Patent Publication Number: US-2023157598-A1

Title: Glucose sensor

Description:
TECHNICAL FIELD 
     This disclosure relates to glucose sensors. 
     BACKGROUND 
     Glucose sensors are configured to detect and/or quantify the amount of glucose in a patient&#39;s body (e.g., interstitial glucose or possibly blood glucose), which enables patients and medical personnel to monitor physiological conditions within the patient&#39;s body. In some examples, it may be beneficial to monitor glucose levels on a continuing basis (e.g., in a diabetic patient). Thus, glucose sensors have been developed for use in obtaining an indication of glucose levels in a diabetic patient. Such indications are useful in monitoring and/or adjusting a treatment regimen, which typically includes administration of insulin to the patient. 
     A patient can measure their blood glucose (BG) using a BG measurement device (i.e., glucose meter), such as a test strip meter. A continuous glucose measurement system (or a continuous glucose monitor (CGM)) may be configured to determine interstitial glucose; although possible for CGM to determine blood glucose. A hospital hemocue may also be used to determine glucose level. CGMs may be beneficial for patients who desire to take more frequent glucose measurements. Some example CGM systems include subcutaneous (or short-term) sensors and implantable (or long-term) sensors. A CGM system may execute an initialization sequence when the CGM is inserted into a patient. The initialization sequence may speed up sensor equilibration and may allow a CGM system to provide reliable glucose measurements earlier. 
     SUMMARY 
     In general, this disclosure describes techniques for determining electrochemical interference of glucose sensors (e.g., a continuous glucose monitor or “CGM”) based on one or more electrical parameters. More particularly, this disclosure describes techniques and devices for determining electrical parameters of a glucose sensor in vitro and/or in vivo and identifying and/or detecting electrochemical interference. 
     In one example, this disclosure describes a method including: monitoring, via a device including an electrochemical cell, an electrical current that is proportional to an impedance of the electrochemical cell; responsive to determining that the electrical current satisfies a threshold, measuring, via the device, a plurality of impedances of the electrochemical cell corresponding to a plurality of frequencies; determining a charge transfer conductance and a solution resistance based on the plurality of impedances at a subset of the corresponding plurality of frequencies; determining the presence of electrochemical interference based on the solution resistance and the charge transfer conductance; and outputting a signal based on the determination of the presence of electrochemical interference. 
     In another example, this disclosure describes a device including: a glucose monitor; a memory; and one or more processors implemented in circuitry and in communication with the memory, the one or more processors configured to: monitor an electrical current that is proportional to an impedance of the glucose monitor; responsive to determining that the electrical current satisfies a threshold, receive one or more measurements of a plurality of impedances of the glucose monitor corresponding to a plurality of frequencies; determine a charge transfer conductance and a solution resistance of the glucose monitor based on the plurality of impedances at as subset of the corresponding plurality of frequencies; determine the presence of electrochemical interference based on the charge transfer conductance and the solution resistance; and output a signal based on the determination of the presence of electrochemical interference. 
     In another example, this disclosure describes a non-transitory computer-readable storage medium having stored thereon instructions that, when executed, configure a processor to: monitor, via a device including an electrochemical cell, an electrical current that is proportional to an impedance of the electrochemical cell; responsive to determining that the electrical current satisfies a threshold, receive one or more measurements from the device of a plurality of impedances of the electrochemical cell corresponding to a plurality of frequencies; determine a charge transfer conductance and a solution resistance of the electrochemical cell based on the plurality of impedances at a subset of the corresponding plurality of frequencies; determine the presence of electrochemical interference based on the charge transfer conductance and the solution resistance; and output a signal based on the determination of the presence of electrochemical interference. 
     The details of one or more examples are set forth in the accompanying drawings and the description below. Other features, objects, and advantages will be apparent from the description and drawings, and from the claims. 
    
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
         FIG.  1    is a block diagram illustrating an example glucose level management system, in accordance with one or more examples described in this disclosure. 
         FIG.  2    is a block diagram illustrating an example glucose sensor, in accordance with one or more examples described in this disclosure. 
         FIG.  3 A  is a block diagram illustrating example sensor electrodes and a voltage being applied to the sensor electrodes. 
         FIG.  3 B  is a cross-sectional view of an example medical device including a monitoring device and insulin pump. 
         FIG.  4    is a circuit diagram illustrating an example electrical circuit model of an electrochemical cell of a monitoring device. 
         FIG.  5    is a Bode plot of example measured EIS data. 
         FIG.  6 A  is a Nyquist plot of an example of measured EIS data. 
         FIG.  6 B  is a Nyquist plot of another example of measured EIS data. 
         FIG.  7 A  is a cross-sectional view of a portion of an example electrochemical cell in an initial state. 
         FIG.  7 B  is a cross-sectional view of a portion of an example electrochemical cell in an interference state. 
         FIG.  7 C  is a cross-sectional view of a portion of an example electrochemical cell in a new state. 
         FIG.  8    is a flowchart illustrating an example method of determining electrochemical interference of an electrochemical cell. 
     
    
    
     DETAILED DESCRIPTION 
     Diabetes patients who use sensor-augmented pump (SAP) therapy may do so by inserting an infusion set and a continuous glucose monitoring (CGM) sensor separately. The burden of two insertions increases the likelihood of adverse effects of skin penetration, reaction to adhesives, and site loss. Combining the insulin delivery with CGM sensing into a single integrated device addresses these concerns. However, a CGM in close proximity to an infusion catheter may experience electrochemical interference. Electrochemical interference can cause the CGM to provide an inaccurate glucose reading, which may lead to imprecise diagnoses if the readings are used to compute insulin dosage. In examples, disclosed herein, electrochemical impedance spectroscopy (EIS) may be used as a technique to detect when interference is occurring so that action may be taken by the device to ensure patient safety. 
     A glucose sensor may include an electrochemical cell which may be used to determine a glucose level of a patient. As one example, the glucose sensor may determine interstitial glucose level. The electrochemical cell may apply electrical energy via one or more electrodes displaced within a fluid and/or tissue of a patient, and based on the impedance, determine the glucose level. However, the one or more electrodes may be susceptible to materials within the infused fluid, which may be a commercially available insulin formulation. A bias voltage applied to the electrodes may be needed for the electrodes to function properly. In the presence this bias voltage, the electrodes may cause oxidation of one or more of the substances within the infused fluid. With sufficient prolonged exposure to the substances, the oxidation can lead to deposits and build-up of a thin film on a surface of an electrode. When the interfering substances are oxidized, they can add or subtract from the signal current coming from the glucose, which can lead to inaccurate glucose readings. With prolonged exposure to the substances, the thin film formed on an electrode can cause a permanent change in response characteristics to the glucose. That is, a change in the electrical response of the electrochemical cell to the presence of an analyte, such as glucose. The materials that deposit and form the thin film may be excipients of insulin, e.g., m-cresol, phenol, glycerin, or other materials such as acetaminophen or ascorbic acid. It is important to note that oxidation of interfering compounds alone leads to a temporary interference while thin film deposits on an electrode lead to a permanent change to the electrochemical response of the sensor. 
     In some examples, a glucose sensor, such as a CGM, and an insulin delivery device, such as an insulin pump, may be packaged together such that the electrode of the glucose sensor may be placed relatively near an insulin delivery site on the patient. Insulin excipient concentration may be greatest nearest the insulin delivery site and may decrease as the excipients diffuse within the patient. In some examples, the higher the concentration of the interfering compounds, the higher the rate of oxidation, and the faster the buildup of a thin film on a glucose sensor electrode causing an increased electrochemical interference. In some examples, even low concentrations of excipients and/or interfering compounds may cause interference followed by a buildup of a thin film on a glucose sensor electrode, e.g., over time, causing progressively increasing electrochemical interference. 
     The thin film buildup of insulin excipients and/or acetaminophen on a glucose electrode may change the dielectric properties of the electrode and the sensor electrical circuit system, thereby causing the electrochemical interference. Electrochemical interference may confound glucose measurement based on an electrical signal, and the presence of electrochemical interference may not be detectable via the electrical signal alone. For example, a CGM may use a signal current to determine the presence and/or amount of glucose at or near an electrode. Changes in the signal current may be caused by increasing and/or decreasing glucose, electrochemical interference, or both. 
     EIS may be used as a technique to measure the electrical impedance of the glucose sensor system as a function of frequency of the current and/or voltage. Electrical impedance as a function of frequency measured via EIS may be used, in conjunction with a properly chosen electrical circuit system model, to infer (e.g., determine and/or calculate) dielectric properties of the glucose sensor as well as certain electrical circuit properties of the model. The presence of electrochemical interference may be determined based on the inferred electrical circuit properties of the system model, e.g., solution resistance, charge transfer conductance, double layer capacitance, and the like. 
     The electrical circuit system model used to determine and/or calculate electrical circuit properties indicative of electrochemical interference based on measured impedance values may be an approximation. For example, the actual physical structure and materials of electrical components of the glucose sensor may be unknown, e.g., at least because of the buildup of the thin film of insulin excipients and/or acetaminophen on one or more electrodes, which may further be a non-homogenous thin film. The accuracy of the approximation may be sensitive to the choice of electrical circuit system model (e.g., the determination/calculation method) and which measured impedance values (e.g., which frequencies and/or frequency ranges) are used in the determination and/or calculation. 
     In accordance with the techniques of the disclosure, a device including an electrochemical cell may be configured to monitor an electrical current that is proportional to an impedance of the electrochemical cell. The device may be configured to measure a plurality of impedances of the electrochemical cell corresponding to a plurality of frequencies in response to determining that the electrical current satisfies a threshold. The device may be configured to determine a charge transfer conductance and a solution resistance of the electrochemical cell based on the plurality of impedances at a subset of the corresponding plurality of frequencies, e.g., fewer than four of the corresponding plurality of frequencies. The device may be configured to determine the presence of electrochemical interference based on the charge transfer conductance and the solution resistance. The device may be configured to output a signal based on the determination of the presence of electrochemical interference. 
     In some examples, the device may be configured to determine a solution resistance based on an impedance value corresponding to a relatively high frequency, and to determine the charge transfer conductance based on the solution resistance and an impedance value corresponding to a relatively low frequency. The device may be configured to determine a double layer capacitance based on the solution resistance, the charge transfer conductance, and on an impedance value of the plurality of impedance values corresponding to a frequency at which the impedance phase is substantially negative 90 degrees. In some examples, the device may be configured to determine an amount of permanent electrochemical interference based on the double layer capacitance and/or changes to double layer capacitance over a period of time. In some examples, the device may be configured to determine the cause of the electrochemical interference, e.g., to determine whether the electrochemical interference is caused by insulin excipients, acetaminophen, or some other interfering compound. For example, the device may be configured to determine a Nyquist slope based on the measured impedances, and to determine whether the electrochemical interference is caused by insulin excipients or acetaminophen based on the Nyquist slope and/or a change of the Nyquist slope over a period of time and/or relative to a previously determined Nyquist slope. 
       FIG.  1    is a block diagram illustrating an example glucose level management system in accordance with one or more examples described in this disclosure.  FIG.  1    illustrates system  110  that includes insulin pump  114 , tubing  116 , infusion set  118 , monitoring device  100  (e.g., a glucose level monitoring device comprising a glucose sensor), and patient device  124 . The infusion set  118  and monitoring device  100  may be integrated into a single device. Insulin pump  114  may be described as a tethered pump, because tubing  116  tethers insulin pump  114  to infusion set  18 . In some examples, rather than utilizing a tethered pump system comprising insulin pump  114 , tubing  116 , infusion set  118 , and/or monitoring device  100 , patient  112  may utilize a patch pump. Instead of delivering insulin via tubing and an infusion set, a pump patch may deliver insulin via a cannula extending directly from an insulin pump. In some examples, a glucose sensor may also be integrated into such an insulin patch pump (e.g., a so-called “all-in-one (AIO) insulin pump”). 
     Patient  112  may be diabetic (e.g., Type 1 diabetic or Type 2 diabetic), and therefore, the glucose level in patient  112  may be controlled with delivery of supplemental insulin. For example, patient  112  may not produce sufficient insulin to control the glucose level or the amount of insulin that patient  112  produces may not be sufficient due to insulin resistance that patient  112  may have developed. 
     To receive the supplemental insulin, patient  112  may carry insulin pump  114  that couples to tubing  116  for delivery of insulin into patient  112 . Infusion set  118  may connect to the skin of patient  112  and include a cannula to deliver insulin into patient  112 . Monitoring device  100  may also be coupled to patient  112  to measure glucose level in patient  112 . Insulin pump  114 , tubing  116 , infusion set  118 , and monitoring device  100  may together form an insulin pump system. One example of the insulin pump system is the MINIMED™ 770G insulin pump system by MEDTRONIC MINIMED, INC. However, other examples of insulin pump systems may be used and the example techniques should not be considered limited to the MINIMED™ 770G insulin pump system. For example, the techniques described in this disclosure may be utilized with any insulin pump and/or glucose monitoring system that includes an in vivo glucose sensor (e.g., a continuous glucose monitor or other in vivo glucose sensor). 
     Monitoring device  100  may include a sensor that is inserted under the skin of patient  112  (e.g., in vivo), such as near the stomach of patient  112  or in the arm of patient  112  (e.g., subcutaneous connection). The sensor of monitoring device  100  may be configured to measure the interstitial glucose level, which is the glucose found in the fluid between the cells of patient  112 . Monitoring device  100  may be configured to continuously or periodically sample the glucose level and rate of change of the glucose level over time. 
     In one or more examples, insulin pump  114 , monitoring device  100 , and/or the various components illustrated in  FIG.  1   , may together form a closed-loop therapy delivery system, which is often referred to as SAP therapy. For example, patient  112  may set a target glucose level, usually measured in units of milligrams per deciliter, on insulin pump  114 . Insulin pump  114  may receive the current glucose level from monitoring device  100  and, in response, may increase or decrease the amount of insulin delivered to patient  112 . For example, if the current glucose level is higher than the target glucose level, insulin pump  114  may increase the insulin. If the current glucose level is lower than the target glucose level, insulin pump  114  may temporarily cease delivery of the insulin. Insulin pump  114  may be considered as an example of an automated insulin delivery (AID) device. Other examples of AID devices may be possible, and the techniques described in this disclosure may be applicable to other AID devices. 
     Insulin pump  114  and monitoring device  100  may be configured to operate together to mimic some of the ways in which a healthy pancreas works. Insulin pump  114  may be configured to deliver basal dosages, which are small amounts of insulin released continuously throughout the day. There may be times when glucose levels increase, such as due to eating or some other activity that patient  112  undertakes. Insulin pump  114  may be configured to deliver bolus dosages on demand in association with food intake or to correct an undesirably high glucose level in the bloodstream. In one or more examples, if the glucose level rises above a target level, then insulin pump  114  may deliver a bolus dosage to address the increase in glucose level. Insulin pump  114  may be configured to compute basal and bolus dosages and deliver the basal and bolus dosages accordingly. For instance, insulin pump  114  may determine the amount of a basal dosage to deliver continuously and then determine the amount of a bolus dosage to deliver to reduce glucose level in response to an increase in glucose level due to eating or some other event. 
     Accordingly, in some examples, monitoring device  100  may sample glucose levels for determining rate of change in glucose level over time. Monitoring device  100  may output the glucose level to insulin pump  114  (e.g., through a wireless link connection like Bluetooth). Insulin pump  114  may compare the glucose level to a target glucose level (e.g., as set by patient  112  or a clinician) and adjust the insulin dosage based on the comparison. In some examples, insulin pump  114  may adjust insulin delivery based on a predicted glucose level (e.g., where glucose level is expected to be in the next 30 minutes). 
     As described above, patient  112  or a clinician may set one or more target glucose levels on insulin pump  114 . There may be various ways in which patient  112  or the clinician may set a target glucose level on insulin pump  114 . As one example, patient  112  or the clinician may utilize patient device  124  to communicate with insulin pump  114 . Examples of patient device  124  include mobile devices, such as smartphones, tablet computers, laptop computers, and the like. In some examples, patient device  124  may be a special programmer or controller (e.g., a dedicated remote control device) for insulin pump  114 . Although  FIG.  1    illustrates one patient device  124 , in some examples, there may be a plurality of patient devices. For instance, system  110  may include a mobile device and a dedicated wireless controller, each of which is an example of patient device  124 . For ease of description only, the example techniques are described with respect to patient device  124  with the understanding that patient device  124  may be one or more patient devices. 
     Patient device  124  may also be configured to interface with monitoring device  100 . As one example, patient device  124  may receive information from monitoring device  100  through insulin pump  114 , where insulin pump  114  relays the information between patient device  124  and monitoring device  100 . As another example, patient device  124  may receive information (e.g., glucose level or rate of change of glucose level) directly from monitoring device  100  (e.g., through a wireless link). 
     In one or more examples, patient device  124  may comprise a user interface with which patient  112  or the clinician may control insulin pump  114 . For example, patient device  124  may comprise a touchscreen that allows patient  112  or the clinician to enter a target glucose level. Additionally or alternatively, patient device  124  may comprise a display device that outputs the current and/or past glucose level. In some examples, patient device  124  may output notifications to patient  112 , such as notifications if the glucose level is too high or too low, as well as notifications regarding any action that patient  112  needs to take. 
     In some examples, monitoring device  100  and insulin pump  114  of an insulin pump system and/or infusion set  118  may be packaged together such that an electrochemical cell or working electrode  160  ( FIG.  3 A ) of the glucose sensor may be placed relatively near an insulin delivery site on the patient. Insulin excipients from insulin doses or boluses may cause the excipients to be oxidized and possibly lead to deposits and build up a thin film on the surface of the electrode of monitoring device  100 , as described above, causing electrochemical interference and a change in the electrical parameters of the glucose sensor. 
     In accordance with the techniques, device, and systems disclosed herein, a monitoring device  100  may be configured to determine the presence of electrochemical interference, and in some examples, determine a cause of the electrochemical interference. Monitoring device  100  may be configured to determine one or more electrical parameters of an electrochemical cell of monitoring device  100 . In some examples, monitoring device  100  may include an interference detection unit  142  configured to determine one or more electrical parameters of an electrochemical cell of monitoring device  100  and the presence and/or cause of electrochemical interference, e.g., as further described below with reference to  FIG.  2   . In some examples, patient device  124  or another device may include interference detection unit  142 , in addition to or instead of monitoring device  100 . Electrical parameters may include, for example, a voltage, an electrical current (e.g., iSig  157  illustrated in  FIG.  3 A ), or an impedance. In general, the electrical current (iSig  157 ) flowing through the sensing (e.g., working) electrode of monitoring device  100  is indicative of the blood glucose level in the patient&#39;s interstitial fluid. In some examples, the sensing electrode may be part of an electrochemical cell configured to measure the voltage, iSig, or impedances. 
     For example, monitoring device  100  may be configured monitor an electrical current that is proportional to an impedance of the electrochemical cell and to measure a plurality of impedances of the electrochemical cell corresponding to a plurality of frequencies, e.g., responsive to determining that the electrical current satisfies a threshold. In other words, as described in more detail, monitoring device  100  may be configured to perform a diagnostic test upon an electrical parameter, e.g., iSig, satisfying a threshold, such as being too low or too high relative to a predetermined expected value range. Monitoring device  100  may be further configured to determine a charge transfer conductance and a solution resistance of the electrochemical cell based on the plurality of impedances at a subset, e.g., fewer than four, of the corresponding plurality of frequencies, determine the presence of electrochemical interference based on the charge transfer conductance and the solution resistance, and output a signal, e.g., to patient device  124 , insulin pump  114 , or any other suitable device, based on the determination of the presence of electrochemical interference. The signal may be information indicative of the presence and/or amount of electrochemical interference, and another device (e.g., patient device  124 , or any other suitable device, may output an alert based on the signal. In some examples, monitoring device  100  may be further configured to determine a Nyquist slope and determine whether the electrochemical interference is caused by insulin excipients or acetaminophen based on the Nyquist slope. 
       FIG.  2    is a block diagram illustrating monitoring device  100  in more detail. In particular,  FIG.  2    is a perspective view of a subcutaneous sensor insertion set and a block diagram of sensor electronics device  130  of monitoring device  100  according to an example of the disclosure. As illustrated in  FIG.  2   , subcutaneous sensor set  10  is provided for subcutaneous placement of an active portion of flexible glucose sensor  12  at a selected site in the body of patient  112 . The subcutaneous or percutaneous portion of sensor set  10  includes a hollow, slotted insertion needle  14 , and cannula  16 . Needle  14  is used to facilitate quick and easy subcutaneous placement of cannula  16  at the subcutaneous insertion site. Inside cannula  16  is glucose sensing portion  18  of glucose sensor  12 , which is configured to expose one or more glucose sensor electrodes  20  to the bodily fluids (e.g., blood or interstitial fluid) of patient  112  through window  22  formed in cannula  16 . In one example, one or more glucose sensor electrodes  20  may include a counter electrode  156 , a reference electrode  158 , and one or more working electrodes  160 . Examples of the counter electrode  156 , reference electrode  158 , and working electrode(s)  160  are described in more detail with respect to  FIG.  3 A . After insertion, insertion needle  14  is withdrawn to leave cannula  16  with glucose sensing portion  18  and glucose sensor electrodes  20  in place at the selected insertion site. 
     In some examples, subcutaneous sensor set  10  facilitates accurate placement of flexible thin film electrochemical glucose sensor  12  of the type used for monitoring specific blood parameters representative of a condition of patient  112 . Glucose sensor  12  monitors glucose levels in the body, and may be used in conjunction with automated or semi-automated medication infusion pumps of the external or implantable type as described above to control delivery of insulin to patient  112 . 
     Examples of flexible electrochemical glucose sensor  12  are constructed in accordance with thin film mask techniques to include elongated thin film conductors embedded or encased between layers of a selected insulative material such as polyimide film or sheet, and membranes. Glucose sensor electrodes  20  at a tip end of glucose sensing portion  18  are exposed through one of the insulative layers for direct contact with patient blood or other body fluids, when glucose sensing portion  18  (or active portion) of glucose sensor  12  is subcutaneously placed at an insertion site. Glucose sensing portion  18  is joined to connection portion  24  that terminates in conductive contact pads, or the like, which are also exposed through one of the insulative layers. In other examples, other types of implantable sensors, such as chemical based, optical based, or the like, may be used. 
     Connection portion  24  and the contact pads are generally adapted for a direct wired electrical connection to a suitable monitor or sensor electronics device  130  for monitoring a condition of patient  112  in response to signals derived from glucose sensor electrodes  20 . Connection portion  24  may be conveniently connected electrically to the monitor or sensor electronics device  130  or by connector block  28 . Thus, in accordance with examples of the disclosure, subcutaneous sensor sets  10  may be configured or formed to work with either a wired or a wireless characteristic monitor system. 
     Glucose sensor electrodes  20  may be used in a variety of sensing applications and may be configured in a variety of ways. For example, glucose sensor electrodes  20  may be used in physiological parameter sensing applications in which some type of biomolecule is used as a catalytic agent. For example, glucose sensor electrodes  20  may be used in a glucose and oxygen sensor having a glucose oxidase (GOx) enzyme catalyzing a reaction with glucose sensor electrodes  20 . Glucose sensor electrodes  20 , along with a biomolecule or some other catalytic agent, may be placed in a human body in a vascular or non-vascular environment. For example, glucose sensor electrodes  20  and biomolecules may be placed in a vein and be subjected to a blood stream, or may be placed in a subcutaneous or peritoneal region of the human body. 
     Sensor electronics device  130  may include measurement processor  132 , display and transmission unit  134 , controller  136 , power supply  138 , and memory  140 . Sensor electronics device  130  may be coupled to the sensor set  10  by cable  102  through a connector that is electrically coupled to connector block  28  of connection portion  24 . In other examples, the cable may be omitted and sensor electronics device  130  may include an appropriate connector for direct connection to connection portion  104  of sensor set  10 . Sensor set  10  may be modified to have connector portion  104  positioned at a different location, e.g., on top of the sensor set to facilitate placement of sensor electronics device  130  over the sensor set. 
     In examples of the disclosure, measurement processor  132 , display and transmission unit  134 , and controller  136  may be formed as separate semiconductor chips. However, other examples may combine measurement processor  132 , display and transmission unit  134 , and controller  136  into a single or multiple customized semiconductor chips. In general, measurement processor  132  may be configured to receive a current, voltage, and/or impedance from glucose sensor electrodes  20 . Glucose sensor electrodes  20  may generate a sensor signal indicative of a concentration of a physiological characteristic being measured. For example, the sensor signal may be indicative of a glucose reading. The sensor signal may be measured at a working electrode  160  of glucose sensor electrodes  20 . In an example of the disclosure, the sensor signal may be a current (e.g., iSig) measured at the working electrode  160 . In another example of the disclosure, the sensor signal may be a voltage measured at the working electrode  160  of glucose sensor electrodes  20 . 
     Electrical parameters of monitoring device  100  may include impedance parameters. An example of an impedance parameter may include EIS. EIS may provide additional information in the form of sensor impedance and impedance-related parameters at a plurality of different frequencies. Moreover, for certain ranges of frequencies, impedance and/or impedance-related data may indicate electrochemical interference. Determination of electrochemical interference enables correction of the electrochemical interference to improve the reliability of the sensor glucose value and to assess the condition, health, age, and efficiency of the sensor. For example, analysis of impedance data in the context of an appropriate electrical circuit model provides information on the presence of electrochemical interference of a sensor of monitoring device  100  and information on a cause of the electrochemical interference when the interference is present. 
     Measurement processor  132  receives the sensor signal (e.g., a measured current, voltage, and/or impedance) after the sensor signal is measured at glucose sensor electrodes  20  (e.g., a working electrode  160 ). Measurement processor  132  may receive the sensor signal and calibrate the sensor signal utilizing reference values. For example, measurement processor  132  may calibrate the sensor signal utilizing reference values based on a known analyte quantity, e.g., a zero glucose measurement to determine a baseline sensor signal. In some examples, changes to the sensor over time may change the responsivity of the glucose sensor, changing the sensor signal and glucose measurement accuracy. Measurement processor  132  may utilize the reference values to adjust for changes over time. In some examples, monitoring device  100  may update and or adjust the reference values, e.g., using EIS data or other data. In an example of the disclosure, the reference values are stored in a reference memory (e.g., memory  140 ) and provided to measurement processor  132 . Based on the sensor signals and the reference values, measurement processor  132  may determine a glucose measurement. Measurement processor  132  store the glucose measurements in memory  140 . The sensor measurements may be sent to display and transmission unit  134  to be either displayed on a display in a housing of monitoring device  100  or transmitted to an external device. 
     Memory  140  may be any type of memory device and may be configured to store glucose measurements produced by measurement processor  132 , reference values used to determine glucose measurements from sensor signals, or other data used and/or produced by measurement processor  132  and/or controller  136 . In some examples, memory  140  may further store software and/or firmware that is executable by measurement processor  132  and/or controller  136 . 
     Sensor electronics device  130  may be a monitor which includes a display to display physiological characteristics readings. In some examples, sensor electronics device  130  may be remote from sensor set  10  and communicatively connected to sensor set  10 , e.g., via a wired or wireless connection. For example, sensor electronics device  130  may also be installed in a desktop computer, a pager, a television including communications capabilities, a laptop computer, a server, a network computer, a personal digital assistant (PDA), a portable telephone including computer functions, an infusion pump including a display, a glucose sensor including a display, and/or a combination infusion pump/glucose sensor. Sensor electronics device  130  may be housed in a mobile phone, a network device, a home network device, or an appliance connected to a home network. 
     Power supply  138  may be a battery. The battery can include three series silver oxide  357  battery cells. In other examples, different battery chemistries may be utilized, such as lithium based chemistries, alkaline batteries, nickel metalhydride, or the like, and a different number of batteries may be used. Sensor electronics device  130  provides power to the sensor set  10  via power supply  138  through cable  102  and cable connector  104 . 
     Controller  136  may be a processor, digital signal processors (DSPs), application specific integrated circuits (ASICs), field programmable gate arrays (FPGAs), or any other equivalent integrated or discrete logic circuitry. In some examples controller  136  may be configured to cause a specific voltage or current to be output to glucose sensor electrodes  20 . Glucose sensor electrodes  20  may receive the voltage level or value. In an example of the disclosure, a counter electrode  156  of glucose sensor electrodes  20  may receive the reference voltage from power supply  138 . The application of the voltage level causes glucose sensor electrodes  20  to create a sensor signal (e.g., a current through a working electrode  160 ) indicative of a concentration of a physiological characteristic being measured (e.g., blood glucose). 
       FIG.  3 A  is a block diagram illustrating example sensor electrodes and a bias voltage being applied to the sensor electrodes according to an example of the disclosure. In the examples shown, example sensor electrodes include counter electrode  156 , reference electrode  158 , and working electrodes  160 , which may be examples of glucose sensor electrodes  20  and may be used in a glucose and oxygen sensor having a glucose oxidase (GOx) enzyme catalyzing a reaction with electrodes  156 ,  158 ,  160 . In the example in  FIG.  3 A , an operational amplifier (op amp)  150  or other servo controlled device may connect to glucose sensor electrodes  20  through a circuit/electrode interface  152 . Op amp  150 , utilizing feedback through glucose sensor electrodes  20 , attempts to maintain a prescribed voltage between reference electrode  158  and a working electrode  160  (e.g., VSET) by adjusting the voltage at counter electrode  156 . In some examples, the voltage at reference electrode  158  is 850 mv. 
     Current  157  (iSig) may then flow from a counter electrode  156  to a working electrode  160 . Counter electrode  156  balances the chemical reaction that is occurring at working electrode  160 . Measurement processor  132  of  FIG.  2    may measure current  157  to determine the electrochemical reaction between glucose sensor electrodes  20 . The circuitry disclosed in  FIG.  3 A  may be utilized in a long-term or implantable sensor or may be utilized in a short-term or subcutaneous sensor. 
     Returning to  FIG.  2   , as discussed above, due to electrochemical interference, monitoring device  100  may provide inaccurate readings to patient  112 . As such, interference detection unit  142  may be configured to detect electrochemical interference and a cause of electrochemical interference. Either of measurement processor  132  and/or controller  136  may be configured to execute interference detection unit  142 . Although interference detection unit  142  is illustrated as software that executes on measurement processor  132  and/or controller  136 , in some examples, interference detection unit  142  may be fixed-function circuitry that is formed within monitoring device  100  (e.g., within measurement processor  132  and/or controller  136  or independent of measurement processor  132  and/or controller  136 ). In some examples, inference detection unit  142  may be firmware that measurement processor  132  and/or controller  136  execute. 
     In accordance with the techniques of this disclosure, interference detection unit  142  is configured to monitor an electrical parameter of the electrical chemical cell of monitoring device  100 , e.g., an electrical current that is proportional to the impedance of the electrochemical cell such as iSig  157 . For example, measurement processor  132  may provide a sensor signal to controller device  150 . In one example, the sensor signal is a current (iSig  157 ) through a working electrode  160  of glucose sensor electrodes  20 . Controller  136  may accumulate current values over a period of time and may calculate a rate of change of the current values. For example, controller  136  may calculate the slope of a plot of the current (e.g., iSig  157 ). 
     In other examples, controller  136  may accumulate and measure changes in EIS (real and imaginary impedance at different frequencies), voltage at a counter electrode  156 , and/or current through a background electrode. A background electrode is similar to a working electrode  160 , but does not include Gox layer for breaking down and sensing glucose. Like current through a working electrode  160 , larger slopes/changes in these other sensor signals may indicate a need for a higher VSET, whole lower slopes/changes in these other sensor signals may indicate a need for a lower VSET at the working electrode  160 . Interference detection unit  142  may be configured to monitor EIS, voltage, and/or current through a background electrode similar to monitoring iSig  157  as described herein. 
     In some examples, sensor electronics device  130  may monitor fewer than all of the electrical parameters of monitoring device  100 , e.g., sensor electronics device  130  may monitor just iSig  157  and audit other electrical parameters at certain points in time or in response to an occurrence such as a monitored parameter (e.g., iSig  157 ) satisfying a threshold. Interference detection unit  142  is further configured to measure a plurality of impedances of the electrochemical cell, e.g., via EIS, if iSig  157  satisfies a threshold. 
     For example, a spike in iSig  157  may indicate a rise in glucose, or a spike in iSig  157  may indicate a rise in interferents such as insulin excipients. The threshold value may be predetermined, at least initially, and stored in memory  140 , and may be a value at which other electrical parameters may be measured/audited to determine the presence of electrochemical interference. The threshold value may be adjusted over time, e.g., so as to compensate for changes to the causes of electrochemical interference over time such as changes to a thin film of insulin excipients deposited on an electrode of the electrochemical cell, e.g., any of electrodes  156 ,  158 ,  160 . The threshold value may be predetermined, adjusted, or determined based on previous iSig  157  measurements, e.g., for comparison to determine if there is a change to an average value of an iSig  157  spike, or based on any other information indicating an iSig  157  value at which a diagnostic test should be performed to determine whether electrochemical interference is present and/or has changed. In other words, sensor electronics device  130  may monitor iSig  157  and electrical parameters (e.g. EIS) to determine whether a spike in iSig  157  is due to glucose, and/or electrochemical interference. 
     Interference detection unit  142  may utilize electrical model components calculated based on impedance measurements at a plurality of frequencies to determine the presence and, in some examples, the cause of electrochemical interference. For example, interference detection unit  142  may determine a charge transfer conductance, a solution resistance, and a double layer capacitance based on an electrical circuit model representing the electrical chemical cell, e.g., electrical circuit model  400  illustrated and described below with reference to  FIG.  4   . 
     Electrical circuit model components may be idealized components, e.g., relating to simplified, idealized electrical components such as uniform resistors, capacitors, and inductors. The electrical phenomena occurring within an electrochemical cell may vary from that of an electrical circuit model because the electrical components of the electrical chemical cell may not be, and may not behave, as simple resistors, capacitors, and inductors. For example, nonuniformities in a fluid (e.g., interstitial fluid) may cause the resistance of the fluid to vary spatially, temporally, and at different electrical frequencies (e.g., spectrally, or according to a spectral response). Similarly, a thin film buildup on an electrode of the electrical cell may not be spatially, temporally, and at different electrical frequencies, e.g., modifying the electrode to be a non-uniform electrode. As such, electrical circuit model components such as charge transfer conductance, solution resistance, and double layer capacitance are simplifications of actual electrical phenomena occurring within the electrochemical cell. The actual electrical circuit model components of the electrochemical cell may be prohibitively complex to directly measure, and the accuracy of calculated electrical circuit model components in representing the actual electrical phenomena of the electrochemical cell depends on how those components are calculated, which depends on, or is informed by, the electrical circuit model chosen. In turn, the accuracy of determining whether electrochemical interference and a cause of electrochemical interference depends on the accuracy of the calculated electrical circuit model components of the chosen electrical circuit model. 
     In some examples, interference unit  142  is configured to determine component values for components of an electrical circuit model based on an electrical circuit model of the electrochemical cell that does not include either of a constant phase element or a Warburg impedance. For example, interference unit  142  may be configured to calculated each of the solution resistance, charge transfer conductance, and double layer capacitance as non-constant phase elements. In some examples, interference unit  142  may be configured to calculate electrical circuit model components based on an electrical circuit model in which the solution resistance is in series with a parallel combination of the double layer capacitance and a charge transfer resistance (e.g., as illustrated in  FIG.  4   ). The charge transfer resistance is proportional to the inverse of the charge transfer conductance. 
     Interference unit  142  is further configured to determine electrical circuit model components, e.g., a charge transfer conductance, a solution resistance, and/or a double layer capacitance based on the measured impedances at fewer than four frequencies. As described below, based on an electrical circuit model such as electrical circuit model  400 , interference unit  142  may determine the charge transfer conductance based on impedance data at a low frequency (e.g., using equation 1 below) and the solution resistance, which interference unit  142  may determine based on impedance data at a high frequency as described below. Interference unit  142  may determine the double layer capacitance based on impedance data at a frequency at which the impedance has a corresponding to phase that is closest to negative 90 degrees (e.g., using equation 2 below), which may be the impedance at the low frequency used to determine the charge transfer conductance. In other words, interference unit  142  may be configured to determine a charge transfer conductance, a solution resistance, and/or a double layer capacitance based on measured impedances at two frequencies, and may use more impedance data (e.g., at other frequencies) to determine such electrical circuit model components, e.g., to reduce uncertainty in the calculated electrical circuit model components. 
     For example, interference unit  142  may be configured to determine the solution resistance based on an impedance value corresponding to a relatively high frequency, e.g., a measured impedance value at a frequency that is greater than 500 Hz, or is at least 1 kilohertz (kHz) and less than or equal to 8 kHz. Interference unit  142  may be configured to determine the charge transfer conductance based on the solution resistance and based on an impedance value of the plurality of impedance values corresponding to a relatively low frequency, e.g., at least 0.1 Hz and less than or equal to 8 kHz, or at least 0.1 Hz and less than or equal to 100 Hz. Interference unit  142  may be configured to determine the double layer capacitance based on the solution resistance, the charge transfer conductance, and based on an impedance value of the plurality of impedance values at which the impedance phase is substantially negative 90 degrees. Interference unit  142  is further configured to determine an amount of electrochemical interference based on the double layer capacitance. 
     In some examples, interference unit  142  is configured to determine changes in electrochemical interference over time. For example, interference unit  142  may be configured to measure a first plurality of impedances at a first time, and determine a first charge transfer conductance and a first solution resistance of the electrochemical cell based on the first plurality of impedances at fewer than four of the corresponding plurality of frequencies, and to determine a first double layer capacitance based on the first solution resistance and charge transfer conductance and on the impedance value of the first plurality of impedance values corresponding to a frequency at which the impedance phase is substantially negative 90 degrees (e.g., negative 50 to 40 degrees). Interference unit  142  may be configured to then measure a second plurality of impedances at a second time, and determine a second charge transfer conductance and a second solution resistance of the electrochemical cell based on the second plurality of impedances at fewer than four of the corresponding plurality of frequencies, and to determine a second double layer capacitance based on the second solution resistance and charge transfer conductance and on the impedance value of the second plurality of impedance values corresponding to a frequency at which the impedance phase is substantially negative 90 degrees. Interference unit  142  may be configured to determine both a first amount of electrochemical interference at the first time based on the first double layer capacitance, and a second amount of electrochemical interference at the second time based on the second double layer capacitance. Interference unit  142  may be configured to further track the amount of electrochemical interference as a function of time, and store the results, e.g., in memory  140 . 
     In some examples, interference unit  142  is further configured to determine a cause of electrochemical interference. For example, interference unit  142  may be configured to determine a Nyquist slope, e.g., based on the measured impedances at the plurality of frequencies, and to determine whether the electrochemical interference is caused by insulin excipients or acetaminophen. Acetaminophen may not cause a change to an electrode of monitoring device  100 , but rather may cause a change in the electrical properties of the solution (e.g., the analyte or interstitial fluid), e.g., similar to glucose. In other words, the presence of both glucose and acetaminophen may be detectable by monitoring device  100 , e.g., via iSig  157 , but glucose and acetaminophen may not be distinguishable from each other based on iSig  157  alone. The cause of electrochemical interference due to acetaminophen may be an electrochemical interference of the analyte, e.g., the interstitial fluid, rather than a change to an electrode of the electrochemical cell of monitoring device  100 . As such, electrochemical interference due to acetaminophen may not be discernable based on changing electrical circuit model components of the electrochemical cell, e.g., the charge transfer conductance, solution resistance, and double layer capacitance. 
     An increased concentration of glucose, e.g., in the interstitial fluid, may cause the Nyquist slope, e.g., determined via EIS data measured by monitoring device  100 , to increase, whereas an increased concentration of acetaminophen may cause the Nyquist slope to decrease. Interference unit  142  may track and compare Nyquist slopes determined from EIS data (e.g., impedances as a plurality of frequencies) measured at different times, and may determine whether an iSig  157  signal, event, spike, change, feature, or the like, is due to acetaminophen based on a Nyquist slope, a change in Nyquist slope over time, and/or a rate of change of Nyquist slope. In some examples, interference unit  142  may be configured to determine that electrochemical interference is caused by acetaminophen based on Nyquist slope, iSig  157 , and a lack of change in the electrical circuit model components (e.g., a lack of charge transfer conductance, solution resistance, and double layer capacitance indicating a lack of a thin film buildup or changes to an electrode). In some examples, interference unit  142  may be configured to determine that electrochemical interference is caused by acetaminophen, insulin excipient, or both, based on any or all of Nyquist slope, Nyquist slope change, rate of Nyquist slope change, iSig  157 , and either a change or lack of change in the electrical circuit model components. 
       FIG.  3 B  is a cross-sectional view of an example medical device  200  including a monitoring device and insulin pump. In the example shown, medical device  200  includes a CGM and an insulin delivery device packaged together such that the electrode of the glucose sensor is placed relatively near an insulin delivery site on the patient. Medical device  200  may inserted into patient  112  a single time and include both insulin delivery and glucose monitoring functionalities, e.g., so that patient  112  doesn&#39;t need to have two different devices inserted, e.g., two different insertions. In the example shown, medical device  200  includes housing  202 , sensing portion  204 , and delivery lumen  206 . 
     Housing  202  may be configured to house a CGM (not shown) and insulin pump (not shown), such that sensing portion  204  and delivery lumen  206  may be inserted into patient  112  and separated laterally by a distance D. 
     Sensing portion  204  may include sensor electrodes  256 ,  258 , and  260 . In the example shown, sensing portion  204  includes three counter electrodes  256 A,  256 B, and  256 C (collectively referred to as “counter electrodes  256 ”), and three working electrodes  260 A,  260 B, and  260 C, (collectively referred to as “working electrodes  260 ”), which may form three glucose sensors, e.g., working-counter electrode pairs providing three separate sensor signals (iSigs). Sensing portion  204  also includes reference electrode  258 . Each of counter electrodes  256 , reference electrode  258 , and working electrodes  260  may be substantially similar to counter electrode  156 , reference electrode  158 , and working electrodes  160  described above with reference to  FIG.  3 A . Sensing portion  204  may be connected to a CGM housed within housing  202 . 
     Delivery lumen  206  may be connected to an infusion set and/or an insulin pump housed within housing  202 , and may be configured to deliver insulin via one or more apertures in fluid communication with a lumen of delivery lumen  206  and inserted within patient  112 . In the example shown, delivery lumen  206  may output insulin at distal end  208 . 
     Insulin excipient concentration may be greatest nearest the insulin delivery site and may decrease as the excipients diffuse within the patient. In some examples, insulin excipients may be deposited on one or more of counter electrodes  256 , reference electrode  258 , and working electrodes  260 , e.g., if D is small enough such that the excipients concentration is high enough near those electrodes, and cause electrochemical interference. 
     In some examples, housing  202  may be configured to have a lateral separation distance D between sensing portion  204  and insulin delivery lumen  206  of  5  millimeters or greater. For example, housing  202  may be configured to have a separation distance D of 10 millimeters, or 11 millimeters, or greater. In some examples, separation distance D between sensing portion  204  and insulin delivery lumen  206  may be less than 5 millimeters. 
     In examples in which D is small enough such that insulin excipients may cause electrochemical interference, medical device  200  may be configured to determine the presence and/or amount of electrochemical interference. Medical device  200  may further be configured to output a signal, e.g., information indicative of the presence and/or amount of electrochemical interference, to another device, based on the determination of the presence and/or amount of electrochemical interference. In some examples, medical device  200  may be further configured to output an alert based on the determination of the presence and/or amount of electrochemical interference, and in some examples another device may be configured to output an alert based on the signal. 
       FIG.  4    is a circuit diagram illustrating an example electrical circuit model  400  of an electrochemical cell of monitoring device  100 . Electrical circuit model  400  includes a resistor  402  approximating solution resistance (Rs), a resistor  404  approximating charge transfer resistance (Rct, e.g., the reciprocal of the charge transfer conductance Yct, namely, 1/Yct), a capacitor  406  approximating double layer capacitance  406  (Cdl), and expression  410  is an analytic expression for the impedance of an electrical current of electrical circuit model  400 . In the example shown, resistor  402  is in series with a parallel combination of resistor  404  and capacitor  406 , e.g., modeling the electrochemical cell as a solution resistance in series with a parallel combination of the double layer capacitance and a charge transfer resistance. 
     As described above, the accuracy of an electrical circuit model in approximating the actual physical structure and materials of electrical components of the electrochemical cell of monitoring device  100  may be sensitive to the choice of electrical circuit model components and their arrangement, and which measured impedance values (e.g., which frequencies and/or frequency ranges) are used in the determination and/or calculation. For example, electrical circuit model  400  approximates the electrical structure of the electrochemical cell as a resistor in series with a parallel combination of another resistor and a capacitor, and without any constant phase elements or a Warburg impedance. In some examples, including additional electrical circuit model components, such as a Warburg impedance or a constant phase element, in an electrical circuit model may result in a different calculation/result of one or more other electrical circuit model components (e.g., the solution resistance, charge transfer resistance, and/or double layer capacitance) as compared with electrical circuit model  400  based on the same electrical parameter measurements (e.g., impedance or EIS data). In some examples, electrical circuit model  400  simplifies determination of electrical circuit model components and improves the accuracy of determination of the presence and amount of electrochemical interference based on the determination of the electrical circuit model components based on measurement of electrical parameters (impedance) of the electrochemical cell. 
     Expression  410  is an example analytic relation between impedance and electrical circuit model components  402 - 406 . In examples described herein, the presence and amount of electrochemical interference is determined based on electrical circuit model components  402 - 406  or changes to electrical circuit model components  402 - 406 , which in turn are determined via measured impedances, e.g., at a first time and a second time. 
     Electrical circuit model components  402 - 406  may be determined, e.g., by processing circuitry such as measurement processor  132  and/or controller  136 , via fewer than four impedance values corresponding to the impedance of the electrochemical circuit at fewer than four frequencies. For example, the solution resistance Rs (e.g., resistor  402 ) may be determined at a measured impedance at a relatively high frequency, e.g., a frequency of at least 1 kilohertz (kHz) and less than or equal to 8 kHz. In some examples, the solution resistance may be determined based on an impedance measured at a frequency higher than 8 kHz. In the example shown, the impedance of electrical circuit model  400  at a relatively high frequency is substantially the solution resistance, e.g., the charge transfer resistance is substantially close to zero at high frequencies and a good approximation of the solution resistance Rs is the real part of the measured impedance. 
     The charge transfer resistance Rct may be determined according to equation 1 below using impedance values at any frequency, where Im(Z) is the imaginary part of the impedance (e.g., the reactance), Re(Z) is the real part of the impedance, and tan phi is Im(Z)/Re(Z). It is often convenient to evaluate Rct at a relatively low frequency. For example, the charge transfer resistance Rct (e.g., resistor  404 ) may be determined at a measured impedance at a relatively low frequency, e.g., a frequency of at least 0.1 hertz (Hz) and less than or equal to 100 Hz. In some examples, the Rct may be determined based on an impedance measured at a frequency less than 0.1 Hz, although it may not be practical to do so, e.g., impedances at lower frequencies may take a prohibitively long time to measure. For example, the impedance of electrical circuit model  400  at low frequencies, e.g., less than 0.1 Hz, is substantially the addition of the solution resistance and the charge transfer resistance, however, it may take greater than 10 seconds to obtain a measurement. For example, the impedance may be measured with a periodic (e.g., often sinusoidal) input current signal, and it is often desirable to measure over several cycles, e.g., 3 or more cycles. A low frequency measurement at low frequencies less than 0.1 Hz may then take 30 seconds or more. 
     
       
         
           
             
               
                 
                   Rct 
                   = 
                   
                     - 
                     
                       
                         R 
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                                     ⁡ 
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                               2 
                             
                           
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     By way of conceptual description, at relatively high frequencies, electrical current follows the path of least resistance through capacitor  406 , and the real part of the impedance is substantially equal to the resistance of resistor  402 . At relatively low frequencies, e.g., approaching a frequency of zero or direct current (DC), electrical current cannot flow through capacitor  406  and follows a path including resistor  404 , and the real part of the impedance at low frequencies is substantially equal to the addition of Rs and Rct. 
     In the example shown, the double layer capacitance Cdl (e.g., capacitor  406 ) may be determined based on the solution resistance Rs, the charge transfer resistance Rct (e.g., as 1/Yct or the reciprocal of the charge transfer conductance), and a measured impedance at a frequency at which the impedance phase is substantially negative 90 degrees. In some examples, the double layer capacitance Cdl may be determined using an impedance measured at any frequency according to equation 2 below, where ω is the angular frequency ω=2*pi*f, and f is the frequency (e.g., in hertz). In some examples, a frequency at which the impedance phase is substantially negative 90 degrees may be a relatively low frequency. For example, a capacitor has a phase of or about −90 degrees (e.g., the voltage lags the current by 90 degrees), and Cdl may be approximated as an ideal capacitor. As illustrated in the Bode plot of  FIG.  5    below, the phase of the example measured impedance approaches −90 degrees as the frequency approaches zero. In some examples, Cdl may be determined using the same impedance used for determining the solution resistance. In other words, the electrical circuit model components Rs, Rct, and Cdl may be determined based on two measured impedance values, namely, the measured impedance corresponding to a relatively low frequency and the measured impedance corresponding to a relatively high frequency. In some examples, Cdl may be determined based on multiple impedance values measured at multiple frequencies. 
     
       
         
           
             
               
                 
                   Cdl 
                   = 
                   
                     
                       1 
                       
                         ω 
                         ⁢ 
                         Rcl 
                       
                     
                     ⁢ 
                     
                       ( 
                       
                         
                           Im 
                           ⁡ 
                           ( 
                           Z 
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                           Rs 
                           - 
                           
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     In some examples, Cdl may be used to determine long-term or permanent changes to monitoring device  100 . For example, processing circuitry may determine whether the performance and/or one or more electrical parameters (e.g., iSig  157 ) have changed based on Cdl. In some examples, processing circuitry may determine an amount of electrochemical interference, short-term or long-term, based on Cdl. An amount of electrochemical interference may include a change to the responsivity of the electrochemical cell of monitoring device  100 , e.g., a bias or offset of iSig  157  relative to an initial condition or state of the electrochemical cell in the absence of electrochemical interference. For example, a change in iSig  157  may be due to electrochemical interference, the presence of an analyte such as glucose (e.g., a normal measurement), or both. Processing circuitry may be configured to determine an amount of signal contribution to iSig  157  from electrochemical interference based on Cdl or a change in Cdl. In some examples, monitoring device  100  and processing circuitry may be configured to determine a first Cdl at a first time based on a first set of measured EIS data (e.g., plurality of impedance measurements at a plurality of frequencies) and to determine a second Cdl at a second time after the first time and based on a second set of measured EIS. Processing circuitry may be configured to determine an amount of electrochemical interference based on a change between the first and second Cdl values from the first time to the second time. 
     In some examples, processing circuitry may be configured to compensate for electrochemical interference based on Cdl, e.g., to determine the amount of electrochemical interference and reconfigure configuration parameters of monitoring device  100  so as to determine or read glucose correctly in the presence of electrochemical interference. 
       FIG.  5    is a Bode plot of example measured EIS data of an example monitoring device  100 . In the example shown, plot  502  is the modulus of the impedance and plot  504  is the phase of the impedance. Plot  502  is a log-log plot, that is, the log of the modulus of the impedance is plotted versus the log of frequency, and plot  504  is the phase in degrees plotted versus the log of the frequency. In the example shown, as the frequency increases to relatively high frequencies, e.g., equal to or more than 1 kHz, the phase approaches zero degrees and the modulus approaches Rs. As the frequency decreases to relatively low frequencies, the phase approaches −90 degrees, and the modulus approaches Rs+Rct. In the example shown, the measured data does not include frequencies low enough to such that at the lowest frequency, the modulus of the impedance is substantially equal to Rs+Rct. As described above, Rct of electrical circuit model  400  may be determined based on measured impedances at lower frequencies than the example Bode plot, however, it may be impractical to do so, and equation 1 above may be used to determine Rct based on an impedance measured at any frequency. The lower the frequency of impedance measurement, the more accurate the results for Rct. Due to physical limitations of measurement, equation 1 may be used to estimate the value of Rct if data from sufficiently low frequencies are not available such that the Rs value can simply be subtracted from the impedance magnitude at said low frequency. 
       FIGS.  6 A and  6 B  are a Nyquist plots of examples of measured EIS data. The example Nyquist plots  602  and  604  of  FIG.  6 A  illustrate electrochemical interference caused by acetaminophen, and the example Nyquist plots  606  and  608  of  FIG.  6 B  illustrate electrochemical interference caused by insulin excipients. In each of the plots  602 - 608  illustrated in  FIGS.  6 A and  6 B , the EIS data is plotted as the imaginary part of the impedance versus the real part of the impedance for a plurality of impedances at a plurality of frequencies. The frequencies increase for each datapoint shown as the datapoints increase in both real and imaginary magnitude. 
     In the examples shown in  FIG.  6 A , electrochemical interference caused by acetaminophen causes an increase in the slope of the Nyquist plot of the EIS data relative to EIS data without interference. For example, Nyquist plot  602  is a plot of EIS data without electrochemical interference, and Nyquist plot  604  is a plot of the EIS data with electrochemical interference caused by acetaminophen, e.g., acetaminophen is added to a solution (e.g., such as interstitial fluid) before or while EIS data corresponding to plot  604  is measured. As illustrated by directional arrow  612 , the presence of acetaminophen causes the Nyquist plot of the EIS data to increase in slope from the initial condition without interference (e.g., Nyquist plot  602 ) to an interference condition (e.g., Nyquist plot  604 ). 
     In the examples shown in  FIG.  6 B , electrochemical interference caused by insulin excipients causes a decrease in the slope of the Nyquist plot of the EIS data relative to EIS data without interference. As illustrated in  FIG.  6 B , Nyquist plot  606  is a plot of EIS data without electrochemical interference, and Nyquist plot  608  is a plot of the EIS data with electrochemical interference caused by insulin excipients, e.g., an insulin dose/bolus including insulin and insulin excipients is added to a solution (e.g., such as interstitial fluid) before or while EIS data corresponding to plot  608  is measured. In some examples, the EIS data corresponding to plots  602  and  606  may be the same EIS data, and plots  602  and  606  may be same. As illustrated by directional arrow  614 , the presence of insulin excipients causes the Nyquist plot of the EIS data to decrease in slope from the initial condition without interference (e.g., Nyquist plot  606 ) to an interference condition (e.g., Nyquist plot  608 ). 
     In the examples shown, electrochemical interference caused by acetaminophen or insulin excipients are distinguishable from each other based on Nyquist slope. In the examples shown, electrochemical interference caused by acetaminophen or insulin excipients cause an opposite effect on the Nyquist slope of EIS data, and processing circuitry may determine whether electrochemical interference is caused by acetaminophen or insulin excipients based on Nyquist slope of measured EIS data, e.g., relative to a known or periodically audited non-interference measured EIS data. 
       FIGS.  7 A- 7 C  illustrate the buildup of a thin film on an electrode of an electrochemical cell due to insulin excipients, and are described concurrently below.  FIG.  7 A  is a cross-sectional view of a portion of an example electrochemical cell in an initial state,  FIG.  7 B  is a cross-sectional view of a portion of an example electrochemical cell in an interference state,  FIG.  7 C  is a cross-sectional view of a portion of an example electrochemical cell in a new state. In the examples shown, the new state illustrated in  FIG.  7 C  may be a persistent, long-term, or permanent new state of the electrochemical cell. 
     In the example shown, the electrochemical cell of monitoring device  100  is in an initial state, and has a particular charge transfer resistance (and charge transfer conductance) and a particular double layer capacitance which may be approximated by the electrical circuit model components  404 ,  406 , namely, charge transfer resistance resistor  404  and double layer capacitance capacitor  406 . In operation without electrochemical interference, the electrochemical cell outputs iSig  157  in response to the presence and/or amount of an analyte within interstitial fluid  170 , e.g., glucose. In the example shown, interstitial fluid  170  comprises mostly water, e.g., water molecules  172 . In the example shown, iSig  157  (not shown in  FIG.  7 A ) or changes to iSig  157  may be proportional to an amount of glucose present or changes to the amount of glucose present in interstitial fluid  170 . 
     When a bolus of insulin is provided to the patient, e.g., via insulin pump  116 , interstitial fluid  170  may contain insulin and insulin excipients such as phenol and m-cresol. When these interfering compounds come in contact with sensor electrodes, the bias voltage may cause them to oxidize to phenolic radicals  172  and m-cresolic radicals  174 , as shown in  FIG.  7 B . As illustrated, the presence of phenolic radicals  172  and m-cresolic radicals  174  causes additional charge transfer to transfer to the sensor electrodes, which causes the charge transfer resistance  404  to reduce, the double layer capacitance  406  to increase, and iSig  157  to increase. Device  130  may sense iSig  157 . In some examples, as insulin causes patient  112  to absorb the glucose, the glucose concentration within interstitial fluid  170  decreases, causing iSig  157  to decrease. However, the insulin excipients cause iSig  157  to increase (e.g., the electrochemical interference with the measurement of the analyte of interest). After a time, the phenolic radicals  172  and m-cresolic radicals  174  may electropolymerize and deposit on electrode  156  as illustrated in  FIG.  7 C , and/or on electrode  160  (not shown), and build up a thin film  180 . Thin film  180  may change the electrical responsivity of the electrochemical cell. As illustrated in  FIG.  7 C , thin film  180  may cause the charge transfer resistance Rct of the electrochemical cell to increase, and the double layer capacitance of the electrochemical cell to decrease, changing the responsivity of the electrochemical cell to an analyte within solution  170 . Namely, for the same concentration of an analyte, such as glucose, within solution  170 , the signal response iSig  157  of the electrochemical cell including thin film  180  as illustrated in  FIG.  7 C  will be less than the signal response iSig  157  of the electrochemical cell without thin film  180  as illustrated in  FIG.  7 A . In other words, the insulin excipients can cause both short term effects due to oxidation, and long term effects due to depositing as a thin film  180 , which can change the long-term or permanent electrical configuration of the electrochemical cell, e.g., the insulin excipients cause long-term electrochemical interference illustrated in  FIG.  7 C , and insulin excipients in solution  170  cause short-term electrochemical interference as illustrated in  FIG.  7 B , e.g., while the insulin excipients remain in solution. 
       FIG.  8    is a flowchart illustrating an example method of determining electrochemical interference of an electrochemical cell. Although the example technique of  FIG.  8    is described with respect to system  110 , monitoring device  100 , and sensor electronics device  130  of  FIGS.  1  and  2   , the example technique of  FIG.  8    may be performed with any type of monitoring device and/or glucose sensor, e.g., including processing circuitry such as measurement processor  132  and/or controller  136  configured to execute the technique. In some examples, the example technique of  FIG.  8    may be performed by processing circuitry (e.g., measurement processor  132 ), configured to execute instructions stored in memory (e.g., memory  140 ), such as interference detection unit  142 . 
     Measurement processor  132  monitors an electrical current that is proportional to an impedance of an electrochemical cell of monitoring device  100  ( 802 ). For example, measurement processor  132  may monitor iSig  157 . Measurement processor  132  determines whether the electrical current satisfies a threshold, and measures a plurality of impedances of the electrochemical cell at a plurality of frequencies responsive to the electrical current satisfying the threshold ( 804 ). For example, measurement processor  132  may compare iSig  157  to an electrical current threshold stored in memory  140 , and measurement processor may cause controller  136  to measure EIS data. 
     Measurement processor  132  determines a charge transfer conductance and a solution resistance based on the plurality of impedances at fewer than four of the corresponding plurality of frequencies ( 806 ). For example, as described above, measurement processor  132  may determine a solution resistance Rs component  402  of electrical circuit model  400  (e.g., as a model of the electrochemical cell of monitoring device  100 ) based on an impedance at a relatively high frequency, e.g., a frequency of at least 500 Hz, and the frequency may additionally be less than or equal to 8 kHz. Measurement processor  132  may determine a charge transfer conductance by determining its reciprocal, e.g., a charge transfer resistance Rct component  404  of electrical circuit model  400  based on Rs and an impedance at a relatively low frequency, e.g., a frequency less than or equal to 100 Hz. In some examples, measurement processor  132  may determine Rct based on Rs and a frequency that is additionally equal to or more than 0.1 Hz, e.g., in order to obtain an impedance value at a low enough frequency over a relatively short time with use of equation 1. 
     In some example, measurement processor  132  may also determine a Nyquist slope, e.g., based on the measured EIS data at ( 806 ). In other examples, measurement processor  132  may also determine the Nyquist slope after determining the presence of electrochemical interference, e.g., after ( 808 ) below. 
     Measurement processor  132  determines the presence of electrochemical interference based on the solution resistance and the charge transfer conductance ( 808 ). For example, measurement processor  132  may determine that electrochemical interference is present based on a change to the solution resistance Rs and/or charge transfer resistance Rct, e.g., by comparison to previously measured Rs, Rct values, or by comparison to a predetermined threshold Rs and/or Rct that may be stored in memory  140 . In some examples, measurement processor  132  may determine the presence of electrochemical interference based on a rate of change of Rs and/or Rct. For example, if measurement processor  132  determines particular values for Rs and Rct based on the currently measured EIS data and those values, or changes to those values from previous values determined via previous EIS data do not satisfy a threshold, measurement processor  132  and may determine the presence of electrochemical interference based on a rate of change of Rs and/or Rct over time. 
     If measurement processor  132  determines that electrochemical interference is not present, or has not changed, at ( 808 ), measurement processor  132  may update any signal compensation information or configuration information of monitoring device  100  based on the currently measured EIS data and/or any determined quantities (such as Rs and Rct) at branch ( 810 ). The method may then proceed to ( 800 ) with measurement processor  132  continuing and/or resuming monitoring of the electrical current that is proportional to an impedance of the electrochemical cell. 
     If measurement processor  132  determines that electrochemical interference is present, or has changed, at ( 808 ), measurement processor  132  may output a signal ( 812 ). For example, measurement processor  132  may cause monitoring device to output a signal to patient device  124 . Patient device  124  may be configured the receive the signal, and based on the signal, output an audible alert sound, output a visual alert indicator (e.g., such as activating or causing an LED to illuminate and/or flash), output information to a user interface, output a message to one or more device, and the like. In some examples, measurement processor  132  output a signal and monitoring device  100 , medical device  200 , or any other suitable device, may be configured to receive the signal, determine whether to cause an alert to be output based on the signal, and to output an audible alert sound, output a visual alert indicator, output information to a user interface, output a message to one or more device, and the like. In some examples, the signal may comprise information indicative of the presence and/or amount of electrochemical interference. 
     Measurement processor  132  determines a cause of the electrochemical interference ( 814 ). For example, measurement processor  132  may determine a Nyquist slope based on the measured EIS data and compare the slope, or a change or rate of change of the slope, with previously determined Nyquist slopes determined based on previously measured EIS data, or with a Nyquist slope threshold. Measurement processor  132  may determine that electrochemical interference is caused by acetaminophen based on determining an increased Nyquist slope ( 814 ), and measurement processor  132  may determine that electrochemical interference is caused by insulin excipients based on determining a decreased Nyquist slope ( 816 ). 
     Additionally, measurement processor  132  may determine an amount of electrochemical interference at ( 814 ). For example, measurement processor  132  may determine a double layer capacitance Cdl component  406  of the electrical circuit model  400  based on the solution resistance Rs, the charge transfer conductance Rct, and on an impedance value of the plurality of impedance values (e.g., the EIS data) corresponding to a frequency at which the impedance phase is substantially negative 90 degrees. In some examples, measurement processor  132  may determine an amount of electrochemical interference based on a change or rate of change of Cdl, e.g., based on Cdl values determined based on EIS data measured at different times. For example, measurement processor  132  may wait for a period time, cause controller  136  to measure a second set of EIS data, determine a second set of Rs, Rct, and Cdl values as described above, and determine an amount of electrochemical interference based on first and second double layer capacitance values. 
     If measurement processor  132  determines the cause of the electrochemical interference to be acetaminophen, the method may proceed to ( 804 ) and measurement processor  132  may measure a new plurality of impedances, e.g., a new EIS data set. For example, measurement processor  132  may operate in a loop between ( 804 ) and ( 814 ) until the acetaminophen concentration reduces such that it no longer causes interference. Measurement processor  132  may then determine that electrochemical interference is not present at ( 808 ) and continue at branch ( 810 ) as described above. 
     If measurement processor  132  determines the cause of the electrochemical interference to be insulin excipients, measurement processor  132  may determine and log or store a duration of the electrochemical interference ( 816 ). Additionally, measurement processor  132  may determine that the electrochemical interference is long-term, and determine compensation for the electrochemical interference, e.g., compensation for iSig  157  or the threshold comparator at ( 804 ), and/or electrical circuit model components Rs, Rct, Cdl, or any other configuration parameters of monitoring device  100 . The method may then proceed to ( 804 ) and measurement processor  132  may measure a new plurality of impedances, e.g., a new EIS data set. For example, measurement processor  132  may operate in a loop between ( 804 ) and ( 816 ) until the insulin excipient concentration reduces such that it no longer causes interference, or until measurement processor  132  determines that long-term electrochemical interference is compensated for. For example, measurement processor  132  may implement the compensation at ( 804 ) such that a different iSig  157  no longer satisfies the threshold, or at ( 808 ) via electrical circuit model components such measurement processor  132  determines electrochemical interference is no longer present (e.g., via determining that it is compensated for), and the method may continue at branch ( 810 ) as described above. 
     Other illustrative examples of the disclosure are described below. 
     Example 1: A method includes monitoring, via a device including an electrochemical cell, an electrical current that is proportional to an impedance of the electrochemical cell; responsive to determining that the electrical current satisfies a threshold, measuring, via the device, a plurality of impedances of the electrochemical cell corresponding to a plurality of frequencies; determining a charge transfer conductance and a solution resistance based on the plurality of impedances at fewer than four of the corresponding plurality of frequencies; determining the presence of electrochemical interference based on the solution resistance and the charge transfer conductance; and outputting an alert based on the determination of the presence of electrochemical interference. 
     Example 2: The method of example 1, wherein determining the solution resistance comprises determining the solution resistance based on an impedance value of the plurality of impedance values corresponding to a relatively high frequency. 
     Example 3: The method of example 2, wherein the relatively high frequency comprises a frequency of at least 1 kilohertz (kHz) and less than or equal to 8 kHz. 
     Example 4: The method of any one of examples 1 through 3, wherein determining the charge transfer conductance comprises determining the charge transfer conductance based on the solution resistance and based on an impedance value of the plurality of impedance values corresponding to a relatively low frequency. 
     Example 5: The method of example 4, wherein the relatively low frequency comprises a frequency of at least 0.1 hertz (Hz) and less than or equal to 100 Hz. 
     Example 6: The method of any one of examples 1 through 5, further includes determining a double layer capacitance based on the solution resistance, the charge transfer conductance, and on an impedance value of the plurality of impedance values corresponding to a frequency at which the impedance phase is substantially negative 90 degrees. 
     Example 7: The method of example 6, further comprising determining an amount of electrochemical interference based on the double layer capacitance. 
     Example 8: The method of example 7, wherein the plurality of impedances corresponding to a plurality of frequencies is a first plurality of impedances measured at a first time, wherein the charge transfer conductance is a first charge transfer conductance, wherein the solution resistance is a first solution resistance, where the double layer capacitance is a first double layer capacitance, wherein determining the amount of electrochemical interference comprises: measuring, via the device, a second plurality of impedances of the electrochemical cell corresponding to the plurality of frequencies at a second time; and determining a second charge transfer conductance and a second solution resistance of the electrochemical cell based on the second plurality of impedances at fewer than four of the corresponding plurality of frequencies; determining a second double layer capacitance based on the second solution resistance, the second charge transfer conductance, and on the impedance value of the second plurality of impedance values corresponding to a frequency at which the impedance phase is substantially negative 90 degrees; and determining the amount of electrochemical interference based on the first double layer capacitance and the second double layer capacitance. 
     Example 9: The method of any one of examples 1 through 8, further includes determining a Nyquist slope; and determining whether the electrochemical interference is caused by at least one insulin excipient or acetaminophen based on the Nyquist slope. 
     Example 10: A device includes a glucose monitor; a memory; and one or more processors implemented in circuitry and in communication with the memory, the one or more processors configured to: monitor an electrical current that is proportional to an impedance of the glucose monitor; responsive to determining that the electrical current satisfies a threshold, receive one or more measurements of a plurality of impedances of the glucose monitor corresponding to a plurality of frequencies; determine a charge transfer conductance and a solution resistance of the glucose monitor based on the plurality of impedances at fewer than four of the corresponding plurality of frequencies; determine the presence of electrochemical interference based on the charge transfer conductance and the solution resistance; and output an alert based on the determination of the presence of electrochemical interference. 
     Example 11: The device of example 10, wherein the one or more processors are further configured to determine the solution resistance based on an impedance value of the plurality of impedance values corresponding to a relatively high frequency. 
     Example 12: The device of example 11, wherein the relatively high frequency comprises a frequency of at least 1 kilohertz (kHz) and less than or equal to 8 kHz. 
     Example 13: The device of any one of examples 10 through 12, wherein the one or more processors are further configured to determine the charge transfer conductance based on the solution resistance and based on an impedance value of the plurality of impedance values corresponding to a relatively low frequency. 
     Example 14: The device of example 13, wherein the relatively low frequency comprises a frequency of at least 0.1 hertz (Hz) and less than or equal to 100 Hz. 
     Example 15: The device of any one of examples 10 through 14, wherein the one or more processors are further configured to: determine a double layer capacitance based on the solution resistance, the charge transfer conductance, and on an impedance value of the plurality of impedance values corresponding to a frequency at which the impedance phase is substantially negative 90 degrees. 
     Example 16: The device of example 15, wherein the one or more processors are further configured to determine an amount of electrochemical interference based on the double layer capacitance. 
     Example 15: The device of example 16, wherein the plurality of impedances corresponding to a plurality of frequencies is a first plurality of impedances measured at a first time, wherein the charge transfer conductance is a first charge transfer conductance, wherein the solution resistance is a first solution resistance, where the double layer capacitance is a first double layer capacitance, wherein the one or more processors are further configured to: receive one or more measurements of a second plurality of impedances of the electrochemical cell corresponding to the plurality of frequencies at a second time; determine a second charge transfer conductance and a second solution resistance of the electrochemical cell based on the second plurality of impedances at fewer than four of the corresponding plurality of frequencies; determine a second double layer capacitance based on the second solution resistance, the second charge transfer conductance, and on the impedance value of the second plurality of impedance values corresponding to a frequency at which the impedance phase is substantially negative 90 degrees; and determine the amount of electrochemical interference based on the first double layer capacitance and the second double layer capacitance. 
     Example 18: The device of any one of examples 10 through 17, wherein the one or more processors are further configured to: determine a Nyquist slope; and determine whether the electrochemical interference is caused by at least one insulin excipient or acetaminophen based on the Nyquist slope. 
     Example 19: A non-transitory computer-readable storage medium having stored thereon instructions that, when executed, configure a processor to: monitor, via a device including an electrochemical cell, an electrical current that is proportional to an impedance of the electrochemical cell; responsive to determining that the electrical current satisfies a threshold, receive one or more measurements from the device of a plurality of impedances of the electrochemical cell corresponding to a plurality of frequencies; determine a charge transfer conductance and a solution resistance of the electrochemical cell based on the plurality of impedances at fewer than four of the corresponding plurality of frequencies; determine the presence of electrochemical interference based on the charge transfer conductance and the solution resistance; and output an alert based on the determination of the presence of electrochemical interference. 
     Example 20: The non-transitory computer-readable storage medium of example 19 having stored thereon further instructions that, when executed, configure a processor to: determine the solution resistance based on an impedance value of the plurality of impedance values corresponding to a relatively high frequency; and determine the charge transfer conductance based on the solution resistance and based on an impedance value of the plurality of impedance values corresponding to a relatively low frequency. 
     The techniques described in this disclosure may be implemented, at least in part, in hardware, software, firmware or any combination thereof. For example, various aspects of the described techniques may be implemented within one or more processors, including one or more microprocessors, digital signal processors (DSPs), application specific integrated circuits (ASICs), field programmable gate arrays (FPGAs), or any other equivalent integrated or discrete logic circuitry, as well as any combinations of such components. The term “processor” or “processing circuitry” may generally refer to any of the foregoing logic circuitry, alone or in combination with other logic circuitry, or any other equivalent circuitry. A control unit comprising hardware may also perform one or more of the techniques of this disclosure. 
     Such hardware, software, and firmware may be implemented within the same device or within separate devices to support the various operations and functions described in this disclosure. In addition, any of the described units, modules or components may be implemented together or separately as discrete but interoperable logic devices. Depiction of different features as modules or units is intended to highlight different functional aspects and does not necessarily imply that such modules or units must be realized by separate hardware or software components. Rather, functionality associated with one or more modules or units may be performed by separate hardware or software components, or integrated within common or separate hardware or software components. 
     The techniques described in this disclosure may also be embodied or encoded in a computer-readable medium, such as a computer-readable storage medium, containing instructions. Instructions embedded or encoded in a computer-readable medium may cause a programmable processor, or other processor, to perform the method, e.g., when the instructions are executed. Computer-readable media may include non-transitory computer-readable storage media and transient communication media. Computer readable storage media, which is tangible and non-transitory, may include random access memory (RAM), read only memory (ROM), programmable read only memory (PROM), erasable programmable read only memory (EPROM), electronically erasable programmable read only memory (EEPROM), flash memory, a hard disk, a CD-ROM, a floppy disk, a cassette, magnetic media, optical media, or other computer-readable storage media. It should be understood that the term “computer-readable storage media” refers to physical storage media, and not signals, carrier waves, or other transient media. 
     Various examples have been described. These and other examples are within the scope of the following claims.