Continuous analyte monitoring sensor system

Abstract

Disclosed herein are systems and methods for a continuous analyte monitoring system for measuring a concentration of a first analyte and a concentration of a second analyte in a host. One such system utilizes a working electrode and a reference electrode to measure glucose and oxygen concentrations in a bodily fluid of the host. The system includes a sensor control circuit that applies a first bias condition to the sensor to measure a first signal generated by the sensor indicative of the concentration of the first analyte. The sensor control circuit also applies a second bias condition to the sensor to measure a second signal generated by the sensor indicative of the concentration of the second analyte in the host.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 321,340, entitled "CONTINUOUS ANALYTE MONITORING SENSOR SYSTEMS AND METHODS OF USING THE SAME," filed March 18, 2022, and claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 478,047, entitled "CONTINUOUS ANALYTE MONITORING SENSOR SYSTEMS AND METHODS OF USING THE SAME," filed December 30, 2022, both of which are incorporated by reference in their entireties herein.

[0002] (Technical field of the invention) The present disclosure relates generally to systems and methods for determining an analyte concentration in a host. [Background technology]

[0003] Monitoring of various systems functioning within a host can help monitor the overall health of the host. As an example, continuous monitoring of analytes associated with diabetes can help patients monitor their health. Diabetes is a metabolic disease associated with the production or use of insulin in the body. Insulin is a hormone that allows the body to use glucose for energy or store glucose as fat.

[0004] When a person eats a meal containing carbohydrates, the food is processed by the digestive system, producing glucose in the blood. Blood glucose can be used for energy or stored as fat. The body normally maintains blood glucose levels in a range that provides enough energy to support bodily functions and avoids problems that can result from glucose levels that are too high or too low. Regulation of blood glucose levels depends on the production and use of insulin, which regulates the movement of blood glucose into cells.

[0005] When the body does not produce enough insulin or is unable to effectively use the insulin that is present, blood glucose levels can rise above the normal range. The condition of having blood glucose levels higher than what is considered normal or healthy is called "hyperglycemia". Chronic hyperglycemia can lead to many health problems, such as cardiovascular disease, cataracts and other eye diseases, nerve damage (neuropathy), and kidney damage. Hyperglycemia can also lead to acute problems, such as diabetic ketoacidosis (a condition in which the body becomes too acidic due to the presence of glucose in the blood and ketone bodies, which are produced when the body can no longer use glucose). The condition of blood glucose levels lower than normal is called "hypoglycemia". Severe hypoglycemia can lead to acute crises that can result in seizures or death.

[0006] Diabetic patients may receive insulin to manage blood glucose levels. Insulin may be received, for example, through manual injection with a needle. Wearable insulin pumps are also available. Diet and exercise also affect blood glucose levels. Glucose sensors provide estimated glucose concentration levels and can be used as guidance by the patient or caregiver.

[0007] Diabetes is sometimes referred to as "Type 1" and "Type 2". Type 1 diabetes patients may be able to use insulin when it is present, but due to problems with the insulin-producing beta cells of the pancreas, the body is unable to produce sufficient amounts of insulin. Type 2 diabetes patients may produce some insulin, but due to reduced sensitivity to insulin, the patient is "insulin resistant". As a result, even though insulin is present in the body, the insulin is not used well by the patient's body and does not effectively regulate blood sugar levels.

[0008] The blood glucose concentration value may be monitored with a continuous analyte monitoring system, such as a continuous glucose monitor, which may provide the wearer (patient) with information such as an estimated blood glucose level or a trend in the estimated blood glucose level. Summary of the Invention [Means for solving the problem]

[0009] Example 1 is a continuous analyte monitoring system for measuring a concentration of a first analyte and a concentration of a second analyte in a host, the continuous analyte monitoring system comprising a sensor having a working electrode extending along a central axis, a reference electrode, and a sensor control circuit, the sensor control circuit configured to perform operations including applying a first bias condition to the sensor and accessing a first signal generated by the sensor in vivo while the first bias condition is applied to the sensor, the first signal being indicative of a concentration of the first analyte in the host; applying a second bias condition to the sensor, the second bias condition being different from the first bias condition; and accessing by the sensor control circuit a second signal generated by the sensor in vivo while the second bias condition is applied to the sensor, the second signal being indicative of a concentration of a second analyte in the host, the second analyte being different from the first analyte.

[0010] In Example 2, which can be combined with other Examples herein, the subject matter of Example 1 optionally includes that the first analyte is glucose and the second analyte is oxygen.

[0011] In Example 3, which can be combined with other Examples herein, the subject matter of any one or more of Examples 1-2 optionally includes wherein the reference electrode is configured to support a redox reaction and the working electrode is configured to support an oxidation reaction.

[0012] In Example 4, which may be combined with other Examples herein, the subject matter of any one or more of Examples 1-3 optionally includes a reference electrode extending coaxially along the central axis.

[0013] In Example 5, which may be combined with other examples herein, the subject matter of any one or more of Examples 1-4 optionally includes the reference electrode being configured to operate in an ex vivo location.

[0014] In Example 6, which can be combined with other examples herein, the subject matter of any one or more of Examples 1-5 optionally includes that the working electrode, the reference electrode, or both, are substantially planar.

[0015] In Example 7, which can be combined with other Examples herein, the subject matter of any one or more of Examples 1-6 optionally includes a counter electrode in electrical communication with the working electrode, the reference electrode, or both.

[0016] In Example 8, which can be combined with other examples herein, the subject matter of any one or more of Examples 1-7 optionally includes an enzyme layer at least partially covering the working electrode.

[0017] In Example 9, which may be combined with other examples herein, the subject matter of Example 8 optionally includes that the enzyme layer includes an oxidase.

[0018] In Example 10, which can be combined with other examples herein, the subject matter of any one or more of Examples 8-9 optionally includes a resistive layer at least partially covering the enzyme layer.

[0019] In Example 11, which can be combined with other examples herein, the subject matter of any one or more of Examples 1-10 optionally includes, wherein the working electrode comprises platinum and tantalum, and the reference electrode comprises silver and silver chloride.

[0020] In Example 12, which may be combined with other examples herein, the subject matter of any one or more of Examples 1-11 optionally includes at least a portion of the working electrode and the reference electrode configured to be exposed to at least one of glucose or oxygen.

[0021] In Example 13 that may be combined with other Examples herein, the subject matter of any one or more of Examples 1 to 12 optionally includes a buckling strength of the sensor within a range of 0.010 lbf to 0.10 lbf.

[0022] In Example 14, which can be combined with other examples herein, the subject matter of any one or more of Examples 1-13 optionally includes, when configured in the first bias condition, the working electrode is biased at about 0.50 V to about 0.70 V relative to the reference electrode, and when configured in the second bias condition, the working electrode is biased at about −0.3 V to about −0.2 V relative to the reference electrode.

[0023] In Example 15, which may be combined with other examples herein, the subject matter of any one or more of Examples 1-14 optionally includes a transmitter capable of transmitting data acquired during the first bias condition, the second bias condition, or both, to the device.

[0024] Example 16, which can be combined with other examples herein, is a method of continuous analyte monitoring, the method including: biasing an in vivo sensor to a first bias condition by a sensor control circuit, the sensor comprising a working electrode and a reference electrode extending coaxially along a central axis; accessing by the sensor control circuit a first signal generated by the sensor while the first bias condition is applied to the sensor, the first signal being indicative of a concentration of a first analyte; biasing by the sensor control circuit to a second bias condition different from the first bias condition; and accessing by the sensor control circuit a second signal generated by the sensor while the second bias condition is applied to the sensor, the second signal being indicative of a concentration of a second analyte, the second analyte being different from the first analyte.

[0025] In Example 17, which can be combined with other examples herein, the subject matter of Example 16 optionally includes the first bias condition having a first polarity and the second bias condition having a second polarity that is opposite the first polarity.

[0026] In Example 18, which may be combined with other examples herein, the subject matter of any one or more of Examples 16-17 optionally includes biasing the sensor to a first bias condition comprising applying a positive potential difference between the working electrode and the reference electrode.

[0027] In Example 19, which may be combined with other examples herein, the subject matter of Example 18 optionally includes, wherein the positive potential difference is within the range of about 0.50V to 0.70V.

[0028] In Example 20, which may be combined with other examples herein, the subject matter of any one or more of Examples 16-19 optionally includes, where biasing the sensor to a second bias condition includes applying a negative potential difference between the working electrode and the reference electrode.

[0029] In Example 21, which can be combined with other Examples in this specification, the subject of Example 20 is that the negative potential difference is within the range of about -0.3 to -0.2V.

[0030] In Example 22, which may be combined with other examples herein, the subject matter of any one or more of Examples 16-21 optionally includes that the sensor is configured to be present in a living body.

[0031] In Example 23, which may be combined with other examples herein, the subject matter of any one or more of Examples 16-22 optionally includes switching the sensor between a first bias condition and a second bias condition.

[0032] In Example 24, which may be combined with other examples herein, the subject matter of Example 23 optionally includes that switching between the first bias condition and the second bias condition includes executing a first bias condition program and a second bias condition program, respectively.

[0033] Example 25, which can be combined with other examples herein, is a continuous analyte monitoring system for measuring a concentration of at least one analyte, the continuous analyte monitoring system comprising a sensor including a working electrode extending along a central axis, a reference electrode, and a solid electrolyte layer at least partially covering at least one of the working electrode and the reference electrode.

[0034] In Example 26, which may be combined with other examples herein, the subject matter of Example 25 optionally includes a sensor control circuit configured to perform operations including applying a bias condition to the sensor and accessing a signal generated by the sensor in vivo and biased to the bias condition, the signal being indicative of a concentration of an analyte.

[0035] In Example 27, which may be combined with other examples herein, the subject matter of any one or more of Examples 25-26 optionally includes where the analyte is oxygen.

[0036] In Example 28, which may be combined with other examples herein, the subject matter of any one or more of Examples 25-27 optionally includes a reference electrode extending coaxially along the central axis.

[0037] In Example 29, which may be combined with other examples herein, the subject matter of any one or more of Examples 25-28 optionally includes wherein the working electrode, the reference electrode, or both, are substantially planar.

[0038] In Example 30, which may be combined with other examples herein, the subject matter of any one or more of Examples 25-29 optionally includes a counter electrode in electrical communication with the working electrode, the reference electrode, or both.

[0039] In Example 31, which can be combined with other examples herein, the subject matter of any one or more of Examples 25-30 optionally includes an enzyme layer at least partially covering the working electrode, the reference electrode, or both.

[0040] In Example 32, which can be combined with other examples herein, the subject matter of any one or more of Examples 25-31 optionally includes, where the solid electrolyte layer includes a polymer electrolyte.

[0041] In Example 33, which can be combined with other examples herein, the subject matter of any one or more of Examples 25-32 optionally includes, where the working electrode comprises platinum and tantalum, and the reference electrode comprises silver and silver chloride.

[0042] In Example 34, which can be combined with other examples herein, the subject matter of any one or more of Examples 25-33 optionally includes a solid electrolyte layer disposed between and in electrical communication with the working electrode and the reference electrode.

[0043] In Example 35, which may be combined with other examples herein, the subject matter of any one or more of Examples 25-34 optionally includes exposing at least a portion of the working electrode and at least a portion of the reference electrode to the analyte.

[0044] In Example 36 that may be combined with other examples herein, the subject matter of any one or more of Examples 25 to 35 optionally includes a buckling strength of the sensor within the range of 0.010 lbf to 0.10 lbf.

[0045] In Example 37, which may be combined with other examples herein, the subject matter of any one or more of Examples 25-36 optionally includes a transmitter capable of transmitting data acquired during the bias condition to a display device.

[0046] In Example 38, which may be combined with other examples herein, the subject matter of any one or more of Examples 25-37 optionally includes where the reference electrode and the working electrode are separated by a membrane.

[0047] In Example 39, which can be combined with other examples herein, the subject matter of Example 38 optionally includes that the membrane includes a polymer.

[0048] Example 40, which can be combined with other examples herein, is a method of using a continuous analyte monitoring system, the method including: biasing an in vivo sensor to a bias condition by a sensor control circuit, the sensor comprising a working electrode extending along a central axis and a reference electrode; a solid electrolyte layer at least partially covering at least one of the working electrode and the reference electrode; accessing by the sensor control circuit a signal generated by the sensor in vivo while a first bias condition is applied, the signal being indicative of a concentration of an analyte, and accessing by the sensor control circuit a signal generated by the sensor in vivo while a second bias condition is applied to the sensor, the signal being indicative of a concentration of the analyte.

[0049] In Example 41, which may be combined with other examples herein, the subject matter of Example 40 optionally includes where the analyte is oxygen.

[0050] In Example 42, which may be combined with other examples herein, the subject matter of Example 41 optionally includes where the oxygen is interstitial oxygen.

[0051] In Example 43, which may be combined with other examples herein, the subject matter of any one or more of Examples 40-42 optionally includes a reference electrode extending coaxially along the central axis.

[0052] In Example 44, which may be combined with other examples herein, the subject matter of any one or more of Examples 40-43 optionally includes wherein the reference electrode is configured to reside ex vivo.

[0053] In Example 45, which may be combined with other examples herein, the subject matter of any one or more of Examples 40-44 optionally includes wherein the working electrode, the reference electrode, or both, are substantially planar.

[0054] In Example 46, which may be combined with other examples herein, the subject matter of any one or more of Examples 40-45 optionally includes a counter electrode in electrical communication with the working electrode, the reference electrode, or both.

[0055] In Example 47, which may be combined with other examples herein, the subject matter of any one or more of Examples 40-46 optionally includes an enzyme layer at least partially covering the working electrode, the reference electrode, or both.

[0056] In Example 48, which may be combined with other examples herein, the subject matter of any one or more of Examples 40-47 optionally includes, where the solid electrolyte layer includes a polymer electrolyte.

[0057] In Example 49, which may be combined with other examples herein, the subject matter of any one or more of Examples 40-48 optionally includes, wherein the working electrode comprises platinum and tantalum and the reference electrode comprises silver and silver chloride.

[0058] In Example 50, which may be combined with other examples herein, the subject matter of any one or more of Examples 40-49 optionally includes a solid electrolyte layer disposed between and in electrical communication with the working electrode and the reference electrode.

[0059] In Example 51, which may be combined with other examples herein, the subject matter of any one or more of Examples 40-50 optionally includes exposing at least a portion of the working electrode and at least a portion of the reference electrode to the analyte.

[0060] In Example 52, which may be combined with other examples herein, the subject matter of any one or more of Examples 40 to 51 optionally includes, a buckling strength of the sensor within the range of 0.010 lbf to 0.10 lbf.

[0061] In Example 53, which may be combined with other examples herein, the subject matter of any one or more of Examples 40 to 52 optionally includes a transmitter capable of transmitting data acquired during the bias condition to a display device.

[0062] Example 54, which can be combined with other examples herein, is a method of calibrating an analyte sensor, the method including: exposing the analyte sensor to a first known analyte concentration, the analyte sensor comprising a working electrode extending along a central axis and a reference electrode; a solid electrolyte layer at least partially covering at least one of the working electrode and the reference electrode; accessing a first sensor signal generated by the analyte sensor while the analyte sensor is exposed to the first known analyte concentration; exposing the analyte sensor to a second known analyte concentration; accessing a second sensor signal generated by the analyte sensor while the analyte sensor is exposed to the second known analyte concentration; and determining a calibration parameter using the first signal and the second signal.

[0063] In Example 55, which may be combined with other examples herein, the subject matter of Example 54 includes that the calibration parameters optionally describe a linear relationship between the amount of signal produced by the analyte sensor and the analyte concentration.

[0064] In Example 56, which may be combined with other examples herein, the subject matter of any one or more of Examples 54-55 optionally includes the calibration parameters including sensitivity, the sensitivity describing the analyte concentration per unit of sensor signal.

[0065] In Example 57, which may be combined with other examples herein, the subject matter of any one or more of Examples 54-56 optionally includes accessing a third sensor signal generated by the analyte sensor in vivo, and determining a concentration of the analyte in vivo using the third sensor signal and the calibration parameters.

[0066] In Example 58, which may be combined with other examples herein, the subject matter of any one or more of Examples 54-57 optionally includes where the analyte of the known analyte concentration is oxygen.

[0067] In Example 59, which may be combined with other examples herein, the subject matter of any one or more of Examples 54-58 optionally includes wherein the working electrode, the reference electrode, or both, are substantially planar.

[0068] In Example 60, which can be combined with other examples herein, the subject matter of any one or more of Examples 54-59 optionally includes, where the solid electrolyte layer includes a polymer electrolyte.

[0069] In Example 61, which may be combined with other examples herein, the subject matter of any one or more of Examples 54-60 optionally includes, where the working electrode comprises platinum and tantalum, and the reference electrode comprises silver and silver chloride.

[0070] In Example 62, which can be combined with other examples herein, the subject matter of any one or more of Examples 54-61 optionally includes a solid electrolyte layer disposed between and in electrical communication with the working electrode and the reference electrode.

[0071] In Example 63, which may be combined with other examples herein, the subject matter of any one or more of Examples 54-62 optionally includes exposing at least a portion of the working electrode and at least a portion of the reference electrode to the analyte.

[0072] Example 64 is a continuous analyte monitoring system for measuring a concentration of a first analyte and a concentration of a second analyte in a host, the continuous analyte monitoring system comprising a sensor including a working electrode extending along a central axis, a reference electrode, and a sensor control circuit, the sensor control circuit applying a first bias condition between the working electrode and the reference electrode, the first bias condition having a first polarity and a first magnitude, accessing a first signal generated by the sensor in vivo while the first bias condition is applied to the sensor, the first signal being indicative of a concentration of the first analyte in the host, and applying a second bias condition between the working electrode and the reference electrode. and applying a second bias condition having a second polarity and a second magnitude, the second polarity being opposite to the first polarity; accessing, by a sensor control circuit, a second signal generated by the sensor in vivo while the second bias condition is applied to the sensor, the second signal being indicative of a concentration of a second analyte in the host, the second analyte being different from the first analyte; and applying a third bias condition between the working electrode and the reference electrode, the third bias condition having a third polarity and a third magnitude, the third polarity being equal to the first polarity and the third magnitude being greater than the first magnitude.

[0073] The subject matter of Example 65, Example 64, which may be combined with other examples herein, optionally includes where the first analyte is glucose or lactate and the second analyte is oxygen.

[0074] The subject matter of any one or more of Example 66 and Examples 64-65, which may be combined with other examples herein, optionally includes the reference electrode being configured to support a redox reaction and the working electrode being configured to support an oxidation reaction.

[0075] The subject matter of any one or more of Example 67 and Examples 46-66, which may be combined with other Examples herein, optionally includes a reference electrode extending coaxially along the central axis.

[0076] The subject matter of any one or more of Example 68 and Examples 64-67, which may be combined with other examples herein, optionally includes the reference electrode being configured to operate in an ex vivo location.

[0077] The subject matter of any one or more of Example 69 and Examples 64-68, which may be combined with other examples herein, optionally includes that the working electrode, the reference electrode, or both, are substantially planar.

[0078] The subject matter of any one or more of Example 70 and Examples 64-69, which may be combined with other examples herein, optionally further includes a counter electrode in electrical communication with the working electrode, the reference electrode, or both.

[0079] The subject matter of any one or more of Example 71 and Examples 64-70, which may be combined with other examples herein, optionally further includes an enzyme layer at least partially covering the working electrode.

[0080] The subject matter of Example 72, Example 71, which may be combined with other examples herein, optionally includes that the enzyme layer includes an oxidase, a dehydrogenase, or a mixture thereof.

[0081] The subject matter of any one or more of Example 73 and Examples 71-72, which may be combined with other examples herein, optionally further includes a resistance layer at least partially covering the enzyme layer.

[0082] The subject matter of any one or more of Example 74 and Examples 64-73, which may be combined with other examples herein, optionally includes wherein the working electrode comprises platinum, palladium, rhodium, iridium, tantalum, or a mixture thereof, and the reference electrode comprises silver and silver chloride.

[0083] The subject matter of any one or more of Example 75 and Examples 64-74, which may be combined with other examples herein, optionally includes at least a portion of the working electrode and the reference electrode configured to be exposed to at least one of glucose, lactate, and oxygen.

[0084] The subject matter of any one or more of Example 76 and Examples 64 to 75, which may be combined with other examples herein, optionally includes that the buckling strength of the sensor is within the range of 0.010 lbf to 0.10 lbf.

[0085] The subject matter of any one or more of Example 77 and Examples 64-76, which may be combined with other examples herein, optionally includes where the first polarity is positive from the working electrode to the reference electrode and the second polarity is negative from the working electrode to the reference electrode.

[0086] The subject matter of any one or more of Example 78 and Examples 64 to 77, which may be combined with other examples herein, optionally includes that the first magnitude is about 0.5V to about 0.7V.

[0087] The subject matter of any one or more of Example 79 and Examples 64 to 78, which may be combined with other examples herein, optionally includes that the second magnitude is about −0.3 V to about −0.2 V.

[0088] The subject of Example 80, any one or more of Examples 64-79, which may be combined with any other example herein, optionally including the third magnitude being about 0.7 V to about 1.2 V.

[0089] The subject matter of Example 81 and Examples 64-80, which may be combined with other examples herein, optionally includes further comprising a transmitter capable of transmitting data acquired during the first bias condition, the second bias condition, the third bias condition, or a combination thereof to the device.

[0090] The subject matter of any one or more of Example 82 and Examples 64-81, which may be combined with other examples herein, optionally includes the third bias condition being applied for an amount of time that is shorter than the amount of time that each of the first bias condition and the second bias condition is applied.

[0091] The subject matter of any one or more of Example 83 and Examples 64-82, which may be combined with other examples herein, optionally includes the first bias condition being applied for a time period ranging from about 4 minutes to about 80 minutes, the second bias condition being applied for a time period ranging from about 10 seconds to about 10 minutes, and the third bias condition being applied for a time period ranging from about 5 seconds to about 60 seconds.

[0092] The subject matter of any one or more of Example 84 and Examples 64 to 83, which may be combined with other Examples herein, optionally includes the first bias condition being applied for a time period ranging from about 4 minutes to about 30 minutes, the second bias condition being applied for a time period ranging from about 10 seconds to about 2 minutes, and the third bias condition being applied for a time period ranging from about 10 seconds to about 60 seconds.

[0093] The subject matter of any one or more of Example 85 and Examples 64 to 84, which may be combined with other examples herein, optionally includes the second bias condition being applied for a time period ranging from about 1 minute to about 10 minutes, and the third bias condition being applied for a time period ranging from about 10 seconds to about 60 seconds.

[0094] The subject matter of any one or more of Example 86 and Examples 64 to 85, which may be combined with other examples herein, optionally includes the second bias condition being applied for a time period ranging from about 1 minute to about 4 minutes, and the third bias condition being applied for a time period ranging from about 10 seconds to about 60 seconds.

[0095] The subject matter of any one or more of Example 87 and Examples 64-86, which may be combined with other Examples herein, optionally includes the second bias condition being applied for a time in a range of about 3 times to about 9 times greater than the third bias condition.

[0096] The subject matter of any one or more of Example 88 and Examples 64-87, which may be combined with other Examples herein, optionally includes the second bias condition being applied for a time in a range of about 5 times to about 7 times greater than the third bias condition.

[0097] The subject matter of Example 89 and any one or more of Examples 64-88, which may be combined with other examples herein, optionally further includes a solid electrolyte layer at least partially covering at least one of the working electrode and the reference electrode.

[0098] The subject matter of any one or more of Example 90 and Example 89, which may be combined with other examples herein, optionally includes that the solid electrolyte layer comprises a polymer electrolyte.

[0099] The subject matter of Example 91 and Examples 89-90, which may be combined with other Examples herein, optionally includes a solid electrolyte layer disposed between and in electrical communication with the working and reference electrodes.

[0100] The subject matter of any one or more of Example 92 and Examples 89-91, which may be combined with other examples herein, optionally includes the reference electrode and the working electrode being separated by a membrane.

[0101] The subject matter of Example 93, which may be combined with other examples herein, optionally includes that the membrane comprises a polymer.

[0102] Example 94 is a method for continuous analyte monitoring, the method including applying a first bias condition between a working electrode and a reference electrode extending coaxially along a central axis of an in vivo sensor, the first bias condition having a first polarity and a first magnitude, accessing, by a sensor control circuit, a first signal generated by the sensor in vivo while the first bias condition is applied to the sensor, the first signal being indicative of a concentration of a first analyte in a host, and applying a second bias condition between the working electrode and the reference electrode, the second bias condition having a second polarity and a second magnitude. and applying, by a sensor control circuit, a second signal generated by the sensor in vivo while the second bias condition is applied to the sensor, the second signal being indicative of a concentration of a second analyte in the host, the second analyte being different from the first analyte; and applying a third bias condition between the working electrode and the reference electrode, the third bias condition having a third polarity and a third magnitude, the third polarity being equal to the first polarity and the third magnitude being greater than the first magnitude.

[0103] The subject matter of Example 95, Example 94, which may be combined with other examples herein, optionally includes the first bias condition and the third bias condition having a first polarity and the second bias condition having a second polarity that is opposite to the first polarity.

[0104] The subject matter of any one or more of Example 96 and Examples 94-95, which may be combined with other examples herein, optionally includes biasing the sensor to the first bias condition and the third bias condition includes applying a positive potential difference between the working electrode and the reference electrode.

[0105] The subject matter of Example 97, Example 96, which may be combined with other examples herein, optionally includes that the positive potential difference of the first bias condition is within the range of about 0.5 V to 0.7 V relative to the reference electrode.

[0106] The subject matter of any one or more of Example 98, Example 96, and Example 97, which may be combined with other Examples herein, optionally includes a positive potential difference of the third bias condition within a range of about 0.7 V to about 1.2 V relative to the reference electrode.

[0107] The subject matter of Example 99, Examples 94-98, which may be combined with other examples herein, optionally includes where biasing the sensor to a second bias condition includes applying a negative potential difference between the working electrode and the reference electrode.

[0108] The subject matter of Example 100, Example 99, which may be combined with other examples herein, optionally includes that the negative potential difference is within the range of about -0.3 to -0.2 V relative to the reference electrode.

[0109] The subject matter of any one or more of Example 101 and Examples 94-100, which may be combined with other Examples herein, optionally includes the first bias condition being applied for a time period ranging from about 4 minutes to about 80 minutes, the second bias condition being applied for a time period ranging from about 10 seconds to about 10 minutes, and the third bias condition being applied for a time period ranging from about 5 seconds to about 60 seconds.

[0110] The subject matter of any one or more of Example 102, Examples 94 to 101, which may be combined with other Examples herein, optionally includes the first bias condition being applied for a time period ranging from about 4 minutes to about 30 minutes, the second bias condition being applied for a time period ranging from about 10 seconds to about 2 minutes, and the third bias condition being applied for a time period ranging from about 10 seconds to about 60 seconds.

[0111] The subject matter of any one or more of Example 103 and Examples 94 to 102, which may be combined with other Examples herein, optionally includes the second bias condition being applied for a time period ranging from about 1 minute to about 10 minutes, and the third bias condition being applied for a time period ranging from about 10 seconds to about 60 seconds.

[0112] The subject matter of any one or more of Example 104 and Examples 94 to 103, which may be combined with other Examples herein, optionally includes the second bias condition being applied for a time period ranging from about 1 minute to about 4 minutes, and the third bias condition being applied for a time period ranging from about 10 seconds to about 60 seconds.

[0113] The subject matter of any one or more of Example 105 and Examples 94-104, which may be combined with other examples herein, optionally includes the second bias condition being applied for a time in a range of about 3 times to about 9 times greater than the third bias condition.

[0114] The subject matter of any one or more of Example 106 and Examples 94-105, which may be combined with other Examples herein, optionally includes the second bias condition being applied for a time in a range of about 5 times to about 7 times greater than the third bias condition.

[0115] The subject matter of any one or more of Example 107 and Examples 94 to 106, which may be combined with other examples in this specification, optionally includes that the sensor is configured to be present in a living body.

[0116] The subject matter of any one or more of Example 108 and Examples 94 to 107, which may be combined with other examples herein, optionally includes further including switching the sensor between a first bias condition, a second bias condition, and a third bias condition.

[0117] The subject matter of any one or more of Example 109 and Example 108, which may be combined with other examples in the present specification, optionally includes that switching between the first bias condition, the second bias condition, and the third bias condition includes executing a first bias condition program, a second bias condition program, and a third bias condition, respectively.

[0118] The subject matter of any one or more of Example 110 and Examples 108 to 109, which may be combined with other examples herein, optionally further includes executing a fourth bias condition program following executing the third bias condition.

[0119] The subject matter of Example 111, Example 110, which may be combined with other examples herein, optionally includes that the fourth bias condition includes a positive potential difference substantially equal to the positive potential difference of the first bias condition.

[0120] Example 112 includes the subject matter of any one or more of Examples 94-111, which may be optionally combined with other examples herein, wherein the sensor further comprises a solid electrolyte layer at least partially covering at least one of the working electrode and the reference electrode.

[0121] Example 113 includes the subject matter of example 112, which may optionally be combined with other examples herein, wherein the solid electrolyte layer includes a polymer electrolyte.

[0122] Example 114 includes the subject matter of any one or more of Examples 112-113, which may be optionally combined with any other examples herein, wherein a solid electrolyte layer is disposed between and in electrical communication with the working electrode and the reference electrode.

[0123] The subject matter of any one or more of Example 115 and Examples 110-114, which may be combined with other examples herein, optionally includes where the reference electrode and the working electrode are separated by a membrane.

[0124] The subject matter of Example 116 and Example 115, which may be combined with other examples herein, optionally includes that the membrane comprises a polymer.

[0125] In the drawings, which are not necessarily drawn to scale, like numerals may describe like components in different figures. Like numerals with different letter suffixes may represent different instances of the like components. The drawings illustrate generally, by way of example, but not by way of limitation, various aspects described in the present document. [Brief description of the drawings]

[0126] [Figure 1] 1 illustrates an example of an environment including a continuous analyte monitoring system according to various aspects of the present disclosure. [Diagram 2] 2 illustrates an example of a medical device system including the continuous analyte monitoring system of FIG. 1 according to various aspects of the present disclosure. [Diagram 3] 1 illustrates an example of a continuous analyte monitoring system that may be implanted in a host, according to various aspects of the present disclosure. [Figure 4A] 1 illustrates an example of a continuous analyte monitoring system according to various aspects of the present disclosure. [Figure 4B] 1 illustrates an example of a continuous analyte monitoring system according to various aspects of the present disclosure. [Figure 4C] 1 illustrates an example of a continuous analyte monitoring system according to various aspects of the present disclosure. [Figure 4D] 1 illustrates an example of a continuous analyte monitoring system according to various aspects of the present disclosure. [Figure 4E] 1 illustrates an example of a continuous analyte monitoring system according to various aspects of the present disclosure. [Figure 4F] 1 illustrates an example of a continuous analyte monitoring system according to various aspects of the present disclosure. [Figure 4G] 1 illustrates an example of a continuous analyte monitoring system according to various aspects of the present disclosure. [Figure 4H] 1 illustrates an example of a continuous analyte monitoring system according to various aspects of the present disclosure. [Figure 4I] 1 illustrates an example of a continuous analyte monitoring system according to various aspects of the present disclosure. [Figure 4J] 1 illustrates an example of a continuous analyte monitoring system according to various aspects of the present disclosure. [Diagram 5] 1 illustrates an example of an exemplary sensor system arranged to selectively transition between a first configuration for measuring a first analyte and a second configuration for measuring a second analyte, in accordance with various aspects of the present disclosure. [Figure 6] 6 illustrates an example of a process flow that may be implemented in the sensor system of FIG. 5 according to various aspects of the present disclosure. [Figure 7] 6 illustrates an example of a process flow that may be implemented in the sensor system of FIG. 5 according to various aspects of the present disclosure. [Figure 8] 6 illustrates an example of a process flow that may be implemented in the sensor system of FIG. 5 according to various aspects of the present disclosure. [Figure 9A] 1 illustrates an example of a continuous analyte monitoring system including a solid electrolyte layer, according to various aspects of the present disclosure. [Figure 9B] 1 illustrates an example of another continuous analyte monitoring system including a solid electrolyte layer, according to various aspects of the present disclosure. [Figure 9C]1 illustrates an example of another continuous analyte monitoring system including a solid electrolyte layer, according to various aspects of the present disclosure. [Figure 10A] 1 illustrates an example of a single-sided coplanar analyte sensor according to various aspects of the present disclosure. [Figure 10B] 1 illustrates an example of a single-sided coplanar analyte sensor according to various aspects of the present disclosure. [Figure 10C] 1 illustrates an example of a single-sided coplanar analyte sensor according to various aspects of the present disclosure. [Figure 10D] 1 illustrates an example of a single-sided coplanar analyte sensor according to various aspects of the present disclosure. [Figure 10E] 1 illustrates an example of a single-sided coplanar analyte sensor according to various aspects of the present disclosure. [Figure 10F] 1 illustrates an example of a single-sided coplanar analyte sensor according to various aspects of the present disclosure. [Figure 10G] 1 illustrates an example of a single-sided coplanar analyte sensor according to various aspects of the present disclosure. [Figure 11] 1 illustrates an example of a calibration process for a continuous analyte monitoring system according to various aspects of the present disclosure. [Figure 12] 1 illustrates another continuous analyte monitoring system embodiment according to various aspects of the present disclosure. [Figure 13] 1 illustrates an example of a computing device hardware architecture in accordance with various aspects of the present disclosure. [Figure 14A] 1 illustrates the linear relationship between oxygen current versus oxygen concentration at different glucose concentrations and days, according to various aspects of the present disclosure. [Figure 14B] 1 illustrates the linear relationship between oxygen current versus oxygen concentration at different glucose concentrations and days, according to various aspects of the present disclosure. [Figure 14C] 1 illustrates the linear relationship between oxygen current versus oxygen concentration at different glucose concentrations and days, according to various aspects of the present disclosure. [Figure 14D] 1 illustrates the linear relationship between oxygen current versus oxygen concentration at different glucose concentrations and days, according to various aspects of the present disclosure. [Figure 14E] 1 illustrates the linear relationship between oxygen current versus oxygen concentration at different glucose concentrations and days, according to various aspects of the present disclosure. [Figure 14F] 1 illustrates the linear relationship between oxygen current versus oxygen concentration at different glucose concentrations and days, according to various aspects of the present disclosure. [Figure 15] 1 is a flow chart illustrating one embodiment of a process for biasing an analyte sensor. [Figure 16] 1 is a graph illustrating a voltage cycle of a continuous analyte sensor according to various aspects of the present disclosure. [Figure 17A] 1 is a graph showing glucose current measurements in odd cycles (without an overvoltage step) compared to those in even cycles (with an overvoltage step) according to various embodiments of the present disclosure. [Figure 17B] 16B is an enlarged portion of the graph of FIG. 16A according to various embodiments of the present disclosure. [Figure 18A] 1 illustrates an example of transient current values ​​corresponding to glucose concentration at multiple times after an oxygen concentration measurement is completed. [Figure 18B] 1 illustrates an example of transient current values ​​corresponding to glucose concentration at multiple times after an oxygen concentration measurement is completed. [Figure 19] 13 illustrates an example of a mathematical fit of glucose sensitivity versus current transients for a variety of different timestamps. [Figure 20A] 1 illustrates an example of transient current values ​​corresponding to oxygen concentration at multiple times after a glucose concentration is measured. [Figure 20B] 1 illustrates an example of transient current values ​​corresponding to oxygen concentration at multiple times after a glucose concentration is measured. [Figure 21] 1 illustrates an example of an exponential 3P decay plot used to fit data to predict glucose current decay after reversing the bias voltage. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0127] Various embodiments described herein are directed to continuous analyte monitoring systems and methods of use for continuous analyte monitoring systems. The continuous analyte monitoring system is placed in contact with a bodily fluid of a host to measure the concentration of an analyte, such as glucose, in the bodily fluid. In some embodiments, the continuous analyte monitoring system is inserted under the skin of a host (e.g., in vivo) and placed in contact with interstitial fluid under the skin to measure the concentration of an analyte in the interstitial fluid.

[0128] As used herein, the terms and phrases "analyte measuring device," "biosensor," "sensor," "sensing region," and "sensing mechanism" are broad terms and phrases that are to be given their ordinary and customary meaning to one of skill in the art (and are not to be limited to any special or customized meaning) and refer to, but are not limited to, a region of an analyte monitoring device that is responsible for the detection of, or the transduction of a signal associated with, a particular analyte or combination of analytes. In one embodiment, such devices are capable of providing specific quantitative, semi-quantitative, qualitative, or semi-qualitative analytical information using biological recognition elements combined with a transduction (detection) element.

[0129] As used herein, the term "about" allows for some variability in values ​​or ranges, e.g., within 10%, within 5%, or within 1% of a stated value or a stated range limit, and includes the precisely stated value or range. As used herein, the term "substantially" refers to a majority or majority, such as at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. As used herein, the term "substantially free" can mean having no or an insignificant amount of the material, such that the amount of material present does not affect the material properties of the composition including the material, and can be about 0 weight percent (wt%) to about 5 wt% of the composition is the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or about 4.5 wt% or less, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less, or about 0 wt%.

[0130] As used herein, the terms "adhere" and "attach" are broad terms and are to be given their ordinary and accustomed meaning to those of skill in the art (and are not to be limited to any special or customized meaning), including, but not limited to, holding, joining, or fastening, for example, by adhering, bonding, grasping, interpenetrating, or fusing.

[0131] As used herein, the term "analyte" is a broad term and is to be given its ordinary and customary meaning to one of skill in the art (and is not to be limited to any special or customized meaning) and refers to, but is not limited to, a substance or chemical component in a biological fluid (e.g., blood, interstitial fluid, cerebrospinal fluid, lymphatic fluid, or urine) that may be analyzed. Analytes may include naturally occurring substances, man-made substances, metabolites, and / or reaction products. In some examples, the analyte for measurement by the sensing regions, devices, and methods is glucose. However, other analytes are contemplated as well, including but not limited to: carboxyprothrombin; acylcarnitines; adenine phosphoribosyltransferase; adenosine deaminase; albumin; alpha-fetoprotein; amino acid profile (arginine (Krebs cycle), histidine / urocanic acid, homocysteine, phenylalanine / tyrosine, tryptophan); andrenostenedione; antipyrine; arabinitol enantiomers; arginase; benzoylecgonine (cocaine); biotinidase; biopterin; blood electrolytes (including but not limited to sodium and potassium); c-reactive protein; carnitine; carnosinase; CD4; ceruloplasmin; chenodeoxycholic acid; chloroquine; cholesterol; cholinesterase; conjugated 1-β hydroxy-cholic acid; cortisol; cholinesterase; creatine kinase;creatine kinase MM isoenzyme;cyclosporine A;d-penicillamine;deethylchloroquine;dehydroepiandrosterone sulfate;DNA (acetylation polymorphism, alcohol dehydrogenase, alpha 1-antitrypsin, cystic fibrosis, Duchenne / Becker muscular dystrophy, glucose-6-phosphate dehydrogenase, hemoglobin A, hemoglobin S, hemoglobin C, hemoglobin D, hemoglobin E, hemoglobin F, D-Punjab, beta-thalassemia, hepatitis B virus, HCMV, HIV-1, HTLV-1, Leber's hereditary optic neuropathy, MCAD, RNA, PKU, Plasmodium vivax, 21-deoxycortisol);desbutylhalofantrine;dihydropteridine reductase;diphtheria / tetanus antitoxin;erythrocyte arginase;erythrocyte protoporphyrin;Esterase D; fatty acids / acylglycines; free beta-human chorionic gonadotropin; free erythrocyte porphyrins; free thyroxine (FT4); free tri-iodothyronine (FT3); fumarylacetoacetase; galactose / gal-1-phosphate; galactose-1-phosphate uridyltransferase; gentamicin; glucose-6-phosphate dehydrogenase; glutathione; glutathione peroxidase; glycerol, glycocholate; glycosylated hemoglobin; halofantrine; hemoglobin variants; hexosaminidase A; human erythrocyte carbonic anhydrase I; 17-acetylglucosamine; Lufa-hydroxyprogesterone; hypoxanthine phosphoribosyltransferase; immunoreactive trypsin; beta-hydroxybutyrate; ketones, lactate; lead; lipoproteins ((a), B / A-1, β); lysozyme; mefloquine; netilmicin; phenobarbitone; phenytoin; phytanic acid / pristanic acid; progesterone; prolactin; prolidase; purine nucleoside phosphorylase; quinine; reverse triiodothyronine (reverse tri-iodothyronine, rT3); selenium; serum pancreatic lipase; sisomicin; somatomedin C; specific antibodies (adenovirus, antinuclear antibody, anti-zeta antibody, arbovirus, pseudorabies virus, dengue virus, guinea worm, tapeworm, ameba histolytica, enterovirus, giardiasis, Helicobacter pylori, hepatitis B virus, herpes virus, HIV-1, IgE (atopic disease), influenza virus, Leishmania donovani, Leptospirosis, measles / mumps / rubella, Mycobacterium leprae, Mycobacterium leprae, pneumoniae Coplasma, myoglobin, Onchocerca volvulus, parainfluenza virus, malaria parasite, poliovirus, Pseudomonas aeruginosa, respiratory syncytial virus, Rickettsia (tsutsugamushi disease), Schistosoma mansoni, Toxoplasma gondii, Treponema pallidum, Trypanosoma cruzi / rangeli, vesicular stomatitis virus, Wuchereria bancrofti, yellow fever virus); specific antigens (Hepatitis B virus, HIV-1); succinylacetone; sulfadoxine; theophylline; thyrotropin (TSH); thyroxine (T4);Other analytes are contemplated as well, including, but not limited to, thyroxine-binding globulin; trace elements; transferrin; UDP-galactose-4-epimerase; urea; uroporphyrinogen I synthase; vitamin A; white blood cells; and zinc protoporphyrin. Salts, sugars, proteins, fats, vitamins, and hormones naturally present in blood or interstitial fluids can also constitute analytes in certain embodiments. Analytes can be naturally present in biological fluids, e.g., metabolites, hormones, antigens, antibodies, and the like. Alternatively, analytes can be introduced into the body. For example, contrast agents for imaging, radioisotopes, chemical agents, fluorocarbon-based synthetic blood, or drugs or pharmaceutical compositions, including, but not limited to, insulin; ethanol; cannabis (marijuana, tetrahydrocannabinol, hashish); inhalants (nitrous oxide, amyl nitrite, butyl nitrite, chlorohydrocarbons, hydrocarbons); cocaine (crack cocaine); stimulants (amphetamine, methamphetamine, Ritalin, Silurt, Preludine, Didrex, Prestate, Boranil, Sandrex, Pregin); antidepressants (barbiturates, tranquilizers such as methaqualone, valium, librium, miltuna, serax, equanil, tranxine; hallucinogens (phencyclidine, lysergic acid, mescaline, peyote, psilocybin); narcotics (heroin, codeine, morphine, opium, meperidine, percocet, percodan, tasionex, fentanyl, darvon, talwin, lomotil); synthetic narcotics (fentanyl, meperidine, amphetamine, methamphetamine, and phencyclidine analogues, e.g., ecstasy); anabolic steroids;and nicotine. Metabolites of drugs and pharmaceutical compositions are also contemplated analytes. Analytes such as neurochemicals and other chemicals produced in the body, such as ascorbic acid, uric acid, dopamine, noradrenaline, 3-methoxytyramine (3MT), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5HT), 5-hydroxyindoleacetic acid (FHIAA), and histamine, may also be analyzed.

[0132] As used herein, the term "bioactive agent" is a broad term and is to be given its ordinary and accustomed meaning to those of skill in the art (and is not to be limited to any special or customized meaning), and refers to, but is not limited to, any substance that has an effect on or elicits a response from living tissue.

[0133] As used interchangeably herein, the phrases "biointerface membrane" and "biointerface layer" and "biointerface / drug-releasing membrane" and "biointerface / drug-releasing layer" are broad phrases that are to be given their ordinary and accustomed meaning to one of ordinary skill in the art (and are not to be limited to any special or customized meaning) and refer to, but are not limited to, a permeable membrane or layer that serves as an interface between a host tissue and an implantable device.

[0134] As used herein, the phrase "barrier cell layer" is a broad phrase that is to be given its ordinary and customary meaning to one of skill in the art (and is not to be limited to any special or customized meaning) and refers, without limitation, to the portion of the foreign body reaction that forms a coherent monolayer of cells (e.g., macrophages and foreign body giant cells) that substantially blocks the transport of molecules and other substances into the implantable device.

[0135] As used herein, the term "biostable" is a broad term that is to be given its ordinary and accustomed meaning to those of skill in the art (and is not to be limited to any special or customized meaning), and refers to, but is not limited to, materials that are relatively resistant to degradation by processes encountered in the living body.

[0136] As used herein, the term "bioresorbable" or "bioabsorbable" is a broad term that is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning) and refers to, but is not limited to, materials that can be absorbed or lose substances in a biological system.

[0137] As used herein, the phrase "cell process" is a broad phrase and is to be given its ordinary and customary meaning to one of skill in the art (and is not to be limited to any special or customized meaning), and refers to, but is not limited to, the pseudopodia of cells.

[0138] As used herein, the phrase "cell attachment" is a broad phrase and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning), and refers to, but is not limited to, the adhesion of cells and / or cell processes to a material at a molecular level and / or the attachment of cells and / or cell processes to a microporous or macroporous material surface. One example of a material used in the prior art that promotes cell attachment to a porous surface is the BIOPORE™ cell culture support marketed by Millipore (Bedford, MA) and described in U.S. Patent No. 5,741,330 to Brauker et al. As used herein, the term "coaxial" should be broadly interpreted to include sensor architectures having elements aligned along a shared axis around a core that can be configured to have a circular, elliptical, triangular, polygonal, or other cross-section, and such elements can include electrodes, insulating layers, or other elements that can be positioned circumferentially around a core layer, such as a core electrode or core polymer wire.

[0139] As used herein, the term "co-continuous" is a broad term that is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning) and refers to, but is not limited to, a solid portion or cavity that allows for a three-dimensional unbroken curve to be drawn between the two sides of the membrane.

[0140] As used herein, the phrase "continuous analyte sensing" is a broad phrase and is to be given its ordinary and customary meaning to one of skill in the art (and is not to be limited to any special or customized meaning) and refers to a period during which monitoring of analyte concentration is performed continuously, continuously, and / or intermittently (but periodically), e.g., for a period of time ranging from about 5 seconds or less to about 10 minutes or more, preferably about 10, 15, 20, 25, 30, 35, 40, 45, 5 This refers to, but is not limited to, 0, 55, or 60 seconds to about 1.25, 1.50, 1.75, 2.00, 2.25, 2.50, 2.75, 3.00, 3.25, 3.50, 3.75, 4.00, 4.25, 4.50, 4.75, 5.00, 5.25, 5.50, 5.75, 6.00, 6.25, 6.50, 6.75, 7.00, 7.25, 7.50, 7.75, 8.00, 8.25, 8.50, 8.75, 9.00, 9.25, 9.50, or 9.75 minutes. Further examples of continuous analyte sensors can be found, for example, in U.S. Pat. No. 8,828,201 to Simpson et al., U.S. Pat. No. 9,131,885 to Simpson et al., U.S. Pat. No. 9,237,864 to Simpson et al., and U.S. Pat. No. 9,763,608 to Simpson et al., each of which is incorporated by reference in its entirety herein.

[0141] As used herein, the term "coupled" may refer to two or more system elements or components that are configured to be at least one of electrically, mechanically, thermally, or otherwise attached.

[0142] As used herein, the term "removably coupled" may refer to two or more system elements or components that are configured or configured to be electrically, mechanically, thermally, or otherwise attached and detached without damaging any of the coupled elements or components. As used herein, the term "permanently coupled" may refer to two or more system elements or components that are configured or attached electrically, mechanically, thermally, operatively, chemically, or otherwise attached, but cannot be separated without damaging at least one of the coupled elements or components.

[0143] As used herein, the phrase "defined edge" is a broad phrase that is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning) and refers to, but is not limited to, an abrupt, distinct edge or boundary between layers, domains, coatings, or portions. A "defined edge" is in contrast to a gradual transition between layers, domains, coatings, or portions.

[0144] As used herein, the term "discontinuous" is a broad term and is to be given its ordinary and accustomed meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning), and refers to, but is not limited to, cut, interrupted, or separated portions, layers, coatings, or domains.

[0145] As used herein, the term "distal" is a broad term and is to be given its ordinary and accustomed meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning), and refers to, but is not limited to, an area that is spaced relatively far from a reference point such as an origin or attachment point.

[0146] As used herein, the term "domain" is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning) and refers to, but is not limited to, a region of a membrane system that can be a layer, multiple layers, uniform or non-uniform gradients (e.g., anisotropic regions of a membrane), or a portion of a membrane configured to perform one or more functions. The domains discussed herein can be formed as a single layer, as two or more layers, as a bilayer pair, or as combinations thereof.

[0147] As used herein, the term "drift" is a broad term and is given its ordinary and customary meaning to those skilled in the art (and is not limited to any special or customized meaning) and refers to, but is not limited to, a gradual increase or decrease in a signal over time that is unrelated to changes in host systemic analyte concentration, such as, for example, host postprandial glucose concentration. Without wishing to be bound by theory, it is believed that drift may be the result of a local decrease in glucose transport to the sensor, for example, due to cellular infiltration surrounding the sensor. It is also believed that an insufficient amount of interstitial fluid surrounds the sensor, which results in, for example, reduced oxygen and / or glucose transport to the sensor. An increase in local interstitial fluid may slow or reduce drift, thus improving sensor performance. Drift may also be the result of the sensor electronics or algorithmic models used to compensate for noise or other anomalies that may occur in picoamp range electrical signals.

[0148] As used interchangeably herein, the phrases "drug release membrane" and "drug release layer" are each broad terms and are given their ordinary and customary meaning to one of ordinary skill in the art (and are not limited to any special or customized meaning), including, but not limited to, a permeable or semi-permeable membrane that is permeable to one or more bioactive agents. In one embodiment, the "drug release membrane" and "drug release layer" may be composed of two or more domains and may be several microns or thicker. In one embodiment, the drug release layer and / or drug release membrane are substantially the same as the biointerface layer and / or biointerface membrane. Examples of drug release layers and membranes can be found in pending U.S. Patent Application Publication No. 2022-0296867, entitled "DRUG RELEASING MEMBRANE FOR ANALYTE SENSOR," filed March 17, 2022, which is incorporated by reference in its entirety, and pending U.S. Patent Application No. 17 / 945585, entitled "DRUG RELEASING MEMBRANE FOR ANALYTE SENSOR," filed March 17, 2022, which is incorporated by reference in its entirety.

[0149] As used herein, the term "electrochemically reactive surface" is a broad term and is given its ordinary and customary meaning to those skilled in the art (and is not limited to any special or customized meaning), and refers to, but is not limited to, the surface of an electrode on which an electrochemical reaction occurs. At the working electrode, hydrogen peroxide produced by an enzyme-catalyzed reaction of an analyte, whose reaction is to be detected, can create a measurable electronic current. For example, in the detection of glucose, glucose oxidase produces hydrogen peroxide (H2O2) as a by-product. H2O2 reacts with the surface of the working electrode to produce two protons (2H+), two electrons (2e-), and one oxygen molecule (O2), which creates the electronic current that is detected. At the counter electrode, a reducible species, e.g., O2, is reduced at the electrode surface to balance the current generated by the working electrode.

[0150] As used herein, the term "host" is a broad term and is to be given its ordinary and accustomed meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning), and refers to a mammal, preferably a human, but is not limited to such a mammal.

[0151] As used herein, the terms "interferent" and "interfering species" are broad terms and are to be given their ordinary and customary meaning to one of skill in the art (and are not to be limited to any special or customized meaning), and refer to, but are not limited to, effects and / or species that interfere with the measurement of an analyte of interest in a sensor, producing a signal that does not accurately represent the analyte measurement. In one example of an electrochemical sensor, an interfering species is a compound that has an oxidation potential that overlaps with the analyte being measured.

[0152] The term "in vivo" refers, without limitation, to the portion of the device (eg, a sensor) that is adapted for insertion into and / or presence within the body of a host.

[0153] The term "ex vivo" refers to a portion of a device (eg, a sensor) that is adapted to reside and / or exist outside the living body of a host.

[0154] As used herein, the phrase "membrane system" is a broad phrase and is to be given its ordinary and customary meaning to one of skill in the art (and is not to be limited to any special or customized meaning), and refers to, but is not limited to, a permeable or semi-permeable membrane that is permeable to one or more analytes, which may include two or more domains and may be formed from one or more materials to a thickness of several microns or more. In one example, the membrane is permeable to oxygen and, optionally, for example, to glucose or one or more other analytes. In one example, the membrane system includes an immobilized glucose oxidase enzyme that allows a reaction to occur between glucose and oxygen, thereby allowing glucose concentration to be measured.

[0155] As used herein, the term "noise" is a broad term and is used in its ordinary sense, including, but not limited to, signals detected by the sensor or sensor electronics that are independent of analyte concentration and may result in degradation of sensor performance. One type of noise is observed for several hours (e.g., about 2 to about 24 hours) after sensor insertion. After the first 24 hours, the noise may disappear or decrease, but in some hosts, the noise may persist for about 3 to 4 days. In some cases, the noise may be reduced using predictive modeling, artificial intelligence, and / or algorithmic means. In other cases, the noise may be reduced by addressing immune response factors associated with the presence of the implanted sensor, such as using a drug-releasing layer having at least one bioactive agent. For example, the noise of one or more exemplary biosensors as disclosed herein may be determined and then compared qualitatively or quantitatively. As an example, upon obtaining a raw signal time series at a fixed sampling interval (in pA), a smoothed version of the raw signal time series may be obtained, for example, by applying a third order low-pass digital Chebyshev type II filter. Other smoothing algorithms may also be used. At each sampling interval, the absolute difference in pA can be calculated to provide a smoothed time series. This smoothed time series can be converted to units of mg / dL (units of "noise") using the glucose sensitivity time series in units of pA / mg / dL, which is derived by optimizing a mathematical model between the raw signal and a reference blood glucose measurement (e.g., obtained from a blood glucose meter). Optionally, the time series can be aggregated, for example, by hour or day, as desired. Comparison of corresponding time series between different exemplary biosensors having a drug-releasing layer and one or more bioactive agents of the present disclosure provides a qualitative or quantitative determination of the noise improvement.

[0156] As used herein, the terms "non-bioresorbable" or "non-bioabsorbable" are broad terms and are to be given their ordinary and accustomed meaning to those of skill in the art (and are not to be limited to any special or customized meaning), and refer to, but are not limited to, materials that are not substantially absorbed or do not substantially lose substance in a biological system.

[0157] As used herein, the terms "non-zwitterionic dipole" and "non-zwitterionic dipolar compound" are broad terms and are to be given their ordinary and customary meaning to one of ordinary skill in the art (and are not to be limited to any special or customized meaning), and refer to, but are not limited to, compounds in which a neutral molecule of the compound has positive and negative charges at different locations within the molecule. The positive and negative charges within the molecule can be any charge that is not zero but is less than a full unit charge.

[0158] As used herein, the terms "operably connected" and "operably linked" are broad terms and are to be given their ordinary and customary meaning to one of ordinary skill in the art (and are not to be limited to any special or customized meaning), and refer to, but are not limited to, one or more components that are linked to another component in a manner that facilitates the transmission of a signal between the components. For example, one or more electrodes can be used to detect an analyte in a sample and convert that information into a signal, which can then be transmitted to an electronic circuit. In this example, the electrodes are "operably linked" to the electronic circuit.

[0159] The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances when the event or circumstance does and does not occur. As used herein, the term "planar" should be interpreted broadly to describe a sensor architecture having a substrate including a first side and a second side, and a plurality of elements disposed on one or more sides of the substrate, where the elements may or may not be electrically or otherwise coupled, and where the elements may include conductive or insulating layers or elements configured to operate as a circuit.

[0160] As used herein, the term "polyampholytic polymer" is a broad term and is given its ordinary and customary meaning to those skilled in the art (and is not limited to any special or customized meaning), and refers to, but is not limited to, a polymer that contains both cationic and anionic groups. Such polymers can be prepared to have an approximately equal number of positive and negative charges, and thus the surface of such polymers can be approximately net neutrally charged. Alternatively, such polymers can be prepared to have either an excess of positive or negative charges, and thus the surface of such polymers can be net positive or net negative, respectively.

[0161] As used herein, the term "polymerizable group" is a broad term and is given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to any special or customized meaning), and refers to, but is not limited to, a functional group that allows for the polymerization of a monomer with itself to form a homopolymer, or with a different monomer to form a copolymer. Depending on the type of polymerization method used, the polymerizable group may be selected from alkenes, alkynes, epoxides, lactones, amines, hydroxyls, isocyanates, carboxylic acids, anhydrides, silanes, halides, aldehydes, and carbodiimides.

[0162] As used herein, the term "polyzwitterion" is a broad term and is given its ordinary and customary meaning to those skilled in the art (and is not limited to any special or customized meaning), and refers to, but is not limited to, polymers in which the repeat units of the polymer chain are zwitterionic moieties. Polyzwitterions are also known as polybetaines. Polyzwitterions are a type of polyampholytic polymer because they have both cationic and anionic groups. However, they are unique because the cationic and anionic groups are both part of the same repeat unit, which means that polyzwitterions have the same number of cationic and anionic groups, whereas other polyampholytic polymers can have more of one ionic group than the other. Polyzwitterions also have cationic and anionic groups as part of the repeat unit. A polyampholytic polymer need not have cationic groups attached to anionic groups; they can be on different repeat units and thus distributed apart from one another at random intervals, or one ionic group can outnumber the other.

[0163] As used herein, the term "proximal" is a broad term and is given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to any special or customized meaning), and refers to, but is not limited to, the spatial relationship between various elements compared to a particular reference point. For example, some embodiments of the device include a membrane system having a biological interface layer and an enzyme layer. If the sensor is considered to be the reference point and the enzyme layer is positioned closer to the sensor than the biological interface layer, then the enzyme layer is more proximal to the sensor than the biological interface layer.

[0164] As used herein, the phrases and terms "processor module" and "microprocessor" are broad terms and are to be given their ordinary and customary meaning to one of ordinary skill in the art (and are not to be limited to any special or customized meaning) and refer to, but are not limited to, computer systems, state machines, processors, and the like designed to perform arithmetic or logical operations using logic circuitry that responds to and processes basic instructions that drive a computer. The use of a processor module or microprocessor can improve the functionality of an analyte sensor, a battery, a measurement circuit, a processor, a memory, or a combination thereof.

[0165] As used herein, the term "sensing membrane" is a broad term and is given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to any special or customized meaning), and refers to, but is not limited to, a permeable or semi-permeable membrane that may include one or more domains within a membrane system, is composed of a material having a thickness of several microns or more, and is permeable to reactants and / or co-reactants used in determining an analyte of interest. As an example, the sensing membrane may include immobilized glucose oxidase enzyme that catalyzes an electrochemical reaction with glucose and oxygen to allow for the measurement of glucose concentration. In some further examples, the sensing membrane may include an oxidase, a dehydrogenase, or a mixture thereof that can react with lactate.

[0166] As used herein, the term "invasive" is a broad term that is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning) and refers to, but is not limited to, a medical procedure that invades (enters) the body, usually by cutting or puncturing the skin or by inserting an instrument into the body.

[0167] As used herein, the term "minimally invasive" is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning) and refers to, but is not limited to, procedures that minimize incisions to reduce trauma to the body. This type of procedure may be performed, for example, using thin needles and endoscopes to visually guide the procedure.

[0168] As used herein, the term "non-invasive sensing techniques" is a broad term and is to be given its ordinary and customary meaning to one skilled in the art (and is not to be limited to any special or customized meaning) and refers to, but is not limited to, techniques for sensing internal conditions or analytes with minimal incision to reduce trauma to the body. Examples of such techniques can include optically stimulated fluorescence, microneedle dissection, and / or transdermal monitoring of glucose. As used herein, the term "polyelectrolyte" is a broad term and is to be given its ordinary and customary meaning to one skilled in the art (and is not to be limited to any special or customized meaning) and refers to, but is not limited to, polymers whose repeat units have electrolyte groups. For example, polycations and polyanions are polyelectrolytes. Polyelectrolytes dissociate in aqueous solution, causing the polymer to be charged. Thus, polyelectrolyte properties are similar to both electrolytes and polymers, and are sometimes referred to as polysalts.

[0169] As used herein, the term "semi-continuous" is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning) and refers to, but is not limited to, a portion, coating, domain, or layer that includes one or more continuous and discontinuous portions, coatings, domains, or layers. For example, a coating that is disposed around but not over a sensing area is "semi-continuous."

[0170] As used herein, the term "sensing membrane" is a broad term and is to be given its ordinary and customary meaning to one of skill in the art (and is not to be limited to any special or customized meaning), and refers to, but is not limited to, a permeable or semi-permeable membrane that may contain one or more domains, is composed of a material having a thickness of several microns or more, and is permeable to reactants and / or co-reactants used in determining an analyte of interest. As an example, the sensing membrane may include immobilized glucose oxidase enzyme that catalyzes an electrochemical reaction with glucose and oxygen to allow for the measurement of glucose concentration.

[0171] As used herein, the terms "signal medium" or "transmission medium" are broad terms and are to be given their ordinary and accustomed meaning to those skilled in the art (and are not limited to any special or customized meaning), and refer to forms of modulated data signals, carrier waves, and the like, without limitation.

[0172] As used herein, the term "modulated data signal" is a broad term given its ordinary and accustomed meaning to those skilled in the art (and is not limited to a special or customized meaning) and refers to a signal that has one or more of its characteristics set or changed in such a manner as to encode information in the signal.

[0173] The terms "machine-readable medium," "computer-readable medium," and "device-readable medium" mean the same thing and may be used interchangeably in this disclosure, and as used herein are broad terms that are to be given their ordinary and accustomed meaning to those of skill in the art (and are not limited to any special or customized meaning) and refer to both machine storage media and signal media, without limitation. Thus, the term includes both storage devices / media and carrier waves / modulated data signals.

[0174] As used herein, the term "electrical contact" is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning), and refers to, but is not limited to, materials that are in sufficient contact to allow an electromagnetic signal to propagate between the materials. In some embodiments, the electromagnetic signal may be an electric current. In other embodiments, the electromagnetic signal is an inductive signal or other wireless signal.

[0175] When an analyte sensor of a continuous monitoring system is exposed to one or more analytes, an electrochemical reaction between the analyte sensor and at least one analyte causes the analyte sensor to generate a raw sensor signal indicative of the analyte concentration. The raw sensor signal can be a current flowing between two or more electrodes of the analyte sensor. The analyte sensor can have a different number of electrodes. For example, a three-electrode analyte sensor can include a working electrode, a counter electrode, and a reference electrode. In the presence of one or more analytes, the electrochemical reaction causes a current to flow between the electrodes, and the raw sensor signal is or is based on the generated current. The current can flow primarily between the working electrode and the counter electrode, and the reference electrode provides a stable reference potential. In a two-electrode configuration, an exemplary analyte sensor includes a working electrode and a reference electrode. The reference electrode conducts current in the same way as the counter electrode in a three-electrode configuration and provides a stable reference potential in the same way as the reference electrode in a three-electrode configuration. Thus, the reference electrode in a two-electrode configuration may also be referred to as a counter reference electrode. Here, the term reference electrode may refer to a reference electrode in a three-electrode configuration, a counter-reference electrode in a two-electrode configuration, or a similar electrode in other configurations.

[0176] In use, the sensor electronics apply a bias condition between the working electrode and a reference (e.g., counter reference) electrode. The applied bias promotes an electrochemical reaction between the analyte and the analyte sensor, resulting in a current flow between the working electrode and the reference (e.g., counter reference) electrode. In one example, the current flow comprises all of the raw sensor signal. In another example, the raw sensor signal comprises the current flow in addition to one or more other components.

[0177] Measuring multiple analytes continuously can be beneficial in a variety of situations. For example, wearing multiple sensors can be cumbersome, or existing sensors may not be configured to detect two or more analytes simultaneously or alternately. Additionally, measuring the concentration of different analytes can involve two or more different electrochemical reactions, which can make using a single sensor difficult under some circumstances. In some examples, the concentration of a first analyte and a second analyte can be known, and this data is used in concert to predict adverse health events, deliver medication, or take other actions. However, in other examples, the concentration of one analyte can be known while the concentration of a second analyte can be unknown. Being able to measure the concentration of multiple analytes using the same sensor to perform continuous analyte monitoring addresses this concern. In one example, the multi-analyte monitoring system discussed herein facilitates the measurement of different analytes by varying the bias of the electrodes, providing an easy and quick device for analyte measurement. In some examples, the ability to measure oxygen concentration can be enhanced by including a solid electrolyte layer. In this example, the solid electrolyte layer can help minimize the risk of electrical shorts caused by redox reactions between the electrodes used to measure the oxygen concentration. In this manner, without being bound to any particular theory, it is believed that the solid electrolyte layer helps to suppress dendrite growth in the electrodes.

[0178] Analyte Sensor Environment FIG. 1 illustrates an example environment 100 including an analyte sensor system 102. The analyte sensor system 102 is coupled to a host 101, which may be a human patient. In some embodiments, the host 101 has a temporary or permanent diabetic condition or other health condition that makes analyte monitoring useful. In some embodiments, the host 101 is a diabetic patient. In some embodiments, the host 101 is a jogger, climber, etc., who is monitoring oxygen levels. In some embodiments, the host 101 is a pulmonary patient.

[0179] The analyte sensor system 102 includes an analyte sensor 104. In some examples, the analyte sensor 104 is or includes a glucose sensor configured to measure a glucose concentration in the host 101. In other examples, the analyte sensor is or includes an oxygen sensor configured to measure an oxygen concentration in the host 101. Also, in some examples, the analyte sensor 104 is a multi-analyte sensor capable of measuring concentrations of different analytes in the host 101, for example, under different bias conditions as described herein. In examples where the analyte sensor 104 is configured to measure glucose, the glucose detected can be D-glucose. However, in some example configurations, the analyte sensor 104 can detect any stereoisomer or blend of stereoisomers of glucose, as well as any glucose in open chain, cyclic, or mixtures thereof.

[0180] At least a portion of the analyte sensor 104 may be exposed to the analyte at the host 101 in any suitable manner. In some embodiments, the analyte sensor 104 may be fully implanted under the skin of the host 101. In other embodiments, the analyte sensor 104 may be worn on the body of the host 101 ex vivo (e.g., on the body but not under the skin). Also, in some embodiments, the analyte sensor 104 is a transcutaneous device (e.g., having a sensor that resides at least partially under or in the skin of the host). In the embodiment of FIG. 1, the analyte sensor system 102 also includes sensor electronics 106. In some embodiments, the sensor electronics 106 and the analyte sensor 104 are provided in a single integrated package. In other embodiments, the analyte sensor 104 and the sensor electronics 106 are provided as separate components or modules. For example, the analyte sensor system 102 may include a disposable (e.g., single-use) sensor attachment unit (FIG. 3) that may include an analyte sensor 104, components for attaching the analyte sensor 104 to a host (e.g., an adhesive pad), and / or an attachment structure configured to receive a sensor electronics unit that includes some or all of the sensor electronics 106 shown in FIG. 2. The sensor electronics unit may be reusable. The sensor electronics 106 may be programmed and / or configured to perform various operations as described herein. For example, the sensor electronics 106 may apply bias conditions to the analyte sensor 104, receive a raw sensor signal from the analyte sensor 104, convert the raw sensor signal to a corresponding analyte concentration, and / or the like.

[0181] The analyte sensor 104 may use any known method, including invasive, minimally invasive, or non-invasive sensing techniques (e.g., optically stimulated fluorescence, microneedle, transdermal monitoring of glucose) to provide a raw sensor signal indicative of the concentration of the analyte within the host 101. The raw sensor signal may be converted into calibrated and / or filtered analyte concentration data that is used to provide a useful value of the analyte concentration (e.g., an estimated blood glucose concentration level and / or an estimated dissolved oxygen concentration level) to a user, such as a host or caretaker (e.g., a parent, relative, guardian, teacher, doctor, nurse, or any other individual interested in the health status of the host 101).

[0182] In some examples, the analyte sensor 104 is or includes a continuous glucose monitoring sensor. In some other examples, the analyte sensor 104 is or includes a continuous oxygen concentration sensor. In some further examples, the analyte sensor 104 may be switched between a glucose sensing mode and an oxygen sensing mode. Depending on the example, the modes discussed herein may also be described as "configurations." The analyte sensor may be or include a subcutaneous, transcutaneous (e.g., transdermal), and / or intravascular device. In some aspects, such a sensor or device may repeatedly (e.g., periodically or intermittently) analyze sensor data. The analyte sensor 104 may use any glucose and / or oxygen measurement method, including enzymatic, chemical, physical, electrochemical, spectrophotometric, polarimetric, calorimetric, iontophoretic, radiometric, immunochemical, etc. In various embodiments, the analyte sensor system 102 may be or may include a continuous glucose monitor sensor available from DEXCOM® (e.g., a DEXCOM G5® sensor, a DEXCOM G6® sensor, a DEXCOM G7™ sensor, and / or variations thereof). In some further embodiments, the analyte sensor 104 may be configured to detect lactate.

[0183] The environment 100 may also include a second medical device 108. The second medical device 108 may be or may include a drug delivery device, such as an insulin pump or an insulin pen. In some examples, the second medical device 108 includes one or more sensors, such as another analyte sensor, a heart rate sensor, a respiration sensor, a motion sensor (e.g., an accelerometer), a posture sensor (e.g., a three-axis accelerometer), an acoustic sensor (e.g., to capture ambient or internal sounds), etc. The second medical device 108 may be, for example, wearable on a watch, glasses, contact lenses, a patch, a wristband, an ankle band, or another wearable item, or may be incorporated into a handheld device (e.g., a smartphone). In some examples, the medical device 108 includes a multi-sensor patch that can detect, for example, one or more of an analyte level (e.g., glucose, lactate, ketones, uric acid, creatinine, glycerol, insulin, or other substances), heart rate, respiration (e.g., using impedance), activity (e.g., using an accelerometer), posture (e.g., using an accelerometer), galvanic skin response, tissue fluid levels (e.g., using impedance or pressure).

[0184] In some examples, the analyte sensor system 102 and the second medical device 108 are in communication with each other, i.e., the analyte sensor system 102 and the second medical device 108 are communicatively coupled to enable bidirectional communication. Communication between the analyte sensor system 102 and the second medical device 108 may occur via any suitable wired connection and / or via wireless communication signals 110. For example, the analyte sensor system 102 may be configured to communicate via radio frequency (e.g., Bluetooth, Medical Implant Communication System (MICS), Wi-Fi, near field communication (NFC), radio frequency identification (RFID), Zigbee, Z-Wave, or other communication protocols), optical (e.g., infrared), acoustic (e.g., ultrasound), or cellular protocols (e.g., Code Division Multiple Access (CDMA) or Global System for Mobiles (GSM)), or a wired connection (e.g., serial, parallel, etc.).

[0185] In some examples, the environment 100 also includes a wearable sensor 130. The wearable sensor 130 may include a sensor circuit (e.g., a sensor circuit configured to detect a glucose concentration or other analyte concentration) and a communication circuit, which may be, for example, an NFC circuit. In some examples, information from the wearable sensor 130 may be retrieved from the wearable sensor 130 using a user computing device 132, such as a smartphone, configured to communicate with the wearable sensor 130 via the communication circuit of the wearable sensor when the user computing device 132 is placed near the wearable sensor 130. For example, swiping the user computing device 132 over the sensor 130 may retrieve sensor data from the wearable sensor 130 using NFC or other suitable wireless communication. Using NFC communication may reduce power consumption by the wearable sensor 130 and may reduce the size of a power source (e.g., a battery or capacitor) in the wearable sensor 130 or may extend the usable life of the power source. In some examples, the wearable sensor 130 may be wearable on the upper arm, as shown. In some examples, the wearable sensor 130 may additionally or alternatively be on the patient's upper torso (e.g., over the heart or over the lungs), which may facilitate detection of, for example, heart rate, respiration, or posture. The wearable sensor 136 may also be on the lower body (e.g., the leg).

[0186] In some examples, an array or network of sensors may be associated with the patient. For example, one or more of the analyte sensor system 102, the medical device 108, the wearable device 120, such as a wristwatch, and the additional wearable sensor 130 may communicate with each other via wired or wireless (e.g., Bluetooth, MICS, NFC, or any of the other options described above) communication. The additional wearable sensor 130 may be any of the examples described above with respect to the medical device 108. The analyte sensor system 102, the medical device 108, and the additional wearable sensor 130 on the host 101 are provided for purposes of illustration and description and are not necessarily drawn to scale.

[0187] The environment 100 may also include one or more computing devices, such as a handheld smart device (e.g., smart device) 112, a tablet 114, a smart pen 116 (e.g., an insulin delivery pen with processing and communication capabilities), a computer 118, a wearable device 120 such as a wristwatch, or a peripheral medical device 122 (which may be a proprietary device such as a proprietary user device available from DexCom), any of which may communicate with the analyte sensor system 102 via wireless communication signals 110 and may also communicate with a server system (e.g., a remote data center) or remote terminal 128 over a network 124 to facilitate communication with a remote user (not shown), such as a technical support staff member or a clinician.

[0188] The wearable device 120 may include an activity sensor, a heart rate monitor (e.g., an optical or electrode-based sensor), a respiration sensor (e.g., an acoustic or electrode-based sensor), a location sensor (e.g., GPS), or other sensors.

[0189] In some examples, environment 100 includes a server system 126. Server system 126 may include one or more computing devices, such as one or more server computing devices. In some examples, server system 126 is used to collect analyte data from analyte sensor system 102 and / or analyte or other data from multiple other devices, perform analysis on the collected data, generate or apply one or more universal or individualized models for glucose levels, and communicate such analysis, models, or information based thereon back to one or more of the devices in environment 100. In some examples, server system 126 collects inter-host and / or intra-host break-in data and generates one or more break-in characteristics, as described herein.

[0190] The environment 100 may also include a wireless access point (WAP) 138 that is used to communicatively couple one or more of the analyte sensor system 102, the network 124, the server system 126, the medical device 108, or any of the peripheral devices mentioned above. For example, the WAP 138 may provide Wi-Fi and / or cellular connectivity within the environment 100. Other communication protocols, such as NFC or Bluetooth, may also be used between devices of the environment 100.

[0191] Analyte Sensor System FIG. 2 illustrates an example of a medical device system 200 including the analyte sensor system 102 of FIG. 1. In the example of FIG. 2, the analyte sensor system 102 includes a sensor electronics 106 and a sensor mounting unit 290. Although specific examples of the division of components between the sensor mounting unit 290 and the sensor electronics 106 are shown, it is understood that in some examples, the sensor mounting unit 290 or the sensor electronics 106 may include additional components, and some of the components shown in the sensor electronics 106 (e.g., a battery or a supercapacitor) may alternatively or additionally (e.g., redundantly) be provided in the sensor mounting unit 290. Also, in some examples, the analyte sensor system 102 may be an integrated system in which the analyte sensor 104 is integrated with the sensor electronics 106. In some examples of the integrated analyte sensor system 102, the sensor mounting unit 290 is omitted and the analyte sensor 104 is mounted on the same substrate or other unit as the sensor electronics 106.

[0192] 2, the sensor mounting unit 290 includes the analyte sensor 104 and a battery 292. In some embodiments, the sensor mounting unit 290 may be replaceable and the sensor electronics 106 may include debounce circuitry (e.g., a gate with hysteresis or delay) to, for example, avoid repeated power-up or power-down processes when repeatedly connected and disconnected, or to avoid processing noisy signals associated with removing or replacing a battery.

[0193] The sensor electronics 106 may also include a control circuit 204. The control circuit 204 is configured to control various operations in the analyte sensor system 102. For example, the control circuit 204 may be configured to control the application of a bias potential and / or other bias conditions to the analyte sensor 104 via a potentiostat or other suitable components of the measurement circuit 202, interpret a raw sensor signal from the analyte sensor 104, and / or compensate for environmental factors. The control circuit 204 may also store information in or retrieve information from the data storage memory 210. In various embodiments, the data storage memory 210 may be integrated with the memory 208 or may be a separate memory circuit, such as a non-volatile memory circuit (e.g., flash RAM). Examples of systems and methods for processing sensor analyte data are described in more detail herein and in U.S. Pat. Nos. 7,310,544 and 6,931,327.

[0194] The control circuitry 204 may include suitable hardware for controlling the operation of the analyte sensor system 102 as described herein. In some embodiments, the control circuitry 204 includes one or more processors. The one or more processors may be configured to retrieve the instructions 206 from the memory 208 and execute the instructions 206 to control the operation of the analyte sensor system 102 as described herein. In some embodiments, the control circuitry 204 includes logic gates for implementing a state machine or other suitable processing hardware.

[0195] The sensor electronics 106 may also include a sensor 212, which may be coupled to the control circuitry 204. The sensor 212 may be any suitable sensor, such as, for example, a temperature sensor, an accelerometer, a position sensor, a blood pressure sensor, a heart rate sensor, a respiration sensor, or another suitable sensor. Although one sensor 212 is shown in FIG. 2, some embodiments may include multiple sensors in the sensor electronics 106, such as, for example, a temperature sensor and an accelerometer, multiple temperature sensors, and / or the like.

[0196] The sensor electronics 106 may also include a power source, such as a capacitor or battery 214, which may be integrated into the sensor electronics 106, may be removable, or may be part of a separate electronics unit. The battery 214 (or other power storage component, e.g., a capacitor) may optionally be rechargeable via a wired or wireless (e.g., inductive or ultrasonic) recharging system 216. The recharging system 216 may harvest energy or receive energy from an external or on-board source. In various examples, the recharging circuitry may include a circuit that harvests energy from a triboelectric charging circuit, a piezoelectric charging circuit, an RF charging circuit, an optical charging circuit, an ultrasonic charging circuit, a thermal charging circuit, a thermal collection circuit, or a communication circuit. In some examples, the recharging circuitry may recharge a rechargeable battery using power provided from a replaceable battery (e.g., a battery provided with the base component).

[0197] The sensor electronics 106 may also include one or more supercapacitors in the sensor electronics unit (shown) or in the sensor mounting unit 290. For example, the supercapacitor may allow for energy to be drawn from the battery 214 in a very consistent manner to extend the life of the battery 214. The battery 214 may recharge the supercapacitor after it has provided energy to the communication or control circuitry 204, so that the supercapacitor is ready to provide energy during a subsequent period of high load. In some embodiments, the supercapacitor may be configured in parallel with the battery 214. The device may be configured to draw energy from the supercapacitor as opposed to the battery 214. In some embodiments, the supercapacitor may be configured to receive energy from a rechargeable battery for short-term storage and transfer energy to the rechargeable battery for long-term storage.

[0198] The sensor electronics 106 may also include wireless communication circuitry 218, which may include, for example, a wireless transceiver operably coupled to an antenna. The wireless communication circuitry 218 may be operably coupled to the control circuitry 204 and may be configured to wirelessly communicate with one or more peripheral devices or other medical devices, such as an insulin pump or a smart insulin pen. The wireless communication circuitry 218 may be configured to communicate according to any suitable wireless protocol or technique, including, for example, via radio frequency, optical, acoustic, etc.

[0199] 2, medical device system 200 also includes an optional peripheral device 250. Peripheral device 250 may be any suitable user computing device, such as, for example, a wearable device (e.g., an activity monitor), such as wearable device 120. In other examples, peripheral device 250 may be a handheld smart device (e.g., a smartphone or other device, such as a proprietary handheld device available from Dexcom), tablet 114, smart pen 116, or computer 118, as shown in FIG.

[0200] Peripheral device 250 may include a UI 252, a memory circuit 254, a processor 256, a wireless communication circuit 258, a sensor 260, or any combination thereof. Peripheral device 250 does not necessarily include all of the components shown in Figure 2. Peripheral device 250 may also include a power source, such as a battery.

[0201] The UI 252 may be provided, for example, using any suitable input / output device of the peripheral device 250, such as a touch screen interface, a microphone (e.g., for receiving voice commands), or a speaker, a vibration circuit, or any combination thereof. The UI 252 may receive information (e.g., instructions, glucose values) from a host or another user. The UI 252 may also deliver information to the host or other user, for example, by displaying UI elements on the UI 252. For example, the UI elements may show glucose and / or other analyte concentration values, glucose or other analyte trends, glucose or other analyte alerts, etc. Trends may be shown by UI elements such as arrows, graphs, charts, etc.

[0202] The processor 256 may be configured to present information to or receive input from the host 101 or other users via the UI 252. The processor 256 may also be configured to store and retrieve information in the memory circuit 254, such as communication information (e.g., pairing information or data center access information), user information, sensor data, or trends. The wireless communication circuit 258 may include a transceiver and antenna configured to communicate via a wireless protocol, such as any of the wireless protocols described herein. The sensors 260 may include, for example, an accelerometer, a temperature sensor, a position sensor, a biosensor, or a blood glucose sensor, a blood pressure sensor, a heart rate sensor, a respiration sensor, or other physiological sensor.

[0203] The peripheral devices 250 may be configured to receive and display sensor information that may be transmitted by the sensor electronics 106 (e.g., in a customized data package transmitted to a display device based on respective preferences). The sensor information (e.g., blood glucose concentration level) or alerts or notifications (e.g., “high glucose level”, “low glucose level”, or “decline rate alert”) may be communicated via the UI 252 (e.g., via a visual display, sound, or vibration). In some examples, the peripheral devices 250 may be configured to display or otherwise communicate the sensor information communicated from the sensor electronics 106 (e.g., in a data package transmitted to a respective display device). For example, the peripheral devices 250 may transmit processed data (e.g., an estimated analyte concentration value that may be determined by processing raw sensor data), such that a device receiving the data may not need to further process the data to determine usable information (such as an estimated analyte concentration value). In other examples, the peripheral devices 250 may process or interpret the received information (e.g., to issue an alert based on a glucose value or glucose trend). In various embodiments, the peripheral device 250 may receive information directly from the sensor electronics 106 or over a network (e.g., via a cellular or Wi-Fi network that receives information from the sensor electronics 106 or from a device that is communicatively coupled to the sensor electronics 106).

[0204] 2, medical device system 200 includes an optional medical device 270. For example, optional medical device 270 may be used in addition to or in place of peripheral device 250. Medical device 270 may be or include any suitable type of medical or other computing device, including, for example, medical device 108, peripheral medical device 122, wearable device 120, wearable sensor 130, or wearable sensor 136 shown in FIG. 1. Medical device 270 may include a UI 272, a memory circuit 274, a processor 276, a wireless communication circuit 278, a sensor 280, a therapy circuit 282, or any combination thereof.

[0205] Like UI 252, UI 272 may be provided using any suitable input / output device of medical device 270, such as a touch screen interface, a microphone or speaker, a vibration circuit, or any combination thereof. UI 272 may receive information from a host or another user (e.g., glucose values, alert settings, calibration codings). UI 272 may also deliver information to the host or other user, such as by displaying UI elements on UI 252. For example, UI elements may show glucose or oxygen or other analyte concentration values, glucose or other analyte trends, glucose or other analyte alerts, etc. Trends may be shown by UI elements such as arrows, graphs, charts, etc.

[0206] The processor 276 may be configured to present information to or receive input from a user via the UI 272. The processor 276 may also be configured to store and retrieve information, such as communication information (e.g., pairing information or data center access information), user information, sensor data, or trends, in the memory circuit 274. The wireless communication circuit 278 may include a transceiver and antenna configured to communicate via a wireless protocol, such as any of the wireless protocols described herein.

[0207] The sensor 280 may include, for example, an accelerometer, a temperature sensor, a position sensor, a biosensor, or a blood glucose sensor, a blood pressure sensor, a heart rate sensor, a respiration sensor, or other physiological sensor. The medical device 270 may include more than one sensor (or memory or other components), although only one sensor 280 is shown in the example of FIG. 2. In various examples, the medical device 270 may be a smart handheld glucose sensor (e.g., a blood glucose meter), a drug pump (e.g., an insulin pump), or other physiological sensor device, a therapy device, or a combination thereof.

[0208] In examples where the medical device 270 is or includes an insulin pump, the pump and the analyte sensor system 102 may communicate bidirectionally (e.g., the pump may request a change in the analyte transmission protocol, e.g., request data points or request data on a more frequent schedule), or the pump and the analyte sensor system 102 may communicate using one-way communication (e.g., the pump may receive analyte concentration level information from the analyte sensor system). In one-way communication, the glucose value may be incorporated into the advertisement message and encrypted with a pre-shared key. In two-way communication, the pump may request values ​​that the analyte sensor system 102 may share in response to a request from the pump, or may obtain and share, and any or all of these communications may be encrypted using one or more pre-shared keys. The insulin pump may receive and track analyte (e.g., glucose) values ​​transmitted from the analyte sensor system 102 using one-way communication to the pump for one or more of a variety of reasons. For example, the insulin pump may suspend or activate insulin administration based on glucose values ​​below or above a threshold.

[0209] In some examples, the medical device system 200 includes two or more peripheral devices and / or medical devices, each of which receives information directly or indirectly from the analyte sensor system 102. Because different display devices have different user interfaces, the content of the data package (e.g., the amount, format, and / or type of data displayed, alarms, etc.) may be customized (e.g., programmed differently by the manufacturer and / or end user) for each particular device. For example, referring now to the example of FIG. 1, multiple different peripheral devices may wirelessly communicate directly with the sensor electronics 106 (e.g., on-skin sensor electronics 106 physically connected to the continuous analyte sensor 104, etc.) during a sensor session, may enable multiple different types and / or levels of display and / or functionality associated with the displayable sensor information, or may conserve battery power of the sensor system 102, and one or more designated devices may communicate with the analyte sensor system 102 and relay (i.e., share) information to other devices, either directly or via a server system (e.g., a networked data center) 126.

[0210] Continuous analyte sensor FIG. 3 illustrates an embodiment of a transcutaneous sensing system including one or more sensors 334 that may be implanted in a host. The mounting unit 314 may be adhered to the skin of the host using an adhesive pad 308. The adhesive pad 308 may be formed from a stretchable material that may be removably attached to the skin using an adhesive. The electronics unit 318 may be mechanically coupled to the mounting unit 314. In some embodiments, the electronics unit 318 and the mounting unit 314 are arranged in a manner similar to the sensor electronics 106 and the sensor mounting unit 290 shown in FIGS. 1 and 2. The analyte sensor 334 may be formed as a coaxial sensor as shown in FIGS. 4A-4J. In other embodiments, the analyte sensor 334 may be formed as a planar sensor with conductive elements on one or both sides in various configurations.

[0211] At least the layers discussed in Figures 4A-4G may be formed via one or more pasting / dipping / coating operations, for example, using a die metered dip coating process. In other examples, electroplating may be used to form some layers and pasting, dipping, or other coating operations may be used to form other layers during an iterative process. Examples of methods of forming the sensors and sensor systems discussed herein may be found in currently pending U.S. patent application Ser. No. 16 / 452,364 to Boock et al., which is incorporated by reference in its entirety.

[0212] 4A-4C illustrate one embodiment of a continuous analyte sensor 334 (e.g., an in vivo portion) that includes an elongated conductive body 402. The elongated conductive body 402 includes a core 410 (see FIG. 4B) and a first layer 412 that at least partially surrounds the core. The first layer 412 includes a working electrode (e.g., located within a window 406) and a membrane 408 located over the working electrode that is configured and arranged for multi-axis bending. In some embodiments, the core 410 and the first layer 412 can be a single material (e.g., platinum). In some embodiments, the elongated conductive body 402 is a composite of at least two materials, such as a composite of two conductive materials or a composite of at least one conductive material and at least one non-conductive material. In some embodiments, the elongated conductive body 402 includes multiple layers. In certain embodiments, there are at least two concentric (e.g., annular) layers, such as a core 410 formed from a first material and a first layer 412 formed from a second material. However, in some embodiments, additional layers can be included. In some embodiments, the layers are coaxial.

[0213] Although the elongated conductive body 402 is illustrated in FIGS. 4A-4C as having a circular cross section, in other embodiments, the cross section of the elongated conductive body can be oval, rectangular, triangular, polyhedral, star-shaped, C-shaped, T-shaped, X-shaped, Y-shaped, irregular, etc. In one embodiment, a conductive wire electrode is used as the core. To such a coated electrode, two additional conductive layers can be added (e.g., with an intervening insulating layer providing for electrical isolation). The conductive layers may be made of any suitable material. In certain embodiments, it may be desirable to use a conductive layer that includes conductive particles (e.g., particles of a conductive material) in a polymer or other binder.

[0214] 4A-4C, in some embodiments, the first layer 412 is formed from an electrically conductive material. The working electrode 438 is an exposed portion of a surface of the first layer. Thus, the first layer is formed from a material configured to provide a suitable electroactive surface for the working electrode.

[0215] As shown in Figures 4B and 4C, the second layer 404 surrounds at least a portion of the first layer 412, thereby defining the boundaries of the working electrode. In some embodiments, the second layer 404 serves as an insulator and is formed from an insulating material, such as polyimide, polyurethane, parylene, or any other known insulating material. For example, in one embodiment, the second layer is disposed on the first layer and configured such that the working electrode is exposed through a window 406. In another embodiment, an elongated conductive body is provided that includes a core, a first layer, and a second layer, and the working electrode is exposed (e.g., formed) by removing a portion of the second layer, thereby forming a window 406 through which the electroactive surface of the working electrode (e.g., the exposed surface of the first layer) is exposed. In some embodiments, the working electrode is exposed (e.g., window 406 is formed) by removing a portion of the second layer and (optionally) a third layer. Removal of coating material from one or more layers of the elongated conductive body (e.g., to expose the electroactive surface of the working electrode) may be performed by hand, by excimer laser, chemical etching, laser ablation, grit blasting, or the like.

[0216] In some aspects, the sensor further includes a third layer 414 that includes a conductive material. In further aspects, the third layer may include a reference electrode, which may be formed from a silver-containing material applied over the second layer (e.g., an insulator). The silver-containing material may include any of a variety of materials and may be in a variety of forms, such as, for example, commercially available silver / silver chloride (Ag / AgCl)-polymer paste, paint, polymer-based conductive mixture, and / or ink. The third layer may be processed using a paste / dip / coating step, for example, using a die-metered dip coating process. In one aspect, the Ag / AgCl polymer paste is applied to the elongated body by dip coating the elongated body (e.g., using a meniscus coating technique) and then drawing the body through a die to regulate the coating to a precise thickness. In some aspects, multiple coating steps are used to build up the coating to a predetermined thickness. Such a drawing method may be utilized to form one or more of the electrodes in the device depicted in FIG. 4B.

[0217] In some embodiments, the Ag / AgCl particles are mixed into a polymer, such as polyurethane, polyimide, etc., to form a silver-containing material for the reference electrode. In some embodiments, the third layer is cured, for example, by using an oven or other curing process. In some embodiments, a coating of a fluid-permeable polymer having conductive particles (e.g., carbon particles) therein is applied over the reference electrode and / or the third layer. A layer of insulating material is, in some embodiments, disposed over a portion of the silver-containing material.

[0218] Such reference electrodes wear out over time as the silver ions of the silver chloride are converted to metallic silver. As the silver ions are depleted, the reference electrode capacitance decreases and the stability of the reference electrode is reduced, resulting in a decrease in the linearity of the analyte sensitivity. By changing this polarity of the bias potential on the reference electrode while in the oxygen sensing mode, the reference electrode can be regenerated by reversing the conversion of silver ions to metallic silver. In this way, the metallic silver is oxidized to silver ions to advantageously regenerate the capacitance of the reference electrode during the oxygen sensing mode.

[0219] As shown in Figures 4C and 4D, the sensor also includes a membrane 408 that covers at least a portion of the working electrode.

[0220] FIG. 4B is an illustration showing layers that have been cut away, but in a manufacturing process, material typically obtained has all layers terminating at a tip. A step of removing layers 404 and 414 may be performed to form a window. FIG. 4D illustrates the result of this removal / cutting process in a side / cross-sectional view. In such manufacturing methods with continuous strands, the sensor may be singulated after the removal step. In some aspects, if the core is metal, an end cap of insulating or other isolating material may be used on the tip, e.g., by dipping, spraying, shrink tubing, crimp wrapping, etc. If the core is polymeric (e.g., a hydrophobic material), an end cap may not be necessary. For example, in the sensor depicted in FIG. 4D, an end cap (e.g., of a polymer or insulating material) or other structure may be provided over the core (e.g., if the core 410 is not insulating). FIG. 4E may be considered to build on the general structure as depicted in FIG. 4B, in that two or more additional layers are added to create one or more additional electrodes. Also, methods of selectively removing two or more windows to form two or more electrodes may be used. For example, by adding another conductive layer 417 and an insulating layer 419 under the reference electrode layer 414, two electrodes (e.g., a first and a second working electrode) may be formed, resulting in a dual-electrode sensor. A dual electrolyte sensor may be configured in which each working electrode detects a signal from a different analyte. In other examples, the operations discussed herein may be used to form, for example, a counter electrode, or an electrode for measuring an additional analyte (e.g., oxygen), etc. FIG. 4F illustrates a sensor with an additional conductive layer 417 (compare with FIGS. 4B-4D), where the window has been selectively removed to expose the working electrode 412 and conductive layer 417 between the reference electrode (including multiple segments) 414, with a small amount of insulator 404, 419 exposed in between. FIG. 4G illustrates another embodiment in which selective removal of various layers is performed in a stepwise manner to expose the electrode 412 and conductive layer 417 as well as the insulators 404, 419 along the length of the elongate body.

[0221] The buckling strength of the analyte sensor 334 can be in the range of about 0.010 lbf to about 0.10 lbf, or about 0.02 lbf to about 0.06 lbf, or less than, equal to, or greater than about 0.01, 0.02, 0.03, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, or 0.10 lbf.

[0222] FIG. 4H illustrates an embodiment of the sensor of FIG. 4A on line BB, showing the exposed electroactive surface of at least the working electrode 438 (also referred to as the first layer 412) surrounded by the sensing member 430 (also referred to as the third layer 114). Generally, the sensing member 430 of the present disclosure includes multiple domains, each having one or more layers, such as an interference domain 444, an enzyme domain 446, and a resistance domain 448. In some embodiments, the sensing member 430 may include additional domains, such as a reference electrode domain 445, a cell impermeable domain (not shown), an optional oxygen domain (not shown), an optional drug releasing membrane 470, and / or an optional biointerface membrane (not shown). A reference electrode may be part of the sensing member 430. However, it is understood that sensing members 430 modified for other sensors, for example, by including various combinations of types and constituent domains, are within the scope of the present disclosure.

[0223] In some embodiments, one or more domains of the sensing membrane are formed from materials such as silicone, polytetrafluoroethylene, ethylene tetrafluoroethylene copolymers, polyolefins, polyesters, polycarbonates, biostable polytetrafluoroethylene, homopolymers, copolymers, terpolymers of polyurethane, polypropylene (PP), polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polybutylene terephthalate (PBT), polymethylmethacrylate (PMMA), polyether ether ketone (PEEK), polyurethanes, cellulosic polymers, poly(ethylene oxide), poly(propylene oxide), and copolymers and blends thereof, polysulfones, and block polymers thereof, including, for example, diblock, triblock, alternating, random, and graft copolymers.

[0224] The sensing member 430 may be deposited on the electroactive surface of the electrode material using known thin or thick film techniques (e.g., spraying, electrodeposition, dipping, roll-to-roll processing, other in-line processing, etc.). Note that the sensing member 430 surrounding the working electrode 438 need not be of the same structure as the sensing member 430 surrounding the reference electrode, etc. For example, the enzyme domain deposited over the working electrode 438 may be deposited such that it is deposited over the working electrode but not over the reference and / or counter electrodes.

[0225] In the illustrated embodiment, the sensor including the sensing member 430 is an enzyme-based electrochemical sensor. In this embodiment, the working electrode 438 measures products (including but not limited to hydrogen peroxide) produced by the enzyme-catalyzed reaction of glucose. The detected products generate a measurable electronic current. As an example, in detecting glucose, glucose oxidase produces hydrogen peroxide (H2O2) as a by-product. The produced H2O2 reacts with the surface of the working electrode 438 to release two protons (2H + ), 2 electrons (2e - ), and one oxygen molecule (O2), which produces an electronic current that is detected, as described in more detail above and as will be understood by one of skill in the art. In some embodiments, one or more potentiostats are used to monitor the electrochemical reaction at the electroactive surface of the working electrode. The potentiostat applies a constant potential to the working electrode 438 and its associated reference electrode to determine the current produced at the working electrode 438. The current produced at the working electrode 438 (and flows through the circuit to the counter electrode) is substantially proportional to the amount of H2O2 that diffuses to the working electrode 438. The output signal may include, for example, a raw data stream that is used to provide a useful value of the measured analyte concentration in the host to the host or a third party (e.g., a medical professional or guardian, etc.).

[0226] In addition to the reactions described herein above for detecting glucose concentration, the sensors described herein can detect oxygen concentration. According to some embodiments, measuring the oxygen concentration involves two first order reactions that occur at the working electrode. O2+4H + +4e - →2H2O- called "oxygen current" H2O2+2H + +2e - →2H2O- called "H2O2 reduction current" The two reactions above are balanced by a reaction occurring at the reference electrode. Ag+Cl - →e - +AgCl In short, "total reduction current" = "oxygen current" + "H2O2 reduction current". To determine how much of the "total reduction current" is "oxygen current" and how much is "H2O2 reduction current", an equivalence can be established: "H2O2 reduction current" = "H2O2 oxidation current". "Oxygen current" can be calculated as follows: Oxygen current = total reduction current - H2O2 oxidation current The resulting "oxygen current" has a linear relationship with the bulk oxygen concentration when oxygen reduction is under oxygen mass transport control. Once the value of the "oxygen current" is calculated, the current value may be converted to an oxygen concentration value. As described further herein, detection of glucose or oxygen concentration may be driven by selectively applying a potential difference (alternatively referred to as a voltage) between the electrodes. In one example, a positive potential difference drives a reaction to detect glucose concentration and a negative potential difference (e.g., of opposite polarity) drives a reaction to detect oxygen concentration.

[0227] 14A-14F illustrate the linear relationship between oxygen current versus oxygen concentration at different glucose concentrations and days. For example, FIG. 14A shows the relationship between oxygen current versus glucose concentration of 150 mg / dL on days 2-4. FIG. 14B shows the relationship between oxygen current versus glucose concentration of 250 mg / dL on days 4-6. FIG. 14C shows the relationship between oxygen current versus glucose concentration of 350 mg / dL on days 6-8. FIG. 14D shows the relationship between oxygen current versus glucose concentration of 40 mg / dL on days 8-10. FIG. 14E shows the relationship between oxygen current versus glucose concentration of 150 mg / dL on days 10-12. FIG. 14F shows the relationship between oxygen current versus glucose concentration of 250 mg / dL on days 12-14. In FIG. 14A-14F, the current from the reduction reaction is presented as a negative current, and all currents due to the oxidation reaction are presented as a positive current.

[0228] 4I illustrates an embodiment of the sensor of FIG. 4A on line CC showing the non-exposed electroactive surface of at least the working electrode 438 surrounded by the sensing member 430 including multiple domains or layers, e.g., interference domain 444, enzyme domain 446, and resistance domain 448. In other embodiments, the sensing member 420 can include one or more additional domains / membranes, such as an electrode domain, a cell impermeable domain (not shown), an oxygen domain (not shown), a drug releasing membrane 470, and / or a biointerface membrane (not shown), as described in more detail below. As shown in FIG. 4C, the drug releasing membrane 470 is positioned adjacent to the working electrode 438 surface and does not cover the working electrode 438 or multiple domains or layers of the sensing membrane 430, e.g., interference domain 444, enzyme domain 446, and resistance domain 448. In one embodiment, the drug releasing membrane 470 is positioned at the distal end 437 of the sensor 434.

[0229] 4J shows the exposed electroactive surface of at least the working electrode 438 surrounded by a sensing membrane. Similar to the circular sensor shown in FIG. 4B, planar versions can include a sensing membrane with multiple layers or domains. For example, planar versions can include an interference domain 444, an enzyme domain 446, and a resistance domain 448 in addition to other variations of domains, such as a drug-releasing membrane 470 as discussed above.

[0230] In some embodiments, the sensor may be configured for transcutaneous or short-term subcutaneous implantation and may have a thickness of about 0.5 μm to about 8 μm, sometimes about 4 μm to about 6 μm. In one sensor configured for fluid communication with the host's circulatory system, the thickness may be about 1.5 μm to about 25 μm, sometimes about 3 to about 15 μm. In some embodiments, the biointerface / drug-release layer or any other layer of the electrode may have a consistent thickness, while in other embodiments, it is contemplated that the thickness may vary horizontally and / or vertically relative to the sensing area. For example, in some embodiments, the presence and / or thickness of the biointerface / drug-release layer may vary along the longitudinal axis of the electrode end.

[0231] 5 illustrates an example of a sensor system 500 arranged to selectively transition between a first configuration for measuring a first analyte and a second configuration for measuring a second analyte. The sensor system 500 may be arranged similarly to various sensor systems described herein, such as, for example, the analyte sensor system 102. The sensor system 500 comprises an analyte sensor 504 and a control circuit 502. The control circuit 502 may comprise a processor or other circuit components for controlling the analyte sensor 504. The control circuit 502 may also comprise a bias circuit for generating a bias signal provided to the analyte sensor 504 according to one or more bias conditions.

[0232] The analyte sensor 504 may include electrodes 506, 508 and optional electrode 512. The analyte sensor 504 may be configured similarly to various other analyte sensors described herein, such as, for example, those including a solid electrolyte layer as described further herein. In a three-electrode configuration, the control circuit 502 may provide a bias condition to the analyte sensor 504 by providing a potential difference between the working electrode 506 and the reference electrode 512. Providing the bias condition to the analyte sensor 504 may encourage an electrochemical reaction that results in a current between the working electrode 506 and the counter electrode 508. In a two-electrode configuration (e.g., when the reference electrode 512 is omitted), the control circuit 502 may provide a bias condition by providing a potential difference between the working electrode and the counter electrode 508, which may act as a reference-counter electrode as described herein. The bias condition may encourage an electrochemical reaction that results in a current between the working electrode 506 and the reference-counter electrode 508.

[0233] In some examples, the control circuitry 502 is configured to selectively vary bias conditions provided to the analyte sensor 504 to cause the analyte sensor 504 to generate sensor signals (e.g., currents) indicative of concentrations of different analytes. For example, under a first bias condition, the analyte sensor 504 generates a sensor signal indicative of a concentration of a first analyte. Under a second bias condition, the analyte sensor 504 generates a sensor signal indicative of a concentration of a second analyte different from the first analyte. In some examples, the first bias condition is a positive potential and the working electrode 506 is driven to a higher potential than the reference electrode (which may be the reference-counter electrode 508 in a two-electrode configuration or the reference electrode 512 in a three-electrode configuration). The first bias condition may be used to detect a first analyte (e.g., glucose) and the second bias condition may be used to detect a second analyte (e.g., oxygen).

[0234] As referred to herein, the analyte sensor 334 can selectively measure the concentration of oxygen or glucose in the interstitial fluid. The ability to alternate between an oxygen measurement mode (for sensing the oxygen concentration in the interstitial fluid) and a glucose measurement mode (for sensing the glucose concentration in the interstitial fluid) is a result of the bias conditions applied to the working electrode 438 relative to a reference electrode (e.g., reference electrode 512). In one embodiment, when the system 500 is configured in a glucose measurement mode, the working electrode 438 of the sensing member 430 and the reference electrode are biased to a potential difference of less than, equal to, or greater than about 0.20 V to about 0.90 V, about 0.50 V to about 0.70 V, about 0.55 V to about 0.65 V relative to the reference electrode, about 0.20 V, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, or about 0.90 V relative to the reference electrode. In the oxygen measurement mode, the working electrode 438 is biased at a voltage less than, equal to, or greater than about -0.90 V to about -0.05 V, about -0.30 V to about -0.20 V, about -0.25 V to about -0.23 V relative to the reference electrode, about -0.90 V, -0.85, -0.80, -0.75, -0.70, -0.65, -0.60, -0.55, -0.50, -0.45, -0.40, -0.35, -0.30, -0.25, -0.20, -0.15, -0.10, or -0.05 V relative to the reference electrode.

[0235] The analyte sensor 334 may be configured to switch between the glucose and oxygen sensing modes using a sensor control circuit that executes a respective algorithm for each mode to transition from the glucose measurement mode to the oxygen sensing mode or from the oxygen sensing mode to the glucose sensing mode to achieve the relative bias described above. The analyte sensor 334 may be configured to alternate between the glucose and oxygen measurement modes according to a predetermined schedule, or a user may manually alternate between the glucose and oxygen measurement modes. The analyte sensor 334 may be configured to be in each of the glucose and oxygen measurement modes for equal or unequal amounts of time.

[0236] In some examples, one cycle in which the analyte sensor 334 alternates between the glucose measurement mode and the oxygen measurement mode can last for a time in the range of 60 minutes to 180 minutes, 100 minutes to 140 minutes, or for a time less than, equal to, or greater than 60 minutes, 65 minutes, 70 minutes, 75 minutes, 80 minutes, 85 minutes, 90 minutes, 95 minutes, 100 minutes, 105 minutes, 110 minutes, 115 minutes, 120 minutes, 125 minutes, 130 minutes, 135 minutes, 140 minutes, 145 minutes, 150 minutes, 155 minutes, 160 minutes, 165 minutes, 170 minutes, 175 minutes, or 180 minutes. As an illustrative example, if the cycle lasts for a total of 120 minutes, the glucose measurement mode can last for 117 minutes and the oxygen sensing mode can last for 3 minutes. Minimizing the amount of time the analyte sensor 334 is in the oxygen measurement mode helps ensure that the same local conditions (glucose and oxygen concentrations) near the analyte sensor 334 are compared to the conditions in the glucose sensing mode immediately before switching to the oxygen sensor mode.

[0237] In various embodiments, each of the working electrode 438 and the reference electrode can include many different materials. In one embodiment, the working electrode 438 includes platinum and tantalum, and the reference electrode includes silver and silver chloride. In this embodiment, the analyte sensor 334 can be used to selectively measure oxygen and glucose levels in the interstitial tissue. In some further embodiments, the working electrode 438 can include platinum, palladium, rhodium, iridium, tantalum, or mixtures thereof.

[0238] FIG. 6 illustrates an example of a process flow 600 that may be performed in the sensor system 500 of FIG. 5. In operation 602, the control circuit 502 applies a first bias condition to the analyte sensor 504. In some examples, applying the first bias condition to the analyte sensor 504 includes applying a potential between a working electrode and a reference electrode. In operation 604, a sensor signal is accessed from the analyte sensor 504 under the first bias condition applied in operation 602. In operation 608, a concentration of the first analyte is determined using the sensor signal. In operation 610, a second bias condition is applied to the analyte sensor 504. In operation 612, a sensor signal is accessed from the analyte sensor 504 under the second bias condition. In operation 614, a concentration of the second analyte is determined using the signal accessed from the second bias condition applied in operation 610.

[0239] FIG. 7 illustrates an example of a process flow 700 that may be performed in the sensor system 500 of FIG. 5. In operation 702, the control circuitry 502 accesses an indication of the analytes to be measured. The indication of the analytes to be measured may be accessed in any suitable manner. In some examples, a host or other user provides the indication of the analytes using one or more computing devices in communication with the sensor system 500, such as, for example, a smart device, tablet, smart pen, computer, wearable device, peripheral medical device, and / or the like. In other examples, the indication of the analytes to be measured may be generated by the control circuitry 502. For example, the control circuitry 502 may measure the first and second analytes periodically according to a determined schedule. The control circuitry 502 may generate the indication of the analytes based on which analyte should be measured at a given time.

[0240] Also, in some examples, the control circuitry 502 may generate an indication of the analyte being measured in response to the condition at the analyte sensor 504. Consider an example in which the analyte sensor 504 is configurable to measure glucose and oxygen. In this example, excessive oxygen concentration at the analyte sensor 504 while the analyte sensor 504 is configured to measure glucose may degrade the sensor signal generated by the analyte sensor 504. For example, silver ions may migrate to platinum and destroy the ability for current to flow between the electrodes. In this example, the control circuitry 502 may determine whether the sensor signal has degraded while the analyte sensor 504 is configured to measure glucose. If the sensor signal has degraded, the control circuitry 502 may reconfigure the analyte sensor 504 to measure oxygen. The resulting determination of oxygen concentration may be used to diagnose a degraded signal observed during glucose measurement.

[0241] At operation 704, the control circuitry 502 determines whether the accessed indication refers to a first analyte or a second analyte. If the accessed indication refers to a first analyte, the control circuitry 502 applies a first bias condition to the analyte sensor 504 at operation 706. If the accessed indication refers to a second analyte, the control circuitry 502 applies a second bias condition to the analyte sensor 504 at operation 708. The first bias condition may configure the analyte sensor 504 to generate a sensor signal indicative of a concentration of the first analyte, and the second bias condition may configure the analyte sensor 504 to generate a sensor signal indicative of a concentration of the second analyte. In an example where the first analyte is glucose, for example, the first bias condition may include applying a positive potential difference between the working electrode 506 and the reference-counter electrode and / or the reference electrode. In an embodiment where the second analyte is oxygen, for example, the second bias condition may include applying a negative potential difference between the working electrode 506 and the reference-counter electrode and / or the reference electrode. In operation 710, the control circuit 502 may access a sensor signal generated while the analyte sensor 504 is under the first bias condition or the second bias condition. In operation 712, the control circuit 502 utilizes the sensor signal to determine the concentration of the selected analyte, for example, as described herein.

[0242] In some embodiments, the process may include a third bias condition because, in certain embodiments, for example, when switching from a glucose measurement mode to an oxygen measurement mode and back to a glucose measurement mode, it may take time for the sensor to reach electrochemical equilibrium when returning to the glucose measurement mode. If electrochemical equilibrium is not reached quickly, the accuracy of the sensor may be affected.

[0243] FIG. 15 is a flow chart illustrating one embodiment of a process 1500 for biasing an analyte sensor. In operation 1502, the control circuit 502 may apply a first bias condition to the analyte sensor, for example, between the working electrode 438 and the reference electrode 414. The first bias condition has a first polarity and a first magnitude. In operation 1504, the control circuit 502 may access a first signal generated by the sensor in vivo while the first bias condition is applied to the sensor. The first signal may be indicative of a concentration of the first analyte in the host. In operation 1506, the control circuit 502 may apply a second bias condition to the analyte sensor, for example, between the working electrode and the reference electrode. The second bias condition has a second polarity and a second magnitude, the second polarity being opposite to the first polarity. In operation 1508, the control circuit 502 may access a second signal generated by the sensor in vivo while the second bias condition is applied to the sensor. The second signal may be indicative of a concentration of a second analyte in the host. The second analyte may be oxygen where the first analyte is glucose or lactate. In operation 1510, the control circuit 502 may apply a third bias condition to the analyte sensor, for example, between the working electrode 438 and the reference electrode 414. The third bias condition has a third polarity and a third magnitude. The third polarity may be equal to the first polarity of the first bias condition. The third magnitude may be greater than the first magnitude of the first bias condition.

[0244] In some embodiments, the first polarity is positive from the working electrode 438 to the reference electrode 414. The second polarity is negative from the working electrode to the reference electrode. As an example, the magnitude of the first bias condition can be in the range of about 0.5V to about 0.7V, the magnitude of the second bias condition can be in the range of about -0.3V to about -0.2V, and the magnitude of the third bias condition can be in the range of about 0.7V to about 1.2V.

[0245] The third bias condition may be applied for a shorter amount of time than the time each of the first and second bias conditions are applied. The relatively short duration of the third bias condition aids in achieving the aforementioned electrochemical equilibrium. The second bias condition may be applied for a time ranging from about 3 times to about 9 times greater, or from 5 times to 7 times greater, than the third bias condition. As non-limiting examples, the second bias condition may be applied for a time ranging from about 1 minute to about 10 minutes, or from 2 minutes to 4 minutes, while the third bias condition is applied for a time ranging from about 10 seconds to about 60 seconds, or from about 15 seconds to about 45 seconds. Any data acquired during the first, second, and / or third bias conditions may be transmitted by a transmitter capable of transmitting data acquired during the first bias condition, the second bias condition, the third bias condition, or a combination thereof, to the device.

[0246] FIG. 16 is a chart 1600 illustrating an example bias signal that may be provided to an analyte sensor, for example, according to process flow 1500. Chart 1600 includes a horizontal axis indicating time and a vertical axis indicating the magnitude of the bias condition. In the example of FIG. 16, the magnitude of the bias condition is measured in volts. During a first period 1616, a first bias condition 1602 having a first magnitude 1610 is applied to the analyte sensor. During a second period 1618, a second bias condition 1604 having a second magnitude 1612 is applied to the analyte sensor. During a third period 1620, a third bias condition having a third magnitude 1614 is applied to the analyte sensor. As illustrated in the embodiment of FIG. 16, the first magnitude 1610 of the first bias condition 1602 is positive and the second magnitude 1612 of the second bias condition 1604 is negative, such that the polarities of the first bias condition 1602 and the second bias condition 1604 are opposite. Also illustrated in the embodiment of FIG. 16, the third magnitude 1614 of the third bias condition 1608 is greater than the first magnitude 1610 of the first bias condition. The first magnitude 1610 and the third magnitude 1614 are both positive and therefore have the same polarity. In some embodiments, the bias condition configurations described in FIG. 16 and FIG. 17 may be provided in a periodic manner. For example, referring to FIG. 16, the first bias condition 1602 may be applied again after expiration of the period 1620. The first bias condition 1602 may be applied again for a time equal to the time of the period 1616, after which the second bias condition 1604 may be applied, followed by the third bias condition 1608, and so on.

[0247] FIG. 8 illustrates an example of a process flow 800 that may be performed in the sensor system 500 of FIG. 5. In operation 802, the control circuitry 502 applies a bias. An indication of the analytes to be measured may be accessed in any suitable manner. In some examples, a host or other user provides an indication of the analytes using one or more computing devices in communication with the sensor system 500, such as, for example, a smart device, tablet, smart pen, computer, wearable device, peripheral medical device, and / or the like. In other examples, the indication of the analytes to be measured may be generated by the control circuitry 502. For example, the control circuitry 502 may measure the first and second analytes periodically according to a determined schedule. The control circuitry 502 may generate an indication of the analytes based on which analyte should be measured at a given time.

[0248] In operation 804, the control circuit 502 accesses a first signal under a first bias condition. In operation 806, the control circuit 502 determines an analyte concentration using the accessed signal. In operation 808, the control circuit 502 may determine whether to analyze a second analyte. This may occur automatically or by user input.

[0249] If a second analyte is to be analyzed, a second bias condition may be applied by the control circuitry in operation 810. A signal generated from applying the second bias is accessed in operation 812, and the concentration of the analyte is determined in operation 814. Operations 810, 812, and 814 are accessed in a similar manner as operations 802, 804, and 806.

[0250] The structure of the analyte sensor 334 may be modified to enhance its ability to measure oxygen concentrations in interstitial tissue. This may be accomplished by physically separating the working electrode 438 and the reference electrode. This may be further accomplished by at least partially covering the working electrode 438, the reference electrode, or both with a solid electrolyte layer. FIGS. 9A-9C are illustrations showing various embodiments of the analyte sensor 334 including the modifications described above to enhance the ability of the analyte sensor 334 to measure oxygen concentrations in interstitial tissue. The analyte sensor 334 shown in FIGS. 9A-9C may be formed as a planar sensor having one or more electrodes configured along a central axis shared with the sensor substrate. In different embodiments, the analyte sensor 334 may include a variety of cross-sectional geometries, including circular, elliptical, polygonal, or other extrusion or deposition (e.g., chemical vapor deposition, physical vapor deposition, etc.) cross-sectional geometries.

[0251] 9A illustrates an example of an analyte sensor 900A. The exemplary analyte sensor 900A includes a working electrode 902, an interference domain 904, and a reference electrode 906. The working electrode 902 is partially covered by the interference domain 904. The working electrode can include any of the materials described herein above with respect to the working electrode 438. The interference domain 904 can include polymeric materials such as silicone, polytetrafluoroethylene, ethylene tetrafluoroethylene copolymers, polyolefins, polyesters, polycarbonates, biostable polytetrafluoroethylene, homopolymers, copolymers, terpolymers of polyurethane, polypropylene (PP), polyvinyl chloride (PVC), polyvinylidene fluoride (PVDF), polybutylene terephthalate (PBT), polymethyl methacrylate (PMMA), polyether ether ketone (PEEK), polyurethane, cellulosic polymers, poly(ethylene oxide), poly(propylene oxide), and copolymers and blends thereof, polysulfones, and block copolymers thereof, including, for example, diblock, triblock, alternating, random, and graft copolymers, and the like. The reference electrode 906 can include any material capable of performing an oxidation reaction to complement the reduction reaction at the working electrode 902. For example, the reference electrode 906 can include silver and silver chloride.

[0252] In the depicted embodiment, at least a portion of the working electrode 902 and the reference electrode 906 are covered with a solid electrolyte layer 908. In one embodiment, the solid electrolyte layer 908 includes a polyelectrolyte. A polyelectrolyte refers to a polymer whose repeating units have electrolyte groups. For example, polycations and polyanions are polyelectrolytes. Polyelectrolytes dissociate in aqueous solution, causing the polymer to be charged. Thus, polyelectrolytes properties are similar for both electrolytes and polymers, and are sometimes referred to as polysalts. Examples of polyelectrolytes suitable for use in the solid electrolyte layer 908 are polyacrylic acid, polyethyleneimine, carboxymethylcellulose, polyphosphates, mixtures thereof, and copolymers thereof. Specific examples of repeating units that may be included in the polyelectrolyte include acrylamide repeating units, and acrylate repeating units include tetrafluoroethylene-perfluoro-3,6-dioxa-4-methyl-7-octenesulfonic acid copolymers (also classified under the trade name NAFION).

[0253] The solid electrolyte layer 908 can be an electrical contact with physiological tissue to complete a circuit between the working electrode 902 and the reference electrode 900 by allowing the passage of ionic current. Additionally, the solid electrolyte layer 908 can be permeable to oxygen in gaseous form. The inclusion of the solid electrolyte layer 908 can also enable the analyte sensor 900A to include a gas-permeable diffusion layer 910 over the working electrode 902. The gas-permeable diffusion layer 910 can function to exclude all solvated interfering species and biomolecules. The gas-permeable diffusion layer 910 can be tunable to achieve a range of permeabilities in some embodiments and can be fabricated from other polymeric materials for incorporation of drug release or oxidase enzyme systems.

[0254] The oxidase enzyme system can be present in the enzyme layer 912. The enzyme layer can be an optional component, but when present, the enzyme layer 912 can include an oxidase. Oxidase refers to an enzyme that catalyzes an oxidation-reduction reaction. Examples of oxidases include cytochrome c oxidase, glucose oxidase, monoamine oxidase, cytochrome P450 oxidase, NADPH oxidase, xanthine oxidase, L-gulonolactone oxidase, laccase, lysyl oxidase, polyphenol oxidase, and sulfhydryl oxidase. If the analyte sensor 800A is being used to measure glucose, the enzyme layer 912 can include glucose oxidase.

[0255] 9B and 9C illustrate examples of alternative configurations of analyte sensors. For example, FIG. 9B shows analyte sensor 900B. Analyte sensor 900B includes many of the same components as analyte sensor 900A. However, analyte sensor 900B additionally includes a resistive layer 914. Resistive layer 914 can at least partially cover diffusion layer 910.

[0256] The resistive layer 914 includes a semi-permeable membrane that controls the flux of oxygen and glucose to the underlying enzyme layer 912, making the oxygen non-rate-limiting excess. As a result, the upper linearity limit of glucose measurement is extended to values ​​much higher than would be achieved without the resistive domain. In some embodiments, the resistive layer 914 exhibits an oxygen to glucose permeability ratio of about 50:1 or less to about 400:1 or more, or about 200:1. As a result, one-dimensional reactant diffusion is sufficient to provide an excess of oxygen at all reasonable glucose and oxygen concentrations found in the subcutaneous matrix.

[0257] In some embodiments, the resistive layer 914 includes a polyurethane membrane having both hydrophilic and hydrophobic regions. The combination of hydrophobic and hydrophilic regions can be configured to control the diffusion of glucose and oxygen to the enzyme layer 912. Examples of suitable hydrophobic polymer components include polyurethanes and polyether urethane ureas.

[0258] When the resistive layer 914 comprises a polyurethane, the flux of oxygen, glucose, or both therethrough can be further controlled by adding a crystallization-retarding co-chain extender component to the polyurethane. An example of a crystallization-retarding co-chain extender component is 2-methyl-1,3-propanediol, which allows the polyurethane composition to be dissolved in common solvents and dip-coated for use in biosensor membrane applications. The co-chain extender component disposed in the thermoplastic polyurethane composition can allow for tuning of the degree of phase separation and crystallization of the hard segment domains, the morphology, and therefore the analyte permeability (e.g., O2 permeability / diffusivity reduction) of the thermoplastic polyurethane copolymer in biosensor membrane applications.

[0259] Thermoplastic polyurethanes are generally prepared by reacting a) at least one hydroxyl-terminated intermediate polyol component, such as a hydroxyl-terminated polyester, polyether, polycarbonate, polycaprolactone, or polysiloxane, in combination with b) a polyisocyanate component, c) a primary chain extender component, d) a crystallization-retarding co-chain extender component, and optionally a catalyst.

[0260] Thermoplastic polyurethanes include polyols, which include, but are not limited to, hydroxyl-terminated polyesters, hydroxyl-terminated polyethers, hydroxyl-terminated polycarbonates, hydroxyl-terminated polycaprolactones, hydroxyl-terminated polyolefins, and hydroxyl-terminated polysiloxanes.

[0261] Polyurethanes are derived from isocyanates. Diisocyanates are preferred to form large linear polyurethane chains. The diisocyanates can be aromatic, cycloaliphatic, aliphatic, or combinations thereof having 2 to 20 carbon atoms. Examples include, but are not limited to, diphenylmethane-4,4' diisocyanate (MDI); toluene-2,4-diisocyanate (TDI); toluene-2,6-diisocyanate (TDI); methylene bis(4-cyclohexyl isocyanate (H12MDI); 3-isocyanatomethyl-3,5,5-trimethyl-cyclohexyl isocyanate (IPDI); 1,6-hexane diisocyanate (HDI); naphthalene-1,5 diisocyanate (NDI); 1,3- and 1,4-phenylene diisocyanate; xylene diisocyanate (XDI); 1,4-cyclohexyl diisocyanate (CHDI); 1,4-bis(isocyanatomethyl)cyclohexane (1,4-H6XDI) 3,3'-dimethyl-4,4'-biphenyl diisocyanate (TODI); and isomers and mixtures or combinations thereof.

[0262] Chain extenders used in the polyurethane formulations described herein. They also participate in the formation of crystalline hard block domains and the resulting hard segment domain phase separation, resulting in thermoplastic polyurethanes with desirable mechanical properties. Suitable chain extenders are unbranched, unsubstituted, straight chain symmetric alkanediols containing no heteroatoms, having a total of about 2 to about 6 carbon atoms. Examples include 1,2-ethanediol, 1,6-hexanediol, 1,3-propanediol, 1,5-propanediol, and preferably 1,4-butanediol. The chain extender is present in the mixture to form the polyurethane in a range of from about 0.5 wt % to about 20 wt %, from about 5 wt % to about 15 wt %, less than, equal to, or greater than about 0.5 wt %, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, or about 20 wt %.

[0263] Crystallization-retarding co-chain extenders are generally sterically hindered such that hard segment domain crystal formation is interrupted or delayed, allowing for improved solvent solubility and more copolymer hard and soft segment phase intermixing.

[0264] The crystallization retarding component is a short chain or monomeric diol that is branched, substituted, and / or contains a heteroatom (atom other than carbon). Crystallization retarding components include, but are not limited to, dipropylene glycol, tripropylene glycol, diethylene glycol, triethylene glycol, cis-trans isomers of cyclohexyldimethylol, neopentyl glycol, and substituted alkanediols such as 2-methyl-1,3-propanediol, 3-methyl-1,5-pentanediol, 1,3-butanediol, and 2-methyl-2,4-pentanediol. Any branched or substituted alkanediol having from about 2 to about 12 carbon atoms in the backbone may be utilized. See Figures 4-6 for the chemical structures of selected chain extenders.

[0265] FIG. 9C illustrates an example of an analyte sensor 900C that includes a second enzyme layer 916. The analyte sensor 900C includes many of the same components as the analyte sensors 900A and 900B, and additionally includes a second enzyme layer 916. The second enzyme layer 916 may be at least partially covered with a resistive layer 914. The second enzyme layer may include any of the enzymes described herein above with respect to the enzyme layer 912. In some examples, the second enzyme layer 916 may function to catalyze a reaction in which the analyte of interest reacts to form a product that can further react when in contact with the enzyme layer 912. This may increase the accuracy of the analyte sensor 900C. Alternatively, the second enzyme layer 916 may function to catalyze a reaction of an interferent to a product that is not catalyzed when in contact with the enzyme layer 912, causing a false signal to be generated by the analyte sensor 900C.

[0266] Any of the continuous analyte sensors discussed herein, including analyte sensors 900A-C, may be calibrated in vitro. Calibration is discussed with reference to FIG. 11, which illustrates an example of a calibration process 1101. Calibration may include exposing any of the analyte sensors 900A-C to a first known analyte concentration in operation 1102. For example, a portion of any of the analyte sensors 900A-C may be exposed to a liquid solution in which an analyte of interest has been dissolved. For example, the liquid solution may have a known dissolved oxygen content or a known dissolved glucose content. Following the exposure, a first sensor signal is accessed as it is generated by any of the analyte sensors 900A-C in operation 1104. Thereafter, any of the analyte sensors 900A-C is exposed to a second known analyte concentration, which may be the same or different from the first known analyte concentration, in operation 1108. Similar to the first known analyte concentration, the second known analyte concentration can have a known dissolved oxygen content or a known dissolved glucose content. Following the exposing, a second sensor signal is accessed as it is generated by any of the analyte sensors 900A-C in operation 1110. This process may be repeated any number of times to generate any number of signals.

[0267] After all signals have been accessed, calibration parameters are determined in operation 1113. The calibration parameters may include a linear relationship between the amount of signal produced by the analyte sensors 900A-C and the analyte concentration. The calibration parameters may include sensitivity, which describes the analyte concentration per unit of sensor signal. In some aspects, the calibration may be defined by solving for the equation y=mx+b, where the value of b represents the baseline of the signal. In certain embodiments, the value of b (i.e., the baseline) may be zero or about zero. This may be the result of, for example, a baseline subtraction electrode or a low bias potential setting. As a result, for these aspects, the calibration may be defined by solving for the equation y=mx. Once the calibration parameters are determined, any of the sensors 900A-C may be deployed in vivo. Upon deployment, at least a third sensor signal is accessed. The concentration of the analyte of interest is then determined using the calibration parameters.

[0268] The analyte sensors 334, 900A, 900B, and 900C are depicted as having a coaxial structure relative to the working electrode 438 or 902 and the reference electrode 906, as well as other components. As mentioned herein, components such as the working electrode 438 or 902, the reference electrode 906, and other components, including the core on which one or more electrodes are positioned, can be planar. The planar structure can generally conform to a planar square profile, a planar triangular profile, a planar rectangular profile, or any higher order planar polygonal profile.

[0269] Planar structures are shown in Figures 10A-10G. Planar analyte sensors can be easily manufactured and produce reproducible results. Planar analyte sensors can be configured to monitor, including continuously monitor, at least one analyte, and in some examples, two or more analytes. Planar analyte sensors can be configured differently and described based on the geometry of their electrode layout. Sensor types can include single-sided or double-sided layouts. In single-sided layouts, the electrodes can be conductive traces and can be in a coplanar, stacked, or staggered configuration. In double-sided layouts, the electrodes can be in a coplanar, stacked, or staggered configuration, as well as a configuration with connector pads on one side of the sensor, or a configuration with connector pads on both sides of the sensor.

[0270] 10A-10G illustrate a single-sided coplanar analyte sensor assembly 1000 in an embodiment. The sensor assembly can have a first end 1012 and a second end 1014. The sensor assembly 1000 can include a substrate 1010, conductive traces 1021, connector pads 1022, a working electrode 1024, a counter electrode 1026, an insulator 1030, and a reference electrode 1040. In the sensor assembly 1000, a single-sided planar configuration is used. In the sensor assembly 1000, a three-electrode sensor is shown having a working electrode (WE) 1024, a counter electrode (CE) 1026, and a reference electrode (RE) 1040. In the sensor assembly 1000, the electrodes are on the same plane.

[0271] 10A-10D depict top schematic views of the sensor assembly 1000 being produced. 10E-10G depict cross-sectional schematic views of the sensor assembly 1000 at various points along the length of the sensor assembly 1000.

[0272] The sensor assembly 1000 extends between a first end 1012 and a second end 1014 and can be substantially planar along its length. The first end 1012 can be a connection end, such as to allow electrical connection of the sensor assembly 1000 to a reader, computer, or other component for interpreting signals detected by the sensor assembly 1000. The first end 1012 can house one or more connection pads 1022.

[0273] The second end 1014 can be a sensing end for connection to or implantation into a patient, such as for detecting glucose or other analytes. The second end 1014 can house the electrodes 1024, 1026, and 1040. The second end 1014 can be an implantable portion of the sensor assembly 1000. The first end 1012 of the sensor having the connector pads 1022 can be a proximal end of the sensor assembly 1000. The second end 1014 having the implantable portion of the sensor including the sensing electrodes can be a distal end of the sensor assembly 1000.

[0274] As shown in FIG. 10A, the substrate 1010 can extend between a first end 1012 and a second end 1014. The substrate 1010 can be a relatively flat material, for example, the substrate 1010 can be a thin flexible layer for housing other components. In some cases, the substrate 1010 can be a polymer film, such as a liquid crystal polymer (LCP), polyimide (PI), polyethylene terephthalate (PET), combinations thereof, or similar polymer films. The substrate 1010 can have a thickness of about 25 to about 450 μm, such as a thickness of about 75 to 100 μm. In some embodiments, a substrate thickness of about 40 μm to about 80 μm can be used.

[0275] The conductive traces 1021, connector pads 1022, working electrodes 1024, and counter electrodes 1026 may be made from a conductive layer constructed on a substrate. The connector pads 1022 may be located on or at the first end 1012 of the assembly 1000 and allow for electrical connection of the sensor assembly 1000. The working electrodes 1024 and counter electrodes 1026 may be sensing electrodes exposed at the second end 1014 of the assembly 1000 for implantation and sensing of an analyte in a patient environment. The conductive traces 1021 may connect the electrodes 1024, 1026 to the connector pads 1022.

[0276] As shown in FIG. 4B, a conductive layer may be constructed on the substrate 1010 with the conductive traces 1021, connector pads 1022, working electrode 1024, and counter electrode 1026 in a single plane or layer. The conductive layer may be made of sputtered metal, such as a titanium / gold / platinum or platinum / gold / platinum sputtered metal layer. In this case, the associated sensing surface, such as the working electrode 1024, may have platinum exposed for electrical connection and sensing. The reference electrode 1040 may be deposited on the base metal pad and connected via an additional conductive trace.

[0277] In some examples, the conductive layer is formed from a single conductor, such as gold or platinum. In other examples, the conductive layer may be formed from two or more materials, such as a thin palladium layer covered with gold and platinum. The composition, geometry, and exposed conductor surface may depend on the manufacturing method, the desired mechanical properties, and the requirements of the sensing chemistry. For example, the base conductive material may be formed from a cheaper material, such as silver, which is covered with platinum in strategic locations for the active sensing surface. In some cases, gold may be plated as the base conductor, which may be covered with platinum to provide both mechanical robustness and an active sensing surface for sensing hydrogen peroxide.

[0278] The conductive layer, including the working electrode 1024, counter electrode 1026, connector pad 1022, and conductive traces 1021, may be formed by a variety of techniques, such as plating, sputtering, or printing. Standard photolithography techniques, laser ablation, or printing (e.g., inkjet or screen printing) may be used to form the patterned structures of the conductive layer.

[0279] While specific electrode designations are shown in the supporting documentation, it should be understood that size, shape, and electrode identity may vary depending on the specific use case, such as the specific analyte to be determined. The typical size and shape of the sensor is 3-4 mm wide at the proximal end (connector end) and 300-500 μm wide at the narrow implantable distal end. The overall length of the sensor is generally 15-25 mm, depending on the requirements of the mounting / insertion tool.

[0280] As shown in FIG. 10C, an insulator 1030 may be laminated over the conductive layer if desired. The insulating material may be referred to as a "solder mask," "dielectric," or "insulator." These materials may be used to protect the conductive traces from exposure to the sample matrix and environment, as well as to improve the accuracy and reliability of the measurement by defining the sensing electrode area. An opening 1031 may be created for later deposition of a reference electrode 1040.

[0281] Here, the insulator 1030 may be made of an electrically insulating material deposited on top of the conductive layer to protect the conductive traces 1021 and to define openings for the connector pads 1022 and the electrodes 1024, 1026, as well as an opening 1031 for the reference electrode 1040. The insulator 1030 may be, for example, a thin layer of solder mask.

[0282] As shown in FIG. 10D, the reference electrode 1040 material may be deposited over a designated reference electrode opening in the insulator 1030. The reference electrode 1040 material may be, for example, a silver / silver chloride blend. It may be deposited over a designated sensing electrode pad. This reference electrode material may be deposited by a printing technique, such as screen printing, or by separate dispensing, such as with a jet valve dispenser.

[0283] 10E-10G depict cross sections of the assembly 1000 at various points along the body of the assembly. FIG. 10E shows a cross section at line EE of FIG. 10D at a central portion of the assembly 1000. In this portion of the assembly 1000, the conductive trace 1021 can be seen between the insulator 1030 and the substrate 1010. FIG. 10F shows a cross section at line FF of FIG. 10D near the second end 1014 of the assembly 1000. In this portion of the assembly 1000, the reference electrode 1040 can be seen on top of the conductive trace 1021. FIG. 10G depicts a cross section of the assembly at line GG near the second end 1014. Here, the working electrode 1024 can be seen. The assembly 1000 is a single-sided, flush configuration for the electrodes 1024, 1026, 1040.

[0284] Additionally, in some embodiments, some components of the analyte sensors 334, 900A, 900B, and 900C may be completely separate from one another. For example, Figure 11 illustrates an embodiment of an analyte sensor system 1100 having a reference electrode 112 configured to contact the skin of a host.

[0285] The analyte sensor system 1100 can be beneficial in that it can reduce the risk of silver migrating from the reference electrode 1112 to the working electrode 1106. For example, in a configuration in which the reference electrode is positioned subcutaneously, silver ions can be generated and can migrate to the working electrode 1106 where they are reduced and deposited. This would prevent current from flowing between the electrodes, thus making it impossible to determine the analyte concentration.

[0286] The configuration shown in Figure 12 includes a reference electrode 1212 configured to be placed in contact with the external surface of the host's skin. This may reduce the risk of silver migration, which may result in short circuits in some embodiments. Thus, the physical separation provided by the host's skin provides physical separation of the electrodes and inhibits migration of silver ions to the working electrode.

[0287] As shown in FIG. 12, the analyte sensor 1200 includes a mounting unit 1202 that includes many of the same components as the mounting unit 314 described herein above. The mounting unit 1202 may be attached to an external surface of the host's skin (ex vivo) by an adhesive patch 1210. The implantable probe 1204 includes a working electrode 1206 that may be positioned in a manner similar to the working electrodes 438 and / or 902 described herein. The reference electrode 1212 is adapted to be attached to an external surface of the host's skin (ex vivo). The reference electrode 1212 may be formed of any metal suitable for carrying out the oxidation reactions described herein. In some examples, the metal of the reference electrode may be at least partially surrounded by a conductive gel.

[0288] The interference domain 1214 may perform a similar role in the analyte sensors 900A-C. Another potential advantage of placing the reference electrode 1212 ex vivo, for example on the external surface of the host's skin, is that the footprint of the in vivo portion of the analyte sensor 1200 inside the host is reduced since less hardware needs to be embedded therein. In contrast, in FIGS. 9A-C, all of the illustrated components are adapted to be disposed in vivo. This may reduce the design complexity of the analyte sensor 1200 and potentially increase the host's comfort. In some alternative embodiments, at least a portion of the reference electrode 1212 may be inserted into the host's skin, but not to the same extent as the working electrode 1206 is inserted. This again may reduce the footprint of the analyte sensor 1200 and potentially increase the host's comfort.

[0289] Sensors 900A-C and 1200 are discussed primarily in the context of their use to detect interstitial oxygen concentrations. However, depending on the enzymes located in the respective enzyme layers, any of sensors 900A-C and 1200 may be used to detect interstitial glucose levels. However, it has been found that at least solid electrolyte layer 908 has a particularly beneficial and unexpected effect in measuring interstitial oxygen levels.

[0290] 13 illustrates an example of a hardware architecture 1300 in which a set or sequence of instructions may be executed to cause a machine to perform any one of the embodiments of the methods discussed herein. The hardware architecture 1300 may be implemented in a variety of computing devices, including those described herein, including handheld smart devices (e.g., smart devices), tablets, smart pens (e.g., insulin delivery pens with processing and communication capabilities), computers, wearable devices such as watches, or peripheral medical devices.

[0291] The architecture 1300 may operate as a stand-alone device or may be connected (e.g., networked) to other machines. In a networked deployment, the architecture 1300 may operate in the capacity of either a server machine or a client machine in a server-client network environment, or as a peer machine in a peer-to-peer (or distributed) network environment. The architecture 1300 may be implemented in a personal computer (PC), a tablet PC, a hybrid tablet, a set-top box (STB), a personal digital assistant (PDA), a mobile phone, a web appliance, a network router, a network switch, a network bridge, a watch, a hat, or other jewelry, an article of clothing, an accessory, or a wearable technology such as an Internet-of-things (IoT) device, or any machine capable of executing instructions (sequential or otherwise) that specify actions to be taken by the machine.

[0292] The exemplary architecture 1300 includes a processor unit 1302 that includes at least one processor (e.g., a central processing unit (CPU), a graphics processing unit (GPU), or both, a processor core, a compute node). The architecture 1300 may further include a main memory 1304 and a static memory 1306 that communicate with each other via a link 1308 (e.g., a bus). The architecture 1300 may further include a video display unit 1310, an input device 1312 (e.g., a keyboard), and a UI navigation device 1314 (e.g., a mouse). In some embodiments, the video display unit 1310, the input device 1312, and the UI navigation device 1314 are incorporated into a touch screen display. The architecture 1300 may additionally include a storage device 1316 (e.g., a drive unit), a signal generating device 1318 (e.g., a speaker), a network interface device 1320, and one or more sensors (not shown), such as a Global Positioning System (GPS) sensor, a compass, an accelerometer, or other sensors.

[0293] In some embodiments, the processor unit 1302, or another suitable hardware component, may support hardware interrupts. In response to a hardware interrupt, the processor unit 1302 may, for example, suspend its processing and execute an ISR, as described herein.

[0294] The storage device 1316 includes a machine-readable medium 1322 on which is stored one or more sets of data structures and instructions 1324 (e.g., software) that embody or are used in any one or more of the methods or functions described herein. The instructions 1324 may also reside, completely or at least partially, within the main memory 1304, within the static memory 1306, and / or within the processor unit 1302 during its execution by the architecture 1300, with the main memory 1304, the static memory 1306, and the processor unit 1302 also constituting machine-readable media.

[0295] Executable Instructions and Machine Storage Media Various memories (i.e., 1304, 1306, and / or memory of processor unit 1302) and / or storage device 1316 may store one or more sets of instructions and data structures (e.g., instructions) 1324 that embody or are used by any one or more of the methods or functions described herein. These instructions, when executed by processor unit 1302, cause various operations to be performed to implement the disclosed embodiments.

[0296] As used herein, the terms "machine storage medium," "device storage medium," and "computer storage medium" (collectively referred to as "machine storage medium 1322") mean the same thing and may be used interchangeably in this disclosure. These terms refer to single or multiple storage devices and / or media (e.g., centralized or distributed databases and / or associated caches and servers) that store executable instructions and / or data, as well as cloud-based storage systems or storage networks that include multiple storage devices or devices. Thus, the term is intended to include, but is not limited to, solid-state memory, optical media, and magnetic media (including memory that is internal or external to the processor). Particular examples of machine-readable medium 1322 include non-volatile memory, examples of which include semiconductor memory devices, such as erasable programmable read-only memory (EPROM), electrically erasable programmable read-only memory (EEPROM), FPGAs, and flash memory devices; magnetic disks, such as internal hard disks and removable disks; magneto-optical disks; and CD-ROM and DVD-ROM disks.

[0297] Computer-Readable Medium The instructions 1324 may be further transmitted or received over a communications network 1326 using a transmission medium via the network interface device 1320 using any one of a number of well-known transfer protocols (e.g., HTTP). Examples of communications networks include LANs, WANs, the Internet, cellular networks, plain old telephone service (POTS) networks, and wireless data networks (such as Wi-Fi, 3G, 4G LTE / LTE-A, 5G, or WiMAX networks). The term "transmission medium" is intended to include intangible media capable of storing, encoding, or carrying instructions for a machine to execute, as well as digital or analog communications signals or other intangible media for facilitating communication of such software. EXAMPLES

[0298] The benefits of the third bias operation described herein above with respect to Figures 15 and 16 were evaluated by running a complete sequence including an odd cycle (first bias condition) where the waveform was 57 minutes of glucose mode at 0.6 V + 3 minutes of O2 mode at -0.2 V (second bias condition), followed by an even cycle + 56.5 minutes where the waveform had a 30 second overvoltage step at 0.8 V (third bias condition).

[0299] For all tested sensors (n=8), even cycles including an overvoltage step (0.8 V for 30 seconds) illustrated faster stabilization of the glucose signal compared to adjacent odd cycles (48 hours) within the test window. There was no significant effect on O2 measurements. The test buffer was 250 mg / dL glucose in sensor drift buffer at 36° C. under 1.8 ppm O2. FIG. 17A shows the glucose signal measurements in odd cycles (without overvoltage step) compared to those in even cycles (with overvoltage step). FIG. 17B is an expanded plot of a portion of FIG. 17A.

[0300] To quantify the stabilization time, the first derivative of glucose current versus time was plotted for odd and even cycles, Where:

[0301]

number

[0302] The stabilization time of the glucose current from cycle 13 to cycle 14 is reduced from 450 s to 200 s, where stabilization is defined as the first derivative within 2 pA.

[0303] To verify the benefit of the overvoltage step, the same waveform was further subjected to two different glucose concentrations (40 mg / dL and 400 mg / dL). As with the first run, the cycle including the overvoltage step showed a significant reduction in the stabilization time for the glucose current within the test window.

[0304] To further verify the advantage of the overvoltage step, two more different waveforms were tested under 250 mg / dL glucose for 14 days. For each waveform, the sensors were divided into three groups: overvoltage group (with overvoltage step), dual mode group (with reversed bias), and control group (glucose mode only). The overvoltage group illustrated a faster stabilization of glucose current compared to the dual sensing group. Furthermore, the overvoltage group and dual mode group did not significantly increase the spread of glucose sensitivity.

[0305] It has been determined that applying an overvoltage step between reversed biases for dual sensing can be used to accelerate the rate at which electrochemical equilibrium is reached and the stabilization of the glucose current. This technique can be performed with different glucose concentrations (e.g., 40 mg / dL, 250 mg / dL, and 400 mg / dL) and different waveforms (10 min, 15 min, and 1 hr).

[0306] The transient current can be used to predict the estimated analyte concentration level before reaching electrochemical equilibrium and stabilization of the analyte current. For example, the transient glucose current can be used to predict the estimated glucose concentration level before reaching steady state. In one application, the average of the current over a certain period (e.g., 5 seconds) during the transient period is used to extrapolate the current at its steady state via a predefined mathematical formula. Alternatively, mathematical or physical fitting (e.g., by the Cotterell equation) can be applied to extract parameters that can generate a prediction of the current at a later stage.

[0307] 18A and 18B illustrate examples of transient raw current values ​​corresponding to glucose concentration at multiple time points after the oxygen concentration measurement is completed. A steady bias voltage of 0.6V is applied to the analyte sensor, and the true glucose concentration is measured multiple times (300 seconds, 450 seconds, 600 seconds, 750 seconds, and 900 seconds) after the oxygen concentration measurement is completed (i.e., after the bias voltage is reversed). As shown in FIG. 18A, the glucose raw current is collected at different timestamps after the reversal, i.e., 300 seconds, 450 seconds, 600 seconds, 750 seconds, and 900 seconds. As shown in FIG. 18B, the glucose current versus actual glucose concentration illustrates a strong linear relationship at glucose concentrations (0 mg / dL, 40 mg / dL, 160 mg / dL, 280 mg / dL, and 400 mg / dL). The slope of the linear fit depicted for glucose sensitivity corresponds to the different timestamps.

[0308] 19 illustrates an example of a mathematical fit of glucose sensitivity versus transient current for various different timestamps. This model allows for predicting an estimated glucose concentration level at steady state conditions by measuring the transient current and determining the timestamp. In other words, the transient current and time stand allow the glucose sensitivity to be extrapolated to provide an estimated glucose concentration level before the actual steady state is reached.

[0309] 20A and 20B illustrate examples of transient raw current values ​​corresponding to oxygen concentration at multiple time points after completion of the glucose concentration measurement. A steady bias voltage of -0.2V is applied to the analyte sensor and the true oxygen concentration is measured multiple times (30 seconds, 60 seconds, 90 seconds, 120 seconds, and 180 seconds) after completion of the glucose concentration measurement (i.e., after the bias voltage is reversed). As shown in FIG. 20B, the oxygen current versus actual oxygen concentration illustrates a strong linear relationship at oxygen concentrations between 0 and 2.0 ppm.

[0310] FIG. 21 illustrates an example of an exponential 3P decay plot used for fitting to predict glucose current decay after reversing the bias voltage. As shown in FIG. 21, the fitting model is extracted by using the raw data from 0 seconds to 300 seconds, and the prediction model is y=7.089+0.927*Exp(-0.00517*x), where x is time in seconds. For example, as shown in FIG. 21, the predicted current at 824 seconds is 7.102 nA. The true data collected is 7.11 nA. Therefore, the error is within 0.2%.

[0311] As used herein, the terms "a," "an," or "the" are used to include one or more, unless the context clearly dictates otherwise. The term "or" is used to refer to a non-exclusive "or," unless otherwise indicated. In addition, expressions or terms used herein and not otherwise defined are for descriptive purposes only and should not be understood as limiting. Any use of section headings is intended to aid in the reading of the document and should not be construed as limiting, and information associated with a section heading may occur within or outside of that particular section.

[0312] All publications, patents, and patent documents referenced herein are incorporated by reference in their entirety as if each was individually incorporated by reference. In the event of inconsistent usage between this document and those documents so incorporated by reference, the usage in the incorporated references should be considered supplementary to the usage in this document, and in the event of any irreconcilable discrepancy, the usage in this document will control.

[0313] In the methods described herein, operations may be performed in any order without departing from the principles of the present disclosure, unless a temporal or operational order is explicitly recited. Moreover, specified operations may be performed simultaneously unless express claim language recites that they be performed separately. For example, a claimed operation of performing X and a claimed operation of performing Y may be performed simultaneously in a single operation, with the resulting process falling within the literal scope of the claimed process. [Explanation of symbols]

[0314] 100 Environment 101 Host 102 Analyte Sensor System 104 Analyte Sensors 106 Sensor Electronics 108 Medical Devices 110 Radio communication signals 112 Computing Devices 114 tablets 116 Smart Pen 118 Computer 120 Wearable Devices 122 Peripheral medical devices 124 Network 126 Server System 128 Remote Terminal 130 additional wearable sensors 132 User Computer Devices 138 Wireless Access Points 200 Medical Device Systems 308 Adhesive Pad 314 Mounting unit 318 Electronic Equipment Unit 334 Analyte Sensors 1200 Analyte Sensor 1202 Mounting Unit 1204 Implantable Probe 1206 Working electrode 1210 Adhesive Patch 1212 Reference electrode 1214 Interference Domain 1300 Architecture

Claims

1. A continuous analyte monitoring system for measuring the concentration of a first analyte and the concentration of a second analyte in a host, wherein the continuous analyte monitoring system is A sensor having an action electrode extending along the central axis, and a reference electrode, It comprises a sensor control circuit, and the sensor control circuit is Applying a first bias condition between the working electrode and the reference electrode, wherein the first bias condition has a first polarity and a first magnitude. Accessing a first signal generated by the sensor in a living organism while the first bias condition is applied to the sensor, wherein the first signal indicates the concentration of a first analyte in the host. Applying a second bias condition between the working electrode and the reference electrode, wherein the second bias condition has a second polarity and a second magnitude, and the second polarity is opposite to the first polarity. The sensor control circuit accesses a second signal generated by the sensor in a living organism while the second bias condition is applied to the sensor, wherein the second signal indicates the concentration of a second analyte in the host, and the second analyte is different from the first analyte. A continuous analyte monitoring system configured to perform an operation that includes applying a third bias condition between the working electrode and the reference electrode, wherein the third bias condition has a third polarity and a third magnitude, the third polarity being equal to the first polarity and the third magnitude being greater than the first magnitude.

2. The continuous analyte monitoring system according to claim 1, wherein the first analyte is glucose or lactate, and the second analyte is oxygen.

3. The continuous analyte monitoring system according to claim 1 or 2, wherein the reference electrode is configured to support a redox reaction, and the working electrode is configured to support an oxidation reaction.

4. The continuous analyte monitoring system according to claim 1 or 2, wherein the reference electrode extends coaxially along the central axis.

5. The continuous analyte monitoring system according to claim 1 or 2, wherein the reference electrode is configured to operate in an in vivo location.

6. The continuous analyte monitoring system according to claim 1 or 2, wherein the working electrode, the reference electrode, or both are substantially planar.

7. The continuous analyte monitoring system according to claim 1 or 2, further comprising a counter electrode electrically in communication with the working electrode, the reference electrode, or both thereof.

8. The continuous analyte monitoring system according to claim 1 or 2, further comprising an enzyme layer that at least partially covers the working electrode.

9. The continuous analyte monitoring system according to claim 8, wherein the enzyme layer comprises oxidase, dehydrogenase, or a mixture thereof.

10. The continuous analyte monitoring system according to claim 8, further comprising a resistance layer that at least partially covers the enzyme layer.

11. The continuous analyte monitoring system according to claim 1 or 2, wherein the working electrode comprises platinum, palladium, rhodium, iridium, tantalum, or a mixture thereof, and the reference electrode comprises silver and silver chloride.

12. The continuous analyte monitoring system according to claim 1 or 2, wherein at least a portion of the working electrode and the reference electrode are configured to be exposed to at least one of glucose, lactate, and oxygen.

13. The continuous analyte monitoring system according to claim 1 or 2, wherein the buckling strength of the sensor is in the range of 0.010 lbf to 0.10 lbf.

14. The continuous analyte monitoring system according to claim 1 or 2, wherein the first polarity is positive from the working electrode toward the reference electrode, and the second polarity is negative from the working electrode toward the reference electrode.

15. The continuous analyte monitoring system according to claim 1 or 2, wherein the first magnitude is approximately 0.5V to approximately 0.7V.

16. The continuous analyte monitoring system according to claim 1 or 2, wherein the second magnitude is approximately -0.3V to approximately -0.2V.

17. The continuous analyte monitoring system according to claim 1 or 2, wherein the third magnitude is approximately 0.7V to approximately 1.2V.

18. The continuous analyte monitoring system according to claim 1 or 2, further comprising a transmitter capable of transmitting data acquired between the first bias condition, the second bias condition, the third bias condition, or a combination thereof to a device.

19. The continuous analyte monitoring system according to claim 1 or 2, wherein the third bias condition is applied for a shorter duration than the duration for which each of the first and second bias conditions is applied.

20. The first bias condition is applied for a period of time ranging from approximately 4 minutes to approximately 80 minutes. The second bias condition is applied for a period of time ranging from approximately 10 seconds to approximately 10 minutes. The continuous analyte monitoring system according to claim 1 or 2, wherein the third bias condition is applied for a period of time ranging from approximately 5 seconds to approximately 60 seconds.

21. The first bias condition is applied for a period of time ranging from approximately 4 minutes to approximately 30 minutes. The second bias condition is applied for a period of time ranging from approximately 10 seconds to approximately 2 minutes. The continuous analyte monitoring system according to claim 1 or 2, wherein the third bias condition is applied for a period of time ranging from approximately 10 seconds to approximately 60 seconds.

22. The second bias condition is applied over a period of time ranging from approximately 1 minute to approximately 10 minutes. The continuous analyte monitoring system according to claim 1 or 2, wherein the third bias condition is applied for a period of time ranging from approximately 10 seconds to approximately 60 seconds.

23. The second bias condition is applied over a period of time ranging from approximately 1 minute to approximately 4 minutes. The continuous analyte monitoring system according to claim 1 or 2, wherein the third bias condition is applied for a period of time ranging from approximately 10 seconds to approximately 60 seconds.

24. The continuous analyte monitoring system according to claim 1 or 2, wherein the second bias condition is applied over a period of time approximately 3 to 9 times longer than the third bias condition.

25. The continuous analyte monitoring system according to claim 1 or 2, wherein the second bias condition is applied for a period of time approximately 5 to 7 times longer than the third bias condition.

26. The continuous analyte monitoring system according to claim 1 or 2, further comprising a solid electrolyte layer that at least partially covers at least one of the working electrode and the reference electrode.

27. The continuous analyte monitoring system according to claim 26, wherein the solid electrolyte layer includes a polymer electrolyte.

28. The continuous analyte monitoring system according to claim 26, wherein the solid electrolyte layer is disposed between the working electrode and the reference electrode and is electrically in communication with the working electrode and the reference electrode.

29. The continuous analyte monitoring system according to claim 26, wherein the reference electrode and the working electrode are separated by a membrane.

30. The continuous analyte monitoring system according to claim 29, wherein the membrane comprises a polymer.

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