Subcutaneous glucose electrode
DCFirst Claim
1. An electrochemical sensor comprising:
- one or more non-corroding metal or carbon electrodes;
a sensing layer comprising an enzyme coupled to each electrode; and
a biocompatible layer comprising a biocompatible hydrogel chemically bound to the sensing layer of each electrode.
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Abstract
A small diameter flexible electrode designed for subcutaneous in vivo amperometric monitoring of glucose is described. The electrode is designed to allow “one-point” in vivo calibration, i.e., to have zero output current at zero glucose concentration, even in the presence of other electroreactive species of serum or blood. The electrode is preferably three or four-layered, with the layers serially deposited within a recess upon the tip of a polyamide insulated gold wire. A first glucose concentration-to-current transducing layer is overcoated with an electrically insulating and glucose flux limiting layer (second layer) on which, optionally, an immobilized interference-eliminating horseradish peroxidase based film is deposited (third layer). An outer (fourth) layer is biocompatible.
1519 Citations
74 Claims
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1. An electrochemical sensor comprising:
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one or more non-corroding metal or carbon electrodes;
a sensing layer comprising an enzyme coupled to each electrode; and
a biocompatible layer comprising a biocompatible hydrogel chemically bound to the sensing layer of each electrode. - View Dependent Claims (2, 3)
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4. An analyte measurement system comprising:
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an electrochemical sensor including two or more non-corroding metal or carbon electrodes, each electrode adapted for subcutaneous implantation in an animal, and a non-leachable analyte-responsive enzyme disposed on each of the electrodes; and
a device for comparing signals generated at the two or more electrodes.
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5. An electrochemical sensor comprising:
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one or more non-corroding metal or carbon electrode;
a sensing layer coupled to each electrode wherein the sensing layer comprises a non-leachable redox enzyme; and
a microfiltration device for transporting a fluid sample into contact with the sensing layer of at least one of the electrodes. - View Dependent Claims (6, 7, 8)
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9. An electrochemical sensor for measuring an analyte in an animal, comprising:
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one or more analyte responsive electrodes, at least one of said analyte-responsive electrodes adapted for subcutaneous implantation in an animal, each of the analyte responsive electrodes comprising a non-corroding metal or carbon electrode, and a sensing layer covering at least a portion of each non-corroding metal or carbon electrode, comprising a redox enzyme and a redox compound, wherein the redox enzyme and redox compound are non-leachable by fluids in the body of the animal at a pH of between about 6.5 and about 7.8. - View Dependent Claims (10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 54, 55, 56, 57, 58, 59, 60, 62, 63, 74)
one or more alarms, each alarm coupled to one or more of the non-corroding metal or carbon electrodes. -
39. The electrochemical sensor of claim 38, wherein one or more of the alarms is configured to activate if a signal generated at one of the electrodes coupled to the alarm is outside a predetermined range.
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40. The electrochemical sensor of claim 38, wherein at least one of the alarms is configured to activate if a signal generated at the electrode indicates a blood glucose concentration above a predetermined concentration.
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41. The electrochemical sensor of claim 38, wherein at least one of the alarms is configured to activate if a signal generated at the electrode indicates an increase in glucose concentration with time over a predetermined rate.
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42. The electrochemical sensor of claim 38, wherein at least one of the alarms is configured to activate if a signal generated at the electrode indicates a changing glucose concentration that accelerates over time above a predetermined acceleration.
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43. The electrochemical sensor of claim 38, wherein at least one of the alarms is configured to activate if a signal generated at the electrode indicates a blood glucose concentration below a predetermined concentration.
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44. The electrochemical sensor of claim 38, wherein at least one of the alarms is configured to activate if a signal generated at the electrode indicates a decrease in glucose concentration with time over a predetermined rate.
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45. The electrochemical sensor of claim 38, wherein at least one of the alarms is configured to activate if a signal generated at the electrode indicates hypoglycemia or impending hypoglycemia.
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46. The electrochemical sensor of claim 38, wherein at least one of the alarms is configured to activate if a signal generated at the electrode indicates hyperglycemia or impending hyperglycemia.
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47. The electrochemical sensor of claim 38, wherein the sensor of the system comprises two or more non-corroding metal or carbon electrodes and one or more alarms each coupled to two or more of the non-corroding metal or carbon electrodes.
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48. The electrochemical sensor of claim 47, wherein at least one of the alarms is configured to activate if any two of the non-corroding metal or carbon electrodes to which the alarm is coupled generate electrical signals that differ by greater a predetermined amount for a predetermined period of time.
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49. The electrochemical sensor of claim 47, wherein at least one of the alarms is configured to activate if any two of the non-corroding metal or carbon electrodes to which the alarm is coupled generate electrical signals that differ by greater than about 10% for a predetermined period of time.
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50. The electrochemical sensor of claim 47, wherein at least one of the alarms is configured to activate if any two of the non-corroding metal or carbon electrodes to which the alarm is coupled generate electrical signals that differ by greater than about one standard deviation for a predetermined period of time.
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51. The electrochemical sensor of claim 48, wherein the predetermined period of time is greater than about 10 minutes.
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54. A method of measuring the concentration of a biochemical in an animal comprising:
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contacting body fluid of the animal with the electrochemical sensor of claim 9 to generate an electrical signal; and
determining from the generated electrical signal the concentration of a biochemical in the body fluid.
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55. The method of claim 54, wherein the body fluid is blood, plasma, or serum.
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56. The method of claim 54, wherein the measuring is intermittent.
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57. The method of claim 54, wherein the contacting includes implanting the electrode subcutaneously in the animal.
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58. The method of claim 54, further comprising placing a reference electrode or combined reference and counter electrode on or in the skin of the animal.
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59. The method of claim 54, wherein the biochemical to be detected is glucose.
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60. The method of claim 54, wherein the biochemical to be detected is lactate.
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62. The method of claim 54, wherein the sensor has two or more non-corroding metal or carbon electrodes and substantially simultaneous readings of the two or more non-corroding metal or carbon electrodes are accepted as correctly measuring the concentration of the biochemical when the two or more readings do not differ by more than a specified percentage of the measured electrical signals.
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63. The method of claim 56, wherein the sensor has two or more non-corroding metal or carbon electrodes and readings of the two or more non-corroding metal or carbon electrodes that do not differ by more than about 20% or by more than about one standard deviation are accepted as correctly measuring the concentration of the biochemical.
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74. The electrochemical sensor of claim 9, further comprising one or more reference or reference/counter electrodes, at least one of said reference or reference/counter electrodes adapted for placement on the surface of the animal.
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52. A method of calibrating an electrochemical sensor, comprising the steps of:
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withdrawing a single calibration sample from an animal;
assaying an analyte concentration of the single calibration sample; and
correlating the assayed analyte concentration to a signal generated by one or more implanted working electrodes of an electrochemical sensor, each working electrode having an analyte-responsive enzyme disposed thereon. - View Dependent Claims (53, 61, 70, 71, 72, 73)
a non-corroding metal or carbon electrode, and a sensing layer covering at least a portion of each non-corroding metal or carbon electrode, comprising a redox enzyme and a redox compound;
wherein the redox enzyme and redox compound are non-leachable by fluids in the body of the animal at a pH of between about 6.5 and about 7.8.
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61. The method of claim 54, wherein the sensor is capable of being calibrated by the method of claim 52.
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70. The method of claim 52, wherein a baseline current of the one or more working electrodes is 0.5 nA or less.
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71. The method of claim 52, wherein a baseline current is 1.5% or less of a total current of the one or more working electrodes at 10 mM analyte concentration.
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72. The method of claim 52, wherein a baseline current is 5% or less of a total current of the one or more working electrodes over a physiological analyte concentration range.
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73. The method of claim 52, wherein the one or more working electrodes are subcutaneously implanted.
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64. A method for the analysis of a bioanalyte, comprising:
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providing an analyte measurement system comprising two or more subcutaneously implantable electrodes;
subcutaneously implanting two or more electrodes in the body of an animal;
obtaining readings from each of the electrodes at substantially one point in time;
comparing two or more of the readings from the electrodes; and
accepting those readings which do not vary by more than a predetermined degree. - View Dependent Claims (65, 66, 67, 68, 69)
an electrochemical sensor including two or more non-corroding metal or carbon electrodes, each electrode adapted for subcutaneous implantation in an animal, and a non-leachable analyte-responsive enzyme disposed on each of the electrodes; and
a device for comparing signals generated at the two or more electrodes.
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66. The method of claim 64, wherein the readings are obtained continuously.
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67. The method of claim 64, wherein the readings are obtained intermittently.
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68. The method of claim 64, wherein the method further comprises
measuring a temperature near one or more electrodes at substantially the same point in time as obtaining the readings from the electrodes, and correcting the readings from the electrodes based on the measured temperature. -
69. The method of claim 64, wherein the sensor is capable of calibration by a method of calibrating an electrochemical sensor, comprising the steps of:
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withdrawing a single calibration sample from an animal;
assaying an analyte concentration of the single calibration sample; and
correlating the assayed analyte concentration to a signal generated by one or more implanted working electrodes of an electrochemical sensor, each working electrode having an analyte-responsive enzyme disposed thereon.
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Specification