Patent Application
20230301553
The present disclosure relates generally to systems and methods for measuring analyte concentrations in a host.
Monitoring of various systems functioning in a host can be helpful to monitor the overall health of the host. As an example, continuous monitoring of analytes associated with diabetes can help a patient monitor their health. Diabetes is a metabolic condition relating to the production or use of insulin by the body. Insulin is a hormone that allows the body to use glucose for energy, or store glucose as fat.
When a person eats a meal that contains carbohydrates, the food is processed by the digestive system, which produces glucose in the person's blood. Blood glucose can be used for energy or stored as fat. The body normally maintains blood glucose levels in a range that provides sufficient energy to support bodily functions and avoids problems that can arise when glucose levels 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.
When the body does not produce enough insulin, or when the body is unable to effectively use insulin that is present, blood sugar levels can elevate beyond normal ranges. The state of having a blood sugar level higher than what is considered normal or healthy is called “hyperglycemia.” Chronic hyperglycemia can lead to a number of health problems, such as cardiovascular disease, cataract and other eye problems, nerve damage (neuropathy), and kidney damage. Hyperglycemia can also lead to acute problems, such as diabetic ketoacidosis—a state in which the body becomes excessively acidic due to the presence of blood glucose and ketones, which are produced when the body cannot use glucose. The state of having lower than normal blood glucose levels is called “hypoglycemia.” Severe hypoglycemia can lead to acute crises that can result in seizures or death.
A diabetes patient can receive insulin to manage blood glucose levels. Insulin can be received, for example, through a manual injection with a needle. Wearable insulin pumps are also available. Diet and exercise also affect blood glucose levels. A glucose sensor can provide an estimated glucose concentration level, which can be used as guidance by a patient or caregiver.
Diabetes conditions are sometimes referred to as “Type 1” and “Type 2.” A Type 1 diabetes patient may be able to use insulin when it is present, but the body is unable to produce sufficient amounts of insulin, because of a problem with the insulin-producing beta cells of the pancreas. A Type 2 diabetes patient may produce some insulin, but the patient has become “insulin resistant” due to a reduced sensitivity to insulin. The result is that even though insulin is present in the body, the insulin is not sufficiently used by the patient's body to effectively regulate blood sugar levels.
Blood sugar concentration levels may be monitored with a continuous analyte monitoring system, such as a continuous glucose monitor. A continuous glucose monitor may provide the wearer (patient) with information, such as an estimated blood glucose level or a trend of estimated blood glucose levels.
Example 1 is a continuous analyte monitoring system for measuring a concentration of a first analyte and concentration of a second analyte in a host, the continuous analyte monitoring system comprising: a sensor comprising a working electrode extending along a central axis; and a reference electrode; and a sensor control circuit, the sensor control circuit configured to perform operations comprising: applying a first bias condition to the sensor; accessing a first signal generated by the sensor in vivo while the first bias condition is applied to the sensor, the first signal indicating a concentration of a first analyte at the host; applying a second bias condition to the sensor, the second bias condition being different than 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 indicating a concentration of a second analyte at the host, the second analyte being different than the first analyte.
In Example 2, which can be combined with other examples herein, the subject matter of Example 1 optionally includes wherein the first analyte is glucose and the second analyte is oxygen.
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 the working electrode is configured to support an oxidation reaction.
In Example 4, which can be combined with other examples herein, the subject matter of any one or more of Examples 1-3 optionally includes wherein the reference electrode extends coaxially along the central axis.
In Example 5, which can be combined with other examples herein, the subject matter of any one or more of Examples 1-4 optionally includes wherein the reference electrode is configured to operate in an ex vivo position.
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 wherein the working electrode, the reference electrode, or both are substantially planar.
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.
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.
In Example 9, which can be combined with other examples herein, the subject matter of Example 8 optionally includes wherein the enzyme layer comprises an oxidase.
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 resistance layer at least partially covering the enzyme layer.
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.
In Example 12, which can be combined with other examples herein, the subject matter of any one or more of Examples 1-11 optionally includes wherein at least a portion of the working electrode and the reference electrode are configured to be exposed to at least one of glucose or oxygen.
In Example 13, which can be combined with other examples herein, the subject matter of any one or more of Examples 1-12 optionally includes wherein buckling strength of the sensor is in a range of 0.010 lbf to 0.10 lbf.
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 wherein: 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 −0.3V to about −0.2V, relative to the reference electrode.
In Example 15, which can 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 obtained during the first bias condition, the second bias condition, or both to a device.
Example 16, which can be combined with other examples herein, is a method of continuous analyte monitoring, the method comprising: biasing an in vivo sensor, by a sensor control circuit, to a first bias condition, the sensor comprising: a working electrode extending coaxially along a central axis; and a reference electrode; 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 indicating a concentration of a first analyte; biasing the sensor, by the sensor control circuit, to a second bias condition different than 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 indicating a concentration of a second analyte, the second analyte being different than the first analyte.
In Example 17, which can be combined with other examples herein, the subject matter of Example 16 optionally includes wherein the first bias condition has a first polarity and the second bias condition has a second polarity that is the opposite of the first polarity.
In Example 18, which can be combined with other examples herein, the subject matter of any one or more of Examples 16-17 optionally includes wherein the biasing of the sensor to the first bias condition comprises applying a positive potential difference between the working electrode and the reference electrode.
In Example 19, which can be combined with other examples herein, the subject matter of Example 18 optionally includes wherein the positive potential difference is in a range of from about 0.50 V to 0.70 V.
In Example 20, which can be combined with other examples herein, the subject matter of any one or more of Examples 16-19 optionally includes wherein the biasing of the sensor to the second bias condition comprises applying a negative potential difference between the working electrode and the reference electrode.
In Example 21, which can be combined with other examples herein, the subject matter of Example 20 wherein the negative potential difference is in a range of from about −0.3 to −0.2V
In Example 22, which can be combined with other examples herein, the subject matter of any one or more of Examples 16-21 optionally includes wherein the sensor is configured to reside in vivo.
In Example 23, which can be combined with other examples herein, the subject matter of any one or more of Examples 16-22 optionally includes switching the sensor between first bias condition and the second bias condition.
In Example 24, which can be combined with other examples herein, the subject matter of Example 23 optionally includes wherein switching between the first bias condition and the second bias condition comprises executing a first bias condition program and a second bias condition program, respectively.
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 comprising a working electrode extending along a central axis; a reference electrode; and a solid-state electrolyte layer at least partially covering at least one of the working electrode and the reference electrode.
In Example 26, which can be combined with other examples herein, the subject matter of Example 25 optionally includes a sensor control circuit, the sensor control circuit configured to perform operations comprising: 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 indicating a concentration of an analyte.
In Example 27, which can be combined with other examples herein, the subject matter of any one or more of Examples 25-26 optionally includes wherein the analyte is oxygen.
In Example 28, which can be combined with other examples herein, the subject matter of any one or more of Examples 25-27 optionally includes wherein the reference electrode extends coaxially along the central axis.
In Example 29, which can 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.
In Example 30, which can 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.
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.
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 wherein the solid-state electrolyte layer comprises a polyelectrolyte.
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 wherein the working electrode comprises platinum and tantalum and the reference electrode comprises silver and silver chloride.
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 wherein the solid-state electrolyte layer is disposed between and in electrical communication with the working electrode and reference electrode.
In Example 35, which can be combined with other examples herein, the subject matter of any one or more of Examples 25-34 optionally includes wherein at least a portion of the working electrode and a portion of the reference electrode are exposed to the analyte.
In Example 36, which can be combined with other examples herein, the subject matter of any one or more of Examples 25-35 optionally includes wherein buckling strength of the sensor is in a range of 0.010 lbf to 0.10 lbf.
In Example 37, which can 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 obtained during the bias condition to a display device.
In Example 38, which can be combined with other examples herein, the subject matter of any one or more of Examples 25-37 optionally includes wherein the reference electrode and the working electrode are separated by a membrane.
In Example 39, which can be combined with other examples herein, the subject matter of Example 38 optionally includes wherein the membrane comprises a polymer.
Example 40, which can be combined with other examples herein, is a method of using a continuous analyte monitoring system, the method comprising: biasing an in vivo sensor, by a sensor control circuit, to a bias condition, the sensor comprising: a working electrode extending along a central axis; and a reference electrode; a solid-state electrolyte layer partially covering at least one of the working electrode and the reference electrode; and accessing by the sensor control circuit a signal generated by the sensor in vivo while the first bias condition is applied, the signal indicating a concentration of an analyte; and accessing, by the sensor control circuit, a signal generated by the sensor in vivo while the second bias condition is applied to the sensor, the signal indicating a concentration of an analyte.
In Example 41, which can be combined with other examples herein, the subject matter of Example 40 optionally includes wherein the analyte is oxygen.
In Example 42, which can be combined with other examples herein, the subject matter of Example 41 optionally includes wherein the oxygen is interstitial oxygen.
In Example 43, which can be combined with other examples herein, the subject matter of any one or more of Examples 40-42 optionally includes wherein the reference electrode extends coaxially along the central axis.
In Example 44, which can 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.
In Example 45, which can 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.
In Example 46, which can 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.
In Example 47, which can 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.
In Example 48, which can be combined with other examples herein, the subject matter of any one or more of Examples 40-47 optionally includes wherein the solid-state electrolyte layer comprises a polyelectrolyte.
In Example 49, which can 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.
In Example 50, which can be combined with other examples herein, the subject matter of any one or more of Examples 40-49 optionally includes wherein the solid-state electrolyte layer is disposed between and in electrical communication with the working electrode and reference electrode.
In Example 51, which can be combined with other examples herein, the subject matter of any one or more of Examples 40-50 optionally includes wherein at least a portion of the working electrode and a portion of the reference electrode are exposed to the analyte.
In Example 52, which can be combined with other examples herein, the subject matter of any one or more of Examples 40-51 optionally includes wherein buckling strength of the sensor is in a range of 0.010 lbf to 0.10 lbf.
In Example 53, which can be combined with other examples herein, the subject matter of any one or more of Examples 40-52 optionally includes a transmitter capable of transmitting data obtained during the bias condition to a display device.
Example 54, which can be combined with other examples herein, is a method of calibrating an analyte sensor, the method comprising: 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-state 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.
In Example 55, which can be combined with other examples herein, the subject matter of Example 54 optionally includes wherein the calibration parameter describes a linear relationship between an amount of signal produced by the analyte sensor and analyte concentration.
In Example 56, which can be combined with other examples herein, the subject matter of any one or more of Examples 54-55 optionally includes the calibration parameter comprises a sensitivity, the sensitivity describing an analyte concentration per unit of sensor signal.
In Example 57, which can 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 parameter.
In Example 58, which can be combined with other examples herein, the subject matter of any one or more of Examples 54-57 optionally includes wherein the analyte of the known analyte concentration is oxygen.
In Example 59, which can 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.
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 wherein the solid-state electrolyte layer comprises a polyelectrolyte.
In Example 61, which can be combined with other examples herein, the subject matter of any one or more of Examples 54-60 optionally includes wherein the working electrode comprises platinum and tantalum and the reference electrode comprises silver and silver chloride.
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 wherein the solid-state electrolyte layer is disposed between and in electrical communication with the working electrode and reference electrode.
In Example 63, which can be combined with other examples herein, the subject matter of any one or more of Examples 54-62 optionally includes wherein at least a portion of the working electrode and a portion of the reference electrode are exposed to the analyte.
Example 64 is continuous analyte monitoring system for measuring a concentration of a first analyte and concentration of a second analyte in a host, the continuous analyte monitoring system comprising: a sensor comprising a working electrode extending along a central axis; and a reference electrode; and a sensor control circuit, the sensor control circuit configured to perform operations comprising: 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 indicating a concentration of a first analyte at the host; 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, the second polarity being opposite the first polarity; 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 indicating a concentration of a second analyte at the host, the second analyte being different than 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 equivalent to the first polarity and the third magnitude being greater than the first magnitude.
Example 65, which can be combined with other examples herein, the subject matter of Example 64, optionally includes wherein the first analyte is glucose or lactate and the second analyte is oxygen.
Example 66, which can be combined with other examples herein, the subject matter of any one or more of Examples 64-65, optionally includes wherein the reference electrode is configured to support a redox reaction the working electrode is configured to support an oxidation reaction.
Example 67, which can be combined with other examples herein, the subject matter of any one or more of Examples 46-66, optionally includes wherein the reference electrode extends coaxially along the central axis.
Example 68, which can be combined with other examples herein, the subject matter of any one or more of Examples 64-67, optionally includes wherein the reference electrode is configured to operate in an ex vivo position.
Example 69, which can be combined with other examples herein, the subject matter of any one or more of Examples 64-68, optionally includes wherein the working electrode, the reference electrode, or both are substantially planar.
Example 70, which can be combined with other examples herein, the subject matter of any one or more of Examples 64-69, optionally includes further comprising a counter electrode in electrical communication with the working electrode, the reference electrode, or both.
Example 71, which can be combined with other examples herein, the subject matter of any one or more of Examples 64-70, optionally includes further comprising an enzyme layer at least partially covering the working electrode.
Example 72, which can be combined with other examples herein, the subject matter of Example 71, optionally includes wherein the enzyme layer comprises an oxidase, dehydrogenase, or a mixture thereof.
Example 73, which can be combined with other examples herein, the subject matter of any one or more of Examples 71-72, optionally includes further comprising a resistance layer at least partially covering the enzyme layer.
Example 74, which can be combined with other examples herein, the subject matter of any one or more of Examples 64-73, 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.
Example 75, which can be combined with other examples herein, the subject matter of any one or more of Examples 64-74, optionally includes 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.
Example 76, which can be combined with other examples herein, the subject matter of any one or more of Examples 64-75, optionally includes wherein a buckling strength of the sensor is in a range of 0.010 lbf to 0.10 lbf.
Example 77, which can be combined with other examples herein, the subject matter of any one or more of Examples 64-76, optionally includes the first polarity being positive from the working electrode to the reference electrode and the second polarity being negative from the working electrode to the reference electrode.
Example 78, which can be combined with other examples herein, the subject matter of any one or more of Examples 64-77, optionally includes the first magnitude being between about 0.5 V and about 0.7 V.
Example 79, which can be combined with other examples herein, the subject matter of any one or more of Examples 64-78, optionally includes the second magnitude being between about −0.3V and about −0.2V.
Example 80, which can be combined with other examples herein, the subject matter of any one or more of Examples 64-79, optionally includes the third magnitude being between about 0.7V and to about 1.2V.
Example 81, which can be combined with other examples herein, the subject matter of Examples 64-80, optionally includes further comprising a transmitter capable of transmitting data obtained during the first bias condition, the second bias condition, the third bias condition, or a combination thereof to a device.
Example 82, which can be combined with other examples herein, the subject matter of any one or more of Examples 64-81, optionally includes wherein the third bias condition is applied for an amount of time that is less than a time that each of the first bias condition and the second bias condition are applied.
Example 83, which can be combined with other examples herein, the subject matter of any one or more of Examples 64-82, optionally includes wherein the first bias condition is applied for a time in a range of from about 4 minutes to about 80 minutes; the second bias condition is applied for a time in range of from about 10 seconds to about 10 minutes; and the third bias condition is applied for a time in a range of from about 5 seconds to about 60 seconds.
Example 84, which can be combined with other examples herein, the subject matter of any one or more of Examples 64-83, optionally includes wherein the first bias condition is applied for a time in a range of from about 4 minutes to about 30 minutes; the second bias condition is applied for a time in range of from about 10 seconds to about 2 minutes; and the third bias condition is applied for a time in a range of from about 10 seconds to about 60 seconds.
Example 85, which can be combined with other examples herein, the subject matter of any one or more of Examples 64-84, optionally includes wherein the second bias condition is applied for a time in range of from about 1 minute to about 10 minutes; and the third bias condition is applied for a time in a range of from about 10 seconds to about 60 seconds.
Example 86, which can be combined with other examples herein, the subject matter of any one or more of Examples 64-85, optionally includes wherein the second bias condition is applied for a time in range of from about 1 minute to about 4 minutes; and the third bias condition is applied for a time in a range of from about 10 seconds to about 60 seconds.
Example 87, which can be combined with other examples herein, the subject matter of any one or more of Examples 64-86, optionally includes wherein the second bias condition is applied for a time ranging from about 3 times to about 9 times greater than the third bias condition.
Example 88, which can be combined with other examples herein, the subject matter of any one or more of Examples 64-87, optionally includes wherein the second bias condition is applied for a time ranging from about 5 times to about 7 times greater than the third bias condition.
Example 89, which can be combined with other examples herein, the subject matter of any one or more of Examples 64-88, optionally includes further comprising a solid-state electrolyte layer at least partially covering at least one of the working electrode and the reference electrode.
Example 90, which can be combined with other examples herein, the subject matter of any one or more of Example 89, optionally includes wherein the solid-state electrolyte layer comprises a polyelectrolyte.
Example 91, which can be combined with other examples herein, the subject matter of Examples 89-90, optionally includes wherein the solid-state electrolyte layer is disposed between and in electrical communication with the working electrode and reference electrode.
Example 92, which can be combined with other examples herein, the subject matter of any one or more of Examples 89-91, optionally includes wherein the reference electrode and the working electrode are separated by a membrane.
Example 93, which can be combined with other examples herein, the subject matter of Example 92, optionally includes wherein the membrane comprises a polymer.
Example 94 is a continuous analyte monitoring, the method comprising: applying a first bias condition between a working electrode extending coaxially along a central axis and a reference electrode 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 indicating a concentration of a first analyte at a host; 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, the second polarity being opposite the first polarity; 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 indicating a concentration of a second analyte at the host, the second analyte being different than 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 equivalent to the first polarity and the third magnitude being greater than the first magnitude.
Example 95 which can be combined with other examples herein, the subject matter of Example 94, optionally includes wherein the first bias condition and the third bias condition have a first polarity and the second bias condition has a second polarity that is the opposite of the first polarity.
Example 96, which can be combined with other examples herein, the subject matter of any one or more of Examples 94-95 optionally includes wherein the biasing of the sensor to the first bias condition and the third bias condition comprises applying a positive potential difference between the working electrode and the reference electrode.
Example 97, which can be combined with other examples herein, the subject matter of Example 96, optionally includes wherein the positive potential difference of the first bias condition is in a range of from about 0.5 V to 0.7 V, relative to the reference electrode.
Example 98, which can be combined with other examples herein, the subject matter of any one or more of Examples 96 97, optionally includes wherein the positive potential difference of the third bias condition is in a range of from about 0.7 V to about 1.2 V, relative to the reference electrode.
Example 99, which can be combined with other examples herein, the subject matter of Examples 94-98, optionally includes wherein the biasing of the sensor to the second bias condition comprises applying a negative potential difference between the working electrode and the reference electrode.
Example 100, which can be combined with other examples herein, the subject matter of Example 99, optionally includes wherein the negative potential difference is in a range of from about −0.3 to −0.2V, relative to the reference electrode.
Example 101, which can be combined with other examples herein, the subject matter of any one or more of Examples 94-100, optionally includes wherein the first bias condition is applied for a time in a range of from about 4 minutes to about 80 minutes; the second bias condition is applied for a time in range of from about 10 seconds to about 10 minutes; and the third bias condition is applied for a time in a range of from about 5 seconds to about 60 seconds.
Example 102, which can be combined with other examples herein, the subject matter of any one or more of Examples 94-101, optionally includes wherein the first bias condition is applied for a time in a range of from about 4 minutes to about 30 minutes; the second bias condition is applied for a time in range of from about 10 seconds to about 2 minutes; and the third bias condition is applied for a time in a range of from about 10 seconds to about 60 seconds.
Example 103, which can be combined with other examples herein, the subject matter of any one or more of Examples 94-102, optionally includes wherein the second bias condition is applied for a time in range of from about 1 minute to about 10 minutes; and the third bias condition is applied for a time in a range of from about 10 seconds to about 60 seconds.
Example 104, which can be combined with other examples herein, the subject matter of any one or more of Examples 94-103, optionally includes wherein the second bias condition is applied for a time in range of from about 1 minute to about 4 minutes; and the third bias condition is applied for a time in a range of from about 10 seconds to about 60 seconds.
Example 105, which can be combined with other examples herein, the subject matter of any one or more of Examples 94-104, optionally includes wherein the second bias condition is applied for a time ranging from about 3 times to about 9 times greater than the third bias condition.
Example 106, which can be combined with other examples herein, the subject matter of any one or more of Examples 94-105, optionally includes wherein the second bias condition is applied for a time ranging from about 5 times to about 7 times greater than the third bias condition.
Example 107, which can be combined with other examples herein, the subject matter of any one or more of Examples 94-106, optionally includes wherein the sensor is configured to reside in vivo.
Example 108, which can be combined with other examples herein, the subject matter of any one or more of Examples 94-107, optionally includes further comprising switching the sensor between first bias condition, the second bias condition, and the third bias condition.
Example 109, which can be combined with other examples herein, the subject matter of any one or more of Example 108, optionally includes wherein switching between the first bias condition, the second bias condition, and the third bias condition comprises executing a first bias condition program, a second bias condition program, and a third bias condition respectively.
Example 110, which can be combined with other examples herein, the subject matter of any one or more of Examples 108-109, optionally includes further comprising executing a fourth bias condition program following executing the third bias condition.
Example 111, which can be combined with other examples herein, the subject matter of Example 110, optionally includes wherein the fourth bias condition comprises a positive potential difference that is substantially equivalent to the positive potential difference of the first bias condition.
Example 112, optionally includes which can be combined with other examples herein, the subject matter of any one or more of Examples 94-111, wherein the sensor further comprises a solid-state electrolyte layer at least partially covering at least one of the working electrode and the reference electrode.
Example 113, optionally includes which can be combined with other examples herein, the subject matter of Example 112, wherein the solid-state electrolyte layer comprises a polyelectrolyte.
Example 114, optionally includes which can be combined with other examples herein, the subject matter of any one or more of Examples 112-113, wherein the solid-state electrolyte layer is disposed between and in electrical communication with the working electrode and reference electrode.
Example 115, which can be combined with other examples herein, the subject matter of any one or more of Examples 110-114, optionally includes wherein the reference electrode and the working electrode are separated by a membrane.
Example 116, which can be combined with other examples herein, the subject matter of Example 115, optionally includes wherein the membrane comprises a polymer.
In the drawings, which are not necessarily drawn to scale, like numerals may describe similar components in different views. Like numerals having different letter suffixes may represent different instances of similar components. The drawings illustrate generally, by way of example, but not by way of limitation, various aspects described in the present document.
Various examples described herein are directed to continuous analyte monitoring systems and methods of use for continuous analyte monitoring systems. A continuous analyte monitoring system is placed in contact with bodily fluid of a host to measure a concentration of an analyte, such as glucose, in the bodily fluid. In some examples, the continuous analyte monitoring system is inserted under the skin (e.g., in vivo) of the host and placed in contact with interstitial fluid below the skin to measure the concentration of the analyte in the interstitial fluid.
The terms and phrases “analyte measuring device,” “biosensor,” “sensor,” “sensing region,” and “sensing mechanism” as used herein are broad terms and phrases, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to the area of an analyte-monitoring device responsible for the detection of, or transduction of a signal associated with, a particular analyte or combination of analytes. In one example, such devices are capable of providing specific quantitative, semi-quantitative, qualitative, semi qualitative analytical information using a biological recognition element combined with a transducing (detecting) element.
The term “about” as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range, and includes the exact stated value or range. The term “substantially” as used herein refers to a majority of, or mostly, as in 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%. The term “substantially free of” as used herein can mean having none or having a trivial amount of, such that the amount of material present does not affect the material properties of the composition including the material, such that about 0 weight percentage (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 less than or equal to about 4.5 wt %, 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 %.
The terms “adhere” and “attach” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not be limited to a special or customized meaning), and refer without limitation to hold, bind, or stick, for example, by gluing, bonding, grasping, interpenetrating, or fusing.
The term “analyte” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a substance or chemical constituent in a biological fluid (for example, blood, interstitial fluid, cerebral spinal fluid, lymph fluid or urine) that can be analyzed. Analytes can include naturally occurring substances, artificial 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 a carboxyprothrombin; acylcarnitine; adenine phosphoribosyl transferase; adenosine deaminase; albumin; alpha-fetoprotein; amino acid profiles (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; creatinine, creatine kinase; creatine kinase MM isoenzyme; cyclosporin A; d-penicillamine; de-ethylchloroquine; dehydroepiandrosterone sulfate; DNA (acetylator 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 hereditary optic neuropathy, MCAD, RNA, PKU, Plasmodium vivax, 21-deoxycortisol); desbutylhalofantrine; dihydropteridine reductase; diptheria/tetanus antitoxin; erythrocyte arginase; erythrocyte protoporphyrin; esterase D; fatty acids/acylglycines; free β-human chorionic gonadotropin; free erythrocyte porphyrin; free thyroxine (FT4); free tri-iodothyronine (FT3); fumarylacetoacetase; galactose/gal-1-phosphate; galactose-1-phosphate uridyltransferase; gentamicin; glucose-6-phosphate dehydrogenase; glutathione; glutathione perioxidase; glycerol, glycocholic acid; glycosylated hemoglobin; halofantrine; hemoglobin variants; hexosaminidase A; human erythrocyte carbonic anhydrase I; 17-alpha-hydroxyprogesterone; hypoxanthine phosphoribosyl transferase; immunoreactive trypsin; beta-hydroxybutyrate; ketone, lactate; lead; lipoproteins ((a), B/A-1, β); lysozyme; mefloquine; netilmicin; phenobarbitone; phenytoin; phytanic/pristanic acid; progesterone; prolactin; prolidase; purine nucleoside phosphorylase; quinine; reverse tri-iodothyronine (rT3); selenium; serum pancreatic lipase; sissomicin; somatomedin C; specific antibodies (adenovirus, anti-nuclear antibody, anti-zeta antibody, arbovirus, Aujeszky's disease virus, dengue virus, Dracunculus medinensis, Echinococcus granulosus, Entamoeba histolytica, enterovirus, Giardia duodenalis, Helicobacter pylori, hepatitis B virus, herpes virus, HIV-1, IgE (atopic disease), influenza virus, Leishmania donovani, leptospira, measles/mumps/rubella, Mycobacterium leprae, Mycoplasma pneumoniae, Myoglobin, Onchocerca volvulus, parainfluenza virus, Plasmodium falciparum, poliovirus, Pseudomonas aeruginosa, respiratory syncytial virus, rickettsia (scrub typhus), Schistosoma mansoni, Toxoplasma gondii, Treponema pallidum, Trypanosoma cruzi/rangeli, vesicular stomatitis virus, Wuchereria bancrofti, yellow fever virus); specific antigens (hepatitis B virus, HIV-1); succinyl acetone; sulfadoxine; theophylline; thyrotropin (TSH); thyroxine (T4); thyroxine-binding globulin; trace elements; transferrin; UDP-galactose-4-epimerase; urea; uroporphyrinogen I synthase; vitamin A; white blood cells; and zinc protoporphyrin. Salts, sugar, protein, fat, vitamins, and hormones naturally occurring in blood or interstitial fluids can also constitute analytes in certain examples. The analyte can be naturally present in the biological fluid, for example, a metabolic product, a hormone, an antigen, an antibody, and the like. Alternatively, the analyte can be introduced into the body, for example, a contrast agent for imaging, a radioisotope, a chemical agent, a fluorocarbon-based synthetic blood, or a drug or pharmaceutical composition, including but not limited to insulin; ethanol; cannabis (marijuana, tetrahydrocannabinol, hashish); inhalants (nitrous oxide, amyl nitrite, butyl nitrite, chlorohydrocarbons, hydrocarbons); cocaine (crack cocaine); stimulants (amphetamines, methamphetamines, Ritalin, Cylert, Preludin, Didrex, PreState, Voranil, Sandrex, Plegine); depressants (barbiturates, methaqualone, tranquilizers such as Valium, Librium, Miltown, Serax, Equanil, Tranxene); hallucinogens (phencyclidine, lysergic acid, mescaline, peyote, psilocybin); narcotics (heroin, codeine, morphine, opium, meperidine, Percocet, Percodan, Tussionex, Fentanyl, Darvon, Talwin, Lomotil); designer drugs (analogs of fentanyl, meperidine, amphetamines, methamphetamines, and phencyclidine, for example, Ecstasy); anabolic steroids; and nicotine. The metabolic products of drugs and pharmaceutical compositions are also contemplated analytes. Analytes such as neurochemicals and other chemicals generated within the body can also be analyzed, such as, for example, 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.
The term “bioactive agent” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to any substance that has an effect on or elicits a response from living tissue.
The phrases “biointerface membrane” and “biointerface layer” and “biointerface/drug releasing membrane” and “biointerface/drug releasing layer” as used interchangeably herein is a broad phrase, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a permeable membrane or layer that functions as an interface between host tissue and an implantable device.
The phrase “barrier cell layer” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a part of a foreign body response that forms a cohesive monolayer of cells (for example, macrophages and foreign body giant cells) that substantially block the transport of molecules and other substances to the implantable device.
The term “biostable” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to materials that are relatively resistant to degradation by processes that are encountered in vivo.
The terms “bioresorbable” or “bioabsorbable” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to materials that can be absorbed, or lose substance, in a biological system.
The phrase “cell processes” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to pseudopodia of a cell.
The phrase “cellular attachment” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to adhesion of cells and/or cell processes to a material at the molecular level, and/or attachment of cells and/or cell processes to microporous material surfaces or macroporous material surfaces. One example of a material used in the prior art that encourages cellular attachment to its porous surfaces is the BIOPORE™ cell culture support marketed by Millipore (Bedford, Mass.), and as described in Brauker et al., U.S. Pat. No. 5,741,330. The term “coaxial” as used herein is to be construed broadly 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 such elements can include electrodes, insulating layers, or other elements that can be positioned circumferentially around the core layer, such as a core electrode or core polymer wire.
The term “co-continuous” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a solid portion or cavity wherein an unbroken curved line in three dimensions can be drawn between two sides of a membrane.
The phrase “continuous analyte sensing” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to the period in which monitoring of analyte concentration is continuously, continually, and/or intermittently (but regularly) performed, for example, from about every 5 seconds or less to about 10 minutes or more, preferably from about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 second 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 in, for example, U.S. Pat. No. 8,828,201, Simpson, et al.; U.S. Pat. No. 9,131,885 Simpson, et al.; U.S. Pat. No. 9,237,864, Simpson, et al.; and U.S. Pat. No. 9,763,608, Simpson, et al., each of which is incorporated by reference in its entirety herein
The term “coupled” as used herein 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.
The term “removably coupled” as used herein may refer to two or more system elements or components that are configured to be or have been electrically, mechanically, thermally, or otherwise attached and detached without damaging any of the coupled elements or components. The term “permanently coupled” as used herein may refer to two or more system elements or components that are configured to be or have been electrically, mechanically, thermally, operably, chemically, or otherwise attached but cannot be uncoupled without damaging at least one of the coupled elements or components.
The phrase “defined edges” as used herein is a broad phrase, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to abrupt, distinct edges or borders among layers, domains, coatings, or portions. “Defined edges” are in contrast to a gradual transition between layers, domains, coatings, or portions.
The term “discontinuous” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to disconnected, interrupted, or separated portions, layers, coatings, or domains.
The term “distal” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a region spaced relatively far from a point of reference, such as an origin or a point of attachment.
The term “domain” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a region of the membrane system that can be a layer, multiple layers, a uniform or non-uniform gradient (for example, an anisotropic region 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 pairs of bi-layers, or as combinations thereof
The term “drift” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a progressive increase or decrease in signal over time that is unrelated to changes in host systemic analyte concentrations. For example, such as host postprandial glucose concentrations. While not 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, due to cellular invasion, which surrounds the sensor, for example. It is also believed that an insufficient amount of interstitial fluid is surrounding the sensor, which results in reduced oxygen and/or glucose transport to the sensor, for example. An increase in local interstitial fluid may slow or reduce drift and thus improve sensor performance. Drift may also be the result of sensor electronics, or algorithmic models used to compensate for noise or other anomalies that can occur with electrical signals in the picoamp range.
The phrases “drug releasing membrane” and “drug releasing layer” as used interchangeably herein are each a broad phrase, and each are to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a permeable or semi-permeable membrane which is permeable to one or more bioactive agents. In one example, the “drug releasing membrane” and “drug releasing layer” can be comprised of two or more domains and may be a few microns thickness or more. In one example the drug releasing layer and/or drug releasing membrane are substantially the same as the biointerface layer and/or biointerface membrane. Examples of drug releasing layers and membranes may be found in pending U.S. Patent Publication Number: 2022-0296867, titled “DRUG RELEASING MEMBRANE FOR ANALYTE SENSOR,” filed Mar. 17, 2022, incorporated by reference in its entirety herein; as well as in pending U.S. application Ser. No. 17/945,585, titled “DRUG RELEASING MEMBRANE FOR ANALYTE SENSOR,” filed Mar. 17, 2022, incorporated by reference in its entirety herein.
The term “electrochemically reactive surface” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to the surface of an electrode where an electrochemical reaction takes place. In a working electrode, hydrogen peroxide produced by an enzyme-catalyzed reaction of an analyte being detected reacts can create a measurable electronic current. For example, in the detection of glucose, glucose oxidase produces hydrogen peroxide (H2O2) as a byproduct. The H2O2 reacts with the surface of the working electrode to produce two protons (2H+), two electrons (2e−) and one molecule of oxygen (O2), which produces the electronic current being detected. In a counter electrode, a reducible species, for example, O2 is reduced at the electrode surface so as to balance the current generated by the working electrode.
The term “host” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to mammals, preferably humans.
The terms “interferants” and “interfering species” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to effects and/or species that interfere with the measurement of an analyte of interest in a sensor to produce a signal that does not accurately represent the analyte measurement. In one example of an electrochemical sensor, interfering species are compounds with an oxidation potential that overlaps with the analyte to be measured.
The term “in vivo” without limitation refers to the portion of a device (for example, a sensor) adapted for insertion into and/or existence within a living body of a host.
The term “ex vivo” refers to a portion of a device (for example, a sensor) adapted to remain and/or exist outside of a living body of a host.
The phrase “membrane system” as used herein is a broad phrase, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a permeable or semi-permeable membrane that can be comprised of two or more domains and may be formed from one or more materials to a thickness of a few microns or more, which is permeable to one or more analytes. In one example, the membrane is permeable to oxygen and is optionally permeable to, e.g., glucose or one or more other analytes. In one example, the membrane system comprises an immobilized glucose oxidase enzyme, which enables a reaction to occur between glucose and oxygen whereby a concentration of glucose can be measured.
The term “noise,” as used herein, is a broad term and is used in its ordinary sense, including, without limitation, a signal detected by the sensor or sensor electronics that is unrelated to analyte concentration and can result in reduced sensor performance. One type of noise has been observed during the few hours (e.g., about 2 to about 24 hours) after sensor insertion. After the first 24 hours, the noise may disappear or diminish, but in some hosts, the noise may last for about three to four days. In some cases, noise can be reduced using predictive modeling, artificial intelligence, and/or algorithmic means. In other cases, noise can be reduced by addressing immune response factors associated with the presence of the implanted sensor, such as using a drug releasing layer with at least one bioactive agent. For example, noise of one or more exemplary biosensors as presently disclosed can be determined and then compared qualitatively or quantitatively. By way of example, obtaining a raw signal timeseries with a fixed sampling interval (in units of pA), a smoothed version of the raw signal timeseries can be obtained, e.g., by applying a 3rd order lowpass digital Chebyshev Type II filter. Other smoothing algorithms can be used. At each sampling interval, an absolute difference, in units of pA, can be calculated to provide a smoothed timeseries. This smoothed timeseries can be converted into units of mg/dL, (the unit of “noise”), using a glucose sensitivity timeseries, in units of pA/mg/dL, where the glucose sensitivity timeseries is derived by optimizing a mathematical model between the raw signal and reference blood glucose measurements (e.g., obtained from Blood Glucose Meter). Optionally, the time series can be aggregated as desired, e.g., by hour or day. Comparison of corresponding time series between different exemplary biosensors with the presently disclosed drug releasing layer and one or more bioactive agents provides for qualitative or quantitative determination of improvement of noise.
The terms “nonbioresorbable” or “nonbioabsorbable” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to materials that are not substantially absorbed, or do not substantially lose substance, in a biological system.
The terms “non-zwitterionic dipole” and “non-zwitterionic dipolar compound” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refer without limitation to compounds in which a neutral molecule of the compound have a positive and negative electrical charge at different locations within the molecule. The positive and negative electrical charges within the molecule can be any non-zero, but less than full unit, charges.
The terms “operably connected” and “operably linked” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to one or more components linked to another component(s) in a manner that facilitates transmission of signals 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; the signal can then be transmitted to an electronic circuit. In this example, the electrode is “operably linked” to the electronic circuit.
The term “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. The term “planar” as used herein is to be interpreted broadly to describe sensor architecture having a substrate including a first side and a second side, and a plurality of elements arranged on one or more sides of the substrate, the elements may or may not be electrically or otherwise coupled, where the elements can include conductive or insulating layers or elements configured to operate as a circuit.
The term “polyampholytic polymer” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to polymers comprising both cationic and anionic groups. Such polymers can be prepared to have about equal numbers of positive and negative charges, and thus the surface of such polymers can be about net neutrally charged. Alternatively, such polymers can be prepared to have an excess of either positive or negative charges, and thus the surface of such polymers can be net positively or negatively charged, respectively.
The term “polymerization group” used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a functional group that permits polymerization of the monomer with itself to form a homopolymer or together with different monomers to form a copolymer. Depending on the type of polymerization methods employed, the polymerization group can be selected from alkene, alkyne, epoxide, lactone, amine, hydroxyl, isocyanate, carboxylic acid, anhydride, silane, halide, aldehyde, and carbodiimide.
The term “polyzwitterions” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to polymers where a repeating unit of the polymer chain is a zwitterionic moiety. Polyzwitterions are also known as polybetaines. Since polyzwitterions have both cationic and anionic groups, they are a type of polyampholytic polymer. They are unique, however, because the cationic and anionic groups are both part of the same repeating unit, which means a polyzwitterion has the same number of cationic groups and anionic groups whereas other polyampholytic polymers can have more of one ionic group than the other. Also, polyzwitterions have the cationic group and anionic group as part of a repeating unit. Polyampholytic polymers need not have cationic groups connected to anionic groups, they can be on different repeating units and thus may be distributed apart from one another at random intervals, or one ionic group may outnumber the other.
The term “proximal” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to the spatial relationship between various elements in comparison to a particular point of reference. For example, some examples of a device include a membrane system having a biointerface layer and an enzyme layer. If the sensor is deemed to be the point of reference and the enzyme layer is positioned nearer to the sensor than the biointerface layer, then the enzyme layer is more proximal to the sensor than the biointerface layer.
The phrases and terms “processor module” and “microprocessor” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to a computer system, state machine, processor, or the like designed to perform arithmetic or logic operations using logic circuitry that responds to and processes the basic instructions that drive a computer. The use of the processor module or microprocessor can improve the function of an analyte sensor, battery, measurement circuit, processor, memory, or a combination thereof.
The term “sensing membrane” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a permeable or semi-permeable membrane that can comprise one or more domains in a membrane system and that is constructed of materials having a thickness of a few microns or more, and that are permeable to reactants and/or co-reactants employed in determining the analyte of interest. As an example, a sensing membrane can comprise an immobilized glucose oxidase enzyme, which catalyzes an electrochemical reaction with glucose and oxygen to permit measurement of a concentration of glucose. In some further examples, a sensing membrane can include an oxidase, dehydrogenase, or a mixture thereof that can react with lactate.
The term “invasive” as used herein is a broad term, and is to be given its ordinary and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a medical procedure that invades (enters) the body, usually by cutting or puncturing the skin or by inserting instruments into the body.
The term “minimally-invasive” as used herein is a broad term, and is to be given its ordinary and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a procedure minimizing incisions to reduce trauma to the body. This type of procedure, for example, can be performed using thin-needles and an endoscope to visually guide the procedure.
The term “non-invasive sensing techniques” as used herein is a broad term, and is to be given its ordinary and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to techniques for sensing an internal condition or analyte(s) while minimizing incisions to reduce trauma to the body. Examples of such techniques can include optically excited fluorescence, microneedle incision, and/or transdermal monitoring of glucose). The term “polyelectrolyte” as used herein is a broad term, and is to be given its ordinary and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to polymers whose repeating units bear an electrolyte group. For example, polycations and polyanions are polyelectrolytes. Polyelectrolytes dissociate in aqueous solutions, making the polymers charged. Polyelectrolyte properties are thus similar to both electrolytes and polymers and are sometimes called polysalts.
The term “semi-continuous” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a portion, coating, domain, or layer that includes one or more continuous and noncontinuous portions, coatings, domains, or layers. For example, a coating disposed around a sensing region but not about the sensing region is “semi-continuous.”
The term “sensing membrane” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a permeable or semi-permeable membrane that can comprise one or more domains and that is constructed of materials having a thickness of a few microns or more, and that are permeable to reactants and/or co-reactants employed in determining the analyte of interest. As an example, a sensing membrane can comprise an immobilized glucose oxidase enzyme, which catalyzes an electrochemical reaction with glucose and oxygen to permit measurement of a concentration of glucose.
The term “signal medium” or “transmission medium” as used herein is a broad term, and is to be given its ordinary and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a form of modulated data signal, carrier wave, and so forth.
The term “modulated data signal” as used herein is a broad term, and is to be given its ordinary and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a signal that has one or more of its characteristics set or changed in such a matter as to encode information in the signal.
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, and are to be given its ordinary and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refers without limitation to both machine-storage media and signal media. Thus, the terms include both storage devices/media and carrier waves/modulated data signals.
The term “electrical contact” as used herein is a broad term, and is to be given its ordinary and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refers without limitation to materials that are sufficient contact so as to allow an electromagnetic signal to propagate between the materials. In some examples, the electromagnetic signal may be a current. In other examples, the electromagnetic signal is an induced or other wireless signal.
When an analyte sensor of the 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 indicating the analyte concentration. The raw sensor signal may be a current that flows between two or more electrodes of the analyte sensor. Analyte sensors may have different numbers of electrodes. For example, a three-electrode analyte sensor may 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, where the raw sensor signal is, or is based on, the current generated. The current may flow primarily between the working electrode and the counter electrode, with the reference electrode providing a stable reference potential. In a two-electrode configuration an example analyte sensor includes a working electrode and a reference electrode. The reference electrode conducts current, similar to the counter electrode in a three-electrode configuration, and provides a stable reference potential, like the reference electrode in a three-electrode configuration. Accordingly, the reference electrode in a two-electrode arrangement is sometimes referred to as a counter-reference electrode. Herein, the term reference electrode may refer to the reference electrode of a three-electrode configuration, the counter-reference electrode of a two-electrode configuration, or similar electrodes in other configurations.
In use, sensor electronics apply a bias condition between the working electrode and the reference (e.g., counter-reference) electrode. The applied bias promotes the electrochemical reaction between the analyte and the analyte sensor, resulting in a current between the working electrode and the reference (e.g., counter-reference) electrode. In one example, the current comprises all of the raw sensor signal. In another example, the raw sensor signal includes the current in addition to one or more other elements.
Continuously measuring multiple analytes can be beneficial in a variety of contexts. For example, it may be cumbersome to wear multiple sensors, or existing sensors may not be configured to detect, in either a simultaneous or alternating fashion, two or more analytes. Additionally, measuring concentrations of different analytes can involve two or more different electrochemical reactions, which under some circumstances can make it difficult to use a single sensor. In some examples, a concentration of a first analyte and a second analyte may be known, and this data used in concert to predict adverse health events, deliver medication, or other actions. However, in other examples, the concentration of one analyte may be known while a concentrate of a second analyte is unknown. Being able to measure the concentrations of multiple analytes using the same sensor to perform continuous analyte monitoring addresses said concerns. In one example, the multi-analyte monitoring systems discussed herein facilitate the measurement of the different analytes by varying the bias of the electrodes provides an easy and rapid device for analyte measurement. In some examples, the ability to measure oxygen concentration can be enhanced by including a solid-state electrolyte layer. In this example, the solid-state electrolyte layer can help to minimize the risk of an electrical short being caused by the oxidation-reduction reaction between the electrodes used to measure oxygen concentration. In this manner, without being bound to any particular theory, it is believed that the solid-state electrolyte layer helps inhibit dendrite growth at the electrode.
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, 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 that can measure the concentration of different analytes in the host 101, for example, under different bias conditions as described herein. In examples where the analyte sensor 104 is arranged to measure glucose, the glucose detected can be D-glucose. However, in some example arrangements, the analyte sensor 104 may detect any stereoisomer or blend of stereoisomers of glucose as well as any glucose in an open-chain form, cyclic form, or a mixture thereof.
At least a portion the analyte sensor 104 can be exposed to analyte at the host 101 in any suitable way. In some examples, the analyte sensor 104 is fully implantable under the skin of the host 101. In other examples, the analyte sensor 104 is wearable ex vivo on the body of the host 101 (e.g., on the body but not under the skin). Also, in some examples, the analyte sensor 104 is a transcutaneous device (e.g., with a sensor residing at least partially under or in the skin of a host). In the example of
The analyte sensor 104 may use any known method, including invasive, minimally-invasive, or non-invasive sensing techniques (e.g., optically excited fluorescence, microneedle, transdermal monitoring of glucose), to provide a raw sensor signal indicative of the concentration of the analyte in the host 101. The raw sensor signal may be converted into calibrated and/or filtered analyte concentration data used to provide a useful value of the analyte concentration (e.g., estimated blood glucose concentration level and/or estimated dissolved oxygen concentration level) to a user, such as the host or a caretaker (e.g., a parent, a relative, a guardian, a teacher, a doctor, a nurse, or any other individual that has an interest in the wellbeing of the host 101).
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 can be switched between a glucose sensing mode and an oxygen sensing mode. Depending upon the example, the modes discussed herein may also be described a “configuration.” The analyte sensor can be or include a subcutaneous, transdermal (e.g., transcutaneous), and/or intravascular device. In some aspects, such a sensor or device may recurrently (e.g., periodically or intermittently) analyze sensor data. The analyte sensor 104 may use any method of glucose and/or oxygen measurement, including enzymatic, chemical, physical, electrochemical, spectrophotometric, polarimetric, calorimetric, iontophoretic, radiometric, immunochemical, and the like. In various examples, the analyte sensor system 102 may be or include a continuous glucose monitor sensor available from DEXCOM®, (e.g., the DEXCOM G5® sensor, the DEXCOM G6® sensor, the DEXCOM G7™ sensor and/or variations thereof). In some further examples, analyte sensor 104 can be configured to detect lactate.
The environment 100 may also include a second medical device 108. The second medical device 108 may be or 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., accelerometer), posture sensor (e.g., 3-axis accelerometer), acoustic sensor (e.g., to capture ambient sound or sounds inside the body). The second medical device 108 may be wearable, e.g., on a watch, glasses, contact lens, patch, wristband, 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 may, for example, detect one or more of an analyte level (e.g., glucose, lactate, ketone, uric acid, creatinine, glycerol, insulin, or other substance), 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).
In some examples, the analyte sensor system 102 and the second medical device 108 communicate with one another, that is, the analyte sensor system 102 and the second medical device 108 are communicatively coupled such as to enable two-way communication. Communication between the analyte sensor system 102 and second medical device 108 may occur over any suitable wired connection and/or via a wireless communication signal 110. For example, the analyte sensor system 102 may be configured to communicate using 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), optically (e.g., infrared), sonically (e.g., ultrasonic), or a cellular protocol (e.g., Code Division Multiple Access (CDMA) or Global System for Mobiles (GSM)), or via a wired connection (e.g., serial, parallel, etc.).
In some examples, the environment 100 also includes a wearable sensor 130. The wearable sensor 130 can 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, for example, be an NFC circuit. In some examples, information from the wearable sensor 130 may be retrieved from the wearable sensor 130 using a user computer device 132, such as a smart phone, that is configured to communicate with the wearable sensor 130 via the wearable sensor's communication circuit, for example, when the user computer device 132 is placed near the wearable sensor 130. For example, swiping the user computer device 132 over the sensor 130 may retrieve sensor data from the wearable sensor 130 using NFC or other suitable wireless communication. The use of NFC communication may reduce power consumption by the wearable sensor 130, which may reduce the size of a power source (e.g., battery or capacitor) in the wearable sensor 130 or extend the usable life of the power source. In some examples, the wearable sensor 130 may be wearable on an upper arm as shown. In some examples, a wearable sensor 130 may additionally or alternatively be on the upper torso of the patient (e.g., over the heart or over a lung), which may, for example, facilitate detecting heart rate, respiration, or posture. A wearable sensor 136 may also be on the lower body (e.g., on a leg).
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, medical device 108, wearable device 120 such as a watch, and an additional wearable sensor 130 may communicate with one another 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 medical device 108. The analyte sensor system 102, medical device 108, and additional wearable sensor 130 on the host 101 are provided for illustration and description and are not necessarily drawn to scale.
The environment 100 may also include one or more computing devices, such as a hand-held smart device (e.g., smart device) 112, tablet 114, smart pen 116 (e.g., insulin delivery pen with processing and communication capability), computer 118, a wearable device 120 such as a watch, or 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 a wireless communication signal 110, and may also communicate over a network 124 with a server system (e.g., remote data center) or with a remote terminal 128 to facilitate communication with a remote user (not shown) such as a technical support staff member or a clinician.
The wearable device 120 may include an activity sensor, a heart rate monitor (e.g., light-based sensor or electrode-based sensor), a respiration sensor (e.g., acoustic- or electrode-based), a location sensor (e.g., GPS), or other sensors.
In some examples, the environment 100 includes a server system 126. The server system 126 can include one or more computing devices, such as one or more server computing devices. In some examples, the server system 126 is used to collect analyte data from the analyte sensor system 102 and/or analyte or other data from the plurality of other devices, and to perform analytics on collected data, generate, or apply one or more of universal or individualized models for glucose levels, and communicate such analytics, models, or information based thereon back to one or more of the devices in the environment 100. In some examples, the server system 126 gathers inter-host and/or intra-host break-in data to generate one or more break-in characteristics, as described herein.
The environment 100 may also include a wireless access point (WAP) 138 used to communicatively couple one or more of analyte sensor system 102, network 124, server system 126, medical device 108 or any of the peripheral devices described above. For example, WAP 138 may provide Wi-Fi and/or cellular connectivity within environment 100. Other communication protocols, such as NFC or Bluetooth, may also be used among devices of the environment 100.
In the example shown in
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 application of bias potentials and/or other bias conditions to the analyte sensor 104 via a potentiostat or other suitable component(s) at the measurement circuit 202, interpret raw sensor signals from the analyte sensor 104, and/or compensate for environmental factors. The control circuit 204 may also save information in data storage memory 210 or retrieve information from data storage memory 210. In various examples, data storage memory 210 may be integrated with 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.
The control circuit 204 may include suitable hardware for controlling the operations of the analyte sensor system 102, as described herein. In some examples, the control circuit 204 includes one or more processors. The one or more processors may be configured to retrieve instructions 206 from memory 208 and execute the instructions 206 to control the operations of the analyte sensor system 102 as described herein. In some examples, the control circuit 204 includes logic gates for implementing a state machine or other suitable processing hardware.
The sensor electronics 106 may also include a sensor 212, which may be coupled to the control circuit 204. The sensor 212 may be any suitable sensor such as, for example, a temperature sensor, an accelerometer, a location sensor, a blood pressure sensor, a heart rate sensor, a respiration sensor, or another suitable sensor. Although one sensor 212 is shown in
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, or may be removable, or part of a separate electronics unit. The battery 214 (or other power storage component, e.g., capacitor) may optionally be rechargeable via a wired or wireless (e.g., inductive or ultrasound) recharging system 216. The recharging system 216 may harvest energy or may receive energy from an external source or on-board source. In various examples, the recharge circuit may include a triboelectric charging circuit, a piezoelectric charging circuit, an RF charging circuit, a light charging circuit, an ultrasonic charging circuit, a heat charging circuit, a heat harvesting circuit, or a circuit that harvests energy from the communication circuit. In some examples, the recharging circuit may recharge the rechargeable battery using power supplied from a replaceable battery (e.g., a battery supplied with a base component).
The sensor electronics 106 may also include one or more supercapacitors in the sensor electronics unit (as shown), or in the sensor mounting unit 290. For example, the supercapacitor may allow energy to be drawn from the battery 214 in a highly consistent manner to extend the life of the battery 214. The battery 214 may recharge the supercapacitor after the supercapacitor delivers energy to the communication circuit or to the control circuit 204, so that the supercapacitor is prepared for delivery of energy during a subsequent high-load period. In some examples, the supercapacitor may be configured in parallel with the battery 214. A device may be configured to draw energy from the supercapacitor, as opposed to the battery 214. In some examples, a 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.
The sensor electronics 106 may also include a wireless communication circuit 218, which may for example include a wireless transceiver operatively coupled to an antenna. The wireless communication circuit 218 may be operatively coupled to the control circuit 204 and may be configured to wirelessly communicate with one or more peripheral devices or other medical devices, such as an insulin pump or smart insulin pen. The wireless communication circuit 218 may be configured to communicate according to any suitable wireless protocol or technique including, for example, via radio frequency, optically, sonically, etc.
In the example of
The 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. The peripheral device 250 may not necessarily include all the components shown in
The UI 252 may, for example, be provided using any suitable input/output device or devices of the peripheral device 250 such as, for example, a touch-screen interface, a microphone (e.g., to receive voice commands), or a speaker, a vibration circuit, or any combination thereof. The UI 252 may receive information from the host or another user (e.g., instructions, glucose values). The UI 252 may also deliver information to the host or other user, for example, by displaying UI elements at the UI 252. For example, UI elements can indicate glucose and/or other analyte concentration values, glucose or other analyte trends, glucose, or other analyte alerts, etc. Trends can be indicated by UI elements such as arrows, graphs, charts, etc.
The processor 256 may be configured to present information to the host 101 or other user, or receive input from the host 101 or other user, via the UI 252. The processor 256 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, or other information in the memory circuit 254. 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 sensor 260 may, for example, include an accelerometer, a temperature sensor, a location sensor, biometric sensor, or blood glucose sensor, blood pressure sensor, heart rate sensor, respiration sensor, or other physiologic sensor.
The peripheral device 250 may be configured to receive and display sensor information that may be transmitted by sensor electronics 106 (e.g., in a customized data package that is transmitted to the display devices based on their respective preferences). Sensor information (e.g., blood glucose concentration level) or an alert or notification (e.g., “high glucose level”, “low glucose level” or “fall rate alert” may be communicated via the UI 252 (e.g., via visual display, sound, or vibration). In some examples, the peripheral device 250 may be configured to display or otherwise communicate the sensor information as it is communicated from the sensor electronics 106 (e.g., in a data package that is transmitted to respective display devices). For example, the peripheral device 250 may transmit data that has been processed (e.g., an estimated analyte concentration level that may be determined by processing raw sensor data), so that a device that receives the data may not be required to further process the data to determine usable information (such as the estimated analyte concentration level). In other examples, the peripheral device 250 may process or interpret the received information (e.g., to declare an alert based on glucose values or a glucose trend). In various examples, the peripheral device 250 may receive information directly from 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).
In the example of
Similar to the UI 252, the UI 272 may be provided using any suitable input/output device or devices of the medical device 270 such as, for example, a touch-screen interface, a microphone, or a speaker, a vibration circuit, or any combination thereof. The UI 272 may receive information from the host or another user (e.g., glucose values, alert preferences, calibration coding). The UI 272 may also deliver information to the host or other user, for example, by displaying UI elements at the UI 252. For example, UI elements can indicate glucose, or oxygen, or other analyte concentration values, glucose or other analyte trends, glucose, or other analyte alerts, etc. Trends can be indicated by UI elements such as arrows, graphs, charts, etc.
The processor 276 may be configured to present information to a user, 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, or other information in the memory circuit 274. The wireless communication circuit 278 may include a transceiver and antenna configured communicate via a wireless protocol, such as any of the wireless protocols described herein.
The sensor 280 may, for example, include an accelerometer, a temperature sensor, a location sensor, biometric sensor, or blood glucose sensor, blood pressure sensor, heart rate sensor, respiration sensor, or other physiologic sensor. The medical device 270 may include two or more sensors (or memories or other components), even though only one sensor 280 is shown in the example in
In examples where medical device 270 is or includes an insulin pump, the pump and analyte sensor system 102 may be in two-way communication (e.g., so the pump can request a change to an analyte transmission protocol, e.g., request a data point or request data on a more frequent schedule), or the pump and 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, a glucose value may be incorporated in an advertisement message, which may be encrypted with a previously-shared key. In a two-way communication, a pump may request a value, which the analyte sensor system 102 may share, or obtain and share, in response to the request from the pump, and any or all of these communications may be encrypted using one or more previously-shared keys. An insulin pump may receive and track analyte (e.g., glucose) values transmitted from analyte sensor system 102 using one-way communication to the pump for one or more of a variety of reasons. For example, an insulin pump may suspend or activate insulin administration based on a glucose value being below or above a threshold value.
In some examples, the medical device system 200 includes two or more peripheral devices and/or medical devices that each receive information directly or indirectly from the analyte sensor system 102. Because different display devices provide many different user interfaces, the content of the data packages (e.g., amount, format, and/or type of data to be displayed, alarms, and the like) may be customized (e.g., programmed differently by the manufacturer and/or by an end user) for each particular device. For example, referring now to the example of
The layers discussed in at least
While the elongated conductive body 402 is illustrated in
Referring again to
As shown in
In some aspects, the sensor further comprises a third layer 414 comprising a conductive material. In further aspects, the third layer may comprise a reference electrode, which may be formed of a silver-containing material that is applied onto the second layer (e.g., an insulator). The silver-containing material may include any of a variety of materials and be in various forms, such as, silver/silver chloride (Ag/AgCl)-polymer pastes, paints, polymer-based conducting mixture, and/or inks that are commercially available, for example. The third layer can be processed using a pasting/dipping/coating step, for example, using a die-metered dip coating process. In one aspect, an Ag/AgCl polymer paste is applied to an elongated body by dip-coating the body (e.g., using a meniscus coating technique) and then drawing the body through a die to meter 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 can be utilized for forming one or more of the electrodes in the device depicted in
In some aspects, Ag/AgCl particles are mixed into a polymer, such as polyurethane, polyimide, or the like, to form the silver-containing material for the reference electrode. In some aspects, the third layer is cured, for example, by using an oven or other curing process. In some aspects, a covering of fluid-permeable polymer with conductive particles (e.g., carbon particles) therein is applied over the reference electrode and/or third layer. A layer of insulating material is located over a portion of the silver-containing material, in some aspects.
Over time, such a reference electrode becomes depleted, as silver ions of the silver chloride are converted to silver metal. As silver ions are depleted, reference electrode capacity decreases, reducing the stability of the reference electrode such that analyte sensitivity becomes less linear. By changing this polarity of the bias potential on the reference electrode while in oxygen sensing mode, the reference electrode is able to regenerate by reversing the conversion of silver ions to silver metal. In this manner, silver metal is oxidized to silver ions to advantageously regenerate the capacity of reference electrode while oxygen sensing mode.
As shown in
A bucking strength of the analyte sensor 334 can be in a range of from about 0.010 lbf to 0.10 lbf, or from about 0.02 lbf to about 0.06 lbf, or from 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.
In some examples, one or more domains of the sensing membranes are formed from materials such as silicone, polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene, polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene, homopolymers, copolymers, terpolymers of polyurethanes, 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 copolymers thereof including, for example, di-block, tri-block, alternating, random, and graft copolymers.
The sensing member 430 can be deposited on the electroactive surfaces of the electrode material using known thin or thick film techniques (for example, spraying, electro-depositing, dipping, roll-to-roll processing, other inline processing, or the like). It is noted that the sensing member 430 that surrounds the working electrode 438 does not have to be the same structure as the sensing member 430 that surrounds a 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 is not deposited over the reference and/or counter electrodes.
In the illustrated example, the sensor including the sensing member 430 is an enzyme-based electrochemical sensor. In this example the working electrode 438 measures a product (including but not limited to hydrogen peroxide) produced by the enzyme-catalyzed reaction of glucose. The product detected creates 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 producing two protons (2H+), two electrons (2e−) and one molecule of oxygen (O2), which produces the electronic current being detected). as described in more detail above and as is appreciated by one skilled in the art. In some examples, one or more potentiostats are employed to monitor the electrochemical reaction at the electroactive surface of the working electrode(s). 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 that is produced at the working electrode 438 (and flows through the circuitry to the counter electrode) is substantially proportional to the amount of H2O2 that diffuses to the working electrode 438. The output signal is may include a raw data stream that is used to provide a useful value of the measured analyte concentration in a host to the host or to a third party such as a medical professional or a guardian, for example.
In addition to the reaction described herein above for detecting glucose concentrations, the sensor described herein can detect oxygen concentrations. According to some examples, measuring oxygen concentrations includes two primary reactions take place on the working electrode:
O2+4H++4e−→2H2O—referred to as the “oxygen current”
H2O2+2H++2e−→2H2O—referred to as the “H2O2 reduction current”
The above two reactions are balanced by the reaction taking place on the reference electrode:
Ag+Cl−→e−+AgCl
In sum “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,” the following equivalence can be established: “H2O2 reduction current”=“H2O2 oxidizing current.” The “oxygen current” can be calculated as:
oxygen current=total reduction current−H2O2 oxidizing 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 “oxygen current” is calculated, the current value can be converted into an oxygen concentration value. As described further herein, detection of glucose concentrations or oxygen concentrations can be driven by selectively applying potential difference (alternatively referred to as a voltage) across the electrodes. In one example, a positive potential difference drives the reaction for detecting glucose concentrations and negative potential difference (e.g., an opposite polarity) drives the reaction for detecting oxygen concentrations.
In some examples, the sensor can be configured for transcutaneous or short-term subcutaneous implantation, and can have a thickness from about 0.5 μm to about 8 μm, and sometimes from about 4 μm to about 6 μm. In one sensor configured for fluid communication with a host's circulatory system, the thickness can be from about 1.5 μm to about 25 μm, and sometimes from about 3 to about 15 μm. It is also contemplated that in some examples, the biointerface/drug releasing layer or any other layer of the electrode can have a thickness that is consistent, but in other examples, the thickness can vary horizontally and/or vertically with reference to the sensing region. For example, in some examples, the presence and/or thickness of the biointerface/drug releasing layer can vary along the longitudinal axis of the electrode end.
The analyte sensor 504 may comprise electrodes 506, 508 and optional electrode 512. The analyte sensor 504 may be arranged, for example, similar to various other analyte sensors described herein such as, for example those include a solid-state electrolyte layer as described further herein. In a three-electrode arrangement, 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 prompt an electrochemical reaction resulting in a current between the working electrode 506 and the counter electrode 508. In a two-electrode arrangement (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 prompt an electrochemical reaction that results in a current between the working electrode 506 and the reference-counter electrode 508.
In some examples, the control circuit 502 is configured to selectively change the bias condition provided to the analyte sensor 504 to cause the analyte sensor 504 to generate a sensor signal (e.g., current) indicating concentrations of different analytes. For example, under a first bias condition, the analyte sensor 504 generates a sensor signal indicating a concentration of the first analyte. Under a second bias condition, the analyte sensor 504 generates a sensor signal indicating a concentration of the second analyte different than the first analyte. In some examples, the first bias condition is a positive potential, where the working electrode 506 is driven to a potential higher than the reference electrode (which may be the reference-counter electrode 508 in a two-electrode arrangement or the reference electrode 512 in a three-electrode arrangement). The first bias condition can be used to detect the first analyte (e.g., glucose) and the second bias condition can be used to detect the second analyte (e.g., oxygen).
As mentioned herein, the analyte sensor 334 is capable of selectively measuring the concentration of oxygen or glucose in the interstitial fluid. The ability to alternate between an oxygen measurement mode (to sense the concentration of oxygen in the interstitial fluid) and a glucose measurement mode (to sense the concentration of glucose in the interstitial fluid) is a result of the bias condition applied to the working electrode 438 relative to the reference electrode (e.g., the reference electrode 512). In one example, when the system 500 is configured in the glucose measurement mode the working electrode 438 and reference electrode of sensing member 430 are biased to a potential difference of about 0.20 V to about 0.90 V, relative to the reference electrode, about 0.50 V to about 0.70 V about 0.55 V to about 0.65 V, less than, equal to, or greater than 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 about −0.90 V to about −0.05 V, relative to the reference electrode, about −0.30 V to about −0.20 V, about −0.25 V to about −0.23 V, less than, equal to, or greater than 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.
The analyte sensor 334 can be configured to transition from the glucose measurement mode to the oxygen sensing mode or from the oxygen sensing mode to the glucose sensing mode to switch between the glucose measurement mode and the oxygen sensing mode using a sensor control circuit executing respective algorithms for each mode to achieve the described relative bias. The analyte sensor 334 can be configured to alternate between the glucose measurement mode and the oxygen measurement mode according to a predetermined schedule or a user can manually alternate between the glucose measurement mode and the oxygen measurement mode. The analyte sensor 334 can be configured to be in each of the glucose measurement mode and the oxygen measurement mode for equal amounts of time or uneven amounts of time.
In some examples, one cycle where the analyte sensor 334 alternates between the glucose measurement mode and the oxygen measurement mode can last for a time in a range of 60 minutes to 180 minutes, 100 minutes to 140 minutes, less than, equal to, or greater than 60 minutes, 65, 70 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, or 180 minutes. As an illustrative example if the cycle lasts for 120 minutes total, the glucose measurement mode can last for 117 minutes and the oxygen sensing mode can last for 3 minutes. Minimizing the amount of time that the analyte sensor 334 is in the oxygen measurement mode and help to ensure that the same local conditions (glucose and oxygen concentrations) near the analyte sensor 334 are compared to the conditions at glucose sensing mode just before switching to oxygen sensor mode.
In various examples, each of the working electrode 438 and the reference electrode can include many different materials. In one example, the working electrode 438 includes platinum and tantalum and the reference electrode includes silver and silver chloride. In this example, the analyte sensor 334 can be used to selectively measure oxygen and glucose levels in interstitial tissue. In some further examples, the working electrode 438 can include platinum, palladium, rhodium, iridium, tantalum, or a mixture thereof.
Also, in some examples, the control circuit 502 may generate an indication of an analyte to be measured in response to a 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, an excessive concentration of oxygen 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 can migrate to the platinum and destroy the ability for a current to flow between the electrodes. In this example, the control circuit 502 may determine if the sensor signal has degraded while the analyte sensor 504 is configured to measure glucose. If the sensor signal has degraded, the control circuit 502 may reconfigure the analyte sensor 504 to measure oxygen. The resulting determining of oxygen concentration may be used to diagnose the degraded signal observed during glucose measurement.
At operation 704, the control circuit 502 determines if the accessed indication references a first analyte or a second analyte. If the accessed indication references the first analyte, the control circuit 502 applies a first bias condition to the analyte sensor 504 at operation 706. If the accessed indication references a second analyte, the control circuit 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 examples 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 examples 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. At operation 710, the control circuit 502 may access a sensor signal generated while the analyte sensor 504 is under the first bias condition or second bias condition. At operation 712, the control circuit 502 determines a concentration of the selected analyte utilizing the sensor signal, for example, as described herein.
In some examples the process can include a third bias condition. This is because in certain examples if switching for example from a glucose measuring mode, to oxygen measuring mode, and back to glucose measuring mode, it may take time for a sensor to reach electrochemical equilibrium when back in glucose measuring mode. If electrochemical equilibrium is not reached quickly, then the accuracy of the sensor may be impacted.
In some examples, 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 examples, a magnitude of the first bias condition can be in a range of from about 0.5 V and about 0.7 V; a magnitude of the second bias condition can be in a range of from about −0.3V and about −0.2V; a magnitude of the third bias condition can be in a range of from about 0.7V and to about 1.2V.
The third bias condition may be applied for an amount of time that is less than a time that each of the first bias condition and the second bias condition are applied. The relatively short duration of the third bias condition helps to achieve 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 5 times to 7 times greater than the third bias condition. As non-limiting examples, the second bias condition can applied for a time in range of from about 1 minute to about 10 minutes or 2 minutes to 4 minutes while the third bias condition is applied for a time in a range of from about 10 seconds to about 60 seconds or about 15 seconds to about 45 seconds. Any data obtained during the first, second, and/or third bias conditions can be transmitted by a transmitter capable of transmitting data obtained during the first bias condition, the second bias condition, the third bias condition, or a combination thereof to a device.
At operation 804, the control circuit 502 the first signal is accessed under the first bias condition. At operation 806 the control circuit 502 determines the analyte concentration using the accessed signal. At operation 808 the control circuit 502 may determine whether to analyze a second analyte. This may happen automatically or by user input.
If a second analyte is analyzed, a second bias condition can be applied by the control circuit at operation 810. The signal generated from applying the second bias is accessed at operation 812 and the concentration of the analyte is determined at operation 814. Operations 810, 812, and 814 are accessed in a manner similar to those of operations 802, 804, and 806.
The structure of the analyte sensor 334 can be modified to enhance its ability to measure the concentration of oxygen in the interstitial tissue. This can be accomplished by physically separating the working electrode 438 and the reference electrode. This can further be accomplished by at least partially covering the working electrode 438, reference electrode, or both with a solid-state electrolyte layer.
In the depicted example, at least a portion of the working electrode 902 and the reference electrode 906 are covered with a solid-state electrolyte layer 908. In one example, solid-state electrolyte layer 908 includes a polyelectrolyte. A polyelectrolyte refers to polymers whose repeating units bear an electrolyte group. For example, polycations and polyanions are polyelectrolytes. Polyelectrolytes dissociate in aqueous solutions, making the polymers charged. Polyelectrolyte properties are thus similar to both electrolytes and polymers and are sometimes called polysalts. Examples of suitable polyelectrolytes for use at the solid-state electrolyte layer 908 are polyacrylic acids, polyethyleneimines, carboxymethylcellulose, polyphosphates, mixtures thereof, and copolymers thereof. Specific examples of repeating units that can be included in polyelectrolytes include acrylamide repeating units, acrylate repeating units include tetrafluoroethylene-perfluoro-3,6-dioxa-4-methyl-7-octenesulfonic acid copolymer (also categorized under the tradename NAF ION).
The solid-state electrolyte layer 908 may be in 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-state electrolyte layer 908 can be permeable to oxygen in gaseous form. Including the solid-state electrolyte layer 908 can also allow the analyte sensor 900A to include a gas permeable diffusion layer 910 atop the working electrode 902. The gas permeable diffusion layer 910 may function to exclude all solvated interfering species and biomolecules. The gas permeable diffusion layer 910, in some examples, is tunable to achieve a range of permeabilities and can be fabricated from other polymeric materials for drug release or the incorporation of oxidase enzyme systems.
An oxidase enzyme system can be present in enzyme layer 912. The enzyme layer can be an optional component, but where present the enzyme layer 912 can include an oxidase. An 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.
The resistance layer 914 includes a semi permeable membrane that controls the flux of oxygen and glucose to the underlying enzyme layer 912, rendering oxygen in a non-rate-limiting excess. As a result, the upper limit of linearity of glucose measurement is extended to a much higher value than that which is achieved without the resistance domain. In some examples, the resistance layer 914 exhibits an oxygen-to-glucose permeability ratio of from about 50:1 or less to about 400:1 or more, or about 200:1. As a result, one-dimensional reactant diffusion is adequate to provide excess oxygen at all reasonable glucose and oxygen concentrations found in the subcutaneous matrix.
In some examples, the resistance layer 914 includes a polyurethane membrane with both hydrophilic and hydrophobic regions. The combination of the hydrophobic regions and the 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.
If the resistance layer 914 includes a polyurethane, the flux of oxygen, glucose, or both therethrough can be further controlled by adding a crystallization slowing co-chain extender component to the polyurethane. An example of a crystallization slowing co-chain extender component is 2-methyl-1,3-propanediol, which allows the polyurethane compositions 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 compositions can allow for modulation of thermoplastic polyurethane copolymer degree of hard segment domain phase separation and crystallization, morphology, and thus analyte permeability (e.g. decreased O2 permeability/diffusivity) in biosensor membrane applications.
The thermoplastic polyurethanes are generally prepared by combining and reacting a) a polyol component of at least one hydroxyl terminated intermediate such as hydroxyl terminated polyester, polyether, polycarbonate, polycaprolactone, or polysiloxane with b) a polyisocyanate component, c) a primary chain extender component, d) a crystallization slowing co-chain extender component, and optionally a catalyst.
The thermoplastic polyurethanes include a polyol, which includes but are not limited to hydroxyl terminated polyesters, hydroxyl terminated polyethers, hydroxyl terminated polycarbonates, hydroxyl terminated polycaprolactones, hydroxyl terminated polyolefins, and hydroxyl terminated polysiloxanes.
The polyurethanes are derived from an isocyanate. In order to form large linear polyurethane chains, diisocyanates are suitable. Diisocyanates can be aromatic, cycloaliphatic, aliphatic, or combinations thereof having from 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-cyclohexylisocyanate (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-phenylenediisocyanate; xylene diisocyanate (XDI); 1,4-cyclohexyl diisocyanate (CHDI); 1,4-bis (isocyanato methyl) cyclohexane (1,4-H6XDI); 3,3′-Dimethyl-4,4′-biphenyldiisocyanate (TODI); and isomers and mixtures or combinations thereof.
Chain extenders used in the polyurethane formulations described herein. They are also responsible for formation of crystalline hard block domains and consequent hard segment domain phase separation leading to thermoplastic polyurethanes with desirable mechanical properties. Suitable chain extenders are unbranched, unsubstituted, straight chain symmetric alkane diols free of heteroatoms which have a total from 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 extenders are present in mixture for forming the polyurethane in a range of from about 0.5 wt % to about 20 wt %, 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 %.
The crystallization slowing co-chain extender is generally sterically hindered so that hard segment domain crystalline formation is interrupted or delayed allowing for improved solvent solubility and more copolymer hard segment and soft segment phase mixing.
The crystallization slowing components are short chain or monomeric diols which are branched, substituted, and/or contain heteroatoms (atoms other than carbon). Crystallization slowing components include but are not limited to dipropylene glycol, tripropylene glycol, diethylene glycol, triethylene glycol, cis-trans-isomers of cyclohexyl dimethylol, neopentyl glycol and substituted alkane diols such as 2-methyl-1,3-propanediol, 3-methyl-1,5-pentanediol, 1,3-butane diol, and 2-methyl-2,4-pentane diol. Any branched or substituted alkane diols having from about 2 up to about 12 carbon atoms in the main chain can be utilized. Please see
Any of the continuous analyte sensors discussed herein including the analyte sensors 900A-900C can be calibrated ex vivo. The calibration is discussed with reference to
After all signals are accessed, a calibration parameter is determined at operation 1113. The calibration parameter may include a linear relationship between an amount of signal produced by the analyte sensor 900A-900C and the analyte concentration. The calibration parameter can include the sensitivity in which the sensitivity describes an analyte concentration per unit of sensor signal. In some aspects a calibration may be defined by solving for the equation y=mx+b, the value of b represents the baseline of the signal. In certain aspects, the value of b (i.e., the baseline) can be zero or about zero. This can be the result of a baseline-subtracting electrode or low bias potential settings, for example. As a result, for these aspects, calibration can be defined by solving for the equation y=mx. Once the calibration parameter is determined any of the sensors 900A-900C can be deployed in vivo. Upon deployment at least a third senor signal is accessed. The concentration of the analyte of interest is then determined using the calibration parameter.
The analyte sensors 334, 900A, 900B, and 900C have been depicted as having a coaxial construction with respect to the working electrode 438 or 902 and reference electrode 906, and other components. As mentioned herein, components such as the working electrode 438 or 902 reference electrode 906, and other components including a core on which the one or more electrodes are positioned can be planar. The planar structure can conform to a generally, planar square profile, planar triangular profile, planar rectangular profile, or any higher order planar polygonal profile.
Planar structures are shown in
The sensor assembly 1000 can extend between the first end 1012 and the second end 1014 and be substantially planar along its length. The first end 1012 can be, for example, a connection end, such as for allowing electrical connection of the sensor assembly 1000 to a reader, computer, or other component for interpretation of signals detected with the sensor assembly 1000. The first end 1012 can host one or more connection pads 1022.
The second end 1014 can be, for example, a sensing end, for connection with or implantation in a patient, such as for detecting glucose or other analytes. The second end 1014 can host the electrodes 1024, 1026, and 1040. The second end 1014 can be the implantable portion of the sensor assembly 1000. The first end 1012 of the sensor that has the connector pads 1022 can be the proximal end of the sensor assembly 1000. The second end 1014 with the implantable portion of the sensor that contains the sensing electrodes can be the distal end of the sensor assembly 1000.
Shown in
The conductive traces 1021, connector pads 1022, working electrode 1024, and counter electrode 1026 can be made from a conductive layer built on the substrate. The connector pads 1022 can be situated on or at the first end 1012 of the assembly 1000 and allow for electrical connection of the sensor assembly 1000. The working electrode 1024 and the counter electrode 1026 can 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 can connected the electrodes 1024, 1026, to the connector pads 1022.
Shown in
In some examples, the conductive layer is formed from a single conductor, such as gold or platinum. In other examples, the conductive layer or can be formed from more than one material, such as a thin palladium layer that is covered with gold and platinum. The composition, geometry, and exposed conductor surfaces can depend on the manufacturing method, desired mechanical properties, and requirements of the sensing chemistry. For example, the base conductive material can be formed by a less expensive material, such as silver, which is covered in strategic locations by platinum for the active sensing surfaces. In some cases, gold can be plated as the base conductor, which is can be covered with platinum in order to provide both mechanical robustness and an active sensing surface for sensing hydrogen peroxide.
The conductive layer, including the working electrode 1024, counter electrode 1026, connector pads 1022, and conductive traces 1021, can be formed by a variety of techniques, such as plating, sputtering, or printing. To form the structure of patterning of the conductive layers, standard photolithographic techniques, laser ablation, or printing (e.g., inkjet or screen printing) can be used.
Although certain electrode designations are shown in the supporting document, it should be understood that the size, shape, and electrode identity can be changed depending on a specific use case, such as a particular analyte to be determined. The general size and shape of the sensor is 3 to 4 mm wide at the proximal end (connector end) and 300-500 μm wide in the narrow implantable distal end. The overall length of the sensor is dependent on the requirements of the wearable/inserter but are generally between 15 and 25 mm.
Shown in
Here, the insulator 1030 can be made of an electrically insulating material deposited on top of the conductive layer to protect the conductive traces 1021 and define the openings for the connector pads 1022, and the electrodes 1024, 1026, in addition to an opening 1031 for the reference electrode 1040. The insulator 1030 can be, for example, a thin layer of solder mask.
Shown in
Additionally, in some examples, some components of the analyte sensors 334, 900A, 900B, and 900C can be completely separated from each other. For example,
The analyte sensor system 1100 can be beneficial in that it may reduce the risk of silver migrating from the reference electrode 1112 to the working electrode 1106. For example, in arrangements where the reference electrode is positioned subcutaneously, silver ions may generate and can migrate to the working electrode 1106 where they are reduced and deposited. This prevents current from flowing between the electrodes, thus making it impossible to determine analyte concentration.
The arrangement shown in
As shown in
The interference domain 1214 can perform a similar role in the analyte sensors 900A-900C. Another potential benefit of locating the reference electrode 1212 ex-vivo, for example, on the external surface of a host's skin is that the footprint of an in-vivo portion of the analyte sensor 1200, inside the host, is reduced because less hardware needs to be implanted therein. By contrast in
The sensors 900A-900C and 1200 are discussed primarily in the context of being used to detect interstitial oxygen concentrations. However, depending on the enzyme located in their respective enzyme layers, any of the sensors 900A-900C and 1200 can be used to detect interstitial glucose levels. It has been found, however, that at least the solid-state electrolyte layer 908 has a particularly beneficial, and unexpected, effect in measuring interstitial oxygen levels.
The architecture 1300 may operate as a standalone 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 or a client machine in server-client network environments, or it may act as a peer machine in peer-to-peer (or distributed) network environments. The architecture 1300 can 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 telephone, a web appliance, a network router, a network switch, a network bridge, wearable technology such as a watch, hat, or other piece of jewelry, item of clothing, accessory, or Internet-of-things (IoT) device, or any machine capable of executing instructions (sequential or otherwise) that specify operations to be taken by that machine.
The example architecture 1300 includes a processor unit 1302 comprising at least one processor (e.g., a central processing unit (CPU), a graphics processing unit (GPU), or both, processor cores, compute nodes). The architecture 1300 may further comprise a main memory 1304 and a static memory 1306, which communicate with each other via a link 1308 (e.g., bus). The architecture 1300 can 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 examples, the video display unit 1310, input device 1312, and UI navigation device 1314 are incorporated into a touchscreen display. The architecture 1300 may additionally include a storage device 1316 (e.g., a drive unit), a signal generation 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, compass, accelerometer, or other sensor.
In some examples, the processor unit 1302 or another suitable hardware component may support a hardware interrupt. In response to a hardware interrupt, the processor unit 1302 may pause its processing and execute an ISR, for example, as described herein.
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) embodying or used by any one or more of the methodologies or functions described herein. The instructions 1324 can 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 execution thereof by the architecture 1300, with the main memory 1304, the static memory 1306, and the processor unit 1302 also constituting machine-readable media.
The various memories (i.e., 1304, 1306, and/or memory of the processor unit(s) 1302) and/or storage device 1316 may store one or more sets of instructions and data structures (e.g., instructions) 1324 embodying or used by any one or more of the methodologies or functions described herein. These instructions, when executed by processor unit(s) 1302 cause various operations to implement the disclosed examples.
As used herein, the terms “machine-storage medium,” “device-storage medium,” “computer-storage medium” (referred to collectively as “machine-storage medium 1322”) mean the same thing and may be used interchangeably in this disclosure. The terms refer to a single or multiple storage devices and/or media (e.g., a centralized or distributed database, 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 apparatus or devices. The terms shall accordingly be taken to include, but not be limited to, solid-state memories, and optical and magnetic media, including memory internal or external to processors. Specific examples of a machine-readable medium 1322 include non-volatile memory, including by way of example semiconductor memory devices, e.g., erasable programmable read-only memory (EPROM), electrically erasable programmable read-only memory (EEPROM), FPGA, and flash memory devices; magnetic disks such as internal hard disks and removable disks; magneto-optical disks; and CD-ROM and DVD-ROM disks.
The instructions 1324 can further be 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 communication networks include a LAN, a WAN, the Internet, mobile telephone networks, plain old telephone service (POTS) networks, and wireless data networks (e.g., Wi-Fi, 3G, 4G LTE/LTE-A, 5G or WiMAX networks). The term “transmission medium” shall be taken to include any intangible medium that is capable of storing, encoding, or carrying instructions for execution by the machine, and includes digital or analog communications signals or other intangible media to facilitate communication of such software.
The benefit of the third bias operation discussed herein above with respect to
For all the tested sensors (n=8), the even cycles, which contains overpotential step (30 s at 0.8 V), demonstrated faster stabilization of glucose signal compared with the neighboring odd cycles within testing window (48 h). There was no significant impact on O2 measurement. The testing buffer is 250 mg/dL glucose in sensor drifting buffer at 36° C. under 1.8 ppm O2.
To quantify the stabilization time, 1st derivative of glucose current vs time was plotted for the odd and even cycle,
where 1st derivative=Δy/Δx (Δy=raw current difference within 30 s, Δx=30 s).
The stabilization time of glucose current from cycle 13 to cycle 14 was reduced from 450 s to 200 s, where the stabilization is defined as the 1st derivation within 2 pA.
To validate the benefit of the overpotential step, the same waveform was under two more different glucose concentrations (40 mg/dL and 400 mg/dL). Similar to the first run, the cycle that contains overpotential step showed significantly reduced the stabilization time for glucose current within the testing window.
To further validate the benefit of the overpotential step, two more different waveforms were tested under 250 mg/dL glucose over 14 days. For each waveform, sensors were split into three groups, the overpotential group (with overpotential step); the dual mode group (with flipping bias); and the control group (glucose mode only). The overpotential group demonstrated faster stabilization of glucose current compared with the dual sensing group. Moreover, the overpotential group and dual mode group doesn't significantly increase the spread of glucose sensitivity.
It was determined that applying an overpotential step between flipping bias for dual sensing can be used to accelerate the rate of reaching electrochemical equilibrium and stabilization of the glucose current. This technique is feasible at different glucose concentrations (e.g. 40 mg/dL, 250 mg/dL and 400 mg/dL), as well as different waveforms (10 min, 15 min and 1 h).
Before reaching electrochemical equilibrium and stabilization of the analyte current, transient currents can be used to predict the estimated analyte concentration level. For example, the transient glucose current can be used to predict the estimated glucose concentration level prior to reaching steady state. In one application, the average of current over a certain period (5 seconds, for example) during the transient period is used to extrapolate the current at its steady state via a pre-defined mathematical equation. Alternatively, a mathematical or physical fitting (via Cottrell equation, for example) can be applied to extract parameters that can generate a prediction of current at a later stage.
In this document, the terms “a,” “an,” or “the” are used to include one or more than one unless the context clearly dictates otherwise. The term “or” is used to refer to a nonexclusive “or” unless otherwise indicated. In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting; information that is relevant to a section heading may occur within or outside of that particular section.
All publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference. In the event of inconsistent usages between this document and those documents so incorporated by reference, the usage in the incorporated reference should be considered supplementary to that of this document; for irreconcilable inconsistencies, the usage in this document controls.
In the methods described herein, the acts can be carried out in any order without departing from the principles of the disclosure, except when a temporal or operational sequence is explicitly recited. Furthermore, specified acts can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed act of doing X and a claimed act of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process.
This application claims priority to and the benefit of U.S. Provisional Patent Application Ser. No. 63/321,340, filed Mar. 18, 2022, entitled “CONTINUOUS ANALYTE MONITORING SENSOR SYSTEMS AND METHODS OF USING THE SAME,” and claims priority to and the benefit of U.S. Provisional Patent Application Ser. No. 63/478,047, filed Dec. 30, 2022, entitled “CONTINUOUS ANALYTE MONITORING SENSOR SYSTEMS AND METHODS OF USING THE SAME,” both of which are hereby incorporated by reference in their entirety.
| Number | Date | Country | |
|---|---|---|---|
| 63321340 | Mar 2022 | US | |
| 63478047 | Dec 2022 | US |
