Patent Publication Number: US-2023135297-A1

Title: Electrode systems for electrochemical sensors

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     Any and all applications for which a foreign or domestic priority claim is identified in the Application Data Sheet as filed with the present application are hereby incorporated by reference under 37 CFR 1.57. For example, this application claims priority to U.S. Provisional Application No. 63/263,277, titled ELECTRODE SYSTEMS FOR ELECTROCHEMICAL SENSORS and filed on Oct. 29, 2021, the entire content of which is incorporated by reference herein in its entirety and for all purposes and forms a part of this specification. 
    
    
     FIELD OF THE DISCLOSURE 
     The present disclosure relates to physiological monitoring devices. More specifically, this disclosure relates to glucose monitoring devices and methods of making the same. 
     BACKGROUND 
     Diabetes is a chronic disease that impacts many individuals, both adults and children. The management of diabetes may include the measurement of glucose within the interstitial space including blood and/or interstitial fluid of a patient and administration of insulin to the patient. A closed loop insulin administration system includes both a sensor to take glucose measurements from the interstitial space including blood and/or interstitial fluid of the patient and an insulin administration device which administers insulin to the patient based on the glucose measurements. Closed loop insulin administration systems allow individuals impacted by diabetes to go about daily life with much less worry about their insulin or glucose levels which can vastly improve a diabetic&#39;s quality of life. 
     SUMMARY 
     The present disclosure provides an electrode system for an electrochemical sensor. The electrode system can include a working electrode comprising a first layer comprising gold and a second layer comprising platinum; a reference electrode comprising silver; and a counter electrode comprising gold. The first layer comprising gold can have a thickness of about 2.5-3.5 μm, and the second layer comprising platinum can have a thickness of about 80-120 Å. The working electrode and the reference electrode can be positioned on one side of a substrate. The counter electrode can be positioned on an opposite side of the substrate relative to the working electrode and the reference electrode. 
     In some aspects, the electrochemical sensor can be a glucose sensor. In some aspects, the thickness of the first layer comprising gold can be about 3 μm. In some aspects, the thickness of the second layer comprising platinum can be about 100 Å. In some aspects, the reference electrode can have a thickness of about 2.5-3.5 μm. In some aspects, the counter electrode can have a thickness of about 2.5-3.5 μm. In some aspects, the reference electrode can have a thickness of about 2.5-3.5 μm. In some aspects, the substrate can comprise two base layers. In some aspects, at least one of the two base layers can comprise polyimide (PI), polyethylene (PE), or polyethylene terephthalate (PET). 
     In some aspects, the electrode system can further comprise a first polymer layer covering part of the working electrode and reference electrode. In some aspects, the first polymer layer can comprise polyimide (PI). In some aspects, the electrode system can further comprise a second polymer layer covering part of the counter electrode. In some aspects, the second polymer layer can comprise polyimide (PI). 
     In some aspects, a glucose sensor is provided. The glucose sensor can comprise an electrode system comprising a substrate; a working electrode positioned on one side of the substrate; a reference electrode positioned on the same side of the substrate as the working electrode; and a counter electrode positioned on an opposite side of the substrate relative to the working electrode and reference electrode. The working electrode can comprise a first gold layer and a second platinum layer. In some aspects, the first gold layer can have a thickness of about 2.5-3.5 μm. In some aspects, the second platinum layer can have a thickness of about 80-120 Å. In some aspects, the reference electrode can comprise silver. In some aspects, the counter electrode can comprise gold. In some aspects, the reference electrode can have a thickness of about 2.5-3.5 μm. In some aspects, the counter electrode can have a thickness of about 2.5-3.5 μm. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       Various aspects will be described hereinafter with reference to the accompanying drawings. These aspects are illustrated and described by example only, and are not intended to limit the scope of the disclosure. In the drawings, similar elements have similar reference numerals. 
         FIG.  1 A  illustrates a view of interleaved operation of insulin administration systems on a patient. 
         FIG.  1 B  illustrates an example disease management system that may be part of a disease management environment or used as an interleaved device. 
         FIG.  2    illustrates an example implementation of a disease management system. 
         FIG.  3    illustrates an example layout of components of a disease management system. 
         FIG.  4    illustrates an example analyte sensor seal and mount for an implementation of a disease management system. 
         FIG.  5 A- 5 C  illustrate different views of an example electrode system for an analyte sensor. 
         FIG.  5 D  illustrates different layers of an example electrode system for an analyte sensor. 
         FIG.  6 A  show the working electrode and reference electrode in an example electrode system. 
         FIG.  6 B  illustrates the dimensions of the working electrode and reference electrode in an example electrode system. 
         FIG.  7 A  show the working electrode and reference electrode partly covered by a polymer layer in an example electrode system 
         FIG.  7 B  illustrates the dimensions of the working electrode and reference electrode partly covered by a polymer layer in an example electrode system. 
         FIG.  8 A  show the counter electrode partly covered by a polymer layer in an example electrode system. 
         FIG.  8 B  illustrates the dimensions of the counter electrode partly covered by a polymer layer in an example electrode system. 
     
    
    
     DETAILED DESCRIPTION 
     The present disclosure will now be described with reference to the accompanying figures, wherein like numerals refer to like elements throughout. The following description is merely illustrative in nature and is in no way intended to limit the disclosure, its application, or uses. Furthermore, the devices, systems, and/or methods disclosed herein can include several novel features, no single one of which is solely responsible for its desirable attributes or which is essential to practicing the devices, systems, and/or methods disclosed herein. 
     Aspects of the disclosure will now be set forth in detail with respect to the figures and various examples. One of skill in the art will appreciate, however, that other configurations of the devices and methods disclosed herein will still fall within the scope of this disclosure even if not described in the same detail. Aspects of various configurations discussed do not limit the scope of the disclosure herein, which is instead defined by the claims following this description. 
     Definition 
     As used herein, common abbreviations are defined as follows:
         ° C. Temperature in degrees Centigrade   CE Counter electrode   RE Reference electrode   WE Working electrode   CGM Continuous glucose monitoring   DAN Diamino naphthalene   GO x  Glucose oxidase   H 2 O 2  Hydrogen peroxide       

     Disclosed herein are electrode systems for an electrochemical sensor, for example, an analyte sensor, such as a glucose sensor. In some configurations, the analyte sensor may be integrated into a disease management system or other device configured to monitor a patient state and deliver medication on an ongoing or temporary basis. While reference may be made to a specific disease, such as diabetes, systems and methods described herein may be applicable to other diseases and conditions. 
     While in some examples, systems and methods described herein may reference monitoring or sensing of a specific parameter or blood analyte, such as glucose, other physiological conditions, physiological states, physiological parameters, physiological markers, blood analytes, the like or a combination thereof may be monitored or determined in addition or in the alternative to glucose. Similarly, while in some examples, reference may be made to a specific type of sensor, such as a glucose sensor, other analyte sensors may additionally or alternatively be used. For example, a glucose sensor may be configured to additionally measure other analytes. Additionally or alternatively, while reference may be made to specific types of invasive or non-invasive sensors, such as an invasive glucose sensor, any type of invasive or non-invasive sensor may be used, such as a non-invasive analyte sensor. 
     A. Example Disease Management System 
       FIG.  1 A  illustrates a disease management system that may include one or more redundant disease management systems that may include standalone or combined glucose sensor and/or insulin administration systems. The disease management system may include a first disease management system  1002  and a second disease management system  1004 . 
       FIG.  1 B  shows a block diagram of an example disease management system  1101 . A disease management system  1101  may be configured to measure one or more physiological parameters of a patient (such as pulse, skin temperature, or other values), measure one or more analytes present in the blood of a patient (such as glucose, lipids, or other analyte) and administer medication (such as insulin, glucagon, or other medication). In some examples, a disease management system  1101  may be configured to communicate with one or more hardware processors that may be external to the disease management system  1101 , such as a cloud-based processor or user device. 
     As illustrated in  FIG.  1 B , a disease management system  1101  may include an analyte sensor  1120 . The analyte sensor  1120  may be configured to detect analytes in the patient&#39;s blood. For example, an analyte sensor  1120  can include a glucose sensing probe configured to pierce the surface of the skin  1121 . In some examples, a disease management system  1101  may include a plurality of analyte sensors  1120  to detect one or more analytes. In some examples, an analyte sensor  1120  may be configured to detect a plurality of analytes. Sensed analytes may include, but are not limited to, glucose, insulin, and other analytes. An analyte sensor  1120  may be configured to communicate with an analyte detector  1126 . The analyte detector  1126  may be configured to receive a signal of one or more analyte sensors  1120  in order to measure one or more analytes in the blood of the patient. The analyte detector  1126  may be configured to communicate with the controller  1138 . For example, the analyte detector  1126  may be configured to, for example, send analyte values to the controller  1138  and receive control signals from the controller. Other detailed description of the disease management system  1101  can be found in U.S. Patent Application Publication No. 2021/0236729 A1, which is incorporated here by reference in its entirety. 
       FIG.  2    illustrates an example implementation of a disease management system  1103  and applicator  1190  for applying a disease management system  1103  to a patient. In the illustrated example, an applicator  1190  may be configured to mate with the disease management system  1103 . In some examples, a disease management system  1103  may include one or more needles  1158  that may include one or more analyte sensors (such as a glucose sensor)  1156 . In some examples, the disease management system  1103  may include a base plate  1166  and an adhesive layer  1168  below the base plate  1166  to provide adhesion of the disease management system  1103  to the patient&#39;s skin. A housing of the disease management system  1103  may consist of a combination of flexible and rigid material so as to both provide support for the components of the disease management system  1103  and allow conforming, at least in part, of the disease management system  1103  to the skin of the patient. 
     In addition or in the alternative to one or more of the implementations described above, a disease management system may be combined into a compact design, such as illustrated in  FIG.  3   .  FIG.  3    illustrates cross sectional and perspective views of an example embodiment of a disease management system  100 . The disease management system  100  can include a combined glucose monitor and insulin pump. As illustrated by  FIG.  3   , a disease management system  100  can include a battery  4204 , a PCBA  4202 , an analyte sensor and needle mount  4206 , an adhesive latch mechanism  4208 , a buzzer  4210  and water resistant film or layer, a vibration motor  4209 , a medication pouch assembly  4216 , a pouch puncture assembly  4214 , one or more light pipes  4218 , a cannula and needle  4222 , and a pump assembly  4220 . 
       FIG.  4    illustrates an example analyte sensor and mount  4206  of a disease management system. In some examples, an analyte sensor and needle mount  4206  can include a gasket  4450 . The gasket can be configured to seal the sensor from external fluids that may otherwise flow into the disease management system. In some examples, an analyte sensor and needle mount  4206  may include features to position the analyte sensor and needle properly. For example, an analyte sensor and needle mount  4206  may include portions  4454  configured to position the sensor properly so as to avoid upward shift of the sensor before, during, or after insertion. In some examples, one or more of a needle and sensor can include dimples  4456  or other positioning features to help prevent a sensor from touching the needle and being damages when the needle is withdrawn. 
     B. Example Electrode System for Electrochemical Sensors 
     An analyte sensor, such as a glucose sensor is an amperometric electrochemical biosensor generating a current from the electrochemical reaction between glucose and a glucose oxidase layer on a working electrode (WE). The reference electrode (RE) eliminates the potential arising from the solution medium. The counter electrode (CE) acts as a reference half-cell to supply the required current for the electrochemical reaction, whereas the WE acts as a sensing half-cell to produce the current. The glucose monitoring device described herein comprises at least two electrodes—the working electrode and the reference electrode. 
       FIGS.  5 A- 5 C  illustrate different views of an example electrode system  500  comprising a working electrode  510 , reference electrode  520  and a counter electrode  530 .  FIG.  5 A  shows a working electrode  510  and a reference electrode  520  on one side of the substrate.  FIG.  5 B  shows a counter electrode  530  on the other side of the substrate.  FIG.  5 C  illustrates the side view of the example electrode system  500 , as well as the sizes and thickness of different layers. As a non-limiting example, the length of an example electrode system li may be about 8 mm, the thickness of layers  540  and  550  h 1  may be about 120 μm, the thickness of all the layers h 2  may be about 170 μm, the thickness h 3  of layers  550 ,  530  and  570  h 3  may be about 60 μm, the thickness of layer  570  h 4  may be about 20 μm. 
     To address the comfort of a user having to use a sensor device, the reduction in size (diameter) of sensor electrodes is important, as is the durability of the probe design to withstand the rigors of a physically active patient and importance of repeatable accuracy and economical production of these probes to keep CGM unit costs reasonable for typical patients. Systems and methods described herein help address the above concerns. 
     Advantageously, placing the working electrode and reference electrode on the opposite side of the substrate relative to the counter electrode can help downsize the glucose sensor comparing to placing all three electrodes on one side of the substrate, which is important for a user&#39;s comfort. For example, if the glucose sensor is placed in a needle to be inserted into a patient&#39;s body such as in a wearable device like the disease management system  1103 , the size of the glucose sensor may partially determine the diameter of the needle and a miniaturized sensor may help alleviate the patient&#39;s pain and improve the comfort level, especially when the patient needs to wear the device for relatively long time. 
       FIG.  5 D  illustrates different layers in an example electrode system  500 . As shown in  FIG.  5 D , the electrode system  500  may comprise a first polymer layer  560 , a working electrode  510 , a reference electrode  520 , a second polymer layer  540 , a third polymer layer  550 , a counter electrode  530 , and a fourth polymer layer  570 . 
     In some aspects, the thickness of the first polymer layer  560  is about 10-30 μm, about 15-25 μm, about 15 μm, about 20 μm, about 25 μm, about 30 μm, or any other thickness. In some aspects, the first polymer layer  560  may comprise polyimide (PI) or other equivalent polymer. 
     In some aspects, the working electrode  510  and/or the reference electrode  520  may comprise one or more metals. In some further aspects, the working electrode  510  and/or the reference electrode  520  may comprise platinum (Pt), gold (Au), silver (Ag), rhodium (Rh), iridium (Jr), or combinations thereof. 
     In one aspect, the working electrode  510  may comprise Pt. In some aspects, the working electrode  510  may comprise both Pt and Au. In another aspect, the working electrode  510  comprises both Pt and Ir. In some aspects, the working electrode  510  may comprise two different metal layers. In some aspects, the bottom metal layer of a working electrode  510  may be Au and the top metal layer of the working electrode  510  may be Pt. In some aspects, the thickness of the bottom metal layer may be about 2-4 μm, about 2.5-3.5 μm, about 2 μm, about 2.5 μm, about 3 μm, about 3.5 μm, about 4 μm, or any other thickness. In some aspects, the thickness of the top metal layer may be about 50-150 Å, about 80-120 Å, about 50 Å, about 70 Å, about 90 Å, about 100 Å, about 120 Å, about 150 Å, or any other thickness. In some aspects, the thickness of the top metal layer may be much less than the thickness of the bottom metal layer. The ratio of the thickness of the top metal layer to the thickness of the bottom metal layer may be less than about 1/500, 1/300, 1/100, or less than any other ratio. Such a two-layer working electrode configuration can provide a platinum electrode surface for glucose detection and other better qualities such as higher electrical conductivity comparing to a pure platinum electrode. It might also cost less to manufacture this two-layer electrode comparing to manufacturing a pure platinum electrode. 
     In some aspects, the reference electrode  520  may comprise silver. In some aspects, the thickness of the reference electrode in the reference electrode may be about 2-4 μm, about 2.5-3.5 μm, about 2.5 μm, about 3 μm, about 3.5 μm, about 4 μm, or any other thickness. In some aspects, the thickness of the working electrode  510  and the reference electrode  520  may be similar. In another aspect, the reference electrode may comprise silver and silver chloride (Ag/AgCl). 
       FIG.  6 A  shows the working electrode  510  and reference electrode  520  in the example electrode system  500 . In some aspects, the reference electrode  520  may comprise an electrode part  812 , a connector part  820 , and a wire part  816  connecting the electrode part  812  and the connector part  820 . In some aspects, the connector part  820  may be used to connect to the electrical circuits of the system. In some aspects, the width of the wire part  816  w 3  may be about 0.06-0.12 mm, about 0.06-0.10 mm, about 0.06 mm, 0.08 mm, 0.10 mm, 0.12 mm, or any other width. In some aspects, the length of the wire part  816  is about 6.5-7.4 mm, about 6.5 mm-7.0 mm, about 6.5 mm, 6.8 mm, 7.1 mm, 7.4 mm, or any other length. In some aspects, the connector part  820  and the electrode part  812  may be asymmetric. In some aspects, the width of the connector part  820  may be about 0.24-0.36 mm, about 0.28-0.32 mm, about 0.24 mm, about 0.30 mm, about 0.36 mm, or any other width. In some aspects, the length of the connector part  820  l 6  may be about 0.5-0.7 mm, about 0.5 mm, about 0.6 mm, about 0.7 mm, or any other length. In some aspects, the length of the electrode part  812  l 2  may be about 1.4-1.6 mm, about 1.4 mm, about 1.5 mm, about 1.6 mm, or any other length. In some aspects, the reference electrode  520  may have other shapes. 
     With continued reference to  FIG.  6 A , in some aspects, the working electrode  510  may comprise an electrode part  810 , a connector part  818 , and a wire part  814  connecting the electrode part  810  and the connector part  818 . In some aspects, the connector part  818  may be used to connect to the electrical circuits of the system. In some aspects, the working electrode  510  may be arranged to encompass the reference electrode  520  without contacting the reference electrode  520 . In some aspects, the length of the wire part  814  may be about 8.5-9.5 mm, about 8.5 mm, about 9.0 mm, about 9.5 mm, or any other length. In some aspects, the length of the electrode part  810  l 4  may be about 1.3-1.5 mm, about 1.3 mm, about 1.4 mm, about 1.5 mm, or any other length. In some aspects, the length of the connector part  818  l 3  may be about 0.5-0.7 mm, about 0.5 mm, about 0.6 mm, about 0.7 mm, or any other length. In some aspects, the working electrode  510  may comprise other shapes. 
       FIG.  6 B  illustrates the dimensions of a working electrode  510  and a reference electrode  520  in an example electrode system. As a non-limiting example, the length of the electrode part  812  l 2  is about 1.5 mm, the length of the connector part  818  l 3  is about 0.6 mm, the length of the electrode part  810  l 4  is about 1.4 mm, the length l 5  is about 0.06, the length l 6  is about 0.6 mm, the width of the electrode system w 1  is about 0.36 mm, the width w 2  is about 0.06 mm, the width w 3  is about 0.08 mm. 
       FIG.  7 A  illustrates a plan view of an example electrode system  500  viewed from the side of first polymer layer  560  and the dimensions. In some aspects, the first polymer layer  560  may cover the wire parts  814  and  816  of the working electrode  510  and reference electrode  520  respectively. In some aspects, the length of first polymer layer  560  may be about  3 .5-3.9 mm, about 3.5 mm, about 3.7 mm, about 3.9 mm, or any other lengths. The first polymer layer  560  may provide protection of the electrodes. 
       FIG.  7 B  illustrates the dimensions of the first polymer layer  560  in an example electrode system. As a non-limiting example, the length l 8  is about 1.4 mm, the length l 7  is about 3 mm. 
     Referring back to  FIG.  5 D , in some aspects, the thickness of the second polymer layer  540  is about 50-70 μm, about 55-65 μm, about 50 μm, about 55 μm, about 60 μm, about 65 μm, or any other thickness. In some aspects, the second polymer layer  540  may comprise polyimide (PI), polyethylene (PE), polyethylene terephthalate (PET), or other equivalent polymer. 
     With continued reference to  FIG.  5 D , in some aspects, the thickness of the third polymer layer  550  is about 50-70 μm, about 55-65 μm, about 50 μm, about 55 μm, about 60 μm, about 65 μm, or any other thickness. In some aspects, the third polymer layer  550  may comprise polyimide (PI), polyethylene (PE), polyethylene terephthalate (PET), or other equivalent polymer. In some aspects, the thickness of the second and third polymer layer may be similar. In some aspects, the second and third polymer layer may serve as the substrate together. In some aspects, the second and third polymer layer may be combined as one single layer, and the thickness of this single layer maybe the sum of the thickness of the second and third polymer layer. In some aspects, the third polymer layer may be omitted from the electrode system. 
     With continued reference to  FIG.  5 D , the counter electrode  530  may comprise one or more metals described herein. In one aspect, the counter electrode comprises gold. In some aspects, the thickness of the counter electrode  530  may be about 2-4 μm, about 2.5-3.5 μm, about 2 μm, about 2.5 μm, about 3 μm, about 3.5 μm, about 4 μm, and or other thickness. In some aspects, the counter electrode  530  may be omitted from the electrode system. 
     With continued reference to  FIG.  5 D , in some aspects, the thickness of the fourth polymer layer  570  may be about 15-30 μm, about 25-35 μm, about 15 μm, about 20 μm, about 25 μm, about 30 μm, or any other thickness. In some aspects, the fourth polymer layer  570  may comprise polyimide (PI) or other equivalent polymer. 
       FIG.  8 A  illustrates a plan view of an example electrode system viewed from the side of fourth polymer layer  570  and the counter electrode  530 . As shown in  FIG.  8 A , in some aspects, the counter electrode  530  may comprise a rectangular shape. In some aspects, the length of the rectangular shape may be about 7-10 mm, about 7 mm, about 8 mm, about 9 mm, about 10 mm, or any other length. In some aspects, the width of the rectangular shape w 4  may be about 0.2-0.36 mm, about 0.20 mm, 0.26 mm, 0.3 mm, 0.36 mm, or any other width. In some aspects, the fourth polymer layer  570  can cover part of the counter electrode  530 . In some aspects, the length of the fourth polymer layer  570  may be about 4.0-4.9 mm, about 4.0-4.5 mm, about 4.0 mm, about 4.3 mm, about 4.6 mm, or any other length. The fourth polymer layer  570  may provide protection of the counter electrode. 
       FIG.  8 B  illustrates the dimensions of fourth polymer layer  570  and the counter electrode  530 . As an non-limiting example, the width of the counter electrode  530  w 4  is about  0 .26 mm, the length l 9  is about 0.7, the length l 10  is about 3 mm. 
     C. Surface Characteristics of Example Electrode System 
     The surface characteristics of working electrodes are important for all subsequent steps of fabrication of the CGM sensor. Any deposits of organic material, chemical impurities and oxidized metal can lead to irregular electrical conductivity along the surface due to different surface adsorption characteristics towards the analyte (for electrochemical deposition, electro-polymerization, electrochemical area determinations, etc.); irregular physical adsorption of inner selective layers (PoPD, cellulose acetate, Nafion™, polyphenol etc.); or irregularities in distribution of the hydroxyl groups on the Pt wire surface, which is critical for uniform oxidation rates of H 2 O 2 . There are various protocols of cleaning the surface of working electrodes, including but not limited to: a) mechanical agitation in 100% acetone and deionized water using titanium-tip sonication; b) soaking in concentrated nitric acid to dissolve residual organic matter and to etch the platinum surface slightly; and c) electrochemical conditioning/activation of the surface by performing multiple cycles of cyclic voltammetry between −0.2 [V] to 1.145 [V] in 1 M sulfuric acid (H 2 SO 4 ). 
     Therefore, the electrochemical oxidation reactions of most redox species are preferred at potentials close to those of the platinum oxide (Pt(O)) surface formation for greatest response. 
     Electrochemical species undergo electrocatalytic oxidation at the Pt surface through the reaction with oxygen, which may come from bulk water or from surface oxides on the electrode formed by anodic activation of the Pt surface. Having the oxide layer on the Pt surface accelerates the electrochemical charge transfer reactions because of readily available platinum oxide. In the first step of this cyclic mechanism, H 2 O 2  reacts with the surface of Pt to form Pt(O), releasing one molecule of H 2 O. In the second step, a second molecule of H 2 O 2  reduces Pt(O) to metallic Pt, releasing a second molecule of second H 2 O and O 2 . The first reaction is a rate-limiting step in this two-part reaction. Incorporating Pt(O) at the surface (activation) exhibit a faster rate of H 2 O 2  decomposition because the rate limiting step of the reaction is skipped in the first cycle. 
     There are many potential parallel/competing Pt based H 2 O 2  electrochemical oxidation reaction mechanisms. The anodic activation of Pt can be achieved by application of cyclic voltammetry, where the electrode is anodized by scanning the potential in the anodic region and/or holding the potential for some time at the anodic limit. In one example, during Pt cleaning procedure with 1 M H 2 SO 4 , the cyclic voltammetry scans were stopped at the final high anodic potential of 1.145 V vs Ag/AgCl. At this potential a uniform Pt(O) layer and an activated working electrode surface is formed. 
     To detect H 2 O 2 , GOx enzymatic layer will be deposited on the platinum electrode, along with other layers for normalizing the glucose signal, which will act as the working electrode (WE). A three-electrode configuration includes two other electrodes; a solid-state silver/silver chloride (Ag/AgCl) as a reference electrode (RE) against which the potential of the working electrode is maintained at a constant value; and a counter electrode (CE) made of any stable/noble metal (Au, Pt, stainless steel or others) which acts as a conduit to pass the current between the working electrode and itself. When the working electrode surface is held at the operating potential of the CGM (+0.6V) with respect to Ag/AgCl, H 2 O 2  oxidizes to O 2  and releases two electrons per molecule of H 2 O 2 . 
       2AgCl+2e − →2Ag+2Cl − 
 
     However, at this potential other endogenous redox active species such as ascorbic acid, uric acid as well as exogenous redox active species such as acetaminophen also undergo reduction/oxidation at the electrode surface. This can lead to an increase or decrease in the amperometric signal. As described herein, the incorporation of a second permeability-layer and/or an oxygen-replenishing layer can substantially reduce or eliminate the signal caused by the interference by blocking these interfering species from reaching the electrode surface. As described herein, CGM sensor interference can be reduced/eliminated by adding a combination of enzymes that specifically catalyze the decomposition of the following interfering molecules in the outer layers of the sensor before they reach the electrode: ascorbic acid, uric acid, or acetaminophen, hydroxyurea, cholesterol, creatinine, dopamine, ethylenediaminetetraacedic acid (EDTA), gentisic acid, heparin, or salicylic acid, or combinations thereof. The enzymes specific for each of the interfering molecules may be add to one or more of the second-permeability selective layer (inner selective layer), the GOx enzymatic layer, the first-permeability selective layer (outer perm-selective layer), or the outer protective layer. 
     The enzyme GOx may be deposited and trapped onto the surface of the WE wire using some combination of electro-deposition, electro-polymerization, and physical adsorption of a polymer such as o-phenylenediamine, aniline, or other polymer. The inclusion of the polymer may have multiple purposes. For example, the polymerized mesh may physically trap the GOx enzyme and adsorb it to the WE surface. In another example, the polymer backbone may be electrically conductive and facilitate the transfer of electrons to the WE. Additionally or alternatively, other polymer layers constructed of, for example, Nafion, Cellulose acetate, the like or a combination thereof, deposited below or above the GOx deposition layer may normalize the levels of glucose and oxygen. These other polymer layers may help linearize a current response to physiologically relevant glucose concentrations. Additionally or alternatively, the other polymer layers, (such as cellulose acetate) may protect the activated WE metal surface. This protection is beneficial because the activated surface of the WE is important in developing a sensitive glucose sensor because the reaction of the working electrode surface with hydrogen peroxide is primarily responsible for the creation of the electrical signal which is measured by the electrical circuits of the system. 
     In another example, a sensor may be configured to remove or reduce the CGM&#39;s dependence on dissolved oxygen and help substitute the function of oxygen with the use of a small molecule, sometimes referred to as the “mediator”. The mediator may function in a similar fashion to oxygen in the context of the sensor system to facilitate the transfer of electrons from the enzyme (GOx) catalytic center to the electrode. The mediator may be fabricated into the sensor head in a proportion that may enable this functionality. In some examples, the proportion may be empirically determined. The mediator may be constructed out of molecules that can accept electrons in a stable manner and/or give up the electrons in certain conditions, such as at the electrode surface. A mediator can include any number of materials, such as ferrocene, ferricyanide, Osmium based transition metal complexes or the like. In some examples, the enzyme (GOx), the mediator(s) and/or polymers may be covalently bound to the metal electrode to form the sensor for detecting glucose. In this sensor configuration, construction may also be encapsulated with multiple layers of polymers (such as Nafion). The layers of polymers may serve specific purposes. Additionally or alternatively, the polymers may limit the concentration of glucose at the enzyme to linearize the current response to various concentrations of glucose. In some examples, the addition of mediators may include additional steps to ensure biocompatibility of the mediator molecules along with the stability of the sensor fabrication to keep the molecules from leeching after invasive implantation. In some examples, an electrode that includes a mediator may be constructed using a of Gold (Au), Pt/Ir, or Pt/Au electrode. 
     Advantageously, the selected polymer layers and GOx are biocompatible. Similarly, Pt, Au and Ag are noble metals with excellent biocompatibility. 
     Various methods of recording electrical signal may be used. For example, cyclic voltammometry, amperometry, voltammetry, or another method of recording electrical signal may be used. A method may be selected based on parameters such as reproducibility and accuracy of glucose concentrations over the lifetime of the sensor. 
     A CGM sensor may detect and convert concentrations of glucose to a proportional electrical signal (current or potential) by a series of electron transfer steps between GOx, FAD, peroxide molecules and finally to the working electrode. However, this proportionality constant is sensitive to a range of physical and biochemical parameters. These parameters may be controlled and standardized during fabrication in order to help produce more consistent signal. For example, such parameters and example (but not exclusive) method(s) of standardizing these parameters for fabrication can include, but are not limited to: 1) geometry and size of the sensor head, which may be evaluated by cyclic voltammometry of a known and well-behaved redox compound like ferrocene or potassium ferrocyanide for consistency; 2) amount of glucose oxidase enzyme captured on the sensor head, which may be evaluated by electrical signal detected on the working electrode to known concentrations of peroxide and compared with the glucose response; 3) applied voltage between the working electrode and the reference electrode, wherein the working voltage can be determined by cycling through or probing of various voltages for a known concentration of glucose; 4) polymer coating(s) that may normalize the concentration of glucose and oxygen, which can be evaluated based on the linearization of electrical response to glucose concentration with various concentration of polymer coatings; 5) the surface “activation” and preservation of platinum electrode that oxidizes hydrogen peroxide, wherein the inclusion of cellulose acetate polymer coating of working electrode may protect the surface “activation” in a functioning glucose sensor for the purposes of standardization and consistency; 6) the polymer coating that filters out interfering species such as ascorbic acid, urea, acetaminophen, wherein a Nafion polymer coating may be utilized to reduce interference in electrical measurements; 7) the conducting polymer that provides an efficient “pathway” for the electrons to reach the platinum electrode, some polymers such as PANI, PoPD and other polymers that may include conducting polymers may be used for this purpose; 8) the local diffusion behavior of glucose and oxygen near the sensor, wherein the diffusion behavior can be characterized by comparing the electrical response of the constructed sensor to standard equations of electrochemistry; 9) leeching or degradation of polymer layers, mediators and glucose oxidase enzyme, wherein the binding strength of the components of the sensor will be characterized by following the “leakage” of these components during long-term usage and incubation of the sensor in in-vitro buffer or blood/plasma. UV/Vis spectroscopy, chemical determination, Raman spectroscopy and atomic force microscopy are some of the biophysical methods that can be used to characterize this phenomenon; 10) the drift/stability of the reference electrode (Ag/AgCl), wherein the Ag/AgCl reference electrode is constructed with any number of methods and wherein the electrodes may be calibrated against industry leading, low-noise and long-term stable commercial Ag/AgCl electrodes; 11) temperature and pH of the measurement location, which can be accounted for in testing in an electrochemical cell to test for the temperature and pH consistent with the human body (pH 7.4 and 37° C.); 12) depth of penetration of the sensor into the ISF. Ideally, the depth of insertion of the sensor head should be fairly precisely controlled using the applicator. This depth will partially determine the lag time of glucose values between blood and ISF. Location of the CGM (abdomen vs arm) is another factor that determines lag. 
     When constructing the electrochemical probe, the use of specific metals and electrode surface platting may be used to achieve a desired signal return. Some metals that may be used for this purpose include but are not limited to Platinum, Gold, Silver, and Silver-Chloride. Other combinations of metals and surface platting may also be possible. Other iterations could include other materials, such as electrodes made of carbon nanotubes, graphene electrodes, gold nanoparticles deposited on other metallic surfaces, glassy carbon, Zinc Oxide nanorods, indium tin oxide, the like or a combination thereof. 
     Once the probe is constructed of the correct combination of metal electrodes, many probe designs also require the application of chemical agents and buffers to either exaggerate or manage the gain of the electro-chemical reaction to target the desired molecule; in this case Glucose. 
     D. Terminology 
     Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. The use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting. The use of the term “having” as well as other forms, such as “have”, “has,” and “had,” is not limiting. The terms “comprising,” “including,” “having,” and the like are synonymous and are used inclusively, in an open-ended fashion, and do not exclude additional elements, features, acts, operations, and so forth. That is, the above terms are to be interpreted synonymously with the phrases “having at least” or “including at least.” For example, when used in the context of a process, the term “comprising” means that the process includes at least the recited steps, but may include additional steps. When used in the context of a device, the term “comprising” means that the device includes at least the recited features or components, but may also include additional features or components. Also, the term “or” is used in its inclusive sense (and not in its exclusive sense) so that when used, for example, to connect a list of elements, the term “or” means one, some, or all of the elements in the list. Further, the term “each,” as used herein, in addition to having its ordinary meaning, can mean any subset of a set of elements to which the term “each” is applied. 
     Conditional language, such as “can,” “could,” “might,” or “may,” unless specifically stated otherwise, or otherwise understood within the context as used, is generally intended to convey that certain aspects include, while other aspects do not include, certain features, elements, or steps. Thus, such conditional language is not generally intended to imply that features, elements, or steps are in any way required for one or more aspects or that one or more aspects necessarily include logic for deciding, with or without user input or prompting, whether these features, elements, or steps are included or are to be performed in any particular embodiment. 
     Conjunctive language such as the phrase “at least one of X, Y, and Z,” unless specifically stated otherwise, is otherwise understood with the context as used in general to convey that an item, term, etc. may be either X, Y, or Z. Thus, such conjunctive language is not generally intended to imply that certain aspects require the presence of at least one of X, at least one of Y, and at least one of Z. 
     Language of degree used herein, such as the terms “approximately,” “about,” “generally,” and “substantially” as used herein represent a value, amount, or characteristic close to the stated value, amount, or characteristic that still performs a desired function or achieves a desired result. For example, the terms “approximately”, “about”, “generally,” and “substantially” may refer to an amount that is within less than 10% of, within less than 5% of, within less than 1% of, within less than 0.1% of, and within less than 0.01% of the stated amount. 
     The term “and/or” as used herein has its broadest least limiting meaning which is the disclosure includes A alone, B alone, both A and B together, or A or B alternatively, but does not require both A and B or require one of A or one of B. As used herein, the phrase “at least one of” A, B, “and” C should be construed to mean a logical A or B or C, using a non-exclusive logical or. 
     The term “temperature independent” as used herein, means that the reading or measurement of the glucose level by the glucose monitoring device or the response of the glucose sensor is not affect or not substantially affected by the change of temperature. In other words, the sensor is insensitive the change of temperature (e.g., change of body temperature as a result of physiological conditions such as hypothermia and hyperpyrexia). In some aspects, the temperature independent property of the glucose monitoring device is maintained within the operating temperature range of the device (e.g., from about 30° C. to about 45° C., from about 33° C. to about 43° C., from about 35° C. to about 41° C., or from about 36° C. to about 40° C. In some aspects, the change of temperature (per ° C.) results in less than 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1% or 0.01% change in the response of the sensor, or the measurement/reading provided by the device, when all the other parameters remain the same (e.g., the glucose concentration is constant). 
     Any methods disclosed herein need not be performed in the order recited. The methods disclosed herein include certain actions taken by a practitioner; however, they can also include any third-party instruction of those actions, either expressly or by implication. 
     The methods and tasks described herein may be performed and fully automated by a computer system. The computer system may, in some cases, include multiple distinct computers or computing devices (for example, physical servers, workstations, storage arrays, cloud computing resources, etc.) that communicate and interoperate over a network to perform the described functions. Each such computing device typically includes a processor (or multiple processors) that executes program instructions or modules stored in a memory or other non-transitory computer-readable storage medium or device (for example, solid state storage devices, disk drives, etc.). The various functions disclosed herein may be embodied in such program instructions, and/or may be implemented in application-specific circuitry (for example, ASICs or FPGAs) of the computer system. Where the computer system includes multiple computing devices, these devices may, but need not, be co-located. The results of the disclosed methods and tasks may be persistently stored by transforming physical storage devices, such as solid state memory chips and/or magnetic disks, into a different state. The computer system may be a cloud-based computing system whose processing resources are shared by multiple distinct business entities or other users. 
     While the above detailed description has shown, described, and pointed out novel features, it can be understood that various omissions, substitutions, and changes in the form and details of the devices or algorithms illustrated can be made without departing from the spirit of the disclosure. As can be recognized, certain portions of the description herein can be embodied within a form that does not provide all of the features and benefits set forth herein, as some features can be used or practiced separately from others. The scope of certain implementations disclosed herein is indicated by the appended claims rather than by the foregoing description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope.