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