Patent Grant
12343143
The embodiments described herein relate generally to systems and methods for processing sensor data from continuous analyte sensors and for self-calibration.
Diabetes mellitus is a chronic disease, which occurs when the pancreas does not produce enough insulin (Type I), or when the body cannot effectively use the insulin it produces (Type II). This condition typically leads to an increased concentration of glucose in the blood (hyperglycemia), which can cause an array of physiological derangements (e.g., kidney failure, skin ulcers, or bleeding into the vitreous of the eye) associated with the deterioration of small blood vessels. Sometimes, a hypoglycemic reaction (low blood sugar) is induced by an inadvertent overdose of insulin, or after a normal dose of insulin or glucose-lowering agent accompanied by extraordinary exercise or insufficient food intake.
A variety of sensor devices have been developed for continuously measuring blood glucose concentrations. Conventionally, a diabetic person carries a self-monitoring blood glucose (SMBG) monitor, which typically involves uncomfortable finger pricking methods. Due to a lack of comfort and convenience, a diabetic will often only measure his or her glucose levels two to four times per day. Unfortunately, these measurements can be spread far apart, such that a diabetic may sometimes learn too late of a hypoglycemic or hyperglycemic event, thereby potentially incurring dangerous side effects. In fact, not only is it unlikely that a diabetic will take a timely SMBG measurement, but even if the diabetic is able to obtain a timely SMBG value, the diabetic may not know whether his or her blood glucose value is increasing or decreasing, based on the SMBG alone.
Heretofore, a variety of glucose sensors have been developed for continuously measuring glucose values. Many implantable glucose sensors suffer from complications within the body and provide only short-term and less-than-accurate sensing of blood glucose. Similarly, transdermal sensors have run into problems in accurately sensing and reporting back glucose values continuously over extended periods of time. Some efforts have been made to obtain blood glucose data from implantable devices and retrospectively determine blood glucose trends for analysis; however these efforts do not aid the diabetic in determining real-time blood glucose information. Some efforts have also been made to obtain blood glucose data from transdermal devices for prospective data analysis, however similar problems have occurred.
In a first aspect, a method is provided for calibrating sensor data generated by a continuous analyte sensor, comprising: generating sensor data using a continuous analyte sensor; iteratively determining, with an electronic device, a sensitivity value of the continuous analyte sensor as a function of time by applying a priori information comprising sensor sensitivity information; and calibrating the sensor data based at least in part on the determined sensitivity value.
In an embodiment of the first aspect or any other embodiment thereof, calibrating the sensor data is performed iteratively throughout a substantially entire sensor session.
In an embodiment of the first aspect or any other embodiment thereof, iteratively determining a sensitivity value is performed at regular intervals or performed at irregular intervals, as determined by the a priori information.
In an embodiment of the first aspect or any other embodiment thereof, iteratively determining a sensitivity value is performed throughout a substantially entire sensor session.
In an embodiment of the first aspect or any other embodiment thereof, determining a sensitivity value is performed in substantially real time.
In an embodiment of the first aspect or any other embodiment thereof, the a priori information is associated with at least one predetermined sensitivity value that is associated with a predetermined time after start of a sensor session.
In an embodiment of the first aspect or any other embodiment thereof, at least one predetermined sensitivity value is associated with a correlation between a sensitivity determined from in vitro analyte concentration measurements and a sensitivity determined from in vivo analyte concentration measurements at the predetermined time.
In an embodiment of the first aspect or any other embodiment thereof, the a priori information is associated with a predetermined sensitivity function that uses time as input.
In an embodiment of the first aspect or any other embodiment thereof, time corresponds to time after start of a sensor session.
In an embodiment of the first aspect or any other embodiment thereof, time corresponds to at least one of time of manufacture or time since manufacture.
In an embodiment of the first aspect or any other embodiment thereof, the sensitivity value of the continuous analyte sensor is also a function of at least one other parameter.
In an embodiment of the first aspect or any other embodiment thereof, the at least one other parameter is selected from the group consisting of: temperature, pH, level or duration of hydration, curing condition, an analyte concentration of a fluid surrounding the continuous analyte sensor during startup of the sensor, and combinations thereof.
In an embodiment of the first aspect or any other embodiment thereof, calibrating the sensor data is performed without using reference blood glucose data.
In an embodiment of the first aspect or any other embodiment thereof, the electronic device is configured to provide a level of accuracy corresponding to a mean absolute relative difference of no more than about 10% over a sensor session of at least about 3 days, and wherein reference measurements associated with calculation of the mean absolute relative difference are determined by analysis of blood.
In an embodiment of the first aspect or any other embodiment thereof, the sensor session is at least about 4 days.
In an embodiment of the first aspect or any other embodiment thereof, the sensor session is at least about 5 days.
In an embodiment of the first aspect or any other embodiment thereof, the sensor session is at least about 6 days.
In an embodiment of the first aspect or any other embodiment thereof, the sensor session is at least about 7 days.
In an embodiment of the first aspect or any other embodiment thereof, the sensor session is at least about 10 days.
In an embodiment of the first aspect or any other embodiment thereof, the mean absolute relative difference is no more than about 7% over the sensor session.
In an embodiment of the first aspect or any other embodiment thereof, the mean absolute relative difference is no more than about 5% over the sensor session.
In an embodiment of the first aspect or any other embodiment thereof, the mean absolute relative difference is no more than about 3% over the sensor session.
In an embodiment of the first aspect or any other embodiment thereof, the a priori information is associated with a calibration code.
In an embodiment of the first aspect or any other embodiment thereof, the a priori sensitivity information is stored in the sensor electronics prior to use of the sensor.
In a second aspect, a system is provided for implementing the method of the first aspect or any embodiments thereof.
In a third aspect, a method is provided for calibrating sensor data generated by a continuous analyte sensor, the method comprising: generating sensor data using a continuous analyte sensor; determining, with an electronic device, a plurality of different sensitivity values of the continuous analyte sensor as a function of time and of sensitivity information associated with a priori information; and calibrating the sensor data based at least in part on at least one of the plurality of different sensitivity values.
In an embodiment of the third aspect or any other embodiment thereof, calibrating the continuous analyte sensor is performed iteratively throughout a substantially entire sensor session.
In an embodiment of the third aspect or any other embodiment thereof, the plurality of different sensitivity values are stored in a lookup table in computer memory.
In an embodiment of the third aspect or any other embodiment thereof, determining a plurality of different sensitivity values is performed once throughout a substantially entire sensor session.
In an embodiment of the third aspect or any other embodiment thereof, the a priori information is associated with at least one predetermined sensitivity value that is associated with a predetermined time after start of a sensor session.
In an embodiment of the third aspect or any other embodiment thereof, the at least one predetermined sensitivity value is associated with a correlation between a sensitivity determined from in vitro analyte concentration measurements and a sensitivity determined from in vivo analyte concentration measurements at the predetermined time.
In an embodiment of the third aspect or any other embodiment thereof, the a priori information is associated with a predetermined sensitivity function that uses time as input.
In an embodiment of the third aspect or any other embodiment thereof, time corresponds to time after start of a sensor session.
In an embodiment of the third aspect or any other embodiment thereof, time corresponds to time of manufacture or time since manufacture.
In an embodiment of the third aspect or any other embodiment thereof, the plurality of sensitivity values are also a function of at least one parameter other than time.
In an embodiment of the third aspect or any other embodiment thereof, the at least one other parameter is selected from the group consisting of: temperature, pH, level or duration of hydration, curing condition, an analyte concentration of a fluid surrounding the continuous analyte sensor during startup of the sensor, and combinations thereof.
In an embodiment of the third aspect or any other embodiment thereof, calibrating the continuous analyte sensor is performed without using reference blood glucose data.
In an embodiment of the third aspect or any other embodiment thereof, the electronic device is configured to provide a level of accuracy corresponding to a mean absolute relative difference of no more than about 10% over a sensor session of at least about 3 days; and wherein reference measurements associated with calculation of the mean absolute relative difference are determined by analysis of blood.
In an embodiment of the third aspect or any other embodiment thereof, the sensor session is at least about 4 days.
In an embodiment of the third aspect or any other embodiment thereof, the sensor session is at least about 5 days.
In an embodiment of the third aspect or any other embodiment thereof, the sensor session is at least about 6 days.
In an embodiment of the third aspect or any other embodiment thereof, the sensor session is at least about 7 days.
In an embodiment of the third aspect or any other embodiment thereof, the sensor session is at least about 10 days.
In an embodiment of the third aspect or any other embodiment thereof, the mean absolute relative difference is no more than about 7% over the sensor session.
In an embodiment of the third aspect or any other embodiment thereof, the mean absolute relative difference is no more than about 5% over the sensor session.
In an embodiment of the third aspect or any other embodiment thereof, the mean absolute relative difference is no more than about 3% over the sensor session.
In an embodiment of the third aspect or any other embodiment thereof, the a priori information is associated with a calibration code.
In a fourth aspect, a system is provided for implementing the method of the third aspect or any embodiments thereof.
In a fifth aspect, a method is provided for processing data from a continuous analyte sensor, the method comprising: receiving, with an electronic device, sensor data from a continuous analyte sensor, the sensor data comprising at least one sensor data point; iteratively determining a sensitivity value of the continuous analyte sensor as a function of time and of an at least one predetermined sensitivity value associated with a predetermined time after start of a sensor session; forming a conversion function based at least in part on the sensitivity value; and determining an analyte output value by applying the conversion function to the at least one sensor data point.
In an embodiment of the fifth aspect or any other embodiment thereof, the iteratively determining a sensitivity of the continuous analyte sensor is performed continuously.
In an embodiment of the fifth aspect or any other embodiment thereof, iteratively determining a sensitivity is performed in substantially real time.
In an embodiment of the fifth aspect or any other embodiment thereof, the method further comprises determining a baseline of the continuous analyte sensor, and wherein the conversion function is based at least in part on the baseline.
In an embodiment of the fifth aspect or any other embodiment thereof, determining a baseline of the continuous analyte sensor is performed continuously.
In an embodiment of the fifth aspect or any other embodiment thereof, determining a sensitivity of the continuous analyte sensor and determining a baseline of the analyte sensor are performed at substantially the same time.
In an embodiment of the fifth aspect or any other embodiment thereof, the at least one predetermined sensitivity value is set at a manufacturing facility for the continuous analyte sensor.
In an embodiment of the fifth aspect or any other embodiment thereof, the method further comprises receiving at least one calibration code; and applying the at least one calibration code to the electronic device at a predetermined time after start of the sensor session.
In an embodiment of the fifth aspect or any other embodiment thereof, iteratively determining a sensitivity is performed at regular intervals or performed at irregular intervals, as determined by the at least one calibration code.
In an embodiment of the fifth aspect or any other embodiment thereof, the at least one calibration code is associated with the at least one predetermined sensitivity.
In an embodiment of the fifth aspect or any other embodiment thereof, the at least one calibration code is associated with a predetermined sensitivity function that uses time of the function of time as input.
In an embodiment of the fifth aspect or any other embodiment thereof, time corresponds to time after start of the sensor session.
In an embodiment of the fifth aspect or any other embodiment thereof, time corresponds to time of manufacture or time since manufacture.
In an embodiment of the fifth aspect or any other embodiment thereof, the sensitivity value of the continuous analyte sensor is also a function of at least one other parameter.
In an embodiment of the fifth aspect or any other embodiment thereof, the at least one other parameter is selected from the group consisting of: temperature, pH, level or duration of hydration, curing condition, an analyte concentration of a fluid surrounding the continuous analyte sensor during startup of the sensor, and combinations thereof.
In a sixth aspect, a system is provided for implementing the method of the fifth aspect or any embodiments thereof.
In a seventh aspect, a method is provided for calibrating a continuous analyte sensor, the method comprising: receiving sensor data from a continuous analyte sensor; forming or receiving a predetermined sensitivity profile corresponding to a change in sensor sensitivity to an analyte over a substantially entire sensor session, wherein the predetermined sensitivity profile is a function of at least one predetermined sensitivity value associated with a predetermined time after start of the sensor session; and applying, with an electronic device, the sensitivity profile in real-time calibrations.
In an embodiment of the seventh aspect or any other embodiment thereof, the at least one predetermined sensitivity value, the predetermined sensitivity profile, or both are set at a manufacturing facility for the continuous analyte sensor.
In an embodiment of the seventh aspect or any other embodiment thereof, the method further comprises receiving at least one calibration code; and applying the at least one calibration code to the electronic device at a predetermined time after start of the sensor session.
In an embodiment of the seventh aspect or any other embodiment thereof, the at least one calibration code is associated with the at least one predetermined sensitivity.
In an embodiment of the seventh aspect or any other embodiment thereof, the at least one calibration code is associated with a predetermined sensitivity function that uses time as input.
In an embodiment of the seventh aspect or any other embodiment thereof, the sensitivity profile is a function of time.
In an embodiment of the seventh aspect or any other embodiment thereof, time corresponds to time after start of the sensor session.
In an embodiment of the seventh aspect or any other embodiment thereof, time corresponds to time of manufacture or time since manufacture.
In an embodiment of the seventh aspect or any other embodiment thereof, the sensitivity value is a function of time, the predetermined sensitivity value, and at least one parameter selected from the group consisting of: temperature, pH, level or duration of hydration, curing condition, an analyte concentration of a fluid surrounding the continuous analyte sensor during startup of the sensor, and combinations thereof.
In an eighth aspect, a system is provided for implementing the method of the seventh aspect or any embodiments thereof.
In a ninth aspect, a method is provided for processing data from a continuous analyte sensor, the method comprising: receiving, with an electronic device, sensor data from a continuous analyte sensor, the sensor data comprising at least one sensor data point; receiving or forming a sensitivity profile corresponding to a change in sensor sensitivity over a substantially entire sensor session; forming a conversion function based at least in part on the sensitivity profile; and determining an analyte output value by applying the conversion function to the at least one sensor data point.
In an embodiment of the ninth aspect or any other embodiment thereof, the sensitivity profile is set at a manufacturing facility for the continuous analyte sensor.
In an embodiment of the ninth aspect or any other embodiment thereof, the method comprises receiving at least one calibration code; and applying the at least one calibration code to the electronic device at a predetermined time after start of the sensor session.
In an embodiment of the ninth aspect or any other embodiment thereof, the at least one calibration code is associated with the at least one predetermined sensitivity.
In an embodiment of the ninth aspect or any other embodiment thereof, the at least one calibration code is associated with the sensitivity profile.
In an embodiment of the ninth aspect or any other embodiment thereof, the sensitivity profile is a function of time.
In an embodiment of the ninth aspect or any other embodiment thereof, time corresponds to time after start of the sensor session.
In an embodiment of the ninth aspect or any other embodiment thereof, time corresponds to time of manufacture or time since manufacture.
In an embodiment of the ninth aspect or any other embodiment thereof, the sensitivity is a function of time and at least one parameter is selected from the group consisting of: temperature, pH, level or duration of hydration, curing condition, an analyte concentration of a fluid surrounding the continuous analyte sensor during startup of the sensor, and combinations thereof.
In a tenth aspect, a system is provided for implementing the method of the ninth aspect or any embodiments thereof.
In an eleventh aspect, a system is provided for monitoring analyte concentration in a host, the system comprising: a continuous analyte sensor configured to measure analyte concentration in a host and to provide factory-calibrated sensor data, the factory-calibrated sensor data being calibrated without reference blood glucose data; wherein the system is configured to provide a level of accuracy corresponding to a mean absolute relative difference of no more than about 10% over a sensor session of at least about 3 days, wherein reference measurements associated with calculation of the mean absolute relative difference are determined by analysis of blood.
In an embodiment of the eleventh aspect or any other embodiment thereof, the sensor session is at least about 4 days.
In an embodiment of the eleventh aspect or any other embodiment thereof, the sensor session is at least about 5 days.
In an embodiment of the eleventh aspect or any other embodiment thereof, the sensor session is at least about 6 days.
In an embodiment of the eleventh aspect or any other embodiment thereof, the sensor session is at least about 7 days.
In an embodiment of the eleventh aspect or any other embodiment thereof, the sensor session is at least about 10 days.
In an embodiment of the eleventh aspect or any other embodiment thereof, the mean absolute relative difference is no more than about 7% over the sensor session.
In an embodiment of the eleventh aspect or any other embodiment thereof, the mean absolute relative difference is no more than about 5% over the sensor session.
In an embodiment of the eleventh aspect or any other embodiment thereof, the mean absolute relative difference is no more than about 3% over the sensor session.
In a twelfth aspect, a method for determining a property of a continuous analyte sensor, the method comprising: applying a bias voltage to an analyte sensor; applying a voltage step above the bias voltage to the analyte sensor; measuring, using sensor electronics, a signal response of the voltage step; determining, using the sensor electronics, a peak current of the signal response; determining, using the sensor electronics, a property of the sensor by correlating the peak current to a predetermined relationship.
In an embodiment of the twelfth aspect or any other embodiment thereof, correlating the peak current to the predetermined relationship comprises calculating an impedance of the sensor based on the peak current and correlating the sensor impedance to the predetermined relationship.
In an embodiment of the twelfth aspect or any other embodiment thereof, the property of the sensor is a sensitivity of the sensor or a temperature of the sensor.
In an embodiment of the twelfth aspect or any other embodiment thereof, the peak current is a difference between a magnitude of the response prior to the voltage step and a magnitude of the largest measured response resulting from the voltage step.
In an embodiment of the twelfth aspect or any other embodiment thereof, the predetermined relationship is an impedance-to-sensor sensitivity relationship, and wherein the property of the sensor is a sensitivity of the sensor.
In an embodiment of the twelfth aspect or any other embodiment thereof, the method further comprises compensating sensor data using the determined property of the sensor.
In an embodiment of the twelfth aspect or any other embodiment thereof, the compensating comprises correlating a predetermined relationship of the peak current to sensor sensitivity or change in sensor sensitivity and modifying a value or values of the sensor data responsive to the correlated sensor sensitivity or change in sensor sensitivity.
In an embodiment of the twelfth aspect or any other embodiment thereof, predetermined relationship is a linear relationship over time of use of the analyte sensor.
In an embodiment of the twelfth aspect or any other embodiment thereof, the predetermined relationship is a non-linear relationship over time of use of the analyte sensor.
In an embodiment of the twelfth aspect or any other embodiment thereof, wherein the predetermined relationship is determined by prior testing of sensors similar to the analyte sensor.
In an embodiment of the thirteenth aspect or any other embodiment thereof, the sensor system comprises instructions stored in computer memory, wherein the instructions, when executed by one or more processor of the sensor system, cause the sensor system to implement the method of the twelfth aspect or any embodiment thereof.
In a fourteenth aspect, a method is provided for calibrating an analyte sensor, the method comprising: applying a time-varying signal to the analyte sensor; measuring a signal response to the applied signal; determining, using sensor electronics, a sensitivity of the analyte sensor, the determining comprising correlating at least one property of the signal response to a predetermined sensor sensitivity profile; and generating, using sensor electronics, estimated analyte concentration values using the determined sensitivity and sensor data generated by the analyte sensor.
In an embodiment of the fourteenth aspect or any other embodiment thereof, the sensitivity profile comprises varying sensitivity values over time since implantation of the sensor.
In an embodiment of the fourteenth aspect or any other embodiment thereof, the predetermined sensitivity profile comprises a plurality of sensitivity values.
In an embodiment of the fourteenth aspect or any other embodiment thereof, the predetermined sensitivity profile is based on sensor sensitivity data generated from studying sensitivity changes of analyte sensors similar to the analyte sensor.
In an embodiment of the fourteenth aspect or any other embodiment thereof, the method further comprises applying a bias voltage to the sensor, wherein the time-varying signal comprises a step voltage above the bias voltage or a sine wave overlaying a voltage bias voltage.
In an embodiment of the fourteenth aspect or any other embodiment thereof, the determining further comprises calculating an impedance value based on the measured signal response and correlating the impedance value to a sensitivity value of the predetermined sensitivity profile.
In an embodiment of the fourteenth aspect or any other embodiment thereof, the method further comprises applying a DC bias voltage to the sensor to generate sensor data, wherein the estimating analyte concentration values includes generating corrected sensor data using the determined sensitivity.
In an embodiment of the fourteenth aspect or any other embodiment thereof, the method further comprises applying a conversion function to the corrected sensor data to generate the estimated analyte concentration values.
In an embodiment of the fourteenth aspect or any other embodiment thereof, the method further comprises forming a conversion function based at least in part of the determined sensitivity, and wherein the conversion function is applied to the sensor data to generate the estimated analyte concentration values.
In an embodiment of the fourteenth aspect or any other embodiment thereof, the property is a peak current value of the signal response.
In an embodiment of the fourteenth aspect or any other embodiment thereof, the determining further comprises using at least one of performing a Fast Fourier Transform on the signal response data, integrating at least a portion of a curve of the signal response, and determining a peak current of the signal response.
In an embodiment of the fourteenth aspect or any other embodiment thereof, the determining further comprises selecting the predetermined sensitivity profile based on the determined sensor property from a plurality of different predetermined sensitivity profiles.
In an embodiment of the fourteenth aspect or any other embodiment thereof, the selecting includes performing a data association analysis to determine a correlation between the determined sensor property and each of the plurality of different predetermined sensitivity profiles and wherein the selected predetermined sensitivity profile has the highest correlation.
In an embodiment of the fourteenth aspect or any other embodiment thereof, the method further comprises generating estimated analyte concentration values using the selected sensitivity profile.
In an embodiment of the fourteenth aspect or any other embodiment thereof, the method further comprises determining a second sensitivity value using the selected sensitivity profile, wherein a first set of estimated analyte concentration values is generated using the determined sensitivity value and sensor data associated with a first time period, and wherein a second set of concentration values is generated using the second sensitivity value and sensor data associated with a second time period.
In a fifteenth aspect, a sensor system is provided for implementing the method of the fourteenth aspect or any embodiments thereof.
In an embodiment of the fifteenth aspect or any other embodiment thereof, the sensor system comprises instructions stored in computer memory, wherein the instructions, when executed by one or more processors of the sensor system, cause the sensor system to implement the method of the fourteenth aspect or any embodiment thereof.
In a sixteenth aspect, a method is provided for determining whether an analyte sensor system is functioning properly, the method comprising: applying a stimulus signal to the analyte sensor; measuring a response to the stimulus signal; estimating a value of a sensor property based on the signal response; correlating the sensor property value with a predetermined relationship of the sensor property and a predetermined sensor sensitivity profile; and initiating an error routine if the correlation does not exceed a predetermined correlation threshold.
In an embodiment of the sixteenth aspect or any other embodiment thereof, correlating includes performing a data association analysis.
In an embodiment of the sixteenth aspect or any other embodiment thereof, the error routine comprises displaying a message to a user indicating that the analyte sensor is not functioning properly.
In an embodiment of the sixteenth aspect or any other embodiment thereof, the sensor property is an impedance of the sensor membrane.
In a seventeenth aspect, a sensor system is provided configured to implement the method of the sixteenth aspect or any embodiment thereof.
In an embodiment of the seventeenth aspect or any other embodiment thereof, the sensor system comprises instructions stored in computer memory, wherein the instructions, when executed by one or more processors of the sensor system, cause the sensor system to implement the method of the sixteenth aspect or any embodiment thereof.
In an eighteenth aspect, a method is provided for determining a temperature associated with an analyte sensor, the method comprising: applying a stimulus signal to the analyte sensor; measuring a signal response of the signal; and determining a temperature associated with of the analyte sensor, the determining comprising correlating at least one property of the signal response to a predetermined relationship of the sensor property to temperature.
In an embodiment of the eighteenth aspect or any other embodiment thereof, the method further comprises generating estimated analyte concentration values using the determined temperature and sensor data generated from the analyst sensor.
In an embodiment of the eighteenth aspect or any other embodiment thereof, the generating includes compensating the sensor data using the determined temperature and converting the compensated sensor data to the generated estimated analyte values using a conversion function.
In an embodiment of the eighteenth aspect or any other embodiment thereof, the generating includes forming or modifying a conversion function using the determined temperature and converting the sensor data to the generated estimated analyte values using the formed or modified conversion function.
In an embodiment of the eighteenth aspect or any other embodiment thereof, the method further comprises measuring a temperature using a second sensor, wherein the determining further comprises using the measured temperature to determine the temperature associated with the analyte sensor.
In an embodiment of the eighteenth aspect or any other embodiment thereof, the second sensor is a thermistor.
In a nineteenth aspect, a sensor system is provided configured to implement the methods of the eighteenth aspect or any embodiment thereof.
In an embodiment of the nineteenth aspect or any other embodiment thereof, the sensor system comprises instructions stored in computer memory, wherein the instructions, when executed by one or more processors of the sensor system, cause the sensor system to implement the method of the eighteenth aspect or any embodiment thereof.
In a twentieth aspect, a method is provided for determining moisture ingress in an electronic sensor system, comprising: applying a stimulus signal having a particular frequency or a signal comprising a spectrum of frequencies to an analyte sensor; measuring a response to the stimulus signal; calculating, using sensor electronics, an impedance based on the measured signal response; determining, using sensor electronics, whether the impedance falls within a predefined level corresponding to moisture ingress; initiating, using sensor electronics, an error routine if the impedance exceeds one or both of the respective predefined levels
In an embodiment of the twentieth aspect or any other embodiment thereof, the method further comprises the error routine includes one or more of triggering an audible alarm and a visual alarm on a display screen to alert a user that the sensor system may not be functioning properly.
In an embodiment of the twentieth aspect or any other embodiment thereof, the stimulus signal has a predetermined frequency.
In an embodiment of the twentieth aspect or any other embodiment thereof, the stimulus signal comprises a spectrum of frequencies.
In an embodiment of the twentieth aspect or any other embodiment thereof, the calculated impedance comprises a magnitude value and a phase value, and wherein the determination comprises comparing the impedance magnitude value to a predefined impedance magnitude threshold and the phase value to a predefined phase threshold.
In an embodiment of the twentieth aspect or any other embodiment thereof, the calculated impedance is a complex impedance value.
In a twenty-first aspect, a sensor system is provided configured to implement the methods of the twentieth aspect or any embodiment thereof.
In an embodiment of the twenty-first aspect or any other embodiment thereof, the sensor system comprises instructions stored in computer memory, wherein the instructions, when executed by one or more processors of the sensor system, cause the sensor system to implement the method of the twentieth aspect or any embodiment thereof.
In an twenty-second aspect, a method is provided for determining membrane damage of an analyte sensor using a sensor system, comprising: applying a stimulus signal to an analyte sensor; measuring a response to the stimulus signal; calculating, using sensor electronics, an impedance based on the signal response; determining, using the sensor electronics, whether the impedance falls within a predefined level corresponding to membrane damage; and initiating, using the sensor electronics, an error routine if the impedance exceeds the predefined level.
In an embodiment of the twenty-second aspect or any other embodiment thereof, the error routine includes triggering one or more of an audible alarm and a visual alarm on a display screen.
In an embodiment of the twenty-second aspect or any other embodiment thereof, the stimulus signal has a predetermined frequency.
In an embodiment of the twenty-second aspect or any other embodiment thereof, the stimulus signal comprises a spectrum of frequencies.
In an embodiment of the twenty-second aspect or any other embodiment thereof, the calculated impedance comprises a magnitude value and a phase value, and wherein the determination comprises comparing the impedance magnitude value to a predefined impedance magnitude threshold and the phase value to a predefined phase threshold.
In an embodiment of the twenty-second aspect or any other embodiment thereof, the calculated impedance is a complex impedance value.
In a twenty-third aspect, a sensor system is provided configured to implement the methods of the twenty-second aspect or any embodiment thereof.
In an embodiment of the twenty-third aspect or any other embodiment thereof, the sensor system comprises instructions stored in computer memory, wherein the instructions, when executed by one or more processors of the sensor system, cause the sensor system to implement the method of the twenty-second aspect or any embodiment thereof.
In a twenty-fourth aspect, a method for determining reuse of an analyte sensor, comprising, applying a stimulus signal to an analyte sensor, measuring a response of the stimulus signal; calculating an impedance response based on the response; comparing the calculated impedance to a predetermined threshold; initiating a sensor reuse routine if it is determined that the impedance exceeds the threshold.
In an embodiment of the twenty-fourth aspect or any other embodiment thereof, the sensor reuse routine includes triggering an audible and/or visual alarm notifying the user of improper sensor reuse.
In an embodiment of the twenty-fourth aspect or any other embodiment thereof, the sensor reuse routing includes causing a sensor system to fully or partially shut down and/or cease display of sensor data on a user interface of the sensor system.
In a twenty-fifth aspect, a sensor system is provided configured to implement the methods of the twenty-fourth aspect or any embodiments thereof.
In an embodiment of the twenty-fifth aspect or any other embodiment thereof, the sensor system comprises instructions stored in computer memory, wherein the instructions, when executed by one or more processors of the sensor system, cause the sensor system to implement the method of the twenty-fourth aspect or any embodiments thereof.
In a twenty-sixth aspect, a system is provided for determining reuse of an analyte sensor, comprising, applying a stimulus signal to an analyte sensor; measuring a response of the stimulus signal; calculating an impedance based on the response; using a data association function to determine a correlation of the calculated impedance to one or more recorded impedance values; and initiating a sensor reuse routine if it is determined that the correlation is above a predetermined threshold.
In an embodiment of the twenty-sixth aspect or any other embodiment thereof, the sensor reuse routine includes triggering an audible and/or visual alarm notifying the user of improper sensor reuse.
In an embodiment of the twenty-sixth aspect or any other embodiment thereof, the sensor reuse routing includes causing a sensor system to fully or partially shut down and/or cease display of sensor data on a user interface of the sensor system.
In an embodiment of the twenty-sixth aspect or any other embodiment thereof, the sensor system comprises instructions stored in computer memory, wherein the instructions, when executed by one or more processors of the sensor system, cause the sensor system to implement the method of the twenty-fifth aspect.
In a twenty-seventh aspect, a method is provided for applying an overpotential to an analyte sensor, comprising, applying a stimulus signal to an analyte sensor, measuring a response of the stimulus signal; determining a sensor sensitivity or change in sensor sensitivity based on the response; and applying an over potential to the sensor based on the determined sensitivity or sensitivity change.
In an embodiment of the twenty-seventh aspect or any other embodiment thereof, the determining further comprises calculating an impedance based on the response and determining the sensitivity or sensitivity change based on the impedance.
In an embodiment of the twenty-seventh aspect or any other embodiment thereof, the determining the sensitivity or sensitivity change further comprises correlating the impedance to a predetermined impedance to sensitivity relationship.
In an embodiment of the twenty-seventh aspect or any other embodiment thereof, the applying comprises determining or modifying a length of time the over potential is applied to the sensor.
In an embodiment of the twenty-seventh aspect or any other embodiment thereof, the applying comprises determining or modifying a magnitude of the over potential applied to the sensor.
In a twenty-eighth aspect, a sensor system is provided configured to implement the methods of the twenty-seventh aspect or any embodiments thereof.
In an embodiment of the twenty-eighth aspect or any other embodiment thereof, the sensor system comprises instructions stored in computer memory, wherein the instructions, when executed by one or more processors of the sensor system, cause the sensor system to implement the method of the twenty-seventh aspect or any embodiment thereof.
In a twenty-ninth aspect, a method is provided for determining a property of a continuous analyte sensor, the method comprising: applying a stimulus signal to a first analyte sensor having a first working electrode and a first reference electrode; measuring a signal response of the stimulus signal using a second analyte sensor having a second working electrode and a second reference electrode; and determining a property of the first sensor by correlating the response to a predetermined relationship.
In an embodiment of the twenty-ninth aspect or any other embodiment thereof, the method further comprises generating sensor data by applying a bias voltage to the first working electrode and measuring a response to the bias voltage.
In an embodiment of the twenty-ninth aspect or any other embodiment thereof, the method further comprises calibrating the sensor data using the determined property.
In an embodiment of the twenty-ninth aspect or any other embodiment thereof, the determined property is one of an impedance and a temperature.
In an embodiment of the twenty-ninth aspect or any other embodiment thereof, the method further comprises determining sensor membrane damage using the determined property.
In an embodiment of the twenty-ninth aspect or any other embodiment thereof, the method further comprises determining moisture ingress in a sensor system encompassing the first and second analyte sensors using the determined property.
In a thirtieth aspect, a sensor system is provided configured to implement the methods of one of the twenty-ninth aspect or any embodiments thereof.
In an embodiment of the thirtieth aspect or any other embodiment thereof, the sensor system comprises instructions stored in computer memory, wherein the instructions, when executed by one or more processors of the sensor system, cause the sensor system to implement the method of the twenty-ninth aspect or any embodiments thereof.
In a thirty-first aspect, a method is provided for determining a scaling used in a continuous analyte sensor system, the method comprising: applying a first stimulus signal to a first working electrode of an analyte sensor; measuring a response to the first stimulus signal; applying a second stimulus signal to a second working electrode of the analyte sensor; measuring a response to the first stimulus signal; determining, using sensor electronics, a scaling factor based on the measured responses to the first and second stimulus signals; and using the scaling factor to generate estimated analyte values based on sensor data generated by the analyte sensor.
In an embodiment of the thirty-first aspect or any other embodiment thereof, the method further comprises the method is performed periodically.
In an embodiment of the thirty-first aspect or any other embodiment thereof, the determining comprises calculating a first impedance using the response to the first stimulus signal and calculating a second impedance using the response to the second stimulus signal, and wherein the scaling factor is a ratio of the first impedance and the second impedance.
In an embodiment of the thirty-first aspect or any other embodiment thereof, the first working electrode has a membrane comprising an enzyme configured to react with the analyte and the second working electrode has a membrane does not have the enzyme.
In an embodiment of the thirty-first aspect or any other embodiment thereof, determining the scaling factor comprises updating a previous scaling factor based on the measured responses to the first and second stimulus signals.
In an embodiment of the thirty-first aspect or any other embodiment thereof, scaling factor is an acetaminophen scaling factor, wherein the method further comprises updating a further scaling factor based on the acetaminophen scaling factor, and wherein the further scaling factor applied to the sensor data to generate the estimated analyte values.
In a thirty-second aspect, a sensor system is provided configured to implement the methods of the thirty-first aspect or any embodiments thereof.
In an embodiment of the thirty-second aspect or any other embodiment thereof, the sensor system comprises instructions stored in computer memory, wherein the instructions, when executed by one or more processors of the sensor system, cause the sensor system to implement the method of the thirty-first aspect or any embodiment thereof.
In a thirty-third aspect, a method is provided for calibrating an analyte sensor, the method comprising: applying a predetermined signal to an analyte sensor; measuring a response to the applied signal; determining, using sensor electronics, a change in impedance associated with a membrane of the analyte sensor based on the measured response; calculating a sensitivity change of the analyte sensor based on the determined impedance; calculating a corrected sensitivity based on the calculated sensitivity change and a previously used sensitivity of the analyte sensor; and generating estimated analyte values using the corrected sensitivity.
In an embodiment of the thirty-third aspect or any other embodiment thereof, calculating the sensitivity change comprises applying a non-linear compensation function.
In an embodiment of the thirty-third aspect or any other embodiment thereof, the non-linear compensation function is expressed as the equation ΔS=(a*log(t)+b)*ΔI, where ΔS is the change in sensitivity, t is a time since calibration of the analyte sensor. ΔI is the determined change in impedance, and a and b are a predetermined coefficients.
In an embodiment of the thirty-third aspect or any other embodiment thereof, a and b are determined by prior testing of similar analyte sensors.
In a thirty-fourth aspect, a sensor system is provided configured to implement the methods of the thirty-third aspect or any embodiments thereof.
In an embodiment of the thirty-fourth aspect or any other embodiment thereof, the sensor system comprises instructions stored in computer memory, wherein the instructions, when executed by one or more processors of the sensor system, cause the sensor system to implement the method of the thirty-third aspect or any embodiments thereof.
In a thirty-fifth aspect, a method is provided for calibrating an analyte sensor, comprising: generating sensor data using a subcutaneous analyte sensor; forming or modifying a conversion function, wherein pre-implant information, internal diagnostic information, and/or external reference information are used as inputs to form or modify the conversion function; and calibrating the sensor data using the conversion function.
In an embodiment of the thirty-fifth aspect or any other embodiment thereof, the pre-implant information comprises information selected from the group consisting of: a predetermined sensitivity profile associated with the analyte sensor, a previously determined relationship between a measured sensor property and sensor sensitivity, one or more previously determined relationships between a measured sensor property and sensor temperature; sensor data obtained from previously used analyte sensors, a calibration code associated with the analyte sensor, patient specific relationships between the analyte sensor and one or more of sensitivity, baseline, drift and impedance, information indicative of a site of sensor implantation; time since manufacture of the analyte sensor, and information indicative of the analyte being exposed to temperature or humidity.
In an embodiment of the thirty-fifth aspect or any other embodiment thereof, the internal diagnostic information comprises information selected from the group consisting of: stimulus signal output; sensor data indicative of an analyte concentration measured by the sensor; temperature measurements using the sensor or a separate sensor, sensor data generated by a redundant sensor, where the redundant sensor is designed to be substantially the same as analyte sensor, sensor data generated by an auxiliary sensors, where the auxiliary sensor is having a different modality as the analyte sensor; a time since the sensor was implanted or connected to sensor electronics coupled to the sensor, data representative of a pressure on the sensor or sensor system generated by a pressure sensor; data generated by an accelerometer; a measure of moisture ingress; and a measure of noise in an analyte concentration signal.
In an embodiment of the thirty-fifth aspect or any other embodiment thereof, the reference information comprises information selected from the group consisting of: real-time and/or prior analyte concentration information obtained from a reference monitor, information relating to a type/brand of reference monitor used to provide reference data; information relating to an amount of carbohydrate consumed by a user; information received from a medicament delivery device, glucagon sensitivity information, and information gathered from population based data.
In a thirty-sixth aspect, a sensor system is provided configured to implement the methods of the thirty-fifth aspect or any embodiments thereof.
In an embodiment of the thirty-sixth aspect or any other embodiment thereof, the sensor system comprises instructions stored in computer memory, wherein the instructions, when executed by one or more processors of the sensor system, cause the sensor system to implement the method of the thirty-fifth aspect or any embodiment thereof.
These and other features and advantages will be appreciated, as they become better understood by reference to the following detailed description when considered in connection with the accompanying drawings, wherein:
In order to facilitate an understanding of the embodiments described herein, a number of terms are defined below.
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 are 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 may include naturally occurring substances, artificial substances, metabolites, and/or reaction products. In some embodiments, the analyte for measurement by the sensor heads, devices, and methods disclosed herein is glucose. However, other analytes are contemplated as well, including but not limited to acarboxyprothrombin; acylcamitine; 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; c-reactive protein; carnitine; carnosinase; CD4; ceruloplasmin; chenodeoxycholic acid; chloroquine; cholesterol; cholinesterase; conjugated 1-β hydroxy-cholic acid; cortisol; 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, analyte-6-phosphate dehydrogenase, hemoglobinopathies, A,S,C,E, D-Punjab, beta-thalassemia, hepatitis B virus, HCMV, HIV-1, HTLV-1, Leber hereditary optic neuropathy, MCAD, RNA, PKU, Plasmodium vivax, sexual differentiation, 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; analyte-6-phosphate dehydrogenase; glutathione; glutathione perioxidase; glycocholic acid; glycosylated hemoglobin; halofantrine; hemoglobin variants; hexosaminidase A; human erythrocyte carbonic anhydrase I; 17 alpha-hydroxyprogesterone; hypoxanthine phosphoribosyl transferase; immunoreactive trypsin; 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 duodenalisa, 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, Trepenoma pallidium, Trypanosoma cruzi/rangeli, vesicular stomatis virus, Wuchereria bancrofti, yellow fever virus); specific antigens (hepatitis B virus, HIV-1); succinylacetone; 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 may also constitute analytes in certain embodiments. The analyte may be naturally present in the biological fluid, for example, a metabolic product, a hormone, an antigen, an antibody, and the like. Alternatively, the analyte may 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 (barbituates, 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 may 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), and 5-Hydroxyindoleacetic acid (FHIAA).
The terms “continuous analyte sensor.” and “continuous glucose sensor.” 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 device that continuously or continually measures a concentration of an analyte/glucose and/or calibrates the device (e.g., by continuously or continually adjusting or determining the sensor's sensitivity and background), for example, at time intervals ranging from fractions of a second up to, for example, 1, 2, or 5 minutes, or longer.
The term “biological sample.” 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 sample derived from the body or tissue of a host, such as, for example, blood, interstitial fluid, spinal fluid, saliva, urine, tears, sweat, or other like fluids.
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 animals, including humans.
The term “membrane system.” 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 be comprised of two or more domains and is typically constructed of materials of a few microns thickness or more, which may be permeable to oxygen and are optionally permeable to glucose. In one example, the membrane system comprises an immobilized glucose oxidase enzyme, which enables an electrochemical reaction to occur to measure a concentration of glucose.
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 regions of a membrane that can be layers, uniform or non-uniform gradients (for example, anisotropic), functional aspects of a material, or provided as portions of the membrane.
The term “sensing region,” 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 region of a monitoring device responsible for the detection of a particular analyte. In one embodiment, the sensing region generally comprises a non-conductive body, at least one electrode, a reference electrode and a optionally a counter electrode passing through and secured within the body forming an electroactive surface at one location on the body and an electronic connection at another location on the body, and a membrane system affixed to the body and covering the electroactive surface.
The term “electroactive 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 one embodiment, a working electrode measures hydrogen peroxide (H2O2) creating a measurable electronic current.
The term “baseline,” 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 component of an analyte sensor signal that is not related to the analyte concentration. In one example of a glucose sensor, the baseline is composed substantially of signal contribution due to factors other than glucose (for example, interfering species, non-reaction-related hydrogen peroxide, or other electroactive species with an oxidation potential that overlaps with hydrogen peroxide). In some embodiments wherein a calibration is defined by solving for the equation y=mx+b, the value of b represents the baseline of the signal. In certain embodiments, 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 embodiments, calibration can be defined by solving for the equation y=mx.
The term “inactive enzyme,” 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 an enzyme (e.g., glucose oxidase, GOx) that has been rendered inactive (e.g., by denaturing of the enzyme) and has substantially no enzymatic activity. Enzymes can be inactivated using a variety of techniques known in the art, such as but not limited to heating, freeze-thaw, denaturing in organic solvent, acids or bases, cross-linking, genetically changing enzymatically critical amino acids, and the like. In some embodiments, a solution containing active enzyme can be applied to the sensor, and the applied enzyme subsequently inactivated by heating or treatment with an inactivating solvent.
The term “non-enzymatic,” 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 lack of enzyme activity. In some embodiments, a “non-enzymatic” membrane portion contains no enzyme; while in other embodiments, the “non-enzymatic” membrane portion contains inactive enzyme. In some embodiments, an enzyme solution containing inactive enzyme or no enzyme is applied.
The term “substantially,” 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 being largely but not necessarily wholly that which is specified.
The term “about,” 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 when associated with any numerical values or ranges, refers without limitation to the understanding that the amount or condition the terms modify can vary some beyond the stated amount so long as the function of the disclosure is realized.
The term “ROM,” 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 read-only memory, which is a type of data storage device manufactured with fixed contents. ROM is broad enough to include EEPROM, for example, which is electrically erasable programmable read-only memory (ROM).
The term “RAM,” 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 data storage device for which the order of access to different locations does not affect the speed of access. RAM is broad enough to include SRAM, for example, which is static random access memory that retains data bits in its memory as long as power is being supplied.
The term “A/D Converter,” 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 hardware and/or software that converts analog electrical signals into corresponding digital signals.
The terms “raw data stream” and “data stream.” 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 an analog or digital signal directly related to the analyte concentration measured by the analyte sensor. In one example, the raw data stream is digital data in counts converted by an A/D converter from an analog signal (for example, voltage or amps) representative of an analyte concentration. The terms broadly encompass a plurality of time spaced data points from a substantially continuous analyte sensor, which comprises individual measurements taken at time intervals ranging from fractions of a second up to, for example, 1, 2, or 5 minutes or longer.
The term “counts,” 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 unit of measurement of a digital signal. In one example, a raw data stream measured in counts is directly related to a voltage (for example, converted by an A/D converter), which is directly related to current from a working electrode.
The term “sensor electronics.” 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 components (for example, hardware and/or software) of a device configured to process data. In the case of an analyte sensor, the data includes biological information obtained by a sensor regarding the concentration of the analyte in a biological fluid. U.S. Pat. Nos. 4,757,022, 5,497,772 and 4,787,398 describe suitable electronic circuits that can be utilized with devices of certain embodiments.
The term “potentiostat,” 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 an electrical system that applies a potential between the working and reference electrodes of a two- or three-electrode cell at a preset value and measures the current flow through the working electrode. The potentiostat forces whatever current is necessary to flow between the working and counter electrodes to keep the desired potential, as long as the needed cell voltage and current do not exceed the compliance limits of the potentiostat.
The term “operably connected,” 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 one or more components being linked to another component(s) in a manner that allows transmission of signals between the components. For example, one or more electrodes can be used to detect the amount of glucose in a sample and convert that information into a signal; the signal can then be transmitted to an electronic circuit. In this case, the electrode is “operably linked” to the electronic circuit. These terms are broad enough to include wired and wireless connectivity.
The term “filtering,” 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 modification of a set of data to make it smoother and more continuous and remove or diminish outlying points, for example, by performing a moving average of the raw data stream.
The term “algorithm,” 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 computational processes (for example, programs) involved in transforming information from one state to another, for example using computer processing.
The term “calibration,” 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 process of determining the graduation of a sensor giving quantitative measurements (e.g., analyte concentration). As an example, calibration may be updated or recalibrated over time to account for changes associated with the sensor, such as changes in sensor sensitivity and sensor background. In addition, calibration of the sensor can involve, automatic, self-calibration. e.g., without using reference analyte values after point of use.
The terms “sensor data.” 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 data received from a continuous analyte sensor, including one or more time-spaced sensor data points.
The terms “reference analyte values” and “reference data.” 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 reference data from a reference analyte monitor, such as a blood glucose meter, or the like, including one or more reference data points. In some embodiments, the reference glucose values are obtained from a self-monitored blood glucose (SMBG) test (for example, from a finger or forearm blood test) or a YSI (Yellow Springs Instruments) test, for example.
The terms “interferents” 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, producing a false positive signal.
The term “sensor session,” 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 of time the sensor is applied to (e.g. implanted in) the host or is being used to obtain sensor values. For example, in some embodiments, a sensor session extends from the time of sensor implantation (e.g. including insertion of the sensor into subcutaneous tissue and placing the sensor into fluid communication with a host's circulatory system) to the time when the sensor is removed.
The terms “sensitivity” or “sensor sensitivity,” 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 an amount of signal produced by a certain concentration of a measured analyte, or a measured species (e.g., H2O2) associated with the measured analyte (e.g., glucose). For example, in one embodiment, a sensor has a sensitivity of from about 1 to about 300 picoAmps of current for every 1 mg/dL of glucose analyte.
The term “sensitivity profile” or “sensitivity curve,” 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 a representation of a change in sensitivity over time
Overview
Conventional in vivo continuous analyte sensing technology has typically relied on reference measurements performed during a sensor session for calibration of the continuous analyte sensor. The reference measurements are matched with substantially time corresponding sensor data to create matched data pairs. Regression is then performed on the matched data pairs (e.g., by using least squares regression) to generate a conversion function that defines a relationship between a sensor signal and an estimated glucose concentration.
In critical care settings, calibration of continuous analyte sensors is often performed by using, as reference, a calibration solution with a known concentration of the analyte. This calibration procedure can be cumbersome, as a calibration bag, separate from (and an addition to) an IV (intravenous) bag, is typically used. In the ambulatory setting, calibration of continuous analyte sensors has traditionally been performed by capillary blood glucose measurements (e.g., a finger stick glucose test), through which reference data is obtained and input into the continuous analyte sensor system. This calibration procedure typically involves frequent finger stick measurements, which can be inconvenient and painful.
Heretofore, systems and methods for in vitro calibration of a continuous analyte sensor by the manufacturer (e.g., factory calibration), without reliance on periodic recalibration, have for the most part been inadequate with respect to high levels of sensor accuracy. Part of this can be attributed to changes in sensor properties (e.g., sensor sensitivity) that can occur during sensor use. Thus, calibration of continuous analyte sensors has typically involved periodic inputs of reference data, whether they are associated with a calibration solution or with a finger stick measurement. This can be very burdensome to the patient in the ambulatory setting or the hospital staff in the critical care setting.
Described herein are continuous analyte sensors that are capable of continuous, automatic self-calibration during a sensor session and capable of achieving high levels of accuracy, without (or with reduced) reliance on reference data from a reference analyte monitor (e.g., from a blood glucose meter). In some embodiments, the continuous analyte sensor is an invasive, minimally invasive, or non-invasive device. The continuous analyte sensor can be a subcutaneous, transdermal, or intravascular device. In certain embodiments, one or more of these devices may form a continuous analyte sensor system. For instance, the continuous analyte sensor system may be comprised of a combination of a subcutaneous device and a transdermal device, a combination of a subcutaneous device and an intravascular device, a combination of a transdermal device and an intravascular device, or a combination of a subcutaneous device, a transdermal device, and an intravascular device. In some embodiments, the continuous analyte sensor can analyze a plurality of intermittent biological samples (e.g., blood samples). The continuous analyte sensor can use any glucose-measurement method, including methods involving enzymatic, chemical, physical, electrochemical, spectrophotometric, polarimetric, calorimetric, iontophoretic, and radiometric mechanisms, and the like.
In certain embodiments, the continuous analyte sensor includes one or more working electrodes and one or more reference electrode, which operate together to measure a signal associated with a concentration of the analyte in the host. The output signal from the working electrode is typically a raw data stream that is calibrated, processed, and used to generate an estimated analyte (e.g., glucose) concentration. In certain embodiments, the continuous analyte sensor may measure an additional signal associated with the baseline and/or sensitivity of the sensor, thereby enabling monitoring of baseline and/or additional monitoring of sensitivity changes or drift that may occur in a continuous analyte sensor over time.
In some embodiments, the sensor extends through a housing, which maintains the sensor on the skin and provides for electrical connection of the sensor to sensor electronics. In one embodiment, the sensor is formed from a wire. For example, the sensor can include an elongated conductive body, such as a bare elongated conductive core (e.g., a metal wire) or an elongated conductive core coated with one, two, three, four, five, or more layers of material, each of which may or may not be conductive. The elongated sensor may be long and thin, yet flexible and strong. For example, in some embodiments the smallest dimension of the elongated conductive body is less than about 0.1 inches, 0.075 inches, 0.05 inches, 0.025 inches, 0.01 inches, 0.004 inches, or 0.002 inches. Other embodiments of the elongated conductive body are disclosed in U.S. Patent Application Publication No. 2011/0027127, which is incorporated herein by reference in its entirety. Preferably, a membrane system is deposited over at least a portion of electroactive surfaces of the sensor 102 (including a working electrode and optionally a reference electrode) and provides protection of the exposed electrode surface from the biological environment, diffusion resistance (limitation) of the analyte if needed, a catalyst for enabling an enzymatic reaction, limitation or blocking of interferants, and/or hydrophilicity at the electrochemically reactive surfaces of the sensor interface. Disclosures regarding the different membrane systems that may be used with the embodiments described herein are described in U.S. Patent Publication No. US-2009-0247856-A1, which is incorporated herein by reference in its entirety.
Calibrating sensor data from continuous analyte sensors generally involves defining a relationship between sensor-generated measurements (e.g., in units of nA or digital counts after A/D conversion) and one or more reference measurement (e.g., in units of mg/dL or mmol/L). In certain embodiments, one or more reference measurements obtained shortly after the analyte sensor is manufactured, and before sensor use, are used for calibration. The reference measurement may be obtained in many forms. For example, in certain embodiments, the reference measurement may be determined from a ratio or correlation between the sensitivity of a sensor (e.g., from a certain sensor lot) with respect to in vivo analyte concentration measurements and the sensitivity of another sensor (e.g., from the same lot made in substantially the same way under substantially same conditions) with respect to in vitro analyte concentration measurements at a certain time period. By providing a continuous analyte sensor with a predetermined in vivo to in vitro ratio and a predetermined sensitivity profile (as described in more detail elsewhere herein), self-calibration of the sensor can be achieved in conjunction with high levels of sensor accuracy.
With self-calibration, the need for recalibration, by using reference data during a sensor session, may be eliminated, or else lessened, such that recalibration may be called for only in certain limited circumstances, such as when sensor failure is detected. Additionally or alternatively, in some embodiments, the continuous analyte sensor may be configured to request and accept one or more reference measurements (e.g., from a finger stick glucose measurement or a calibration solution) at the start of the sensor session. In some embodiments, use of a reference measurement at the start of the sensor session in conjunction with a predetermined sensor sensitivity profile can eliminate or substantially reduce the need for further reference measurements.
With certain implantable enzyme-based electrochemical glucose sensors, the sensing mechanism depends on certain phenomena that have a generally linear relationship with glucose concentration, for example: (1) diffusion of an analyte through a membrane system situated between an implantation site (e.g., subcutaneous space) and an electroactive surface, (2) rate of an enzyme-catalyzed reaction of the analyte to produce a measured species within the membrane system (e.g., the rate of a glucose oxidase-catalyzed reaction of glucose with O2 which produces gluconic acid and H2O2), and (3) diffusion of the measured species (e.g., H2O2) to the electroactive surface. Because of this generally linear relationship, calibration of the sensor is obtained by solving the equation:
y=mx+b
wherein y represents the sensor signal (counts), x represents the estimated glucose concentration (mg/dL), m represents the sensor sensitivity to analyte concentration (counts/mg/dL), and b represents the baseline signal (counts). As described elsewhere herein, in certain embodiments, the value b (i.e., the baseline) can be zero or about zero. As a result, for these embodiments, calibration can be defined by solving for the equation y=mx.
In some embodiments, the continuous analyte sensor system is configured to estimate changes or drift in sensitivity of the sensor for an entire sensor session as a function of time (e.g., elapsed time since start of the sensor session). As described elsewhere herein, this sensitivity function plotted against time may resemble a curve. Additionally or alternatively, the system can also be configured to determine sensor sensitivity changes or drift as a function of time and one or more other parameters that can also affect sensor sensitivity or provide additional information about sensor sensitivity. These parameters can affect sensor sensitivity or provide additional information about sensor sensitivity prior to the sensor session, such as parameters associated with the sensor fabrication (e.g., materials used to fabricate sensor membrane, the thickness of the sensor membrane, the temperature at which the sensor membrane was cured, the length of time the sensor was dipped in a particular coating solution, etc.). In certain embodiments, some of the parameters involve information, obtained prior to the sensor session, which can be accounted for in a calibration code that is associated with a particular sensor lot. Other parameters can be associated with conditions surrounding the sensor after its manufacture, but before the sensor session, such as, for example, the level of exposure of the sensor to certain levels of humidity or temperature while the sensor is in a package in transit from the manufacturing facility to the patient. Yet other parameters (e.g., sensor membrane permeability, temperature at the sample site, pH at the sample site, oxygen level at the sample site, etc.) can affect sensor sensitivity or provide additional information about sensor sensitivity during the sensor session.
Determination of sensor sensitivity at different times of a sensor session based on the predetermined sensor sensitivity profile can be performed prior to the sensor session or at the start of the sensor session. Additionally, in certain embodiments, determination of sensor sensitivity, based on the sensor sensitivity profile, can be continuously adjusted to account for parameters that affect sensor sensitivity or provide additional information about sensor sensitivity during the sensor session. These determinations of sensor sensitivity change or drift can be used to provide self-calibration, update calibration, supplement calibration based on measurements (e.g., from a reference analyte monitor), and/or validate or reject reference analyte measurements from a reference analyte monitor. In some embodiments, validation or rejection of reference analyte measurements can be based on whether the reference analyte measurements are within a range of values associated with the predetermined sensor sensitivity profile.
Some of the continuous analyte sensors described herein may be configured to measure a signal associated with a non-analyte constant in the host. Preferably, the non-analyte constant signal is measured beneath the membrane system on the sensor. In one example of a continuous glucose sensor, a non-glucose constant that can be measured is oxygen. In some embodiments, a change in oxygen transport, which can be indicative of a change or drift in the sensitivity of the glucose signal, can be measured by switching the bias potential of the working electrode, an auxiliary oxygen-measuring electrode, an oxygen sensor, or the like.
Additionally, some of the continuous analyte sensors described herein may be configured to measure changes in the amount of background noise in the signal. Detection of changes which exceed a certain threshold can provide the basis for triggering calibration, updating calibration, and/or validating or rejecting inaccurate reference analyte values from a reference analyte monitor. In one example of a continuous glucose sensor, the background noise is composed substantially of signal contribution from factors other than glucose (for example, interfering species, non-reaction-related hydrogen peroxide, or other electroactive species with an oxidation potential that overlaps with hydrogen peroxide). Namely, the continuous glucose sensor is configured to measure a signal associated with the baseline (which includes substantially all non-glucose related current generated), as measured by the sensor in the host. In some embodiments, an auxiliary electrode located beneath a non-enzymatic portion of the membrane system is used to measure the baseline signal. The baseline signal can be subtracted from the glucose+baseline signal to obtain a signal associated entirely or substantially entirely with glucose concentration. Subtraction may be accomplished electronically in the sensor using a differential amplifier, digitally in the receiver, and/or otherwise in the hardware or software of the sensor or receiver as described in more detail elsewhere herein.
Together, by determining sensor sensitivity based on a sensitivity profile and by measuring a baseline signal, the continuous analyte sensor can be continuously self-calibrated during a sensor session without (or with reduced) reliance on reference measurements from a reference analyte monitor or calibration solution.
Determination of Sensor Sensitivity
As described elsewhere herein, in certain embodiments, self-calibration of the analyte sensor system can be performed by determining sensor sensitivity based on a sensitivity profile (and a measured or estimated baseline), so that the following equation can be solved:
y=mx+b
wherein y represents the sensor signal (counts), x represents the estimated glucose concentration (mg/dL), m represents the sensor sensitivity to the analyte (counts/mg/dL), and b represents the baseline signal (counts). From this equation, a conversion function can be formed, whereby a sensor signal is converted into an estimated glucose concentration.
It has been found that a sensor's sensitivity to analyte concentration during a sensor session will often change or drift as a function of time.
Referring back to the study associated with
With the sensors tested in this study, the change in sensor sensitivity (expressed as a percentage of a substantially steady state sensitivity), over a time defined by a sensor session, resembled a logarithmic growth curve. It should be understood that other continuous analyte sensors fabricated with different techniques, with different specifications (e.g., different membrane thickness or composition), or under different manufacturing conditions, may exhibit a different sensor sensitivity profile (e.g., one associated with a linear function). Nonetheless, with improved control over operating conditions of the sensor fabrication process, high levels of reproducibility have been achieved, such that sensitivity profiles exhibited by individual sensors of a sensor population (e.g., a sensor lot) are substantially similar and sometimes nearly identical.
It has been discovered that the change or drift in sensitivity over a sensor session is not only substantially consistent among sensors manufactured in substantially the same way under substantially same conditions, but also that modeling can be performed through mathematical functions that can accurately estimate this change or drift. As illustrated in
In some embodiments, a sensor may undergo an in vitro sensor sensitivity drift test, in which the sensor is exposed to changing conditions (e.g., step changes of glucose concentrations in a solution), and an in vitro sensitivity profile of the sensor is generated over a certain time period. The time period of the test may substantially match an entire sensor session of a corresponding in vivo sensor, or it may encompass a portion of the sensor session (e.g., the first day, the first two days, or the first three days of the sensor session, etc.). It is contemplated that the above-described test may be performed on each individual sensor, or alternatively on one or more sample sensors of a sensor lot. From this test, an in vitro sensitivity profile may be created, from which an in vivo sensitivity profile may be modeled and/or formed.
From the in vivo or in vitro testing, one or more data sets, each comprising data points associating sensitivity with time, may be generated and plotted. A sensitivity profile or curve can then be fitted to the data points. If the curve fit is determined to be satisfactory (e.g., if the standard deviation of the generated data points is less a certain threshold), then the sensor sensitivity profile or curve may be judged to have passed a quality control and suitable for release. From there, the sensor sensitivity profile can be transformed into an estimative algorithm function or alternatively into a look-up table. The algorithm function or look-up table can be stored in a computer-readable memory, for example, and accessed by a computer processor.
The estimative algorithm function may be formed by applying curve fitting techniques that regressively fit a curve to data points by adjusting the function (e.g., by adjusting constants of the function) until an optimal fit to the available data points is obtained. Simply put, a “curve” (i.e., a function sometimes referred to as a “model”) is fitted and generated that relates one data value to one or more other data values and selecting parameters of the curve such that the curve estimates the relationship between the data values. By way of example, selection of the parameters of the curve may involve selection of coefficients of a polynomial function. In some embodiments, the curve fitting process may involve evaluating how closely the curve determined in the curve fitting process estimates the relationship between the data values, to determine the optimal fit. The term “curve.” 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 to a function or a graph of a function, which can involve a rounded curve or a straight curve, i.e., a line.
The curve may be formed by any of a variety of curve fitting techniques, such as, for example, the linear least squares fitting method, the non-linear least squares fitting method, the Nelder-Mead Simplex method, the Levenberg-Marquardt method, and variations thereof. In addition, the curve may be fitted using any of a variety of functions, including, but not limited to, a linear function (including a constant function), logarithmic function, quadratic function, cubic function, square root function, power function, polynomial function, rational function, exponential function, sinusoidal function, and variations and combinations thereof. For example, in some embodiments, the estimative algorithm comprises a linear function component which is accorded a first weight w1, a logarithmic function component which is accorded a second weight w2, and an exponential function component which is accorded a third weight w3. In further embodiments, the weights associated with each component can vary as a function of time and/or other parameters, but in alternative embodiment, one or more of these weights are constant as a function of time.
In certain embodiments, the estimative algorithm function's correlation (e.g., R2 value), which is a measure of the quality of the fit of the curve to the data points, with respect to data obtained from the sample sensors, may be one metric used to determine whether a function is optimal. In certain embodiments, the estimative algorithm function formed from the curve fitting analysis may be adjusted to account for other parameters, e.g., other parameters that may affect sensor sensitivity or provide additional information about sensor sensitivity. For example, the estimative algorithm function may be adjusted to account for the sensitivity of the sensor to hydrogen peroxide or other chemical species.
Estimative algorithms formed and used to accurately estimate an individual sensor's sensitivity, at any time during a sensor session, can be based on factory calibration and/or based on a single early reference measurement (e.g., using a single point blood glucose monitor). In some embodiments, sensors across a population of continuous analyte sensors manufactured in substantially the same way under substantially same conditions exhibit a substantially fixed in vivo to in vitro sensitivity relationship. For example, in one embodiment, the in vivo sensitivity of a sensor at a certain time after start of sensor use (e.g., at t=about 5, 10, 15, 30, 60, 120, or 180 minutes after sensor use) is consistently equal to a measured in vitro sensitivity of the sensor or of an equivalent sensor. From this relationship, an initial value of in vivo sensitivity can be generated, from which an algorithmic function corresponding to the sensor sensitivity profile can be formed. Put another way, from this initial value (which represents one point in the sensor sensitivity profile), the rest of the entire sensor sensitivity profile can be determined and plotted. The initial value of in vivo sensitivity can be associated with any portion of the sensor sensitivity profile. In certain embodiments, multiple initial values of in vivo sensitivities, which are time-spaced apart, and which correspond to multiple in vitro sensitivities, can be calculated and combined together to generate the sensor sensitivity profile.
In some embodiments, as illustrated in
With other embodiments, although the in vivo to in vitro sensitivity relationship was not equal, the relationship nonetheless involved a consistently fixed ratio. By having a substantially fixed in vivo to in vitro sensitivity relationship, some of the sensors described herein can be factory calibrated by evaluating the in vitro sensitivity characteristic (e.g., one or more sensitivity values measured at certain time periods) of a sensor from a particular sensor lot at a manufacturing facility, defining the in vivo sensitivity characteristic of other sensors in the same sensor lot based on its relationship with the measured in vitro sensitivity characteristic, and storing this calculated in vivo sensitivity characteristic onto electronics associated with the sensors (e.g., in computer memory of a sensor electronics, discussed more elsewhere herein, configured to be operably coupled to the sensor during sensor use).
Accordingly, with information obtained prior to the sensor session relating to an in vivo to in vitro sensor sensitivity relationship and a predetermined sensor sensitivity profile, factory calibration is achieved in conjunction with high levels of sensor accuracy. For example, in some embodiments, the sensor was capable of achieving an accuracy corresponding to a mean absolute relative difference of no more than about 10% over a sensor session of at least about 3 days, and sometimes at least about 4, 5, 6, 7, or 10 days. In some embodiments, the sensor was capable of achieving an accuracy, over a over a sensor session of at least about 3 days, corresponding to a mean absolute relative difference of no more than about 7%, 5%, or 3%. With factory calibration, the need for recalibration may be eliminated, or else required only in certain circumstances, such as in response to detection of sensor failure.
With reference back to the study associated with
As illustrated in
While individual sensors of a sensor group manufactured under substantially identical conditions have been found to generally exhibit a substantially similar or a nearly identical sensor sensitivity profile and have a substantially similar or a nearly identical in vivo to in vitro sensor sensitivity relationship, it has been found that at times the actual sensor sensitivity (i.e., sensitivity expressed as an actual sensitivity value, and not as a percentage of a substantially steady state sensitivity) can vary between sensors. For example, even though individual sensors may have been manufactured under substantially identical conditions, they can have different sensitivity characteristics during use if they are exposed to different environment conditions (e.g., exposure to radiation, extreme temperature, abnormal dehydration conditions, or any environment that can damage the enzyme in the sensor membrane or other parts of the sensor, etc.) during the time period between sensor fabrication and sensor use.
Accordingly, to compensate for potential effects resulting from these conditions, in certain embodiments, the continuous analyte sensors are configured to request and accept one or more reference measurements (e.g., from a finger stick glucose measurement or from a calibration solution) at the start of the sensor session. For example, the request for one or more reference measurements can be made at about 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, etc., after activation of the sensor. In some embodiments, sensor electronics are configured to process and use the reference data to generate (or adjust) a sensor sensitivity profile in response to the input of one or more reference measurements into the sensor. For example, if a reference measurement of glucose concentration is taken and input into the sensor at time=x, an algorithmic function of sensor sensitivity can be generated by matching the sensor sensitivity profile at time=x with the reference measurement. Use of the one of the one or more reference measurements at the start of the sensor in conjunction with a predetermined sensor sensitivity profile permits self-calibration of the sensor without or with a reduced need for further reference measurements.
Alternatively, instead of a fixed sensitivity value, the in vivo to in vitro sensor sensitivity relationship may be defined as a function of time between completion of sensor fabrication (or the time calibration check was performed on sensors from the same lot) and the start of the sensor session. As shown in
Information obtained prior to the sensor session can also include information relating to certain sensor characteristics or properties. By way of example and not to be limiting, information obtained prior to the sensor session may include the particular materials used to fabricate the sensor (e.g., materials used to form the sensor membrane), the thickness of the sensor membrane, the membrane's permeability to glucose or other chemical species, the in vivo or in vitro sensor sensitivity profile of another sensor made in substantially the same way under substantially same conditions, etc. In certain embodiments, information obtained prior to the sensor session can include information relating to the process conditions under which the sensor is fabricated. This information can include, for example, the temperature at which the sensor membrane was cured, the length of time the sensor was dipped in a particular coating solution, etc. In other embodiments, information obtained prior to the sensor session can relate to patient physiological information. For example, the patient's age, body mass index, gender, and/or historic patient sensitivity profiles, can be used as parameters to form the sensor sensitivity profile. Other information obtained prior to the sensor session that may also be used includes information relating to sensor insertion, such as, for example, location (e.g., abdomen vs. back) or depth of sensor insertion.
In general, the sensor sensitivity functions can be created by theoretical or empirical methods, or both, and stored as functions or as look-up-tables, thereby allowing for sensor self-calibration that eliminates (or substantially reduces) the need for reference measurements. The sensor sensitivity functions can be generated at the manufacturing facility and shipped with the system or generated by the system shortly prior to (or during) use. The term “self-calibration,” 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 calibration of a sensor or device which is performed by a control system manufacturer or installer, the sensor manufacturer, or anyone other than the user of the sensor. The sensor calibration can be performed on the individual sensor on which the control system is installed, or it can be performed on a reference sensor, for example one from the same sensor lot, and the calibration functions can be transferred from one control system to another. In some embodiments, systems may be shipped with some self-calibration functions and then have others added by the sensor user. Also, sensor systems may be shipped with self-calibration functions and only need adjustments or touch-up calibrations during use.
In certain embodiments, the sensor sensitivity profile may be adjusted during sensor use to account for, in real-time, certain parameters that may affect sensor sensitivity or provide additional information about sensor sensitivity. These parameters may include, but are not limited to, parameters associated with sensor properties, such as, for example, sensor membrane permeability or the level of sensor hydration, or parameters associated with patient physiological information, such as, for example, patient temperature (e.g., temperature at the sample site or skin temperature). pH at the sample site, hematocrit level, or oxygen level at the sample site. In some embodiments, the continuous analyte sensor may be fitted with a thermistor on an ex vivo portion of the sensor and a thermal conductive line that extends from the thermistor to the sample site.
In some embodiments, calibration methods can be improved by algorithmically quantifying each unique sensor/user environment. Quantification can be achieved by generation or adjustment of the sensitivity profile, which may involve an inference engine involving a causal probabilistic network such as a Bayesian network. A Bayesian network includes a conditional probability-based network that relies on the Bayes theorem to characterize the likelihood of different outcomes based on known prior probabilities (e.g., prevalence of observed in vivo sensitivities under certain parameter conditions) and newly acquired information (e.g., occurrence or nonoccurrence of the aforementioned conditions).
In certain embodiments, quantification is achieved through the application of an analytical Bayesian framework to data already existing within the system algorithm. Quantification can involve: (1) wedge (e.g., maximum or minimum) values for parameters related to sensitivity and baseline; (2) sensitivity values calculated during a sensor session; and (3) baselines calculated during the sensor session. In some embodiments, the first set of wedge values are based on parameter distributions of “prior” data (e.g., data collected from previous clinical studies). By using a Bayesian network, a system can learn from data collected during the sensor session, and adapt the wedge values (or other algorithm parameters and/or constraints) to a particular sensor/user environment. In turn, the system's calibration method can be improved to have better accuracy, reliability, and overall performance.
In one embodiment, the Bayesian framework used involves using known prior information to establish a framework and then accounting for gathered new information to make inferences from their combination (i.e., combination of prior and new information), to generate posterior information. When the prior information and the new information are mathematically related and combined to form posterior information that can be represented functionally, the relationship is defined as conjugate. The Bayesian framework of one embodiment employs conjugate distributional relationships that result in the posterior distributional parameters (e.g., mean, variance) being directly available. This can be advantageous under a computationally restrictive space where both time and resources are constrained.
In some embodiments, under the Bayesian framework, in which the wedge parameters follow a prior substantially normal distribution for each parameter, and in which the algorithmically calculated sensitivity and baseline values follow their own substantially normal distribution representing the new information, an independent posterior distribution for sensitivity and/or baseline can be generated. These two posterior distributions are then used in parallel to construct glucose threshold values used for accepting, rejecting, or modifying a user's manual calibration entry (e.g., entry from a fingerstick measurement). In certain embodiments, the posterior distributions of sensitivity and baseline can also be used for semi-self-calibration, thereby reducing the number of fingerstick measurements required for manual calibration.
In one exemplary embodiment, from prior information, the wedge min/max values for a sensor's sensitivity to glucose are known to be A and B at the 95% confidence interval in a substantially normal distribution. Using algorithmically calculated sensitivity values as new information, the previous three, four, five, six, seven, or more sensitivity values calculated through manual calibration can be used as new information to generate a posterior distribution, which will typically have reduced variability than the distribution based on prior information, and which is a direct quantification of a unique sensor/user environment. Because of reduced variability, the posterior distribution generated will typically have wedge values, which should be closer together than the difference between A and B. i.e., the wedge values of the distribution generated from prior information. This tightening of the difference between the wedge values between the prior distribution and the posterior distribution allow the system to more reliably reject manual calibration entries that are clearly erroneous, such as, for example, a calibration entry of 60 mg/dL that was intended by the user to be an entry of 160 mg/dL
Bayesian networks use causal knowledge and model probabilistic dependence and independence relationships between different events.
During sensor use, the confidence interval curves 730, 730′, and/or 730″ may be used to form the sensitivity profile 710, which provides an estimated sensitivity value at a given time. In turn the estimated sensitivity value may be used to calibrate the sensor, which allows for processing of sensor data to generate a glucose concentration value that is displayed to the user. In some embodiments, a first estimated sensitivity profile 710, formed from the confidence interval curves 730, 730′, and/or 730″, may be used to monitor and display glucose concentrations. In addition, one or more of the confidence interval curves 730, 730′, 730″, or combinations thereof, can be used to form a second estimated sensitivity profile that, while possibly not as accurate as the first estimated sensitivity profile, is nonetheless more likely to result in the detection of a hypoglycemic or hyperglycemic range than the first estimated sensitivity profile 710.
Determination of Baseline
A variety of types of noise can occur when a sensor is implanted in a host. Some implantable sensors measure a signal (e.g., counts) that comprises two components, the baseline signal and the analyte signal. The baseline signal is substantially comprised of a signal contribution from factors other than the measure analyte (e.g., interfering species, non-reaction-related hydrogen peroxide, or other electroactive species with an oxidation potential that overlaps with the analyte or co-analyte). The analyte signal (e.g., glucose signal) is substantially comprised of a signal contribution from the analyte. Consequently, because the signal includes these two components, calibration can be performed to determine the analyte (e.g., glucose) concentration by solving for the equation y=mx+b, wherein the value of b represents the baseline of the signal. In some circumstances, the baseline is comprised of constant and non-constant non-analyte factors. Generally, it is desirable to reduce or remove the background signal, to provide a more accurate analyte concentration to the patient or health care professional.
In certain embodiments, an analyte sensor (e.g., glucose sensor) is configured for insertion into a host for measuring an analyte in the host. The sensor includes a working electrode disposed beneath an active enzymatic portion of a membrane on the sensor, an auxiliary electrode disposed beneath an inactive- or non-enzymatic portion of the membrane on the sensor, and sensor electronics operably connected to the working and auxiliary electrodes. The sensor electronics are configured to process signals from the electrodes to generate an analyte (e.g., glucose) concentration estimate that substantially excludes signal contribution from non-glucose related noise artifacts.
In some embodiments, the working electrode is configured to generate via sensor electronics a first signal associated with both the analyte and non-analyte related electroactive compounds that have a oxidation potential less than or similar to a first oxidation potential. The auxiliary electrode is configured to generate a second signal associated with the non-analyte related electroactive compounds. Non-analyte related electroactive compounds can be any compound, present in the sensor's local environment, which has an oxidation potential less than or similar to the oxidation potential of the measured species (e.g., H2O2). While not wishing to be bound by theory, it is believed that with a glucose-measuring electrode, both the signal directly related to the enzyme-catalyzed reaction of glucose (which produces H2O2 that is oxidized at the first working electrode) and signals from unknown compounds that are in the extracellular milieu surrounding the sensor can be measured. These unknown compounds can be constant or non-constant (e.g., intermittent or transient) in concentration and/or effect. In some circumstances, it is believed that some of these unknown compounds can be related to the host's disease state. For example, it is known that blood chemistry can change dramatically during/after a heart attack (e.g., pH changes, changes in the concentration of various blood components/protein, and the like). As another example, the transcutaneous insertion of a needle-type sensor can initiate a cascade of events that includes the release of various reactive molecules by macrophages. Other compounds that can contribute to the non-glucose related signal are compounds associated with the wound healing process, which can be initiated by implantation/insertion of the sensor into the host, as described in more detail with reference to U.S. Patent Publication No. US-2007-0027370-A1.
As described above, the auxiliary electrode is configured to generate a second signal associated with the non-analyte related electroactive compounds that have an oxidation potential less than or similar to the first oxidation potential. Non-analyte related electroactive species can include interfering species, non-reaction-related species (e.g., H2O2) that correspond to the measured species, and other electroactive species. Interfering species includes any compound that is not directly related to the electrochemical signal generated by the enzyme-catalyzed reaction of the analyte, such as, electroactive species in the local environment produced by other bodily processes (e.g., cellular metabolism, wound healing, a disease process, and the like). Non-reaction-related species includes any compound from sources other than the enzyme-catalyzed reaction, such as, H2O2 released by nearby cells during the course of the cells' metabolism, H2O2 produced by other enzymatic reactions (e.g., extracellular enzymes around the sensor or such as can be released during the death of nearby cells or such as can be released by activated macrophages), and the like. Other electroactive species includes any compound that has an oxidation potential less than or similar to the oxidation potential of H2O2.
The non-analyte signal produced by compounds other than the analyte (e.g., glucose) is considered as background noise and can obscure the signal related to the analyte, thereby contributing to sensor inaccuracy. As described in greater detail elsewhere herein, background noise can include both constant and non-constant components and can be removed to accurately calculate the analyte concentration.
In certain embodiments, the analyte sensor system is configured in a way (e.g., with a certain symmetry, coaxial design, and/or integral formation) such that the working and auxiliary electrodes are influenced by substantially the same external/environmental factors, thereby enabling substantially equivalent measurement of both the constant and non-constant species/noise. This allows for the substantial elimination of noise on the sensor signal by using sensor electronics described elsewhere herein. In turn, the substantial reduction or elimination of signal effects associated with noise, including non-constant noise (e.g., transient, unpredictable biologically related noise) increases accuracy of continuous sensor signals.
In some embodiments, sensor electronics are operably connected to the working and auxiliary electrodes. The sensor electronics may be configured to measure the current (or voltage) to generate the first and second signals. Collectively, the first and second signals can be used to produce glucose concentration data without substantial signal contribution from non-glucose-related noise. This can be performed, for example, by subtraction of the second signal from the first signal to produce a signal associated with analyte concentration and without substantial noise contribution, or by alternative data analysis techniques.
In other embodiments, the sensor electronics are operably connected to one or more working electrodes only, as an auxiliary electrode is not needed. For example, the sensor membrane in some embodiments may comprise polymers that contain mediators and enzymes that chemically attach to the polymers. The mediator used may oxidize at lower potentials than hydrogen peroxide, and thus fewer oxidizable interferents are oxidized at these low potentials. Accordingly, in some embodiments, a very low baseline (i.e., a baseline that approaches a zero baseline and that does not receive substantial signal contribution from non-glucose-related noise) may be achieved, thereby potentially eliminating (or reducing) the need for an auxiliary electrode that measures signal contribution from non-glucose-related noise.
The sensor electronics can be comprised of a potentiostat, A/D converter, RAM, ROM, transceiver, processor, and/or the like. The potentiostat may be used to provide a bias to the electrodes and to convert the raw data (e.g., raw counts) collected from the sensor to an analyte concentration value (e.g., a glucose concentration value expressed in units of mg/dL). The transmitter may be used to transmit the first and second signals to a receiver, where additional data analysis and/or calibration of analyte concentration can be processed. In certain embodiments, the sensor electronics may perform additional operations, such as, for example, data filtering and noise analysis.
In certain embodiments, the sensor electronics may be configured to analyze an analyte equivalent baseline or normalized baseline, instead of the baseline. The normalized baseline is calculated as the b/m or y-intercept divided by slope (from the equation y=mx+b). The unit for analyte equivalent baseline may be expressed as the analyte concentration unit (mg/dL), which correlates with the output of the continuous analyte sensor. By using the analyte equivalent baseline (normalized baseline), the influence of glucose sensitivity on the baseline may be eliminated, thereby making it possible to evaluate the baselines of different sensors (e.g., from the same sensor lot or from different sensor lots) with different glucose sensitivities.
Although some embodiments have been described herein which employ an auxiliary electrode to allow for the subtraction of a baseline signal from a glucose+baseline signal, it should be understood that the use of this electrode is optional and may not be used in other embodiments. For example, in certain embodiments, the membrane system covering the working electrode is capable of substantially blocking interferents, and substantially reducing the baseline to a level that is negligible, such that the baseline can be estimated. Estimation of the baseline can be based on an assumption of the sensor's baseline at physiological conditions associated with a typical patient. For example, baseline estimation can be modeled after in vivo or in vitro measurements of baseline in accordance with certain physiological levels of interferents that are inherent in the body.
With some embodiments, it has been found that not only does the sensor's sensitivity tend to drift over time, but that the sensor's baseline also drifts over time. Accordingly, in certain embodiments, the concepts behind the methods and systems used to predict sensitivity drift can also be applied to create a model that predicts baseline drift over time. Although not wishing to be bound by theory, it is believed that the total signal received by the sensor electrode is comprised of a glucose signal component, an interference signal component, and a electrode-related baseline signal component that is a function of the electrode and that is substantially independent of the environment (e.g., extracellular matrix) surrounding the electrode. As noted above, the term “baseline,” as used herein, refers without limitation to the component of an analyte sensor signal that is not related to the analyte concentration. Accordingly, the baseline, as the term is defined herein, is comprised of the interference signal component and the electrode-related baseline signal component. While not wishing to be bound by theory, it is believed that increased membrane permeability typically not only results in an increased rate of glucose diffusion across the sensor membrane, but also to an increased rate of diffusion of interferents across the sensor membrane. Accordingly, changes in sensor membrane permeability over time which causes sensor sensitivity drift, will similarly also likely cause the interference signal component of the baseline to drift. Simply put, the interference signal component of the baseline is not static, and is typically changing as a function of time, which, in turn, causes the baseline to also drift over time. By analyzing how each of the aforementioned components of the baseline reacts to changing conditions and to time (e.g., as a function of time, temperature), a predictive model can be developed to predict how the baseline of a sensor will drift during a sensor session. By being able to prospectively predict both sensitivity and baseline of the sensor, it is believed that a self-calibrating continuous analyte sensor can be achieved. i.e., a sensor that does not require use of reference measurements (e.g., a fingerstick measurement) for calibration.
Calibration Code
The process of manufacturing continuous analyte sensors may sometimes be subjected to a degree of variability between sensor lots. To compensate for this variability, one or more calibration codes may be assigned to each sensor or sensor set to define parameters that can affect sensor sensitivity or provide additional information about the sensitivity profile. The calibration codes can reduce variability in the different sensors, ensuring that the results obtained from using sensors from different sensors lots will be generally equal and consistent by applying an algorithm that adjusts for the differences. In one embodiment, the analyte sensor system may be configured such that one or more calibration codes are to be manually entered into the system by a user. In other embodiments, the calibration codes may be part of a calibration encoded label that is adhered to (or inserted into) a package of multiple sensors. The calibration encoded label itself may be read or interrogated by any of a variety of techniques, including, but not limited to, optical techniques, RFID (Radio-frequency identification), or the like, and combinations thereof. These techniques for transferring the code to the sensor system may be more automatic, accurate, and convenient for the patient, and less prone to error, as compared to manual entry. Manual entry, for instance, possesses the inherent risk of an error caused by a patient or hospital staff entering the wrong code, which can lead to an incorrect calibration, and thus inaccurate glucose concentration readings. In turn, this may result in a patient or hospital staff taking an inappropriate action (e.g., injecting insulin while in a hypoglycemic state).
In some embodiments, calibration codes assigned to a sensor may include a first calibration code associated with a predetermined logarithmic function corresponding to a sensitivity profile, a second calibration code associated with an initial in vivo sensitivity value, and other calibration codes, with each code defining parameter that affects sensor sensitivity or provides information about sensor sensitivity. The other calibration codes may be associated with any priori information or parameter described elsewhere herein and/or any parameter that helps define a mathematical relationship between the measured signal and analyte concentration.
In some embodiments, the package used to store and transport a continuous analyte sensor (or sensor set) may include detectors configured to measure certain parameters that may affect sensor sensitivity or provide additional information about sensor sensitivity or other sensor characteristics. For example, in one embodiment, the sensor package may include a temperature detector configured to provide calibration information relating to whether the sensor has been exposed to a temperature state greater than (and or less than) one or more predetermined temperature values. In some embodiments, the one or more predetermined temperature value may be greater than about 75° F., greater than about 80° F., greater than about 85° F., greater than about 90° F., greater than about 95° F., greater than about 100° F. greater than about 105° F., and/or greater than about 110° F. Additionally or alternatively, the one or more predetermined temperature value may be less than about 75° F., less than about 70° F., less than about 60° F., less than about 55° F., less than about 40° F., less than about 32° F., less than about 10° F., and/or less than about 0° F. In certain embodiments, the sensor package may include a humidity exposure indicator configured to provide calibration information relating to whether the sensor has been exposed to humidity levels greater than or less than one or more predetermined humidity values. In some embodiments, the one or more predetermined humidity value may be greater than about 60% relative humidity, greater than about 70% relative humidity, greater than about 80% relative humidity, and/or greater than about 90% relative humidity. Alternatively or additionally, the one or more predetermined humidity value may be less than about 30% relative humidity, less than about 20% relative humidity, and/or less than about 10% relative humidity.
Upon detection of exposure of the sensor to certain levels of temperature and/or humidity, a corresponding calibration code may be changed to account for possible effects of this exposure on sensor sensitivity or other sensor characteristics. This calibration code change may be automatically performed by a control system associated with the sensor package. Alternatively, in other embodiments, an indicator (e.g., a color indicator) that is adapted to undergo a change (e.g., a change in color) upon exposure to certain environments may be used. By way of example and not to be limiting, the sensor package may include an indicator that irreversibly changes color from a blue color to a red color, upon exposure of the package to a temperature greater than about 85° F. and also include instructions to the user to enter a certain calibration code when the indicator has a red color. Although exposure to temperature and humidity are described herein as examples of conditions that may be detected by the sensor package, and used to activate a change in calibration code information, it should be understood that other conditions may also be detected and used to activate a change in calibration code information.
In certain embodiments, the continuous analyte system may comprise a library of stored sensor sensitivity functions or calibration functions associated with one or more calibration codes. Each sensitivity function or calibration function results in calibrating the system for a different set of conditions. Different conditions during sensor use may be associated with temperature, body mass index, and any of a variety of conditions or parameters that may affect sensor sensitivity or provide additional information about sensor sensitivity. The library can also include sensitivity profiles or calibrations for different types of sensors or different sensor lots. For example, a single sensitivity profile library can include sub-libraries of sensitivity profiles for different sensors made from different sensor lots and/or made with different design configurations (e.g., different design configurations customized for patients with different body mass index).
Determining Sensor Properties and Calibrating Sensor Data Using One or More Stimulus Signals
Some embodiments apply one or more stimulus signals to a sensor to determine properties of a sensor and/or calibrate sensor data. The term “stimulus signal,” 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 are not to be limited to a special or customized meaning), and refers without limitation to a signal (e.g., any time-varying or spatial-varying quantity, such as an electric voltage, current or field strength) applied to a system being used (e.g., an analyte sensor) to cause or elicit a response.
Non-limiting examples of stimulus signals that can be used in the embodiments described herein can be a waveform including one or more of: a step increase in voltage of a first magnitude, a step decrease in voltage of a second magnitude (where the first and second magnitudes can be the same or different), an increase in voltage over time at first rate, a gradual decrease in voltage over time having a second rate (where the first rate and the second rate can be different or the same), one or more sine waves overlayed on the input signal having the same or different frequencies and/or amplitudes and the like. A response to the stimulus signal can then be measured and analyzed (the response is also referred to herein as the “signal response”). The analysis can include one or more of calculating impedance values, capacitance values, and correlating the signal response to one or more predetermined relationships. As used herein, the term “impendence value” can mean a value for expressing an electrical impedance, including but not limited to, a value that only represents a magnitude of impedance or a value that express both magnitude and phase of impendence, should impendence be represented in a polar form, or expresses a real impendence only or both a real and complex impendence, should impedance be represented in a Cartesian form. Based on the calculated impedance values, capacitance values and/or predetermined relationships, various sensor properties can be determined and/or characterized, such as one or more of the sensor properties discussed herein.
The sensor information can then be used to determine if the analyte sensor is functioning properly or not, and/or to calibrate the sensor. For example, the techniques described herein can be used to generate calibration information (e.g., one or more of baseline, sensor sensitivity, and temperature information) that can in turn be used to form or modify a conversion function, or calibration factor, used to convert sensor data (e.g., in units of electrical current) into blood glucose data (e.g., glucose concentration values in units of mg/dL or mmol/L), as described in more detail elsewhere herein. The sensor information can alternatively or additionally be used to first correct uncalibrated sensor data (e.g., raw sensor data) and then apply a conversion function to convert the corrected, uncalibrated data to calibrated sensor data (e.g., glucose concentration values in units of glucose concentration).
For example, one technique that can be used to determine properties of a system being used (e.g., an analyte sensor) is Electrochemical Impedance Spectroscopy (EIS). EIS is an electrochemical technique based on the measurement of electrical impedance of the system being used over a range of different frequencies. Changes in the system being used can reflect changes in the frequency spectrum. As an example, a reduction in impedance may be observed at a particular frequency over a time period if the system being used has a sensitivity change over that period of time. Other techniques can also be used to determine properties of a system being used as discussed further below.
As one illustrative example of how a stimulus signal can be used to determine sensor properties, reference will now be made to a schematic diagram of an equivalent sensor circuit model 900 illustrated in
Based on this information, one can determine a state of particular properties of the sensor by applying a stimulus signal of a particular frequency or comprising a plurality of frequencies to the sensor and determining a sensor impedance based on the signal response. For instance, a capacitance of a sensor having the characteristics of the Bode plot of
Reference will now be made to
In an alternative embodiment, instead of calculating a sensor impedance based on the peak current, the peak current can be correlated to one or more predetermined sensor relationships to determine a property of the sensor, such as the sensor's sensitivity. That is, in the alternative embodiment, the step of calculating the one or more impendence characteristics is omitted.
The relationship between a signal response resulting from a stimulus signal in the form of a voltage step and a sensor membrane resistance of embodiments of analyte sensors will now be discussed further with reference to
In one embodiment, a change in current, Δi, measured as the difference between the magnitude of the current response 1402 prior to the voltage step and the peak current 1404 resulting from the voltage step, can then be used to estimate the sensor membrane resistance, such as Rmembrane in
Rmembrane=Δv/Δi
As discussed above, Δv is the step voltage increase and Δi is the change in current response due to the step voltage increase.
Although not wishing to be bound by theory, it is believed that certain embodiments of sensors provide a direct relationship between a change in current in response to a voltage step to the sensor's membrane impendence characteristics (e.g., resistance).
As a non-limiting example of such a relationship, the following description refers back to sensor circuit model 900 of
Thus, because the membrane resistance, Rmembrane, is essentially the resistance of the circuit 900 at the time of the voltage step, it has been found that the value of Rmembrane can be estimated using Ohms Law using the known value of the step increase. Δv, and the measured change in current response, Δi, due to the voltage step.
a. Sensitivity
As discussed herein, a sensor's sensitivity to analyte concentration during a sensor session can often change as a function of time. This change in sensitivity can manifest itself as an increase in current for a particular level of sensitivity. In some embodiments, the sensitivity increases during the first 24-48 hours with a relative change in tens of percents. In order to provide an accurate analyte concentration reading to a user, system calibrations using reference meters (e.g., strip-based blood glucose measurements) may be needed. Typically, the rate of calibrations can be 1, 2 or more calibrations a day.
As discussed further below, a relationship between sensitivity and impedance has been observed in embodiments of analyte sensors. Although not wishing to be bound by theory, embodiments of analyte sensors are believed to have a relationship between an impedance of a sensor's membrane and the diffusivity of the membrane. For example, a change in impedance of an analyte sensor can indicate a proportional change in diffusivity of the analyte sensor's membrane. Further, an increase in diffusivity can yield an increased transport of the analyte being measured (e.g., glucose) through the membrane, resulting in an increased sensor output current. That is, a change in diffusivity can result in a proportional change in sensor sensitivity. It is noted that other factors may also contribute to changes in sensitivity apart from just changes in diffusivity of the sensor membrane, depending upon the characteristics of sensor and the environment in which the sensor is used.
A relationship between sensitivity and impedance can be used to estimate a sensor sensitivity value and/or correct for sensitivity changes of the sensor over time, resulting in increased accuracy, a reduction in required calibrations or both. In addition to detection of sensitivity, some embodiments can detect other characteristics of an analyte sensor system based on measurements of electrical impedance over one or more frequencies. These characteristics include, but are not limited to, temperature, moisture ingress into sensor electronics components and sensor membrane damage.
In some exemplary embodiments, a relationship between a sensor's impedance and the sensor's sensitivity can be used to calculate and compensate for sensitivity changes of an analyte sensor. For example, a change in impedance of an analyte sensor can correspond to a proportional change in sensitivity of the sensor. In addition, an absolute value of an impedance of an analyte sensor can correspond to an absolute value of the analyte sensor's sensitivity and the corresponding sensitivity value can be determined based on a predetermined relationship determined from prior studies of similar sensors. Sensor data can then be compensated for changes in sensitivity based on an impedance-to-sensitivity relationship.
It should be understood that process 1500 is but one example of using an impedance of a sensor to compensate for changes in sensor sensitivity, and that various modifications can be made to process 1500 that fall within the scope of the embodiments For example, an established impedance-to-sensitivity relationship can be used to determine a sensitivity value of the sensor being used, and the sensitivity value can then be used to modify or form a conversion function used to convert a sensor signal of the sensor being used into one or more estimated glucose concentration values. In addition, instead of calculating an impedance based on the stimulus signal response, one or more properties of the stimulus signal response (e.g., peak current value, counts, etc.) can be directly correlated to a sensitivity based on a predetermined relationship between the stimulus signal property and the sensitivity.
Some embodiments use one or more impedance values of the sensor to form, modify or select a sensitivity profile of an analyte sensor. As discussed above, a sensor can have a sensitivity profile that indicates the sensor's change in sensitivity over time. Although sensors made in substantially the same way under substantially the same conditions can exhibit similar sensitivity profiles, the profiles can still vary. For example, the environment in which a particular sensor is used can cause the sensor's sensitivity profile to differ from other, similar sensors. Accordingly, some embodiments can, for example, select a sensitivity profile out of a plurality of predetermined sensitivity profiles based on a correlation of the calculated one or more impedance values to the selected sensitivity profile. Further, some embodiments modify a sensor sensitivity profile already associated with the analyte sensor being used to more closely predict the sensor's sensitivity profile, where the modification is based on the one or more impedance values.
Further to step 1608, various techniques can be used to determine the sensitivity profile. One exemplary technique can compare the one or more calculated impedance values to a plurality of different predicted sensitivity profiles and select a predicted sensitivity profile that best fits the one or more calculated impedance values. The plurality of different predicted sensitivity profiles can be predetermined and stored in computer memory of sensor electronics, for example. Another technique that can be used includes using an estimative algorithm to predict or determine a sensitivity profile based on the one or more calculated impedance values. A further technique includes determining a sensitivity profile by modifying a sensitivity profile associated with the sensor being used (e.g., a sensor profile previously used to generate estimated glucose values using the sensor). Modifying the sensitivity profile can include using an estimative algorithm to modify the sensitivity profile to more closely track the sensitivity profile of the sensor being used based on the one or more calculated impedance values.
Some embodiments compare one or more impedance values of an analyte sensor being used to a predetermined or predicted sensitivity profile associated with the sensor to determine if the sensor is functioning properly. As discussed above, a sensor can be predicted to have a particular sensitivity profile based on, for example, a study of sensitivity changes over time of sensors made in substantially the same way and used under substantially the same conditions. However, it can be determined that a sensor is functioning improperly—due to, for example, improper sensor insertion, damage to the sensor during shipping, manufacturing defects and the like—if the sensor is found not to be sufficiently tracking its predicted sensitivity profile based on sensitivities derived from impedance measurements of the sensor. Put another way, it can be determined that a sensor is not functioning properly if one or more impedance values of a sensor's membrane do not sufficiently correspond to a predicted sensitivity profile (e.g., because the impedance of a sensor membrane can indicate a sensitivity of the sensor) of the sensor.
Further to step 1708 of process 1700, various statistical analysis techniques can be used to determine a correspondence of the one or more impedance values to the predicted sensitivity profile. As one example, correspondence can be determined based on whether a sensitivity value derived from the calculated impedance value (e.g., derived from a predetermined relationship of impedance and sensitivity) differs by no less than a predetermined threshold amount from a predicted sensitivity value as determined from the predicted sensitivity profile. The predetermined threshold amount can be in terms of an absolute value or a percentage. As another example, correspondence can be determined based on a data association function. The term “data association function.” as used herein, is a broad term and is used in its ordinary sense, including, without limitation, a statistical analysis of data and particularly its correlation to, or deviation from, from a particular curve. A data association function can be used to show data association. For example, sensor sensitivity data derived from impedance measurements described herein may be analyzed mathematically to determine its correlation to, or deviation from, a curve (e.g., line or set of lines) that defines a sensor sensitivity profile; this correlation or deviation is the data association. Examples of a data association function that can be used includes, but is not limited to, linear regression, non-linear mapping/regression, rank (e.g., non-parametric) correlation, least mean square fit, mean absolute deviation (MAD), and mean absolute relative difference. In one such example, the correlation coefficient of linear regression is indicative of the amount of data association of sensitivity data derived from impedance measurements from a sensitivity profile, and thus the quality of the data and/or sensitivity profile. Of course, other statistical analysis methods that determine a correlation of one or more points to a curve can be used in process 1700 in addition to those described herein.
As discussed above, processes 1600 and 1700 can use one or more impedance values. When more than one impedance value is used, each impedance value can be time-spaced from the other impedance value(s). In other words, one impedance value can be taken at a first point in time t1 (indicative of a sensor impedance at time t1), a second impedance value can be taken at a second, later point in time t2 (indicative of a sensor impedance at time t2), and third impedance value taken at a third, even later point in time t3 (indicative of a sensor impedance at time t3), and so on. Further, the time between t1 and t2 can be a first amount of time and the time between t2 and t3 can be a second amount of time that is either the same or different than the first amount of time. The time-spaced impedance values can then be used separately or combined using a statistical algorithm (e.g., calculating an average or median value of the time-spaced values). The separate values or combined value can then be used to determine a sensitivity value and/or sensitivity profile in step 1608 of process 1600 or determine a correspondence with a sensitivity profile in step 1708 of process 1700, for example. Additionally or alternatively, more than one of the impedance values can be taken at substantially the same time, but each derived using a different measurement technique, such as using two of the measurement techniques described herein. For example, a first impedance can be calculated using a step voltage technique as described in the process of
b. Temperature
Some embodiments can use signal processing techniques to determine a temperature of the sensor. For example, a stimulus signal can be applied to a sensor and a signal response measured and, based on the signal response, a temperature of the sensor can be derived.
An impedance of a sensor membrane, as determined using one of the techniques described with reference to
A relationship between sensor sensitivity and different temperatures can be mathematically modeled (e.g., by fitting a mathematical curve to data using one of the modeling techniques described herein), and the mathematical model can then be used to compensate for temperature effects on the sensor sensitivity. That is, a sensitivity of a sensor (which is affected by the sensor's temperature) can be determined based on associating a measured impedance of the sensor to the mathematical curve. The predetermined relationship between impedance and temperature can be determined by studying impedances of similar sensors over a range of temperatures. Sensor data can then be converted to estimated analyte concentration values based on the determined sensor sensitivity.
As a non-limiting example, some embodiments of analyte sensors can have an essentially linear relationship of impedance to temperature after a sensor run-in period (e.g., a period of time after sensor implantation in which the sensor stabilizes, which can last one to five hours in some embodiments). The slope of the linear relationship can be established by studying sensors made in substantially the same way as the sensor being used over a range of temperatures. Thus, a sensor temperature can be estimated by measuring an impedance value of the sensor's membrane and applying the impedance value to the established linear relationship. Other embodiments can have a non-linear relationship of impedance to temperature and with these other embodiments the relationship can be characterized using an established non-linear relationship.
Some embodiments can compare a first sensor temperature, where the first temperature is derived from an impedance measurement of an analyte sensor, with a second sensor temperature, where the second sensor temperature is derived independent from the impedance measurement. The second estimated temperature can be measured using a thermistor, for example. In the example of using a thermistor, the thermistor can be configured to measure an in vivo or ex vivo temperature, and can be located on the analyte sensor or separate from the analyte sensor. As non-limiting examples, the thermistor can be integral with the analyte sensor, positioned on the surface of the skin of a host adjacent to an insertion site in which the analyte sensor is implanted, positioned on the skin of the host at a location away from the insertion site or spaced apart from the host entirely, such as on a handheld device carried by the host. Factors contributing to a change in sensor sensitivity or a change in other sensor properties can then be determined or confirmed based, at least in part, on the comparison of the first and second temperatures.
c. Moisture Ingress
In some embodiments, moisture ingress into sensor electronics can be determined based on measuring an impedance of the sensor at a particular frequency or range of frequencies. Should the measured impedance not correspond sufficiently with predetermined impedance value(s), then a sensor system operatively connected to the sensor can initiate a moisture ingress error routine. Correspondence can be determined using one or more threshold, a data association function, and the like. Further, it should be noted that it has been found that impedance phase information can provide beneficial information in determining moisture egress. Accordingly, in some embodiments, the impedance measurement can be broken into separate impendence magnitude and phase components, and one or both impendence components can be compared to predetermined values to determine the correspondence.
Although the above description describes calculating separate impedance and phase values, it is understood that the above process 1900 can determine a complex impedance value and determine a correspondence of the determined complex impedance value to one or more predetermined complex impedance value(s), such as by using a data association function or comparing the determined complex impedance to a threshold or range of predetermined complex impendence values. The error routine can then be initiated responsive to the correspondence.
d. Membrane Damage
In some embodiments, membrane damage can be detected based on measuring an impedance at a particular frequency or range of frequencies. Should the measured impedance not correspond sufficiently with predetermined one or more impedance values, then a sensor system operatively connected to the sensor can initiate a membrane damage error routine. Correspondence can be determined using a data association function.
Although the above description describes using separate impedance magnitude and phase values, it is understood that the above process 2000 can use a complex impedance value and determine a correspondence of the complex impedance value to a predetermined values or levels. The error routine can be initiated responsive to the determined correspondence.
e. Sensor Reuse
In some embodiments, sensor reuse can be detected. Embodiments of glucose sensors described herein may have a defined life in which a sensor can provide reliable sensor data. After the defined life, the sensor may no longer be reliable, providing inaccurate sensor data. To prevent use beyond the predefined life, some embodiments notify a user to change the sensor after it has been determined that the sensor should no longer be used. Various methods can be used to determine whether a sensor should no longer be used, such as a predetermined amount of time transpiring since the sensor was first used (e.g., when first implanted into a user or when first electrically connected to a sensor electronics module) or a determination that the sensor is defective (e.g., due to membrane rupture, unstable sensitivity and the like). Once it is determined that the sensor should no longer be used, the sensor system can notify a user that a new sensor should be used by audibly and/or visually prompting a user to use a new sensor and/or shutting down a display or ceasing to display sensor data on the display, for example. However, a user may try to reuse the same sensor instead of using a new sensor. This can be dangerous to the user because the sensor may provide inaccurate data upon which the user may rely.
Accordingly, some embodiments can be configured determine sensor reuse based at least in part on one or more measurements of the impedance of the sensor. As discussed in more detail elsewhere herein, the impedance that relates to the membrane resistance of a sensor is typically initially high and then gradually decreases as the sensor is run-in. Thus, in one embodiment, sensor re-use can be detected if an impedance measured soon after sensor implantation is greater than what a sensor should typically have when a sensor is initially implanted, as this can indicate that the sensor had already been used.
The sensor reuse routine of step 2112 can include triggering an audible and/or visual alarm notifying the user of improper sensor reuse. The alarm can also inform the user why sensor reuse may be undesirable, such as potentially providing inaccurate and unreliable sensor readings. The sensor reuse routine 2112 can alternatively or additionally cause the sensor system to fully or partially shut down and/or cease display of sensor data on a user interface of the sensor system.
In an embodiment, recent impedance measurement information (e.g., one or more recent impedance measurement values) of a previously-used sensor (such as the sensor used immediately prior to the newly implanted sensor) or a predetermined sensor profile can be stored in computer memory and compared to impedance measurement information of a newly implanted sensor (e.g., what is supposed to be a newly used sensor). It can then be determined that the sensor is being reused should the comparison indicate that the impedances of the previously used sensor at a time close to when the use of the prior sensor was discontinued (e.g., removed) and the newly inserted sensor are too similar using, for example, a data association function, as a new sensor should have a significantly different impedance soon after initial implantation than the impedance of the previously used sensor substantially prior to its discontinuation of use. If it is determined that the sensor is being reused, then the sensor system can trigger an error routine, which can include notifying the user via audible and/or visual alarms using a user interface of the sensor system of improper sensor reuse and prompting the user to use a new sensor, as discussed above with respect to step 2112.
The sensor reuse routine of step 2212 can include triggering an audible and/or visual alarm notifying the user of improper sensor reuse. The alarm can also inform the user why sensor reuse may be undesirable, such as potentially providing inaccurate and unreliable sensor readings. The sensor reuse routine 2212 can alternatively or additionally cause the sensor system to fully or partially shut down and/or cease display of sensor data on a display of the sensor system.
f. Sensor Overpotential
Some embodiments apply an overpotential routine based on one or more measured impedances of the sensor membrane. It has been found that applying an overpotential (e.g., a voltage potential greater than the bias potential applied to the sensor when used for continuous analyte sensing) to some embodiments of analyte sensors can aid in stabilizing the analyte sensor, thereby reducing a run-in period of the sensor. The overpotential may need to be discontinued once the sensor has sufficiently stabilized, otherwise damage to the sensor can occur. Accordingly, one or more impedance measurements of the sensor can be used to determine a sensitivity or change in sensitivity of the sensor. Any of the techniques described herein, such as those described with reference to
g. Multi-Electrode or Multi-Sensor Configuration
Some embodiments of sensor systems comprise a plurality of sensor electrodes. For example, as discussed above, in addition to an analyte sensing electrode, some embodiments can include an auxiliary electrode to allow for the subtraction of a baseline signal from an analyte+baseline signal. Some embodiments can also include one or more redundant analyte sensors.
In accordance with one embodiment, a first stimulus signal can be applied to a first sensor and a second stimulus signal can be applied to a second sensor. The first sensor can be configured to sense an analyte concentration (e.g., glucose) and, in this regard, can generate an analyte+baseline signal. The second sensor can be an auxiliary sensor configured to measure a baseline signal that can be subtracted from the signal of the first sensor. In addition, the first stimulus signal can have the same waveform or different waveform than the second stimulus signal. A response to the first stimulus signal and a response to the second stimulus signal can each be measured and recorded. The first response and the second response can be processed, and sensor characteristics can be determined based on the processing, such as impedance values associated with each sensor. The processing can include a comparison (e.g., using a data association function described herein) of the first and second response signals to one another and/or compare each of the first and second response signals to established relationships. The sensor characteristics can include any of the sensor characteristics described herein, including a sensitivity value or sensitivity change of the first and/or second electrodes, a temperature of the first and/or second electrodes, magnitude of detected membrane damage of the first electrode, and the like. Further, sensor data can be compensated for changes in sensor characteristics, such as changes in sensor sensitivity, based on the processing of the first and second response signals.
As illustrated in
Further to
Alternatively or in addition, a first stimulus signal can be applied to the first sensor 2302 and measured using the second sensor 2310 and a second stimulus signal can be applied to the second sensor 2310 and measured using the first sensor 2302. The first and second stimulus signals can be essentially the same or can be different. The responses to each of the first and second stimulus signals can then be used to determine a sensor property, such as any of the senor properties discussed herein.
The sensor to which the stimulus signal is applied can also be used to measure a response to the stimulus signal in addition to the other sensor measuring a response to the stimulus signal. For example, a first stimulus signal can be applied to the first sensor 2302 and first and second responses to the first stimulus signal can be measured by the first sensor 2302 and the second sensor 2310, respectively. The first and second responses can then be used to determine sensor properties discussed herein of either or both of the first sensor 2302 and second sensor 2310.
h. Scaling Factor
In some embodiments, a scaling factor can be used to correct differences in responses of a dual-electrode analyte sensor. In some embodiments, a dual-electrode analyte sensor that can be used is a reference sensor/system, whereby reference data can be provided for calibration (e.g., internal to the system), without the use of an external (e.g., separate from the system) analyte-measuring device. In some embodiments, the dual-electrode analyte sensor includes a first electrode that includes an enzyme reactive with a particular analyte (which can be referred to as the plus-enzyme electrode) and a second electrode that does not include the enzyme (which can be referred to as the minus-enzyme electrode).
In some embodiments, the sensor system (such as a sensor electronics module of the sensor system) is configured to determine a scaling factor (k). Briefly, a scaling factor defines a relationship between the electrodes of the dual-electrode analyte sensor. Accordingly, in some embodiments, the sensor system is configured to calibrate the analyte sensor data using the scaling factor, such that the calibrated sensor data does not include inaccuracies that can arise due to differences between the first and second working electrodes, respectively. That is, the scaling factor can be used to calculate estimated analyte values based on data generated by the sensor system
U.S. Patent Publication No. US-2009-0242399-A1, the contents of which are hereby incorporated by reference in its entirety, describes in more detail dual-electrode analyte sensor systems, scaling factors and methods for using scaling factors that can be used in some embodiments.
In accordance with some embodiments, the membrane impedance of each electrode of a dual-electrode system can be used to determine or update a scaling factor. The scaling factor can then be used to calculate estimated analyte concentration values based on data generated by the sensor system.
The following illustrates an exemplary process for determining a scaling factor using impendence in accordance with one embodiment. First, membrane impedance is measured for both electrodes of a dual-electrode sensor system. Techniques described herein, such as those described with reference to
It has been found that acetaminophen can interfere with glucose measurements using some sensor embodiments. It has also been found that acetaminophen response can be proportional to its diffusion through a sensor membrane and sensor impedance can be indicated of membrane impedance. Thus, the above illustrative process for determining a scaling factor can be used to periodically determine an acetaminophen scaling factor by determining a ratio of the plus-enzyme and minus-enzyme electrode impedance. The acetaminophen scaling factor can be used to update a scale factor, such as one of those described above, used to calculate estimated glucose concentrations.
i. Calibration
An exemplary calibration process in accordance with some embodiments will now be discussed with reference to
In process 2400, pre-implant information 2402 can mean information that was generated prior to implantation of the sensor(s) presently being calibrated. Pre-implant information 2402 can include any of the following types of information:
In process 2400, internal diagnostic information 2402 can mean information generated by the sensor system in which the implanted analyte sensor (the data of which is being calibrated) is being used. Internal diagnostic information 2402 can include any of the following types of information:
In process 2400, external reference information 2402 can mean information generated from sources while the implanted analyte sensor (the data of which is being calibrated) is being used. External reference information 2402 can include any of the following types of information:
Embodiments of the present invention are described above and below with reference to flowchart illustrations of methods, apparatus, and computer program products. It will be understood that each block of the flowchart illustrations, and combinations of blocks in the flowchart illustrations, can be implemented by execution of computer program instructions. These computer program instructions may be loaded onto a computer or other programmable data processing apparatus (such as a controller, microcontroller, microprocessor or the like) in a sensor electronics system to produce a machine, such that the instructions which execute on the computer or other programmable data processing apparatus create instructions for implementing the functions specified in the flowchart block or blocks. These computer program instructions may also be stored in a computer-readable memory that can direct a computer or other programmable data processing apparatus to function in a particular manner, such that the instructions stored in the computer-readable memory produce an article of manufacture including instructions which implement the function specified in the flowchart block or blocks. The computer program instructions may also be loaded onto a computer or other programmable data processing apparatus to cause a series of operational steps to be performed on the computer or other programmable apparatus to produce a computer implemented process such that the instructions which execute on the computer or other programmable apparatus provide steps for implementing the functions specified in the flowchart block or blocks presented herein.
In some embodiments, a sensor system is provided for continuous measurement of an analyte (e.g., glucose) in a host that includes: a continuous analyte sensor configured to continuously measure a concentration of the analyte in the host and a sensor electronics module physically connected to the continuous analyte sensor during sensor use. In one embodiment, the sensor electronics module includes electronics configured to process a data stream associated with an analyte concentration measured by the continuous analyte sensor in order to process the sensor data and generate displayable sensor information that includes raw sensor data, transformed sensor data, and/or any other sensor data, for example. The sensor electronics module can include electronics configured to process a data stream associated with an analyte concentration measured by the continuous analyte sensor in order to process the sensor data and generate displayable sensor information that includes raw sensor data, transformed sensor data, and/or any other sensor data, for example. The sensor electronics module can include a processor and computer program instructions to implement the processes discussed herein, including the functions specified in the flowchart block or blocks presented herein.
In some embodiments, a receiver, which can also be referred to as a display device, is in communication with the sensor electronics module (e.g., via wired or wireless communication). The receiver can be an application-specific hand-held device, or a general purpose device, such as a P.C., smart phone, tablet computer, and the like. In one embodiment, a receiver can be in data communication with the sensor electronics module for receiving sensor data, such as raw and/or displayable data, and include a processing module for processing and/or display the received sensor data. The receiver can also and include an input module configured to receive input, such as calibration codes, reference analyte values, and any other information discussed herein, from a user via a keyboard or touch-sensitive display screen, for example, and can also be configured to receive information from external devices, such as insulin pumps and reference meters, via wired or wireless data communication. The input can be processed alone or in combination with information received from the sensor electronics module. The receiver's processing module can include a processor and computer program instructions to implement any of the processes discussed herein, including the functions specified in the flowchart block or blocks presented herein.
Embodiments are further detailed in the following Examples, which are offered by way of illustration and are not intended to limit the invention in any manner. As disclosed herein, studies have been conducted using a Gamry potentiostat system to analyze complex impedance of glucose sensors placed in a buffer. The Gamry potentiostat system is commercially available from Gamry under the model name Ref600. The buffer is a modified isolyte having a known concentration of glucose. In many of the examples, the glucose concentration is about 100 mg/dL. The impedance measurement error in the examples was found to be about 1 to 5% by testing the system with a known impedance.
Although some of the following examples were performed on a lab bench, the sensors under test are configured to be used in vivo to continuously or substantially continuously measure a glucose concentration of a host.
Analyte sensors used in the following examples were selected from different types of sensors. The sensors under test include sensors taken from different sensor lots, where sensors from a first lot may have been made in a different way and under different conditions, which can result in sensors for different lots exhibiting different sensitivity profiles. Further, some of the sensors studied in these examples are configured for placement in transcutaneous tissue of a host to measure the host's glucose concentration, while other sensors are configured to measure an intravenous blood glucose concentration of a host. In the following experiments, sensors intended to be used to measure an intravenous blood glucose concentration can be referred to as an “IVBG sensor type” and sensors intended to measure a blood glucose concentration in transcutaneous tissue of a host can be referred to as a “transcutaneous sensor type.”
Example 1 illustrates a relationship between sensitivity of a sensor and an impedance of the sensor. In this example, an IVBG sensor was connected to a Gamry potentiostat system and placed in a in a buffer solution of a modified isolyte having a glucose concentration of 100 mg/dL. The temperature during the experiment was 37 C. An impedance spectrum was captured at fixed intervals of time. The impedance spectrum analyzed in this experiment ranged from 1 Hz to 100 kHz and measurements of the sensor impedance and sensor sensitivity were taken at 15 minute intervals over a period of about 1200 minutes.
Reference is now made to
The sensitivity and impedance values of
Further to
As can be seen in
A computer-implemented estimative algorithm function can be used to model a relationship between the change in sensitivity and change in impedance values of the sensor data generated by Sensors A-G. The estimative algorithm function may be formed by applying curve fitting techniques that regressively fit a curve to data points by adjusting the function (e.g., by adjusting constants of the function) until an optimal fit to the available data points is obtained, as discussed above with respect to forming an estimative curve for a sensitivity profile. Additionally or alternatively, the relationship can be modeled into a look-up table stored in computer memory.
Further to
Accordingly, Example 2 illustrates that a change in sensitivity to change in impedance relationship determined at a first temperature can be used to compensate for sensitivity drift at temperatures different from the first temperature.
Example 5 pertains to prospective calibration. Further, in this experiment, calibration of sensor data is based on a change of sensitivity to change in impedance relationship previously derived from sensors from a different sensor lot. That is, in Example 3, the estimative curve 2802 is used to compensate data obtained using Sensors R-U, each of which was selected from a fourth sensor lot, the fourth sensor lot was not included in the group of sensors used to derive the estimative curve 2802. Example 5 shows that data can be calibrated using a change in sensitivity to change in impedance relationship derived from different sensor types than the type of sensor being calibrated. This can indicate that a sensor factory calibration code need not be used to compensate for sensitivity drift.
Prospective calibration of sensors will now be discussed with reference to
Thus, Example 5 indicates that using a change in sensitivity to change in impedance relationship derived from sensors selected from different lots than the sensor being calibrated can never-the-less significantly compensate for sensor sensitivity drift. It should be noted that curve 3702 is a straight line. It is contemplated that non-linear fits or correlations can be used instead, which may yield better results.
As illustrated in
The relationship between sensor sensitivity and different temperatures can then be mathematically modeled (e.g., by fitting a mathematical curve to data using one of the modeling techniques used herein), and the mathematical model can then be used to compensate for temperature effects on the sensor sensitivity. That is, a sensitivity of a sensor (which is affected by the sensor's temperature) can be determined based on a measured impedance of the sensor applied to the mathematical curve. Sensor data can then be converted to estimated glucose values based on the determined sensor sensitivity.
Further to
Example 6 involves detection of moisture ingress in components of sensor electronics used to drive a sensor. In this example, an input signal is applied to the sensor having a frequency ranging from 100 Hz to 1 kHz. A response of the signal is then measured over the range of frequencies and both impedance and phase change derived therefrom. Next, contacts typically positioned inside a sealed section of a sensor electronics module are wetted. The frequency of an input signal is varied between 100 and 1000 Hz. A response is once again measured and both impedance and phase change is derived.
In a first experiment, the contacts were wetted to the point of causing a gross failure of the sensor. The current of the sensor increased from 2.3 nA when dry to 36 nA when wetted. In a second experiment, the contacts were only slightly wetted, where the current of the sensor increased from 2.3 nA when dry to 6 nA when wetted.
Example 7 involves detection of sensor membrane damage using impedance measurements. In this example, the impedance of an analyte sensor is measured over a range of frequencies ranging from 100 to 1 kHz. A portion of the sensor's membrane is then cut using a razor blade to cause membrane damage. The impedance of the sensor is once again measured over the same range of frequencies. The impedance measurements of the sensor before the membrane is cut are then compared to the measurements of the sensor after the membrane is cut to determine whether the impedance can be used to detect membrane damage.
Laboratory experiments showed that there is an inverse relationship between the changes in sensor sensitivity (drift) and the changes in impedance. Based on the measured impedance, the sensor sensitivity drift could be compensated using either linear or non-linear sensor sensitivity-impedance correlation.
The linear correlation can be expressed as the equation ΔS=a*ΔI+b, where a and b can be pre-determined coefficients determined from prior testing of similar sensors. The non-linear correlation can be expressed as ΔS=(a*log(t)+b)*ΔI, where a and b are pre-determined constants determined from prior testing of similar sensors. The prior testing of similar sensors was performed using in vitro bench testing and the constants were derived using conventional computer plotting techniques in this experiment.
The linear and non-linear equations are derived from the relationships of change in sensitivity and change of impedance at time t since the last calibration. The percent the change of sensitivity at time t is expressed as:
ΔS=% change in sensitivity=(Sensitivity at t−Sc)/Sc*100%
where Sc is a sensitivity determined at calibration, and t is the time since the last calibration.
The sensor impendence change from time t is expressed as:
ΔI=% impedance change=(impedance at t−Ic)/Ic*100%
where Ic is an impedance at the time of calibration.
To calculate the linear correlation, conventional computer plotting software was used to plot change in sensitivity (y-axis) versus change in impendence (x-axis) based on in vitro test data and determine the linear best fit of the data. In this experiment, the linear best fit was ΔS=−4.807*ΔI−0.742. The linear best fit can is used as the linear sensitivity-to-impedance correlation.
To calculate the non-linear correlation, conventional computer plotting software was used to plot change in sensitivity over change in impedance ΔS/□ΔI (y-axis) versus log(t). The linear best fit of the plotted data is then determined using the plotting software to yield ΔS/□ΔI=a*log(t)+b, from which the change is sensitivity is derived: ΔS=(a*log(t)+b)*ΔI. In this experiment, the plotting software yielded ΔS/ΔI=−1.175*log(t)−1.233. From this equation, ΔS is derived: ΔS=(−1.175*log(t)−1.233)*ΔI.
The linear or non-linear correlation can then be applied to correct for changes in sensitivity of the sensor using impedance measurements of the sensor.
The first branch beings at block 5004, where sensor data is generated using the continuous glucose sensor in the form of current or counts. The first branch then proceeds to decision block 5006, where process 5000 determines whether a calibration is needed. In this experiment, a calibration is determined to be needed one hour and 24 hours after sensor insertion. If it is determined that calibration is not needed, then the first branch essentially ends. On the other hand, if it is determined that calibration is required, then process 5000 acquires a reference measurement using a finger stick meter at blocks 5008 and 5010. Sensor data corresponding in time to the reference measurement (at time Tc) is determined at block 5012 and used to calculate a sensor sensitivity. Sc, along with the reference data at block 5014.
The second branch of process 5000 begins with measuring an impendence of the sensor at block 5016. The impedance is measured using the peak current technique discussed in this application with reference to
The first and second branches of process 5000 then merge at block 5028 where a corrected sensitivity is determined. The corrected sensitivity is then used to convert sensor data in units of current or counts to an estimated glucose value in units of glucose concentration.
Process 5000 is repeated for each sensor data point that is converted into an estimated glucose value.
In this experiment, sensor performance improvement by impedance compensation is demonstrated below. The sensors were tested using continuous glucose sensors placed in sheep serum for 2 days. The sensor sensitivity was calculated at 1 hour and 24 hours. In
Some embodiments disclosed herein continuously or iteratively apply a stimulus signal during a continuous sensor session or use and extrapolate information from the output associated with the stimulus, such as using a peak current measurement. EIS, etc. Although certain electrochemical analysis techniques were described herein, it is understood that many other techniques can be used instead to detect characteristics of sensors described herein, such as voltammetry, chronopotentiometry, current or potential step techniques, differential chrono-potentiometry, oxygen absorption rate measurements, potential/current sweep or pulse methods, etc.
While the disclosure has been illustrated and described in detail in the drawings and foregoing description, such illustration and description are to be considered illustrative or exemplary and not restrictive. The disclosure is not limited to the disclosed embodiments. Variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed disclosure, from a study of the drawings, the disclosure and the appended claims.
All references cited herein are incorporated herein by reference in their entirety. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material.
Unless otherwise defined, all terms (including technical and scientific terms) 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 unless expressly so defined herein. It should be noted that the use of particular terminology when describing certain features or aspects of the disclosure should not be taken to imply that the terminology is being re-defined herein to be restricted to include any specific characteristics of the features or aspects of the disclosure with which that terminology is associated. Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term ‘including’ should be read to mean ‘including, without limitation,’ ‘including but not limited to,’ or the like; the term ‘comprising’ as used herein is synonymous with ‘including,’ ‘containing,’ or ‘characterized by,’ and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term ‘having’ should be interpreted as ‘having at least;’ the term ‘includes’ should be interpreted as ‘includes but is not limited to;’ the term ‘example’ is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; adjectives such as ‘known’, ‘normal’, ‘standard’, and terms of similar meaning should not be construed as limiting the item described to a given time period or to an item available as of a given time, but instead should be read to encompass known, normal, or standard technologies that may be available or known now or at any time in the future; and use of terms like ‘preferably,’ ‘preferred,’ ‘desired,’ or ‘desirable,’ and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function of the invention, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the invention. Likewise, a group of items linked with the conjunction ‘and’ should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as ‘and/or’ unless expressly stated otherwise. Similarly, a group of items linked with the conjunction ‘or’ should not be read as requiring mutual exclusivity among that group, but rather should be read as ‘and/or’ unless expressly stated otherwise.
Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments.
With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity. The indefinite article “a” or “an” does not exclude a plurality. A single processor or other unit may fulfill the functions of several items recited in the claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.
It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases “at least one” and “one or more” to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles “a” or “an” limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases “one or more” or “at least one” and indefinite articles such as “a” or “an” (e.g., “a” and/or “an” should typically be interpreted to mean “at least one” or “one or more”); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should typically be interpreted to mean at least the recited number (e.g., the bare recitation of “two recitations,” without other modifiers, typically means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to “at least one of A, B, and C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone. A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). In those instances where a convention analogous to “at least one of A, B, or C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “a system having at least one of A, B. or C” would include but not be limited to systems that have A alone, B alone. C alone. A and B together. A and C together, B and C together, and/or A. B. and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and/or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or “B” or “A and B.”
All numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification are to be understood as being modified in all instances by the term ‘about.’ Accordingly, unless indicated to the contrary, the numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of any claims in any application claiming priority to the present application, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.
Furthermore, although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it is apparent to those skilled in the art that certain changes and modifications may be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention to the specific embodiments and examples described herein, but rather to also cover all modification and alternatives coming with the true scope and spirit of the invention.
Any and all priority claims identified in the Application Data Sheet, or any correction thereto, are hereby incorporated by reference under 37 CFR 1.57. This application is a continuation of U.S. application Ser. No. 17/398,628, filed Aug. 10, 2021, which is a continuation of U.S. application Ser. No. 16/951,759, filed Nov. 18, 2020, which is a continuation of U.S. application Ser. No. 16/586,434, filed Sep. 27, 2019, now abandoned, which is a continuation of U.S. application Ser. No. 16/460,943, filed Jul. 2, 2019, now U.S. Pat. No. 10,561,354, which is a continuation of U.S. application Ser. No. 16/405,887, filed May 7, 2019, now U.S. Pat. No. 10,682,084, which is a continuation of U.S. application Ser. No. 15/994,905, filed May 31, 2018, now U.S. Pat. No. 10,327,688, which is a continuation of U.S. application Ser. No. 14/860,392, filed Sep. 21, 2015, now U.S. Pat. No. 10,004,442, which is a continuation of U.S. application Ser. No. 13/446,977, filed Apr. 13, 2012, now U.S. Pat. No. 9,149,220, which is a continuation of U.S. application Ser. No. 13/446,848, filed Apr. 13, 2012, now U.S. Pat. No. 9,801,575, which claims the benefit of U.S. Provisional application Ser. No. 61/476,145, filed Apr. 15, 2011. Each of the aforementioned applications is incorporated by reference herein in its entirety, and each is hereby expressly made a part of this specification.
| Number | Name | Date | Kind |
|---|---|---|---|
| 52641 | Gates | Feb 1866 | A |
| 62334 | Holmes | Feb 1867 | A |
| 65604 | Reynolds | Jun 1867 | A |
| 3581062 | Aston | May 1971 | A |
| 3926760 | Allen et al. | Dec 1975 | A |
| 3949388 | Fuller | Apr 1976 | A |
| 3960497 | Acord | Jun 1976 | A |
| 3978856 | Michel | Sep 1976 | A |
| 4036749 | Anderson | Jul 1977 | A |
| 4055175 | Clemens et al. | Oct 1977 | A |
| 4129128 | McFarlane | Dec 1978 | A |
| 4245634 | Albisser et al. | Jan 1981 | A |
| 4327725 | Cortese et al. | May 1982 | A |
| 4344438 | Schultz | Aug 1982 | A |
| 4349728 | Phillips et al. | Sep 1982 | A |
| 4373527 | Fischell | Feb 1983 | A |
| 4392849 | Petre et al. | Jul 1983 | A |
| 4425920 | Bourland et al. | Jan 1984 | A |
| 4441968 | Emmer et al. | Apr 1984 | A |
| 4462048 | Ross | Jul 1984 | A |
| 4478976 | Goertz et al. | Oct 1984 | A |
| 4494950 | Fischell | Jan 1985 | A |
| 4509531 | Ward | Apr 1985 | A |
| 4527240 | Kvitash | Jul 1985 | A |
| 4538616 | Rogoff | Sep 1985 | A |
| 4545382 | Higgins et al. | Oct 1985 | A |
| 4619793 | Lee | Oct 1986 | A |
| 4671288 | Gough | Jun 1987 | A |
| 4703756 | Gough et al. | Nov 1987 | A |
| 4711245 | Higgins et al. | Dec 1987 | A |
| 4731051 | Fischell | Mar 1988 | A |
| 4731726 | Allen, III | Mar 1988 | A |
| 4749985 | Corsberg | Jun 1988 | A |
| 4757022 | Shults et al. | Jul 1988 | A |
| 4759366 | Callaghan | Jul 1988 | A |
| 4777953 | Ash et al. | Oct 1988 | A |
| 4779618 | Mund et al. | Oct 1988 | A |
| 4854322 | Ash et al. | Aug 1989 | A |
| 4871351 | Feingold | Oct 1989 | A |
| 4890620 | Gough | Jan 1990 | A |
| 4925268 | Iyer et al. | May 1990 | A |
| 4935345 | Guilbeau et al. | Jun 1990 | A |
| 4947845 | Davis | Aug 1990 | A |
| 4953552 | DeMarzo | Sep 1990 | A |
| 4986271 | Wilkins | Jan 1991 | A |
| 4995402 | Smith et al. | Feb 1991 | A |
| 5000180 | Kuypers et al. | Mar 1991 | A |
| 5002054 | Ash et al. | Mar 1991 | A |
| 5019974 | Beckers | May 1991 | A |
| 5050612 | Matsumura | Sep 1991 | A |
| 5055171 | Peck | Oct 1991 | A |
| 5068536 | Rosenthal | Nov 1991 | A |
| 5077476 | Rosenthal | Dec 1991 | A |
| 5082550 | Rishpon et al. | Jan 1992 | A |
| 5106365 | Hernandez | Apr 1992 | A |
| 5112455 | Cozzette et al. | May 1992 | A |
| 5113869 | Nappholz et al. | May 1992 | A |
| 5122925 | Inpyn | Jun 1992 | A |
| 5135004 | Adams et al. | Aug 1992 | A |
| 5148812 | Verrier et al. | Sep 1992 | A |
| 5165407 | Wilson et al. | Nov 1992 | A |
| 5196025 | Ranalletta et al. | Mar 1993 | A |
| 5199428 | Obel et al. | Apr 1993 | A |
| 5202261 | Musho et al. | Apr 1993 | A |
| 5203326 | Collins | Apr 1993 | A |
| 5204264 | Kaminer | Apr 1993 | A |
| 5210778 | Massart | May 1993 | A |
| 5231988 | Wernicke et al. | Aug 1993 | A |
| 5237123 | Miller | Aug 1993 | A |
| 5246867 | Lakowicz et al. | Sep 1993 | A |
| 5262035 | Gregg et al. | Nov 1993 | A |
| 5262305 | Heller et al. | Nov 1993 | A |
| 5264105 | Gregg et al. | Nov 1993 | A |
| 5279294 | Anderson et al. | Jan 1994 | A |
| 5285792 | Sjoquist et al. | Feb 1994 | A |
| 5293877 | O'Hara et al. | Mar 1994 | A |
| 5299571 | Mastrototaro | Apr 1994 | A |
| 5313953 | Yomtov et al. | May 1994 | A |
| 5314441 | Cusack et al. | May 1994 | A |
| 5318583 | Rabenau et al. | Jun 1994 | A |
| 5320715 | Berg | Jun 1994 | A |
| 5320725 | Gregg et al. | Jun 1994 | A |
| 5322063 | Allen et al. | Jun 1994 | A |
| 5328460 | Lord et al. | Jul 1994 | A |
| 5330634 | Wong et al. | Jul 1994 | A |
| 5340722 | Wolfbeis et al. | Aug 1994 | A |
| 5342789 | Chick et al. | Aug 1994 | A |
| 5352349 | Inamoto et al. | Oct 1994 | A |
| 5356217 | Sheffield | Oct 1994 | A |
| 5356786 | Heller et al. | Oct 1994 | A |
| 5360404 | Novacek et al. | Nov 1994 | A |
| 5360405 | Yoon | Nov 1994 | A |
| 5365426 | Siegel et al. | Nov 1994 | A |
| 5372427 | Padovani et al. | Dec 1994 | A |
| 5376070 | Purvis et al. | Dec 1994 | A |
| 5379238 | Stark | Jan 1995 | A |
| 5384547 | Lynk, Jr. et al. | Jan 1995 | A |
| 5390671 | Lord et al. | Feb 1995 | A |
| 5391250 | Cheney, II et al. | Feb 1995 | A |
| 5400795 | Murphy et al. | Mar 1995 | A |
| 5408999 | Singh et al. | Apr 1995 | A |
| 5411647 | Johnson et al. | May 1995 | A |
| 5422829 | Pollock | Jun 1995 | A |
| 5425749 | Adams | Jun 1995 | A |
| 5425868 | Pedersen | Jun 1995 | A |
| 5431160 | Wilkins | Jul 1995 | A |
| 5431921 | Thombre | Jul 1995 | A |
| 5438983 | Falcone | Aug 1995 | A |
| 5462645 | Albery et al. | Oct 1995 | A |
| 5472317 | Field et al. | Dec 1995 | A |
| 5489414 | Schreiber et al. | Feb 1996 | A |
| 5497772 | Schulman et al. | Mar 1996 | A |
| 5505828 | Wong et al. | Apr 1996 | A |
| 5507288 | Bocker et al. | Apr 1996 | A |
| 5509410 | Hill et al. | Apr 1996 | A |
| 5514718 | Lewis et al. | May 1996 | A |
| 5520191 | Karlsson et al. | May 1996 | A |
| 5527334 | Kanner et al. | Jun 1996 | A |
| 5531878 | Vadgama et al. | Jul 1996 | A |
| 5543326 | Heller et al. | Aug 1996 | A |
| 5552997 | Massart | Sep 1996 | A |
| 5568400 | Stark et al. | Oct 1996 | A |
| 5568806 | Cheney, II et al. | Oct 1996 | A |
| 5569186 | Lord et al. | Oct 1996 | A |
| 5582184 | Erickson et al. | Dec 1996 | A |
| 5586553 | Halili et al. | Dec 1996 | A |
| 5593852 | Heller et al. | Jan 1997 | A |
| 5601435 | Quy | Feb 1997 | A |
| 5609575 | Larson et al. | Mar 1997 | A |
| 5628310 | Rao et al. | May 1997 | A |
| 5628890 | Carter et al. | May 1997 | A |
| 5640954 | Pfeiffer et al. | Jun 1997 | A |
| 5645077 | Foxlin | Jul 1997 | A |
| 5653239 | Pompei et al. | Aug 1997 | A |
| 5660163 | Schulman et al. | Aug 1997 | A |
| 5665222 | Heller et al. | Sep 1997 | A |
| 5711001 | Bussan et al. | Jan 1998 | A |
| 5711861 | Ward | Jan 1998 | A |
| 5720295 | Greenhut et al. | Feb 1998 | A |
| 5733259 | Valcke et al. | Mar 1998 | A |
| 5735285 | Albert et al. | Apr 1998 | A |
| 5741211 | Renirie et al. | Apr 1998 | A |
| 5772586 | Heinonen et al. | Jun 1998 | A |
| 5785660 | Van Lake et al. | Jul 1998 | A |
| 5791344 | Schulman et al. | Aug 1998 | A |
| 5792065 | Xue et al. | Aug 1998 | A |
| 5820551 | Hill et al. | Oct 1998 | A |
| 5822715 | Worthington et al. | Oct 1998 | A |
| 5891047 | Lander et al. | Apr 1999 | A |
| 5891048 | Nigam et al. | Apr 1999 | A |
| 5899855 | Brown | May 1999 | A |
| 5914026 | Blubaugh, Jr. et al. | Jun 1999 | A |
| 5918603 | Brown | Jul 1999 | A |
| 5925021 | Castellano et al. | Jul 1999 | A |
| 5935224 | Svancarek et al. | Aug 1999 | A |
| 5942979 | Luppino | Aug 1999 | A |
| 5957854 | Besson et al. | Sep 1999 | A |
| 5960797 | Kramer et al. | Oct 1999 | A |
| 5961451 | Reber et al. | Oct 1999 | A |
| 5964993 | Blubaugh, Jr. et al. | Oct 1999 | A |
| 5965380 | Heller et al. | Oct 1999 | A |
| 5971922 | Arita et al. | Oct 1999 | A |
| 5980728 | Farber et al. | Nov 1999 | A |
| 5984940 | Davis et al. | Nov 1999 | A |
| 5990422 | Komori et al. | Nov 1999 | A |
| 5995860 | Sun et al. | Nov 1999 | A |
| 6001067 | Shults et al. | Dec 1999 | A |
| 6016443 | Ekwall et al. | Jan 2000 | A |
| 6021350 | Mathson | Feb 2000 | A |
| 6024699 | Surwit et al. | Feb 2000 | A |
| 6038469 | Karlsson et al. | Mar 2000 | A |
| 6049727 | Crothall | Apr 2000 | A |
| 6071391 | Gotoh et al. | Jun 2000 | A |
| 6073031 | Helstab et al. | Jun 2000 | A |
| 6083710 | Heller et al. | Jul 2000 | A |
| 6088608 | Schulman et al. | Jul 2000 | A |
| 6091976 | Pfeiffer et al. | Jul 2000 | A |
| 6093172 | Funderburk et al. | Jul 2000 | A |
| 6103033 | Say et al. | Aug 2000 | A |
| 6108577 | Benser | Aug 2000 | A |
| 6112116 | Fischell et al. | Aug 2000 | A |
| 6115622 | Minoz | Sep 2000 | A |
| 6115628 | Stadler et al. | Sep 2000 | A |
| 6117290 | Say et al. | Sep 2000 | A |
| 6119028 | Schulman et al. | Sep 2000 | A |
| 6120676 | Heller et al. | Sep 2000 | A |
| 6121009 | Heller et al. | Sep 2000 | A |
| 6121611 | Lindsay et al. | Sep 2000 | A |
| 6122351 | Schlueter, Jr. et al. | Sep 2000 | A |
| 6128526 | Stadler et al. | Oct 2000 | A |
| 6134461 | Say et al. | Oct 2000 | A |
| 6143164 | Heller et al. | Nov 2000 | A |
| 6144837 | Quy | Nov 2000 | A |
| 6159147 | Lichter et al. | Dec 2000 | A |
| 6161095 | Brown | Dec 2000 | A |
| 6162611 | Heller et al. | Dec 2000 | A |
| 6175752 | Say et al. | Jan 2001 | B1 |
| 6186982 | Gross et al. | Feb 2001 | B1 |
| 6200265 | Walsh et al. | Mar 2001 | B1 |
| 6212416 | Ward et al. | Apr 2001 | B1 |
| 6219574 | Cormier et al. | Apr 2001 | B1 |
| 6223283 | Chaiken et al. | Apr 2001 | B1 |
| 6224562 | Lurie et al. | May 2001 | B1 |
| 6233486 | Ekwall et al. | May 2001 | B1 |
| 6248067 | Causey, III et al. | Jun 2001 | B1 |
| 6249705 | Snell | Jun 2001 | B1 |
| 6254586 | Mann et al. | Jul 2001 | B1 |
| 6256538 | Ekwall | Jul 2001 | B1 |
| 6264606 | Ekwall et al. | Jul 2001 | B1 |
| 6270455 | Brown | Aug 2001 | B1 |
| 6272379 | Fischell et al. | Aug 2001 | B1 |
| 6275717 | Gross et al. | Aug 2001 | B1 |
| 6283761 | Joao | Sep 2001 | B1 |
| 6284478 | Heller et al. | Sep 2001 | B1 |
| 6293925 | Safabash et al. | Sep 2001 | B1 |
| 6295506 | Heinonen et al. | Sep 2001 | B1 |
| 6299757 | Feldman et al. | Oct 2001 | B1 |
| 6306104 | Cunningham et al. | Oct 2001 | B1 |
| 6309884 | Cooper et al. | Oct 2001 | B1 |
| 6329161 | Heller et al. | Dec 2001 | B1 |
| 6338790 | Feldman et al. | Jan 2002 | B1 |
| 6348640 | Navot et al. | Feb 2002 | B1 |
| 6359444 | Grimes | Mar 2002 | B1 |
| 6360888 | McIvor et al. | Mar 2002 | B1 |
| 6361503 | Starobin et al. | Mar 2002 | B1 |
| 6366794 | Moussy et al. | Apr 2002 | B1 |
| 6368141 | Vanantwerp et al. | Apr 2002 | B1 |
| 6377828 | Chaiken et al. | Apr 2002 | B1 |
| 6377852 | Bornzin et al. | Apr 2002 | B1 |
| 6377894 | Deweese et al. | Apr 2002 | B1 |
| 6379301 | Worthington et al. | Apr 2002 | B1 |
| 6381493 | Stadler et al. | Apr 2002 | B1 |
| 6387048 | Schulman et al. | May 2002 | B1 |
| 6405066 | Essenpreis et al. | Jun 2002 | B1 |
| 6413393 | Van Antwerp et al. | Jul 2002 | B1 |
| 6424847 | Mastrototaro et al. | Jul 2002 | B1 |
| 6427088 | Bowman, IV et al. | Jul 2002 | B1 |
| 6440068 | Brown et al. | Aug 2002 | B1 |
| 6461496 | Feldman et al. | Oct 2002 | B1 |
| 6471689 | Joseph et al. | Oct 2002 | B1 |
| 6478736 | Mault | Nov 2002 | B1 |
| 6484046 | Say et al. | Nov 2002 | B1 |
| 6486661 | Chia et al. | Nov 2002 | B2 |
| 6501983 | Natarajan et al. | Dec 2002 | B1 |
| 6503381 | Gotoh et al. | Jan 2003 | B1 |
| 6514460 | Fendrock | Feb 2003 | B1 |
| 6514718 | Heller et al. | Feb 2003 | B2 |
| 6520326 | McIvor et al. | Feb 2003 | B2 |
| 6540891 | Stewart et al. | Apr 2003 | B1 |
| 6544212 | Galley et al. | Apr 2003 | B2 |
| 6551494 | Heller et al. | Apr 2003 | B1 |
| 6558320 | Causey, III et al. | May 2003 | B1 |
| 6558321 | Burd et al. | May 2003 | B1 |
| 6558351 | Steil et al. | May 2003 | B1 |
| 6560471 | Heller et al. | May 2003 | B1 |
| 6561978 | Conn et al. | May 2003 | B1 |
| 6562001 | Lebel et al. | May 2003 | B2 |
| 6564105 | Starkweather et al. | May 2003 | B2 |
| 6565509 | Say et al. | May 2003 | B1 |
| 6571128 | Lebel et al. | May 2003 | B2 |
| 6572542 | Houben et al. | Jun 2003 | B1 |
| 6574490 | Abbink et al. | Jun 2003 | B2 |
| 6576101 | Heller et al. | Jun 2003 | B1 |
| 6577899 | Lebel et al. | Jun 2003 | B2 |
| 6579690 | Bonnecaze et al. | Jun 2003 | B1 |
| 6585644 | Lebel et al. | Jul 2003 | B2 |
| 6591125 | Buse et al. | Jul 2003 | B1 |
| 6592745 | Feldman et al. | Jul 2003 | B1 |
| 6595919 | Berner et al. | Jul 2003 | B2 |
| 6600997 | Deweese et al. | Jul 2003 | B2 |
| 6605200 | Mao et al. | Aug 2003 | B1 |
| 6605201 | Mao et al. | Aug 2003 | B1 |
| 6607509 | Bobroff et al. | Aug 2003 | B2 |
| 6607543 | Purcell et al. | Aug 2003 | B2 |
| 6610012 | Mault | Aug 2003 | B2 |
| 6616819 | Liamos et al. | Sep 2003 | B1 |
| 6618934 | Feldman et al. | Sep 2003 | B1 |
| 6622045 | Snell et al. | Sep 2003 | B2 |
| 6633772 | Ford et al. | Oct 2003 | B2 |
| 6635014 | Starkweather et al. | Oct 2003 | B2 |
| 6641533 | Causey, III et al. | Nov 2003 | B2 |
| 6648821 | Lebel et al. | Nov 2003 | B2 |
| 6650471 | Doi | Nov 2003 | B2 |
| 6654625 | Say et al. | Nov 2003 | B1 |
| 6656114 | Poulsen et al. | Dec 2003 | B1 |
| 6658396 | Tang et al. | Dec 2003 | B1 |
| 6659948 | Lebel et al. | Dec 2003 | B2 |
| 6668196 | Villegas et al. | Dec 2003 | B1 |
| 6675030 | Ciurczak et al. | Jan 2004 | B2 |
| 6676816 | Mao et al. | Jan 2004 | B2 |
| 6687546 | Lebel et al. | Feb 2004 | B2 |
| 6689056 | Kilcoyne et al. | Feb 2004 | B1 |
| 6694191 | Starkweather et al. | Feb 2004 | B2 |
| 6695860 | Ward et al. | Feb 2004 | B1 |
| 6698269 | Baber et al. | Mar 2004 | B2 |
| 6702857 | Brauker et al. | Mar 2004 | B2 |
| 6721582 | Trepagnier et al. | Apr 2004 | B2 |
| 6730200 | Stewart et al. | May 2004 | B1 |
| 6731985 | Poore et al. | May 2004 | B2 |
| 6733446 | Lebel et al. | May 2004 | B2 |
| 6736957 | Forrow et al. | May 2004 | B1 |
| 6740075 | Lebel et al. | May 2004 | B2 |
| 6741877 | Shults et al. | May 2004 | B1 |
| 6746582 | Heller et al. | Jun 2004 | B2 |
| 6749740 | Liamos et al. | Jun 2004 | B2 |
| 6758810 | Lebel et al. | Jul 2004 | B2 |
| 6764581 | Forrow et al. | Jul 2004 | B1 |
| 6770030 | Schaupp et al. | Aug 2004 | B1 |
| 6773671 | Lewis et al. | Aug 2004 | B1 |
| 6790178 | Mault et al. | Sep 2004 | B1 |
| 6809653 | Mann et al. | Oct 2004 | B1 |
| 6810290 | Lebel et al. | Oct 2004 | B2 |
| 6811533 | Lebel et al. | Nov 2004 | B2 |
| 6811534 | Bowman, IV et al. | Nov 2004 | B2 |
| 6813519 | Lebel et al. | Nov 2004 | B2 |
| 6850790 | Berner et al. | Feb 2005 | B2 |
| 6850859 | Schuh | Feb 2005 | B1 |
| 6862465 | Shults et al. | Mar 2005 | B2 |
| 6865407 | Kimball et al. | Mar 2005 | B2 |
| 6873268 | Lebel et al. | Mar 2005 | B2 |
| 6881551 | Heller et al. | Apr 2005 | B2 |
| 6882940 | Potts et al. | Apr 2005 | B2 |
| 6892085 | McIvor et al. | May 2005 | B2 |
| 6893396 | Schulze et al. | May 2005 | B2 |
| 6893545 | Gotoh et al. | May 2005 | B2 |
| 6895263 | Shin et al. | May 2005 | B2 |
| 6895265 | Silver | May 2005 | B2 |
| 6912413 | Rantala et al. | Jun 2005 | B2 |
| 6923763 | Kovatchev et al. | Aug 2005 | B1 |
| 6931327 | Goode, Jr. et al. | Aug 2005 | B2 |
| 6932892 | Chen et al. | Aug 2005 | B2 |
| 6932894 | Mao et al. | Aug 2005 | B2 |
| 6936006 | Sabra | Aug 2005 | B2 |
| 6942518 | Liamos et al. | Sep 2005 | B2 |
| 6950708 | Bowman, IV et al. | Sep 2005 | B2 |
| 6954662 | Freger et al. | Oct 2005 | B2 |
| 6958705 | Lebel et al. | Oct 2005 | B2 |
| 6960192 | Flaherty et al. | Nov 2005 | B1 |
| 6968294 | Gutta et al. | Nov 2005 | B2 |
| 6971274 | Olin | Dec 2005 | B2 |
| 6974437 | Lebel et al. | Dec 2005 | B2 |
| 6990366 | Say et al. | Jan 2006 | B2 |
| 6990422 | Laletin et al. | Jan 2006 | B2 |
| 6997907 | Safabash et al. | Feb 2006 | B2 |
| 6998247 | Monfre et al. | Feb 2006 | B2 |
| 7003336 | Holker et al. | Feb 2006 | B2 |
| 7003340 | Say et al. | Feb 2006 | B2 |
| 7003341 | Say et al. | Feb 2006 | B2 |
| 7010345 | Hill et al. | Mar 2006 | B2 |
| 7011630 | Desai et al. | Mar 2006 | B2 |
| 7016713 | Gardner et al. | Mar 2006 | B2 |
| 7016720 | Kroll | Mar 2006 | B2 |
| 7022072 | Fox et al. | Apr 2006 | B2 |
| 7022219 | Mansouri et al. | Apr 2006 | B2 |
| 7024245 | Lebel et al. | Apr 2006 | B2 |
| 7025425 | Kovatchev et al. | Apr 2006 | B2 |
| 7029443 | Kroll | Apr 2006 | B2 |
| 7029444 | Shin et al. | Apr 2006 | B2 |
| 7041068 | Freeman et al. | May 2006 | B2 |
| 7041468 | Drucker et al. | May 2006 | B2 |
| 7043287 | Khalil et al. | May 2006 | B1 |
| 7052472 | Miller et al. | May 2006 | B1 |
| 7052483 | Wojcik | May 2006 | B2 |
| 7056302 | Douglas | Jun 2006 | B2 |
| 7074307 | Simpson et al. | Jul 2006 | B2 |
| 7076300 | Kroll et al. | Jul 2006 | B1 |
| 7081195 | Simpson et al. | Jul 2006 | B2 |
| 7092891 | Maus et al. | Aug 2006 | B2 |
| 7096064 | Deno et al. | Aug 2006 | B2 |
| 7098803 | Mann et al. | Aug 2006 | B2 |
| 7103412 | Kroll | Sep 2006 | B1 |
| 7108778 | Simpson et al. | Sep 2006 | B2 |
| 7110803 | Shults et al. | Sep 2006 | B2 |
| 7113821 | Sun et al. | Sep 2006 | B1 |
| 7118667 | Lee | Oct 2006 | B2 |
| 7120483 | Russell et al. | Oct 2006 | B2 |
| 7123950 | Mannheimer | Oct 2006 | B2 |
| 7134999 | Brauker et al. | Nov 2006 | B2 |
| 7136689 | Shults et al. | Nov 2006 | B2 |
| 7142911 | Boileau et al. | Nov 2006 | B2 |
| 7144404 | Whitson et al. | Dec 2006 | B2 |
| 7150755 | Levaughn et al. | Dec 2006 | B2 |
| 7153265 | Vachon | Dec 2006 | B2 |
| 7167818 | Brown | Jan 2007 | B2 |
| 7171274 | Starkweather et al. | Jan 2007 | B2 |
| 7183102 | Monfre et al. | Feb 2007 | B2 |
| 7190988 | Say et al. | Mar 2007 | B2 |
| 7192450 | Brauker et al. | Mar 2007 | B2 |
| 7198606 | Boecker et al. | Apr 2007 | B2 |
| 7223276 | List et al. | May 2007 | B2 |
| 7225535 | Feldman et al. | Jun 2007 | B2 |
| 7226978 | Tapsak et al. | Jun 2007 | B2 |
| 7253680 | Laletin | Aug 2007 | B2 |
| 7258673 | Racchini et al. | Aug 2007 | B2 |
| 7267665 | Steil et al. | Sep 2007 | B2 |
| 7272436 | Gill et al. | Sep 2007 | B2 |
| 7276029 | Goode, Jr. et al. | Oct 2007 | B2 |
| 7278983 | Ireland et al. | Oct 2007 | B2 |
| 7295867 | Berner et al. | Nov 2007 | B2 |
| 7297114 | Gill et al. | Nov 2007 | B2 |
| 7297136 | Wyrick | Nov 2007 | B2 |
| 7299082 | Feldman et al. | Nov 2007 | B2 |
| 7303549 | Flaherty et al. | Dec 2007 | B2 |
| 7310544 | Brister et al. | Dec 2007 | B2 |
| 7317938 | Lorenz et al. | Jan 2008 | B2 |
| 7335294 | Heller et al. | Feb 2008 | B2 |
| 7338639 | Burke et al. | Mar 2008 | B2 |
| 7354420 | Steil et al. | Apr 2008 | B2 |
| 7364592 | Carr-Brendel et al. | Apr 2008 | B2 |
| 7366556 | Brister et al. | Apr 2008 | B2 |
| 7379765 | Petisce et al. | May 2008 | B2 |
| 7390667 | Burke et al. | Jun 2008 | B2 |
| 7402153 | Steil et al. | Jul 2008 | B2 |
| 7407811 | Burke et al. | Aug 2008 | B2 |
| 7424318 | Brister et al. | Sep 2008 | B2 |
| 7460898 | Brister et al. | Dec 2008 | B2 |
| 7467003 | Brister et al. | Dec 2008 | B2 |
| 7468125 | Kraft et al. | Dec 2008 | B2 |
| 7471972 | Rhodes et al. | Dec 2008 | B2 |
| 7474992 | Ariyur | Jan 2009 | B2 |
| 7481819 | Koeppel et al. | Jan 2009 | B2 |
| 7488601 | Burke et al. | Feb 2009 | B2 |
| 7494465 | Brister et al. | Feb 2009 | B2 |
| 7494816 | Burke et al. | Feb 2009 | B2 |
| 7497827 | Brister et al. | Mar 2009 | B2 |
| 7499002 | Blasko et al. | Mar 2009 | B2 |
| 7502644 | Gill et al. | Mar 2009 | B2 |
| 7519408 | Rasdal et al. | Apr 2009 | B2 |
| 7519478 | Bartkowiak et al. | Apr 2009 | B2 |
| 7523004 | Bartkowiak et al. | Apr 2009 | B2 |
| 7524287 | Bharmi | Apr 2009 | B2 |
| 7530964 | Lavi et al. | May 2009 | B2 |
| 7547281 | Hayes et al. | Jun 2009 | B2 |
| 7569030 | Lebel et al. | Aug 2009 | B2 |
| 7583990 | Goode, Jr. et al. | Sep 2009 | B2 |
| 7591801 | Brauker et al. | Sep 2009 | B2 |
| 7599726 | Goode, Jr. et al. | Oct 2009 | B2 |
| 7613491 | Boock et al. | Nov 2009 | B2 |
| 7615007 | Shults et al. | Nov 2009 | B2 |
| 7618369 | Hayter et al. | Nov 2009 | B2 |
| 7620438 | He | Nov 2009 | B2 |
| 7630748 | Budiman | Dec 2009 | B2 |
| 7632228 | Brauker et al. | Dec 2009 | B2 |
| 7635594 | Holmes et al. | Dec 2009 | B2 |
| 7637868 | Saint et al. | Dec 2009 | B2 |
| 7640048 | Dobbles et al. | Dec 2009 | B2 |
| 7653425 | Hayter et al. | Jan 2010 | B2 |
| 7699775 | Desai et al. | Apr 2010 | B2 |
| 7699964 | Feldman et al. | Apr 2010 | B2 |
| 7711493 | Bartkowiak et al. | May 2010 | B2 |
| 7736310 | Taub | Jun 2010 | B2 |
| 7749445 | Masters | Jul 2010 | B2 |
| 7751864 | Buck, Jr. | Jul 2010 | B2 |
| 7766829 | Sloan et al. | Aug 2010 | B2 |
| 7771352 | Shults et al. | Aug 2010 | B2 |
| 7774038 | Wang et al. | Aug 2010 | B2 |
| 7774145 | Brauker et al. | Aug 2010 | B2 |
| 7776559 | Childers et al. | Aug 2010 | B2 |
| 7778679 | Schulman et al. | Aug 2010 | B2 |
| 7778680 | Goode, Jr. et al. | Aug 2010 | B2 |
| 7826981 | Goode, Jr. et al. | Nov 2010 | B2 |
| 7838639 | Tschopp et al. | Nov 2010 | B2 |
| 7846132 | Gravesen et al. | Dec 2010 | B2 |
| 7850652 | Liniger et al. | Dec 2010 | B2 |
| 7857760 | Brister et al. | Dec 2010 | B2 |
| 7866025 | James et al. | Jan 2011 | B2 |
| 7866026 | Wang et al. | Jan 2011 | B1 |
| 7885697 | Brister et al. | Feb 2011 | B2 |
| 7885698 | Feldman | Feb 2011 | B2 |
| 7889069 | Fifolt et al. | Feb 2011 | B2 |
| 7894870 | Lucisano et al. | Feb 2011 | B1 |
| 7899511 | Shults et al. | Mar 2011 | B2 |
| 7905833 | Brister et al. | Mar 2011 | B2 |
| 7914450 | Goode, Jr. et al. | Mar 2011 | B2 |
| 7920906 | Goode, Jr. et al. | Apr 2011 | B2 |
| 7938797 | Estes | May 2011 | B2 |
| 7946984 | Brister et al. | May 2011 | B2 |
| 7974672 | Shults et al. | Jul 2011 | B2 |
| 7985330 | Wang et al. | Jul 2011 | B2 |
| 7990828 | Su et al. | Aug 2011 | B2 |
| 7996158 | Hayter et al. | Aug 2011 | B2 |
| 8000763 | Mazza et al. | Aug 2011 | B2 |
| 8025658 | Chong et al. | Sep 2011 | B2 |
| 8026104 | Wu et al. | Sep 2011 | B2 |
| 8060173 | Goode, Jr. et al. | Nov 2011 | B2 |
| 8079961 | Saikley et al. | Dec 2011 | B2 |
| 8103471 | Hayter | Jan 2012 | B2 |
| 8112240 | Fennell | Feb 2012 | B2 |
| 8114268 | Wang et al. | Feb 2012 | B2 |
| 8116837 | Huang | Feb 2012 | B2 |
| 8140312 | Hayter et al. | Mar 2012 | B2 |
| 8149117 | Fennell et al. | Apr 2012 | B2 |
| 8160670 | Ouyang et al. | Apr 2012 | B2 |
| 8160834 | Liang et al. | Apr 2012 | B2 |
| 8160900 | Taub et al. | Apr 2012 | B2 |
| 8170803 | Kamath et al. | May 2012 | B2 |
| 8202491 | Masters et al. | Jun 2012 | B2 |
| 8211016 | Budiman | Jul 2012 | B2 |
| 8216137 | Budiman | Jul 2012 | B2 |
| 8216138 | McGarraugh | Jul 2012 | B1 |
| 8219173 | Budiman et al. | Jul 2012 | B2 |
| 8224415 | Budiman | Jul 2012 | B2 |
| 8239166 | Hayter et al. | Aug 2012 | B2 |
| 8249683 | Wang et al. | Aug 2012 | B2 |
| 8255026 | Al-Ali | Aug 2012 | B1 |
| 8260558 | Hayter et al. | Sep 2012 | B2 |
| 8282549 | Brauker et al. | Oct 2012 | B2 |
| 8298172 | Nielsen et al. | Oct 2012 | B2 |
| 8346335 | Harper et al. | Jan 2013 | B2 |
| 8346337 | Heller et al. | Jan 2013 | B2 |
| 8348923 | Kanderian, Jr. et al. | Jan 2013 | B2 |
| 8366682 | Wyrick | Feb 2013 | B2 |
| 8366729 | Levaughn et al. | Feb 2013 | B2 |
| 8372351 | Ow-Wing | Feb 2013 | B2 |
| 8376945 | Hayter et al. | Feb 2013 | B2 |
| 8409140 | Ejlersen et al. | Apr 2013 | B2 |
| 8409145 | Raymond et al. | Apr 2013 | B2 |
| 8417312 | Kamath et al. | Apr 2013 | B2 |
| 8439838 | Mogensen et al. | May 2013 | B2 |
| 8444560 | Hayter et al. | May 2013 | B2 |
| 8457703 | Al-Ali | Jun 2013 | B2 |
| 8461985 | Fennell et al. | Jun 2013 | B2 |
| 8463350 | Kamath et al. | Jun 2013 | B2 |
| 8473022 | Hayter et al. | Jun 2013 | B2 |
| 8478557 | Hayter et al. | Jul 2013 | B2 |
| 8483792 | Slomski et al. | Jul 2013 | B2 |
| 8484005 | Hayter et al. | Jul 2013 | B2 |
| 8500654 | Goldenberg | Aug 2013 | B2 |
| 8515517 | Hayter et al. | Aug 2013 | B2 |
| 8532935 | Budiman | Sep 2013 | B2 |
| 8543354 | Luo et al. | Sep 2013 | B2 |
| 8560037 | Goode, Jr. et al. | Oct 2013 | B2 |
| 8560038 | Hayter et al. | Oct 2013 | B2 |
| 8562567 | Gundberg | Oct 2013 | B2 |
| 8571808 | Hayter | Oct 2013 | B2 |
| 8583205 | Budiman et al. | Nov 2013 | B2 |
| 8593109 | He | Nov 2013 | B2 |
| 8600681 | Hayter et al. | Dec 2013 | B2 |
| 8612163 | Hayter et al. | Dec 2013 | B2 |
| 8615281 | Yodfat et al. | Dec 2013 | B2 |
| 8626257 | Li et al. | Jan 2014 | B2 |
| 8657746 | Roy | Feb 2014 | B2 |
| 8663220 | Wiener et al. | Mar 2014 | B2 |
| 8665091 | Fennell et al. | Mar 2014 | B2 |
| 8682615 | Hayter et al. | Mar 2014 | B2 |
| 8718739 | Harper et al. | May 2014 | B2 |
| 8718965 | Hayter et al. | May 2014 | B2 |
| 8744547 | Budiman et al. | Jun 2014 | B2 |
| 8747363 | Nielsen et al. | Jun 2014 | B2 |
| 8868151 | Telson et al. | Oct 2014 | B2 |
| 8868161 | Thierman | Oct 2014 | B2 |
| 8870822 | Thalmann et al. | Oct 2014 | B2 |
| 8933664 | He | Jan 2015 | B2 |
| 8942778 | Ocvirk et al. | Jan 2015 | B2 |
| 9060719 | Hayter et al. | Jun 2015 | B2 |
| 9113828 | Budiman | Aug 2015 | B2 |
| 9125548 | Hayter | Sep 2015 | B2 |
| 9149220 | Bohm | Oct 2015 | B2 |
| 9161714 | Martini et al. | Oct 2015 | B2 |
| 9295786 | Gottlieb et al. | Mar 2016 | B2 |
| 9314196 | Pryor et al. | Apr 2016 | B2 |
| 9320462 | Harper et al. | Apr 2016 | B2 |
| 9320468 | Hayter et al. | Apr 2016 | B2 |
| 9326709 | Budiman | May 2016 | B2 |
| 9332934 | Hayter et al. | May 2016 | B2 |
| 9339217 | Harper et al. | May 2016 | B2 |
| 9357959 | Hayter et al. | Jun 2016 | B2 |
| 9380971 | He | Jul 2016 | B2 |
| 9380975 | Karbowniczek et al. | Jul 2016 | B2 |
| 9392969 | Hayter et al. | Jul 2016 | B2 |
| 9398872 | Hayter et al. | Jul 2016 | B2 |
| 9399094 | Krag et al. | Jul 2016 | B2 |
| 9408566 | Hayter et al. | Aug 2016 | B2 |
| 9483608 | Hayter et al. | Nov 2016 | B2 |
| 9533092 | Gyrn | Jan 2017 | B2 |
| 9558325 | Hayter et al. | Jan 2017 | B2 |
| 9629578 | Hayter et al. | Apr 2017 | B2 |
| 9662056 | Budiman et al. | May 2017 | B2 |
| 9675285 | Christian | Jun 2017 | B2 |
| 9675290 | Budiman et al. | Jun 2017 | B2 |
| 9730623 | Harper et al. | Aug 2017 | B2 |
| 9737249 | Hayter et al. | Aug 2017 | B2 |
| 9743863 | He | Aug 2017 | B2 |
| 9770211 | Hayter et al. | Sep 2017 | B2 |
| 9788771 | Stafford | Oct 2017 | B2 |
| 9797880 | Hayter et al. | Oct 2017 | B2 |
| 9801571 | Hayter | Oct 2017 | B2 |
| 9801575 | Bohm | Oct 2017 | B2 |
| 9801577 | Budiman et al. | Oct 2017 | B2 |
| 9804148 | Hayter et al. | Oct 2017 | B2 |
| 9804150 | Hayter et al. | Oct 2017 | B2 |
| 9808190 | Bohm et al. | Nov 2017 | B2 |
| 9808574 | Yodfat et al. | Nov 2017 | B2 |
| 9814428 | Budiman | Nov 2017 | B2 |
| 9833181 | Hayter et al. | Dec 2017 | B2 |
| 9839383 | Hayter et al. | Dec 2017 | B2 |
| 9848809 | Bohm et al. | Dec 2017 | B2 |
| 9936910 | Hayter et al. | Apr 2018 | B2 |
| 10002233 | Hayter et al. | Jun 2018 | B2 |
| 10004442 | Böhm | Jun 2018 | B2 |
| 10031002 | Hayter et al. | Jul 2018 | B2 |
| 10045720 | Hayter et al. | Aug 2018 | B2 |
| 10052055 | Li et al. | Aug 2018 | B2 |
| 10076606 | Ambruzs et al. | Sep 2018 | B2 |
| 10078380 | Budiman | Sep 2018 | B2 |
| 10082493 | Harper et al. | Sep 2018 | B2 |
| 10089446 | Budiman | Oct 2018 | B2 |
| 10119956 | Hayter et al. | Nov 2018 | B2 |
| 10143409 | Hayter | Dec 2018 | B2 |
| 10188334 | Budiman et al. | Jan 2019 | B2 |
| 10188794 | Hayter et al. | Jan 2019 | B2 |
| 10194868 | Budiman | Feb 2019 | B2 |
| 10261069 | Hayter et al. | Apr 2019 | B2 |
| 10278630 | Hayter et al. | May 2019 | B2 |
| 10327688 | Böhm | Jun 2019 | B2 |
| 10335075 | Vanslyke et al. | Jul 2019 | B2 |
| 10376637 | Gyrn et al. | Aug 2019 | B2 |
| 10448873 | Bohm et al. | Oct 2019 | B2 |
| 10561354 | Böhm | Feb 2020 | B2 |
| 10610141 | Böhm et al. | Apr 2020 | B2 |
| 10624568 | Böhm et al. | Apr 2020 | B2 |
| 10682084 | Böhm | Jun 2020 | B2 |
| 10682984 | Doi | Jun 2020 | B2 |
| 10722162 | Böhm et al. | Jul 2020 | B2 |
| 10835162 | Bohm et al. | Nov 2020 | B2 |
| 11020031 | Simpson et al. | Jun 2021 | B1 |
| 11051725 | Pace et al. | Jul 2021 | B2 |
| 11627900 | Simpson et al. | Apr 2023 | B2 |
| 20010041831 | Starkweather et al. | Nov 2001 | A1 |
| 20020016534 | Trepagnier et al. | Feb 2002 | A1 |
| 20020019022 | Dunn et al. | Feb 2002 | A1 |
| 20020029058 | Levaughn et al. | Mar 2002 | A1 |
| 20020038101 | Avrahami et al. | Mar 2002 | A1 |
| 20020042090 | Heller et al. | Apr 2002 | A1 |
| 20020065454 | Lebel et al. | May 2002 | A1 |
| 20020068860 | Clark | Jun 2002 | A1 |
| 20020103499 | Perez et al. | Aug 2002 | A1 |
| 20020106709 | Potts et al. | Aug 2002 | A1 |
| 20020120186 | Keimel | Aug 2002 | A1 |
| 20020128594 | Das et al. | Sep 2002 | A1 |
| 20020143266 | Bock | Oct 2002 | A1 |
| 20020143372 | Snell et al. | Oct 2002 | A1 |
| 20020156355 | Gough | Oct 2002 | A1 |
| 20020161288 | Shin et al. | Oct 2002 | A1 |
| 20020169635 | Shillingburg | Nov 2002 | A1 |
| 20020193679 | Malave et al. | Dec 2002 | A1 |
| 20030004403 | Drinan et al. | Jan 2003 | A1 |
| 20030023317 | Brauker et al. | Jan 2003 | A1 |
| 20030023461 | Quintanilla et al. | Jan 2003 | A1 |
| 20030028126 | List | Feb 2003 | A1 |
| 20030032867 | Crothall et al. | Feb 2003 | A1 |
| 20030032874 | Rhodes et al. | Feb 2003 | A1 |
| 20030042137 | Mao et al. | Mar 2003 | A1 |
| 20030050546 | Desai et al. | Mar 2003 | A1 |
| 20030054428 | Monfre et al. | Mar 2003 | A1 |
| 20030065308 | Lebel et al. | Apr 2003 | A1 |
| 20030100821 | Heller et al. | May 2003 | A1 |
| 20030125612 | Fox et al. | Jul 2003 | A1 |
| 20030130616 | Steil et al. | Jul 2003 | A1 |
| 20030134347 | Heller et al. | Jul 2003 | A1 |
| 20030168338 | Gao et al. | Sep 2003 | A1 |
| 20030175987 | Verdonk et al. | Sep 2003 | A1 |
| 20030176933 | Lebel et al. | Sep 2003 | A1 |
| 20030187338 | Say et al. | Oct 2003 | A1 |
| 20030187470 | Chelak et al. | Oct 2003 | A1 |
| 20030191377 | Robinson et al. | Oct 2003 | A1 |
| 20030199744 | Buse et al. | Oct 2003 | A1 |
| 20030199790 | Boecker et al. | Oct 2003 | A1 |
| 20030208113 | Mault et al. | Nov 2003 | A1 |
| 20030212317 | Kovatchev et al. | Nov 2003 | A1 |
| 20030212379 | Bylund et al. | Nov 2003 | A1 |
| 20030216630 | Jersey-Willuhn et al. | Nov 2003 | A1 |
| 20030217966 | Tapsak et al. | Nov 2003 | A1 |
| 20030235817 | Bartkowiak et al. | Dec 2003 | A1 |
| 20040010186 | Kimball et al. | Jan 2004 | A1 |
| 20040010207 | Flaherty et al. | Jan 2004 | A1 |
| 20040011671 | Shults et al. | Jan 2004 | A1 |
| 20040024553 | Monfre et al. | Feb 2004 | A1 |
| 20040039298 | Abreu | Feb 2004 | A1 |
| 20040040840 | Mao et al. | Mar 2004 | A1 |
| 20040045879 | Shults et al. | Mar 2004 | A1 |
| 20040054263 | Moerman et al. | Mar 2004 | A1 |
| 20040064068 | DeNuzzio et al. | Apr 2004 | A1 |
| 20040077962 | Kroll | Apr 2004 | A1 |
| 20040078065 | Kroll | Apr 2004 | A1 |
| 20040093167 | Braig et al. | May 2004 | A1 |
| 20040099529 | Mao et al. | May 2004 | A1 |
| 20040106858 | Say et al. | Jun 2004 | A1 |
| 20040108226 | Polychronakos et al. | Jun 2004 | A1 |
| 20040122353 | Shahmirian et al. | Jun 2004 | A1 |
| 20040133164 | Funderburk et al. | Jul 2004 | A1 |
| 20040135684 | Steinthal et al. | Jul 2004 | A1 |
| 20040138588 | Saikley et al. | Jul 2004 | A1 |
| 20040138716 | Kon et al. | Jul 2004 | A1 |
| 20040142403 | Hetzel et al. | Jul 2004 | A1 |
| 20040146909 | Duong et al. | Jul 2004 | A1 |
| 20040147819 | Caduff et al. | Jul 2004 | A1 |
| 20040152622 | Keith et al. | Aug 2004 | A1 |
| 20040158137 | Eppstein et al. | Aug 2004 | A1 |
| 20040162678 | Hetzel et al. | Aug 2004 | A1 |
| 20040167801 | Say et al. | Aug 2004 | A1 |
| 20040171921 | Say et al. | Sep 2004 | A1 |
| 20040172307 | Gruber | Sep 2004 | A1 |
| 20040176672 | Silver et al. | Sep 2004 | A1 |
| 20040186362 | Brauker et al. | Sep 2004 | A1 |
| 20040186365 | Jin et al. | Sep 2004 | A1 |
| 20040193025 | Steil et al. | Sep 2004 | A1 |
| 20040193090 | Lebel et al. | Sep 2004 | A1 |
| 20040197846 | Hockersmith et al. | Oct 2004 | A1 |
| 20040199059 | Brauker et al. | Oct 2004 | A1 |
| 20040204687 | Mogensen et al. | Oct 2004 | A1 |
| 20040208780 | Faries, Jr. et al. | Oct 2004 | A1 |
| 20040225338 | Lebel et al. | Nov 2004 | A1 |
| 20040236200 | Say et al. | Nov 2004 | A1 |
| 20040249253 | Racchini et al. | Dec 2004 | A1 |
| 20040249420 | Olson et al. | Dec 2004 | A1 |
| 20040254433 | Bandis et al. | Dec 2004 | A1 |
| 20040254434 | Goodnow et al. | Dec 2004 | A1 |
| 20040260478 | Schwamm | Dec 2004 | A1 |
| 20040263354 | Mann et al. | Dec 2004 | A1 |
| 20040267300 | Mace | Dec 2004 | A1 |
| 20050003470 | Nelson et al. | Jan 2005 | A1 |
| 20050004439 | Shin et al. | Jan 2005 | A1 |
| 20050004494 | Perez et al. | Jan 2005 | A1 |
| 20050010087 | Banet et al. | Jan 2005 | A1 |
| 20050010269 | Lebel et al. | Jan 2005 | A1 |
| 20050016276 | Guan et al. | Jan 2005 | A1 |
| 20050027177 | Shin et al. | Feb 2005 | A1 |
| 20050027180 | Goode, Jr. et al. | Feb 2005 | A1 |
| 20050027181 | Goode, Jr. et al. | Feb 2005 | A1 |
| 20050027462 | Goode, Jr. et al. | Feb 2005 | A1 |
| 20050027463 | Goode, Jr. et al. | Feb 2005 | A1 |
| 20050031689 | Shults et al. | Feb 2005 | A1 |
| 20050038332 | Saidara et al. | Feb 2005 | A1 |
| 20050043598 | Goode, Jr. et al. | Feb 2005 | A1 |
| 20050049179 | Davidson et al. | Mar 2005 | A1 |
| 20050049473 | Desai et al. | Mar 2005 | A1 |
| 20050070774 | Addison et al. | Mar 2005 | A1 |
| 20050090607 | Tapsak et al. | Apr 2005 | A1 |
| 20050090850 | Thoes et al. | Apr 2005 | A1 |
| 20050096511 | Fox et al. | May 2005 | A1 |
| 20050096512 | Fox et al. | May 2005 | A1 |
| 20050112169 | Brauker et al. | May 2005 | A1 |
| 20050113653 | Fox et al. | May 2005 | A1 |
| 20050114068 | Chey et al. | May 2005 | A1 |
| 20050115832 | Simpson et al. | Jun 2005 | A1 |
| 20050121322 | Say et al. | Jun 2005 | A1 |
| 20050131346 | Douglas | Jun 2005 | A1 |
| 20050143635 | Kamath | Jun 2005 | A1 |
| 20050149089 | Trissel et al. | Jul 2005 | A1 |
| 20050154271 | Rasdal et al. | Jul 2005 | A1 |
| 20050176136 | Burd et al. | Aug 2005 | A1 |
| 20050177398 | Watanabe et al. | Aug 2005 | A1 |
| 20050182306 | Sloan | Aug 2005 | A1 |
| 20050187720 | Goode, Jr. et al. | Aug 2005 | A1 |
| 20050192494 | Ginsberg | Sep 2005 | A1 |
| 20050192557 | Brauker et al. | Sep 2005 | A1 |
| 20050195930 | Spital et al. | Sep 2005 | A1 |
| 20050196821 | Monfre et al. | Sep 2005 | A1 |
| 20050199494 | Say et al. | Sep 2005 | A1 |
| 20050203360 | Brauker et al. | Sep 2005 | A1 |
| 20050214892 | Kovatchev et al. | Sep 2005 | A1 |
| 20050239154 | Feldman et al. | Oct 2005 | A1 |
| 20050239156 | Drucker et al. | Oct 2005 | A1 |
| 20050241957 | Mao et al. | Nov 2005 | A1 |
| 20050245795 | Goode, Jr. et al. | Nov 2005 | A1 |
| 20050245799 | Brauker et al. | Nov 2005 | A1 |
| 20050245839 | Stivoric et al. | Nov 2005 | A1 |
| 20050245904 | Estes et al. | Nov 2005 | A1 |
| 20050277164 | Drucker et al. | Dec 2005 | A1 |
| 20050277912 | John | Dec 2005 | A1 |
| 20050283114 | Bresina et al. | Dec 2005 | A1 |
| 20050287620 | Heller et al. | Dec 2005 | A1 |
| 20050288725 | Hettrick et al. | Dec 2005 | A1 |
| 20060001538 | Kraft et al. | Jan 2006 | A1 |
| 20060004270 | Bedard et al. | Jan 2006 | A1 |
| 20060007017 | Mann et al. | Jan 2006 | A1 |
| 20060010098 | Goodnow et al. | Jan 2006 | A1 |
| 20060015020 | Neale et al. | Jan 2006 | A1 |
| 20060015024 | Brister et al. | Jan 2006 | A1 |
| 20060016700 | Brister et al. | Jan 2006 | A1 |
| 20060017923 | Ruchti et al. | Jan 2006 | A1 |
| 20060019327 | Brister et al. | Jan 2006 | A1 |
| 20060020186 | Brister et al. | Jan 2006 | A1 |
| 20060020187 | Brister et al. | Jan 2006 | A1 |
| 20060020188 | Kamath et al. | Jan 2006 | A1 |
| 20060020189 | Brister et al. | Jan 2006 | A1 |
| 20060020190 | Kamath et al. | Jan 2006 | A1 |
| 20060020191 | Brister et al. | Jan 2006 | A1 |
| 20060020192 | Brister et al. | Jan 2006 | A1 |
| 20060025662 | Buse et al. | Feb 2006 | A1 |
| 20060025663 | Talbot et al. | Feb 2006 | A1 |
| 20060029177 | Cranford, Jr. et al. | Feb 2006 | A1 |
| 20060031094 | Cohen et al. | Feb 2006 | A1 |
| 20060036139 | Brister et al. | Feb 2006 | A1 |
| 20060036140 | Brister et al. | Feb 2006 | A1 |
| 20060036141 | Kamath et al. | Feb 2006 | A1 |
| 20060036142 | Brister et al. | Feb 2006 | A1 |
| 20060036143 | Brister et al. | Feb 2006 | A1 |
| 20060036144 | Brister et al. | Feb 2006 | A1 |
| 20060036145 | Brister et al. | Feb 2006 | A1 |
| 20060042353 | Marquis et al. | Mar 2006 | A1 |
| 20060091006 | Wang et al. | May 2006 | A1 |
| 20060142651 | Brister et al. | Jun 2006 | A1 |
| 20060155180 | Brister et al. | Jul 2006 | A1 |
| 20060166629 | Reggiardo | Jul 2006 | A1 |
| 20060167365 | Bharmi | Jul 2006 | A1 |
| 20060167517 | Gill et al. | Jul 2006 | A1 |
| 20060167518 | Gill et al. | Jul 2006 | A1 |
| 20060167519 | Gill et al. | Jul 2006 | A1 |
| 20060173260 | Gaoni et al. | Aug 2006 | A1 |
| 20060173406 | Hayes et al. | Aug 2006 | A1 |
| 20060173444 | Choy et al. | Aug 2006 | A1 |
| 20060183984 | Dobbles et al. | Aug 2006 | A1 |
| 20060183985 | Brister et al. | Aug 2006 | A1 |
| 20060189851 | Tivig et al. | Aug 2006 | A1 |
| 20060189863 | Peyser et al. | Aug 2006 | A1 |
| 20060193375 | Lee | Aug 2006 | A1 |
| 20060222566 | Brauker et al. | Oct 2006 | A1 |
| 20060224109 | Steil et al. | Oct 2006 | A1 |
| 20060226985 | Goodnow et al. | Oct 2006 | A1 |
| 20060229512 | Petisce et al. | Oct 2006 | A1 |
| 20060235285 | Brister et al. | Oct 2006 | A1 |
| 20060241517 | Fowler et al. | Oct 2006 | A1 |
| 20060241669 | Stout et al. | Oct 2006 | A1 |
| 20060247508 | Fennell | Nov 2006 | A1 |
| 20060247671 | LeVaughn | Nov 2006 | A1 |
| 20060247685 | Bharmi | Nov 2006 | A1 |
| 20060247985 | Liamos et al. | Nov 2006 | A1 |
| 20060258929 | Goode, Jr. et al. | Nov 2006 | A1 |
| 20060258939 | Pesach et al. | Nov 2006 | A1 |
| 20060258990 | Weber | Nov 2006 | A1 |
| 20060264785 | Dring et al. | Nov 2006 | A1 |
| 20060270922 | Brauker et al. | Nov 2006 | A1 |
| 20060270923 | Brauker et al. | Nov 2006 | A1 |
| 20060272652 | Stocker et al. | Dec 2006 | A1 |
| 20060281985 | Ward et al. | Dec 2006 | A1 |
| 20060287630 | Hommann | Dec 2006 | A1 |
| 20070016381 | Kamath et al. | Jan 2007 | A1 |
| 20070027381 | Stafford | Feb 2007 | A1 |
| 20070032706 | Kamath et al. | Feb 2007 | A1 |
| 20070033074 | Nitzan et al. | Feb 2007 | A1 |
| 20070056858 | Chen et al. | Mar 2007 | A1 |
| 20070060803 | Liljeryd et al. | Mar 2007 | A1 |
| 20070060814 | Stafford | Mar 2007 | A1 |
| 20070066873 | Kamath et al. | Mar 2007 | A1 |
| 20070068807 | Feldman et al. | Mar 2007 | A1 |
| 20070071681 | Gadkar et al. | Mar 2007 | A1 |
| 20070073129 | Shah et al. | Mar 2007 | A1 |
| 20070078320 | Stafford | Apr 2007 | A1 |
| 20070078321 | Mazza et al. | Apr 2007 | A1 |
| 20070078322 | Stafford | Apr 2007 | A1 |
| 20070078323 | Reggiardo et al. | Apr 2007 | A1 |
| 20070095661 | Wang et al. | May 2007 | A1 |
| 20070106135 | Sloan et al. | May 2007 | A1 |
| 20070108048 | Wang et al. | May 2007 | A1 |
| 20070118030 | Bruce et al. | May 2007 | A1 |
| 20070118405 | Campbell et al. | May 2007 | A1 |
| 20070124002 | Estes et al. | May 2007 | A1 |
| 20070129621 | Kellogg et al. | Jun 2007 | A1 |
| 20070149875 | Ouyang et al. | Jun 2007 | A1 |
| 20070156033 | Causey, III et al. | Jul 2007 | A1 |
| 20070163880 | Woo et al. | Jul 2007 | A1 |
| 20070167907 | Deslierres et al. | Jul 2007 | A1 |
| 20070168224 | Letzt et al. | Jul 2007 | A1 |
| 20070169533 | Shah et al. | Jul 2007 | A1 |
| 20070170073 | Wang et al. | Jul 2007 | A1 |
| 20070173706 | Neinast et al. | Jul 2007 | A1 |
| 20070173709 | Petisce et al. | Jul 2007 | A1 |
| 20070173710 | Petisce et al. | Jul 2007 | A1 |
| 20070173712 | Shah et al. | Jul 2007 | A1 |
| 20070173741 | Deshmukh et al. | Jul 2007 | A1 |
| 20070173761 | Kanderian, Jr. et al. | Jul 2007 | A1 |
| 20070179349 | Hoyme et al. | Aug 2007 | A1 |
| 20070179352 | Randlov et al. | Aug 2007 | A1 |
| 20070179434 | Weinert et al. | Aug 2007 | A1 |
| 20070191701 | Feldman et al. | Aug 2007 | A1 |
| 20070191702 | Yodfat et al. | Aug 2007 | A1 |
| 20070197889 | Brister et al. | Aug 2007 | A1 |
| 20070197890 | Boock et al. | Aug 2007 | A1 |
| 20070199818 | Petyt et al. | Aug 2007 | A1 |
| 20070202562 | Curry | Aug 2007 | A1 |
| 20070203407 | Hoss et al. | Aug 2007 | A1 |
| 20070203966 | Brauker et al. | Aug 2007 | A1 |
| 20070208244 | Brauker et al. | Sep 2007 | A1 |
| 20070213657 | Jennewine et al. | Sep 2007 | A1 |
| 20070224700 | Masters | Sep 2007 | A1 |
| 20070227911 | Wang et al. | Oct 2007 | A1 |
| 20070232877 | He | Oct 2007 | A1 |
| 20070232878 | Kovatchev et al. | Oct 2007 | A1 |
| 20070232880 | Siddiqui et al. | Oct 2007 | A1 |
| 20070233013 | Schoenberg | Oct 2007 | A1 |
| 20070233167 | Weiss et al. | Oct 2007 | A1 |
| 20070235331 | Simpson et al. | Oct 2007 | A1 |
| 20070249922 | Peyser et al. | Oct 2007 | A1 |
| 20070255302 | Koeppel et al. | Nov 2007 | A1 |
| 20070255321 | Gerber et al. | Nov 2007 | A1 |
| 20070299617 | Willis | Dec 2007 | A1 |
| 20080000779 | Wang et al. | Jan 2008 | A1 |
| 20080004515 | Jennewine | Jan 2008 | A1 |
| 20080004601 | Jennewine et al. | Jan 2008 | A1 |
| 20080007141 | Deck | Jan 2008 | A1 |
| 20080009692 | Stafford | Jan 2008 | A1 |
| 20080009805 | Ethelfeld | Jan 2008 | A1 |
| 20080012701 | Kass et al. | Jan 2008 | A1 |
| 20080017522 | Heller et al. | Jan 2008 | A1 |
| 20080021666 | Goode, Jr. et al. | Jan 2008 | A1 |
| 20080021972 | Huelskamp et al. | Jan 2008 | A1 |
| 20080027474 | Curry et al. | Jan 2008 | A1 |
| 20080029391 | Mao et al. | Feb 2008 | A1 |
| 20080033254 | Kamath et al. | Feb 2008 | A1 |
| 20080039702 | Hayter et al. | Feb 2008 | A1 |
| 20080045824 | Tapsak et al. | Feb 2008 | A1 |
| 20080051714 | Moberg et al. | Feb 2008 | A1 |
| 20080058625 | McGarraugh et al. | Mar 2008 | A1 |
| 20080064937 | McGarraugh et al. | Mar 2008 | A1 |
| 20080066305 | Wang et al. | Mar 2008 | A1 |
| 20080071156 | Brister et al. | Mar 2008 | A1 |
| 20080071157 | McGarraugh et al. | Mar 2008 | A1 |
| 20080071158 | McGarraugh et al. | Mar 2008 | A1 |
| 20080081000 | MacLeod et al. | Apr 2008 | A1 |
| 20080081977 | Hayter et al. | Apr 2008 | A1 |
| 20080083617 | Simpson et al. | Apr 2008 | A1 |
| 20080086042 | Brister et al. | Apr 2008 | A1 |
| 20080086044 | Brister et al. | Apr 2008 | A1 |
| 20080086273 | Shults et al. | Apr 2008 | A1 |
| 20080097246 | Stafford | Apr 2008 | A1 |
| 20080097289 | Steil et al. | Apr 2008 | A1 |
| 20080102441 | Chen et al. | May 2008 | A1 |
| 20080108942 | Brister et al. | May 2008 | A1 |
| 20080114227 | Haar et al. | May 2008 | A1 |
| 20080115599 | Masters et al. | May 2008 | A1 |
| 20080119703 | Brister et al. | May 2008 | A1 |
| 20080119708 | Budiman | May 2008 | A1 |
| 20080139903 | Bruce et al. | Jun 2008 | A1 |
| 20080139910 | Mastrototaro et al. | Jun 2008 | A1 |
| 20080148873 | Wang | Jun 2008 | A1 |
| 20080154513 | Kovatchev et al. | Jun 2008 | A1 |
| 20080156661 | Cooper et al. | Jul 2008 | A1 |
| 20080161656 | Bruce et al. | Jul 2008 | A1 |
| 20080161664 | Mastrototaro et al. | Jul 2008 | A1 |
| 20080161666 | Feldman et al. | Jul 2008 | A1 |
| 20080167543 | Say et al. | Jul 2008 | A1 |
| 20080167641 | Hansen et al. | Jul 2008 | A1 |
| 20080172205 | Breton et al. | Jul 2008 | A1 |
| 20080177149 | Weinert et al. | Jul 2008 | A1 |
| 20080177165 | Blomquist et al. | Jul 2008 | A1 |
| 20080183060 | Steil et al. | Jul 2008 | A1 |
| 20080183061 | Goode et al. | Jul 2008 | A1 |
| 20080183399 | Goode et al. | Jul 2008 | A1 |
| 20080188731 | Brister et al. | Aug 2008 | A1 |
| 20080188796 | Steil et al. | Aug 2008 | A1 |
| 20080188798 | Weber | Aug 2008 | A1 |
| 20080189051 | Goode et al. | Aug 2008 | A1 |
| 20080194934 | Ray et al. | Aug 2008 | A1 |
| 20080194935 | Brister et al. | Aug 2008 | A1 |
| 20080194936 | Goode et al. | Aug 2008 | A1 |
| 20080194937 | Goode et al. | Aug 2008 | A1 |
| 20080194938 | Brister et al. | Aug 2008 | A1 |
| 20080195232 | Carr-Brendel et al. | Aug 2008 | A1 |
| 20080195967 | Goode et al. | Aug 2008 | A1 |
| 20080197024 | Simpson et al. | Aug 2008 | A1 |
| 20080200788 | Brister et al. | Aug 2008 | A1 |
| 20080200789 | Brister et al. | Aug 2008 | A1 |
| 20080200791 | Simpson et al. | Aug 2008 | A1 |
| 20080201325 | Doniger et al. | Aug 2008 | A1 |
| 20080208025 | Shults et al. | Aug 2008 | A1 |
| 20080208113 | Damiano et al. | Aug 2008 | A1 |
| 20080214910 | Buck | Sep 2008 | A1 |
| 20080214915 | Brister et al. | Sep 2008 | A1 |
| 20080214918 | Brister et al. | Sep 2008 | A1 |
| 20080228051 | Shults et al. | Sep 2008 | A1 |
| 20080228054 | Shults et al. | Sep 2008 | A1 |
| 20080234943 | Ray et al. | Sep 2008 | A1 |
| 20080242961 | Brister et al. | Oct 2008 | A1 |
| 20080242963 | Essenpreis et al. | Oct 2008 | A1 |
| 20080249383 | Sass et al. | Oct 2008 | A1 |
| 20080249473 | Rutti et al. | Oct 2008 | A1 |
| 20080255434 | Hayter et al. | Oct 2008 | A1 |
| 20080255437 | Hayter | Oct 2008 | A1 |
| 20080255438 | Saidara et al. | Oct 2008 | A1 |
| 20080255808 | Hayter | Oct 2008 | A1 |
| 20080256048 | Hayter | Oct 2008 | A1 |
| 20080262469 | Brister et al. | Oct 2008 | A1 |
| 20080267823 | Wang et al. | Oct 2008 | A1 |
| 20080269714 | Mastrototaro et al. | Oct 2008 | A1 |
| 20080275313 | Brister et al. | Nov 2008 | A1 |
| 20080278332 | Fennell et al. | Nov 2008 | A1 |
| 20080281270 | Cross et al. | Nov 2008 | A1 |
| 20080287761 | Hayter et al. | Nov 2008 | A1 |
| 20080287762 | Hayter et al. | Nov 2008 | A1 |
| 20080287763 | Hayter | Nov 2008 | A1 |
| 20080287764 | Rasdal et al. | Nov 2008 | A1 |
| 20080287765 | Rasdal et al. | Nov 2008 | A1 |
| 20080287766 | Rasdal et al. | Nov 2008 | A1 |
| 20080288180 | Hayter et al. | Nov 2008 | A1 |
| 20080288204 | Hayter et al. | Nov 2008 | A1 |
| 20080296155 | Shults et al. | Dec 2008 | A1 |
| 20080300572 | Rankers et al. | Dec 2008 | A1 |
| 20080306368 | Goode, Jr. et al. | Dec 2008 | A1 |
| 20080306434 | Dobbles et al. | Dec 2008 | A1 |
| 20080306435 | Kamath et al. | Dec 2008 | A1 |
| 20080306444 | Brister et al. | Dec 2008 | A1 |
| 20080312841 | Hayter | Dec 2008 | A1 |
| 20080312842 | Hayter et al. | Dec 2008 | A1 |
| 20080312844 | Hayter et al. | Dec 2008 | A1 |
| 20080312845 | Hayter et al. | Dec 2008 | A1 |
| 20080314395 | Kovatchev et al. | Dec 2008 | A1 |
| 20080319279 | Ramsay et al. | Dec 2008 | A1 |
| 20080319295 | Bernstein et al. | Dec 2008 | A1 |
| 20080319296 | Bernstein et al. | Dec 2008 | A1 |
| 20090005665 | Hayter et al. | Jan 2009 | A1 |
| 20090005666 | Shin et al. | Jan 2009 | A1 |
| 20090006034 | Hayter et al. | Jan 2009 | A1 |
| 20090006061 | Thukral et al. | Jan 2009 | A1 |
| 20090012376 | Agus | Jan 2009 | A1 |
| 20090012379 | Goode, Jr. et al. | Jan 2009 | A1 |
| 20090012472 | Ahm et al. | Jan 2009 | A1 |
| 20090018424 | Kamath | Jan 2009 | A1 |
| 20090018425 | Ouyang et al. | Jan 2009 | A1 |
| 20090030293 | Cooper et al. | Jan 2009 | A1 |
| 20090030294 | Petisce et al. | Jan 2009 | A1 |
| 20090033482 | Hayter et al. | Feb 2009 | A1 |
| 20090036747 | Hayter et al. | Feb 2009 | A1 |
| 20090036758 | Brauker et al. | Feb 2009 | A1 |
| 20090036760 | Hayter | Feb 2009 | A1 |
| 20090036763 | Brauker et al. | Feb 2009 | A1 |
| 20090043181 | Brauker et al. | Feb 2009 | A1 |
| 20090043182 | Brauker et al. | Feb 2009 | A1 |
| 20090043525 | Brauker et al. | Feb 2009 | A1 |
| 20090043541 | Brauker et al. | Feb 2009 | A1 |
| 20090043542 | Brauker et al. | Feb 2009 | A1 |
| 20090045055 | Rhodes et al. | Feb 2009 | A1 |
| 20090048503 | Dalal et al. | Feb 2009 | A1 |
| 20090054745 | Jennewine | Feb 2009 | A1 |
| 20090054748 | Feldman | Feb 2009 | A1 |
| 20090054749 | He | Feb 2009 | A1 |
| 20090054753 | Robinson et al. | Feb 2009 | A1 |
| 20090054812 | Mace | Feb 2009 | A1 |
| 20090055149 | Hayter et al. | Feb 2009 | A1 |
| 20090062633 | Brauker et al. | Mar 2009 | A1 |
| 20090062635 | Brauker et al. | Mar 2009 | A1 |
| 20090062767 | Van Antwerp et al. | Mar 2009 | A1 |
| 20090063402 | Hayter | Mar 2009 | A1 |
| 20090069649 | Budiman | Mar 2009 | A1 |
| 20090076356 | Simpson et al. | Mar 2009 | A1 |
| 20090076360 | Brister et al. | Mar 2009 | A1 |
| 20090076361 | Kamath et al. | Mar 2009 | A1 |
| 20090082693 | Stafford | Mar 2009 | A1 |
| 20090085768 | Patel et al. | Apr 2009 | A1 |
| 20090088689 | Carter | Apr 2009 | A1 |
| 20090099436 | Brister et al. | Apr 2009 | A1 |
| 20090105570 | Sloan et al. | Apr 2009 | A1 |
| 20090105636 | Hayter et al. | Apr 2009 | A1 |
| 20090112478 | Mueller, Jr. et al. | Apr 2009 | A1 |
| 20090112626 | Talbot et al. | Apr 2009 | A1 |
| 20090118589 | Ueshima et al. | May 2009 | A1 |
| 20090124877 | Goode, Jr. et al. | May 2009 | A1 |
| 20090124878 | Goode, Jr. et al. | May 2009 | A1 |
| 20090124879 | Brister et al. | May 2009 | A1 |
| 20090124964 | Leach et al. | May 2009 | A1 |
| 20090124979 | Raymond et al. | May 2009 | A1 |
| 20090131768 | Simpson et al. | May 2009 | A1 |
| 20090131769 | Leach et al. | May 2009 | A1 |
| 20090131776 | Simpson et al. | May 2009 | A1 |
| 20090131777 | Simpson et al. | May 2009 | A1 |
| 20090137886 | Shariati et al. | May 2009 | A1 |
| 20090137887 | Shariati et al. | May 2009 | A1 |
| 20090143659 | Li et al. | Jun 2009 | A1 |
| 20090143660 | Brister et al. | Jun 2009 | A1 |
| 20090143725 | Peyser et al. | Jun 2009 | A1 |
| 20090149728 | Van Antwerp et al. | Jun 2009 | A1 |
| 20090156919 | Brister et al. | Jun 2009 | A1 |
| 20090156924 | Shariati et al. | Jun 2009 | A1 |
| 20090163790 | Brister et al. | Jun 2009 | A1 |
| 20090163791 | Brister et al. | Jun 2009 | A1 |
| 20090163855 | Shin et al. | Jun 2009 | A1 |
| 20090164190 | Hayter | Jun 2009 | A1 |
| 20090164239 | Hayter et al. | Jun 2009 | A1 |
| 20090164251 | Hayter | Jun 2009 | A1 |
| 20090171178 | He et al. | Jul 2009 | A1 |
| 20090178459 | Li | Jul 2009 | A1 |
| 20090182217 | Li et al. | Jul 2009 | A1 |
| 20090182517 | Gandhi et al. | Jul 2009 | A1 |
| 20090192366 | Mensinger et al. | Jul 2009 | A1 |
| 20090192380 | Shariati et al. | Jul 2009 | A1 |
| 20090192722 | Shariati et al. | Jul 2009 | A1 |
| 20090192724 | Brauker et al. | Jul 2009 | A1 |
| 20090192745 | Kamath et al. | Jul 2009 | A1 |
| 20090192751 | Kamath et al. | Jul 2009 | A1 |
| 20090198118 | Hayter et al. | Aug 2009 | A1 |
| 20090203981 | Brauker et al. | Aug 2009 | A1 |
| 20090204341 | Brauker et al. | Aug 2009 | A1 |
| 20090216103 | Brister et al. | Aug 2009 | A1 |
| 20090240120 | Mensinger et al. | Sep 2009 | A1 |
| 20090240128 | Mensinger et al. | Sep 2009 | A1 |
| 20090240193 | Mensinger et al. | Sep 2009 | A1 |
| 20090242399 | Kamath et al. | Oct 2009 | A1 |
| 20090242425 | Kamath et al. | Oct 2009 | A1 |
| 20090247855 | Boock et al. | Oct 2009 | A1 |
| 20090247856 | Boock et al. | Oct 2009 | A1 |
| 20090247857 | Harper et al. | Oct 2009 | A1 |
| 20090257911 | Thomas et al. | Oct 2009 | A1 |
| 20090281407 | Budiman | Nov 2009 | A1 |
| 20090287073 | Boock et al. | Nov 2009 | A1 |
| 20090287074 | Shults et al. | Nov 2009 | A1 |
| 20090294277 | Thomas et al. | Dec 2009 | A1 |
| 20090299155 | Yang et al. | Dec 2009 | A1 |
| 20090299156 | Simpson et al. | Dec 2009 | A1 |
| 20090299162 | Brauker et al. | Dec 2009 | A1 |
| 20090299276 | Brauker et al. | Dec 2009 | A1 |
| 20100010324 | Brauker et al. | Jan 2010 | A1 |
| 20100010331 | Brauker et al. | Jan 2010 | A1 |
| 20100010332 | Brauker et al. | Jan 2010 | A1 |
| 20100010529 | Shi | Jan 2010 | A1 |
| 20100023291 | Hayter et al. | Jan 2010 | A1 |
| 20100025174 | Dayton | Feb 2010 | A1 |
| 20100025238 | Gottlieb et al. | Feb 2010 | A1 |
| 20100045231 | He | Feb 2010 | A1 |
| 20100049015 | Martini et al. | Feb 2010 | A1 |
| 20100049021 | Jina et al. | Feb 2010 | A1 |
| 20100057040 | Hayter | Mar 2010 | A1 |
| 20100057041 | Hayter | Mar 2010 | A1 |
| 20100057042 | Hayter | Mar 2010 | A1 |
| 20100057044 | Hayter | Mar 2010 | A1 |
| 20100057057 | Hayter et al. | Mar 2010 | A1 |
| 20100063372 | Potts et al. | Mar 2010 | A1 |
| 20100064764 | Hayter et al. | Mar 2010 | A1 |
| 20100081906 | Hayter et al. | Apr 2010 | A1 |
| 20100081909 | Budiman et al. | Apr 2010 | A1 |
| 20100081953 | Syeda-Mahmood et al. | Apr 2010 | A1 |
| 20100094111 | Heller et al. | Apr 2010 | A1 |
| 20100121167 | McGarraugh | May 2010 | A1 |
| 20100141656 | Krieftewirth | Jun 2010 | A1 |
| 20100145174 | Alferness et al. | Jun 2010 | A1 |
| 20100145377 | Lai et al. | Jun 2010 | A1 |
| 20100152561 | Goodnow et al. | Jun 2010 | A1 |
| 20100160759 | Celentano et al. | Jun 2010 | A1 |
| 20100160761 | Say et al. | Jun 2010 | A1 |
| 20100168538 | Keenan et al. | Jul 2010 | A1 |
| 20100168546 | Kamath et al. | Jul 2010 | A1 |
| 20100169035 | Liang et al. | Jul 2010 | A1 |
| 20100174266 | Estes | Jul 2010 | A1 |
| 20100179402 | Goode, Jr. et al. | Jul 2010 | A1 |
| 20100185178 | Sharp et al. | Jul 2010 | A1 |
| 20100191085 | Budiman | Jul 2010 | A1 |
| 20100191472 | Doniger et al. | Jul 2010 | A1 |
| 20100198034 | Thomas et al. | Aug 2010 | A1 |
| 20100198036 | Kamath et al. | Aug 2010 | A1 |
| 20100198142 | Sloan et al. | Aug 2010 | A1 |
| 20100204557 | Kiaie et al. | Aug 2010 | A1 |
| 20100213057 | Feldman et al. | Aug 2010 | A1 |
| 20100228226 | Nielsen | Sep 2010 | A1 |
| 20100230285 | Hoss et al. | Sep 2010 | A1 |
| 20100234710 | Budiman et al. | Sep 2010 | A1 |
| 20100261987 | Kamath et al. | Oct 2010 | A1 |
| 20100265073 | Harper | Oct 2010 | A1 |
| 20100274107 | Boock et al. | Oct 2010 | A1 |
| 20100274515 | Hoss et al. | Oct 2010 | A1 |
| 20100277342 | Sicurello et al. | Nov 2010 | A1 |
| 20100280441 | Wilinska et al. | Nov 2010 | A1 |
| 20100280782 | Harper | Nov 2010 | A1 |
| 20100313105 | Nekoomaram et al. | Dec 2010 | A1 |
| 20100317952 | Budiman et al. | Dec 2010 | A1 |
| 20100324392 | Yee et al. | Dec 2010 | A1 |
| 20100326842 | Mazza et al. | Dec 2010 | A1 |
| 20100331642 | Bruce et al. | Dec 2010 | A1 |
| 20110021889 | Hoss et al. | Jan 2011 | A1 |
| 20110024043 | Boock et al. | Feb 2011 | A1 |
| 20110024307 | Simpson | Feb 2011 | A1 |
| 20110027127 | Simpson et al. | Feb 2011 | A1 |
| 20110027453 | Boock et al. | Feb 2011 | A1 |
| 20110027458 | Boock et al. | Feb 2011 | A1 |
| 20110028815 | Simpson et al. | Feb 2011 | A1 |
| 20110028816 | Simpson et al. | Feb 2011 | A1 |
| 20110029247 | Kalathil | Feb 2011 | A1 |
| 20110029269 | Hayter et al. | Feb 2011 | A1 |
| 20110040163 | Telson et al. | Feb 2011 | A1 |
| 20110060287 | Ambruzs et al. | Mar 2011 | A1 |
| 20110060530 | Fennell | Mar 2011 | A1 |
| 20110077490 | Simpson et al. | Mar 2011 | A1 |
| 20110077494 | Doniger et al. | Mar 2011 | A1 |
| 20110081726 | Berman | Apr 2011 | A1 |
| 20110082484 | Saravia et al. | Apr 2011 | A1 |
| 20110098656 | Burnell et al. | Apr 2011 | A1 |
| 20110105873 | Feldman et al. | May 2011 | A1 |
| 20110106126 | Love et al. | May 2011 | A1 |
| 20110112696 | Yodfat et al. | May 2011 | A1 |
| 20110144463 | Pesach et al. | Jun 2011 | A1 |
| 20110144683 | Butz et al. | Jun 2011 | A1 |
| 20110148905 | Simmons et al. | Jun 2011 | A1 |
| 20110174638 | Katsuki | Jul 2011 | A1 |
| 20110184268 | Taub | Jul 2011 | A1 |
| 20110190603 | Stafford | Aug 2011 | A1 |
| 20110191044 | Stafford | Aug 2011 | A1 |
| 20110193704 | Harper et al. | Aug 2011 | A1 |
| 20110208027 | Wagner et al. | Aug 2011 | A1 |
| 20110208155 | Palerm et al. | Aug 2011 | A1 |
| 20110213225 | Bernstein et al. | Sep 2011 | A1 |
| 20110224523 | Budiman | Sep 2011 | A1 |
| 20110230735 | Wolfe et al. | Sep 2011 | A1 |
| 20110230741 | Liang et al. | Sep 2011 | A1 |
| 20110257495 | Hoss et al. | Oct 2011 | A1 |
| 20110257895 | Brauker et al. | Oct 2011 | A1 |
| 20110263958 | Brauker et al. | Oct 2011 | A1 |
| 20110288574 | Curry et al. | Nov 2011 | A1 |
| 20110313317 | Callicoat et al. | Dec 2011 | A1 |
| 20110319729 | Donnay et al. | Dec 2011 | A1 |
| 20110319734 | Gottlieb et al. | Dec 2011 | A1 |
| 20110320130 | Valdes et al. | Dec 2011 | A1 |
| 20110320167 | Budiman | Dec 2011 | A1 |
| 20120010642 | Lee et al. | Jan 2012 | A1 |
| 20120078071 | Bohm et al. | Mar 2012 | A1 |
| 20120097554 | Shah et al. | Apr 2012 | A1 |
| 20120108931 | Taub et al. | May 2012 | A1 |
| 20120108934 | Valdes et al. | May 2012 | A1 |
| 20120123692 | Hayter | May 2012 | A1 |
| 20120150123 | Lawrence et al. | Jun 2012 | A1 |
| 20120165626 | Irina et al. | Jun 2012 | A1 |
| 20120165640 | Galley et al. | Jun 2012 | A1 |
| 20120173200 | Breton et al. | Jul 2012 | A1 |
| 20120209099 | Ljuhs et al. | Aug 2012 | A1 |
| 20120215462 | Goode, Jr. et al. | Aug 2012 | A1 |
| 20120239304 | Hayter et al. | Sep 2012 | A1 |
| 20120245447 | Karan et al. | Sep 2012 | A1 |
| 20120265036 | Estes et al. | Oct 2012 | A1 |
| 20120265042 | Neinast et al. | Oct 2012 | A1 |
| 20120277564 | Budiman et al. | Nov 2012 | A1 |
| 20120277565 | Budiman | Nov 2012 | A1 |
| 20120277566 | Kamath et al. | Nov 2012 | A1 |
| 20120283542 | McGarraugh | Nov 2012 | A1 |
| 20120283960 | Budiman | Nov 2012 | A1 |
| 20120291516 | Hayter et al. | Nov 2012 | A1 |
| 20120323098 | Moein et al. | Dec 2012 | A1 |
| 20120330561 | Hayter et al. | Dec 2012 | A1 |
| 20130006112 | Vardy | Jan 2013 | A1 |
| 20130035575 | Mayou et al. | Feb 2013 | A1 |
| 20130060105 | Shah et al. | Mar 2013 | A1 |
| 20130060112 | Pryor et al. | Mar 2013 | A1 |
| 20130116527 | Harper et al. | May 2013 | A1 |
| 20130137953 | Harper et al. | May 2013 | A1 |
| 20130172695 | Nielsen et al. | Jul 2013 | A1 |
| 20130178727 | Hayter et al. | Jul 2013 | A1 |
| 20130184547 | Taub et al. | Jul 2013 | A1 |
| 20130199944 | Petisee | Aug 2013 | A1 |
| 20130231541 | Hayter et al. | Sep 2013 | A1 |
| 20130245412 | Rong et al. | Sep 2013 | A1 |
| 20130253846 | Hayter et al. | Sep 2013 | A1 |
| 20130267809 | Brister et al. | Oct 2013 | A1 |
| 20130281807 | Hayter et al. | Oct 2013 | A1 |
| 20130282322 | Hayter et al. | Oct 2013 | A1 |
| 20130282403 | Hayter et al. | Oct 2013 | A1 |
| 20130324823 | Koski et al. | Dec 2013 | A1 |
| 20130338454 | Hayter et al. | Dec 2013 | A1 |
| 20140005499 | Catt et al. | Jan 2014 | A1 |
| 20140005968 | Budiman | Jan 2014 | A1 |
| 20140018642 | Hayter | Jan 2014 | A1 |
| 20140041441 | Hayter et al. | Feb 2014 | A1 |
| 20140046155 | Hayter et al. | Feb 2014 | A1 |
| 20140046156 | Hayter | Feb 2014 | A1 |
| 20140046157 | Hayter et al. | Feb 2014 | A1 |
| 20140046160 | Terashima et al. | Feb 2014 | A1 |
| 20140046161 | Hayter et al. | Feb 2014 | A1 |
| 20140066736 | Budiman | Mar 2014 | A1 |
| 20140088390 | He | Mar 2014 | A1 |
| 20140088392 | Bernstein et al. | Mar 2014 | A1 |
| 20140088908 | Hayter et al. | Mar 2014 | A1 |
| 20140100796 | Hayter et al. | Apr 2014 | A1 |
| 20140114156 | Bohm et al. | Apr 2014 | A1 |
| 20140121480 | Budiman et al. | May 2014 | A1 |
| 20140121488 | Budiman | May 2014 | A1 |
| 20140207400 | Hayter et al. | Jul 2014 | A1 |
| 20140221966 | Buckingham et al. | Aug 2014 | A1 |
| 20140236536 | Hayter et al. | Aug 2014 | A1 |
| 20140243638 | Harper et al. | Aug 2014 | A1 |
| 20140257059 | Budiman et al. | Sep 2014 | A1 |
| 20150005601 | Hoss et al. | Jan 2015 | A1 |
| 20150006109 | Fennell et al. | Jan 2015 | A1 |
| 20150094555 | He | Apr 2015 | A1 |
| 20150216456 | Budiman | Aug 2015 | A1 |
| 20150241407 | Ou et al. | Aug 2015 | A1 |
| 20150282742 | Hayter et al. | Oct 2015 | A1 |
| 20150366510 | Budiman | Dec 2015 | A1 |
| 20150374299 | Hayter | Dec 2015 | A1 |
| 20160022221 | Ou et al. | Jan 2016 | A1 |
| 20160073941 | Bohm et al. | Mar 2016 | A1 |
| 20160151006 | Harper et al. | Jun 2016 | A1 |
| 20160157758 | Bohm et al. | Jun 2016 | A1 |
| 20160198986 | Bohm et al. | Jul 2016 | A1 |
| 20160206233 | Hayter et al. | Jul 2016 | A1 |
| 20160220189 | Hayter et al. | Aug 2016 | A1 |
| 20160238589 | Harper et al. | Aug 2016 | A1 |
| 20160245791 | Hayter et al. | Aug 2016 | A1 |
| 20160270705 | He | Sep 2016 | A1 |
| 20160296697 | Hayter et al. | Oct 2016 | A1 |
| 20160317069 | Hayter et al. | Nov 2016 | A1 |
| 20170003766 | Budiman | Jan 2017 | A1 |
| 20170027484 | Hayter et al. | Feb 2017 | A1 |
| 20170042456 | Budiman | Feb 2017 | A1 |
| 20170049369 | Hayter et al. | Feb 2017 | A1 |
| 20170124287 | Hayter et al. | May 2017 | A1 |
| 20170127982 | Larson et al. | May 2017 | A1 |
| 20170188909 | Hayter et al. | Jul 2017 | A1 |
| 20170224258 | Hayter et al. | Aug 2017 | A1 |
| 20170258379 | Budiman et al. | Sep 2017 | A1 |
| 20170265790 | Budiman et al. | Sep 2017 | A1 |
| 20170340250 | Hayter et al. | Nov 2017 | A1 |
| 20170347927 | He | Dec 2017 | A1 |
| 20180000389 | Harper et al. | Jan 2018 | A1 |
| 20180008174 | Bohm et al. | Jan 2018 | A1 |
| 20180008201 | Hayter et al. | Jan 2018 | A1 |
| 20180038844 | Hayter et al. | Feb 2018 | A1 |
| 20180042530 | Bohm et al. | Feb 2018 | A1 |
| 20180042531 | Budiman et al. | Feb 2018 | A1 |
| 20180042534 | Hayter | Feb 2018 | A1 |
| 20180045707 | Hayter et al. | Feb 2018 | A1 |
| 20180059093 | Hayter et al. | Mar 2018 | A1 |
| 20180064398 | Budiman | Mar 2018 | A1 |
| 20180085037 | Hayter et al. | Mar 2018 | A1 |
| 20180098721 | Hayter et al. | Apr 2018 | A1 |
| 20180271415 | Bohm et al. | Sep 2018 | A1 |
| 20180328766 | Hayter et al. | Nov 2018 | A1 |
| 20180344220 | Hayter et al. | Dec 2018 | A1 |
| 20180364215 | Harper et al. | Dec 2018 | A1 |
| 20190035488 | Budiman | Jan 2019 | A1 |
| 20190072538 | Hayter et al. | Mar 2019 | A1 |
| 20190083012 | Hayter et al. | Mar 2019 | A1 |
| 20190083015 | Hayter | Mar 2019 | A1 |
| 20190150802 | Budiman et al. | May 2019 | A1 |
| 20190151542 | Hayter et al. | May 2019 | A1 |
| 20190159734 | Budiman | May 2019 | A1 |
| 20190187814 | Budiman | Jun 2019 | A1 |
| 20190192071 | Taub et al. | Jun 2019 | A1 |
| 20190254575 | Hayter et al. | Aug 2019 | A1 |
| 20190261902 | Bohm et al. | Aug 2019 | A1 |
| 20190320948 | Bohm et al. | Oct 2019 | A1 |
| 20190320949 | Bohm et al. | Oct 2019 | A1 |
| 20190336051 | Bohm et al. | Nov 2019 | A1 |
| 20190350499 | Bohm et al. | Nov 2019 | A1 |
| 20190357817 | Bohm et al. | Nov 2019 | A1 |
| 20190357818 | Pryor et al. | Nov 2019 | A1 |
| 20190380627 | Bohm et al. | Dec 2019 | A1 |
| 20200022626 | Bohm et al. | Jan 2020 | A1 |
| 20200037874 | Simpson et al. | Feb 2020 | A1 |
| 20200037934 | Bohm et al. | Feb 2020 | A1 |
| 20200037935 | Bohm et al. | Feb 2020 | A1 |
| 20200037936 | Bohm et al. | Feb 2020 | A1 |
| Number | Date | Country |
|---|---|---|
| 0098592 | Jan 1984 | EP |
| 0127958 | Dec 1984 | EP |
| 0320109 | Jun 1989 | EP |
| 0353328 | Feb 1990 | EP |
| 0390390 | Oct 1990 | EP |
| 0396788 | Nov 1990 | EP |
| 0472411 | Feb 1992 | EP |
| 0286118 | Jan 1995 | EP |
| 0867146 | Sep 1998 | EP |
| 1048264 | Nov 2000 | EP |
| 1419731 | May 2004 | EP |
| 0939602 | Sep 2004 | EP |
| 1475113 | Nov 2004 | EP |
| 1850909 | Apr 2010 | EP |
| 1677668 | Jul 2010 | EP |
| 2069772 | May 2014 | EP |
| 3575796 | Dec 2019 | EP |
| 2003522558 | Jul 2003 | JP |
| 2006346160 | Dec 2006 | JP |
| 2007501028 | Jan 2007 | JP |
| 2008506468 | Mar 2008 | JP |
| 2008253482 | Oct 2008 | JP |
| WO-9625089 | Aug 1996 | WO |
| WO-9635370 | Nov 1996 | WO |
| WO-9715227 | May 1997 | WO |
| WO-9835053 | Aug 1998 | WO |
| WO-9907878 | Feb 1999 | WO |
| WO-9908485 | Feb 1999 | WO |
| WO-9956613 | Nov 1999 | WO |
| WO-0049940 | Aug 2000 | WO |
| WO-0059370 | Oct 2000 | WO |
| WO-0074753 | Dec 2000 | WO |
| WO-0152935 | Jul 2001 | WO |
| WO-0154753 | Aug 2001 | WO |
| WO-0216905 | Feb 2002 | WO |
| WO-03076893 | Sep 2003 | WO |
| WO-03082091 | Oct 2003 | WO |
| WO-2004060455 | Jul 2004 | WO |
| WO-2005010756 | Feb 2005 | WO |
| WO-2005011489 | Feb 2005 | WO |
| WO-2005046780 | May 2005 | WO |
| WO-2005065542 | Jul 2005 | WO |
| WO-2006008505 | Jan 2006 | WO |
| 2006017358 | Feb 2006 | WO |
| WO-2006024671 | Mar 2006 | WO |
| WO-2006038044 | Apr 2006 | WO |
| WO-2006067217 | Jun 2006 | WO |
| WO-2006075016 | Jul 2006 | WO |
| WO-2006077262 | Jul 2006 | WO |
| WO-2006081336 | Aug 2006 | WO |
| WO-2007031125 | Mar 2007 | WO |
| WO-2007097754 | Aug 2007 | WO |
| 2008021913 | Feb 2008 | WO |
| WO-2008065646 | Jun 2008 | WO |
| WO-2008078319 | Jul 2008 | WO |
| WO-2008083379 | Jul 2008 | WO |
| WO-2008086541 | Jul 2008 | WO |
| WO-2008115409 | Sep 2008 | WO |
| WO-2008124597 | Oct 2008 | WO |
| WO-2010022387 | Feb 2010 | WO |
| WO-2010078263 | Jul 2010 | WO |
| WO-2010099507 | Sep 2010 | WO |
| 2012142502 | Oct 2012 | WO |
| Entry |
|---|
| Armour J.C., et al., “Application of Chronic Intravascular Blood Glucose Sensor in Dogs,” Diabetes, Dec. 1990, vol. 39, pp. 1519-1526. |
| Arnold M.A., et al., “Selectivity Assessment of Noninvasive Glucose Measurements Based on Analysis of Multivariate Calibration Vectors,” Journal of Diabetes Science and Technology, vol. 1 (4), Jul. 2007, pp. 454-462. |
| Bennion N., et al., “Alternate Site Glucose Testing: a Crossover Design,” Diabetes Technology & Therapeutics, vol. 4 (1), 2002, pp. 25-33. |
| Blank T.B., et al., “Clinical Results From a Non-Invasive Blood Glucose Monitor,” Optical Diagnostics and Sensing of Biological Fluids and Glucose and Cholesterol Monitoring II, Proceedings of SPIE, vol. 4624, 2002, pp. 1-10. |
| Boyne M.S., et al., “Timing of Changes in Interstitial and Venous Blood Glucose Measured With a Continuous Subcutaneous Glucose Sensor,” Diabetes, vol. 52, Nov. 2003, pp. 2790-2794. |
| Bremer T.M., et al., “Benchmark Data from the Literature for Evaluation of New Glucose Sensing Technologies,” Diabetes Technology & Therapeutics, vol. 3 (3), 2001, pp. 409-418. |
| Brooks S.L., et al., “Development of an On-line Glucose Sensor for Fermentation Monitoring,” Biosensors, vol. 3, 1987/1988, pp. 45-56. |
| Cass A.E.G., et al., “Ferrocene-Mediated Enzyme Electrodes for Amperometric Determination of Glucose,” Analytical Chemistry, vol. 56 (4), Apr. 1984, pp. 667-671. |
| Cheyne E.H., et al., “Performance of a Continuous Glucose Monitoring System During Controlled Hypoglycaemia in Healthy Volunteers,” Diabetes Technology & Therapeutics, vol. 4 (5), 2002, pp. 607-613. |
| Choleau C., et al., “Calibration of a Subcutaneous Amperometric Glucose Sensor Implanted for 7 Days in Diabetic Patients Part 2. Superiority of the One-point Calibration Method,” Biosensors and Bioelectronics, vol. 17 (8), 2002, pp. 647-654. |
| Csoregi E., et al., “Design and Optimization of a Selective Subcutaneously Implantable Glucose Electrode Based on ‘Wired’ Glucose Oxidase,” Analytical Chemistry, vol. 67 (7), Apr. 1, 1995, pp. 1240-1244. |
| Eren-Oruklu M., et al., “Estimation of Future Glucose Concentrations with Subject-Specific Recursive Linear Models,” Diabetes Technology & Therapeutics, vol. 11 (4), 2009, pp. 243-253. |
| Feldman B., et al., “A Continuous Glucose Sensor Based on Wired EnzymeTM Technology—Results from a 3-Day Trial in Patients with Type 1 Diabetes,” Diabetes Technology & Therapeutics, vol. 5 (5), 2003, pp. 769-779. |
| Feldman B., et al., “Correlation of Glucose Concentrations in Interstitial Fluid and Venous Blood During Periods of Rapid Glucose Change,” Abbott Diabetes Care, Inc. Freestyle Navigator Continuous Glucose Monitor Pamphlet, 2004, 1 page. |
| Gamry Instruments, “Basics of Electrochemical Impedance Spectroscopy,” 2007, 30 pages. |
| Georgescu B., et al., “Real-Time Multi-Model Tracking of Myocardium in Echocardiography Using Robust Information Fusion,” Medical Image Computing and Computer-Assisted Intervention, Springer-Verlag Berlin Heidelberg, 2004, pp. 777-785. |
| Goldman J.M., et al., “Masimo Signal Extraction Pulse Oximetry,” Journal of Clinical Monitoring and Computing, vol. 16 (7), 2000, pp. 475-483. |
| Guerci B., et al., “Clinical Performance of CGMS in Type 1 Diabetic Patients Treated by Continuous Subcutaneous Insulin Infusion Using Insulin Analogs,” Diabetes Care, vol. 26, 2003, pp. 582-589. |
| Hoss U., et al., “Continuous Glucose Monitoring in Subcutaneous Tissue Using Factory-Calibrated Sensors: A Pilot Study,” Diabetes Technology & Therapeutics, 2010, vol. 12 (8), pp. 591-597. |
| Hovorka R., et al., “Nonlinear Model Predictive Control of Glucose Concentration in Subjects with Type 1 Diabetes,” Physiological Measurement, vol. 25, Jul. 2004, pp. 905-920. |
| Isermann R., et al., “Trends in the Application of Model-Based Fault Detection and Diagnosis of Technical Processes”, Control Engineering Practice, vol. 5 (5), 1997, pp. 709-719. |
| Isermann R., “Supervision, Fault-Detection and Fault-Diagnosis Methods—An Introduction,” Control Engineering Practice, vol. 5 (5), 1997, pp. 639-652. |
| Johnson P.C., “Peripheral Circulation,” John Wiley & Sons, 1978, p. 198 (5 pages). |
| Jungheim K., et al., “How Rapid Does Glucose Concentration Change in Daily Life of Patients with Type 1 Diabetes?,” Diabetologia, 2002, vol. 45, pp. A250-A276. |
| Jungheim K., et al., “Risky Delay of Hypoglycemia Detection by Glucose Monitoring at the Arm,” Diabetes Care, vol. 24 (7), Jul. 2001, pp. 1303-1304. |
| Kaplan S.M., “Wiley Electrical and Electronics Engineering Dictionary,” IEEE Press, John Wiley & Sons, Inc., 2004, pp. 141, 142, 548 & 549. |
| Kovatchev B.P., et al., “Evaluating the Accuracy of Continuous Glucose-Monitoring Sensors: Continuous Glucose-Error Grid Analysis Illustrated by TheraSense Freestyle Navigator Data,” Diabetes Care, vol. 27 (8), Aug. 2004, pp. 1922-1928. |
| Kovatchev B.P., et al., “Graphical and Numerical Evaluation of Continuous Glucose Sensing Time Lag,” Diabetes Technology & Therapeutics, vol. 11 (3), 2009, pp. 139-143. |
| Kuure-Kinsey M., et al., “A Dual-Rate Kalman Filter for Continuous Glucose Monitoring,” Conf Proc IEEE Eng Med Biol Soc., 2006, vol. 1, pp. 63-66. |
| Lodwig V., et al., “Continuous Glucose Monitoring with Glucose Sensors: Calibration and Assessment Criteria,” Diabetes Technology & Therapeutics, vol. 5 (4), 2003, pp. 572-587. |
| Lortz J., et al., “What is Bluetooth? We Explain the Newest Short-Range Connectivity Technology,” In Smart Computing Learning Series, Wireless Computing, vol. 8 (5), 2002, pp. 72-74. |
| Maher R.C., “A Method for Extrapolation of Missing Digital Audio Data,” Preprints of Papers Presented at the AES Convention, New York, 1993, pp. 1-19. |
| Maher R.C., “Audio Enhancement Using Nonlinear Time-Frequency Filtering,” AES 26th International Conference, Jul. 7-9, 2005, pp. 1-9. |
| Malin S.F., et al., “Noninvasive Prediction of Glucose by Near-Infrared Diffuse Reflectance Spectroscopy,” Clinical Chemistry, vol. 45 (9), 1999, pp. 1651-1658. |
| McGarraugh G., et al., “Glucose Measurements Using Blood Extracted From The Forearm And The Finger,” TheraSense, Inc., 2001, pp. 1-8. |
| McGarraugh G., et al., “Physiological Influences on Off-Finger Glucose Testing”, Diabetes Technology & Therapeutics, vol. 3 (3), 2001, pp. 367-376. |
| McKean B.D., et al., “A Telemetry Instrumentation System for Chronically Implanted Glucose and Oxygen Sensors,” IEEE Transactions on Biomedical Engineering, vol. 35 (7), Jul. 1988, pp. 526-532. |
| Morbiducci U., et al., “Improved Usability of the Minimal Model of Insulin Sensitivity Based on Automated Approach and Genetic Algorithms for Parameter Estimation,” Clinical Science, vol. 112 (4), 2006, 24 pages. |
| Mougiakakou S.G., et al., “A Real Time Simulation Model of Glucose-Insulin Metabolism for Type 1 Diabetes Patients,” Conf Proc IEEE Eng Med Biol Soc. 2005, vol. 1, pp. 298-301. |
| Noujaim S.E., et al., “Accuracy Requirements for a Hypoglycemia Detector: An Analytical Model to Evaluate the Effects of Bias, Precision and Rate of Glucose Change,” Journal of Diabetes Science & Technology, vol. 1 (5), Sep. 2007, pp. 652-668. |
| O'Donoghue M., et al., “Electrochemical Impedance Spectroscopy: Testing Coatings for Rapid Immersion Service,” Materials Performance, Sep. 2003, pp. 36-41. |
| Panteleon A.E., et al., “The Role of the Independent Variable to Glucose Sensor Calibration,” Diabetes Technology & Therapeutics, vol. 5 (3), 2003, pp. 401-410. |
| Park, et al., “Novel Instrumentation in Electrochemical Impedance Spectroscopy and a Full Description of an Electrochemical System,” Pure Appl. Chem., 2006, vol. 78 (5), pp. 1069-1080. |
| Parker R.S., et al., “Robust H∞ Glucose Control in Diabetes Using a Physiological Model,” AlChE Journal, vol. 46 (12), Dec. 2000, pp. 2537-2549. |
| Pickup J.C., et al., “Implantable Glucose Sensors: Choosing the Appropriate Sensor Strategy,” Biosensors, vol. 3, (1987/1988), pp. 335-346. |
| Pickup J.C., et al., “In Vivo Molecular Sensing in Diabetes Mellitus: An Implantable Glucose Sensor with Direct Electron Transfer,” Diabetologia, vol. 32, 1989, pp. 213-217. |
| Pishko M.V., et al., “Amperometric Glucose Microelectrodes Prepared Through Immobilization of Glucose Oxidase in Redox Hydrogels,” Analytical Chemistry, vol. 63 (20), 1991, pp. 2268-2272. |
| Quinn C.P., et al., “Kinetics of Glucose Delivery to Subcutaneous Tissue in Rats Measured with 0.3-mm Amperometric Microsensors,” The American Physiological Society, vol. 269, 1995, pp. E155-E161. |
| Roe J.N., et al., “Bloodless Glucose Measurements,” Critical Reviews™ in Therapeutic Drug Carrier Systems, vol. 15 (3), 1998, pp. 199-241. |
| Sakakida M., et al., “Development of Ferrocene-Mediated Needle-Type Glucose Sensor as a Measure of True Subcutaneous Tissue Glucose Concentrations,” Artif. Organs Today, vol. 2 (2), 1992, pp. 145-158. |
| Sakakida M., et al., “Ferrocene-Mediated Needle Type Glucose Sensor Covered with Newly Designed Biocompatible Membrane,” Sensors and Actuators B, vol. 13-14, 1993, pp. 319-322. |
| Salehi C., et al., “A Telemetry-Instrumentation System for Long-Term Implantable Glucose and Oxygen Sensors,” Analytical Letters, vol. 29 (13), 1996, pp. 2289-2308. |
| Schmidtke D.W., et al., “Measurement and Modeling of the Transient Difference Between Blood and Subcutaneous Glucose Concentrations in the Rat After Injection of Insulin,” Proceedings of the National Academy of Sciences, vol. 95, Jan. 1998, pp. 294-299. |
| Shaw G.W., et al., “In Vitro Testing of a Simply Constructed, Highly Stable Glucose Sensor Suitable for Implantation in Diabetic Patients,” Biosensors & Bioelectronics, vol. 6, 1991, pp. 401-406. |
| Shichiri, et al., “In Vivo Characteristics of Needle-Type Glucose Sensor-Measurements of Subcutaneous Glucose Concentrations in Human Volunteers,” Implantable Glucose Sensors—The State of the Art, Hormone and Metabolic Research Supplement Series, 1988, vol. 20, pp. 17-20. |
| Shichiri M., et al., “Glycaemic Control in Pancreatectomized Dogs with a Wearable Artificial Endocrine Pancreas,” Diabetologia, vol. 24, 1983, pp. 179-184. |
| Shichiri M., et al., “Membrane Design for Extending the Long-Life of an Implantable Glucose Sensor,” Diabetes Nutrition & Metabolism, vol. 2 (4), 1989, pp. 309-313. |
| Shichiri M., et al., “Needle Type Glucose Sensor for Wearable Artificial Endocrine Pancreas,” In Implantable Sensors for Closed-Loop Prosthetic Systems edited by Ko W.H, Chapter 15, 1985, pp. 197-210. |
| Shichiri M., et al., “Telemetry Glucose Monitoring Device with Needle-Type Glucose Sensor: A Useful Tool for Blood Glucose Monitoring in Diabetic Individuals,” Diabetes Care, vol. 9 (3), May-Jun. 1986, pp. 298-301. |
| Shichiri M., et al., “Wearable Artificial Endocrine Pancreas with Needle-Type Glucose Sensor,” Preliminary Communication, Lancet, vol. 2, Nov. 20, 1982, pp. 1129-1131. |
| Shults M.C., et al., “A Telemetry-Instrumentation System for Monitoring Multiple Subcutaneously Implanted Glucose Sensors,” IEEE Transactions on Biomedical Engineering, vol. 41 (10), Oct. 1994, pp. 937-942. |
| Steil G.M., et al., “Closed-Loop Insulin Delivery—the Path of Physiological Glucose Control,” Advanced Drug Delivery Reviews, vol. 56, 2004, pp. 125-144. |
| Steil G.M., et al., “Determination of Plasma Glucose During Rapid Glucose Excursions with a Subcutaneous Glucose Sensor,” Diabetes Technology & Therapeutics, vol. 5 (1), 2003, pp. 27-31. |
| Sternberg R., et al., “Study and Development of Multilayer Needle-type Enzyme Based Glucose Microsensors,” Biosensors, Mar. 20, 1988, vol. 4 (1), pp. 27-40. |
| The Diabetes Control and Complications Trial Research Group, “The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-Term Complications in Insulin-Dependent Diabetes Mellitus,” The New England, Journal of Medicine, vol. 329 (14), Sep. 30, 1993, pp. 977-986. |
| Thompson M., et al., “In Vivo Probes: Problems and Perspectives,” Clinical Biochemistry, vol. 19 (5), Oct. 1986, pp. 255-261. |
| Turner A.P.F., et al., “Diabetes Mellitus: Biosensors for Research and Management,” Biosensors, vol. 1, 1985, pp. 85-115. |
| Updike S.J., et al., “Principles of Long-Term Fully Implanted Sensors with Emphasis on Radiotelemetric Monitoring of Blood Glucose Form Inside a Subcutaneous Foreign Body Capsule (FBC),” Edited by Fraser D M, Biosensors in the Body: Continuous in vivo Monitoring, John Wiley & Sons Ltd., New York, 1997, Chapter 4, pp. 117-137. |
| Velho G., et al., “Strategies for Calibrating a Subcutaneous Glucose Sensor,” Biomed Biochim Acta, vol. 48 (11/12), 1989, pp. 957-964. |
| Whipple G., “Low Residual Noise Speech Enhancement Utilizing Time-Frequency Filtering,” Proceedings of the International Conference on Acoustics, Speech, and Signal Processing, 1994, pp. 15-18. |
| Wilson G.S., et al., “Progress Toward the Development of an Implantable Sensor for Glucose,” Clinical Chemistry, vol. 38 (9), 1992, pp. 1613-1617. |
| Wolfe P.J., et al., “Interpolation of Missing Data Values for Audio Signal Restoration Using a Gabor Regression Model,” 2005 IEEE International Conference on Acoustics, Speech, and Signal Processing, vol. 5, 2005, pp. 517-520. |
| Yoo, et al., “An Electrochemical Impedance Measurement Technique Employing Fourier Transform,” Anal. Chem. 2000, vol. 72, pp. 2035-2041. |
| Chen T., et al., “In Situ Assembled Mass-Transport Controlling Micromembranes and Their Application in Implanted Amperometric Glucose Sensors,” Analytical Chemistry, Aug. 15, 2000, vol. 72, No. 16, pp. 3757-3763. |
| Chen X., et al., “Glucose Microbiosensor Based on Alumina Sol-gel Matrix/Electropolymerized Composite Membrane,” Biosensors and Bioelectronics, vol. 17, 2002, 9 pages. |
| Chung T.D., “In vitro Evaluation of the Continuous Monitoring Glucose Sensors with Perfluorinated Tetrafluoroethylene Coatings,” Bulletin of the Korean Chemical Society, 2003, vol. 24, No. 4, pp. 514-516. |
| Cunningham D.D., et al., “In Vivo Glucose Sensing,” Chemical Analysis, 2010, vol. 174, 466 pages. |
| Facchinetti A., et al., “Enhanced Accuracy of Continuous Glucose Monitoring by Online Extended Kalman Filtering,” Diabetes Technology Therapeutics, Apr. 13, 2010, vol. 12, No. 5, pp. 353-363. |
| Heller A., et al., “Electrochemical Glucose Sensors and Their Applications in Diabetes Management,” Chemical Reviews, 2008, vol. 108, No. 7 pp. 2482-2505. |
| Jimenez C., et al., “Glucose Sensor Based on an Amperometric Microelectrode with Photopolymerizable Enzyme Membrane,” Sensors and Actuators B, vol. 26-27, 1995, pp. 421-424. |
| Knobbe E.J., et al., “The Extended Kalman Filter for Continuous Glucose Monitoring,” Diabetes Technology Therapeutics, Feb. 28, 2005, vol. 7, No. 01, pp. 15-27. |
| Palerm et al., “Hypoglycemia Prediction and Detection Using Optimal Estimation”, Diabetes Technol Ther, 2005, vol. 7(1), pp. 3-14. |
| Rhodes R.K., et al., “Prediction of Pocket-Portable and Implantable Glucose Enzyme Electrode Performance from Combined Species Permeability and Digital Simulation Analysis,” Analytical Chemistry, vol. 66 (9), May 1, 1994, pp. 1520-1529. |
| Yang S., et al., “Glucose Biosensors Based on Oxygen Electrode with Sandwich-Type Membranes,” Annals of Biomedical Engineering, 1995, vol. 23, pp. 833-839. |
| Yang S., et al., “Glucose Biosensors with Enzyme Entrapped in Polymer Coating,” Biomedical Instrument and Technology, March/Apr. 1995, vol. 29 (2), pp. 125-133. |
| Number | Date | Country | |
|---|---|---|---|
| 20230240570 A1 | Aug 2023 | US |
| Number | Date | Country | |
|---|---|---|---|
| 61476145 | Apr 2011 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 17398628 | Aug 2021 | US |
| Child | 18129556 | US | |
| Parent | 16951759 | Nov 2020 | US |
| Child | 17398628 | US | |
| Parent | 16586434 | Sep 2019 | US |
| Child | 16951759 | US | |
| Parent | 16460943 | Jul 2019 | US |
| Child | 16586434 | US | |
| Parent | 16405887 | May 2019 | US |
| Child | 16460943 | US | |
| Parent | 15994905 | May 2018 | US |
| Child | 16405887 | US | |
| Parent | 14860392 | Sep 2015 | US |
| Child | 15994905 | US | |
| Parent | 13446977 | Apr 2012 | US |
| Child | 14860392 | US | |
| Parent | 13446848 | Apr 2012 | US |
| Child | 13446977 | US |
