁇ l or less of the biological sample is drawn back. In another embodiment, the system is configured such that the at least one analyte sensor is exposed to the biological sample when about 200- ⁇ l or less of the biological sample is drawn back. In some embodiments, the at least one sensor is incorporated into the fluid coupler.
  • the at least one sensor is located on an inner surface of the fluid coupler. In some embodiments, the at least one sensor is disposed within a lumen of the fluid coupler. The at least one analyte sensor can be disposed in an orientation substantially parallel to a longitudinal axis of the fluid coupler, or in an orientation substantially perpendicular to the longitudinal axis of the fluid coupler. In some embodiments, the at least one sensor includes an exposed electroactive surface area with a dimension substantially equal to a width of a lumen of the fluid coupler, such as described with reference to Figs. 2M-2P. In some further embodiments, the exposed electroactive surface area intersects the lumen of the fluid coupler.
  • the fluid coupler is configured to provide identification information associated with a flow profile, such as described with reference to Fig. 1OE, herein.
  • the system is configured to program the flow profile of the flow control device in response to automatic receipt of the identification information.
  • the identification information is provided by a mechanical structure of the fluid coupler.
  • a portion of the fluid coupler is configured to form a mechanical interlock with a portion of the flow control device and/or the tubing assembly, wherein formation of the mechanical interlock automatically selects a flow profile associated with the fluid coupler (or with a catheter size, with a type of host (e.g., infant host versus child host versus adult host) and the like).
  • the fluid coupler includes electronics that provide identification information. In still other embodiments, the fluid coupler includes both a mechanical structure and electronics configured to provide the identification information associated with the flow profile. In some embodiments, the fluid coupler includes multiple lumens, wherein the system is configured and arranged to infuse a fluid a fluid in a first lumen of the fluid coupler, and to draw back a biological sample into a second lumen of the fluid coupler. For examples, in embodiments wherein the at least one analyte sensor is located in the second lumen, a hydration, nutrition and/or medicament solution can be infused via the first lumen without substantially affecting the at least one sensor.
  • the system is configured to infuse another solution, such as a calibration, wash or hydration solution through the second lumen of the fluid coupler, such as for washing the sensor and/or for making reference measurements.
  • another solution such as a calibration, wash or hydration solution
  • the at least one analyte sensor includes at least 2, 3, 4, 5, 6, 7, 8, or 9 or more analyte sensors.
  • two or more of the analyte sensors are configured to detect the same analyte, such as for a back-up (e.g., in case a first sensor fails the other sensor can be used) and/or as a quality check (e.g., to make sure the sensors are working substantially the same).
  • the analyte sensors are each configured to measure a different analyte. In still other embodiments, some of the analyte sensors are configured to detect the same analyte, while the remaining analyte sensors are configured to detect different analytes.
  • analyte sensor configuration combinations One skilled in the art appreciates the variety of possible analyte sensor configuration combinations.
  • the system is configured and arranged such that the at least one analyte sensor is located within about 35, 30, 25, 20, 15, 10, 5, 4, 3, 2, or 1-mm or less from a source of the biological sample.
  • the at least one analyte sensor is located (e.g., within the vascular access device), such that the analyte sensor is bathed in the sample when about 1000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 50, 25, 15, 10, or 5- ⁇ l or less of the bodily fluid (e.g., blood) is drawn back.
  • a lumen of the second portion is wider than a lumen of the first portion.
  • the lumen of the fluid coupler is wider than the lumen of the catheter.
  • the second portion is a fluid coupler, wherein the fluid coupler is configured to releasably mate with the catheter.
  • the at least one sensor is incorporated into the second portion.
  • the at least one sensor is located on an inner surface (e.g., the lumenal surface) of the fluid coupler ('e.g., the second portion).
  • the at least one sensor is disposed within a lumen of the fluid coupler (e.g., the second portion).
  • At least a portion of the at least one sensor is disposed in an orientation substantially parallel to a longitudinal axis of the fluid coupler (e g., the second portion). In some embodiments, at least a portion of the at least one sensor is disposed in an orientation substantially perpendicular to a longitudinal axis of the fluid coupler (e.g., the second portion). In some embodiments, the at least one sensor includes an exposed electroactive surface area with a dimension substantially equal to a width of a lumen of the fluid coupler (e.g., the second portion). In some embodiments, the exposed electroactive surface area intersects the lumen of the fluid coupler (e g , the second portion).
  • the fluid coupler (e.g., the second portion) is configured to provide identification information associated with the flow profile.
  • the system is configured to program the flow profile of the flow control device in response to automatic receipt of the identification information (e.g., via a wired or wireless connection and/or triggered by a physical and/or operable connection of the vascular access device (e.g., fluid coupler and/or catheter) with the flow control device and/or system electronics).
  • the identification information is provided by a mechanical structure of the fluid coupler (e.g., the second portion).
  • the identification information is provided by electronics of the fluid coupler (e.g., the second portion).
  • the at least one analyte sensor is configured to measure an analyte selected from the group consisting of albumin, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, CO2, chloride, creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit, lactate, lactate dehydrogenase, magnesium, oxygen, pH, phosphorus, potassium, sodium, total protein, uric acid, a metabolic marker and a drug.
  • an analyte selected from the group consisting of albumin, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, CO2, chloride, creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit, lactate, lactate dehydrogenase
  • the at least one analyte sensor includes at least three analyte sensors located within the second portion of the vascular access device and configured to measure at least three analytes.
  • the second portion of the vascular access device is the second portion of a catheter (e.g., the ex vivo portion, the hub), and the at least three analyte sensors are located therein.
  • the at least one analyte sensor includes at least eight analyte sensors located within the second portion of the vascular access device (e.g., the fluid coupler or the second portion (e g., hub or ex vivo portion) of a catheter) and configured to measure at least eight analytes.
  • the catheter is a peripheral catheter (e.g., for insertion into a vein located in an arm and/or leg) having the analyte sensor located within the catheter hub.
  • the volume that the catheter hub can hold has been restricted (e.g., reduce ⁇ , such as by fabricating the catheter hub with a reduced internal diameter.
  • the sample is drawn back only about 50, 45, 40 or 35-mm (e.g., into the catheter hub, depending upon the length of the catheter), such that the analyte sensor is bathed in the sample.
  • the analyte sensor is located within the lumen of a fluid coupler (e.g., configured for fluid connection with a catheter)
  • a fluid coupler e.g., configured for fluid connection with a catheter
  • the sensor's electrodes are bathed in a sample when the sample is drawn back a distance of about 50, 45, 40, 35 or 30-mm, depending upon the length of the catheter, which correlates with a sample volume of about 500, 450, 400, 350, 300 or 250- ⁇ l or less
  • the catheter when the catheter is coupled to a central catheter (e.g., a catheter for insertion into vessels in the body, such as to access the heart), the distance the sample is drawn back (e.g., to sufficiently contact/bathe the electrodes such that analyte measurements can be taken) is much farther (e.g., relative to the distance of draw-back into a peripheral catheter), since central catheters range from about 12 to about 24-inches in length.
  • a central catheter e.g., a catheter for insertion into vessels in the body, such as to access the heart
  • central catheters range from about 12 to about 24-inches in length.
  • the distance the sample is drawn back includes the entire length of the central catheter (including the catheter's hub) and a portion of the connector, such as but not limited to about 12, 13, 14 or 15 inches, to about 18, 19, 20, 21, 22, 23, 24 or 25-inches or more, depending upon the length of the catheter, which can correspond with a sample volume of about 1.5-ml, 1.25-ml, 1-ml, 900- ⁇ l, 800- ⁇ l, 700- ⁇ l, 600- ⁇ l or 500- ⁇ l or less, depending upon the catheter's size and/or configuration, the fluid coupler's configuration, and the like. If the sensor extends from the fluid coupler into the central catheter, the distance the sample is drawn back is reduced to a portion of the central catheter's length, with a corresponding reduction in sample volume.
  • Fig. 2H is a cross section of a vascular access device including a plurality of analyte sensor 240 in another embodiment.
  • the vascular access device is a connector 250 (e.g., fluid coupler) and/or valve, such as but not limited to a Leur lock, a Y-connector/a T- connector, and an X-connector.
  • the connector 250 e.g., fluid coupler
  • the connector 250 is configured to be coupled/connected to vascular access devices, such that a fluid can pass between two vascular access devices coupled to the connector's two ends.
  • a first end of the connector can be coupled to a catheter or cannula implanted (e.g., pre-implanted) in a host's vem or artery, and a second end of the connector can be coupled to another connector, a valve, IV tubing, and IV bag, a test device, etc.
  • the connector 240 is a fluid coupler, such as described with reference for Figs. 1A-1M and 2M-2S.
  • the connector includes a duct 254 (e.g., lumen) and a proximal orifice 258.
  • a plurality of analyte sensors 240 is disposed within the duct 254. As described with reference to the device shown in Fig.
  • the plurality of analyte sensors can be disposed within the duct 254 using any means known in the art.
  • one or more of the analyte sensors are deposited (e.g., formed) on a surface of the duct 254 (e.g., on an interior surface).
  • one or more of the analyte sensors are applied to the surface of the duct 254.
  • one or more of the analyte sensors is configured to pass through (e.g., intersect) the wall 252 of the connector such that a first portion of the sensor 240 is disposed within the duct 254 and a second portion of the sensor 240 is disposed at the exterior of the connector 250 (described in more detail herein).
  • Fig. 21 is a cross-section of a vascular access device of either Fig. 2G or Fig. 2H taken along line 21 - 21, looking towards the proximal end of the vascular access device.
  • the device includes a duct/lumen 212b/254 defined by a wall 260.
  • the in vivo orifice (also referred to as the proximal orifice with relation to the host) of the device is represented by circle 212b/258.
  • a plurality of sensors can be disposed within the duct, such as but not limited at the in the interior surface of the wall.
  • the device includes two analyte sensors.
  • the device includes 3, 4, 5, 6, 7 or more analyte sensors.
  • one or more of the analyte sensors are configured to be disposed entirely within the duct (e.g., to not protrude out of the duct).
  • one or more analyte sensors can be configured such that a portion thereof protrudes out the duct, such as but not limited to into the lumen of a catheter 212 or through the proximal orifice 212b/258 of the device.
  • a portion or one or more of the sensors can be configured to protrude through the ex vivo orifice (also referred to as the distal orifice with ration to the host) of the device.
  • the analyte sensors 240 disposed within the device can be of any configuration and can use any detection method, including but not limited to electrochemical, enzymatic, optical, radiometric, chemical, physical, immunochemical and the like, including a combination thereof.
  • Fig. 2J is a cross-section of a vascular access device of either Fig. 2G or Fig. 2H taken along line 21 - 21, looking towards the proximal end of the vascular access device, prior to installation of any analyte sensors 240.
  • Fig. 2K depicts the Fig. 2J device after sensor installation.
  • a plurality of sensor sites 262 is located at the surface of the wall 260. While Figs.
  • the sensor sites 262 can be of any configuration, such as but not limited to a portion of the wall's inner surface that is flush with the remaining portion of the inner surface, a textured portion of the inner surface, a channel, a hole, and the like.
  • the sensor sites can have a plurality of configurations. For example, in a device including four sensor sited 262, a first site can have a first configuration, the second and third sites a second configuration, and the fourth site yet another configuration.
  • Fig. 2L is a cross-section of a vascular access device of either Fig. 2G or Fig. 2H taken along line 21 - 21, looking towards the proximal end of the vascular access device, in an alternative embodiment.
  • the sensor sites 262 can be formed to include a plug 264 and/or a breakaway portion of the wall 260, which can be removed to enable sensor installation.
  • a plug/breakaway portion can be pushed and/or punched out of the sensor site and then the sensor installed in the sensor site.
  • removal of a plug/breakaway portion creates a channel through the wall, such that a sensor (at least a portion thereof) can be inserted through the channel and into the duct 254.
  • the portion of an installed sensor remaining on the external side of the wall is configured to functionally connect to sensor electronics, as is appreciated by one skilled in the art. While not wishing to be bound by theory, it is believed that this configuration enables increased accuracy and speed in device assembly because the sensors can be manufactured separately from the device and then installed into the device in a "plug-and-play" fashion.
  • Fig. 2M illustrates another embodiment of the analyte sensor system configured to measure one or more analytes in a bodily fluid of a host, namely a fluid coupler (e.g., connector) 250 having a wall 260, a lumen 254, a first end 258 configured and arranged for fluid communication with a vascular access device, and a second end 256 configured and arranged for fluid communication with an infusion device, such as via IV tubing and/or a tubing assembly, such as described elsewhere herein.
  • a fluid coupler e.g., connector 250 having a wall 260, a lumen 254, a first end 258 configured and arranged for fluid communication with a vascular access device, and a second end 256 configured and arranged for fluid communication with an infusion device, such as via IV tubing and/or a tubing assembly, such as described elsewhere herein.
  • the analyte sensor 240 (e.g., 240a, 240b and/or 240c) is configured and arranged to generate a signal associated with an analyte in a sample of ⁇ a circulatory system of a host (e.g., a bodily fluid such as but not limited to blood), wherein at least a portion of the analyte sensor is disposed within the lumen 254 of the fluid coupler 250.
  • a host e.g., a bodily fluid such as but not limited to blood
  • the device is configured such that, when it is fluidly connected to an implanted catheter, at least a portion of the analyte sensor 240 is located within about 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, 4, 3, 2, or 1-mm or less from the source of the sample, such as from the tip of the inserted catheter. In some embodiments, the analyte sensor is located within about 30-mm or less from a source of the sample.
  • the device is configured such that analyte sensor is bathed in the sample when about 1000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 50, 25, 15, 10, or 5- ⁇ l of the bodily fluid is drawn back.
  • the vascular access device (e.g., a catheter or a fluid coupler) includes a longitudinal axis.
  • the longitudinal axis can extend from the tip 212b of the in vivo portion to the hub orifice 218c.
  • the longitudinal axis can extend from the proximal orifice 258 to the distal orifice 256.
  • the analyte sensor e.g., the electrodes, electroactive surfaces
  • the analyte sensor is disposed in an orientation parallel to the longitudinal axis.
  • the analyte sensor intersects the wall 260, such that the electroactive surface(s) are located along an interior (e.g., luminal) surface of the wall.
  • the electrode can intersect the wall at two points that are separated by a longitudinal distance on the wall, such that the electroactive surface(s) are oriented parallel to the longitudinal axis of the device.
  • one or more of the electrodes can intersect the wall at two points along one side of the device (e.g., 260a or 260b) such that the length of the electrode runs parallel to the longitudinal axis of the device.
  • the electrodes can be spaced about the inner circumference of the lumen, such as but not limited to equidistant from each other, wherein each electrode runs paraHel along the luminal wall in an orientation parallel to the longitudinal axis of the device.
  • one or more sensors can be placed in the device such that a length of the electroactive surfaces of the sensor(s) is parallel to the longitudinal axis of the device.
  • the device could include 2, 3, 4, 5 or more analyte sensors.
  • the reference electrode is disposed remotely from the working and/or counter electrode(s).
  • one reference electrode is configured to function as the reference electrode for two or more analyte sensors.
  • the electrode(s) are disposed within the catheter hub or fluid coupler such that they are oriented perpendicularly to a longitudinal axis of the device.
  • the device can be configured such that the individual electrodes (e.g., 240a, 240b and 240c) intersect wall 260 on opposite sides (e.g., 260a and 260b) of the device, such that each electrode is perpendicular to the longitudinal axis of the fluid coupler.
  • the first and second points can be connected by a line that is perpendicular to the longitudinal axis of the device.
  • the device is configured such that the electroactive surface of each electrode has a surface area having a first dimension (e.g., length or width) substantially equal to a diameter of the lumen of the connector or hub.
  • a first dimension e.g., length or width
  • the length of the electroactive surfaces e.g. window 343 of Fig. 3B
  • the inner diameter of the fluid coupler can be substantially equal to the inner diameter of the fluid coupler.
  • each electrode can be formed, including the membrane, as described herein, inserted through the wall(s) of fluid coupler (e.g., through holes or using a needle to pierce the wall(s) formed of elastomeric material as described herein), such that the electroactive surface is disposed within the lumen, excess electrode material removed from one side (e.g., 260b) and then electrical connection with system electronics (e.g., via soldering electrical wires) on the opposite side (e.g., 260a). While the electrodes of the embodiment illustrated in Fig. 2M are disposed individually, additional configurations are contemplated in the preferred embodiments.
  • the electrodes are bundled and/or twisted, such that the electrodes intersect the wall together.
  • the analyte sensor includes an electrode located within the lumen of the in vivo portion of the catheter, such as at the tip 212b of the catheter.
  • the electrode is located at and/or on the luminal surface of the in viv ⁇ portion of the catheter.
  • the electrodes are deposited on a flexible support, which is inserted into the lumen.
  • the electrodes are deposited on the flexible support when the flexible support having a planar configuration, which is then cut to size, rolled into a cylindrical configuration (such that the electrodes are within the interior of the cylinder), and then inserted into the catheter lumen.
  • the flexible support is formed of an appropriate material to form the in vivo portion of a catheter
  • electrodes are applied to a surface of the material (e.g., when in a planar configuration) using methods known in the art, the material is cut to size, rolled and the cut edges sealed (e.g., by welding or an adhesive), and a catheter hub applied thereto, such that the rolled and sealed flexible support forms the wall of the in vivo portion of the catheter, wherein the electrodes are located on the luminal surface of the electrode wall.
  • Forming the catheter and electrodes in this manner enables easy manufacturing techniques and a variety of electrode configurations, such as but not limited to linear electrodes, circular electrodes, electrodes that spiral along/around the interior of the catheter, and the like.
  • a plurality of analyte sensors can be disposed in the catheter lumen, such that two or more analytes can be measured, or such that redundant sensors (e.g., two or more glucose sensors) can measure a single analyte.
  • Fig. 2N illustrates an embodiment of a fluid coupler configured to include two or more analyte sensors, namely the fluid coupler is divided into two or more channels, each of which includes an analyte sensor.
  • the fluid coupler is divided into two flow channels 254 (e.g., two lumens), each with an analyte sensor disposed therein (e.g., electrode 240a, 240b and 240c).
  • the analyte sensor in one flow channel can be configured to detect glucose and the analyte sensor in the other flow channel can be configured to detect a cardiac marker, in one embodiment.
  • the fluid coupler is divided into three flow channels (e.g., three lumens), each with an analyte sensor disposed therein.
  • additional lumens enables incorporation of additional analyte sensors such that each analyte sensor receives a sample uncontaminated by reagents and/or products and/or for infusion of a medicament.
  • a glucose sensor using GOX to detect glucose generates H 2 O 2 , which can affect the other sensors of the device. If the sensors are located in separate lumens, the H 2 O 2 generated by the glucose sensor cannot affect the sensors located in the other lumens.
  • sample that is drawn back flows into each of the lumens, such that each of the sensors is bathed in sample uncontaminated by reagents and reaction products from another of the sensors.
  • the device is flushed (e.g., with saline or calibrant solution)
  • each of the sensors are washed and does not contaminate another sensor with its reagents/reaction products.
  • the fluid coupler is divided into additional channels, such as a network of 4, 5, 6, 7, 8, 9, 10 or more channels, such that panels of analytes can be continuously measured at the same time.
  • the fluid coupler is miniaturized, thereby providing a micro-scale, multi-sensor device, such that about 5, 10, 15, 20, 25, 30, 40, 50, 100 or more analytes can be continuously monitored simultaneously.
  • This configuration provides certain advantages, such as but not limited to, this device is amenable to high-throughput, modular manufacturing on an assembly line; the device can be connected to a wide variety of catheters currently in use; a plurality of sensors can be used simultaneously; and the device is amenable to custom-made analyte panels (e.g., Hospital #1 wants glucose and oxygen sensors, while Hospital #2 wants glucose, creatinine and temperature sensors).
  • the wall 260 is formed of a self-sealing material (not shown), such that the analyte sensor can be inserted through the wall using a needle.
  • a needle containing the sensor in its barrel can be inserted through the wall, followed by withdrawal of the needle over the sensor, such that the sensor remains inserted through the wall.
  • polymer tubing such as but not limited to silicone tubing, can be used to form the central body of a fluid coupler, and connector ends (e.g., configured for connecting the fluid coupler to a catheter and/or tubing) attached thereto.
  • Figs. 2O and 2P illustrate another method of manufacturing an integrated fluid coupler and analyte sensor device, such as that shown in Fig. 2M.
  • the fluid coupler is formed of two or more mateable portions (e.g., 260-1, 260-2), wherein the first and second mateable portions are configured and arranged to form a seal 26Oe when mated together, such that the lumen is formed 254.
  • the two mateable portions can be formed by injection molding a suitable medical-grade plastic.
  • the two mateable portions 260-1, 260-2 are configured to mate together, such as but not limited to in a clam shell configuration.
  • One or both of the two mateable portions 260-1 , 260-2 includes an indentation 260c on the sealing edge(s) (e.g., mating edges) configured to receive an analyte sensor (and/or an electrode).
  • the two mateable portions each include three indentations, wherein the indentations are configured to receive the electrodes 240.
  • the sensor electrodes are inserted separately (e.g., as opposed to in a bundled or twisted configuration).
  • the electrodes can be spaced along the length of the lumen to optimize fluid flow and analyte detection.
  • the electrodes are spaced equally within the lumen (e.g., the distance between electrodes 240a and 240b is substantially equal to the distance between electrodes 240b and 240c).
  • the device is configured such that the diameter of the lumen is substantially the same as the length of the electroactive surfaces (e.g., which span the lumen). Additional configurations are contemplated, such as non-linear spacing and non-equal spacing of the electrodes.
  • a grommet 26Od can be included at the point at which the electrode intersects the mated wall.
  • the wall surrounding the electrode e.g., at 26Od
  • the seal is fluid-tight.
  • a portion of the wall material is melted by the welding, such that a portion of the melted wall material can soak into the membrane of the electrode Fig.
  • 2P illustrates an alternative method of forming the integrated fluid coupler and analyte sensor device, wherein the two mateable portions 260-1, 260- 2 comprise cylinders configured to mate together such that the analyte sensor 240 spans the lumen 254.
  • a connection between the analyte sensor (and/or individual electrodes) and sens ⁇ r electronics can be made on the exterior surface of the fluid connector.
  • the analyte sensor electrodes are soldered to wires, which in turn make electrical connection with the sensor electronics.
  • the electrodes are clipped off substantially flush with the exterior surface of the wall and a PCB 2Ot (e.g., configured to make suitable electrical connection with each of the electrodes) is attached to the clipped-off ends of the electrodes (e.g., via adhesive or welding), such that the electrical connections are made; the PCB is then used to connect the sensor to sensor electronics.
  • a PCB 2Ot e.g., configured to make suitable electrical connection with each of the electrodes
  • elastomeric contacts can be used to make a connection between the electrodes and sensor electronics, in a manner similar to that illustrated in Figs. IH and IJ. Additional methods of connecting analyte sensors to sensor electronics are appreciated by those skilled in the art.
  • Fig. 2Q illustrates an alternative embodiment of an integrated fluid coupler and analyte sensor device, in which the electrodes are formed of conductive elastomeric material (e.g., contacts 240).
  • a portion of the fluid coupler can be configured with one or more holes 260c to receive the elastomeric contacts.
  • the fluid coupler can be injection molded of plastic, including the holes 260c configured to receive the elastomeric contacts 240.
  • the electrode/elastomeric contacts can be formed of any conductive elastomeric materials, such as but not limited to carbon black elastomer. Each elastomeric contact is configured with an interior side 24Oe and an exterior side 24Od.
  • the interior side is configured and arranged as an electrode, such as one or more working electrodes (plus and/or minus enzyme), a counter electrode or a reference electrode, as described elsewhere herein.
  • the exterior side is configured and arranged for electrical connection with the sensor electronics.
  • the electrode/elastomeric contact can have any useful shape, such that the interior side can be inserted through a hole of the fluid coupler, such that the electroactive surface can be bathed by a sample drawn back into the fluid coupler, and such that the exterior side is sufficiently exposed for making the electrical connection with the sensor electronics.
  • the conductive material can be formed into any shape.
  • the electrode/elastomeric contact can be a ball, or wedge or cylinder. In the embodiment shown in Fig.
  • the electrode/elastomeric contact includes a cylindrical body with a flat electroactive surface at the interior side 24Oe, and sloped or flared sides.
  • the interior side 24Oe is configured and arranged to be substantially flush with the lumenal surface of the fluid conduit wall, such that fluid turbulence, biofouling and/or clotting is/are substantially reduced when the device is in use.
  • the exterior side 24Od includes a flat butt end, which is somewhat larger in diameter than cylindrical body, and a shoulder.
  • the elastomeric material is sufficiently pliable that the elastomeric contact can conform to the structure of the hole, when it is inserted into the hole; such that it makes a substantially water-tight seal with the wall of the fluid coupler.
  • the flared sides are configured to conform to the hole (e.g., an interference fit), such that the conformed side and the shoulder make a water-tight seal with the wall of the fluid conduit.
  • Electrode/elastomeric contacts 240 and sensor electronics can be made with their exterior surfaces by any method known in the art.
  • a PCB 2Ot configured and arranged for electrical contact with the elastomeric contacts is adhered over the elastomeric contacts.
  • a cover such as one configured with a female connector 2On (e.g., see cover 20k in Figs. 1H-1J) is adhered over the PCB, or the PCB is hard-wired to an electrical cable.
  • the electrode/elastomeric contacts are simply soldered to the wires of an electrical cable.
  • conductive traces e.g., vias
  • the exterior surface of the fluid conduit e.g., prior to insertion of the electrode/elastomeric contacts
  • the shoulder of each electrode/elastomeric contact makes an electrical connection with one of the conductive traces.
  • the electrical traces make electrical connections with sensor electronics, as is known to one skilled in the art.
  • electrode/elastomeric contacts 240 enables unique manufacturing methods which are amenable to high through-put, modular manufacturing.
  • the individual electrode/elastomeric contacts are formed and then processed in batches, such as to deposit the electroactive surfaces and membranes on the interior surfaces.
  • a batch of working electrode/elastomeric contacts e.g., 100, 1000, etc.
  • Platinum or other conductive electrode material can then be deposited on the heads, sides and/or entire electrode/elastomeric contacts using suitable means such as electroplating, electrospinning, spraying, and the like, to form the electroactive surfaces.
  • a membrane is applied as one or more layers, using known thin-film or thick-film techniques.
  • Ag/ AgCI particles or other conductive electrode material can be mixed or otherwise formed in or on the material used to form the electrode/elastomeric contacts, or Ag/AgCl can be applied to the interior surfaces of the reference electrode/elastomeric contacts, for example.
  • the electrode/elastomeric contacts are formed by preparing a sheet of the elastomeric conductive material, preparing a surface of the sheet, such as forming an electroactive surface thereon, and then punching the individual electrode/elastomeric contacts from the sheet.
  • Fig. 2R is a cross-section of another embodiment of a fluid coupler including a continuous analyte sensor 240 disposed within the lumen 254.
  • a central body 270 is inserted within the lumen.
  • the central body includes conductive bodies 272 disposed within a non-conductive material.
  • Each conductive body 272 includes a conductive member 273, for making electrical contact with sensor electronics.
  • the sensor electrodes 240 are deposited on the conductive bodies 272, such that when the central body 270 is inserted into the lumen of the fluid coupler, the electrodes are bathed in sample when the sample is drawn back.
  • the conductive members provide stabilization to the central body.
  • the central body and conductive members are configured and arranged such that the lumen is divided into a plurality of chambers (e.g., smaller lumens), such that a plurality of analyte sensors are deposited on the conductive bodies and such that each analyte sensor contacts a separate sample (e.g., uncontaminated by reagents or reaction products from an analyte sensor in another chamber).
  • the central body is configured as an elongated core, such as but not limited to a cylindrical core.
  • the central body 270 is configured as a plurality of conductive bodies 272, which run the length of the central body, bundled in a dielectric material, wherein the conductive members 273 extend out an end of the central body (e.g., rather than out the sides as shown in Fig. 2R).
  • a plurality of analyte sensors can be deposited on the conductive bodies, wherein the central body is inserted into the lumen of the fluid coupler.
  • Fig. 2S illustrates yet another embodiment of an analyte sensor disposed in a fluid coupler, including an electrode support 280 having one or more analyte sensors 240 deposited thereon.
  • the electrode support 280 is configured and arranged to optimize fluid flow there around and to substantially reduce biofouling and/or clotting thereon.
  • the electrode support 280 is cigar or football shaped.
  • the electrodes can be working, counter an ⁇ kir reference electrodes.
  • the electrode support 280 is stabilized by stabilizers 282. While the stabilizers 282 shown in Fig. 2S are "fin" shaped, a variety of other shapes, such as projections, extensions, detents, and the like can be used.
  • the stabilizers substantially maintain the electrode support 280 within the fluid stream such that the electrode support 280 is substantially immobile, such that the flow of fluid about the electrode support 280 is substantially even (e.g., the same rate there around).
  • the device is formed by injection molding, using techniques known in the art.
  • the sensors are placed in a mold, which is configured to hold the sensors in such an orientation that after the injection molding procedure, the sensors will be in the correct location and/or orientation for correct function of the device. After the sensors are placed in the mold, the mold is closed and injected with a material (e.g., molten plastic).
  • a material e.g., molten plastic
  • the wall 260 of the device is thus formed about a portion of each sensor 240, such that a sensing portion of each sensor (e.g., electroactive surface) will be disposed within the duct 212b/258 and another portion of each sensor (e.g., a portion configured for connection to sensor electronics) will be disposed at the exterior of the device.
  • a sensing portion of each sensor e.g., electroactive surface
  • another portion of each sensor e.g., a portion configured for connection to sensor electronics
  • each vascular access device can require a unique flow profile, such that the flow control device infuses and draws back the correct amounts of fluid and/or sample, at the correct time and for the correct lengths of time, to enable optimal sensor operation.
  • a caretaker may select the wrong flow profile for an installed vascular access device; a medical error that might harm the patient
  • the vascular access device is configured and arranged to provide identification information to flow control device, wherein the identification information is associated with the flow profile.
  • the identification information is provided by a mechanical structure (e.g., an engageable mechanical interlock wherein the vascular access device includes one of two portions of the mechanical interlock and the flow control device includes the second of the two portions of the mechanical interlock).
  • the identification information is provided by electronics of the vascular access device (e.g., a bar code (e.g., identified by a bar code scanner incorporated into the flow control device), an RFID chip configured for communication with the electronics of the vascular access device and the like).
  • a flow profile associated with the vascular access device is initiated by the flow control device, after identification of the vascular access device via the identification module.
  • the system is configured to program the flow profile of the flow control device in response to automatic receipt of the identification information (e.g., transmission of the identification information without required user interaction).
  • the identification information e.g., transmission of the identification information without required user interaction.
  • an analyte sensor to be disposed in communication with the host's blood
  • transcutaneous e.g., transdermal
  • wholly implantable analyte sensor devices e.g., the sensor could be integrally formed on the in vivo portion of a subcutaneous device or a wholly implantable device.
  • an enlarged surface area e.g., bulbous end
  • the senor can be configured similarly to the continuous analyte sensors disclosed in co-pending U.S. Patent Publication No. US-2007- 0197889-A1 herein incorporated by reference in its entirety.
  • the sensor includes a distal portion 342, also referred to as the in vivo portion, adapted for insertion into the catheter as described above, and a proximal portion 340, also referred to as an ex vivo portion, adapted to operably connect to the sensor electronics.
  • the sensor includes two or more electrodes: a working electrode 344 and at least one additional electrode, which can function as a counter electrode and/or reference electrode, hereinafter referred to as the reference electrode 346.
  • a membrane system is preferably deposited over the electrodes, such as described in more detail with reference to Figs. 3A to 3C, below.
  • Fig. 3B is an expanded cutaway view of a distal portion of the sensor in one embodiment, showing working and reference electrodes.
  • the sensor is formed from a working electrode 344 (e.g., a wire) and a reference electrode 346 helically wound around the working electrode 344.
  • An insulator 345 is disposed between the working and reference electrodes to provide electrical insulation therebetween. Certain portions of the electrodes are exposed to enable electrochemical reaction thereon, for example, a window 343 can be formed in the insulator to expose a portion of the working electrode 344 for electrochemical reaction.
  • each electrode is formed from a fine wire with a diameter of from about 0.001 inches or less to about 0.050 inches or more, for example, and is formed from, e.g., a plated insulator, a plated wire, or bulk electrically conductive material.
  • the wire used to form a working electrode is about 0 002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.010, 0.015, 0.020, 0.025, 0.030, 0.035, 0.040 or 0.045 inches in diameter.
  • the working electrode comprises a wire formed from a conductive material, such as platinum, platinum-iridium, palladium, graphite, gold, carbon, conductive polymer, alloys, and the like.
  • a conductive material such as platinum, platinum-iridium, palladium, graphite, gold, carbon, conductive polymer, alloys, and the like.
  • the electrodes can by formed by a variety of manufacturing techniques (bulk metal processing, deposition of metal onto a substrate, and the like), it can be advantageous to form the electrodes from plated wire (e.g. , platinum on steel wire) or bulk metal (e.g., platinum wire).
  • electrodes formed from bulk metal wire provide superior performance (e.g., in contrast to deposited electrodes), including increased stability of assay, simplified manufacturability, resistance to contamination (e.g., which can*be introduced in deposition processes), and improved surface reaction (e.g., due to purity of material) without peeling or delamination.
  • the working electrode is formed of platinum-iridium or iridium wire.
  • platinum-iridium and iridium materials are generally stronger (e.g., more resilient and less likely to fail due to stress or strain fracture or fatigue). It is believed that platinum- iridium and/or indium materials can facilitate a wire with a smaller diameter to further decrease the maximum diameter (size) of the sensor (e.g., in vivo portion).
  • a smaller sensor diameter both reduces the risk of clot or thrombus formation (or other foreign body response) and allows the use of smaller catheters.
  • the electroactive window 343 of the working electrode 344 is configured to measure the concentration of an analyte.
  • the working electrode measures the hydrogen peroxide produced by an enzyme catalyzed reaction of the analyte being detected and creates a measurable electronic current
  • glucose oxidase produces hydrogen peroxide as a byproduct
  • hydrogen peroxide 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.
  • the working electrode 344 is covered with an insulating material 345, for example, a non-conductive polymer.
  • insulating material 345 for example, a non-conductive polymer. Dip-coating, spray-coating, vapor- deposition, or other coating or deposition techniques can be used to deposit the insulating material on the working electrode
  • the insulating material comprises parylene, which can be an advantageous polymer coating for its strength, lubricity, and electrical insulation properties.
  • parylene is produced by vapor deposition and polymerization of para-xylylene (or its substituted derivatives). While not wishing to be bound by theory, it is believed that the lubricious (e.g., smooth) coating (e.g., parylene) on the sensors of some embodiments contributes to minimal trauma and extended sensor life.
  • any suitable insulating material can be used, for example, fluorinated polymers, polyethyleneterephthalate, polyurethane, polyimide, other nonconducting polymers, and the like. Glass or ceramic materials can also be employed. Other materials suitable for use include surface energy modified coating systems such as are marketed under the trade names AMC 18, AMC 148, AMC 141, and AMC321 by Advanced Materials Components Express of Bellafonte, PA. In some alternative embodiments, however, the working electrode may not require a coating of insulator.
  • the reference electrode 346 which can function as a reference electrode alone, or as a dual reference and counter electrode, is formed from silver, silver/silver chloride, and the like. In some embodiments, the reference electrode 346 is juxtapositioned and/or twisted with or around the working electrode 344; however other configurations are also possible (e.g., coiled within the fluid connector/hub 18 or within a fluid coupler 20 or an intradermal or on-skin reference electrode). In the illustrated embodiments, the reference electrode 346 is helically wound around the working electrode 344. The assembly of wires is then optionally coated or adhered together with an insulating material, similar to that described above, so as to provide an insulating attachment.
  • a silver wire is formed onto the sensor as described above, and subsequently chloridized to form silver/silver chloride reference electrode.
  • chloridizing the silver wire as described herein enables the manufacture of a reference electrode with optimal in vivo performance Namely, by controlling the quantity and amount of chloridization of the silver to form silver/silver chloride, improved break-in time, stability of the reference electrode and extended life has been shown with some embodiments. Additionally, use of silver chloride as described above allows for relatively inexpensive and simple manufacture of the reference electrode.
  • a portion of the coated assembly structure can be stripped or otherwise removed, for example, by hand, excimer lasing, chemical etching, laser ablation, grit-blasting (e.g., with sodium bicarbonate or other suitable grit), and the like, to expose the electroactive surfaces.
  • grit-blasting e.g., with sodium bicarbonate or other suitable grit
  • a portion of the electrode can be masked prior to depositing the insulator in order to maintain an exposed electroactive surface area.
  • grit blasting is implemented to expose the electroactive surfaces, preferably utilizing a grit material that is sufficiently hard to ablate the polymer material, while being sufficiently soft so as to minimize or avoid damage to the underlying metal electrode (e.g., a platinum electrode)
  • a variety of ⁇ grit" materials can be used (e.g., sand, talc, walnut shell, ground plastic, sea salt, and the like)
  • sodium bicarbonate- is an advantageous grit-material because it is sufficiently hard to ablate, e.g., a parylene coating, without damaging, e.g.. an underlying platinum conductor.
  • sodium bicarbonate blasting includes its polishing action on the metal as it strips the polymer layer, thereby eliminating a cleaning step that might otherwise be necessary.
  • a radial window 343 is formed through the insulating material 345 to expose a circumferential electroactive surface of the working electrode. Additionally, sections of electroactive surface of the reference electrode are exposed. For example, the sections of electroactive surface can be masked during deposition of an outer insulating layer or etched after deposition of an outer insulating layer.
  • cellular attack or migration of cells to the sensor can cause reduced sensitivity and/or function of the device, particularly after the first day of implantation.
  • the exposed electroactive surface is distributed circumferentially about the sensor (e.g., as in a radial window)
  • the available surface area for reaction can be sufficiently distributed so as to minimize the effect of local cellular invasion of the sensor on the sensor signal.
  • a tangential exposed electroactive window can be formed, for example, by stripping only one side of the coated assembly structure.
  • the window can be provided at the tip of the coated assembly structure such that the electroactive surfaces are exposed at the tip of the sensor.
  • Other methods and configurations for exposing electroactive surfaces can also be employed.
  • the working electrode has a diameter of from about 0.001 inches or less to about 0.010 inches or more, preferably from about 0.002 inches to about 0.008 inches, and more preferably from about 0.004 inches to about 0.005 inches.
  • the length of the window can be from about 0.1 mm (about 0.004 inches) or less to about 2 mm (about 0.078 inches) or more, and preferably from about 0.25 mm (about 0.01 inches) to about 0.375 mm (about 0.015 inches).
  • the exposed surface area of the working electrode is preferably from about 0.000013 in 2 (0.0000839cm 2 ) or less to about 0.0025 in 2 (0.016129 cm 2 ) or more (assuming a diameter of from about 0.001 inches to about 0.010 inches and a length of from about 0.004 inches to about 0.078 inches).
  • the preferred exposed surface area of the working electrode is selected to produce an analyte signal with a current in the picoAmp range, such as is described in more detail elsewhere herein.
  • a current in the picoAmp range can be dependent lipoma variety of factors, for example the electronic circuitry design (e.g., sample rate, current draw, A/D converter bit resolution, etc.), the membrane system (e.g., permeability of the analyte through the membrane system), and the exposed surface area of the working electrode.
  • the exposed electroactive working electrode surface area can be selected to have a value greater than or less than the above-described ranges taking into consideration alterations in the membrane system and/or electronic circuitry.
  • it can be advantageous to minimize the surface area of the working electrode while maximizing the diffiisivity of glucose in order to optimize the signal-to-noise ratio while maintaining sensor performance in both high and low glucose concentration ranges
  • the exposed surface area of the working (and/or other) electrode can be increased by altering the cross-section of the electrode itself.
  • the cross-section of the working electrode can be defined by a cross, star, cloverleaf. ribbed, dimpled, ridged, irregular, or other non-circular configuration; thus, for any predetermined length of electrode, a specific increased surface area can be achieved (as compared to the area achieved by a circular cross-section).
  • Increasing the surface area of the working electrode can be advantageous in providing an increased signal responsive to the analyte concentration, which in turn can be helpful in improving the signal-to-noise ratio, for example.
  • additional electrodes can be included within the assembly, for example, a three-electrode system (working, reference, and counter electrodes) and/or an additional working electrode (e.g., an electrode which can be used to generate oxygen, which is configured as a baseline subtracting electrode, or which is configured for measuring additional analytes).
  • a three-electrode system working, reference, and counter electrodes
  • an additional working electrode e.g., an electrode which can be used to generate oxygen, which is configured as a baseline subtracting electrode, or which is configured for measuring additional analytes.
  • U S. Patent Publication No. US-2005-0161346-A1 U.S. Patent Publication No. US-2005-0143635-A1
  • U.S. Patent Publication No. US-2007-0027385-A1 describe some systems and methods for implementing and using additional working, counter, and/or reference electrodes.
  • the two working electrodes are juxtapositioned (e.g., extend parallel to each other), around which the reference electrode is disposed (e.g., helically wound).
  • the working electrodes can be formed in a double-, triple-, quad-, etc. helix configuration along the length of the sensor (for example, surrounding a reference electrode, insulated rod, or other support structure).
  • the resulting electrode system can be configured with an appropriate membrane system, wherein the first working electrode is configured to measure a first signal including glucose and baseline (e.g., background noise) and the additional working electrode is configured to measure a baseline signal consisting of baseline only (e.g., configured to be substantially similar to the first working electrode without an enzyme disposed thereon) In this way, the baseline signal can be subtracted from the first signal to produce a glucose-only signal that is substantially not subject to fluctuations in the baseline and/or interfering species on the signal.
  • a first signal including glucose and baseline (e.g., background noise)
  • the additional working electrode is configured to measure a baseline signal consisting of baseline only (e.g., configured to be substantially similar to the first working electrode without an enzyme disposed thereon)
  • the baseline signal can be subtracted from the first signal to produce a glucose-only signal that is substantially not subject to fluctuations in the baseline and/or interfering species on the signal.
  • the working electrode comprises a tube with a reference electrode disposed or coiled inside, including an insulator therebetween.
  • the reference electrode comprises a tube with a working electrode disposed or coiled inside, including an insulator therebetween Tn another alternative embodiment, a polymer (e.g., insulating) rod is provided, wherein the electrodes are deposited (e.g., electroplated) thereon.
  • a metallic (e.g., steel) rod is provided, coated with an insulating material, onto which the working and reference electrodes are deposited Tn yet another alternative embodiment, one or more working electrodes are helically wound around a reference electrode.
  • the electrodes and membrane systems of the preferred embodiments are coaxially formed, namely, the electrodes and/or membrane system all share the same central axle.
  • a coaxial design of the sensor enables a symmetrical design without a preferred bend radius.
  • the coaxial design of the preferred embodiments do not have a preferred bend radius and therefore are not subject to regular bending about a particular plane (which can cause fatigue failures and the like).
  • non-coaxial sensors can be implemented with the sensor system of the preferred embodiments.
  • 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 the protective slotted sheath is able to insert the sensor into the catheter and subsequently slide back over the sensor and release the sensor from the protective slotted sheath, without complex multi-component designs.
  • the two wires of the sensor are held apart and configured for insertion into the catheter in proximal but separate locations.
  • the separation of the working and reference electrodes in such an embodiment can provide additional electrochemical stability with simplified manufacture and electrical connectivity.
  • One skilled in the art will appreciate that a variety of electrode configurations can be implemented with the preferred embodiments.
  • the reference electrode can be separated from the working electrode, and coiled within a portion of the fluid connector, in some embodiments.
  • the reference electrode is coiled within the fluid connector and adjacent to its first side.
  • the reference electrode is coiled within the fluid connector and adjacent to its second side.
  • the reference electrode is in contact with fluid, such as saline from a saline drip that is flowing into the host, or such as blood that is being withdrawn from the host. While not wishing to be bound by theory, this configuration is believed to be advantageous because the sensor is thinner, allowing the use of smaller catheters and/or a reduced likelihood to thrombus production.
  • the reference electrode 346 can be disposed farther away from the electroactive portion of the working electrode 343 (e.g., closer to the fluid connector).
  • the reference electrode is located proximal to or within the fluid coupler, such as but not limited to, coiled about the catheter adjacent to the fluid coupler or coiled within the fluid coupler and in contact with fluid flowing through the fluid coupler, such as saline. These configurations can also minimize at least a portion of the sensor diameter and thereby allow the use of smaller catheters and reduce the risk of clots.
  • the senor can be configured with additional working electrodes as described in U S Patent Publication No. 118-2005-0143635 ⁇ Al, U.S. Patent No. 7,081,195, and U.S. Patent Publication No. US-2007-0027385-A1, herein incorporated by reference in their entirety.
  • the auxiliary working electrode comprises a wire formed from a conductive material, such as described with reference to the glucose-measuring working electrode above.
  • the reference electrode which can function as a reference electrode alone, or as a dual reference and counter electrode, is formed from silver, Silver/Silver chloride, and the like.
  • the electrodes are juxtapositioned and/or twisted with or around each other; however other configurations are also possible.
  • the auxiliary working electrode and reference electrode can be helically wound around the glucose-measuring working electrode.
  • the auxiliary working electrode and reference electrode can be formed as a double helix around a length of the glucose-measuring working electrode.
  • the assembly of wires can then be optionally coated together with an insulating material, similar to that described above, in order to provide an insulating attachment. Some portion of the coated assembly structure is then stripped, for example using an excimer laser, chemical etching, and the like, to expose the necessary electroactive surfaces.
  • additional electrodes can be included within the assembly, for example, a three-electrode system (including separate reference and counter electrodes) as is appreciated by one skilled in the art.
  • the senor is configured as a dual-electrode system (e.g., Figs. 2M-2O, 2Q-2S, and 3D-3I) configured and arranged to detect two analyte and/or configured as plus-enzyme and minus-enzyme electrodes, as described herein.
  • a first electrode functions as a hydrogen peroxide sensor including a membrane system containing glucose-oxidase disposed thereon, which operates as described herein.
  • a second electrode is a hydrogen peroxide sensor that is configured similar to the first electrode, but with a modified membrane system (without active enzyme, for example). This second electrode provides a signal composed mostly of the baseline signal, b.
  • the baseline signal is (electronically or digitally) subtracted from the glucose signal to obtain a glucose signal substantially without baseline. Accordingly, calibration of the resultant difference signal can be performed by solving the equation y ⁇ mx with a single paired measurement. Calibration of the inserted sensor in* this alternative embodiment can be made less dependent on the values/range of the paired measurements, less sensitive to error in manual blood glucose measurements, and can facilitate the sensor's use as a primary source of glucose information for the user.
  • U.S. Patent Publication No. US-2005-0143635-A1 U.S. Patent Publication No. US-2007-0027385-A1, U.S. Patent Publication No. US-2007-0213611-A1, and U.S. Patent Publication No. US-2008-0083617-A1 each describe systems and methods for subtracting the baseline from a sensor signal, each of which is incorporated herein by reference in its entirety.
  • the analyte sensor is configured to transmit signals obtained from each electrode separately (e.g., without subtraction of the baseline signal) In this way, the receiver can process these signals to determine additional information about the sensor and/or analyte concentration. For example, by comparing the signals from the first and second electrodes, changes in baseline and/or sensitivity can be detected and/or measured and used to update calibration (e.g., without the use of a reference analyte value). In one such example, by monitoring the corresponding first and second signals over time, an amount of signal contributed by baseline can be measured. In another such example, by comparing fluctuations in the correlating signals over time, changes in sensitivity can be detected and/or measured.
  • the reference electrode can be disposed remotely from the working electrode.
  • the reference electrode remains within the fluid flow, but is disposed within the fluid coupler.
  • the reference electrode can be coiled within the fluid coupler such that it is contact with saline flowing into the host, but it is not in physical contact with the host's blood (except when blood is withdrawn from the catheter)
  • the reference electrode is removed from fluid flow, but still maintains bodily fluid contact.
  • the reference electrode can be wired to an adhesive patch that is adhered to the host, such that the reference electrode is in contact with the host's skin.
  • the reference electrode can be external from the system, such as but not limited to in contact with the exterior of the ex viva portion of the system, in fluid or electrical contact with a connected saline drip or other medical device, or in bodily contact, such as is generally done with EKG electrical contacts. While not wishing to be bound by theory, it is believed to locating the reference electrode remotely from the working electrode permits manufacture of a smaller sensor footprint (e.g., diameter) that will have relatively less affect on the host's blood flow, such as less thrombosis, than a sensor having a relatively larger footprint (e.g., wherein both the working electrode and the reference electrode are adjacent to each other and within the blood path).
  • a smaller sensor footprint e.g., diameter
  • in vivo portion of the sensor (e.g., the tip 14a) has an enlarged area (e.g., a bulbous, nail head-shaped, football-shaped, cone-shaped, cylindrical, etc. portion) as compared a substantial portion of the sensor (e.g., diameter of the in vivo portion of the sensor).
  • the sensor tip can be made bulbous by any convenient systems and methods known in the art, such as but not limited to arc welding, crimping, smashing, welding, molding, heating, and plasma arc welding. While not wishing to be bound by theoiy, it is believed that an enlarged sensor tip (e.g., bulbous) will prevent vessel piercing as the sensor is pushed forward into the vessel.
  • the sensor of the preferred embodiments is designed with a minimally invasive architecture so as to minimize reactions or effects on the blood flow (or on the sensor in the blood flow). Accordingly, the sensor designs described herein, consider minimization of dimensions and arrangement of the electrodes and other components of the sensor system, particularly the in vivo portion of the sensor (or any portion of the sensor in fluid contact with the blood flow).
  • a substantial portion of the in vivo portion of the sensor is designed with at least one dimension less than about 0.020, 0.015, 0.012, 0.010, 0.008, 0.006, 0.005, 0.004 inches.
  • a substantial portion of the sensor that is in fluid contact with the blood flow is designed with at least one dimension less than about 0.015, 0.012, 0.010, 0.008, 0.006, 0.005, 0.004, 0.003, 0.002, 0.001 inches.
  • a sensor such as described in more detail with reference to Figs.
  • IA to 1C is formed from a 0.004 inch conductive wire (e.g., platinum) for a diameter of about 0.004 inches along a substantial portion of the sensor (e.g., in vivo portion or fluid contact portion).
  • a sensor such as described in more detail with reference to Figs. IA to 1C is formed from a 0.004 inch conductive wire and vapor deposited with an insulator material for a diameter of about 0.005 inches along a substantial portion of the sensor (e.g., in vivo portion or fluid contact portion), after which a desired electroactive surface area can be exposed.
  • the reference electrode can be located remote from the working electrode (e.g., formed from the conductive wire).
  • Fig. 3C is a cross section of the sensor shown in Fig. 3B, taken at line C - C.
  • a membrane system (see Fig. 3C) is deposited over the electroactive surfaces of the sensor and includes a plurality of domains or layers, such as described in more detail below, with reference to Figs. 3B and 3C.
  • the membrane system can be deposited on the exposed electroactive surfaces using known thin film techniques (for example, spraying, electro-depositing, dipping, and the like).
  • each domain is deposited by dipping the sensor into a solution and drawing out the sensor at a speed that provides the appropriate domain thickness.
  • the membrane system can be disposed over (deposited on) the electroactive surfaces using methods appreciated by one skilled in the art.
  • the membrane system includes a plurality of domains, for example, an electrode domain 347, an interference domain 348, an enzyme domain 349 (for example, including glucose oxidase), and a resistance domain 350, as shown in Fig. 3C, and can include a high oxygen solubility domain, and/or a bioprotective domain (not shown), such as is described in more detail in U.S. Patent Publication No US-2005-0245799-A1, and such as is described in more detail below.
  • the membrane system can be deposited on the exposed electroactive surfaces using known thin film techniques (for example, vapor deposition, spraying, electro-depositing, dipping, and the like).
  • vapor deposition processes e.g., physical and/or chemical vapor deposition processes
  • ultrasonic vapor deposition electrostatic deposition, evaporative deposition, deposition by sputtering, pulsed laser deposition, high velocity oxygen fuel deposition, thermal evaporator deposition, electron beam evaporator deposition, deposition by reactive sputtering molecular beam epitaxy, atmospheric pressure chemical vapor deposition (CVD), atomic layer CVD, hot wire CVD, low-pressure CVD, microwave plasma- assisted CVD, plasma-enhanced CVD, rapid thermal CVD, remote plasma-enhanced CVD, and ultra-high vacuum CVD, for example.
  • CVD atmospheric pressure chemical vapor deposition
  • atomic layer CVD hot wire CVD
  • low-pressure CVD microwave plasma- assisted CVD
  • plasma-enhanced CVD rapid thermal CVD
  • remote plasma-enhanced CVD remote plasma-enhanced CVD
  • ultra-high vacuum CVD for example.
  • the membrane system can be disposed over (or deposited on) the electroactive surfaces using any known method, as will be appreciated by one skilled in the art.
  • one or more domains of the membrane systems are formed fr ⁇ m materials such as described above in connection with the porous layer, 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
  • the membrane system comprises an electrode domain.
  • the electrode domain 347 is provided to ensure that an electrochemical reaction occurs between the electroactive surfaces of the working electrode and the reference electrode, and thus the electrode domain 347 is preferably situated more proximal to the electroactive surfaces than the interference and/or enzyme domain.
  • the electrode domain includes a coating that maintains a layer of water at the electrochemically reactive surfaces of the sensor.
  • the electrode domain is present to provide an environment between the surfaces of the working electrode and the reference electrode, which facilitates an electrochemical reaction between the electrodes.
  • a humectant in a binder material can be employed as an electrode domain; this allows for the full transport of ions in the aqueous environment.
  • the electrode domain can also assist in stabilizing the operation of the sensor by accelerating electrode start-up and drifting problems caused by inadequate electrolyte.
  • the material that forms the electrode domain can also provide an environment that protects against pH-mediated damage that can result from the formation of a large pH gradient due to the electrochemical activity of the electrodes.
  • the electrode domain 347 includes a flexible, water-swellable, hydrogel film having a "dry film” 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 3, 2.5, 2, or 1 microns, or less, to about 3.5, 4, 4 5, or 5 microns or more.
  • “Dry film” thickness refers to the thickness of a cured film cast frora-a coating formulation by standard coating techniques.
  • the electrode domain 347 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., l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)) in the presence of polyvinylpyrrolidone and cured at a moderate temperature of about 5O 0 C.
  • a water-soluble carbodiimide e.g., l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)
  • the electrode domain 347 is formed from a hydrophilic polymer (e.g., a polyamide, a polylactone, a polyimide, a polylactam, a functionalized polyamide, a functionalized polylactone, a functionalized polyimide, a functionalized polylactam or a combination thereof) that renders the electrode domain substantially more hydrophilic than an overlying domain, (e.g., interference domain, enzyme domain).
  • the electrode domain is formed substantially entirely and/or primarily from a hydrophilic polymer Tn some embodiments, the electrode domain is formed substantially entirely from PVP. In some embodiments, the electrode domain is formed entirely from a hydrophilic polymer.
  • Useful hydrophilic polymers include but are not limited to poly-N-vinylpyrrolidone (PVP), poly-N-vinyl- 2-piperidone, poly-N-vinyl-2-caprolactam, poly-N-vinyl-3-methyl-2-caprolactam, poly-N-vinyl-3- methyl-2-piperidone, poly-N-vinyl-4-methyl-2-piperidone, poly-N-vinyl-4-methyl-2-caprolactam, poly-N-vinyl-3-ethyl-2-pyrrolidone, poly-N-vinyl-4,5-dimethyl-2-pyrrolidone, polyvinylimidazole, poly-N,N-dimethylacrylamide, polyvinyl alcohol, polyacrylic acid, polyethylene oxide, poly-2- ethyl-oxazoline, copolymers thereof and mixtures thereof A blend of two or more hydrophilic polymers is preferred in some embodiments.
  • PVP poly-N-vinylpyr
  • the hydrophilic polymer(s) is not crosslinked.
  • crosslinking is preferred, such as by adding a crosslinking agent, such as but not limited to EDC, or by irradiation at a wavelength sufficient to promote crosslinking between the hydrophilic polymer molecules, which is believed to create a more tortuous diffusion path through the domain.
  • An electrode domain formed from a hydrophilic polymer has been shown to substantially reduce break-in time of analyte sensors, for example, a glucose sensor utilizing a cellulosic-based interference domain such as described in more detail elsewhere herein.
  • a uni-component electrode domain formed from a single hydrophilic polymer e : ⁇ g., PVP
  • sensor break-in is the amount of time required (after implantation) for the sensor signal to become substantially representative of the analyte concentration
  • Sensor break-in includes both membrane break-in and electrochemical break-in, which are described in more detail elsewhere herein.
  • break-in time is less than about 2 hours. In other embodiments, break-in time is less than about 1 hour. In still other embodiments, break-in time is less than about 30 minutes, less than about 20 minutes, less than about 15 minutes, less than about 10 minutes, or less. In a preferred embodiment, sensor break-in occurs substantially immediately.
  • the senor in embodiments wherein the break-in time is about 0 minutes (substantially immediately), the sensor can be inserted and begin providing substantially accurate analyte (e.g., glucose) concentrations almost immediately post-insertion, for example, wherein membrane break -in does not limit start-up time.
  • substantially accurate analyte e.g., glucose
  • an electrode domain that is substantially more hydrophilic than the next more distal membrane layer or domain reduces the break-in time of an implanted sensor, by increasing the rate at which the membrane system is hydrated by the surrounding host tissue.
  • increasing the amount of hydrophilicity of the electrode domain relative to the overlaying layer increases the rate of water absorption, resulting in reduced sensor break-in time.
  • the hydrophilicity of the electrode domain can be substantially increased by the proper selection of hydrophilic polymers, based on their hydrophilicity relative to each other and relative to the overlaying layer (e.g., cellulosic-based interference domain), with preferred polymers being substantially more hydrophilic than the overlaying layer.
  • the overlaying layer e.g., cellulosic-based interference domain
  • PVP forms the electrode domain
  • the interference domain is formed from a blend of cellulosic derivatives, such as but not limited to cellulose acetate butyrate and cellulose acetate; it is believed that since PVP is substantially more hydrophilic than the cellulosic- based interference domain, the PVP rapidly draws water into the membrane to the electrode domain, and enables the sensor ⁇ to function with a desired sensitivity and accuracy and starting within a substantially reduced time period after implantation. Reductions in sensor break-in time reduce the amount of time a host must wait to obtain sensor readings, which is particularly advantageous not only in ambulatory applications, but particularly in hospital settings where time is critical.
  • the relative hydrophilicity of the electrode domain as compared to the overlying domain can be modulated by a selection of more hydrophilic materials for formation of the electrode domain (and/or more hydrophobic materials for the overlying domain(s)).
  • an electrode domain with hydrophilic polymer capable of absorbing larger amounts of water can be selected instead of a second hydrophilic polymer that is capable of absorbing less water than the first hydrophilic polymer.
  • the water content difference between the electrode domain and the overlying domain is from about 1% or less to about 90% or more.
  • the water content difference between the electrode domain and the overlying domain is from about 10% or less to about 80% or more. In still other embodiments, the water content difference between the electrode domain and the overlying domain is from about 30% or less to about 60% or more. In preferred embodiments, the electrode domain absorbs 5 wt. % or less to 95 wt. % or more water, preferably 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 wt. % to about 55, 60, 65, 70, 75, 80, 85, 90 or 95 wt. % water than the adjacent (overlying) domain (e.g., the domain that is more distal to the electroactive surface than the electrode domain)
  • the adjacent (overlying) domain e.g., the domain that is more distal to the electroactive surface than the electrode domain
  • the rate of water absorption by a polymer can be affected by other factors, such as but not limited to the polymer's molecular weight.
  • the rate of water absorption by PW is dependent upon its molecular weight, which is typically from about 40 kDa or less to about 360 kDa or more; with a lower molecular weight PVP (e.g., 40 kDa) absorbing water faster than a higher molecular weight PVP.
  • modulating factors, such as molecular weight, that affect the rate of water absorption by a polymer can promote the proper selection of materials for electrode domain fabrication.
  • a lower molecular weight PVP is selected, to reduce break-in time.
  • the electrode domain is deposited by known thin film deposition techniques (e.g., spray coating or dip-coating the electroactive surfaces of the sensor).
  • the electrode domain is formed by dip-coating the electroactive surfaces in an electrode domain solution (e.g., 5, 10, 15, 20, 25 or 30% or more PVP in deionized water) and curing the domain for a time of from about 15 minutes to about 30 minutes at a temperature of from about 40 0 C to about 55°C (and can be accomplished under vacuum (e.g., 20 to 30 mmHg)).
  • an electrode domain solution e.g., 5, 10, 15, 20, 25 or 30% or more PVP in deionized water
  • a preferred insertion rate of from about 1 to about 3 inches per minute into the electrode domain solution, with a preferred dwell time of from about 0.5 to about 2 minutes in the electrode domain solution, and a preferred withdrawal rate of from about 0.25 to about 2 inches per minute from the electrode domain solution provide a functional coating.
  • 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.
  • the electroactive surfaces of the electrode system are dip-coated one time (one layer) and cured at 50°C under vacuum for 20 minutes.
  • the electroactive surfaces of the electrode system is dip-coated and cured at 50°C under vacuum for 20 minutes a first time, followed by dip coating and curing at 50 0 C under vacuum for 20 minutes a second time (two layers)
  • the electroactive surfaces can be dip-coated three or more times (three or more layers).
  • the 1, 2, 3 or more layers of PVP are applied to the electroactive surfaces by spray coating or vapor deposition.
  • a crosslinking agent e.g., EDC
  • EDC can be added to the electrode domain casting solution to promote crosslinking within the domain (e.g., between electrode domain polymer components, latex, etc.). In some alternative embodiments however, no crosslinking agent is used and the electrode domain is not substantially crosslinked.
  • the deposited PVP electrode domain 347 has a "dry film" 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.
  • an independent electrode domain 347 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.
  • 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 (e.g., a non-analyte-related signal).
  • This false positive signal causes the host's analyte concentration (e.g., glucose concentration) to appear higher than the true analyte concentration.
  • False-positive signal is a clinically significant problem in some conventional sensors.
  • the artificially high glucose signal can lead the host to believe that he is euglycemic (or, in some cases, hyperglycemic). As a result, the host can make inappropriate treatment decisions, such as taking no action, when the proper course of action is to begin eating.
  • an artificially high glucose signal caused by the acetaminophen can lead the host to believe that his or her glucose concentration is much higher than it truly is. Again, as a result of the artificially high glucose signal, the host can make inappropriate treatment decisions, such as giving himself too much insulin, which in turn can lead to a dangerous hypoglycemic episode.
  • an interference domain 348 is provided that substantially restricts or blocks the flow of one or more interfering species therethrough; thereby substantially preventing artificial signal increases.
  • Some known interfering species for a glucose sensor include acetaminophen, ascorbic acid, bilirubin, cholesterol, creatinine, dopamine, ephedrine, ibuprofen, L-dopa, methyl dopa, salicylate, tetracycline, tolazamide, tolbutamide, triglycerides, and uric acid.
  • the interference domain of the preferred embodiments is less permeable to one or more of the interfering species than to the measured species, e.g., the product of an enzymatic reaction that is measured at the electroactive surface(s), such as but not limited to H2O2.
  • the interference domain 348 is formed from one or more cellulosic derivatives.
  • Cellulosic derivatives can include, but are not limited to, cellulose esters and cellulose ethers.
  • 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, as well as their copolymers and terpolymers with other cellulosic or non-cellulosic monomers.
  • Cellulose is a polysaccharide polymer of ⁇ -D- glucose. While cellulosic derivatives are generally preferred, other polymeric polysaccharides having similar properties to cellulosic derivatives can also be employed in the preferred embodiments
  • the interference domain 348 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. In some embodiments, a blend of two or more cellulose acetate butyrates having different molecular weights is preferred.
  • a “blend” as defined herein (a composition of two or more substances that are not substantially chemically combined with each other and are capable of being separated) is generally preferred, in certain embodiments a single polymer incorporating different constituents (e.g., separate constituents as monomelic units and/or substituents on a single polymer chain) can be employed instead. Additionally, a casting solution or dispersion of cellulose acetate butyrate at a wt.
  • 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 single solvent e.g., acetone
  • a single solvent is used in casting solutions for forming symmetric membrane layer(s).
  • 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.
  • 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.
  • the interference domain 348 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. In some embodiments, a blend of two or more cellulose acetates having different molecular weights is preferred.
  • 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.
  • 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.
  • the interference domain 348 can be formed from combinations or blends of cellulosic derivatives, such as but not limited to cellulose acetate and cellulose acetate butyrate, or combinations of layer(s) of cellulose acetate and layer(s) of cellulose acetate butyrate.
  • a blend of cellulosic derivatives includes up to about 10 wt. % or more of cellulose acetate. For example, about 1, 2, 3, 4, 5, 6, 7, 8, 9 wt. % or more cellulose acetate is preferred, in some embodiments.
  • the cellulosic derivatives blend includes from about 90 wt. % or less to about 100 wt. % cellulose acetate butyrate.
  • the blend includes about 91 , 92, 93, 94, 95, 96, 97, 98 or 99 wt. % cellulose acetate butyrate.
  • the cellulosic derivative blend includes from about 1.5, 2.0, 2.5, 3.0 or 3.5 wt. % cellulose acetate to about 98.5, 98.0, 97.5, 97.0 or 96.5 wt. % cellulose acetate butyrate.
  • the blend includes from about 4, 4.5, 5, 5.5, 6, 6.5, 7, 7 5 or 8 wt % cellulose acetate to about 96, 95.5, 95, 94.5, 94, 93.3, 93, 92.5 or 92 wt. % cellulose acetate butyrate.
  • the blend includes from about 8.5, 9.0, 9.5, 10.0, 10.5 or 1 1.0 wt. % cellulose acetate to about 91.5, 91.0, 90.5, 90, 89.5 or 89 wt. % cellulose acetate butyrate.
  • preferred blends of cellulose acetate and cellulose acetate butyrate contain from about 1.5 parts or less to about 60 parts or more cellulose acetate butyrate to one part of cellulose acetate. In some embodiments, a blend contains from about 2 parts to about 40 parts cellulose acetate butyrate to one part cellulose acetate. In other embodiments, about 4, 6, 8, 10, 12, 14, 16, 18 or 20 parts cellulose acetate butyrate to one part cellulose acetate is preferred for formation of the interference domain 348 In still other embodiments, a blend having from 22, 24, 26, 28, 30, 32, 34, 36 or 38 parts cellulose acetate butyrate to one part cellulose acetate is preferred. As is discussed elsewhere herein, cellulose acetate butyrate is relatively more hydrophobic than cellulose acetate. Accordingly, the cellulose acetate/cellulose acetate butyrate blend contains substantially more hydrophobic than hydrophilic components.
  • Cellulose acetate butyrate is a cellulosic polymer having both acetyl and butyl groups, in addition to hydroxyl groups. Acetyl groups are more hydrophilic than butyl groups, and hydroxyl groups are more hydrophilic than both acetyl and butyl groups. Accordingly, the relative amounts of acetyl, butyl and hydroxyl groups can be used to modulate the hydrophilicity/hydrophobicity of the cellulose acetate butyrate of the cellulose acetate/cellulose acetate butyrate blend.
  • a cellulose acetate butyrate can be selected based on the compound's relative amounts of acetate, butyrate and hydroxyl groups; and a cellulose acetate can be selected based on the compounds relative amounts of acetate and hydroxyl groups.
  • a cellulose acetate butyrate having about 35 % or less acetyl groups, about 10 % to about 25 % butyl groups, and hydroxyl groups making up the remainder is preferred for formation of the interference domain 348.
  • a cellulose acetate butyrate having from about 25 % to about 34 % acetyl groups and from about 15 to about 20 % butyl groups is preferred.
  • the preferred cellulose acetate butyrate contains from about 28 % to about 30 % acetyl groups and from about 16 to about 18 % butyl groups. In yet another embodiment, the cellulose acetate butyrate can have no acetate groups and from about 20 % to about 60 % butyrate groups. In yet another embodiment, the cellulose acetate butyrate has about 55 % butyrate groups and no acetate groups.
  • a symmetrical interference domain 348 e.g., of cellulosic-derivative blends, such as but not limited to blends of cellulose acetate components and cellulose acetate butyrate components
  • Symmetrical membranes are uniform throughout their entire structure, without gradients of pore densities or sizes, or a skin on one side but not the other, for example.
  • a symmetrical interference domain 348 can be formed by the appropriate selection of a solvent (e.g., no anti-solvent is used), for making the casting solution.
  • Appropriate solvents include solvents belonging to the ketone family that are able to solvate the cellulose acetate and cellulose acetate butyrate.
  • the solvents include but are not limited to acetone, methyl ethyl ketone, methyl n-propyl ketone, cyclohexanone, and diacetone alcohol.
  • Other solvents, such as furans (e.g., tetra-hydro-furan and 1,4-dioxane) may be preferred in some embodiments. In one exemplary embodiment, from about 7 wt % to about 9 wt.
  • % solids e.g., a blend of cellulosic derivatives, such as cellulose acetate and cellulose acetate butyrate
  • a single solvent e.g., acetone
  • from about 10 to about 15% solids are blended with acetone to form the casting solution.
  • from about 16 to about 18% solids are blended with acetone to form the casting solution.
  • a relatively lower or greater weight percent of solids is preferred to form the casting solution, in some embodiments.
  • the casting solution can be applied either directly to the electroactive surface(s) of the sensor or on top of an electrode domain layer (if included in the membrane system).
  • the casting solution can be applied using any known thin film technique, as discussed elsewhere herein.
  • a symmetrical interference domain 348 includes at least one layer; and in some embodiments, two, three or more layers are formed by the sequential application and curing of the casting solution.
  • the concentration of solids in the casting solution can be adjusted to deposit a sufficient amount of solids on the electrode in one layer (e.g., in one dip or spray) to form a membrane layer with sufficient blocking ability, such that the equivalent glucose signal of an interferent (e.g., compounds with an oxidation or reduction potential that overlaps with that of the measured species (e.g., H2O2)), measured by the sensor, is about 60 mg/dL or less.
  • an interferent e.g., compounds with an oxidation or reduction potential that overlaps with that of the measured species (e.g., H2O2)
  • the casting solution's percentage of solids is adjusted such that only a single layer (e.g., dip one time) is required to deposit a sufficient amount of the cellulose acetate/cellulose acetate butyrate blend to form a functional symmetric interference domain that substantially blocks passage therethrough of at least one interferent, such as but not limited to acetaminophen, ascorbic acid, dopamine, ibuprofen, salicylic acid, tolbutamide, tetracycline, creatinine, uric acid, ephedrine, L-dopa, methyl dopa and tolazamide.
  • interferent such as but not limited to acetaminophen, ascorbic acid, dopamine, ibuprofen, salicylic acid, tolbutamide, tetracycline, creatinine, uric acid, ephedrine, L-dopa, methyl dopa and tolazamide.
  • the amount of interference domain material deposited by as single dip is sufficient to reduce the equivalent glucose signal of the interferant (e.g., measured by the sensor) to about 60 mg/dl or less.
  • the interferent's equivalent glucose signal response is 50 mg/dl or less.
  • the interferent produces an equivalent glucose signal response of 40 mg/dl or less.
  • the interferent produces an equivalent glucose signal response of less than about 30, 20 or 10 mg/dl.
  • the interference domain is configured to substantially block acetaminophen passage therethrough, wherein the equivalent glucose signal response of the acetaminophen is less than about 30 mg/dl.
  • the interference domain 348 is configured to substantially block a therapeutic dose of acetaminophen.
  • 'therapeutic dose 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 quantity of any substance required to effect the cure of a disease, to relieve pain, or that will correct the manifestations of a deficiency of a particular factor in the diet, such as the effective dose used with therapeutically applied compounds, such as drugs.
  • a therapeutic dose of acetaminophen can be an amount of acetaminophen required to relieve headache pain or reduce a fever.
  • the interference membrane is configured to block a therapeutic dose of acetaminophen, wherein the equivalent glucose signal response of the acetaminophen is less than about 60 mg/dl. In a preferred embodiment, the interference membrane is configured to block a therapeutic dose of acetaminophen, wherein the equivalent glucose signal response of the acetaminophen is less than about 40 mg/dl. In a more preferred embodiment, the interference membrane is configured to block a therapeutic dose of acetaminophen, wherein the equivalent glucose signal response of the acetaminophen is less than about 30 mg/dl.
  • the hydrophobic and hydrophilic components of the interference domain can be balanced, to promote a desired level of interferent blocking while at the same time maintaining a desired level of analyte sensitivity.
  • the interference domain hydrophobe-hydrophile balance can be manipulated and/or maintained by the proper selection and blending of the hydrophilic and hydrophobic interference domain components (e.g., cellulosic derivatives having acetyl, butyryl, propionyl, methoxy, ethoxy, propoxy, hydroxyl, carboxymethyl, and/or carboxyethyl groups).
  • the hydrophilic and hydrophobic interference domain components e.g., cellulosic derivatives having acetyl, butyryl, propionyl, methoxy, ethoxy, propoxy, hydroxyl, carboxymethyl, and/or carboxyethyl groups.
  • cellulose acetate is relatively more hydrophilic than cellulose acetate butyrate.
  • increasing the percentage of cellulose acetate can increase the hydrophilicity of the cellulose acetate/cellulose acetate butyrate blend, which promotes increased permeability to hydrophilic species, such as but not limited to glucose, H2O2 and some interfere «ts (e.g., acetaminophen).
  • the percentage of cellulose acetate butyrate is increased to increase blocking of interferants, but less permeability to some desired molecules, such as H 2 O 2 and glucose, is also reduced.
  • One method, of manipulating the hydrophobe-hydrophile balance of the interference domain is to select the appropriate percentages of acetyl groups (relatively more hydrophilic than butyl groups), butyl groups (relatively more hydrophobic than acetyl groups) and hydroxyl groups of the cellulose acetate butyrate used to form the interference domain 348. For example, increasing the percentage of acetate groups on the cellulose acetate butyrate will make the cellulose acetate butyrate more hydrophilic. In another example, increasing the percentage of butyl groups on the cellulose acetate butyrate will make the cellulose acetate butyrate more hydrophobic.
  • an interference domain can be configured to be relatively more hydrophobic (and therefore block interferants more strongly) by reducing the percentage of acetyl or hydroxyl groups or by increasing the percentage of butyl groups on the cellulose acetate butyrate used in the casting solution (while maintaining the relative ratio of cellulose acetate to cellulose acetate butyrate).
  • the interference domain 348 is formed of a blend of cellulosic derivatives, wherein the hydrophilic and hydrophobic components of the interference domain are balanced, such that the glucose sensitivity is from about 1 pA/mg/dL to about 100 pA/mg/dL, and at least one interferent is sufficiently blocked from passage through the interference domain such that the equivalent glucose signal response of the at least one interferent is less than about 60 mg/dL.
  • the glucose sensitivity is from about 5 pA/mg/dL to about 25 pA/mg/dL.
  • the glucose sensitivity is from about 5 pA/mg/dL to about 25 pA/mg/dL and the equivalent glucose signal response of the at least one interferent is less than about 40 mg/dL. In a still more preferred embodiments, the glucose sensitivity is from about 5 pA/mg/dL to about 25 pA/mg/dL and the equivalent glucose signal response of the at least one interferent is less than about 30 mg/dL.
  • the balance between hydrophilic and hydrophobic components of the interference domain can be achieved by adjusting the amounts of hydrophilic and hydrophobic components, relative to each other, as well as adjusting the hydrophilic and hydrophobic groups (e.g., acetyl, butyryl, propionyl, methoxy, ethoxy, propoxy, hydroxyl, carboxymethyl, and/or carboxyethyl groups) of the components themselves (e.g., cellulosic derivatives, such as but not limited to cellulose acetate and cellulose acetate butyrate).
  • hydrophilic and hydrophobic groups e.g., acetyl, butyryl, propionyl, methoxy, ethoxy, propoxy, hydroxyl, carboxymethyl, and/or carboxyethyl groups
  • additional polymers such as NAFION®
  • NAFION® can be used in combination with cellulosic derivatives to provide equivalent and/or enhanced function of the interference domain 348.
  • a layer of a 5 wt. % NAFION® casting solution was applied over a previously applied (e.g., and cured) layer of 8 wt. % cellulose acetate, 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.
  • more than one cellulosic derivative can be used to form the interference domain 348 of the preferred embodiments.
  • the formation of the interference domain on a surface utilizes a solvent or solvent system, in order to solvate the cellulosic derivative(s) (or other polymer) prior to film formation thereon.
  • 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).
  • the preferred relative amounts of solvent can be dependent upon the cellulosic derivative (or other polymer) used, its molecular weight, its method for deposition, its desired thickness, and the like.
  • a percent solute of from about 1 wt. % to about 25 wt. % 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 for 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.
  • other polymer types that can be utilized as a base material for the interference domain 348 including polyurethanes, polymers having pendant ionic groups, and polymers having controlled pore size, for example.
  • the interference domain includes a thin, hydrophobic membrane that is non-swellable and restricts diffusion of high molecular weight species.
  • the interference domain 48 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 No. 7,074,307, U.S. Patent Publication No US-2005-0176136-A1, U.S. Patent No. 7,081,195, and U.S. Patent Publication No. US-2005-0143635-A1.
  • a distinct interference domain is not included.
  • the interference domain 348 is deposited either directly onto the electroactive surfaces of the sensor or onto the distal surface of the electrode 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 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
  • 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.
  • the interference domain 348 is deposited by spray or dip coating.
  • the interference domain is formed by dip coating the sensor into an interference domain solution using an insertion rate of from about 0.5 inch/min to about 60 inches/min, preferably 1 inch/min, a dwell time of from about 0 minute to about 2 minutes, preferably about 1 minute, and a withdrawal rate of from about 0.5 inch/minute to about 60 inches/minute, preferably about 1 inch/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)).
  • a 3 -minute cure (i.e., dry) time is preferred between each layer applied.
  • 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. In other embodiments, only one dip is preferred. 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 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.
  • an interference domain is formed from 10 layers of cellulose acetate. In another embodiment, an interference domain is formed from 1 layer of a blend of cellulose acetate and 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.
  • the electroactive surface can be cleaned prior to application of the interference domain 348.
  • the interference domain 348 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 a domain that interfaces with host tissue when implanted in an animal (e.g., a human) due to its stability and biocompatibility.
  • the membrane system further includes an enzyme domain 349 disposed more distally from the electroactive surfaces than the interference domain 348; however other configurations can be desirable.
  • the enzyme domain provides an enzyme to catalyze the reaction of the analyte and its co-reactant, as described in more detail below.
  • the enzyme domain includes glucose oxidase; however other oxidases, for example, galactose oxidase or unease oxidase, can also be used.
  • the sensor's response is preferably limited by neither enzyme activity nor co-reactant concentration. Because enzymes, including glucose oxidase, are subject to deactivation as a function of time even in ambient conditions, this behavior is compensated for in forming the enzyme domain.
  • the enzyme domain is constructed of aqueous dispersions of colloidal polyurethane polymers including the enzyme.
  • 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.
  • the enzyme is immobilized within the domain. See, e.g., U.S. Patent Publication No. US-2005-0054909-AI .
  • 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, 1 1, 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.
  • the enzyme domain can be deposited directly onto the electroactive surfaces.
  • the enzyme domain is deposited by spray or dip coating.
  • 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 0 C to about 55°C (and can be accomplished under vacuum (e.g., 20 to 30 mmHg)).
  • 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.
  • the enzyme domain is formed by dip coating two times (namely, forming two layers) in an enzyme domain solution and curing at 50 0 C under vacuum for 20 minutes.
  • 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.
  • the membrane system includes a resistance domain 350 disposed more distal from the electroactive surfaces than the enzyme domain.
  • a resistance domain 350 disposed more distal from the electroactive surfaces than the enzyme domain.
  • 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.
  • 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.
  • 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.
  • one-dimensional reactant dif ⁇ usion 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)).
  • a lower ratio of oxygen-to-glucose can be sufficient *4o 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.
  • the resistance domain is formed from a silicone composition, such as is described in U.S. Patent Publication No. US-2005-0090607-A1.
  • 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.
  • non-polyurethane type membranes examples 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.
  • the hydrophilic polymer component is polyethylene oxide.
  • 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 s ⁇ ft segment portion of the copolymer used to form the final blend affects the water pick-up and subsequent glucose permeability of the membrane.
  • the resistance domain is formed from a silicone polymer modified to allow analyte (e.g., glucose) transport.
  • analyte e.g., glucose
  • the resistance domain is formed from a silicone polymer/hydrophobic-hydrophilic polymer blend.
  • 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. Patent No. 4,803,243 and U.S.
  • PVP polyvinylpyrrolidone
  • PVP polyhydroxyethyl methacrylate
  • polyvinylalcohol polyacrylic acid
  • polyethers such as polyethylene glycol or polypropylene oxide
  • copolymers thereof including, for example, di
  • the hydrophobic-hydrophilic polymer is a copolymer of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO).
  • PEO poly(ethylene oxide)
  • PPO poly(propylene oxide)
  • 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
  • the copolymers may be optionally substituted with hydroxy substituents.
  • 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®. U.S. Patent Publication No. US-2007-0244379-A1 which is incorporated herein by reference in its entirety, describes systems and methods suitable for the resistance and/or other domains of the membrane system of the 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, 1 1, 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.
  • the resistance domain is deposited onto the enzyme domain by vapor deposition, spray coating, or dip coating.
  • 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.
  • physical vapor deposition e.g., ultrasonic vapor deposition
  • the vapor deposition apparatus and process include an ultrasonic nozzle that produces a mist of micro-droplets in a vacuum chamber.
  • the micro-droplets move turbulently within the vacuum chamber, isotropically impacting and adhering to the surface of the substrate.
  • vapor deposition as described above can be implemented to provide high production throughput of membrane deposition processes (e.g., at least about 20 to about 200 or more electrodes per chamber), greater consistency of the membrane on each sensor, and increased uniformity of sensor performance, for example, as described below.
  • depositing the resistance domain includes formation of a membrane system that substantially blocks or resists ascorbate (a known electrochemical interferant in hydrogen peroxide-measuring glucose sensors). While not wishing to be bound by theory, it is believed that during the process of depositing the resistance domain as described in the preferred embodiments, a structural morphology is formed that is characterized in that ascorbate does not substantially permeate therethrough.
  • ascorbate a known electrochemical interferant in hydrogen peroxide-measuring glucose sensors
  • 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.
  • a solution of resistance domain material including a solvent
  • 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.
  • spraying the resistance domain material and rotating the sensor at least one time by 180° can typically provide adequate coverage by the resistance domain.
  • Spraying the resistance domain material and rotating the sensor at least two times by 120° provides even greater coverage (one layer of 360° coverage), thereby ensuring resistivity to glucose, such as is described in more detail above.
  • the resistance domain is spray coated and subsequently cured for a time of from about 15 minutes to about 90 minutes at a temperature of from about 40 0 C to about 60 0 C (and can be accomplished under vacuum (e.g., from 20 to 30 mniHg)).
  • a cure time of up to about 90 minutes or more can be advantageous to ensure complete drying of the resistance domain.
  • the resistance domain is formed by spray coating at least six layers (namely, rotating the sensor seventeen times by 120° for at least six layers of 360° coverage) and curing at 5O 0 C under vacuum for 60 minutes.
  • the resistance domain can be formed by dip coating or spray coating any layer or plurality of layers, depending upon the concentration of the solution, insertion rate, dwell time, withdrawal rate, and/or the desired thickness of the resulting film. Additionally, curing in a convention oven can also be employed.
  • a variable frequency microwave oven can be used to cure the membrane domains/layers.
  • microwave ovens directly excite the rotational mode of solvents. Consequently, microwave ovens cure coatings from the inside out rather than from the outside in as with conventional convection ovens.
  • This direct rotational mode excitation is responsible for the typically observed "fast" curing within a microwave oven Tn contrast to conventional microwave ovens, which rely upon a fixed frequency of emission that can cause arcing of dielectric (metallic) substrates if placed within a conventional microwave oven,
  • VFM Variable Frequency Microwave
  • VFM curing can increase the rate * and completeness of solvent evaporation from a liquid membrane solution applied to a sensor, as compared to the rate and completeness of solvent evaporation observed for curing in conventional convection ovens.
  • VFM is can be used together with convection oven curing-4o further accelerate cure time.
  • conventional microwave ovens e.g., fixed frequency microwave ovens
  • the preferred embodiments further include an additional treatment step, which can be performed directly after the formation of the interference domain and/or some time after the formation of the entire membrane system (or anytime in between).
  • the additional treatment step is performed during (or in combination with) sterilization of the sensor.
  • the membrane system (or interference domain) is treated by exposure to ionizing radiation, for example, electron beam radiation, UV radiation, X-ray radiation, gamma radiation, and the like.
  • ionizing radiation for example, electron beam radiation, UV radiation, X-ray radiation, gamma radiation, and the like.
  • the membrane can be exposed to visible light when suitable photoinitiators are incorporated into the interference domain. While not wishing to be bound by theory, it is believed that exposing the interference domain to ionizing radiation substantially crosslinks the interference domain and thereby creates a tighter, less permeable network than an interference domain that has not been exposed to ionizing radiation.
  • the membrane system (or interference domain) is crosslinked by forming free radicals, which may include the use of ionizing radiation, thermal initiators, chemical initiators, photoinitiators (e.g., UV and visible light), and the like.
  • Any suitable initiator or any suitable initiator system can be employed, for example, ⁇ -hydroxyketone, ⁇ -aminoketone, ammonium persulfate (APS), redox systems such as APS/bi sulfite, or potassium permanganate.
  • Suitable thermal initiators include but are not limited to potassium persulfate, ammonium persulfate, sodium persulfate, and mixtures thereof.
  • a preferred exposure time is from about 6k or 12kGy to about 25 or 50 kGy, more preferably about 25kGy.
  • Ae exposure is sufficient for substantially crosslinking the interference domain to form free radicals, but does not destroy or significantly break down the membrane or does not significantly damage the underlying electroactive surfaces.
  • UV radiation is employed to treat the membrane
  • UV rays from about 200 nm to about 400 nm are preferred; however values outside of this range can be employed in certain embodiments, dependent upon the cellulosic derivative and/or other polymer used.
  • one or more additional domains can be provided adjacent to the interference domain for preventing delamination that may be caused by the crosslinking treatment.
  • These additional domains can be "tie layers" (i.e., film layers that enhance adhesion of the interference domain to other domains of the membrane system).
  • a membrane system is formed that includes the following domains: resistance domain, enzyme domain, electrode domain, and cellulosic-based interference domain, wherein the electrode domain is configured to ensure adhesion between the enzyme domain and the interference domain.
  • UV radiation of greater than about 290 nm is preferred.
  • photoinitiator from about 0.01 to about 1 wt % photoinitiator is preferred weight-to-weight with a preselected cellulosic polymer (e.g., cellulose acetate); however values outside of this range can be desirable dependent upon the cellulosic polymer selected.
  • a preselected cellulosic polymer e.g., cellulose acetate
  • sterilization of the transcutaneous sensor can be completed after final assembly, utilizing methods such as electron beam radiation, gamma radiation, glutaraldehyde treatment, and the like.
  • the sensor can be sterilized prior to or after packaging.
  • one or more sensors can be sterilized using variable frequency microwave chamber(s), which can increase the speed and reduce the cost of the sterilization process.
  • one or more sensors can be sterilized using ethylene oxide (EtO) gas sterilization, for example, by treating with 100% ethylene oxide, which can be used when the sensor electronics are not detachably connected to the sensor and/or when the sensor electronics must undergo a sterilization process.
  • one or more packaged sets of transcutaneous sens ⁇ rs e.g., 1, 2, 3, 4, or 5 sensors or more are sterilized simultaneously.
  • the therapeutic agent is an anticoagulant.
  • anticoagulant 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 substance the prevents coagulation (e.g., minimizes, reduces, or stops clotting of blood).
  • an anticoagulant is included in the analyte sensor system to prevent coagulation within or on the sensor (e.g., within or on the catheter or within or on the sensor).
  • Suitable anticoagulants for incorporation into the sensor system include, but are not limited to, vitamin K antagonists (e.g., Acenocoumarol, Clorindione, Dicumarol (Dicoumarol), Diphenadione, Ethyl biscoumacetate, Phenprocoumon, Phenindione, Tioclomarol, or Warfarin), heparin group anticoagulants (e.g., Platelet aggregation inhibitors: Antithrombin III, Bemiparin, Dalteparin, Danaparoid, Enoxaparin, Heparin, Nadroparin, Parnaparin, Reviparin, Sulodexide, Tinzaparin), other platelet aggregation inhibitors (e.g., Abciximab, Acetylsalicylic acid
  • heparin is incorporated into the analyte sensor system.
  • heparin is coated on the catheter (inner and/or outer diameter) and/or sensor, for example, by dipping or spraying. While not wishing to be bound by theory, it is believed" that heparin coated on the catheter and/or sensor prevents aggregation and clotting of blood on the analyte sensor system, thereby preventing thromboembolization (e.g., prevention of blood flow by the thrombus or clot) and/or subsequent complications
  • an antimicrobial is coated on the catheter (inner and/or outer diameter) and/or sensor.
  • the therapeutic agent is an antimicrobial.
  • antimicrobial agent means antibiotics, antiseptics, disinfectants and synthetic moieties, and combinations thereof, that are soluble in organic solvents such as alcohols, ketones, ethers, aldehydes, acetonitrile, acetic acid, methylene chloride and chloroform.
  • Classes of antibiotics that can be used include tetracyclines (i.e. minocycline), rifamycins (i.e. rifampin), macrolides (i.e. erythromycin), penicillins (i.e. nafeillin), cephalosporins (i.e. cefazolin).
  • beta-lactam antibiotics i.e. imipenem, aztreonam
  • aminoglycosides i.e. gentamicin
  • chloramphenicol sufonamides (i.e. sulfamethoxazole), glycopeptides (i.e. vancomycin), quinolones (i.e.
  • ciprofloxacin fusidic acid
  • trimethoprim metronidazole
  • metronidazole metronidazole
  • clindamycin metronidazole
  • mupirocin polyenes
  • polyenes i.e. amphotericin B
  • azoles i.e. fluconazole
  • beta-lactam inhibitors i.e. sulbactam
  • antibiotics examples include minocycline, rifampin, erythromycin, nafeillin, cefazolin, imipenem, aztreonam, gentamicin, sulfamethoxazole, vancomycin, ciprofloxacin, trimethoprim, metronidazole, clindamycin, teicoplanin, mupirocin, azithromycin, clarithromycin, ofloxacin, lomefloxacin, norfloxacin, nalidixic acid, sparfloxacin, pefloxacin, amifloxacin, enoxacin, fleroxacin, temafloxacin, tosufloxacin, clinafloxacin, sulbactam, clavulanic acid, amphotericin B, fluconazole, itraconazole, ketoconazole, and nystatin.
  • antiseptics and disinfectants examples include hexachlorophene, cationic bisiguanides (i.e. chlorhexidine, cyclohexidine) iodine and iodophores (i.e. povidoneiodine), para-chloro-meta- xylenol, triclosan, furan medical preparations (i.e. nitrofurantoin, nitrofurazone), methenamine, aldehydes (glutaraldehyde, formaldehyde) and alcohols
  • cationic bisiguanides i.e. chlorhexidine, cyclohexidine
  • iodine and iodophores i.e. povidoneiodine
  • para-chloro-meta- xylenol i.e. nitrofurazone
  • furan medical preparations i.e. nitrofurantoin, nitrofurazone
  • methenamine aldehydes
  • antimicrobial agents can be used alone or in combination of two or more of them.
  • the antimicrobial agents can be dispersed throughout the material of the sensor and/or catheter.
  • the amount of each antimicrobial agent used to impregnate the medical device varies to some extent, but is at least of an effective concentration to inhibit the growth of bacterial and fungal organisms, such as staphylococci, gram-positive bacteria, gram-negative bacilli and Candida.
  • the membrane system of the preferred embodiments preferably include a bioactive agent, which is incorporated into at least a portion of the membrane system, or which is incorporated into the device and adapted to diffuse through the membrane.
  • the bioactive agent is incorporated into the membrane of the preferred embodiments.
  • the bioactive agent is incorporated at the time of manufacture of the membrane system
  • the bioactive agent can be blended prior to curing the membrane system, or subsequent to membrane system manufacture, for example, by coating, imbibing, solvent-casting, or sorption of the bioactive agent into the membrane system.
  • the bioactive agent is preferably incorporated into the membrane system, in some embodiments the bioactive agent can be administered concurrently with, prior to, or after insertion of the device intravascularly, for example, by oral administration, or locally, for example, by subcutaneous injection near the implantation site.
  • a combination of bioactive agent incorporated in the membrane system and bioactive agent administration locally and/or systemically can be preferred in certain embodiments.
  • a bioactive agent can be incorporated into the membrane system, and/or incorporated into the device and adapted to diffuse therefrom, in order to modify the tissue response of the host to the membrane.
  • the bioactive agent is incorporated only into a portion of the membrane system adjacent to the sensing region of the device, over the entire surface of the device except over the sensing region, or any combination thereof, which can be helpful in controlling different mechanisms and/or stages of thrombus formation.
  • the bioactive agent is incorporated into the device proximal to the membrane system, such that the bioactive agent diffuses through the membrane system to the host circulatory system.
  • the bioactive agent can include a carrier matrix, wherein the matrix includes one or more of collagen, a particulate matrix, a resorbable or non-resorbable matrix, a controlled-release matrix, and/or a gel.
  • the carrier matrix includes a reservoir, wherein a bioactive agent is encapsulated within a microcapsule.
  • the carrier matrix can include a system in which a bioactive agent is physically entrapped within a polymer network.
  • the bioactive agent is cross-linked with the membrane system, while in others the bioactive agent is sorbed into the membrane system, for example, by adsorption, absorption, or imbibing.
  • the bioactive agent can be deposited in or on the membrane system, for example, by coating, filling, or solvent casting.
  • ionic and nonionic surfactants ionic and nonionic surfactants, detergents, micelles, emulsifiers, demulsifiers, stabilizers, aqueous and oleaginous carriers, solvents, preservatives, antioxidants, or buffering agents are used to incorporate the bioactive agent into the membrane system.
  • the bioactive agent can be incorporated into a polymer using techniques such as described above, and the polymer can be used to form the membrane system, coatings on the membrane system, portions of the membrane system, and/or any portion of the sensor system.
  • the membrane system can be manufactured using techniques known in the art.
  • the bioactive agent can be sorbed into the membrane system, for example, by soaking the membrane system for a length of time (for example, from about an hour or less to about a week or more, preferably from about 4, 8, 12, 16, or 20 hours to about 1, 2, 3, 4, 5, or 7 days).
  • the bioactive agent can be blended into uncured polymer prior to forming the membrane system.
  • the membrane system is then cured and the bioactive agent thereby cross-linked and/or encapsulated within the polymer that forms the membrane system.
  • microspheres are used to encapsulate the bioactive agent.
  • the microspheres can be formed of biodegradable polymers, most preferably synthetic polymers or natural polymers such as proteins and polysaccharides.
  • polymer is used to refer to both to synthetic polymers and proteins.
  • bioactive agents can be incorporated in (1) the polymer matrix forming the microspheres, (2) microparticle(s) surrounded by the polymer which forms the microspheres, (3) a polymer core within a protein microsphere, (4) a polymer coating around a polymer microsphere, (5) mixed in with microspheres aggregated into a larger form, or (6) a combination thereof.
  • Bioactive agents can be incorporated as particulates or by co- dissolving the factors with the polymer.
  • Stabilizers can be incorporated by addition of the stabilizers to the factor solution prior to formation of the microspheres.
  • the bioactive agent can be incorporated into a hydrogel and coated or otherwise deposited in or on the membrane system.
  • Some hydrogels suitable for use in the preferred embodiments include cross-linked, hydrophilic, three-dimensional polymer networks that are highly permeable to the bioactive agent and are triggered to release the bioactive agent based on-a stimulus.
  • the bioactive agent can be incorporated into the membrane system by solvent casting, wherein a solution including dissolved bioactive agent is disposed on the surface of the membrane system, after which the solvent is removed to form a coating on the membrane surface.
  • the bioactive agent can be compounded into a plug of material, which is placed within the device, such as is described in U.S. Patent No. 4,506,680 and U.S. Patent No. 5,282,844, which are incorporated herein by reference in their entirety.
  • bioactive agents of the preferred embodiments can be optimized for short- and/or long-term release.
  • the bioactive agents of the preferred embodiments are designed to aid or overcome factors associated with short-term effects (e.g., acute inflammation and/or thrombosis) of sensor insertion.
  • the bioactive agents of the preferred embodiments are designed to aid or overcome factors associated with long-term effects, for example, chronic inflammation or build-up of fibrotic tissue and/or plaque material
  • the bioactive agents of the preferred embodiments combine short- and long-term release to exploit the benefits of both.
  • controlled,” “sustained,” or “extended” release of the factors can be continuous or discontinuous, linear or non-linear. This can be accomplished using one or more types of polymer compositions, drug loadings, selections of excipients or degradation enhancers, or other modifications, administered alone, in combination or sequentially to produce the desired effect.
  • Short-term release of the bioactive agent in the preferred embodiments generally refers to release over a period of from about a few minutes or hours to about 2, 3, 4, 5, 6, or 7 days or more.
  • the amount of loading of the bioactive agent into the membrane system can depend upon several factors.
  • the bioactive agent dosage and duration can vary with the intended use of the membrane system, for example, the intended length of use of the device and the like; differences among patients in the effective dose of bioactive agent; location and methods of loading the bioactive agent; and release rates associated with bioactive agents and optionally their carrier matrix. Therefore, one skilled in the art will appreciate the variability in the levels of loading the bioactive agent, for the reasons described above.
  • the preferred level of loading of the bioactive agent into the membrane system can vary depending upon the nature of the bioactive agent.
  • the level of loading of the bioactive agent is preferably sufficiently high such that a biological effect (e.g., thrombosis prevention) is observed. Above this threshold, bioactive agent can be loaded into the membrane system so as to imbibe up to 100% of the solid portions, cover all accessible surfaces of the membrane, and/or fill up to 100% of the accessible cavity space.
  • the level of loading (based on the weight of bioactive agent(s), membrane system, and other substances present) is from about 1 ppm or less to about 1000 ppm or more, preferably from about 2, 3, 4, or 5 ppm up to about 10, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, or 900 ppm.
  • the level of loading can be 1 wt. % or less up to about 50 wt. % or more, preferably from about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 20 wt. % up to about 25, 30, 35, 40, or 45 wt. %.
  • the gel concentration can be optimized, for example, loaded with one or more test loadings of the bioactive agent. It is generally preferred that the gel contain from about 0.1 or less to about 50 wt. % or more of the bioactive agent(s), preferably from about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or 0.9 wt. % to about 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, or 45 wt. % or more bioactive agent(s), more preferably from about 1, 2, or 3 wt. % to about 4 or 5 wt % of the bioactive agent(s). Substances that are not bioactive can also be incorporated into the matrix.
  • the bioactive agent can be released by diffusion through aqueous filled channels generated in the dosage form by the dissolution of the agent or by voids created by the removal of the polymer solvent or a pore forming agent during the original micro-encapsulation.
  • release can be enhanced due to the degradation of the encapsulating polymer. With time, the polymer erodes and generates increased porosity and microstructure within the device. This creates additional pathways for release of the bioactive agent.
  • the senor is designed to be bioinert, e.g., by the use of bioinert materials.
  • Bioinert materials do not substantially cause any response from the host. As a result, cells can live adjacent to the material but do not form a bond with it.
  • Bioinert materials include but are not limited to alumina, zirconia, titanium oxide or other bioinert materials generally used in the "catheter/catheterization" art. While not wishing to be bound by theory, it is believed that inclusion of a bioinert material in or on the sensor can reduce attachment of blood cells or proteins to the sensor, thrombosis or other host reactions to the sensor. Dual-Electrode Analyte Sensors
  • electrochemical analyte sensors provide at least one working electrode and at least one reference electrode, which are configured to generate a signal associated with a concentration of the analyte in the host, such as described herein, 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.
  • the analyte sensors of the preferred embodiments may further measure at least one additional signal.
  • 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.
  • the analyte sensor comprises a first working electrode El and a second working electrode E2, in addition to a reference electrode, which is referred to as a dual- electrode system herein.
  • the first and second working electrodes may be in any useful conformation, as described in U.S. Patent Publication No. US-2007-0027385-A1, U.S. Patent Publication No. US-2007-021361 1-Al, U.S. Patent Publication No. US-2007-0027284-A1, U.S. Patent Publication No. US-2007-0032717-A1, U.S. Patent Publication No. US-2007-0093704- Al, and U.S. Patent Publication No.
  • the first and second working electrodes are twisted and/or bundled.
  • two wire working electrodes can be twisted together, such as in a helix conformation.
  • the reference electrode can then be wrapped around the twisted pair of working electrodes.
  • the first and second working electrodes include a coaxial configuration.
  • the sensor is configured as a dual electrode sensor, such as described in U.S. Patent Publication No. US-2005-0143635-A1, U.S. Patent Publication No.
  • a dual-electrode system can be provided in any planar or non-planar configuration, such as can be appreciated by one skilled in the art, and can be found in U.S. Patent No. 6, 175,752, U.S. Patent No. 6,579,690, U.S. Patent No. 6,484,046, U.S. Patent No. 6,512,939, U.S. Patent No. 6,477,395, U S Patent No. 6,424,847, U.S. Patent No.
  • Fig. 3D illustrates a dual-electrode system in preferred embodiments.
  • the dual-electrode sensor system includes a first working electrode El and the second working electrode E2, both of which are disposed beneath a sensor membrane M02, such as but not limited to a membrane system similar to that described with reference to Fig. 3C and/or Figs. 3F through 31.
  • the first working electrode El is disposed beneath an active enzymatic portion M04 of the sensor membrane M02, which includes an enzyme configured to detect the analyte or an analyte-related compound.
  • the first working electrode El is configured to generate a first signal composed of both signal related to the analyte and signal related to non-analyte electroactive compounds (e g., physiological baseline, interferents, and non-constant noise) that have *an oxidation/reduction potential that overlaps with the oxidation/reduction potential of the analyte.
  • This oxidation/reduction potential may be referred to as a "first oxidation/reduction potential" herein.
  • the second working electrode E2 is disposed beneath an inactive-enzymatic or non- enzymatic portion M06 of the sensor membrane M02.
  • the non-enzymatic portion M06 of the membrane includes either an inactivated form of the enzyme contained in the enzymatic portion M04 of the membrane or no enzyme.
  • the non-enzymatic portion M06 can include a non-specific protein, such as BSA, ovalbumin, milk protein, certain polypeptides, and the like.
  • the non-enzymatic portion M06 generates a second signal associated with noise of the analyte sensor.
  • the noise of the sensor comprises signal contribution due to non-analyte electroactive species (e.g., interferents) that have an oxidation/reduction potential that substantially overlaps the first oxidation/reduction potential (e.g., that overlap with the oxidation/reduction potential of the analyte).
  • the non-analyte related electroactive species comprises at least one species selected from the group consisting of interfering species, non-reaction-related hydrogen peroxide, and other electroactive species.
  • the dual-electrode analyte sensor is a glucose sensor having a first working electrode El configured to generate a first signal associated with both glucose and non-glucose related electroactive compounds that have a first oxidation/reduction potential.
  • Non-glucose related electroactive compounds can be any compound, in the sensor's local environment that has an oxidation/reduction potential substantially overlapping with the oxidation/reduction potential of H 2 O 2 . 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 H 2 O 2 that is oxidized at the working electrode) and signals from unknown compounds that are in the blood 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 known 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).
  • medicaments or infusion fluid components e.g., acetaminophen, ascorbic acid, dopamine, ibuprofen, salicylic acid, tolbutamide, tetracycline, creatinine, uric acid, ephedrine, L-dopa, methyl dopa and tolazamide
  • medicaments or infusion fluid components e.g., acetaminophen, ascorbic acid, dopamine, ibuprofen, salicylic acid, tolbutamide, tetracycline, creatinine, uric acid, ephedrine, L-dopa, methyl dopa and tolazamide
  • the dual-electrode analyte sensor includes a second working electrode E2 that is configured to generate a second signal associated with the non- glucose related electroactive compounds that have the same oxidation/reduction potential as the above-described first working electrode (e.g., para supra).
  • the non- glucose related electroactive species includes at least one of interfering species, non-reaction- related H 2 O 2 , and other electroactive species.
  • 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, a disease process, and the like).
  • Other electroactive species includes any compound that has an oxidation/reduction potential similar to or overlapping that OfH 2 O 2 .
  • the non-analyte signal produced by compounds other than the analyte obscured the signal related to the analyte, contributes to sensor inaccuracy, and is considered background noise.
  • background noise includes both constant and non-constant components and must be removed to accurately calculate the analyte concentration.
  • the senor of the preferred embodiments are designed (e.g., with symmetry, coaxial design and/or integral formation, and interference domain of the membrane described elsewhere herein) 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 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, medicaments, pH fluctuations; O 2 fluctuations, or the like) known to effect the accuracy of conventional continuous sensor signals.
  • 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.
  • the electronics include at least a potentiostat that provides a bias to the electrodes.
  • 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.
  • 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.
  • the dual-electrode sensor is configured such that the first and second working electrodes EI, E2 are equivalently influenced by in vivo environmental factors.
  • the dual-electrode sensor is configured for fluid communication with the circulatory system of the host, such as by implantation in the host's vein or artery via a vascular access device (also referred to as a fluid communication device herein) such as a catheter and/or cannula.
  • the first and second working electrodes El, E2 are configured such that they are equivalently influenced by a variety of environmental factors impinging upon the sensor, such as but not limited to non-analyte related electroactive species (e.g., interfering species, non-reaction- related H 2 O 2 , an other electroactive species).
  • non-analyte related electroactive species e.g., interfering species, non-reaction- related H 2 O 2 , an other electroactive species.
  • the signal component associated with the in vivo environmental factors e.g., non-analyte related species with an oxidation/reduction potential that overlaps with that of the analyte
  • the signal component associated with the in vivo environmental factors can be removed from the signal detected by the first working electrode (e.g., the first signal). This can give a substantially analyte-only signal.
  • the effects of in vivo environmental factors upon the dual-electrode system are discussed in greater detail elsewhere herein with reference to Figs. 3G-3I.
  • the dual-electrode sensor includes electronics (e.g., a processor module, processing memory) that are operably connected to the first and second working
  • the -J41- electrodes are configured to provide the first and second signals to generate analyse concentration data substantially without signal contribution due to non-analyte-related noise.
  • the sensor electronics process and/or analyze the signals from the first and second working electrodes and calculate the portion of the first electrode signal that is due to analyte concentration only.
  • the portion of the first electrode signal that is not due to the analyte concentration can be considered to be background, such as but not limited to noise
  • the system comprising electronics operably connected to the first and second working electrodes; the electronics are configured to process the first and second signals to generate analyte concentration data substantially without signal contribution due to noise.
  • Fig. 3E illustrates one preferred embodiment, the dual- electrode analyte sensor.
  • the sensor comprises a first working electrode El configured to detect the analyte and a second working electrode E2, wherein the first and second working electrodes are formed of two wire working electrodes twisted together to form a "twisted pair.”
  • the first working electrode El is disposed beneath an enzymatic portion of the membrane (not shown) containing an analyte-detecting enzyme.
  • a glucose-detecting enzyme such as GOX, is included in the enzymatic portion of the membrane.
  • the first working electrode El detects signal due to both the analyte and non-analyte-related species that have an oxidation/reduction potential that substantially overlaps with the oxidation/reduction potential of the analyte.
  • the second working electrode E2 is disposed beneath a portion of the membrane comprising either inactivated enzyme (e.g., inactivated by heat, chemical or UV treatment) or no enzyme. Accordingly, the second working electrode E2 detects a signal associated with only the non- analyte electroactive species that have an oxidation/reduction potential that substantially overlaps with that of analyte.
  • the non-analyte (e.g., non-glucose) electroactive species have * an oxidation/reduction potential that overlaps substantially with that of H2O2.
  • a reference electrode R such as a silver/silver chloride wire electrode, is wrapped around the twisted pair.
  • the three electrodes El, E2 and R are connected to sensor electronics (not shown), such as described elsewhere herein.
  • the dual-electrode sensor is configured to provide an analyte-only signal (e.g., glucose-only signal) substantially without a signal component due to the non-analyte electroactive species (e.g., noise).
  • the dual-electrode sensor is operably connected to sensor electronics that process the first and second signals, such that a substantially analyte-only signal is provided (e.g., output to a user).
  • the dual-electrode sensor can be configured for detection of a variety of analytes other than glucose, such as but not limited to urea, creatinine, succinate, glutamine, oxygen, electrolytes, cholesterol, lipids, triglycerides, hormones, liver enzymes, and the like.
  • the surface area of the electroactive portion of the reference (and/or counter) electrode is at least six times the surface area of the working electrodes.
  • 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.
  • the reference (and/or counter) electrode surface area is 1 1, 12, 13, 14, 15, 16, 17, 18, 19 or 20 times the surface area of the working electrodes.
  • the surface area of the reference electrode e.g., R
  • the exposed surface of the reference electrode such as but not limited to the electrode surface facing away from the working electrodes El, E2.
  • 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.
  • 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.
  • Alternative dual-electrode configurations include those illustrated in Figs. 2G-2S, as described herein.
  • the analyte sensor substantially continuously measures the host's analyte concentration.
  • 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.
  • dual-electrode glucose sensor can be manufactured as follows.
  • the working electrodes are first coated with a layer of insulating material (e.g., non-conductive material or dielectric) to prevent direct contact between the working electrodes El, E2 and the reference electrode R.
  • a layer of insulating material e.g., non-conductive material or dielectric
  • the two working electrodes can be twisted and/or bundled to form a twisted pair.
  • a portion of the insulator on an exterior surface of each working electrode is etched away, to expose the electrode's electroactive surface.
  • an enzyme solution e g., containing active GOx
  • enzymes can be inactivated by a variety of means, such as by heat, treatment with inactivating (e.g., denaturing) solvents, proteolysis, laser irradiation or UV irradiation (e g., at 254-320 nm).
  • the enzyme coating one of the electroactive surfaces can be inactivated by masking one of the electroactive surfaces (e.g., electrodes, El, 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.
  • UV light e.g., 254-320 nm; a wavelength that inactivates the enzyme, such as by cross-linking amino acid residues
  • an enzyme solution containing active enzyme is applied to a first electroactive surface (e.g., El) and an enzyme solution containing either inactivated enzyme or no enzyme is applied to the second electroactive surface (e.g., E2).
  • the enzyme-coated first electroactive surface e.g., El
  • the second electroactive surface e.g., E2
  • the sensor electronics can use the data collected from the two working electrodes to calculate the analyte- only signal.
  • cross talk can interfere with analyte/noise detection.
  • cross talk occurs when signal (e.g., in the form of energy and/or a detectable species such as but not limited to H2O2) is transferred from one electrode (e.g., the first working electrode) to another (e.g., the second working electrode), and detected as a signal by the other electrode.
  • the first and second working electrodes El, E2 are separated by diffusion barrier, such as an insulator, a non-conductive material, a reference electrode and/or the like.
  • Fig. 3F illustrates the use of a diffusion barrier to prevent cross talk in a dual-electrode glucose sensor, in one embodiment.
  • the first and second working electrodes El, E2 are disposed beneath a membrane 348 and separated by a diffusion barrier D.
  • glucose is metabolized by the GOx enzyme, which produces H 2 O 2 .
  • the H 2 O 2 produced by the enzymatic reaction can diffuse in any direction through the membrane 348.
  • a portion of the H 2 O 2 diffuses to the surface of the first working electrode and is detected due to the transfer of two electrons to the electrode. Another portion of the H 2 O 2 can diffuse out of the membrane. Since the diffusion barrier D is disposed between the working electrodes, the diffusion barrier substantially blocks diffusion of H 2 O 2 to the second working electrode E2.
  • the diffusion barrier D is a physical diffusion barrier, such as a structure between the working electrodes that blocks glucose and H 2 O 2 from diffusing from the first working electrode El to the second working electrode E2.
  • the diffusion barrier D is a spatial diffusion barrier, such as a distance between the working electrodes that blocks glucose and H 2 O 2 from diffusing from the first working electrode El to the second working electrode E2.
  • the diffusion barrier D is a temporal diffusion barrier, such as a period of time between the activity of the working electrodes such that if glucose or H 2 O 2 diffuses from the first working electrode El to the second working electrode E2, the second working electrode E2 will not substantially be influenced by the H 2 O 2 from the first working electrode El.
  • the dual-electrode sensor comprises --an insulator, such as an electrical insulator, located between the first and second working electrodes, wherein the insulator comprises a physical diffusion barrier.
  • the physical diffusion barrier is configured to structurally block a substantial amount of diffusion of at least one of an analyte (e.g., glucose) and a co-analyte (e.g., H 2 Cb) between the first and second working electrodes.
  • analyte e.g., glucose
  • a co-analyte e.g., H 2 Cb
  • the diffusion barrier comprises a structure that protrudes from a plane that intersects both the first and second working electrodes.
  • the structure that protrudes comprises an electrical insulator and/or an electrode.
  • the dual-electrode sensor comprises an insulator located between the first and second working electrodes, wherein the insulator comprises a diffusion barrier configured to substantially block diffusion of at least one of an analyte and a co-analyte between the first and second working electrodes.
  • the diffusion barrier comprises a temporal diffusion barrier configured to block or avoid a substantial amount of diffusion or reaction of at least one of the analyte and the co-analyte between the first and second working electrodes.
  • the dual-electrode sensor comprises a sensor membrane configured to substantially block diffusion of at least one of an analyte and a co-analyte between the first and second working electrodes by a discontinuity of the sensor membrane between the first and second working electrodes.
  • a discontinuity of the sensor membrane is a type of physical diffusion barrier formed by a portion of the membrane between the two working electrodes, in some embodiments, wherein a discontinuity in the membrane structure blocks diffusion of H2O2 between the electrodes. Discontinuities of sensor membranes are discussed in greater detail with reference to Fig. 31, in the section entitled "Sensor Configurations for Equivalent Measurement of Noise.”
  • the dual-electrode sensor system is configured for fluid communication with a host's circulatory system, such as via a vascular access device.
  • a vascular access device comprises a lumen and at least a portion of the sensor is disposed within the lumen; and in some embodiments, at least a portion of the sensor can extend into the vascular system
  • the vascular access device comprises a hub and the continuous analyte sensor is disposed substantially within the hub.
  • the system includes a fluid coupler configured and arranged to mate with the vascular access device on a first end; wherein the sensor is disposed within a portion of the fluid coupler and/or at a surface of the fluid coupler.
  • the sensor is configured to reside substantially above a plane defined by the host's skin.
  • the sensor is disposed on a surface of the vascular access device
  • the vascular access device is configured for insertion into at least one of an artery, a vein, a fistula, and an extracorporeal circulatory device configured to circulate at least a portion of the host's blood outside of the host's body.
  • the system includes a flow control device in fluid communication with the vascular access device.
  • the flow control device is configured to meter a flow of a fluid (e.g., blood, saline, a reference solution) through the vascular access device.
  • the flow control device is further configured to control fluid contact with the continuous analyte sensor, as is described in the section entitled "Integrated Sensor System.”
  • the sensor electronics are operably connected to the first and second working electrodes.
  • the electronics are configured to calculate at least one analyte sensor data point.
  • the electronics can include a potentiostat, A/D converter, RAM, ROM, transmitter, and the like.
  • 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.
  • the raw counts from a glucose sensor can be converted to milligrams of glucose per deciliter of glucose (e.g., mg/dl).
  • 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.
  • the sensor electronics may perform additional operations, such as but not limited to data smoothing and noise analysis.
  • the dual-electrode sensor includes electronics (e.g., a processor module, processing memory) that are operably connected to the first and second working electrodes and are configured to provide the first and second signals to generate an analyte concentration data substantially without signal contribution due to non-analyte-related noise.
  • the sensor electronics process and/or analyze the signals from the first and second working electrodes and calculate the portion of the first electrode signal that is due to analyte concentration only.
  • the portion of the first electrode signal that is not due to the analyte concentration can be considered to be background, such as but not limited to noise.
  • a dual-electrode sensor system configured for fluid communication with a host's circulatory system (e.g., via a vascular access device)
  • the system comprising electronics operably connected to the first and second working electrodes; the electronics are configured to process the first and second signals to generate analyte concentration data substantially without signal contribution due to noise.
  • the dual-electrode analyte sensor includes a reference sensor/system, as described elsewhere therein, whereby reference data can be provided for calibration (e.g., internal to the system), without the use of an external (e.g., separate from the system) analyte-measuring device.
  • the dual-electrode sensor is a glucose sensor and external glucose data points (e.g., from a hand-held glucose meter or a YSI device) are not required for calibration of a dual-electrode glucose sensor system that includes a reference sensor.
  • the reference sensor is configured to be disposed within the same local environment as the dual-electrode analyte sensor, such that the reference sensor and the dual-electrode analyte sensor can be simultaneously exposed to a sample.
  • the reference sensor/system can be disposed remotely from the dual-electrode sensor.
  • the electronics module is configured to process the reference data with the first and second signals to generate analyte concentration data substantially without signal contribution due to noise.
  • the electronics module is configured to calibrate the dual-electrode analyte sensor data using the reference sensor data, as described elsewhere herein.
  • the electronics module is configured to determine a scaling factor (k) as described in the section entitled “Calibration Systems and Methods.”
  • a scaling factor defines a relationship between the enzymatic portion of the membrane and the non- enzymatic portion of the membrane.
  • the electronics module also referred to as the processor module herein, is configured to and/or comprises programming to calibrate the analyte sensor data using the scaling factor, such that the calibrated sensor data does not include inaccuracies that can arise due to small differences between the plus- and minus- enzyme portions of the membrane at the first and second working electrodes, respectively.
  • the system is configured to calibrate the continuous dual-electrode analyte sensor using a reference fluid (e.g., 602a), as described in the section entitled "integrated sensor system.”
  • the system is configured to calibrate the sensor using single-point calibration, in other embodiments, the system is configured to calibrate the sensor without a reference data point provided by an external analyte monitor (e.g., SMBG, YSI), as described elsewhere herein
  • the system includes a reference sensor configured to generate a signal associated with a reference analyte in the sample (e.g., internal to the system), wherein the continuous analyte sensor is further configured to generate a third signal associated with the reference analyte, and wherein the system is configured to calibrate the continuous analyte sensor using the reference signal and the third signal
  • the reference sensor comprises an optical sensing apparatus, such as but not limited to an optical O 2 sensor.
  • the continuous an optical O 2 sensor such as but not limited to an optical O 2 sensor.
  • the continuous analyte sensor further comprises a bioinert material or a bioactive agent incorporated therein or thereon.
  • Applicable bioactive agent include but are not limited to vitamin K antagonists, heparin group anticoagulants, platelet aggregation inhibitors, enzymes, direct thrombin inhibitors, Dabigatran, Defibrotide, Dermatan sulfate, Fondaparinux, and Rivaroxaban
  • a method for continuously detecting an analyte in the host m vivo using a dual-electrode analyte sensor is provided.
  • a vascular access device e.g., a catheter
  • the sensor is contacted with a sample of the circulatory system, such as a sample of blood withdrawn into the catheter.
  • a first signal is generated by the sensor, wherein the first signal is associated with associated with the analyte and non-analyte related electroactive compounds having a first oxidation/reduction potential in a sample of the circulatory system of the host.
  • the analyte sensor is configured to detect glucose.
  • a second signal is also generated, wherein the second signal is associated with noise of the analyte sensor, wherein the noise comprises signal contribution due to non-analyte related electroactive species with an oxidation/reduction potential that substantially overlaps with the first oxidation/reduction potential in the sample.
  • the first and second signals are processed to provide a processed signal substantially without a signal component associated with noise.
  • the first and second signals are processed to provide a scaling factor, which can then be used to calibrate the first signal.
  • a reference sensor is also contacted with the sample, and a third signal associated with a reference analyte generated.
  • the reference sensor is an optical detection apparatus, such as but not limited to an optical O 2 sensor.
  • the first and second signals can be calibrated using the third and/or reference signal.
  • the processing step comprises evaluating steady-state information and transient information, wherein the first and second signals each comprise steady-state and transient information.
  • the evaluating step includes evaluating at least one of sensitivity information and baseline information, wherein the steady-state information comprises the sensitivity and baseline information.
  • the continuous analyte sensor is configured to detect the analyte by optical means.
  • various types of Raman and/or fluorescent spectroscopic detection are used.
  • glucose can be detected via fiber optic visible fluorescence, using glucose dehydrogenase (GDH) and a modified flavin adenine dinucleotide (FAD) coenzyme system, Concanavalin A, or hexokinase.
  • GDH glucose dehydrogenase
  • FAD modified flavin adenine dinucleotide
  • Concanavalin A Concanavalin A
  • hexokinase hexokinase
  • a fluorescent molecule e.g., a fluorophore
  • ferrocene is modified and used as a mediator in the reaction of GOX (or GHD) with glucose, wherein a pH-sensitive fluorophore is used to detect the reaction.
  • fiber optic probes are constructed by applying membrane systems configured for optical/fluorescent detection to an optical fiber.
  • multiple fiber optic probes are bundled, which enables a variety of integrative and/or subtractive signal correlations/corrections and to enhance error detection. Examples of optical detection can be found in U.S. Patent No. 7,289,836 and U.S. Patent No. 7,149,562, each of which is incorporated by reference herein in its entirety.
  • a continuous analyte detection system including a sensor configured and arranged for fluid contact with a host's circulatory system and a processor module.
  • the sensor comprises both a continuous analyte sensor (e.g., either non-dual-electrode or dual-electrode) and a reference sensor.
  • the system includes a continuous analyte sensor including a working electrode and a reference electrode, and a reference sensor.
  • the system includes a dual-electrode analyte sensor, including first and second working electrodes and a reference electrode, and a reference sensor.
  • the continuous analyte sensor is configured and arranged to generate a first signal associated with a test analyte and a second signal associated with a reference analyte.
  • the test analyte is glucose and the reference analyte is oxygen; thus, the first signal is associated with glucose and the reference signal is associated with oxygen.
  • the reference sensor is configured to generate a reference signal that is also associated with the reference analyte.
  • a “reference analyte” can be any analyte that can be measured by both the analyte sensor and the reference sensor, such those analytes listed under the definition of "analyte” in the section entitled “Definitions.”
  • the reference analyte is one that is relatively stable within the host's body, such as but not limited to O2, succinate, glutamine, and the like.
  • the processor module is configured to and/or comprises programming to process the second signal (e.g., related to the reference analyte) and the reference signal to calibrate the first signal (e.g., related to the analyte).
  • the processor module calibrates the second signal (e.g., the reference analyte signal detected by the analyte sensor) using the reference signal provided by the reference sensor, and then to calibrate the first signal (e.g., the analyte signal) using the second signal.
  • the second signal e.g., the reference analyte signal detected by the analyte sensor
  • the first signal e.g., the analyte signal
  • the system's continuous analyte sensor is a dual-electrode sensor that comprises both first and second working electrodes El, E2.
  • the first working electrode is disposed beneath an active enzymatic portion o£-a sensor membrane and generates a signal (e.g., the first signal) associated with both the analyte (e.g., glucose) and non-analyte related electroactive compounds (e.g., non-glucose compounds that have an oxidation/reduction potential that substantially overlaps with the oxidation/reduction potential of glucose).
  • the analyte e.g., glucose
  • non-analyte related electroactive compounds e.g., non-glucose compounds that have an oxidation/reduction potential that substantially overlaps with the oxidation/reduction potential of glucose
  • the second working is disposed beneath an inactive-enzymatic or a non-enzymatic portion of the sensor membrane and generates a non-analyte-related signal associated with the non-analyte electroactive species.
  • the processor module configured to and/or comprises programming to process signals from the first and second working electrodes, and to thereby generate a first signal substantially without a non-analyte signal component.
  • the second signal (e.g., related to the reference analyte) can be generated by various means.
  • the first working electrode of the dual-electrode analyte sensor is configured to generate both the first signal and the second signal.
  • pulsed amperometric detection including switching, cycling or pulsing the voltage of the electrode in an electrochemical system (e.g., between a positive voltage (e.g., +0.6 for detecting glucose) and a negative voltage (e.g., -0.6 for detecting oxygen) can be employed to determine an oxygen measurement.
  • the first working electrode is configured to generate a signal associated with the analyte when a potential of +0.6mV is applied thereto.
  • the first working electrode becomes an O 2 sensor and measures a signal associate with the amount of O 2 passing through the sensor's membrane system.
  • the dual-electrode analyte sensor is a glucose sensor configured for fluid communication with a host's circulatory system, wherein the sensor is configured to generate a first signal associated with glucose (at the first working electrode El) at an applied potential of O. ⁇ mV, and then to generate a second signal associated with O 2 (also at the first working electrode El) at an applied potential of -O. ⁇ mV.
  • the potential applied to the first working electrode can be switched from +0.6mV to -O. ⁇ mV, such that the first working electrode switches from measuring the analyte-related signal (e.g., glucose) to measuring the second signal (e.g., associated with O 2 ).
  • the second working electrode E2 (e.g., instead of the first working electrode El) is configured to generate the second signal.
  • the dual-electrode analyte sensor is a glucose sensor configured for fluid communication with a host's circulatory system, wherein the sensor is configured to generate a first signal associated with glucose (at the first working electrode El) at an applied potential of O. ⁇ mV, to generate a non-analyte-related signal (at the second working electrode E2) at an applied potential of 0 6m V, and then to generate a second signal associated with O 2 (also at the second working electrode E2) at an applied potential of -O. ⁇ mV.
  • the potential applied to the second working electrode can be switched from O. ⁇ mV to -O. ⁇ mV, such that the second working electrode switches from measuring the non-analyte- related signal to measuring the second signal (e.g., associated with O 2 ).
  • the second signal can be generated by a third working electrode disposed beneath the sensor's membrane.
  • the dual-electrode analyte sensor is a glucose sensor configured for fluid communication with a host's circulatory system, wherein the sensor is configured to generate a first signal associated with glucose (at the first working electrode El) at an applied potential of O. ⁇ mV, to generate a non-analyte-related signal (at the second working electrode E2) at an applied potential of O. ⁇ mV, and then to generate the second signal associated with O> (at the third working electrode, e.g., E3, not shown) at an applied potential of -O. ⁇ mV.
  • switching the applied potential from O. ⁇ mV to -O. ⁇ mV is not required.
  • the system includes a reference sensor.
  • the reference sensor is an optical sensing apparatus, as described above.
  • the reference sensor is configured to detect the reference analyte by any means known in the art, such as but not limited to electrochemical, chemical, physical, immunochemical, calorimetric and/or radiometric means.
  • the reference sensor is disposed in the same local environment as the continuous analyte sensor, but not under the membrane system of the continuous analyte sensor.
  • the reference sensor can be disposed adjacent to the continuous analyte sensor, such that when the continuous analyte sensor is contacted with a sample the reference sensor is simultaneously contacted by the sample.
  • a dual-electrode continuous analyte sensor and a reference sensor are disposed adjacently, such that they can be simultaneously exposed to a sample of the host's circulatory system.
  • a dual-electrode sensor includes a first working electrode configured to detect the analyte (including non-analyte-related noise) and a second working electrode is configured to detect the signal associated with non-analyte-related noise.
  • the first and second working electrodes are bundled and/or twisted, and the reference sensor is disposed adjacent to the first and second working electrodes.
  • either the first or the second working electrodes of the dual-electrode sensor is configured to detect a signal associated with the reference analyte (e.g., a second signal); while in other embodiments, the dual-electrode sensor includes a third working electrode configured to detect the reference analyte (e.g., the second signal).
  • a signal associated with the reference analyte e.g., a second signal
  • the dual-electrode sensor includes a third working electrode configured to detect the reference analyte (e.g., the second signal).
  • the dual-electrode sensor is both a glucose sensor and an O 2 sensor
  • the reference sensor is an optical O 2 sensor.
  • the first working electrode of the dual-electrode sensor is configured to detect a signal associated with both glucose and non-glucose-related electroactive species (in a sample of the host's circulatory system), and the second working electrode is configured to detect the non-glucose related electroactive species.
  • the first working electrode or the second working electrode is configured to detect O 2 , such as via switching the applied potential from 0.6mV to -0.6MV, as described elsewhere herein.
  • the reference sensor which can be bundled with the dual-electrode sensor, is configured to optically detect a reference signal associated with the O 2 concentration of the sample.
  • the dual-electrode sensor instead of using the first or second working electrodes to detect O 2 , the dual-electrode sensor includes a third electrode configured to detect O 2 .
  • the signal related to a reference analyte can be used to calibrate the signals from a continuous analyte sensor, such as in the event of a drift in sensor sensitivity and/or baseline.
  • the signals related to the reference analyte, from the continuous analyte and reference sensors can be processed to determine a calibration factor.
  • the calibration factor can then be used to calibrate the continuous analyte sensor data.
  • the term "calibration factor” 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 mathematical function generated by processing the reference analyte-related signal of the continuous analyte sensor and the reference analyte-related signal of the reference sensor, which can be used to calibrate the continuous analyte sensor data initially and/or responsive to an occurrence of a drift in sensor sensitivity and/or baseline.
  • a method for measuring an analyte in a host is provided.
  • a continuous analyte detection system which includes a continuous analyte sensor and a reference sensor, is provided.
  • the continuous analyte sensor is configured and arranged to generate a first signal associated with a test analyte (e.g., glucose) and a second signal associated with a reference analyte (e.g., O 2 ), and the reference sensor configured to generate a reference signal associated with the reference analyte (e.g., O2).
  • a test analyte e.g., glucose
  • a reference analyte e.g., O 2
  • the detection system is exposed to a sample of a host's circulatory system in vivo.
  • the detection system can be fluidly coupled to a vascular access device implanted in a host's circulatory system, such that a sample of the host's blood can be drawn back an contacted with the detection system.
  • the continuous analyte sensor and the reference sensor are exposed to the sample simultaneously. Accordingly, measurements of the reference analyte can be made at the same time by the continuous analyte and reference sensors.
  • a fluid flow device configured for fluid communication with the circulatory system of the host and to meter a flow of a fluid therethrough is provided.
  • the fluid flow device comprises a vascular access device configured for insertion into either an artery or a vein of the host.
  • a vascular access device configured for insertion into either an artery or a vein of the host.
  • Such fluid flow devices are described in detail in the sensor entitled "Integrated Sensor System.”
  • the fluid flow device is coupled with the continuous analyte detection system, and a sample of the circulatory system of the host is withdrawn
  • the fluid flow device is further configured to meter the flow of a non-bodily fluid through the vascular access device.
  • Non-bodily fluids include a variety of sterile infusion fluids, such as but are not limited to saline, reference solutions such as a glucose solution of defined concentration, nutritional supplements, IV medicaments, and the like.
  • signals are received from the continuous analyte sensor and the reference sensor.
  • the signals received include a first signal (e.g., related to the test analyte, such as but not limited to glucose), a second signal (e.g., related to the reference analyte, such as but not limited to O 2 ) and a reference signal (e.g., related to the reference analyte).
  • the first signal is received from a first working electrode disposed under an enzymatic portion of a membrane system.
  • the first working electrode is disposed beneath a portion of the membrane system including active GOX and detects a first signal associated with the concentration of glucose in the sample.
  • the first working electrode also received the second signal, as described elsewhere herein.
  • the second signal is received from a second working electrode that is also disposed under the membrane system.
  • the second working electrode configured to also receive a non-analyte-related signal.
  • the second working electrode is disposed under a non-enzymatic portion of the membrane system, in some embodiments.
  • the non-analyte-related signal is received from a third working electrode disposed under a non-enzymatic portion of the membrane system.
  • the reference sensor is configured to detect the reference analyte optically.
  • the reference analyte is oxygen. Accordingly, the second signal and the reference signal received are associated with the concentration of oxygen in the sample.
  • a calibration factor is calculated, wherein the calibration factor is associated with a sensitivity and/or baseline of the continuous analyte sensor.
  • the continuous analyte detection system is exposed to a bodily fluid (e.g., blood) and the calculating step includes comparing steady-state information of the first signal and steady-state information of the second signal.
  • the calibration factor can be calculated by examining the transient information of the first and second signals.
  • the continuous analyte detection system is configured to be exposed to a non-bodily fluid, such as saline or a reference fluid, such as to wash the previous blood sample off of the device.
  • a non-bodily fluid such as saline or a reference fluid
  • the non-bodily fluid can be held substantially stagnant (e.g., no flow or very little flow of the fluid past the sensor) for a period of time.
  • the working electrodes of the continuous analyte sensor detect signals associated with non-analyte-related compounds diffusion to the first and second working electrodes.
  • a saline solution containing a defined amount of glucose is used to wash the sensor.
  • the GOX at the first working electrode metabolizes glucose diffusing through the membrane.
  • the reactant e.g., H 2 O 2
  • the signal increase on each of the first and second working electrodes can be compared to calculate the calibration factor. This method for calculating the calibration factor is discussed in greater detail elsewhere herein, with reference to Figs. 3J and 3K.
  • the signal(s) from the continuous analyte sensor are calibrated using the calibration factor.
  • the process of calculating the calibration factor and then using the newly calculated calibration factor to calibrate the signals can be continuous, continual and/or intermittent; such that at time passes the calibration factor and calibration are updated.
  • the system is configured to evaluate changes in membrane sensitivity and/or baseline, to adjust the calculation of analyte concentrations accordingly, whereby the host is provided with more accurate data for use in therapy decision-making.
  • a multi-sensor apparatus configured for the detection of a plurality of analytes in a circulatory system of a host in vivo.
  • Figs. 2G through 2S illustrate some exemplary embodiments of such a device.
  • the multi- sensor apparatus is a vascular access device (e.g., a catheter) or a connector configured for fluid communication with the circulatory system of the host.
  • the multi-sensor apparatus includes a lumen (e.g., a duct) sufficiently large to house the plurality of sensors, as described elsewhere herein.
  • the multi-sensor apparatus comprises a plurality of analyte sensors, wherein the plurality of analyte sensor are configured to detect at least' one analyte and to contact a sample of the host's circulatory system.
  • the multi-sensor apparatus comprises a lumen, an external surface, and two orifices, wherein a first orifice is proximal relative to the host and the second orifice is distal.
  • the proximal orifice is referred to herein as the in vivo orifice and the distal orifice is referred to as the ex vivo orifice.
  • the distal orifice is configured to couple with a fluid flow device (or a component thereof), such as but not limited to a connector or coupler, a valve, IV tubing, a pump, and the like.
  • a fluid flow device such as but not limited to a connector or coupler, a valve, IV tubing, a pump, and the like.
  • the distal orifice e.g., the ex vivo orifice
  • both the proximal and distal orifices are configured to couple with IV equipment.
  • the proximal orifice is configured to couple with a vascular access device (e.g., a catheter/cannula), TV tubing, and/or other connectors, and the distal end is configured to couple with a fluid flow device (e.g., IV tubing, a pump, etc.).
  • a vascular access device e.g., a catheter/cannula
  • TV tubing e.g., TV tubing, and/or other connectors
  • a fluid flow device e.g., IV tubing, a pump, etc.
  • a plurality of analyte sensors are disposed within the lumen of the multi-sensor apparatus.
  • 2, 3, 4, 5, 6, 7, or more sensors can be disposed within the lumen of the multi-sensor apparatus.
  • each of the plurality of analyte sensor is configured to detect a different analyte. In some embodiments, two or more of the plurality of analyte sensors are configured to detect the same analyte, thereby providing redundancy and/or fail-safes in analyte detection and/or sensor function.
  • Fig. 2G provides an exemplary embodiment of a multi-sensor apparatus, namely a catheter, including an in vivo portion configured for insertion into the host and an ex vivo portion 218 (e.g., a connector or hub) configured to remain outside the host's body after implantation/insertion of the in vivo portion into a host.
  • the in vivo portion may also be referred to as the proximal portion/end of the catheter (e.g., with respect to the host) includes an in vivo orifice at or near the catheter's tip, for fluid communication with the host's circulatory system upon implantation into the host's vein or artery, or in an extracorporeal circulatory device.
  • the ex vivo portion of the catheter may also be referred to as the proximal portion (e.g., with respect to the host).
  • a plurality of analyte sensors 240 are disposed within the catheter's connector/hub, such as within the lumen/duct 254 and/or within a widened portion of the catheter's in vivo portion.
  • Fig. 2H provides another exemplary embodiment of a multi-sensor apparatus, namely a connector, such as a Leur lock, a Y-connector, a T-connector, an X-connector, or a valve configured for connecting IV equipment.
  • the multi-sensor apparatus includes a proximal oriSee (e.g., with respect to the host) configured to couple with a vascular access device (e.g., a catheter/cannula) or with various IV equipment, such as IV tubing or another connector, and a distal orifice (e.g., with respect to the host) configured to fluidly couple to other IV equipment, as described herein and is known to one skilled in the art.
  • the analyte sensors 240 are disposed within the multi-sensor apparatus's lumen or duct 254.
  • the analyte sensors can be configured to detect an analyte using any means known in the art, such as but not limited to by enzymatic, chemical, physical, electrochemical, spectrophotometric, polarimetric, calorimetric, radiometric, or immunochemical techniques, or by a combination of these techniques.
  • each sensor can use a different detection technique. For example, a first analyte sensor can detect a first analyte using a first technique, a second analyte sensor can detect a second analyte using a second technique, a third analyte sensor can detect a third analyte using a third technique, and so on.
  • a detection technique can be used by more than one of the analyte sensors, wherein the technique is modified to detect a particular analyte of interest by each of the sensors.
  • a first sensor can be configured to detect glucose enzymatically
  • a second sensor can be configured to detect cholesterol e ⁇ zymatically.
  • one of the plurality of sensors is configured to detect an analyte optically, as described elsewhere herein.
  • two or more of the sensors are configured to detect the same analyte, either by the same or different detection techniques.
  • Figs. 21 through 2L are cross-sections of the multi-sensor apparatus of Figs. 2G and 2H taken along line 2T - 21, looking towards the proximal ends (e g , 212b/258) of the devices.
  • a plurality of analyte sensors 240 is located at the luminal surface of wall 260 (e.g., the interior surface of the hub/connector).
  • one or more of the plurality of sensors is integrally formed with the multi-sensor apparatus.
  • the multi-sensor apparatus includes a plurality of sensor sites 262, wherein each sensor site 262 is configured to receive a sensor.
  • At least one of the plurality of sensor sites 262 comprises a breakaway portion (or a plug) configured for insertion therethrough of a sensor, such that at least a portion of the sensor is disposed within the lumen.
  • One or more of the breakaway portions can be removed, such a by punching them out, to form a channel through the wall 260.
  • the multi-sensor apparatus is manufactured such that one or more of the sensor sites includes a channel (e.g., through the wall), such that a sensor can be inserted there through.
  • the sensor(s) can be installed by insertion through the channel(s).
  • An adhesive, press-fit, clip or other attachment means can be use to secure the sensor(s) in place.
  • a portion of a sensor 240 (e.g., the sensing portion) inserted through the wall 260 is disposed at the surface of the duct/lumen. In some embodiments, the portion of the sensor protrudes into the duct/lumen 254. In some further embodiments, at least another portion of the sensor is disposed at the external surface of the connector/hub. In some embodiments, one or more sensors can be disposed (e.g., installed) within the duct/lumen by adhering the sensor at the surface of the duct/lumen. In some embodiments, one or more of the sensors is deposited at the surface of the duct/lumen using known analyte sensor deposition techniques.
  • conductive traces, leads or wires can be applied/installed, such that the sensor(s) can be connected to device electronics, as is understood by one skilled in the art.
  • the device shown in Figs. IA and IB include a conductive lead 24, for connecting the analyte sensor to electronics.
  • the multi-sensor apparatus is a vascular access device comprising an m vivo portion and an ex vivo portion.
  • the plurality of analyte sensors are disposed only within the ex vivo portion of the device, and thus do not extend into the in vivo portion (e.g., catheter 212). In this embodiment, the plurality of sensors does not extend beyond a plain defined by the host's skin.
  • the in vivo portion of the multi-sensor apparatus includes a widened portion, such as a portion adjacent to and/or near to the hub, and one or more of the plurality of sensors are disposed within the widened portion.
  • one or more of the analyte sensor can be configured to extend into the in vivo portion, and in some embodiments to extend into the host's circulatory system.
  • the multi-sensor apparatus is a connector configured to be disposed outside the host's body. Accordingly, the multi-sensor apparatus does not include an in vivo portion.
  • the multi-sensor apparatus is configured to fluidly couple to a vascular access device at its proximal end and to a flow control device at its distal end, such that the flow control device can meter the flow of a non-bodily fluid (e.g., saline, a glucose solution, etc.) through the device and into the host, as well as withdrawal of blood samples from the host (e.g., such that the sample(s) contact the analyte sensor(s)) send (optionally) reinfusion of the blood samples to the host.
  • a non-bodily fluid e.g., saline, a glucose solution, etc.
  • the multi-sensor apparatus of this embodiment includes a lumen and/or duct, in which the plurality of analyte sensors is disposed.
  • at least one of the plurality of analyte sensors is configured to extend into the lumen of a fluidly coupled catheter; and in some further embodiments to extend through the catheter and into the host's circulatory system.
  • At least one of the plurality of sensors is configured to generate a signal associated with a concentration of an analyte in a sample of the host's circulatory system. More preferably, each of the analyte sensors generates a signal associated with a concentration of each sensor's respective analyte in the blood sample withdrawn from the host.
  • the sensors can be configured to generate signals associated with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more analytes and/or properties of the sample of the host's circulatory system.
  • two or more of the sensors are configured to detect the same analyte, such as to provide system redundancy and/or fail-safes.
  • the analyte sensors can be configured to detect a wide variety of analytes, such as but not limited to glucose, oxygen, CO 2 (carbon dioxide, bicarbonate), pH, creatinine, urea (nitrogen), bilirubin, electrolytes (e.g., sodium, potassium, chloride, phosphorous, magnesium), albumin, total protein, liver enzymes (e.g., alkaline phosphatase, alanine amino transferase, aspartate amino transferase), antibodies against infective agents, fibrinogen, fibronectin, lipids, triglycerides, cholesterol-protein complexes and ratios thereof (e.g., LDL, HDL, chylomycrons), hormones (e.g., T3, T4, TSH, hGH, interleukins, etc.), medicaments, metabolites, and the like.
  • analytes such as but not limited to glucose, oxygen, CO 2 (carbon dioxide, bicarbonate), pH, creatinine,
  • At least one of the plurality of sensors is configured to generate a signal associated with a property of a sample of the host's circulatory system.
  • Blood properties include but are not limited to pH, temperature, oxygen tension, hematocrit, viscosity, clotting, pressure, and the like.
  • the multi-sensor apparatus of the preferred embodiments can be manufactured using a variety of techniques known in the art.
  • the analyte sensors are integrally formed with the multi-sensor apparatus.
  • at least one of the pluralities of sensors is deposited within the lumen of the multi-sensor apparatus, such as in the lumen/duct of the connector of the hub of the device illustrated in Fig. 2G, or in the lumen/duct of the device of Fig. 2H
  • one or more of the analyte sensors is configured to extend out of the connector/hub.
  • one or more analyte sensors 240 can be configured to extend into and/or through the lumen 212a of the catheter 212.
  • one or more analyte sensors 240 can be configured to extend out of the proximal end of the multi- sensor apparatus, such that the sensor(s) can be inserted into and/or through a vascular access device.
  • the non-sensor portion of a multi-sensor apparatus is formed, and then the plurality of sensors are applied/installed.
  • at least one of the pluralities of sensors is deposited within the lumen, such as by screen printing.
  • at least one of the pluralities of sensors is applied to the interior surface of the lumen, such as via an adhesive.
  • the multi-sensor apparatus may be formed about the plurality of analyte sensors, such as by using injection molding.
  • a mold is prepared, including sites for the analyte sensors (e.g., these will be "sensor sites," as described elsewhere herein, when the manufacture process is complete).
  • the sensors Prior to injection molding, the sensors (e.g., previously manufactured) are placed in the sites.
  • the mold is closed and a material, such as but not limited to, e.g., molten plastic, is injected into the mold.
  • the material fills all of the spaces within the mold, including flowing around portions of the analyte sensors, such that when the mold is cooled, the analyte sensors will be held in place by the wall of the multi-sensor apparatus.
  • one or more of the sensors pass through the wall of the multi-sensor apparatus.
  • the sensor can be oriented such that when the injection molding process is completed, the analyte sensor is disposed on the surface of the lumen.
  • one or more of the analyte sensors can be installed in the multi-sensor apparatus during injection molding, followed by application of one or more additional sensors to the lumen of the device.
  • the body of the multi-sensor apparatus such as a fluid coupler, can be formed as mating injection-molded portions/pieces that mate together about sensors placed in sensor receiving sites (e.g., see Figs. 2O-2P).
  • the multi-sensor apparatuses can be formed as shown in Figs. 2Q-2S, as described elsewhere herein, by inserting whole sensors in place of individual electrodes, for example.
  • a method for making a multi-sensor apparatus for the detection of a plurality of analytes in a circulatory system of a host in vivo is provided, in some embodiments
  • a plurality of sensors is first provided.
  • the sensors can be configured to detect one or more analytes using a variety of detection means known to one skilled in the art.
  • a multi-sensor apparatus is formed about the plurality of sensors.
  • the multi- sensor apparatus formed includes a lumen, an external surface, and at least one orifice configured for coupling with a fluid flow device, as described herein.
  • a method for making a multi- sensor apparatus for the detection of a plurality of analytes in a circulatory of a host in vivo includes providing a multi-sensor apparatus comprising a lumen, an external surface, and at least one orifice configured for coupling with a fluid flow device a plurality of sensors; followed by forming a plurality of sensor within and/or on the multi-sensor apparatus
  • a method for detecting of a plurality of analytes in a circulatory of a host in vivo, using a multi-sensor apparatus of the preferred embodiments is provided. Accordingly, a multi-sensor apparatus of the preferred embodiments is applied to the circulatory system of a host As described elsewhere herein, the multi-sensor apparatus includes a lumen and a plurality of sensors, wherein the at least two sensor are disposed above a plane defined by the skin of the host when the multi-sensor apparatus is applied to the host's circulatory system.
  • the multi-sensor apparatus is a catheter with sensors in the hub/connector, which is inserted/implanted into a host's artery/vein.
  • the multi- sensor apparatus is a connector with sensors within its lumen.
  • the multi- sensor apparatus must be fluidly coupled to a vascular access device, so that blood can be withdrawn from the host's artery/vein and then contact the sensors within the connector.
  • a sample e.g., blood
  • the sample is withdrawn from the host's circulatory system. When the sample is withdrawn, it is then contacted with the plurality of sensors.
  • each of the sensors then generates a signal.
  • each sensor is configured to detect an analyte.
  • the signal generated by each sensor is associated with the analyte that sensor was configured to detect.
  • the sensors can be configured to generate the signal using any method know in the art, such as but not limited to electrochemically generating the signal, optically generating the signal, radiochemically generating the signal, physically generating the signal, chemically generating the signal, immunochemically generating the signal, and/or enzymatically generating a signal, or combinations thereof.
  • a withdrawn sample is reinfused into the host.
  • a flow control device can meter the flow of an infusion fluid into the host, and the infusion fluid pushes the withdrawn sample back into the host.
  • the device is configured to dispose of the withdrawn sample, such as by directing the sample to a waste container.
  • an infusion fluid is metered through the multi- sensor apparatus, and infused into the host.
  • the plurality of sensors is washed with the infusion fluid.
  • infusion of about 0.5, 1, 5, 10, 15 ml or more of infusion fluid into the host can effectively wash a previous blood sample off of the plurality of analyte sensor in some embodiments.
  • a variety of infusion fluids can be used, including but not limited to saline, reference fluids, medicaments, parenteral nutrition fluids, hydration fluid and the like.
  • the signal of at least one of the plurality of sensors can be calibrated.
  • a variety of calibration methods can be used.
  • one or more of the analyte sensors can be calibrated using one or more reference data points provided by a device separate from the multi-sensor apparatus/system.
  • a hand-held glucose meter can be used to provide one or more data points for calibrating a glucose sensor disposed in the multi- sensor apparatus.
  • a substantially stable and/or constant analyte found in the host's blood can be used to calibrate one or more of the plurality of analyte sensors.
  • data from a recently disconnected multi-sensor apparatus can be used to calibrate one or more of the sensors of a newly installed/applied multi-sensor apparatus.
  • one of the pluralities of analyte sensors can be used to calibrate one or more of the other sensors.
  • one or more of the sensors can be calibrated by the manufacturer. Additional methods of calibration that can be used with the multi-sensor apparatus of the preferred embodiments are described elsewhere herein. Noise
  • implantable sensors measure a signal (e.g., counts) related to an analyte of interest in a host
  • a signal e.g., counts
  • an electrochemical sensor can measure glucose, creatinine, or urea in a host, such as an animal, especially a human.
  • the signal is converted mathematically to a numeric value indicative of analyte status, such as analyte concentration.
  • noise generally refers to a signal detected by the sensor that is substantially non-analyte related (e.g., non-glucose related). In other words, things other than the analyte concentration substantially cause noise.
  • Noise is clinically important because it can reduce sensor performance, such as by making the analyte concentration appear higher or lower than the actual concentration. For example, if a host is hyperglycemic (e.g., blood sugar too high, greater than -120 mg/dl) or euglycemic (e.g., ⁇ 80-120 mg/dl), noise can cause the host's blood sugar to appear higher than it truly is, which can lead to improper treatment decisions, such as to give the host an excessive insulin dose. An excessive insulin dose, in some circumstances, can lead to a dangerous hypoglycemic state (e.g., blood sugar too low, less than ⁇ 80 mg/dl).
  • a dangerous hypoglycemic state e.g., blood sugar too low, less than ⁇ 80 mg/dl.
  • noise can cause the hosts blood sugar to appear euglycemic or even hyperglycemic, which can also lead to improper treatment decisions, such as not eating when necessary' or taking insulin, for example. Accordingly, since noise can cause error and reduce sensor performance, noise reduction is desirable.
  • Noise is comprised of two components, constant noise and non-constant noise, and can be caused by a variety of factors, ranging from mechanical factors to biological factors. For example, it is known that macro- or micro-motion, ischemia, pH changes, temperature changes, pressure, stress, or even unknown mechanical, electrical, and/or biochemical sources can cause noise.
  • constant noise sometimes referred to as constant background or baseline
  • non- constant noise is caused by transient events, such as during wound healing or in response to an illness, or due to ingestion (e.g., some drug*).
  • noise can be caused by a variety of interfering species (constant or non-constant).
  • Interfering species can be compounds, such as drugs that have been administered to the host, or products of various host metabolic processes.
  • Exemplary interferents include but are not limited to a variety of drugs (e.g., acetaminophen), H2O2 from exterior sources, reactive metabolic species (e g., reactive oxygen and nitrogen species, some hormones, etc.).
  • constant noise-causing factors can have an affect on the sensor signal similar to non-constant noise-causing factors, such as when the concentration of a constant noise-causing factor temporarily increases, such as due to temporary lack of lymph flow (see discussion of intermittent sedentary noise).
  • 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 in-active 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).
  • Noise can be recognized and/or analyzed in a variety of ways.
  • 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. Additional description can also be found in U.S. Patent Publication No US-2007-0032706-A1, both herein incorporated by reference in their entirety. Reduction of Noise
  • Noise can be recognized and substantially reduced and/or eliminated by a variety of sensor configurations and/or methods, such as by using 1) sensor configurations that block and/or remove the interferent, or that specifically detect the noise and 2) mathematical algorithms- that recognize and/or remove the signal noise component.
  • the preferred embodiments provide devices and methods for reducing and/or eliminating noise, such as by blocking interferent passage to the sensor's electroactive surfaces, diluting and/or removing interferents around the sensor and mathematically determining and eliminating the noise signal component.
  • the senor comprises at least two working electrodes (one with and one without enzyme over its electroactive surface) and an interference domain configured to substantially block interferent passage therethrough, such that at least some interferent no longer has a substantial affect on sensor measurements (e.g., at either working electrode).
  • interference domain 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 any mechanism of the membrane system configured to reduce any kind of noise or interferants, such as constant and/or non-constant noise.
  • Noise-reducing mechanisms 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 any sensor system component configuration that reduces and/or eliminates noise on the sensor signal.
  • Such structural configurations include but are not limited to electrode configurations (e.g., two or more working electrodes), membrane configurations (e g., interference domain), algorithmic configurations (e.g., signal processing to remove an identified noise component of the signal), and the like.
  • the interference domain is a component of the membrane system, such as shown in Fig. 3C.
  • the interference domain can be disposed at any level (e.g., layer or domain) of the membrane system (e.g., more proximal or more distal to the electroactive surfaces than as shown in Fig. 3C).
  • the interference domain is combined with an additional membrane domain, such as the resistance domain or the enzyme domain.
  • the senor is configured to reduce noise, including non-constant non- analyte related noise with an overlapping measuring potential with the analyte.
  • noise can occur when a sensor has been implanted in a host.
  • 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-reacti ⁇ n- related hydrogen peroxide, or other electroactive species with an oxidation/reduction potential that overlaps with the analyte or co-analyte).
  • the background is comprised of both constant (e.g., baseline) and non-constant (e.g., noise) factors.
  • constant e.g., baseline
  • non-constant e.g., noise
  • baseline 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 i V).
  • 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/reduction potential that substantially overlaps the oxidation/reduction 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).
  • relatively non-constant factors e.g., the presence of intermittent noise-causing compounds that have an oxidation/reduction potential that substantially overlaps the oxidation/reduction 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 in-active 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).
  • 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 U.S. Patent Publication No. US-2007-0027370-A1, herein incorporated by reference in their entirety.
  • an analyte sensor e.g., glucose sensor
  • the sensor includes a first working electrode disposed beneath an active en2ymatic 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.
  • an analyte sensor e.g., glucose sensor
  • the senor is configured to substantially eliminate (e.g., subtract out) noise due to mechanical factors.
  • Mechanical factors include macro-motion of the sensor, micromotion 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.
  • 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 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).
  • 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).
  • the sensor electronics can use these data to calculate the glucose-only signal, as described elsewhere herein.
  • 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/reduction potential.
  • the oxidation/reduction potential of the non- glucose related electroactive compounds substantially overlaps with the oxidation/reduction potential of H 2 O 2 , which is produced according to the reaction of glucose with GOx and subsequently transfers electrons to the first working electrode (e.g., El; Fig. 3F).
  • the glucose sensor also measures a second signal, which is associated with background noise of the glucose sensor.
  • the background noise is composed of signal contribution due to noise-causing compounds (e g., interferents), non-reaction-related hydrogen peroxide, or other electroactive species with an oxidation/reduction potential that substantially overlaps with the oxidation/reduction potential of H 2 O 2 (the co-analyte).
  • the first and second working electrodes integrally form at least a portion of the sensor, such as but not limited to the in vivo portion of the sensor, as discussed elsewhere herein.
  • the sensor has a diffusion barrier that substantially blocks (e.g., attenuates) diffusion of glucose or H 2 O 2 between the first and second working electrodes.
  • the sensor includes a diffusion barrier configured to be physical, spatial, and/or temporal.
  • Fig. 3F is a schematic illustrating one embodiment of a sensor (e.g., a portion of the in vivo portion of the sensor, such as but not limited to the sensor electroactive surfaces) having one or more components that act as a diffusion barrier (e.g., prevent diffusion of electroactive species from one electrode to another).
  • the first working electrode El is coated with an enzyme layer 348 comprising active enzyme.
  • the first working electrode El is coated with glucose oxidase enzyme (GOx).
  • a second working electrode E2 is separated fr ⁇ m the first working electrode El by a diffusion barrier D, such as but not limited to a physical diffusion barrier (e.g., either a reference electrode or a layer of non-conductive material/insulator).
  • the diffusion barrier can also be spatial or temporal, as discussed elsewhere herein.
  • Glucose and oxygen diffuse into the enzyme layer 348, where they react with GOx, to produce gluconate and H 2 O 2 .
  • At least a portion of the H 2 O 2 diffuses to the first working electrode El, where it is electrochemically oxidized to oxygen and transfers two electrons (e.g., 2e ⁇ ) to the first working electrode El, which results in a glucose signal that is recorded by the sensor electronics (not shown).
  • the remaining H 2 O 2 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 H 2 O 2 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 (El, E2) such that the H 2 O 2 cannot substantially diffuse from the first working electrode El to the second working electrode E2. Accordingly, the possibility of an aberrant signal produced by H 2 O 2 from the first working electrode El (at the second working electrode E2) is reduced or avoided.
  • the senor is provided with a spatial diffusion barrier between electrodes (e.g., the working electrodes).
  • a spatial diffusion barrier can be created by separating the first and second working electrodes by a distance that is too great for the H 2 O 2 to substantially diffuse between the working electrodes.
  • 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.
  • the spatial diffusion barrier is about 0.020 inches to about 0.050 inches.
  • 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
  • a non-conductive material e.g., a polymer structure or coating such as Parylene
  • the senor is an indwelling sensor, such as configured for insertion into the host's circulatory system via a vein or an artery.
  • 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 in U.S. Patent Publication No. US-2008-0083617-A1 which is incorporated by reference herein in its entirety
  • an indwelling analyte sensor such as but not limited to an intravascular glucose sensor to be used from a few hours to ten days or longer.
  • the sensor includes two working electrodes.
  • a first working electrode detects the glucose-related signal (due to active GOx applied to the electroactive surface) as well as non-glucose related signal.
  • the second working electrode detects only the non-glucose related signal (because no active GOx is applied to its electroactive surface).
  • H 2 O 2 is produced on the first working electrode (with active GOx). If the H 2 O 2 diffuses to the second working electrode (the no GOx electrode) an aberrant signal will be detected at this electrode, resulting in reduced sensor activity.
  • a diffusion barrier such as but not limited to a spatial diffusion barrier.
  • Indwelling sensors are described in more detail in copending U.S. Patent Publication No. US-2008-0119703-A1, herein incorporated in its entirety by reference.
  • the location of the active enzyme is dependent upon the orientation of the sensor after insertion into the host's artery or vein.
  • active GOx and the inactive GOX or no GOx
  • active GOx and the inactive GOX would be applied to two working electrodes such that the active GOX would be downstream from the inactive GOX (e.g., relative to the direction of blood flow).
  • H 2 O 2 produced at plus-GOX electroactive surface would be carrier down stream (e.g., away from minus-GOX electroactive surface) and thus not affect the non-enzymatic working electrode.
  • a physical diffusion barrier is provided by a physical structure, -such as an electrode, insulator, and/or membrane.
  • a physical structure such as an electrode, insulator, and/or membrane.
  • an insulator or reference electrode disposed between the working electrodes acts as a diffusion barrier.
  • the diffusion barrier can be a bioprotective membrane (e.g., a membrane that substantially resists, attenuates or blocks the transport of a species (e.g., hydrogen peroxide), sueh as a polyurethane.
  • the diffusion barrier can be a resistance domain, as described in more detail elsewhere herein; namely, a semipermeable membrane that controls the flux of oxygen and an analyte (e.g., glucose) to the underlying enzyme domain.
  • an analyte e.g., glucose
  • a temporal diffusion barrier is provided (e.g., between the working electrodes).
  • temporal diffusion barrier is meant a period of time that substantially prevents an electroactive species (e.g., H2O 2 ) from diffusing from a first working electrode to a second working electrode.
  • 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 is one method for quickly switching voltages, such as described in Bisenberger, M., Brauchle, C; Hampp, N.
  • 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.
  • the glucose sensor includes a reference electrode configured integrally with the first and second working electrodes.
  • the reference electrode can be located remotely from the sensor, as described elsewhere herein.
  • the surface area of the reference electrode is at least six times the surface area of the working electrodes.
  • the sensor includes a counter electrode thafr-is integral to the sensor or is located remote from the sensor, as described elsewhere herein.
  • the glucose sensor detects a first signal associated with glucose and non-glucose related electroactive compounds having a first oxidation/reduction potential (e.g., the oxidation/reduction potential OfH 2 Ch).
  • 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/reduction potential that substantially overlaps with the oxidation/reduction 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 configuied provide at least two functions such as but not limited to electrical conductance, insulation, structural support, and a diffusion barrier
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 ceHular metabolic processes, can generate noise-causing metabolic species (e.g., compounds, substances) that impinge upon the sensor and cause noise on the signal.
  • noise-causing species the levels of which are relatively stable due to production during daily cellular metabolism, generally cause constant noise.
  • some noise-causing species, the levels of which fluctuate due to production by intermittent metabolic process e.g., wound healing or response to infection
  • non-constant noise the levels of which fluctuate due to production by intermittent metabolic process.
  • 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.
  • 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 U.S. Patent Publication No. US-2007- 0235331 -Al, both of which are incorporated herein by reference in their entirety.
  • noise can also be generated within the sensor, namely due to diffusion of a measured species (e.g., H 2 O 2 ) from a first working electrode (e.g., the H2O 2 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).
  • a measured species e.g., H 2 O 2
  • first working electrode e.g., the H2O 2 is generated in an active enzymatic portion of the sensor membrane associated with the first working electrode
  • detection thereby e.g., which is associated with a non-enzymatic portion of the sensor membrane
  • 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.
  • noise has a dual nature.
  • noise occurs randomly (e.g., is scattered, intermittent, dispersed, unevenly distributed) in the local of «an implanted sensor.
  • 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
  • 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- ⁇ m to about 500- ⁇ m).
  • the configuration of the electroactive surfaces (of the working electrodes) can substantially affect noise measurement.
  • the random yet localized nature of noise is discussed in greater detail below.
  • Fig. 3G is a two-dimensional schematic illustrating, on the scale of a sensor and the surrounding tissue (e.g., a generally larger scale), the random nature of noise relative to a dual- electrode sensor, in one exemplary embodiment.
  • This figure is for illustrative purposes only, and should not be considered as a to-scale representation of a particular sensor configuration or of the events discussed herein
  • the dual-electrode analyte sensor includes two electroactive surfaces El, E2 disposed beneath the sensor's membrane. While Fig. 3G illustrates only one dimension of the electroactive surfaces, in some embodiments, the electroactive surfaces (e.g., the surface area of each electroactive surface) can include both a length and a width.
  • the area can include additional dimensions, such as a circumference and/or a height.
  • the sensor can have a planar configuration.
  • the sensor can have a cylindrical, pyramidal, polygonal configuration.
  • the electroactive surfaces El, E2 are shown as boxes as a matter of illustrative convenience, however, electroactive surfaces can be thinner or thicker than illustrated in Fig. 3G or elsewhere herein.
  • the membrane has a thickness Dl and a surface MS.
  • DI can va*y in size, from less than about 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, or 0.010 inches to more than about 0.01 1, 0.012, 0.013, 0.014, 0.015, 0.015, 0.016, 0.017, 0.018, 0.019, 0.020, 0.025, 0.03, 0.035, or 0.050 inches.
  • a preferred membrane thickness is between about 0.001, 0.0012, 0.0014, 0.0016, or 0.0018 inches to about 0.002, 0.0022, 0.0024, 0.0026, 0.0028, or 0.003 inches.
  • Noise-causing species can be generated by and/or at point sources Nl (e.g., noise hot spots) unevenly distributed relative the in vivo portion of the sensor.
  • point sources Nl e.g., noise hot spots
  • some of the point sources Nl are concentrated at one end of electroactive surface EI, while some are distributed more evenly across electroactive surface E2.
  • the point source may be one or more cells (e.g., in contact with the membrane surface MS) that release the noise- causing species during wound healing or another metabolic process, such as when a sensor is implanted in vivo.
  • the implanted sensor can be located within the diffusion distance of one or more noise-causing species produced during a nearby metabolic process.
  • the noise-causing species e.g., a compound consumed by the host
  • the noise-causing species can be carried to the local of the sensor via the circulatory and/or lymph system and diffuse to the sensor (e.g., between cells).
  • Random and/or unequally distributed noise can be generated in a variety of circumstances.
  • a peroxide-generating immune cell could be located adjacent to one electroactive surface but not the other.
  • 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.
  • H2O2 produced by metabolic process when the sensor is implanted in a host
  • the maximum distance that the noise-causing species can diffuse is referred to herein as a "diffusion distance"
  • the sensor electronics are configured to mathematically correct for noise on the sens ⁇ r 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.
  • the calculations will 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 or her 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.
  • the first working electrode includes a first electroactive surface (El, Fig. 3G) disposed beneath an active enzymatic portion (e.g., plus-GOx) of the sensor's membrane, as described elsewhere herein.
  • the first electroactive surface includes a first area (e.g., first electroactive surface area) configured to detect a first signal (e.g., including an analyte- related component and a noise component) having a first noise component related to a noise- causing species.
  • the sensor also includes a second working electrode having a second electroactive surface (E2, Fig. 3G) disposed beneath an inactive-enzymatic or a non-enzymatic portion of the sensor membrane, as described elsewhere herein.
  • an inactive- enzymatic portion of the membrane can include inactivated GOx or no GOx.
  • the second electroactive surface includes a second area (e.g., second electroactive surface area) configured4o generate a second signal having a second noise component related to the noise-causing species.
  • the first and second areas are dimensioned (e.g., sized) to be sufficiently large such that the first and second noise components integrated there across, such that the first and second integrated noise signals (e.g., from the first and second electroactive surfaces, respectively) are substantially equivalent.
  • the first and second integrated noise signals e.g., noise components
  • the first and second electroactive surfaces are dimensioned to integrate noise caused by a plurality of local point sources that produce noise-causing species in vivo.
  • Fig. 3H is a two-dimensional schematic illustrating the localized character of noise species (represented by squiggly arrows N2) generated by a point source Nl, when examined from a cellular scale, as discussed elsewhere herein.
  • Fig. 3H depicts a cross-section of a sensor, in one embodiment, wherein the sensor includes two working electrodes having electroactive surfaces El and E2, and a membrane having surface MS and thickness Dl.
  • Distance D3 separates the electroactive surfaces; the distance between their outer edges is denoted by D4. Note that dimension D2, described above, is not shown in this figure.
  • the sensor of this exemplary embodiment can have a variety of configurations, such as but not limited to planar, cylindrical or polygonal.
  • an electroactive surface's surface area can include but are not limited to length, width, height, and/or circumference.
  • the area of each electroactive surface is defined by a length and a width.
  • the area includes a length or width and a circumference.
  • the area includes length, width and height.
  • the point source e.g., noise hot spot
  • the point source is an individual cell Nl disposed adjacent to the membrane surface MS and generally above and/or over the sensor's electroactive surfaces El, E2.
  • the cell can produce noise-causing substances (e.g., N2) that can diffuse to and affect its local environment.
  • noise-causing substances e.g., N2
  • the ability of a noise-causing substance to affect the local environment is limited by the maximum distance the substance can diffuse (e.g., the substance's diffusion distance).
  • some of the noise-causing substances can diffuse through the sensor membrane and affect the sensor's electroactive surfaces.
  • the electroactive surfaces must be affected by substantially the same microenvironment.
  • the electroactive surfaces will be affected by substantially the same microenvironment, if the electroactive surfaces are configured and arranged such that the electroactive surfaces are sufficiently close together and/or their external edges are sufficiently close together.
  • Fig. 3H shows that the sensor's electroactive surfaces El, E2 are separated by a distance D3 and their outer edges are spaced a distance D4 (e.g., in at least one dimension), in one exemplary embodiment.
  • a point source Nl e.g., a cell
  • the noise-causing species diffusing from the point source can impinge equivalently on both of the electroactive surfaces.
  • the electroactive surfaces are spaced a distance (e.g., relative to each other, DS) such that the electroactive surfaces (e.g., at least a portion of each electroactive surface) detect substantially equivalent noise from a point source.
  • the electroactive surfaces are sufficiently close together (e.g., such that the noise components measured are substantially equal) when the distance between the electroactive surfaces (D3) is between about 0.5-times to about 10-times (or more) the membrane thickness (Dl).
  • the electroactive surfaces are sufficiently close together when DJis about 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-times the membrane thickness.
  • 1)3 is between about 5, 10, 15, 20, 2S, 30, 35, 40, 45, or 50 microns or less to about 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 microns or more.
  • D3 is between about 20 to about 40 microns.
  • D4 is between about 25 microns or less to about 500 microns or more.
  • 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.
  • Fig. 3H illustrates a cross-section of a sensor (e.g., width and height), but doesn't illustrate any additional dimensions (e.g., length).
  • the cross-section could be that of a planar sensor configuration, wherein the sensor also includes an additional dimension that has not been shown, such as but not limited to D2.
  • the sensor can have a non-planar configuration.
  • the working electrodes El, E2 are fabricated from two wires.
  • D4 is the total diameter of the bundled and/or twisted pair of working electrodes. In both types of sensor configurations (e.g., planar and non-planar), if D4 is sufficiently small, then the two working electrodes can be equivalently affected by noise-causing species N2 derived from a point source Nl.
  • dual-electrode sensors can be affected by internally generated noise (e.g., generated by the sensor).
  • 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.
  • 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).
  • this distance is less than a crosstalk diffusion distance of the measured species. In other words, D3 is shorter than the diftusi ⁇ n distance of H 2 O 2 (e.g., the maximum distance H 2 O 2 can diffuse from a first electrode to a second and still cause a signal on the second electrode).
  • 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., H 2 O 2 ) 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.
  • the measurable species e.g., H 2 O 2
  • Fig. 31 is a schematic illustrating a perspective view of a cross-section of a dual-electrode sensor that includes a physical diffusion barrier D, in one exemplary embodiment.
  • wires form the working electrodes El, E2.
  • the working electrodes each include a membrane, including an electrode domain 347, an enzyme domain 248 and a resistance domain 249.
  • El includes a first electrode domain, a first enzyme domain (Plus GOx) and a first resistance domain
  • E2 includes a second electrode domain, a second enzyme domain (No GOx) and a second resistance domain.
  • the electrodes are placed together and coated with an additional resistance domain 249A (e.g., a third resistance domain).
  • the electrodes can be placed and/or held together using a variety of methods, such as bundling, twisting, wrapping, and the like, either alone or in combination.
  • the distances shown are as follows; a thickness of the membrane Dl, at least one dimension of the electroactive surface D2, a distance between the electroactive surfaces D3, and a distance between the outer edges of the electroactive surfaces D4.
  • the first and second electroactive surfaces extend about the circumferences of El and E2 (or portions thereof), respectively
  • the physical diffusion barrier D is disposed between the electroactive surfaces of working electrodes El and E2.
  • the physical diffusion barrier is formed of one or more membrane materials, such as those used in formation ⁇ ⁇ f 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.
  • the physical diffusion barrier includes one or more membrane domains. For example, in the exemplary embodiment of Fig.
  • the physical diffusion barrier is a discontinuous portion of the membrane (e.g., separate, distinct or discontinuous membrane structures) disposed between the first and second electroactive surfaces, and can include one or more membrane portion(s) within distance D3 (e.g., interference and/or resistance domains).
  • D3 e.g., interference and/or resistance domains
  • H2O2 diffusing from the Plus GOX working electrode to the No GOx working electrode must pass through two "sensor membranes" such as the first and second resistance domains disposed on El and E2 respectively, and optionally electrode, interference and/or enzyme domains disposed on E2
  • the physical diffusion barrier includes first and second barrier layers formed independently on the first and second electrodes.
  • the barrier layer is the resistance domain 349.
  • the physical diffusion barrier can be a continuous membrane (and/or membrane domain(s)) disposed between the electroactive surfaces.
  • the physical diffusion barrier attenuates (e g , suppresses, blocks, prevents) diffusion of the H 2 O 2 (e.g., crosstalk) by at least 2-fold.
  • crosstalk is attenuated at least 5-fold.
  • crosstalk is attenuated at least 10- fold.
  • the physical diffusion barrier attenuates crosstalk at least about 50%.
  • 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.
  • 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 El, 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
  • an optional electrode domain 347, an enzyme domain 348 (e.g., plus-GOx), and at least one layer of the resistance domain material 349 e.g., first resistance domain
  • an optional electrode domain 347, an enzyme domain 348 (e.g., no-GOx), and at least one layer of the resistance domain material 349 (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.
  • the physical diffusion barrier D 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.
  • 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).
  • 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.
  • crosstalk is substantially attenuated by a physical diffusion barrier disposed between the working electrodes.
  • 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.
  • a portion of resistance domain deposited on a planar substrate and between working electrodes can attenuate diffusion of the measured species (e.g., H 2 O 2 ) from El to E2, such that the noise measured on El and E2 is equivalent.
  • 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 (e.g., sensitivity of the first and second working electrodes), as described elsewhere herein.
  • the membrane portions associated with the working electrodes e.g., of a dual-electrode sensor
  • can possess different sensitivities e.g., signal sensitivities
  • the areas of the electroactive surfaces may be different sizes, which can also result in non-equivalent signal amplitudes, differences in measured baselines and/or sensitivities between the first and second working electrodes. While such differences in signal baseline and/or 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 349A (e.g., applied continuously over the discontinuous resistance domains 349 described elsewhere herein) is provided, such that the signal sensitivities are equivalent. In the exemplary embodiment shown in Fig.
  • the signal sensitivities are substantially equalized on a sensor including the combination of discontinuous resistance domains (e.g., resistance domains 349, applied independently to El and E2) and a continuous resistance domain 349A (e.g., applied over and/or adjacent to the discontinuous resistance domains).
  • the noise signals detected on both El and E2 will have substantially the same amplitude (e.g., intensity, amount), as described with reference to Example 7, below.
  • the sensitivities (of the working electrodes) are within 40% of each other (e.g.. plus or minus 20%). In a preferred embodiment, the sensitivities (of the working electrodes) are within 20% of each other (e.g., plus or minus 10%). In a more preferred embodiment, the sensitivities (of the working electrodes) are within 10% of each other (e.g., plus or minus 5%).
  • the sensor electrodes can be disposed on a planar, cylindrical, pyramidal or otherwise shaped support.
  • 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.
  • 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.
  • diffusion of the H 2 O2 from the first working electrode El to the electroactive surface of the second working electrode E2 is first attenuated by the resistance domain 349 disposed over the first working electrode El (an independently formed first barrier layer), and then again by the resistance domain 349 disposed over the second working electrode E2 (an independently formed second barrier layer), such that only insubstantial amounts of H 2 O 2 can reach the electroactive surface of the second working electrode.
  • the first and second resistance domains are configured and arranged to reduce diffusion of the measurable species (e.g., H 2 O 2 ) from the first electroactive surface to the second electroactive surface by at least 2-fold.
  • 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.
  • the sensor's working electrodes El, E2 are by an insulator, which insulates the working electrodes from each other. In some embodiments, the insulator is at least a portion of the sensor membrane.
  • a continuous glucose sensor configured for insertion into a host and detecting glucose in the host.
  • 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
  • the second electroactive surface 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.
  • each working electrode is configured to generate a signal having a noise component related to a noise-causing species.
  • the noise-causing species is non-constant and related to a biological process.
  • 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.
  • 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 ⁇ m, in at least one dimension.
  • the first and second areas 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).
  • the first and second areas are configured and arranged to integrate signals detected about a circumference of the sensor.
  • the first and second electroactive surfaces are spaced a distance that is less than a crosstalk diffusion distance of a measured species, such as H 2 O 2 produced in the active enzymatic portion of the membrane.
  • the senor 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.
  • 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.
  • the physical diffusion barrier is a discontinuous portion of the membrane disposed between the first and second electroactive surfaces.
  • 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).
  • 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.
  • the physical diffusion barrier can reduce the diffusion of the measurable species (e.g., crosstalk) by at least 10-fold.
  • 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.
  • 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.
  • 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 4he first and second working electrodes) are substantially equivalent.
  • the distance between the first and second electroactive surfaces is less than about twice the thickness of the membrane.
  • 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 H 2 O 2 produced in the active enzymatic portion of the sensor membrane.
  • 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).
  • 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.
  • the physical diffusion barrier is a discontinuous portion of the membrane disposed between the first and second electroactive surfaces.
  • 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.
  • the physical diffusion barrier includes a first resistance domain formed on the first electrode and a second resistance domain formed on the second electrode.
  • 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.
  • the membrane is an insulator that insulates the first working electrode from the second working electrodes.
  • the first and second areas are sufficiently large that the first and second noise components are substantially equivalent.
  • the analyte sensor system has electronics, also referred to as a "computer system” that can include hardware, firmware, and/or software that enable measurement and processing of data associated with analyte levels in the host Tn one exemplary embodiment, the electronics include a potentiostat, a power source for providing power to the sensor, and other components useful for signal processing. In another exemplary embodiment, the electronics include an RF module for transmitting data from sensor electronics to a receiver remote from the sensor. In another exemplary embodiment, the sensor electronics are wired to a receiver, which records the data and optionally transmits the data to a remote location, such as but not limited to a nurse's station, for tracking the host's progress and to alarm the staff is a hypoglycemic episode occurs.
  • a remote location such as but not limited to a nurse's station
  • the sensor electronics include a processor module configured to and/or comprises programming for processing sensor data, as described elsewhere herein.
  • the sensor electronics include a receiving module for receiving sensor signals, such as but not limited to from the working electrode(s), and/or externally provided reference data points.
  • the processor module can include the receiving module. The processor module and the receiving module can be located together and/or in any combination of sensor electronics local to and/or remote from the sensor.
  • Various components of the electronics of the sensor system can be disposed on or proximal to the analyte sensor, such as but not limited to disposed on the fluid coupler 20 of the system, such as the embodiment shown in Fig. IA.
  • the sensor is integrally formed on the catheter (e g., see Fig. 2A) and the electronics are disposed on or proximal to the connector 218.
  • only a portion of the electronics e.g., the potentiostat
  • the device e.g., proximal to the sensor
  • the remaining electronics are disposed remotely from the device, such as on a stand or by the bedside.
  • a portion of the electronics can be disposed in a central location, such as a nurse's station.
  • some or all of the electronics can be in wired or wireless communication with the sensor and/or other portions of the electronics.
  • a potentiostat disposed on the device can be wired to the remaining electronics (e.g., a processor, a recorder, a transmitter, a receiver, etc.), which reside on the bedside.
  • some portion of the electronics is wirelessly connected to another portion of the electronics, such as by infrared (IR) or RF.
  • IR infrared
  • a potentiostat resides on the fluid coupler and is connected to a receiver by RF; accordingly, a battery, RF transmitter, and/or other minimally necerney electronics are provided with the fluid coupler and the receiver includes an RF receiver.
  • the potentiostat is operably connected to the electrode(s) (such as described above), which biases the sensor to enable measurement of a current signal indicative of the analyte concentration in the host (also referred to as the analog portion)
  • the potentiostat includes a resistor that translates the current into voltage.
  • a current to frequency converter is provided that is configured to continuously integrate the measured current, for example, using a charge counting device.
  • the electronics include an A/D converter that digitizes the analog signal into a digital signal, also referred to as "counts" for processing. Accordingly, the resulting raw data stream in counts, also referred to as raw sensor data, is directly related to the current measured by the potentiostat.
  • the electronics include a processor module that includes the central control unit that controls the processing of the sensor system.
  • the processor module includes a microprocessor, however a computer system other than a microprocessor can be used to process data as described herein, for example an ASIC can be used for some or all of the sensor's central processing.
  • the processor typically provides semi-permanent storage of data, for example, storing data such as sensor identifier (ID) and programming to process data streams (for example, programming for data smoothing and/or replacement of signal artifacts such as is described in U.S. Patent Publication No. US-2005-0043598-A1).
  • the processor additionally can be used for the system's cache memory, for example for temporarily storing recent sensor data.
  • the processor module comprises memory storage components such as ROM, RAM, dynamic-RAM, static-RAM, non-static RAM, EEPROM, rewritable ROMs, flash memory, and the like
  • the processor module comprises a digital filter (e.g., programming), for example, an infinite impulse response (HR) or finite impulse response (FIR) filter, configured to smooth the raw data stream from the A/D converter.
  • digital filters are programmed to filter data sampled at a predetermined time interval (also referred to as a sample rate).
  • time intervals also referred to as a sample rate.
  • the processor module can be programmed to request a digital value from the A/D converter at a predetermined time interval, also referred to as the acquisition time.
  • the values obtained by the processor are advantageously averaged over the acquisition time due the continuity of the current measurement. Accordingly, the acquisition time determines the sample rate of the digital filter.
  • the processor module is configured with a programmable acquisition time, namely, the predetermined time interval for requesting the digital value from the A/D converter is programmable by a user within the digital circuitry of the processor module. An acquisition time of from about 2 seconds to about 512 seconds is preferred; however any acquisition time can be programmed into the processor module.
  • a programmable acquisition time is advantageous in optimizing noise filtration, time lag, and processing/battery power.
  • the processor module is configured to and/or comprises programming to build the data packet for transmission to an outside source, for example, an RF transmission to a receiver.
  • the data packet comprises a plurality of bits that can include a preamble, a unique identifier identifying the electronics unit, the receiver, or both, (e.g., sensor ID code), data (e.g., raw data, filtered data, and/or an integrated value) and/or error detection or correction.
  • the data (transmission) packet has a length of from about 8 bits to about 128 bits, preferably about 48 bits, however, larger or smaller packets can be desirable in certain embodiments.
  • the processor module can be configured to transmit any combination of raw and/or filtered data.
  • the transmission packet contains a fixed preamble, a unique ID of the electronics unit, a single five-minute average (e.g., integrated) sensor data value, and a cyclic redundancy code (CRC).
  • CRC cyclic redundancy code
  • the processor module further comprises a transmitter portion that determines the transmission interval of the sensor data to a receiver, and the like.
  • the transmitter portion which determines the interval of transmission, is configured to be programmable.
  • a coefficient can be chosen (e.g., a number of from about 1 to about 100, or more), wherein the coefficient is multiplied by the acquisition time (or sampling rate), such as described above, to define the transmission interval of the data packet.
  • the transmission interval is programmable from about 2 seconds to about 850 minutes, more preferably from about 30 second to about 5 minutes; however / any transmission interval can be programmable or programmed into the processor module.
  • a variety of alternative systems and methods for providing a programmable transmission interval can also be employed.
  • data transmission can be customized to meet a variety of design criteria (e.g. , reduced battery consumption, timeliness of reporting sensor values, etc.)
  • the processor is further configured to and/or further comprises programming to perform the processing, such as storing data, analyzing data streams, calibrating analyte sensor data, estimating analyte values, comparing estimated analyte values with time corresponding measured analyte values, analyzing a variation of estimated analyte values, downloading data, and controlling the user interface by providing analyte values, prompts, messages, warnings, alarms, and the like.
  • the processor includes hardware and software that performs the processing described herein, for example flash memory provides permanent or semi-permanent storage of data, storing data such as sensor ID, receiver ID, and programming to process data streams (for example, programming for performing estimation and other algorithms described elsewhere herein) and random access memory (RAM) stores the system's cache memory and is helpful in data processing.
  • flash memory provides permanent or semi-permanent storage of data, storing data such as sensor ID, receiver ID, and programming to process data streams (for example, programming for performing estimation and other algorithms described elsewhere herein) and random access memory (RAM) stores the system's cache memory and is helpful in data processing.
  • RAM random access memory
  • some portion of the data processing can be accomplished at another (e.g., remote) processor and can be configured to be in wired or wireless connection therewith.
  • an output module which is integral with and/or operatively connected with the processor, includes programming for generating output based on the data stream received from the sensor system and it's processing incurred in the processor. In some embodiments, output is generated via a user interface.
  • a user interface is provided integral with (e.g., on the patient inserted medical device), proximal to (e.g., a receiver near the medical device including bedside or on a stand), or remote from the sensor electronics (e.g., at a central station such as a nurse's station), wherein the user interface comprises a keyboard, speaker, vibrator, backlight, liquid crystal display (LCD) screen, and one or more buttons.
  • the components that comprise the user interface include controls to allow interaction of the user with the sensor system.
  • the keyboard can allow, for example, input of user information, such as mealtime, exercise, insulin administration, customized therapy recommendations, and reference analyte values.
  • the speaker can produce, for example, audible signals or alerts for conditions such as present and/or estimated hyperglycemic or hypoglycemic conditions.
  • the vibrator can provide, for example, tactile signals or alerts for reasons such as described with reference to the speaker, above.
  • the backlight can*be provided, for example, to aid a user in reading the LCD in low light conditions.
  • the LCD can be provided, for example, to provide the user with visual data output, such as is described in U S. Patent Publication No. US-2005-0203360-A1.
  • the LCD is a touch- activated screen, enabling each selection by a user, for example, from a menu on the screen.
  • the buttons can provide for toggle, menu selection, option selection, mode selection, and reset, for example.
  • a microphone can be provided to allow for voice- activated control.
  • prompts or messages can be displayed on the user interface to convey information to the user, such as reference outlier values, requests for reference analyte values, therapy recommendations, deviation of the measured analyte values from the estimated analyte values, and the like. Additionally, prompts can be displayed to guide the user through calibration or trouble-shooting of the calibration.
  • data output from the output module can provide wired or wireless, one- or two-way communication between the user interface and an external device.
  • the external device can be any device that wherein interfaces or communicates with the user interface.
  • the external device is a computer, and the system is able to download historical data for retrospective analysis by the patient or physician, for example.
  • the external device is a modem or other telecommunications station, and the system is able to send alerts, warnings, emergency messages, and the like, via telecommunication lines to another party, such as a doctor or family member
  • the external device is an insulin pen, and the system is able to communicate therapy recommendations, such as insulin amount and time to the insulin pen.
  • the external device is an insulin pump, and the system is able to communicate therapy recommendations, such as insulin amount and time to the insulin pump.
  • the external device can include other technology or medical devices, for example pacemakers, implanted analyte sensor patches, other infusion devices, telemetry devices, and the like
  • the user interface including keyboard, buttons, a microphone (not shown), and optionally the external device, can be configured to allow input of data.
  • Data input can be helpful in obtaining information about the patient (for example, meal time, insulin administration, and the like), receiving instructions from a physician (for example, customized therapy recommendatioas, targets, and the like), and downloading software updates, for example.
  • Keyboard, buttons, touchscreen, 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 provide useful information to the receiver.
  • Other devices internal or external to the sensor that measure other aspects of a patient's body can be used to provide input helpful in data processing.
  • the user interface can prompt the patient to select an activity most closely related to their present activity, such as medication taken, surgical procedures, and the like, which can be helpful in linking to an individual's physiological patterns, or other data processing.
  • 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, which can be helpful in data processing. Algorithms
  • calibration of an analyte sensor can be required, which includes data processing that converts sensor data signal into an estimated analyte measurement that is meaningful to a user.
  • the sensor system has a computer system (e.g., within the electronics) that receives sensor data (e.g., a data stream), including one or more time-spaced sensor data points, measured by the sensor.
  • the sensor data point(s) can be smoothed (filtered) in certain embodiments using a filter, for example, a finite impulse response (FIR) or infinite impulse response (11R) filter.
  • FIR finite impulse response
  • 11R infinite impulse response
  • the system can receive and store uncalibrated sensor data, however it can be configured to not display any data to the user until initial calibration and, optionally, stabilization of the sensor has been established.
  • the data stream can be evaluated to determine sensor break-in (equilibration of the sensor in vitro or in vivo).
  • the system is configured to receive reference data from a reference analyte monitor, including one or more reference data points, also referred to as calibration information in some embodiments.
  • the monitor can be of any suitable configuration.
  • the reference analyte points can comprise results from a self- monitored blood analyte test (e.g., from a finger stick test, YSI, Beckman Glucose Analyzer, smd the like), such as those described in U.S. Patent No. 6,045,567, U.S. Patent No. 6, 156,051, U.S. Patent No. 6,197,040, U.S. Patent No. 6,284,125, U.S. Patent No.
  • the user can administer a self-monitored blood analyte test to obtain an analyte value (e.g., point) using any suitable analyte sensor, and then enter the numeric analyte value into the computer system.
  • a self-monitored blood analyte test comprises a wired or wireless connection to the computer system so that the user simply initiates a connection between the two devices, and the reference analyte data is passed or downloaded between the self-monitored blood analyte test and the system.
  • the self-monitored analyte test is integral with the receiver so that the user simply provides a blood sample to the receiver, and the receiver runs the analyte test to determine a reference analyte value.
  • the reference data is based on sensor data from another substantially continuous analyte sensor such as described herein, or another type of suitable continuous analyte sensor.
  • the sensors can be employed so that they provide sensor data in discrete or overlapping periods.
  • the sensor data from one continuous sensor can be used to calibrate another continuous sensor, or be used to confirm the validity of a subsequently employed continuous sensor.
  • the sensor system is coupled to a blood analysis device that periodically or intermittently collects a sample of the host's blood (e.g., through the sensor system) and measures the host's glucose concentration.
  • the blood analysis device collects a blood sample from the host about every 30 minutes, every hour, or every few hours (e.g., 2, 3, 4, 5, 6, 8, 9 or 10 hours or longer).
  • the blood analysis device can be activated manually (e.g., by a healthcare worker) to collect and analyze a blood sample from the host.
  • the glucose concentration data generated by the blood analysis device can be used by the sensor system for calibration data.
  • the sensor system* can electronically receive (either wired or wirelessly) these calibration data (from the blood analysis device) In other embodiments, these calibration data can be entered into the sensor system (e.g., sensor system electronics) by hand (e g., manually entered by a healthcare worker).
  • the sensor system is provided with one or more calibration solutions (e.g., glucose solutions).
  • the sensor is shipped in a calibration solution (e.g., soaked). The sensor is activated to calibrate itself (using the calibration solution in which it was shipped) before insertion into the host.
  • the sensor is shipped (e.g., soaked or dry) with one or more vials of calibration solution. The sensor can be soaked (e.g., sequentially) in the vial(s) of calibration solution; calibration data points collected and the sensor calibrated using those calibration points, before inserting the sensor into the host.
  • the senor is a glucose sensor, and it is shipped soaking in a sterile 50 mg/dl glucose solution with two accompanying calibration solutions (e.g., 100 mg/dl and 200 mg/dl sterile glucose solutions). Prior to insertion into the host, calibration data points are collected with the sensor in the 50 mg/dl, 100 mg/dl and 200 mg/dl glucose solutions respectively. The sensor system can be calibrated using the collected calibration data points (e.g., using regression as described in more detail elsewhere herein). In an alternative exemplary embodiment, the sensor is shipped dry (e.g., not soaking in a solution or buffer) with at least one calibration solution, for calibrating the sensor prior to insertion into the host. In some embodiments, a hand held glucose monitor (e.g., SMBG device described herein) can test the calibration solutions to generate calibration data points, which are transferred electronically or manually to the sensor system for calibration.
  • SMBG device e.g., SMBG device described herein
  • a data matching module also referred to as the processor module, is configured to and/or comprises programming to matches reference data (e.g., one or more reference analyte data points) with substantially time corresponding sensor data (e.g., one or more sensor data points) to provide one or more matched data pairs.
  • reference data e.g., one or more reference analyte data points
  • sensor data e.g., one or more sensor data points
  • One reference data point can be matched to one time corresponding sensor data point to form a matched data pair.
  • a plurality of reference data points can be averaged (e.g., equally or non-equally weighted average, mean-value, median, and the like) and matched to one time corresponding sensor data point to form a matched data pair, one reference data point can be matched to a plurality of time corresponding sensor data points averaged to form a matched data pair, or a plurality of reference data points can be averaged and matched to a plurality of time corresponding sensor data points averaged to form a matched data pair.
  • a calibration set module also referred to as the calibration module or processor module, is configured to and/or comprises programming to form an initial calibration set from a set of one or more matched data pairs, which are used to determine the relationship between the reference analyte data and the sensor analyte data.
  • the matched data pairs, which make up the initial calibration set can be selected according to predetermined criteria.
  • the criteria for the initial calibration set can be the same as, or different from, the criteria for the updated calibration sets.
  • the number (n) of data pair(s) selected for the initial calibration set is one.
  • n data pairs are selected for the initial calibration set wherein n is a function of the frequency of the received reference data points.
  • two data pairs make up the initial calibration set or six data pairs make up the initial calibration set.
  • a substantially continuous analyte sensor provides reference data
  • numerous data points are used to provide reference data from more than 6 data pairs (e.g., dozens or even hundreds of data pairs).
  • a substantially continuous analyte sensor provides 288 reference data points per day (every five minutes for twenty-four hours), thereby providing an opportunity for a matched data pair 288 times per day, for example. While specific numbers of matched data pairs are referred to in the preferred embodiments, any suitable number of matched data pairs per a given time period can be employed.
  • a conversion function module also referred to as the conversion module or processor module, is configured to and/or comprises programming to use the calibration set to create a conversion function.
  • the conversion function substantially defines the relationship between the reference analyte data and the analyte sensor data.
  • a variety of known methods can be used with the preferred embodiments to create the conversion function from the calibration set.
  • a variety of regression or other conversion schemes can be implemented herein.
  • the senor is a dual-electrode system.
  • a first electrode functions as a hydrogen peroxide sensor including a membrane system containing glucose-oxidase disposed thereon, which operates as described herein.
  • - ⁇ A second electrode is a hydrogen peroxide sensor that is configured similar to the first electrode, but with a modified membrane system (with the enzyme domain removed, for example). This second electrode provides a signal composed mostly of the baseline signal, b.
  • U.S. Patent Publication No. US-2005-0143635-A1 describes systems and methods for subtracting the baseline from a sensor signal.
  • the analyte sensor is configured to transmit signals obtained from each electrode separately (e.g., without subtraction of the baseline signal) In this way, the receiver can process these signals to determine additional information about the sensor and/or analyte concentration. For example, by comparing the signals from the first and second electrodes, changes in baseline and/or sensitivity can be detected and/or measured and used to update calibration (e.g. , without the use of a reference analyte value). In one such example, by monitoring the corresponding first and second signals over time, an amount of signal contributed by baseline can be measured. In another such example, by comparing fluctuations in the correlating signals over time, changes in sensitivity can be detected and/or measured.
  • the processor module is configured to and/or comprises programming to use a regression equation y—mx+b to calculate the conversion function; however, prior information can be provided for m and/or b, thereby enabling calibration to occur with fewer paired measurements.
  • prior information e.g., obtained from in vivo or in vitro tests
  • prior information can be provided to guide or validate the baseline (b) and/or sensitivity (m) determined from the regression analysis.
  • boundaries can be set for the regression line that defines the conversion function such that working sensors are calibrated accurately and easily (with two points), and non-working sensors are prevented from being calibrated. If the boundaries are drawn too tightly, a working sensor may not enter into calibration. Likewise, if the boundaries are drawn too loosely, the scheme can result in inaccurate calibration or can permit non-working sensors to enter into calibration. For example, subsequent to performing regression, the resulting slope and/or baseline are tested to determine whether they fall within a predetermined acceptable threshold (boundaries). These predetermined acceptable boundaries can be obtained from in vivo or in vitro tests (e.g., by a retrospective analysis of sensor sensitivities and/or baselines collected from a set of sensors/patients, assuming that the set is representative of future data).
  • the senor system does not require initial and/or update calibration by the host; in these alternative embodiments, also referred to as "zero-point calibration" embodiments, use of the sensor system without requiring a reference analyte measurement for initial and/or update calibration is enabled.
  • the systems and methods of the preferred embodiments provide for stable and repeatable sensor manufacture, particularly when tightly controlled manufacturing processes are utilized. Namely, a batch of sensors of the preferred embodiments can be designed with substantially the same baseline (b) and/or sensitivity (m) (+/- 10%) when tested in vitro. Additionally, the sensor of the preferred embodiments can be designed for repeatable m and b in vivo.
  • an initial calibration factor (conversion function) can be programmed into the sensor (sensor electronics and/or receiver electronics) that enables conversion of raw sensor data into calibrated sensor data solely using information obtained prier to implantation (namely, initial calibration does not require a reference analyte value).
  • the sensor is designed to minimize drift of the sensitivity and/or baseline over time in vivo. Accordingly, the preferred embodiments can be manufactured for zero point calibration.
  • a sensor data transformation module also referred to as the calibration module, conversion module, or processor module, is configured to and/or comprises programming to use the conversion function to transform sensor data into substantially real-time analyte value estimates, also referred to as calibrated data, or converted sensor data, as sensor data is continuously (or intermittently) received from the sensor.
  • the sensor data which can be provided to the receiver in "counts," is translated in to estimate analyte value(s) in mg/dL.
  • the offset value at any given point in time can be subtracted from the raw value ⁇ e.g., in counts) and divided by the slope to obtain the estimate analyte value:
  • an output module is configured to and/or comprises programming to provide output to the user via the user interface.
  • the output is representative of the estimated analyte value, which is determined by converting the sensor data into a meaningful analyte value.
  • User output can be in the form of a numeric estimated analyte value, an indication of directional trend of analyte concentration, and/or a graphical representation of the estimated analyte data over a period of time, for example.
  • Other representations of the estimated analyte values are also possible, for example audio and tactile.
  • annotations are provided on the graph; for example, bitmap images are displayed thereon, which represent events experienced by the host. For example, information about meals, medications, insulin, exercise, sensor insertion, sleep, and the like, can be obtained by the receiver (by user input or receipt of a transmission from another device) and displayed on the graphical representation of the host's glucose over time. It is believed that illustrating a host's life events matched with a host's glucose concentration over time can be helpful in educating the host to his or her metabolic response to the various events.
  • the senor utilizes one or more additional electrodes to measure an additional analyte.
  • Such measurements can provide a baseline or sensitivity value for use in calibrating the sensor.
  • baseline and/or sensitivity values can be used to trigger events such as digital filtering of data or suspending display of data, all of which are described in more detail in U.S. Patent Publication No. US-2005-0143635-A1.
  • the saline drip can be changed to a known IV glucose or dextrose solution (e.g., D50 - a 50% dextrose solution, or D5W - a 5% dextrose solution).
  • a known volume of D5W is infused into the host at a known rate over a predetermined period of time (e.g., 5, 10, 15 or 20 minutes, or for shorter or longer periods).
  • the senor measures the signal at the analyte-measuring working electrode.
  • the system knowing the specifications of the infused calibration solution (also referred to as a calibration information in some embodiments), can calibrate the signal to obtain host's glucose concentration as is appreciated by one skilled in the art.
  • two or more glucose or dextrose solutions can be infused, with a corresponding signal being measured during each infusion, to provide additional data for sensor calibration.
  • Calibration can be performed after the sensor has first been inserted into the host, after a break-in time, at two or more different levels (high/low), regularly, intermittently, in response to sensor drift/shift, automatically or any other time when calibration is required.
  • calibration can be determined during sensor break-in, such as described in more detail elsewhere herein.
  • catheters are flushed with saline.
  • the analyte sensor system of the preferred embodiments can be flushed with saline prior to application of control solutions, after which a predetermined amount of glucose solution is flushed by the sensor, as described above, and the sensor is calibrated there from.
  • a blood sample can be withdrawn from an artery or vein, and used to calibrate the sensor, for example, by using a hand-held glucose meter, by an automatic extracorporeal glucose sensor such as but not limited to in conjunction with an automated bedside clinical chemistry device, or by sending the blood sample to the clinical laboratory for glucose analysis, after which the data is input (e.g., into the electronics associated with the sensor system).
  • the sensor can be calibrated (and/or re-calibrated) during use (after initial calibration), for example, by withdrawing one or more blood samples (also referred to as calibration information in some embodiments), through the catheter (see Figs.
  • Blood samples can be withdrawn manually or automatically; additionally or alternatively, blood samples are withdrawn at regular intervals or at selected times, for example, using an extracorporeal blood analysis device as described herein.
  • a calibration solution e.g., 40 mg/dL equivalent glucose, D540 or D5W
  • a calibration solution can be flushed through or by the sensor to enable calibration of the sensor (e.g., at one time, intermittently, or continuously), such as described in more detail above.
  • calibration solution can be flushed manually or automatically through the system; additionally or alternatively, calibration solution can be flushed at regular intervals or at selected times.
  • the system can be provided with a dual lumen, one for saline and another for the control solution. Additionally, the system is configured to automatically switch from the saline to control solution and perform the real-time system calibration, and then switch back to the saline solution.
  • continuous analyte sensors define a relationship between a sensor- generated signal 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.
  • sensitivity m and baseline b changes can occur during in vivo sensor use, which requires calibration updates (e.g., recalibration).
  • any physical properties of the sensor or the fluid surrounding the sensor can influence diffusion or transport of molecules through the membrane, and thereby produce fluctuations in sensitivity and/or baseline, which in turn affect the sensor's calibration.
  • These physical properties include, but are not limited to, blockage of sensor surface area due to cells and/or blood clotting at the membrane, biofouling, blood flow/sheer rate, blood pH, temperature, hematocrit, interfering drugs in the host's system, certain metabolic processes, disrupted host electrolyte balance due to disease and/or trauma, thickness and/or components of the sensor's membrane system, and the like.
  • the sensitivity value is a signal obtained by measuring a constant analyte other than the analyte being measured by the analyte sensor.
  • a constant analyte other than the analyte being measured by the analyte sensor.
  • a non-glucose constant analyte is measured, wherein the signal is measured beneath the membrane system on the glucose sensor.
  • a membrane monitor is provided, which is capable of monitoring changes in the membrane surrounding an implantable device, thereby enabling the measurement of sensitivity changes of an analyte sensor over time.
  • the analyte sensor is provided with an auxiliary electrode (e.g., a second working electrode) configured as a transport-measuring electrode disposed beneath the membrane system.
  • 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 through the membrane system.
  • solute for example, glucose
  • substantially constant analytes or factors include, but are not limited to, oxygen, carboxylic acids (such as urea), amino acids, hydrogen, pH, chloride, baseline, or the like.
  • the transport-measuring electrode provides an independent measure of changes in solute transport to the membrane, and thus sensitivity changes over time.
  • the transport-measuring electrode measures analytes similar to the analyte being measured by the analyte sensor.
  • analytes similar to the analyte being measured by the analyte 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.
  • sensitivity values that can be used as to qualify or quantify solute transport through the membraae of the analyte 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)
  • 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.
  • 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.
  • the change in sensitivity m is measured by measuring a change in oxygen concentration and to indicate when recalibration of the system may be advantageous.
  • oxygen is measured using pulsed amperometric detection on the glucose-measuring working electrode (eliminating the need for a separate auxiliary electrode), such as by switching the applied potential from +0.6mV to -0.6mV.
  • the auxiliary electrode is configured as an oxygen-measuring electrode.
  • a third electrode can be configured as an oxygen-measuring electrode.
  • 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.
  • sensitivity changes in an intravascular dual-electrode continuous analyte sensor can be provided via a reference sensor, such as an oxygen sensor, as described in the section entitled "Optical Detection.”
  • auto-calibration e.g., with ⁇ ut a manual, external (to the system) reference value
  • a dual-electrode continuous analyte sensor is configured to measure baseline b, and changes in sensitivity m are measured ⁇ by exposure of the dual-electrode sensor to the reference/calibration solution.
  • the system is configured for "on demand" auto-calibration, such as via configuring the system such that a user can initiate (e.g., command) auto-calibration via a user interface (e.g., via selection from a menu, pressing a pre-programmed button and the like).
  • a user can initiate (e.g., command) auto-calibration via a user interface (e.g., via selection from a menu, pressing a pre-programmed button and the like).
  • sensitivity changes can be used to update calibration
  • the measured change in transport can be used to update the sensitivity m in the calibration equation.
  • 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.
  • sensitivity values 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.

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Abstract

La présente invention concerne des systèmes et des procédés destinés à être utilisés pour la mesure en continu de substances à analyser du système vasculaire d’un patient. Dans certains modes de réalisation, un système de mesure du glucose en continu (10) comprend un dispositif d’accès vasculaire (12), un détecteur et l’électronique du détecteur, le système étant conçu pour être inséré en communication fluidique avec le système circulatoire d’un patient.
PCT/US2008/082905 2008-03-25 2008-11-07 Détecteur de substances à analyser Ceased WO2009120240A1 (fr)

Applications Claiming Priority (12)

Application Number Priority Date Filing Date Title
US12/055,078 2008-03-25
US12/055,203 2008-03-25
US12/055,078 US20080197024A1 (en) 2003-12-05 2008-03-25 Analyte sensor
US12/055,149 US20080200788A1 (en) 2006-10-04 2008-03-25 Analyte sensor
US12/055,203 US8425416B2 (en) 2006-10-04 2008-03-25 Analyte sensor
US12/055,227 2008-03-25
US12/055,114 US8364231B2 (en) 2006-10-04 2008-03-25 Analyte sensor
US12/055,149 2008-03-25
US12/055,114 2008-03-25
US12/055,227 US8364230B2 (en) 2006-10-04 2008-03-25 Analyte sensor
US12/258,345 US9135402B2 (en) 2007-12-17 2008-10-24 Systems and methods for processing sensor data
US12/258,345 2008-10-24

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WO2011113421A3 (fr) * 2010-03-16 2012-05-03 Barkey Gmbh & Co. Kg Dispositif destiné à chauffer des fluides en écoulement et procédé de fabrication correspondant
US20140074049A1 (en) * 2012-09-11 2014-03-13 Angiodynamics, Inc. Catheter Connector for Measurement of Physiological Signals
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WO2020191494A1 (fr) * 2019-03-26 2020-10-01 Nerv Technology Inc. Systèmes, procédés et dispositifs de prédiction et de détection de complications postopératoires
WO2020205965A1 (fr) * 2019-04-02 2020-10-08 Baxter International Inc. Capteur de fluide amovible dans un ensemble d'administration
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WO2011113421A3 (fr) * 2010-03-16 2012-05-03 Barkey Gmbh & Co. Kg Dispositif destiné à chauffer des fluides en écoulement et procédé de fabrication correspondant
US20140074049A1 (en) * 2012-09-11 2014-03-13 Angiodynamics, Inc. Catheter Connector for Measurement of Physiological Signals
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WO2020191494A1 (fr) * 2019-03-26 2020-10-01 Nerv Technology Inc. Systèmes, procédés et dispositifs de prédiction et de détection de complications postopératoires
WO2020205965A1 (fr) * 2019-04-02 2020-10-08 Baxter International Inc. Capteur de fluide amovible dans un ensemble d'administration
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