Subcutaneous Glucose Electrode

Abstract

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

1 . An electrochemical sensor for measuring an analyte in an animal comprising:
 one or more non-corroding metal or carbon electrodes adapted for at least partial subcutaneous implantation in an animal;   a sensing layer comprising an enzyme disposed adjacent to each electrode; and   wherein the electrochemical sensor has a glucose sensitivity selected from the range of about an order of magnitude less than 61 pA/mg/dL to about 300 pA/mg/dL.   
   
   
       2 . The electrochemical sensor of  claim 1 , wherein the electrochemical sensor has a glucose sensitivity selected from the range of about an order of magnitude less than 61 pA/mg/dL to about an order of magnitude less than 300 pA/mg/dL. 
   
   
       3 . The electrochemical sensor of  claim 1 , wherein the electrochemical sensor has a glucose sensitivity selected from the range of about an order of magnitude less than 97 pA/mg/dL to about 167 pA/mg/dL. 
   
   
       4 . The electrochemical sensor of  claim 1 , wherein the electrochemical sensor has a glucose sensitivity selected from the range of about an order of magnitude less than 78 pA/mg/dL to about 158 pA/mg/dL. 
   
   
       5 . The electrochemical sensor of  claim 1 , wherein the electrochemical sensor has a glucose sensitivity of about an order of magnitude less than 78 pA/mg/dL. 
   
   
       6 . The electrochemical sensor of  claim 1 , wherein the sensitivity does not change by more than about ±5% for 3 days of operation. 
   
   
       7 . The electrochemical sensor of  claim 1 , further comprising a biocompatible layer disposed adjacent to the sensing layer. 
   
   
       8 . The electrochemical sensor of  claim 6 , wherein the biocompatible layer comprises a hydrogel. 
   
   
       9 . The electrochemical sensor of  claim 8 , wherein the hydrogel comprises more than about 20% by weight of water when in equilibrium with physiological body fluids. 
   
   
       10 . The electrochemical sensor of  claim 8 , wherein the hydrogel comprises a crosslinked poly(ethylene oxide). 
   
   
       11 . The electrochemical sensor of  claim 6 , wherein all portions of the sensing layer and the biocompatible layer allow diffusion of an analyte therethrough. 
   
   
       12 . The electrochemical sensor of  claim 6 , wherein the biocompatible layer is chemically bound to the sensing layer. 
   
   
       13 . The electrochemical sensor of  claim 6 , wherein the biocompatible layer is indirectly chemically bound to the sensing layer. 
   
   
       14 . The electrochemical sensor of  claim 6 , wherein the sensor further comprises an interferant eliminating layer and the biocompatible layer is chemically bound to the interferant eliminating layer. 
   
   
       15 . The electrochemical sensor of  claim 6 , wherein the sensor further comprises an analyte flux limiting layer and the biocompatible layer is chemically bound to the analyte flux limiting layer. 
   
   
       16 . The electrochemical sensor of  claim 1 , wherein the sensing layer comprises a hydrogel. 
   
   
       17 . The electrochemical sensor of  claim 16 , wherein the sensing layer comprises glucose oxidase. 
   
   
       18 . The electrochemical sensor of  claim 1 , wherein the outer dimension of the sensor is smaller than about 0.3 mm 
   
   
       19 . The electrochemical sensor of  claim 1 , wherein the non-corroding metal or carbon electrode comprises a wire. 
   
   
       20 . The electrochemical sensor of  claim 19 , wherein the outer diameter of each of the one or more non-corroding metal or carbon electrodes is smaller than about 0.25 mm. 
   
   
       21 . The electrochemical sensor of  claim 1 , wherein the electrochemical sensor further comprises an electrically insulating material coating at least a part of one of the one or more non-corroding metal or carbon electrodes. 
   
   
       22 . The electrochemical sensor of  claim 21 , wherein the electrically insulating material is selected from the group consisting of polyimide, polyester, polyurethane, and perfluorinated polymer. 
   
   
       23 . The electrochemical sensor of  claim 21 , wherein the electrically insulating material disposed on said one or more non-corroding metal or carbon electrodes defines a gap in the coating exposing a non-insulated portion of the electrode. 
   
   
       24 . The electrochemical sensor of  claim 23 , wherein the sensing layer is at least partially disposed on the exposed, non-insulated portion of the electrode. 
   
   
       25 . An electrochemical sensor for measuring an analyte in an animal, comprising:
 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,   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 is non-leachable by fluids in the body of the animal at a pH of between about 6.5 and about 7.8, and   an alarm coupled to the non-corroding metal or carbon electrode configured to activate if a signal generated at the electrode indicates at least one of impending hypoglycemia and impending hyperglycemia.   
   
   
       26 . The electrochemical sensor of  claim 25 , wherein the one or more non-corroding metal or carbon electrodes are flexible. 
   
   
       27 . The electrochemical sensor of  claim 25 , wherein the electrochemical sensor further comprises a biocompatible layer covering the sensing layer of each non-corroding metal or carbon electrode. 
   
   
       28 . The electrochemical sensor of  claim 25 , wherein the sensor further comprises a biocompatible layer 
   
   
       29 . The electrochemical sensor of  claim 28 , wherein the biocompatible layer comprises a hydrogel. 
   
   
       30 . The electrochemical sensor of  claim 25 , wherein the sensing layer comprises a hydrogel. 
   
   
       31 . The electrochemical sensor of  claim 30 , wherein the sensing layer comprises glucose oxidase. 
   
   
       32 . The electrochemical sensor of  claim 25 , wherein the outer dimension of the sensor is smaller than about 0.3 mm 
   
   
       33 . The electrochemical sensor of  claim 25 , wherein the non-corroding metal or carbon electrode comprises a wire. 
   
   
       34 . The electrochemical sensor of  claim 25 , wherein the outer diameter of each of the one or more non-corroding metal or carbon electrodes is smaller than about 0.25 mm. 
   
   
       35 . The electrochemical sensor of  claim 25 , wherein the electrochemical sensor further comprises an electrically insulating material coating at least a part of one of the one or more non-corroding metal or carbon electrodes. 
   
   
       36 . The electrochemical sensor of  claim 35 , wherein the electrically insulating material is selected from the group consisting of polyimide, polyester, polyurethane, and perfluorinated polymer. 
   
   
       37 . The electrochemical sensor of  claim 35 , wherein the electrically insulating material disposed on said one or more non-corroding metal or carbon electrodes defines a gap in the coating exposing a non-insulated portion of the electrode. 
   
   
       38 . The electrochemical sensor of  claim 37 , wherein the sensing layer is at least partially disposed on the exposed, non-insulated portion of the electrode. 
   
   
       39 . A method of calibrating an electrochemical sensor at least partially implanted in an animal, comprising the steps of:
 withdrawing a calibration sample from an animal during a time period, wherein the time period is selected such that the analyte concentration remains substantially constant during the time period;   assaying an analyte concentration of the calibration sample;   correlating the assayed analyte concentration to a signal generated by one or more implanted working electrodes of an electrochemical sensor to calibrate the electrochemical sensor, each working electrode having an analyte-responsive enzyme disposed thereon.   
   
   
       40 . The method of  claim 39 , wherein the sensor is capable of operation for 72 hours without further calibration.