Sensor array system and method for detecting multiple test substances

Abstract

In certain physiological states, multiple test substances may experience regulated abnormalities individually or simultaneously. Therefore, it can be advantageous to analyze multiple test substances simultaneously using a test substance sensor capable of detecting multiple test substances. [Solution] A test substance sensor capable of detecting multiple test substances may include a first working electrode and a second working electrode, a test substance-sensitive active region placed on each working electrode, and a reference electrode and a counter electrode. A test substance sensor including multiple working electrodes but not including a reference electrode and a counter electrode can be used with another sensor including a counter electrode and a reference electrode to share these electrodes.

Description

Background Art

[0001] The detection of various analytes within an individual can sometimes be important for monitoring their health status and well-being. Deviations from normal analyte levels can often indicate underlying physiological conditions such as metabolic states or diseases, or exposure to certain environmental conditions. While a single analyte may cause dysregulation alone for a given physiological state, sometimes multiple analytes may simultaneously exhibit dysregulation due to the same physiological state or associated (related) physiological states. When multiple analytes simultaneously exhibit dysregulation, the degree of dysregulation may vary for each analyte. For these reasons, it may be necessary to monitor each analyte to obtain a sufficient assessment of an individual's health.

[0002] Regular ex vivo analyte monitoring using collected body fluids can be sufficient for observing a given physiological state in many individuals. However, ex vivo analyte monitoring can be inconvenient or painful for some individuals, particularly when body fluid collection or sampling is required relatively frequently (e.g., several times a day). Continuous analyte monitoring using implanted in vivo analyte sensors can be a more desirable approach for individuals with severe analyte dysregulation and / or individuals with rapidly fluctuating analyte levels, but can also be similarly beneficial to other individuals due to the convenience it offers. Continuous analyte monitoring may enable an individual or a physician to proactively address abnormal analyte levels before they lead to more significant health outcomes such as organ damage or failure. Subcutaneous or interstitial or dermal analyte sensors can often provide sufficient measurement accuracy for this purpose while minimizing user discomfort.

[0003] If the appropriate detection chemistry is identified, many test substances become interesting targets for physiological analysis. For this purpose, current-measuring sensors configured to analyze glucose in vivo have been developed and improved in recent years, proving useful for health monitoring in individuals with diabetes. Other test substances that commonly cause dysregulation in conjunction with glucose in individuals with diabetes include, for example, lactate, oxygen, pH, A1c, and ketones. While sensors configured to detect test substances that commonly cause dysregulation in combination with glucose are known, they are not yet sufficiently improved.

[0004] In vivo chemoassay sensors are typically configured to analyze a single chemoassay to provide a specific analysis, and often employ enzymes to provide high specificity for a given chemoassay. Due to this chemoassay specificity, current in vivo chemoassay sensors configured to analyze glucose are generally not effective for analyzing other chemoassays that frequently cause dysregulation in combination with glucose, or other chemoassays resulting from dysregulation of glucose levels. Optimally, current chemoassay monitoring techniques require individuals with diabetes to wear two different in vivo chemoassay sensors, one configured to analyze glucose and the other to analyze another chemoassay of interest. Chemoassay monitoring techniques employing multiple in vivo chemoassay sensors can be very inconvenient for the user. Furthermore, when multiple in vivo chemoassay sensors are used for chemoassay monitoring, there is an additional equipment cost burden, as well as an increased statistical probability that at least one of the individual's in vivo chemoassay sensors will fail.

[0005] Individuals with diabetes are often particularly susceptible to complications, either due to improper management of insulin levels or as a result of having diabetes for extended periods, even with proper management. For example, diabetic neuropathy can lead to eventual renal failure due to hyperglycemia. Diabetic neuropathy is a leading cause of renal failure in the United States, experienced by a significant number of individuals with diabetes within the first 10–20 years of the disease. Diagnostic tests to assess renal function currently rely on measuring elevated creatinine levels in blood and / or urine samples. While it is desirable to detect potential renal failure as early as possible, current diagnostic testing methods typically require long-term monitoring (months to years) to confirm whether creatinine levels are persistently elevated or trending upward over time. The low frequency of current creatinine monitoring may increase the risk of renal failure if abnormal renal function is not detected early enough.

[0006] Ethanol can also play an important role in diabetes management. Where used herein, the term “ethanol” refers to the compound C2H6O, a component of alcoholic beverages. Unless otherwise specified, the terms “alcohol” and “ethanol” are used interchangeably herein. Glucose homeostasis, which maintains blood glucose levels through a balance between insulin and glucagon, is crucial for the function of the central nervous system and various cellular systems, which depend on such homeostasis for proper metabolism. Fluctuations in glucose homeostasis (i.e., hyperglycemia, which is excess blood glucose, and hypoglycemia, which is insufficient blood glucose) can impair organ and cellular function, particularly by interfering with the production, control, and function of insulin and glucose. For example, alcohol can impair glucose production in the liver, and therefore its release, increasing the risk of moderate or severe hypoglycemia. Alcohol can also reduce the effects of insulin, thus increasing the risk of moderate or severe hyperglycemia. Therefore, the relationship between alcohol and glucose may not directly correlate with each other, is personal in many respects (e.g., genetic predisposition), and depends at least on exposure time and concentration. Furthermore, alcohol can impair an individual's ability to recognize or understand symptoms associated with hyperglycemia and hypoglycemia, thus exacerbating health risks to the individual. Understanding alcohol-induced changes in blood glucose control in individuals with diabetes, where glucose levels are spontaneously uncontrolled or lack homeostasis without intervention, can be extremely beneficial.

[0007] Ketones are another class of test substances that commonly cause malregulation in individuals with diabetes. Since glucose and ketone concentrations may not directly correlate with each other in individuals with diabetes who also exhibit ketoacidosis (ketone dysregulation), monitoring both test substances simultaneously can be beneficial and potentially lead to improved health outcomes. In addition to providing health benefits to individuals with diabetes, test substance sensors can be useful for other individuals who wish to monitor their ketone levels, such as those practicing a ketogenic diet. A ketogenic diet is not only beneficial for promoting weight loss but can also help epilepsy patients manage their condition. Simultaneous glucose monitoring during ketogenic diet monitoring may yield relevant benefits.

[0008] Lactate is another test substance whose in vivo levels can change in response to numerous environmental or physiological factors, including, for example, diet, stress, exercise, sepsis or septic shock, infection, hypoxia, and the presence of cancerous tissue. In cases of chronic lactic acid degeneration (e.g., disease), lactate levels can change slowly and can therefore be easily quantified using conventional blood sampling and laboratory measurements. Other lactic acid degenerations may be transient in nature, in which case lactate levels can fluctuate very rapidly and irregularly. Conventional laboratory measurements may be unsuitable for determining lactate levels in such cases because lactate levels may change many times between consecutive measurements, potentially missing an abnormal lactate level and leading to a potentially inaccurate diagnosis. When lactate levels fluctuate rapidly, it is desirable to continuously measure an individual's lactate levels, for example, by using an implantable in vivo lactate sensor. Continuous lactate monitoring can also be beneficial for individuals whose lactate levels change slowly over time. For example, continuous lactate monitoring can avoid the discomfort and expense associated with taking multiple blood samples to analyze lactate levels. [Brief explanation of the drawing]

[0009] The following drawings are included to illustrate certain aspects of the disclosure and should not be viewed as the only embodiments. Numerous modifications, substitutions, combinations, and equivalents in shape and function are possible without departing from the scope of the disclosure. [Figure 1] A diagram of an exemplary detection system, which may include the test substance sensor of this disclosure, is shown. [Figure 2A] A cross-sectional view of an exemplary two-electrode sensor configuration for a substance being tested, having a single working electrode, is shown. [Figure 2B] A cross-sectional view of an exemplary two-electrode sensor configuration for a substance being tested, having a single working electrode, is shown. [Figure 3A] Plan views of both sides of an exemplary test substance sensor having a single working electrode are shown. [Figure 3B] An illustrative perspective view of a connector is shown. [Figure 3C] A cross-sectional view of an exemplary three-electrode sensor configuration for a substance being tested, having a single working electrode, is shown. [Figure 4A] The images show plan views of both sides of an exemplary test substance sensor configuration having two working electrodes. [Figure 4B] An illustrative perspective view of a connector is shown. [Figure 5A] An exploded view of an exemplary test substance sensor configuration having two working electrodes, a counter electrode, and a reference electrode is shown. [Figure 5B] A cross-sectional view of an exemplary test substance sensor configuration having two working electrodes, a counter electrode, and a reference electrode is shown. [Figure 5C] A cross-sectional view of an exemplary test substance sensor configuration having two working electrodes, a counter electrode, and a reference electrode is shown. [Figure 5D] A cross-sectional view of an exemplary test substance sensor configuration having two working electrodes, a counter electrode, and a reference electrode is shown. [Figure 5E] The images show the electrodes before and after the application of the two films. [Figure 5F] The images show the electrodes before and after the application of the two films. [Figure 5G]This shows a top view of a sensor for a substance to be tested, which has a first working electrode and a second working electrode installed on and in contact with the same surface of the substrate. [Figure 5H] This shows a top view of a sensor for a substance being tested, which has a first working electrode, a second working electrode, a counter electrode, and a reference electrode, all positioned on and in contact with the same surface of the substrate. [Figure 6A] This shows a cross-sectional view of a test substance sensor having a sensitive active region placed on a separated working electrode. [Figure 6B] This shows a cross-sectional view of a test substance sensor having different sensitive active regions and membranes, placed on a separated working electrode. [Figure 6C] This shows a cross-sectional view of a test substance sensor having different sensitive active regions and films, mounted on separate working electrodes on the same side of the substrate. [Figure 7A] The image shows electrodes coated with different films. [Figure 7B] The image shows electrodes coated with different films. [Figure 7C] The image shows electrodes coated with different films. [Figure 7D] Exemplary plots of the current response of eight test substance sensors, each containing glucose-sensitive and ketone-sensitive active regions positioned on separate working electrodes, after exposure to 30 mM glucose and 10 mM ketone for two weeks at 37°C are shown. [Figure 8A] This shows the response of electrodes, including glucose-sensitive and ketone-sensitive regions, when exposed to changing glucose and ketone concentrations. [Figure 8B] Figures 7A and 7B show exemplary plots of the current response of electrodes after exposure to 30 mM glucose and 10 mM ketone at 37°C for two weeks. [Figure 8C] Exemplary plots of the average current response for multiple glucose concentrations are shown. [Figure 8D] Exemplary plots of average current responses for multiple ketone concentrations are shown. [Figure 9A]Shows the reaction of an electrode including a glucose-sensitive region and a lactate-sensitive region when exposed to varying glucose and lactate concentrations. [Figure 9B] Shows the reaction of an electrode including a glucose-sensitive region and a lactate-sensitive region when exposed to 30 mM glucose and 5 mM lactate concentrations at 37 °C for 2 weeks. [Figure 9C] Shows an exemplary plot of the average current response to multiple glucose concentrations. [Figure 9D] Shows an exemplary plot of the average current response to multiple lactate concentrations. [Figure 10A] It is a block diagram showing an exemplary embodiment of a sensor control device. [Figure 10B] It is a block diagram showing an exemplary embodiment of a sensor control device. [Figure 10C] It is a block diagram showing an exemplary embodiment of a sensor control device. [Figure 10D] It is a block diagram showing an exemplary embodiment of a sensor control device. [Figure 11] Shows an exploded view of a sensor housing that houses two sensors. [Figure 12] Shows a cross-sectional view of an exemplary analyte sensor configuration having four working electrodes. [Figure 13A] Shows an exploded view of an on-body unit having two sensor housings connected by printed circuit lines. [Figure 13B] Shows an exploded view of an on-body unit having two sensor housings connected by a flex circuit connection. [Figure 13C] Shows a perspective view of an on-body unit having three connected sensor housings.

BEST MODE FOR CARRYING OUT THE INVENTION

[0010] This disclosure generally describes a test substance sensor that employs multiple enzymes to detect multiple test substances, and more specifically, a test substance sensor that employs multiple working electrodes to detect multiple test substances such as glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactic acid. Multiple sensors may also be employed to analyze multiple test substances. In one embodiment, the sensor includes at least two working electrodes and a counter / reference electrode. In another embodiment, the test substance detection system may include multiple sensors. The system may include a primary sensor having at least one, optionally at least two, working electrodes, a counter electrode, and a reference electrode. The system may also include a subsensor that includes at least one, optionally at least two, optionally at least three, and optionally at least four working electrodes, but does not include a counter electrode and a reference electrode. The subsensor can share the counter electrode and reference electrode in the primary sensor because it is embedded and mounted near the primary sensor in the user. The subsensor may be housed in the same housing as the primary sensor. Optionally, the subsensor may be mounted in a separate sensor housing located near the primary sensor's sensor housing, so that the primary sensor and subsensor share the same counter electrode and reference electrode. In an alternative embodiment, multiple subsensors may share the counter electrode and reference electrode of the primary sensor.

[0011] As described above, enzyme-based test substance sensors are generally used to monitor a single test substance, such as glucose, due to their habitual specificity for a particular substrate or class of substrates. Other test substances may be monitored similarly, provided that appropriate sensor forms and detection chemistry are identified. Monitoring multiple test substances is difficult because it requires employing a corresponding number of test substance sensors, each independently detecting one of the test substances. In particular, when monitoring using multiple in vivo test substance sensors, this approach can be problematic or undesirable due to the cost of multiple in vivo test substance sensors, the discomfort experienced by the user when wearing multiple sensors, and the increased statistical probability that at least one of the patient's in vivo test substance sensors will fail.

[0012] Glucose-sensitive chemotransmitter sensors are a well-researched and developing field for better managing and supporting the health of individuals with diabetes. Despite the prevalence of complications in individuals with diabetes, sensor chemistry suitable for in vivo monitoring of other chemotransmitter substances that commonly cause dysregulation in combination with glucose lags significantly behind more advanced glucose detection chemistry. For example, in addition to glucose, creatinine, lactate, ketones, and ethanol may all be of particular interest for monitoring in individuals with diabetes.

[0013] This disclosure provides a test substance sensor and sensor system that reacts to at least two test substances. Specifically, this disclosure provides an on-body test substance sensor for continuous or near-continuous in vivo monitoring of levels of at least two test substances. Analysis of at least two test substance levels by the test substance sensor disclosed herein may provide individuals or healthcare professionals with a more accurate, long-term explanation of various conditions than is possible with routine ex vivo laboratory measurements. For example, analyzing creatinine levels in accordance with this disclosure may enable earlier medical intervention, limiting potential kidney damage and improving an individual's overall health outcome.

[0014] This disclosure provides for monitoring at least two substances, such as glucose and another test substance, using one or more in vivo test substance sensors that react to each test substance, and in a particularly beneficial form, a single test substance sensor that reacts to both test substances in vivo may be used. Advantageously and surprisingly, a test substance sensor having sensing capabilities for both glucose and another on a single sensor tail can be manufactured by employing those disclosed herein.

[0015] Before describing the substance sensors of this disclosure in more detail, a brief overview of suitable in vivo substance sensor configurations and sensor systems using those sensors will be provided first to better understand the embodiments of this disclosure. Figure 1 shows a schematic of an exemplary sensing system which may include a substance sensor of this disclosure, in particular a substance sensor capable of monitoring multiple substances. As shown, the sensing system 100 includes a sensor control unit 102 and a reader 120 configured to communicate with each other via a local communication path or link, which may be wired or wireless, unidirectional or bidirectional, and encrypted or unencrypted. According to some embodiments, the reader 120 may constitute an output medium for viewing the substance concentration and warnings or notifications determined by the sensor 104 or its associated processor, as well as for enabling one or more inputs from a user. The reader 120 may be a multipurpose smartphone or a dedicated electronic reader. Although only one reader 120 is shown, there may be multiple reader 120 in some cases. The reader 120 may also communicate with the remote terminal 170 and / or the trusted computer system 180 via communication paths / links 141 and / or 142, respectively, which may be wired or wireless, unidirectional or bidirectional, and encrypted or unencrypted. The reader 120 may also, or instead, communicate with the network 150 (e.g., a cellular network, the internet, or a cloud server) via communication path / link 151. The network 150 may further be connected to communicate with the remote terminal 170 via communication path / link 152 and / or the trusted computer system 180 via communication path / link 153. Alternatively, the sensor 104 may communicate directly with the remote terminal 170 and / or the trusted computer system 180 without the presence of the intervening reader terminal 120.For example, according to some embodiments, such as those described in U.S. Patent Application Publication No. 2011 / 0213225 and its entirety incorporated therein, the sensor 104 may communicate with a remote terminal 170 and / or a trusted computer system 180 via a direct communication link to a network 150. Any suitable electronic communication protocol may be used for each of the communication paths or links, such as Near Field Communication (NFC), Radio Frequency Identification (RFID), Bluetooth® or Bluetooth® Low Energy protocol, Wi-Fi®, etc. According to some embodiments, the remote terminal 170 and / or the trusted computer system 180 may be accessible to individuals other than the primary user who are interested in the user's test substance levels. The reader 120 may include a display 122 and optionally an input component 121. According to some embodiments, the display 122 may include a touchscreen interface.

[0016] The sensor control device 102 includes a sensor housing 103 that houses the circuitry and a power supply for operating the sensor 104. Optionally, the power supply and / or active circuitry may be omitted. A processor (not shown) may be communicatively connected to the sensor 104 with the processor physically installed in the sensor housing 103 or the reader 120. According to some embodiments, the sensor 104 protrudes from the bottom surface of the sensor housing 103 and extends through an adhesive layer 105 adapted to adhere the sensor housing 103 to a skin-like tissue surface.

[0017] Sensor 104 is adapted to be inserted at least partially into tissue of interest, such as the dermis or subcutaneous layer of the skin. Sensor 104 may have a sensor tail of sufficient length to be inserted into a given tissue to a desired depth. The sensor tail may comprise at least one working electrode and a first test substance-sensitive active region positioned thereon. Optionally, a second test substance-sensitive active region may be placed on the sensor tail, further optionally in combination with a second working electrode, to facilitate the detection of the test substance. A counter electrode may be present in combination with at least one working electrode. Specific electrode configurations on the sensor tail are described in more detail below with reference to Figures 2-5 and Figure 11.

[0018] Referring further to Figure 1, the sensor 104 may automatically transfer data to the reader 120. For example, data on the concentration of the substance being tested may be communicated automatically and periodically, for example, at a certain frequency once the data is acquired, or after a certain period of time has elapsed while the data is stored in memory until transmission (e.g., every minute, every 5 minutes, or at other predetermined intervals). In other embodiments, the sensor 104 may communicate with the reader 120 in a non-automatic manner, without following a set schedule. For example, when the sensor electronics are brought within the communication range of the reader 120, data may be communicated from the sensor 104 using RFID technology. The data may remain stored in the sensor 104's memory until it is communicated to the reader 120. Therefore, the user does not have to keep the reader 120 nearby at all times, and can instead upload data at their convenience. In yet another embodiment, a combination of automatic and non-automatic data transfer may be implemented. For example, data transmission may continue automatically until the reader 120 is no longer within the communication range of the sensor 104.

[0019] An introducer may be present temporarily to facilitate the introduction of the sensor 104 into the tissue. In exemplary embodiments, the introducer may comprise a needle or a similar sharp object. It should be understood that other types of introducers, such as a sheath or blade, may be present in alternative embodiments. More specifically, the needle or other introducer may be present temporarily near the sensor 104 before tissue insertion and then withdrawn. While present, the needle or other introducer may facilitate the insertion of the sensor 104 into the tissue by opening an access path for the sensor 104 to follow. For example, according to one or more embodiments, the needle may facilitate penetration of the epidermis as an access path to the dermis, allowing the implantation of the sensor 104 to be performed. Since the needle or other introducer is withdrawn after opening the access path, it does not pose a sharp object hazard. In exemplary embodiments, a suitable needle may be solid or hollow, beveled or non-beveled, and / or round or non-round in cross-section. In more specific embodiments, a suitable needle may have a cross-sectional diameter and / or tip design comparable to that of an acupuncture needle having a cross-sectional diameter of about 250 microns (μm). However, a suitable needle may have a larger or smaller cross-sectional diameter if required for a particular application.

[0020] In some embodiments, the tip of the needle (while present) may be angled over the end of the sensor 104 so that the needle first penetrates the tissue and opens an access passage for the sensor 104. In other exemplary embodiments, the sensor 104 may be located in a lumen or a groove in the needle, and the needle similarly opens an access path for the sensor 104. In either case, the needle is withdrawn after facilitating sensor insertion.

[0021] The substance sensors disclosed herein may feature different types of active regions (e.g., a glucose-active region and a ketone-active region, a lactate-active region, a creatinine-active region, or an ethanol-active region) on a single working electrode or on two or more separate working electrodes. According to various embodiments of this disclosure, as further described herein, the single-working electrode sensor configuration may employ a two-electrode or three-electrode detection motif. Figures 2A–2B show cross-sectional views of exemplary two-electrode substance sensor configurations having a single working electrode that are compatible for use in several embodiments disclosed herein. As shown, the substance sensor 200 comprises a substrate 212 positioned between a working electrode 214 and a pair / reference electrode 216. Alternatively, the working electrode 214 and the pair / reference electrode 216 may be mounted on the same side of the substrate 212 with a dielectric material in between (configuration not shown). Figure 2A shows a single active region 218. Multiple active regions 218a and 218b (i.e., glucose-sensitive active regions and ketone-sensitive active regions) are spaced laterally apart from each other on the surface of the working electrode 214. In the various sensor configurations shown herein, the active regions 218a and 218b may comprise multiple spots or a single spot configured to detect each test substance. The test substance sensor 200 may be operable to analyze glucose and ketones by any of the electrochemical detection techniques of coulometry, amperometry, voltametry, or potentiometry.

[0022] When a single working electrode is present in the substance sensor, a three-electrode sensor configuration may comprise a working electrode, a counter electrode, and a reference electrode (see Figures 2A and 2B). A related two-electrode sensor configuration may comprise a working electrode and a second electrode, the second electrode may function as both a counter electrode and a reference electrode (i.e., a counter / reference electrode). In both the two-electrode and three-electrode sensor configurations, both the first substance-sensitive active region and the second substance-sensitive active region may be located on a single working electrode. In some embodiments, the various electrodes may be at least partially stacked on top of each other (layered) and / or spaced laterally from each other on the sensor tail. A suitable sensor configuration may be substantially planar or substantially cylindrical in shape, with the first and second substance-sensitive active regions spaced laterally on the working electrode. In all sensor configurations disclosed herein, the various electrodes may be electrically insulated from each other by a dielectric material or similar insulator.

[0023] A sensor for a substance being tested, characterized by multiple working electrodes, may similarly include at least one additional electrode. If one additional electrode is present, that one additional electrode may function as the pair / reference electrode for each of the multiple working electrodes. If two additional electrodes are present, one of the additional electrodes may function as the pair electrode for each of the multiple working electrodes, and the other additional electrode may function as the reference electrode for each of the multiple working electrodes.

[0024] A test substance sensor configuration having a single working electrode will be described in further detail below. Figure 2A is a cross-sectional view of an exemplary two-electrode test substance sensor configuration having a single working electrode, which is compatible with use in several embodiments of the disclosure herein. As shown, the test substance sensor 200 comprises a substrate 212 positioned between a working electrode 214 and a pair / reference electrode 216. Alternatively, the working electrode 214 and the pair / reference electrode 216 may be placed on the same side of the substrate 212 with a dielectric material in between (configuration not shown). The active region 218 is positioned on the working electrode 214. As seen in Figure 2B, if multiple active regions are present on a single working electrode 214, the active regions 218a and 218b (e.g., glucose-sensitive active region and ketone-sensitive active region) are spaced laterally apart from each other on the surface of the working electrode 214. In the various sensor configurations described herein, the active regions 218a and 218b may comprise multiple spots or a single spot configured to detect each test substance. The test substance sensor 200 may be operable to analyze glucose and ketones by any of the electrochemical detection techniques of coulometry, current measurement, voltametri, or potentiometric measurement.

[0025] A sensor having a single working electrode and monitoring a single test substance is shown in Figure 3A. Three electrodes are screen-printed on both sides of a substrate (e.g., a PET substrate) with insulating layers in between. As seen in Figure 3C, the test substance sensor 201 comprises a substrate 212 positioned between the working electrode 214 and the counter electrode 217. Alternatively, the working electrode 214 may be placed on the same side of the substrate 212 as the counter electrode 217, with a dielectric material in between (morphology not shown). A reference electrode 216 is electrically insulated from the working electrode 214 by a dielectric layer 219b. Outer dielectric layers 219a and 219c are positioned on the reference electrode 216 and the counter electrode 217. A test substance-specific sensitive active region 218 (e.g., a glucose-sensitive active region, a creatinine-sensitive active region, or a lactate-sensitive active region) may be positioned as at least one layer on at least a portion of the working electrode 214. As further described herein, the test substance-sensitive active region may comprise multiple spots / regions or a single spot / region configured to detect the test substance. A layer of reference material 230 (e.g., Ag / AgCl) may be present on the reference electrode 216, and the location of the layer of reference material 230 is not limited to the location shown in Figure 3C. As seen in Figure 3B, the connector 250 includes three openings 252, resulting in a connection between the working electrode, the counter electrode and the reference electrode by a printed circuit board (not shown).

[0026] A sensor having two working electrodes and monitoring two test substances is shown in Figure 4A. In this embodiment, the four electrodes are screen-printed on both sides of a substrate (e.g., a PET substrate) with an insulating layer to electrically insulate the electrodes. As seen in Figure 4A, the working electrode 214a and the reference electrode 216 are printed on one side, and the working electrode 214b and the counter electrode 217 are printed on the other side. As seen in Figure 4B, the connector 250 includes four openings 252, resulting in a connection by a printed circuit board (not shown) between the two working electrodes, the counter electrode and the reference electrode.

[0027] Figures 5A and 5B show diagrams of exemplary four-electrode substance sensor configurations, which are compatible for use in the disclosure herein. As shown, the substance sensor 201 comprises a substrate 212 positioned between working electrodes 214a and 214b. Alternatively, working electrodes 214a and 214b may be positioned on the same side of the substrate 212 with a dielectric material in between (configuration not shown). Substance-specific sensitive active regions 218a and / or 218b (e.g., glucose-sensitive, creatinine-sensitive, or lactate-sensitive active regions) may be positioned as at least one layer on at least a portion of the working electrodes 214a and / or 214b. As further described herein, the substance-sensitive active regions may comprise multiple spots / regions or a single spot / region configured to detect the substance. A reference electrode may be positioned on either one of the working electrodes 214a or 214b with a separator layer of dielectric material in between. The counter electrode may be placed on the other of the working electrode 214a or 214b with a dielectric material isolation layer in between. For example, as shown in Figure 5B, dielectric layers 219b and 219c separate electrodes 214a, 214b, 216 and 217 from each other and provide electrical insulation. The outer dielectric layers 219a and 219d are placed on the reference electrode 216 and the counter electrode 217.

[0028] Alternatively, at least one of the electrodes 214a, 214b, 216, and 217 may be mounted on the opposite side of the substrate 212. Thus, in some embodiments, electrodes 214a (working electrode) and 216 (counter electrode) may be mounted on the side of the substrate 212 opposite to electrode 217 (reference electrode), and the working electrode 214b may be mounted on the opposite side of the substrate. A layer of reference material 230 (e.g., Ag / AgCl) may be present on the reference electrode 216, and the location of the reference material layer 230 is not limited to the position shown in Figure 5A. As with the sensor 202 shown in Figure 5B, the test substance-sensitive active region 218 in the test substance sensor 202 may comprise multiple spots or a single spot. In addition, the test substance sensor 202 may be operable to analyze the test substance by any of the electrochemical detection techniques of coulometry, current measurement, voltametry, or potentiometric measurement. While Figure 5B shows electrodes 214a, 214b, 216, and 217 all covered by the film 220, it should be understood that in some embodiments, only the working electrodes 214a and 214b may be covered. Furthermore, the thickness of the film 220 on each of electrodes 214a, 214b, 216, and 217 may be the same or different. As in the two-electrode substance sensor configuration (e.g., Figures 2A and 2B), one or both sides of the substance sensor 202 may be covered by the film 220 in the sensor configuration of Figure 5A, or the entire substance sensor 202 may be covered. Therefore, it should be understood that the multi-electrode sensor configurations shown in Figures 5A and 5B are not limited to the embodiments disclosed herein, and alternative electrode and / or layer configurations exist within the scope of this disclosure.

[0029] Referring further to Figure 5B, the membrane 220 optionally covers at least the test substance-sensitive active regions 218a and 218b, and some or all of the working electrode 214a and / or the working electrode 214b and / or the reference electrode 216 and / or the counter electrode 217, or the entirety of the test substance sensor 202 according to some embodiments. One or both sides of the test substance sensor 202 may be covered by the membrane 220. The membrane 220 may comprise one or more polymer membrane materials having the function of restricting the flow of the test substance into the active regions 218 (i.e., the membrane 220 is a substance migration-restricting membrane with some permeability to the test substance being measured). The composition and thickness of the membrane 220 may be modified to facilitate the flow of the desired test substance into the test substance-sensitive active regions 218a and 218b, thereby providing desired signal intensity and stability. The test substance sensor 200 may be operable to analyze the test substance by any of the following electrochemical detection techniques: coulometry, current measurement, voltametry, or potentiometric measurement.

[0030] Figure 5C shows a diagram of an exemplary four-electrode substance sensor configuration, which is compatible with use in the disclosure herein. As shown, the substance sensor 232 comprises a substrate 212 positioned between a working electrode 214a and a counter electrode 216. The working electrodes 214a and 214b are mounted on the same side of the substrate 212 with a dielectric material 219b in between. The counter electrode 216 and the reference electrode 217 are mounted on the opposite side of the substrate 212 with a dielectric material 219c in between. A substance-specific sensitive active region 218a (e.g., a ketone-sensitive active region) may be positioned as at least one layer on at least a portion of the working electrode 214a. A substance-specific sensitive active region 218b (e.g., glucose-sensitive) may be positioned as at least one layer on at least a portion of the working electrode 214b. The active region 218a (e.g., ketone-sensitive active region) may be located closer to edge A than the test substance-specific sensitive active region 218b (e.g., glucose-sensitive). As further described herein, the test substance-sensitive active region may comprise multiple spots / regions or a single spot / region configured to detect the test substance. As shown in Figure 5C, dielectric layers 219b and 219c separate electrodes 214a, 214b, 216, and 217 from each other and provide electrical insulation. Outer insulating layers 219a and 219d are located above the working electrode 214b and the counter electrode 217. A layer of reference material 230 (e.g., Ag / AgCl) (not shown) may be present above the reference electrode 216 or at another suitable location on the sensor. As shown in Figures 5B and 5C, the spectroscopy-sensitive active region 218 in the spectroscopy sensors 202 and 232 may comprise multiple spots or a single spot. In addition, the spectroscopy sensors 202 and 232 may be operable to analyze the spectroscopy by any of the electrochemical detection techniques, such as coulometry, current measurement, voltametry, or potentiometry.

[0031] Figure 5D shows a diagram of an exemplary four-electrode substance sensor configuration, which is compatible with use in the disclosure herein. As shown, the substance sensor 242 comprises a substrate 212 positioned between a working electrode 214a and a counter electrode 216. The working electrodes 214a and 214b are mounted on the same side of the substrate 212 with a dielectric material 219b in between. The counter electrode 216 and the reference electrode 217 are mounted on the opposite side of the substrate 212 with a dielectric material 219c in between. A substance-specific sensitive active region 218a (e.g., a ketone-sensitive active region) may be positioned as at least one layer on at least a portion of the working electrode 214a. A substance-specific sensitive active region 218b (e.g., glucose-sensitive) may be positioned as at least one layer on at least a portion of the working electrode 214b. The active region 218a (e.g., ketone-sensitive active region) may be located closer to edge A than the test substance-specific sensitive active region 218b (e.g., glucose-sensitive). As further described herein, the test substance-sensitive active region may comprise multiple spots / regions or a single spot / region configured to detect the test substance. As shown in Figure 5C, dielectric layers 219b and 219c separate electrodes 214a, 214b, 216, and 217 from each other and provide electrical insulation. The outer dielectric layers 219a and 219d are located above the working electrode 214b and the counter electrode 217. A layer of reference material 230 (e.g., Ag / AgCl) may be present above the reference electrode 216 or at another suitable location on the sensor. As shown in Figures 5B-5D, the test substance-sensitive active regions 218a and 218b in the test substance sensors 202, 232, and 242 may comprise multiple spots or a single spot. In addition, the test substance sensors 202, 232, and 242 may be operable to analyze the test substance by any of the electrochemical detection techniques of coulometry, current measurement, voltametry, or potentiometric measurement.

[0032] The active region 218a may be closer to end A (the distal end of the sensor inserted into the object) than the active region 218b. The length of the active region 218a may be between approximately 0.7 mm and approximately 1.3 mm, or between approximately 0.8 mm and approximately 1.2 mm, or between approximately 0.9 mm and approximately 1.1 mm, or approximately 0.8 mm, or approximately 0.9 mm, or approximately 1.0 mm, or approximately 1.1 mm, or approximately 1.2 mm. The length of the active region 218b may be longer than the length of the active region 218a. The length of the active region 218b may be between approximately 0.7 mm and approximately 1.5 mm, or between approximately 0.8 mm and approximately 1.4 mm, or between approximately 0.9 mm and approximately 1.3 mm, or approximately 0.8 mm, or approximately 0.9 mm, or approximately 1.0 mm, or approximately 1.1 mm, or approximately 1.2 mm, or approximately 1.3 mm, or approximately 1.4 mm. The active area 218a and the active area 218b are separated by a distance x, which may be between approximately 0.4 mm and approximately 1.1 mm, or between approximately 0.5 mm and approximately 1.0 mm, or between approximately 0.6 mm and approximately 0.9 mm, or between approximately 0.7 mm and approximately 0.9 mm, or approximately 0.4 mm, or approximately 0.5 mm, or approximately 0.6 mm, or approximately 0.7 mm, or approximately 0.8 mm, or approximately 0.9 mm, or approximately 1.0 mm, or at least approximately 0.2 mm, or at least approximately 0.4 mm, or at least approximately 0.6 mm, or at least approximately 0.8 mm (for example, the proximal end of the active area 218a may be separated from the distal end of the active area 218b).

[0033] Sensors 232 and 242 may include two membranes 220 and 222. As seen in Figures 5C and 5D, membrane 222 may cover only a portion of the working electrode 214a, including the active region 218a (e.g., a ketone-sensitive active region). Membrane 220 may cover both the active region 218a (e.g., a ketone-sensitive active region) and the active region 218b (e.g., glucose-sensitive). Membrane 220 may also cover the counter electrode 216 and the reference electrode 217 on the opposite side of the substrate 212. Thus, the active region 218a (e.g., a ketone-sensitive active region) may have a two-layer membrane including membranes 222 and 220, while the active region 218b may have only a single-layer membrane 220. While Figures 5C and 5D show electrodes 214a, 214b, 216, and 217 all covered by film 220, it should be understood that in some embodiments, only working electrodes 214a and 214b may be covered. Furthermore, the thicknesses of films 220 and 222 on each of electrodes 214a, 214b, 216, and 217 may be the same or different from each other. As in the two-electrode substance sensor configuration (e.g., Figures 2A and 2B), one or both sides of the substance sensor 202 may be covered by film 220 in the sensor configuration of Figure 5A, or the entire substance sensor 202 may be covered. Therefore, it should be understood that the multi-electrode sensor configurations shown in Figures 5A and 5B are not limited to the embodiments disclosed herein, and alternative electrode and / or layer configurations exist within the scope of this disclosure.

[0034] Referring further to Figures 5C and 5D, the membrane 222 optionally covers only the active region 218a (e.g., the ketone-sensitive active region) and not the active region 218b (e.g., the glucose-sensitive region). The membrane 220 selectively covers at least the test substance-sensitive active regions 218a and 218b and some or all of the working electrode 214a and / or the working electrode 214b and / or the reference electrode 216 and / or the counter electrode 217, or, according to some embodiments, the entire test substance sensor 202. The membrane 220 may include one or more polymer membrane materials that have the function of restricting the flow of the test substance to the active region 218 (i.e., the membrane 220 is a substance migration restriction membrane with some permeability to the test substance to be measured). The composition and thickness of the membrane 220 may be modified to facilitate the flow of the desired test substance to the test substance-sensitive active regions 218a and 218b, thereby providing desired signal intensity and stability. As shown in Figure 5D, the distal portion 221 of the sensor 242 may be thicker (thickness w compared to w') or have a spherical shape compared to the proximal portion of the sensor tail. The thickness of the distal portion 221 of the sensor 242 may be between approximately 0.203 mm (0.008”) and approximately 0.356 mm (0.014”), or between approximately 0.229 mm (0.009”) and approximately 0.33 mm (0.013”), or between approximately 0.254 mm (0.010”) and approximately 0.33 mm (0.013”), or between approximately 0.254 mm (0.010”) and approximately 0.305 mm (0.012”), or between approximately 0.15 mm and approximately 0.4 mm, or between approximately 0.2 mm and approximately 0.4 mm, or between approximately 0.25 mm and approximately 0.4 mm, or between approximately 0.25 mm and approximately 0.35 mm. The substance sensor may be operable to analyze the substance by any of the electrochemical detection techniques of coulometry, current measurement, voltametry, or potentiometry.

[0035] The film 222 may be immersion-coated on the active region 218a (e.g., a ketone-sensitive active region). For example, the sensor 232 may be partially immersed in the film solution, so that only the end near end A, which includes the active region 218a but does not include the active region 218b, is immersed in the film solution. The coating of film 222 may be achieved in a single immersion procedure, or multiple immersions in the film solution may be required to obtain a high-density film. A wider portion of the sensor 232, 242, which includes both the active regions 218a and 218b, may then be immersed in different film solutions. Thus, the active region 218a located closer to the distal end A will have a two-layer film, while the active region 218b, which is more proximal to the active region 218a, will have a single-layer film. Immersion coating by this method has several advantages. Firstly, the manufacturing process is simplified and efficiency is improved by applying both sensing layers on one side of the substrate 212 without the need to invert the substrate 212. Secondly, this immersion method allows the use of the same membrane immersion equipment for both membrane 222 and membrane 220, simply by changing the membrane solution and adjusting the immersion depth.

[0036] Figure 5E shows a sensor with a ketone active site 218a (having two spots) on the front side closer to the distal end A of the sensor, and a glucose active site 218b (having two spots) on the back side of the sensor, located at a distance further from the distal end A than the ketone active site 218a. In Figure 5E, the sensor is not yet covered by the membrane. As seen in Figure 5F (see dotted line), in the first immersion, the sensor is immersed to a position between the ketone active site 218a and the glucose active site 218b, so that the ketone active site 218a is immersed in the membrane solution, but the glucose active site 218b is not. After any multiple immersions and curing in the first membrane solution, the sensor is immersed in the second solution so that the sensor is immersed to a position proximal to or above the glucose active site 218b, so that both the ketone active site 218a and the glucose active site 218b are immersed. As can be seen in the side view of Figure 5F, the distal portion 221, which has a double-layered film, has a spherical shape or a flared tip with a thickness w, and is larger than the proximal portion of the sensor tail, which has a thickness w' and is covered by only a single-layered film. The thickness w may be between approximately 0.203 mm (0.008") and approximately 0.356 mm (0.014"), or between approximately 0.229 mm (0.009") and approximately 0.33 mm (0.013"), or between approximately 0.254 mm (0.010") and approximately 0.33 mm (0.013"), or between approximately 0.254 mm (0.010") and approximately 0.305 mm (0.012"), or between approximately 0.15 mm and approximately 0.4 mm, or between approximately 0.2 mm and approximately 0.4 mm, or between approximately 0.3 mm and approximately 0.4 mm, or between approximately 0.25 mm and approximately 0.35 mm.In contrast, the thickness w' may be between approximately 0.127 mm (0.005") and approximately 0.254 mm (0.01"), or between approximately 0.127 mm (0.005") and approximately 0.229 mm (0.009"), or between approximately 0.152 mm (0.006") and approximately 0.229 mm (0.009"), or between approximately 0.152 mm (0.006") and approximately 0.203 mm (0.008"), or between approximately 0.178 mm (0.007") and approximately 0.203 mm (0.008"), or between approximately 0.1 mm and approximately 0.3 mm, or between approximately 0.1 mm and approximately 0.25 mm, or between approximately 0.15 mm and approximately 0.25 mm. The difference between w and w' may be between approximately 0.0762 mm (0.003") and approximately 0.127 mm (0.005"), or between approximately 0.0762 mm (0.003") and approximately 0.102 mm (0.004"), or between approximately 0.05 mm and approximately 0.15 mm, or between approximately 0.07 mm and approximately 0.1 mm, or between approximately 0.075 mm and approximately 0.125 mm.

[0037] In another embodiment, as shown in Figures 5G and 5H, the first working electrode 214a and the second working electrode 214b may be placed on the same side of the substrate 212, or they may be placed directly on the surface of the substrate 212, so that the dielectric or insulating layer does not separate the first working electrode 214a and the second working electrode 214b from the same substrate surface. Furthermore, the first working electrode 214a and the second working electrode 214b are not stacked on top of each other and are not separated by a dielectric layer. Rather, the first working electrode 214a and the second working electrode 214b are spatially separated on the same surface of the substrate. Since the first working electrode 214a and the second working electrode 214b can be printed in the same layer on the substrate 212, such arrangement can simplify manufacturing. As shown in Figure 5H, the counter electrode 216 and the working electrode 217 are also spatially separated and may be printed directly on the same side of the substrate (i.e., not stacked), in which case the dielectric layer does not separate the counter electrode 216 and the reference electrode 217 from the surface of the substrate 212 or from each other.

[0038] The test substance sensors disclosed herein may include multiple active regions on either the same working electrode or different working electrodes. The test substance sensors disclosed herein may feature the same type of active region (e.g., two glucose active regions) on a single working electrode or on two or more separate working electrodes. The test substance sensors disclosed herein may feature different types of active regions (e.g., a glucose active region and a ketone active region, or a lactate active region) on a single working electrode or on two or more separate working electrodes. As further described herein according to various embodiments of this disclosure, the single-working electrode sensor configuration may employ a two-electrode or three-electrode detection motif. According to various embodiments of this disclosure, the sensor configuration may appropriately incorporate a first test substance-sensitive active region (e.g., for monitoring glucose) and a second test substance-sensitive active region (e.g., for monitoring ketones). Sensor configurations featuring multiple working electrodes are described hereafter with reference to several drawings.

[0039] In an alternative embodiment, both the working electrode 214a and the working electrode 214b may have the same test substance, such as a glucose-sensitive active region. As shown in Figure 6A, if multiple working electrodes 214a and 214b are present, a sensitive active region for a specific single test substance may be located on both the working electrode 214a and the working electrode 214b. The film 220 may then be immersion coated onto the sensitive active region 218.

[0040] In alternative embodiments, different test substances are analyzed using different working electrodes. As further described herein, although not immediately apparent in Figures 5 and 6, the composition of the membrane 220 may be varied in the active regions 218a and 218b to individually control the flow of the test substance at each location. For example, the membrane 220 may be sprayed and / or printed onto the active regions 218a and 218b, so the composition of the membrane 220 differs at each location. Alternatively, if multiple test substances are being analyzed and multiple working electrodes 214a and 214b are present, a sensitive active region 218a specific to a first test substance, such as a ketone, may be located on the first working electrode, and a sensitive active region 218b specific to a second test substance, such as glucose, may be located on the second working electrode.

[0041] If the active regions are separated from each other and / or spaced apart by this method, substance migration limiting films having different compositions and / or different permeability values ​​can be deposited more rapidly during manufacturing, so sensor configurations employing multiple working electrodes can be very advantageous for incorporating any of multiple different sensitive active regions, according to the disclosures herein. Suitable techniques for depositing substance migration limiting films disclosed herein include, for example, spray coating, paint, striping, inkjet printing, stencil, roller coating, slot stain coating, dipping coating, etc., and some combinations thereof. Referring, for example, to Figure 6B, film 222 may be deposited by stripe coating, and film 220 may be deposited by dipping coating starting from edge A of the substance sensor 200. In particular, film 222 may be striped over the active region 218a using a first coating formulation. Alternatively, film 222 may be coated over the working electrode 214a, for example, by spray coating or paint. The sensor may then be laser-cut to be dipped into a second film 220 that covers the entire tip of the sensor. After partially curing the first coating formulation on the active region 218a to form a film 222, the end A of the substance sensor 200 may be immersed in the second coating formulation to cover both the active region 218a and the active region 218b with the second coating formulation, forming a film 220. Thus, the film 220 may be continuous, characterized by two layers in 218a and homogeneous in the active region 218b. Referring to Figure 6C, for example, if the active regions 218a and 218b are located on the same side of the substrate 212 and separated by a distance x, the films 220 and 222 may be deposited by immersion coating starting from the end A of the substance sensor 200. In particular, the end A of the substance sensor 200 may be immersed (once or multiple times) in the first coating formulation to cover only the active region 218a and not the active region 218b.After partially curing the first coating formulation on the active region 218a to form a film 222, the end A of the substance sensor 200 may be immersed in the second coating formulation to cover both the active region 218a and the active region 218b with the second coating formulation, forming a film 220. Thus, the film 220 may be continuous and characterized by two layers in 218a and homogeneous in the active region 218b. If the film 222 is denser than the film 200, the film 222 will primarily determine the diffusion characteristics around the sensitive active region 218a. Although the active regions 218a and 218b are shown on the same side of the substrate in Figures 5D and 6C, the active regions 218a and 218b may also be on opposite sides of the substrate 212, separated by a distance x measured, for example, along an axis parallel to the substrate 212.

[0042] The membrane 222 may contain polyvinylpyridine and a crosslinking agent such as polyethylene glycol diglycidyl ether (PEGDGE), such as PEGDGE400. The membrane 220 may contain polyvinylpyridine-co-styrene and a crosslinking agent such as polyethylene glycol diglycidyl ether (PEGDGE), such as PEGDGE400.

[0043] If the active regions are separated from each other and / or spaced apart by this method, substance migration limiting films having different compositions and / or different permeability values ​​can be deposited more rapidly during manufacturing, so sensor configurations employing multiple working electrodes can be very advantageous for incorporating any of multiple different sensitive active regions according to the disclosure herein. Suitable techniques for depositing the substance migration limiting films disclosed herein include, for example, spray coating, paint, inkjet printing, stencil, roller coating, dipping coating, etc., and some combinations thereof.

[0044] Figures 7A–7C are photographs of various electrodes coated with different films. Figures 7A–7C contain ketone- and glucose-specific sensitive active regions. Figure 7A shows an electrode with a ketone-sensitive active region, first coated with a PVP film and then with a polyvinylpyrrolidone-co-styrene film. Figure 7B shows an electrode with a glucose-sensitive active region, coated only with a polyvinylpyrrolidone-co-styrene film. The electrodes shown in Figures 7A and 7B are opposite sides of the same sensor tail. Figure 7C shows an electrode with a ketone-sensitive active region, striped-coated with a PVP film. Figure 7C is an example of what the electrode in Figure 7A looks like after being coated with PVP but before being coated with 10Q5. Typical membrane compositions for these electrodes are found in U.S. Patent Application No. 16 / 774,835 (U.S. Publication No. 2020 / 0237275; Reference No. 13548USO1), which is incorporated herein by reference in its entirety for all purposes. Figure 7D is a graph of current sensitivity for eight test substance sensors, each containing glucose-sensitive and ketone-sensitive active regions, positioned on working electrodes separated from each other on the opposite side of the sensor tail, after two weeks of exposure to 30 mM glucose and 10 mM ketone, demonstrating that the distinct membrane requirements for glucose and ketone sensors were achieved by the bilayers described above. Similarly, typical membrane compositions for lactate sensors are found in U.S. Patent Application No. 16 / 259,157 (U.S. Publication No. 2019 / 0320947; Reference No. 13335USO1), which is incorporated herein by reference in its entirety for all purposes. A typical membrane composition for an ethanol sensor is found in U.S. Patent Application No. 16 / 774,909 (U.S. Publication No. 2020 / 0237277; Reference No. 13622USO1), which is incorporated herein by reference in its entirety for all purposes. A typical membrane composition for a creatinine sensor is found in U.S. Patent Application No. 16 / 582,583 (U.S. Publication No. 2020 / 0241015; Reference No. 13547USO1), which is incorporated herein by reference in its entirety for all purposes.Further typical film compositions can be found in U.S. Patent Application No. 16 / 774,841 (U.S. Publication No. 2020 / 0237276; Reference No. 13210USO1), which for all purposes is incorporated herein by reference in its entirety.

[0045] Figures 8A–8D and 9A–9D (see further description in the example) show the calibration graphs formed by the glucose / ketone dual sensor and the glucose / lactate dual sensor, respectively. The calibration graphs demonstrate that these dual sensors, which include multiple working electrodes with glucose-sensitive regions and ketone-sensitive / lactate-sensitive regions, function as expected.

[0046] Exemplary Embodiment of an On-Body Device An in vivo monitoring system may include a sensor that comes into contact with the user's bodily fluids while in vivo and senses the level of a test substance contained therein. The sensor may be part of an on-body device ("OBD" or "on-body device") that resides on the user's body and includes electronics and a power supply that enable and control the sensing of the test substance. On-body devices and similar devices may be referred to, to name a few, as "sensor devices," "on-body electronic devices," "sensor control devices," or "sensor communication devices." As used herein, these terms are not limited to devices having an in vivo test substance sensor and include devices having other types of ex vivo sensors, whether biometric (e.g., photonic test substance sensors, heart rate sensors, temperature sensors, etc.) or non-biometric. The term "on-body" includes devices that are directly on the body (e.g., attached to the skin), devices that are entirely inside the body (e.g., fully implantable devices), or devices that are close to the body, such as wearable devices (e.g., eyeglasses, watches, wristbands or bracelets, collars or necklaces, etc.) or devices that are in a pocket.

[0047] The in vivo monitoring system may also include one or more readers that read information about levels sensed from an on-body device. These readers may process information about the sensed substance and / or display it to the user in any form. These devices and similar items may be described, to name a few, as “handheld readers,” “readers,” “handheld electronics (or handheld terminals),” “portable data processing” devices or units, “information receivers,” “receivers” devices or units (or simply receivers), “relay” devices or units.

[0048] In vivo test substance monitoring systems can be distinguished into “in vitro” systems, which come into contact with a biological sample outside the body, and “ex vivo” systems, which acquire information about a substance in or outside the body but remain entirely outside the body without extracting a biological sample from inside the body. An in vitro system may include a test substance test strip that carries the user's bodily fluids and a measuring device having a port for receiving the test substance test strip to be analyzed to determine the user's test substance level. As described above, the embodiments described herein may be used in in vivo systems, ex vivo systems, in vitro systems, and combinations thereof.

[0049] Figures 10A–D are block schematics illustrating exemplary embodiments of a sensor control device or OBD 102, comprising a test substance sensor 104 and sensor electronics 310 (including a test substance monitoring circuit) that may have most of the processing functions to prepare the final result data for display to the user. In Figure 10A, a single semiconductor chip 301 is shown, which may be a custom application-specific integrated circuit (ASIC). Certain high-level functional units, including an analog front-end (AFE) 302, a power management (or control) circuit 304, a processor 306, and a communication circuit 308 (which may be implemented as a transmitter, receiver, transceiver, passive circuit, or other according to a communication protocol), are shown within the ASIC 301. In this embodiment, both the AFE 302 and the processor 306 are used as the test substance monitoring circuit, but in other embodiments, either circuit may perform the test substance monitoring function. The processor 306 may include one or more processors, microprocessors, controllers, and / or microcontrollers, each of which may be a separate chip or distributed among (and some of) a number of different chips.

[0050] Memory 303 may also be contained within the ASIC 301 and shared by various functional units present within the ASIC 301, or distributed among two or more of them. Memory 303 may be a separate chip. Memory 303 may be volatile memory and / or non-volatile memory. In this embodiment, the ASIC 301 is connected to a power supply 310, which may be a coin cell battery or the like. The AFE 302 works in conjunction with the in vivo substance sensor 104, from which it receives measurement data and outputs the data in digital format to a processor 306 that processes the data sequentially to arrive at final results and trend values ​​for individual glucose values, etc. The data may also be provided to a communication circuit 208 for transmission to a reader 120 (not shown) via an antenna 311, where minimal further processing by a resident software application is required to display the data.

[0051] Figure 10B is a block diagram illustrating an exemplary alternative embodiment of a sensor control device or on-body device ("OBD") 102, having a substance sensor 104 and sensor electronics 310 (including a substance monitoring circuit). The sensor electronics may be implemented on one or more semiconductor chips. In the embodiment of Figure 10B, the sensor electronics 310 reside in a single semiconductor chip 301, which may also be a custom application-specific integrated circuit (ASIC). Certain high-level functional units, including an analog front-end (AFE) 302, a power management (or control) circuit 304, a processor or processing circuit 306, a memory 303, a timing circuit 312, a first communication circuit 302, and a second communication circuit 314, are shown within the ASIC 301. In this embodiment, both the AFE 302 and the processor 306 are used as substance monitoring circuits, but in other embodiments, either circuit (or one other) may perform the substance monitoring function.

[0052] The OBD102 may be implemented in a highly interconnected manner, where the power supply 312 is connected to each component shown in Figure 10B, and these components that communicate or receive data or information or commands (e.g., AFE302, power management circuit 304, processor 306, memory 303, timing circuit 312, first communication circuit 308, and second communication circuit 314) may be communicably connected to any other such components, for example, via one or more communication connections or bus 320. Figure 10B briefly illustrates typical hardware and functions present in a dedicated reader, and those skilled in the art will immediately understand that other hardware and functions (e.g., codecs, drivers, glue logic) may also be included.

[0053] Figure 10C is a block diagram showing an exemplary alternative embodiment of the OBD 102, having a substance sensor 104 and sensor electronics (including a substance monitoring circuit). The sensor electronics may be implemented on one or more semiconductor chips, such as application-specific integrated circuits (ASICs), off-the-shelf (OTS) chips, or programmable devices (e.g., PGA or FPGA). The OBD 102 includes a specific high-level functional unit, which includes an analog front-end (AFE) 302, a power management (or control) circuit 304, a processor or processing circuit 306, a memory 303, a first communication circuit 308, and a second communication circuit 314. In this embodiment, both the AFE 302 and the processor 306 are used as substance monitoring circuits, but in other embodiments, either circuit (or others) may perform the substance monitoring function.

[0054] The OBD102 may be implemented in a highly interconnected manner, where the power supply 310 is connected to each component shown in Figure 10C, and these components that communicate or receive data or information or commands (e.g., AFE302, power management circuit 304, processor 306, memory 303, first communication circuit 308, and second communication circuit 314) may be communicateably connected to any other such components, for example, via one or more communication connections or bus 320. Figure 10C briefly illustrates the typical hardware and functions present in the OBD102, and those skilled in the art will immediately understand that other hardware and functions (e.g., codecs, drivers, glue logic, crystal oscillators, phase-locked loops (PLLs)) may also be included.

[0055] Figure 10D is a block diagram showing another exemplary embodiment of the OBD102, where the OBD102 comprises two semiconductor chips 301 and 361. Chip 301 is an ASIC including an AEF302 and a communication circuit 308 for an NFC link. Chip 361 is a chip including a processor 306, memory 303, a communication circuit 314 for a BT link, and a power management circuit 304. The communication interface may be configured in any desirable way. In one embodiment, chip 361 is a Bluetooth® or BLE radio chip, and the communication interface is a serial interface such as a Serial Peripheral Interface (SPI).

[0056] The communications received by the OBD102 via the NFC link may include commands for the OBD102 to take several actions, such as connecting power to the internal circuits of one or both of the chips 301 and 316, activating the sensor 104, reading data stored in the memory 303 (e.g., measured substance data, data identifying the OBD102 (e.g., software version, serial number, etc.)), performing diagnostics, and setting up Bluetooth® pairing. The commands may be specified in the applicable NFC standard or may be custom commands requiring a custom response. The received communications often require the transmission of a response to be returned to the reader 120.

[0057] In the embodiment shown in Figure 10D, some NFC communications received by the communication circuit 308 may be processed and responded to directly by the ASIC 301 without intervention from the chip 361. However, some commands may require a response generated by a more robust entity, such as the processor 306. In these examples, the ASIC 301 may forward the relevant portion of the received communication to the chip 361 to generate the response. The chip 361 then generates the response, and once the response is obtained, it may output a response to return to the ASIC 301 for transmission from the OBD 102 via the NFC link.

[0058] Communication transmitted via an NFC link may be subject to certain timing limitations. To comply with the ISO 15693 standard, most NFC commands, including, for example, read multiple block commands, read single block commands, custom commands, and proprietary commands, must be responded to within a set time limit. In one embodiment, ISO 15693 specifies that a command must be responded to by a tag within 232 microseconds (μs) from the time the tag receives the command. Situations may arise where the chip 361 takes longer than the set time limit to generate a response. This processing delay can lead to a violation of the set time limit and non-compliance with the NFC standard. This can be a problem specific to cases where the reader 120 is a commercial smartphone, as the smartphone may treat this violation as an error or malfunction, preventing the communication from completing.

[0059] Exemplary embodiments disclosed herein can compensate for this processing delay and maintain compliance by sending one or more responses containing a default payload, which is referred to herein as dummy data. The reader 120 may be programmed or configured to recognize a response in which the payload contains byte values ​​(e.g., ABCD, FFFF) that match the default payload as dummy data, and may continue to monitor the NFC link 141 for response transmissions containing payload data other than dummy data.

[0060] For all of the above embodiments, communication circuits 308 and 314 may be connected to antennas 311 and 316, respectively, which may be on or off the chip. The first communication circuit 308 and antenna 311 are configured to communicate (transmit and / or receive) over a communication link, while the second communication circuit 314 and antenna 316 are configured to communicate over different communication links. In some embodiments, antennas 311 and 316 may be a single shared antenna (e.g., capable of transmitting and receiving over NFC and UHF frequencies). Communication circuits 308 and 314 may be implemented as one or more components (e.g., transmitters, receivers, transceivers, passive circuits, encoders, decoders, and / or other communication circuits) that perform functions for communicating over their respective communication links. Communication circuits 308 and 314 may receive timing information from a timing circuit 312. The timing circuit 312 may include a crystal oscillator, a phase-locked loop (PLL), and / or other circuits that generate a stable frequency for timing purposes.

[0061] In some embodiments, though not limited to these, the communication circuit 308 is passive and uses only the power collected from a transmission received from a second device (e.g., reader 120) to generate and propagate a response transmission to be returned to the second device (e.g., if the communication link is an NFC link). In these embodiments and other embodiments, the communication circuit 314 may be active and use power from the OBD power supply 312 to generate and propagate transmissions to the second device. The active communication circuit 314 allows the OBD 102 to generate transmissions spontaneously and by prompting from another device (e.g., without first receiving a request, polling signal, timing signal, etc., from the second device).

[0062] The processor 306 may include one or more processors, microprocessors, controllers, and / or microcontrollers, each of which may be a separate chip or distributed among (and some of) several different chips. The processor 306 may work in conjunction with communication circuits 308 and 314 to perform analog-to-digital conversion, encoding and decoding, digital signal processing, and other functions that facilitate the conversion of data signals into a format suitable for supply to communication circuits 308 and 314 (e.g., in-phase and perpendicular phase), and then transmit the signals wirelessly. The processor 306 may also work in conjunction with communication circuits 308 and 314 to perform reverse functions necessary for receiving wireless transmissions and converting them into digital data or information.

[0063] The processor 306 may execute software instructions stored in memory 308. These instructions may cause the processor 306 to have communication circuits 308 and 314 transmit communications generated by the processor 306, to read and execute received transmissions, to adjust the timing to that of the timing circuit 312, to collect temperature information from the temperature sensor, to record and / or process measurements from the substance sensor 314, to monitor collected substance data regarding actual or potential warning conditions, to generate and transmit warning instructions using the communication circuit 314, to process data and information received from other devices (e.g., the reader 120), to perform tasks and maintain synchronization with the reader 120, and so on.

[0064] Memory 308 may also be contained within ASIC 301 and shared by various components present within ASIC 301, or distributed among two or more of them. Memory 308 may be a separate chip. Memory 308 may be persistent and may be volatile and / or non-volatile memory. ASIC 301 may be coupled to an arbitrary temperature (or other environmental factor) sensor 321 and a power supply 310, the power supply 310 of which may be a coin cell battery, etc. AFE 302 works in conjunction with an in vivo substance sensor 104, from which it receives measurement data, converts it to a digital format, and outputs it to a digital processor 306 that processes it sequentially in one of the ways described in other parts of this specification in some embodiments. The data may also be provided to communication circuits 308 and 314 for transmission to a reader 120 (not shown) via antennas 311 and 316, where minimal further processing by a resident software application is required, for example, to display the data. Antennas 311 and 316 may be configured according to the requirements of the application and communication protocol. Antennas 311 and 316 may have the same or different forms, for example, printed circuit board (PCD) wire antennas, ceramic antennas, or individual metal antennas. Antennas 311 and 316 may be configured as unipolar antennas, dipolar antennas, F-type antennas, loop antennas, etc.

[0065] Multiple sensors in a single housing In an alternative embodiment, additional substances to be tested can be monitored by adding a second sensor or subsensor that includes one or more working electrodes but does not include a reference electrode or counter electrode. As seen in Figure 11, the subsensor 203 can share the counter electrode and reference electrode in the primary sensor by positioning the subsensor 203 near the primary sensor 202, which includes a reference electrode and a counter electrode, as shown in Figures 3-5. As seen in Figure 12, the subsensor 203 includes four working electrodes 214a, 214b, 214c, and 214d, two on each side of the substrate 212. The working electrodes on the same side of the substrate 212 are separated from each other by dielectric materials 219b and 219c sandwiched between them. The outer dielectric layers 219a and 219d are positioned on working electrodes 214a and 214d. The test substance-specific sensitive active regions 218a-218d (e.g., glucose-sensitive active region, creatinine-sensitive active region, or lactate-sensitive active region) may be arranged as at least one layer on at least a portion of the working electrodes 214a-214d. As further described herein, the test substance-sensitive active region may comprise multiple spots / regions or a single spot / region configured to detect the test substance. Both the primary sensor 202 and the subsensor 203 are housed in the same sensor housing 103 and attached to the patient's skin by an adhesive layer 104. For example, two, three, four or more additional subsensors may be added to the same sensor housing unit to increase the number of test substances being monitored.

[0066] Referring to an embodiment of multiple sensors described for a single housing, as shown in Figure 11, the OBD102 may include any of the sensor electronics described in Figures 10A to 10D. The housing 103 includes an AFE302 that receives test substance data from the working electrode in the primary sensor and the working electrode in the subsensor. The AFE outputs one or more signals relating to the test substance level detected by each of the working electrodes in the primary sensor and the subsensor, using a shared counter electrode and reference electrode in the primary sensor.

[0067] Multiple sensors within multiple housings In an alternative embodiment, additional substances to be tested can be monitored by adding subsensors installed in additional sensor housings connected to or coupled with the sensor housing containing the primary sensor. Similar to the embodiments described above with reference to Figure 11, the subsensor 203 can share the counter electrode and reference electrode in the primary sensor by positioning the subsensor 203 near the primary sensor 202, which includes a reference electrode and a counter electrode, as shown in Figures 3-5, as seen in Figures 13A-13B. As seen in Figure 12, the subsensor 203 includes four working electrodes 214a, 214b, 214c, and 214d, two on each side of the substrate 212. The working electrodes on the same side of the substrate 212 are separated from each other by dielectric materials 219b and 219c sandwiched between them. The outer dielectric layers 219a and 219d are positioned on top of the working electrodes 214a and 214d. The test substance-specific sensitive active regions 218a-218d (e.g., glucose-sensitive, creatinine-sensitive, or lactate-sensitive active regions) may be arranged as at least one layer on at least a portion of the working electrodes 214a-214d. As further described herein, the test substance-sensitive active regions may comprise multiple spots / regions or a single spot / region configured to detect the test substance. In an alternative embodiment shown in Figure 13A, the primary sensor 202 is housed in the primary sensor housing 103a, and the subsensor 203 is housed in a different sensor housing 103b, both of which are attached to the patient's skin by an adhesive layer 104. As in Figure 11, the sensor housing 103b is located near the primary sensor housing 103a, so the subsensor 203 is connected to the AFE 302 located in the primary sensor housing 103a, thereby allowing the subsensor 203 to share the counter electrode and reference electrode within the primary sensor. Therefore, the subsensor housing 103b does not need to house any electronics. Alternatively, the AFE 302 may be installed inside the subsensor housing 103b.As shown in Figure 13A, the conductive wire 303 may be printed on the back of the adhesive layer 104 to connect the subsensor 203 to the AFE 302 installed inside the primary sensor housing 103a. Both the sensor housing 103a and the sensor housing 103b may have connector pins (not shown) at the bottom of the housing to press onto the printed conductive wire terminal pad 303 when the sensor housings are laminated on the back of the skin adhesive patch 104. The printed conductive wire 303 is preferably flexible to adapt to skin movement. The connection (conductive wire) 303 between the primary sensor housing 103a and the subsensor housing 103b is also preferably well isolated and sealed from any moisture, including the contacts, to avoid any moisture leakage that could interfere with the sensor signal. For example, two, three, four or more additional subsensors may be added in additional separate sensor housing units located near the primary sensor housing 103a to increase the number of substances being monitored.

[0068] In an alternative embodiment, as shown in Figure 13B, the subsensor 203 may be connected to the AFE 302 in the primary sensor housing 103a via a flexible circuit connection 305. The connection (conductive wire) 303 between the primary sensor housing 103a and the subsensor housing 103b should be adequately isolated and sealed from any moisture, including the contacts, to avoid any moisture leakage that could interfere with the sensor signal. For example, two, three, four or more additional subsensors may be added in additional individual sensor housing units, and the additional subsensors may be connected to the AFE 302 installed in the primary sensor housing 103a to increase the number of substances being monitored.

[0069] As shown in Figure 13C, the additional subsensor housings 103b and 103c each contain a subsensor connected to the AFE 302 in the primary sensor housing 103a. The subsensors and the AFE installed in the primary sensor housing 103a may be connected or linked by printed circuit lines, small flex circuits, or other systems known in the art. If the primary sensor includes two working electrodes, such as sensor 202, and each of the subsensors housed in 103b and 103c contains a sensor having four working electrodes, then 10 test substances can be monitored. Similarly, if only the above-described connected primary sensor housings are present, connected to a single subsensor housing, then 6 test substances can be monitored.

[0070] In an alternative embodiment, the AFE302 is housed within the subsensor housings 103b, 103c. In this alternative embodiment, the electrodes (working, pair, reference) in the primary sensor 202 may be connected or coupled to the AFE302 for the subsensors as described above (e.g., via printed circuit lines, small flex circuits, or another system known in the art), so that the AFE302 uses the shared pair and reference electrodes in the primary sensor to output one or more signals relating to the level of the substance being tested, as detected by the working electrodes in the primary sensor and the subsensors, respectively.

[0071] Sensitive activity area Different detection chemistry must be immobilized on different sensitive active regions specific to various test substances. The enzyme involved in the detection of the test substance may be covalently bonded to a polymer in or near the sensitive region. Suitable polymers include, but are not limited to, polyvinylpyridine. The covalent polymer can help immobilize the enzyme at a desired position relative to the sensitive active region.

[0072] In any of the exemplary sensor configurations disclosed herein, each of the substance-sensitive active regions includes an electron transfer agent. When both the first and second substance-sensitive active regions are located on the same sensor and / or the same working electrode, the electron transfer agents may be the same or different from each other depending on the specific sensor configuration employed. A suitable electron transfer agent can facilitate the transport of electrons to the working electrode after an enzymatic oxidation or reduction reaction has occurred, thereby indicating the presence of a specific substance and generating a current proportional to the amount of substance present. For example, when the first and second substance-sensitive active regions are located on the same working electrode, the electron transfer agents within each active region may be different from each other (e.g., chemically different so that the electron transfer agents exhibit different redox potentials). When multiple working electrodes are present, the electron transfer agents within each active region may be the same or different from each other, as each working electrode can be independently queried when acquiring a signal. The electron transfer agent may be covalently bonded to a polymer in any of the active regions disclosed herein.

[0073] According to various embodiments of this disclosure, suitable electron transfer agents may include electrolytically reducing ions and electrolytically oxidizing ions, complexes or molecules (e.g., quinones) having redox potentials several hundred millivolts above or below the redox potential of a standard mercury electrode (SCE). According to some embodiments, suitable electron transfer agents may include low-potential osmium complexes, such as those described in U.S. Patents 6,134,461 and 6,605,200, which are incorporated herein by reference in their entirety. Further examples of suitable electron transfer agents include those described in U.S. Patents 6,736,957, 7,501,053 and 7,754,093, the respective disclosures of which are incorporated herein by reference in their entirety. Other suitable electron transfer agents include, for example, metal compounds or complexes of ruthenium, osmium, iron (e.g., polyvinylferrocene or hexacyanoferric acid), or cobalt, and may include, for example, their metallocene compounds. Suitable ligands for the metal complex may also include bidentate or higher-locate ligands such as bipyridine, biimidazole, phenanthroline, or pyridyl(imidazole). Other suitable bidentate ligands may include, for example, amino acids, oxalic acid, acetylacetone, diaminoalkanes, or o-diaminoarenes. Any combination of monodentate, bidentate, tridentate, tetradentate, or higher-locate ligands can be present in the metal complex to achieve the maximum coordination sphere.

[0074] An active region suitable for detecting multiple test substances may also include a polymer to which an electron transfer agent is covalently bonded. Any of the electron transfer agents disclosed herein may include a functional group suitable for promoting covalent bonding to the polymer within the active region. Suitable examples of electron transfer agents bonded to polymers include those described in U.S. Patents 8,444,834, 8,268,143, and 6,605,201, the disclosures of which are incorporated herein by reference in their entirety. Suitable polymers to be included within the active region may include, but are not limited to, polyvinylpyridine (e.g., poly(4-vinylpyridine)), polyvinylimidazole (e.g., poly(1-vinylimidazole)), or any copolymer thereof. Exemplary copolymers that may be suitable to be included within the active region include, for example, those containing monomer units such as styrene, acrylamide, methacrylamide, or acrylonitrile. The polymers within each active region may be the same or different from one another.

[0075] The method of covalent bonding between the electron transfer agent and the polymer within each active region is considered not particularly limited. Covalent bonding of the electron transfer agent to the polymer may be carried out by polymerization of monomer units having the covalently bonded electron transfer agent, or the electron transfer agent may react with the polymer on its own after the polymer has already been synthesized. According to some embodiments, a bifunctional spacer may covalently bond the electron transfer agent to the polymer within the active region, where the first functional group reacts with the polymer (e.g., a functional group capable of quaternizing a pyridine nitrogen atom or an imidazole nitrogen atom), and the second functional group reacts with the electron transfer agent (e.g., a functional group that reacts with a ligand coordinating a metal ion).

[0076] Similarly, one or more enzymes within the active region may be covalently bonded to the polymer. When an enzyme system containing multiple enzymes is present within a given active region, in some embodiments all of the multiple enzymes may be covalently bonded to the polymer, while in other embodiments only some of the multiple enzymes may be covalently bonded to the polymer. For example, one or more enzymes in the enzyme system may be covalently bonded to the polymer, and at least one enzyme may be non-covalently bonded to the polymer, so that the non-covalently bonded enzyme is physically incorporated into the polymer. According to a more specific embodiment, the covalent bonding of an enzyme to a polymer within a given active region may be achieved by crosslinking induced by a suitable crosslinking agent. Suitable crosslinking agents for reaction with free amino groups in the enzyme (e.g., free side-chain amines of lysine) may include, for example, polyethylene glycol diglycidyl ether (PEGDGE) or other polyepoxides, cyanuryl chloride, N-hydroxysuccinimide, imide esters, epichlorohydrin, or derivatized variants thereof. Suitable crosslinking agents for reaction with free carboxylic acid groups in the enzyme may include, for example, carbodiimide. Enzyme crosslinking to polymers generally occurs intermolecularly, but in some embodiments it may occur intramolecularly. In certain embodiments, all of the enzymes described herein may be covalently bonded to the polymer.

[0077] The electron transfer agent and / or enzyme may also be bonded to the polymer within the active region by means other than covalent bonding. In some embodiments, the electron transfer agent and / or enzyme may be ionic or coordinate bonded to the polymer. For example, a charged polymer may be ionically bonded to a reversed electron transfer agent or enzyme. In yet another embodiment, the electron transfer agent and / or enzyme may be physically incorporated into the unbonded polymer. Physically incorporated electron transfer agents and / or enzymes can further appropriately interact with the fluid to facilitate the detection of the test substance without substantially leaching out of the active region.

[0078] Creatinine As described below with reference to Figures 2A and 2B of U.S. Patent Application No. 16 / 582,583 (U.S. Publication No. 2020 / 0241015; Reference No. 13547USO1), which is incorporated in its entirety by reference, the creatinine-sensitive active region may include an enzyme system comprising several enzymes capable of working together to facilitate the detection of creatinine. Creatinine may react reversibly and hydrolytically in the presence of creatinine amide hydrolase (CNH) to produce creatine. Creatine may then undergo catalytic hydrolysis in the presence of creatinine amide hydrolase (CRH) to produce sarcosine. Sarcosine produced by the hydrolysis of creatine may be oxidized in the presence of the oxidized form of sarcosine oxidase (SOX-ox) to produce glycine and formaldehyde, thereby generating the reduced form of sarcosine oxidase (SOX-red) in this process. Hydrogen peroxide may also be produced in the presence of oxygen. The reduced form of sarcosin oxidase can then be reoxidized in the presence of the oxidized form of the electron transfer agent (e.g., Os(III)), thereby generating the corresponding reduced form of the electron transfer agent (e.g., Os(II)), which delivers a flow of electrons to the working electrode.

[0079] ethanol As described below with reference to Figures 5A-5B of U.S. Patent Application No. 16 / 774,909 (Reference No. 13622USO1), which is incorporated in its entirety by reference, the ethanol-sensitive active region may include an enzyme system comprising multiple enzymes capable of working together to facilitate the detection of ethanol. For example, a cooperative enzyme reaction of alcohol oxidase and xanthine oxidase may be used to detect ethanol. The xanthine oxidase may be covalently bonded to the polymer within the active region of the test substance sensor, and the alcohol oxidase may be noncovalently bonded to the polymer within the active region. In addition to the xanthine oxidase, an osmium complex or other transition metal complex capable of exchanging electrons with this enzyme may also be covalently bonded to the polymer. Ethanol reacts with oxidized (active) alcohol oxidase in the presence of a flavin cofactor (FAD already bound to alcohol oxidase), thereby producing reduced alcohol oxidase, acetaldehyde, and hydrogen peroxide. Reduced alcohol oxidase is reoxidized by oxygen molecules, as shown, returning it to its catalytically active oxidized form. The acetaldehyde produced from ethanol by the catalytic reaction then undergoes a secondary reaction with the oxidized form of xanthine oxidase in the presence of a flavin cofactor naturally present with the enzyme. Acetic acid is produced in this process, and xanthine oxidase is converted to a reduced state. Reduced xanthine oxidase may then react with a transition metal electron transfer agent bound to the polymer to transfer electrons to the working electrode, thereby generating an electric current and regenerating the oxidized form of xanthine oxidase. Hydrogen peroxide may be spontaneously removed from the sensor environment by catalase present within the active region. The amount of acetaldehyde produced by the catalytic reaction is proportional to the amount of ethanol originally present. Thus, the electric current generated at the working electrode during the xanthine oxidase oxidation of acetaldehyde may be proportional to the amount of acetaldehyde present, and therefore to the amount of ethanol. The correlation between the working electrode current and the ethanol concentration may be determined by referring to a reference table of currents at known ethanol concentrations, or by using a calibration curve.

[0080] Ketones As described below with reference to Figures 2A-2C of U.S. Patent Application No. 16 / 774,835 (U.S. Publication No. 2020 / 0237275; Reference No. 13548USO1), which is incorporated in its entirety by reference, the ketone-sensitive active region may include an enzyme system comprising several enzymes capable of working together to facilitate ketone detection. For example, β-hydroxybutyrate dehydrogenase (HBDH) and diaphorase may be deposited within the ketone-sensitive active region on the surface of at least one working electrode, as further described herein. The ketone-sensitive active region comprises this pair of cooperative enzymes, the β-hydroxybutyrate dehydrogenase capable of converting β-hydroxybutyrate and oxidized nicotinamide adenine dinucleotide (NAD+) to acetacetate and reduced nicotinamide adenine dinucleotide (NADH), respectively. The enzyme cofactors NAD+ and NADH help to facilitate the cooperative enzyme reaction described herein. NADH may then be reduced mediated by a diaphorase, and the electrons transferred during this process provide a reference for ketone detection at the working electrode. Thus, a 1:1 Moller correspondence exists between the amount of electrons transferred to the working electrode and the amount of converted β-hydroxybutyrate, thereby providing a reference for ketone detection and quantification based on the measured amount of current at the working electrode. The transfer of electrons to the working electrode due to NADH reduction may be carried out through an electron transfer agent such as an osmium (Os) complex, as further described below. Albumin may be present as a stabilizer along with this pair of cooperative enzymes. According to certain embodiments, β-hydroxybutyrate dehydrogenase and diaphorase may be covalently bonded to the polymer within the ketone-sensitive active region of the test substance sensor. NAD+ may or may not be covalently bonded to the polymer; however, if NAD+ is not covalently bonded, it may be physically retained within the ketone-sensitive active region. The membrane covering the ketone-sensitive active region may help retain NAD+ within the ketone-sensitive active region while allowing sufficient internal diffusion of the ketone to enable ketone detection. Suitable membrane polymers for covering the ketone-sensitive active region are further described herein.

[0081] In an alternative system, β-hydroxybutyrate dehydrogenase (HBDH) can convert β-hydroxybutyrate and NAD+ back to acetacetate and NADH, respectively. Instead of electron transfer to the working electrode completed by diaphorase and transition metal electron transfer agents, the reduced form of NADH oxidase (NADHOx(Red)) reacts to produce the corresponding oxidized form (NADHOx(Ox)). Reaction with oxygen molecules may then produce NADHOx(Red) again, which can undergo secondary conversion to hydrogen peroxide under the mediation of superoxide dismutase (SOD) to generate a superoxide. The hydrogen peroxide is then reduced at the working electrode, which can provide a signal that can be correlated with the amount of ketone initially present. According to various embodiments, SOD can be covalently bonded to a polymer within the ketone-sensitive active region. As in the previously described enzyme system, β-hydroxybutyrate dehydrogenase and NADH oxidase may be covalently bound to the polymer within the ketone-sensitive active region, and NAD may or may not be covalently bound to the polymer within the ketone-sensitive active region. If NAD+ is not covalently bound, it may be physically retained within the ketone-sensitive active region, and the membrane polymer facilitates the retention of NAD+ within the ketone-sensitive active region.

[0082] Another enzymatic detection chemistry for ketones may involve using β-hydroxybutyrate dehydrogenase (HBDH) to convert β-hydroxybutyrate and NAD+ to acetacetate and NADH, respectively. In this case, the electron transfer cycle is completed at the working electrode by poly-1,10-phenanthroline-5,6-dione to regenerate NAD. Poly-1,10-phenanthroline-5,6-dione may or may not be covalently bound to the polymer within the ketone-sensitive active region. As in the previously described enzyme system, β-hydroxybutyrate dehydrogenase may be covalently bound to the polymer within the ketone-sensitive active region, and NAD may or may not be covalently bound to the polymer within the ketone-sensitive active region. The inclusion of albumin within the active region may provide remarkable improvements in sensitivity stability. A suitable membrane polymer may promote the retention of NAD+ within the ketone-sensitive active region.

[0083] Lactic acid As shown below in U.S. Patent Application No. 16 / 259,157 (U.S. Publication No. 2019 / 0320947; Reference No. 13335USO1), which is incorporated herein by reference in its entirety, a lactate-sensitive active region may include an enzyme system comprising multiple enzymes capable of working together to facilitate the detection of lactate. The lactate-sensitive active region may facilitate the detection of lactate by exchanging glucose oxidase for lactate oxidase. Such a lactate-sensitive test substance sensor based on modified glucose-sensitive sensor chemistry is described in U.S. Patent No. 9,914,952, co-owned, which is incorporated herein by reference in its entirety. As described herein, improvements in analytical sensitivity and some sensitivity stability to lactate may be achieved by modifying the glucose-sensitive sensor chemistry to include catalase within the active region, where lactate oxidase is present instead. While catalase incorporation is somewhat aided, it does not completely stabilize the long-term sensitivity of the test substance sensor. On the contrary, the lactate signal in catalase-containing test substance sensors decreases by up to approximately 10% over 48 hours of monitoring. Since catalase is known to be sensitive to hydrogen peroxide, the stabilizing effect of catalase in lactate-sensitive test substance sensors is believed to involve removing excess hydrogen peroxide that would otherwise affect the activity of lactate oxidase. While catalase improves the performance of lactate-sensitive test substance sensors, further performance improvements may be needed for such sensors to sense the true potential.

[0084] The performance of lactate-sensitive steroid sensors can be improved by using other stabilizers, such as albumin, instead of catalase, and by modifying the substance transfer limiting membrane deposited over the active region. As described in U.S. Patent Application No. 16 / 259,157 (U.S. Publication No. 2019 / 0320947; Reference No. 13335USO1), previously incorporated by reference, several different membrane chemistry or configurations can facilitate improved steroid sensor performance for lactate steroids.

[0085] According to this disclosure, the test substance may be monitored in any biological fluid of interest, such as dermal fluid, interstitial fluid, plasma, blood, lymph, synovial fluid, cerebrospinal fluid, saliva, bronchoalveolar lavage, amniotic fluid, etc. In certain embodiments, the test substance sensor of this disclosure may be applied to analyze dermal fluid or interstitial fluid to determine the concentration of the test substance in vivo.

[0086] The sensitive active regions of different test substances may be located on the same working electrode on the same sensor or on different working electrodes. In some embodiments of this disclosure, for example, a creatinine-sensitive test substance sensor may further incorporate a glucose-sensitive active region to sense both creatinine and glucose.

[0087] When the first and second test substance-sensitive active regions are located on a single working electrode, one of the active regions may be configured to independently query and facilitate the detection of each test substance, as described below. In particular, the first and second test substance-sensitive active regions may contain different electron transfer agents, resulting in one active region independently generating a signal for the other. Either the first or second test substance-sensitive active region may be configured to independently generate a signal for the other active region.

[0088] In embodiments where a first test substance-sensitive active region and a second test substance-sensitive active region are located on a single working electrode, the redox potential associated with the second test substance-sensitive active region may be at least about 100 mV, or at least about 150 mV, or at least about 200 mV, from the redox potential of the first test substance-sensitive active region. The upper limit of dissociation between the redox potentials is determined by the in vivo working electrochemical window. By having redox potentials of two active regions that are sufficiently far apart in size from each other, electrochemical reactions may occur within the two active regions without substantially inducing an electrochemical reaction in the other active region. Thus, signals from either the first or second test substance-sensitive active region may be generated independently at a redox potential greater than or equal to the corresponding redox potential (lower redox potential) but below the redox potential (higher redox potential) of the other sensitive active region. In contrast, at redox potentials above the other active region (higher redox potentials) that have not been previously investigated, electrochemical reactions can occur within both active regions. Thus, generating a signal above the redox potential may include signal contributions from both the first and second test substance-sensitive active regions, and the observed signal is a composite signal. The signal contribution from one active region above the redox potential (either the first or second sensitive active region) can then be determined by removing the corresponding signals above the redox potential, obtained only from either the first or second test substance-sensitive active region, from the composite signal.

[0089] In a more specific embodiment, when the active regions are located on the same working electrode, the first test substance-sensitive active region and the second test substance-sensitive active region may contain different electron transfer agents, thereby obtaining redox potentials that are sufficiently separated from each other. More specifically, the first test substance-sensitive active region may contain a first electron transfer agent, and the second test substance-sensitive active region may contain a second electron transfer agent, and the first and second electron transfer agents are different from each other. According to various embodiments of this disclosure, the metal centers and / or ligands present in a given electron transfer agent may be modified to provide sufficient separation of the redox potentials between the two regions.

[0090] Ideally, a first and second test substance-sensitive active region located on a single working electrode may be configured to rapidly reach a steady current when the test substance sensor is operated at a given potential. Rapid arrival at a steady current can be facilitated by selecting electron transfer agents for each active region that change their oxidation state immediately upon exposure to a potential above the redox potential. Rapid arrival at a steady current can also be facilitated by making the active regions as thin as possible. For example, an appropriate thinness for a sensitive active region may be from about 0.1 microns (μm) to about 10 microns (μm). In some or other embodiments, rapid arrival at a steady current can be facilitated by including a conductive material, such as carbon nanotubes, graphite, or metal nanoparticles, within one or more active regions. An appropriate amount of conductive molecules may range from about 0.1% to about 50% by weight of the active region, or from about 1% to about 50% by weight, or from about 0.1% to about 10% by weight, or from about 1% to about 10% by weight. Stabilizers may also be employed to enhance sensitive stability.

[0091] The sensitivity (output current) of the substance sensor to each substance can be altered by changing the coverage (area or size) of the active region, the area ratio of the active regions to each other, and the identity, thickness, and / or composition of the substance migration limiting film covering the active region. These parameter changes can be readily implemented by those skilled in the art who recognize the advantages described herein.

[0092] Other embodiments of the test substance sensor disclosed herein may be characterized in that a first test substance-sensitive active region and a second test substance-sensitive active region are located on the surfaces of different working electrodes. Such a test substance sensor may further comprise a second working electrode, a second test substance-sensitive active region disposed on the surface of the second working electrode, and a second film that is permeable to the second test substance and covers the second test substance-sensitive active region. The second test substance-sensitive active region may comprise a second electron transfer agent, a third polymer, and an enzyme covalently bound to the third polymer. When the first and second test substance-sensitive active regions are located on separate working electrodes, the electron transfer agents associated with each active region may be the same or different from each other.

[0093] film Even with controlled and appropriate detection chemistry, incorporating two different types of active regions (either on the same working electrode or on different working electrodes) onto a single test substance sensor is not always straightforward. Test substance sensors often employ a membrane covering the active region to function as a substance transfer limiting membrane and / or to improve biocompatibility. Limiting the access of the test substance to the active region with a substance transfer limiting membrane helps avoid sensor overload (saturation), thereby potentially improving detection performance and accuracy. When analyzing multiple test substances using a single test substance sensor, different test substances beyond a given substance transfer limiting membrane may exhibit different permeability values, potentially resulting in widely and completely different sensitivities for each test substance. Incorporating different substance transfer limiting membranes onto each active region can be problematic in some cases. Surprisingly, and advantageously, certain test substances, such as glucose and creatinine, can be successfully analyzed using compositionally identical substance transfer limiting membranes at each location, thereby simplifying the fabrication of test substance sensors that have the capability to detect both test substances.

[0094] As will be described in more detail below, at least one mass transfer restriction membrane may cover a first test substance-sensitive active region and, optionally, a second test substance-sensitive active region, if present. For example, if present, the glucose-sensitive active region may include a glucose-sensitive enzyme. The mass transfer restriction membrane may also cover an oxygen scavenger (e.g., glucose oxidase), in which case the oxygen scavenger may be sandwiched between the separated membrane layers.

[0095] In vivo spectrometry sensors may also include a membrane deposited on at least the embedded portion of the spectrometry sensor. In one embodiment, the membrane may improve the biocompatibility of the spectrometry sensor. In another embodiment, the membrane may be permeable or semipermeable to the spectrometry of interest, restricting the overall flow of the spectrometry to the active region of the spectrometry sensor. In other words, the membrane may function as a substance migration restriction membrane. Restricting the access of the spectrometry to the active region of the sensor by a substance migration restriction membrane helps to avoid sensor overload (saturation), thereby improving detection performance and accuracy. Such membranes may be highly specialized in restricting the migration of a particular spectrometry, while other substances permeate the membrane at significantly different rates. The differing membrane permeability of various potential spectrometry substances presents a significant obstacle to developing spectrometry sensors configured for the analysis of multiple spectrometry substances. That is, changing membrane permeability values ​​leads to significantly different sensitivities to multiple spectrometry substances, thereby making analysis difficult. The differing sensitivities to multiple test substances can often be partially overcome by using active regions of different sizes (e.g., smaller active regions for highly sensitive / permeable test substances and larger active regions for less sensitive / permeable test substances), but this approach may present significant manufacturing challenges and is not applicable in all cases.

[0096] In certain embodiments of this disclosure, the substance transfer restriction film covering the substance-sensitive active region may comprise at least a crosslinked polyvinylpyridine homopolymer or copolymer containing polyvinylpyridine-co-styrene polymer. Substance transfer restriction films having similar compositions may similarly cover oxygen scavengers such as glucose oxidase. Where a substance transfer restriction film covers each active region, the compositions of the substance transfer restriction films may be the same or different. Suitable techniques for depositing the substance transfer restriction film onto the active region may include, for example, spray coating, paint, inkjet printing, stencil, roller coating, striping, slot stain coating, dipping coating, and some combinations thereof.

[0097] Therefore, a substance sensor capable of detecting multiple substances may include an embedded sensor tail comprising: a first working electrode; a second working electrode, wherein the first and second working electrodes are separated by a substrate; a reference electrode; a counter electrode; a layer of reference material; a first substance-sensitive active region disposed on the surface of the first working electrode; and a second substance-sensitive active region disposed on the surface of the second working electrode.

[0098] A detection method for analyzing multiple test substances involves exposing a test substance sensor to a fluid containing at least a first test substance and a second test substance, wherein the test substance sensor comprises an embedded sensor tail having a first working electrode, a second working electrode, a reference electrode, a counter electrode, a layer of reference material, a first test substance-sensitive active region located on the surface of the first working electrode, and a second test substance-sensitive active region located on the surface of the second working electrode, and the first and second working electrodes are separated by a substrate, and the method involves exposing the test substance sensor and the second The method may include applying potentials (or potentials different from each other) to a first working electrode and a second working electrode; obtaining a first signal that is above the redox potential of the first test substance-sensitive activity region and is proportional to the concentration of the first test substance in the fluid; obtaining a second signal that is above the redox potential of the second test substance-sensitive activity region and is proportional to the concentration of the second test substance in the fluid; and correlating the first signal with the concentration of the first test substance in the liquid and the second signal with the concentration of the second test substance in the liquid. The signals may be measured simultaneously or at different times.

[0099] In an alternative embodiment, the test substance sensor (or subsensor) comprises a first working electrode, a second working electrode electrically insulated from the first working electrode, a first test substance-sensitive active region located on the surface of the first working electrode, and a second test substance-sensitive active region located on the surface of the second working electrode, wherein the subsensor may share the counter electrode and / or reference electrode from another sensor if the sensor tail does not include a counter electrode and / or reference electrode. The sensor may further comprise additional electrodes (e.g., a third working electrode and a fourth working electrode). The third working electrode may further comprise a third test substance-sensitive active region comprising a third electron transfer agent, a third polymer, and an enzyme system comprising a plurality of enzymes capable of working together to facilitate the detection of a third test substance. The fourth working electrode may further comprise a fourth test substance-sensitive active region comprising a fourth electron transfer agent, a fourth polymer, and an enzyme system comprising a plurality of enzymes capable of working together to facilitate the detection of a third test substance.

[0100] A detection method for analyzing multiple test substances may include exposing a test substance sensor to a fluid containing at least a first test substance and a second test substance, wherein the test substance sensor comprises an embedded sensor tail having a first working electrode, a second working electrode, a first test substance-sensitive active region located on the surface of the first working electrode, and a second test substance-sensitive active region located on the surface of the second working electrode, and the test substance sensor does not include a counter electrode or a reference electrode; applying a potential to the first and second working electrodes; obtaining a first signal which is above the redox potential of the first test substance-sensitive active region and is proportional to the concentration of the first test substance in the fluid; obtaining a second signal which is above the redox potential of the second test substance-sensitive active region and is proportional to the concentration of the second test substance in the fluid; and correlating the first signal with the concentration of the first test substance in the liquid and the second signal with the concentration of the second test substance in the liquid. If additional working electrodes are present, the method may include applying potentials to the third and fourth working electrodes; obtaining a third signal having an oxidation-reduction potential above that of the third test substance-sensitive active region and proportional to the concentration of the third test substance in the fluid; obtaining a fourth signal having an oxidation-reduction potential above that of the fourth test substance-sensitive active region and proportional to the concentration of the fourth test substance in the fluid; and correlating the third signal with the concentration of the third test substance in the liquid and the fourth signal with the concentration of the fourth test substance in the liquid.

[0101] In another embodiment, an on-body device of the present disclosure may comprise a housing and a first sensor and a second sensor disposed within the housing, wherein the first sensor comprises an embedded sensor tail comprising a first working electrode, a second working electrode, a shared reference electrode, and a shared counter electrode, and the second sensor comprises an embedded sensor tail comprising a first working electrode and a second working electrode, and the second sensor does not include a counter electrode and a reference electrode. In some embodiments, the second sensor may include a third working electrode and a fourth working electrode. The third and fourth working electrodes may comprise a fifth test substance-sensitive active region disposed on the surface of the third working electrode of the second sensor, and a sixth test substance-sensitive active region disposed on the surface of the fourth working electrode of the second sensor.

[0102] In another embodiment, an on-body device of the present disclosure may include a first housing and a first sensor disposed within the first housing, the first sensor comprising an embedded sensor tail having a first working electrode, a second working electrode, a reference electrode, and a counter electrode; and a second housing and a second sensor disposed within the second housing, the second sensor comprising an embedded sensor tail having a first working electrode and a second working electrode, but without a counter electrode and a reference electrode. In some embodiments, the second sensor may include a third working electrode and a fourth working electrode. The third and fourth working electrodes may include a fifth substance-sensitive active region disposed on the surface of the third working electrode of the second sensor, and a sixth substance-sensitive active region disposed on the surface of the fourth working electrode of the second sensor.

[0103] A detection method for analyzing multiple test substances involves exposing a test substance sensor system to a fluid containing at least a first test substance, a second test substance, a third test substance, and a fourth test substance, wherein the test substance sensor system comprises a first sensor and a second sensor, the first sensor having an embedded sensor tail comprising a first working electrode, a second working electrode, a shared reference electrode, and a shared counter electrode, the second sensor having an embedded sensor tail comprising a first working electrode and a second working electrode, the second sensor not comprising a counter electrode and a reference electrode, each of the first working electrode and the second working electrode of the first sensor having a first test substance-sensitive active region and a second test substance-sensitive active region, each of the first working electrode and the second working electrode of the second sensor having a third test substance-sensitive active region and a fourth test substance-sensitive active region, and the method involves exposing the test substance sensor system to a fluid containing at least a first test substance, a second test substance, a third test substance-sensitive active region, and the fourth The method may also include applying a potential to the first working electrode and the second working electrode of the first sensor and the second sensor, obtaining a first signal whose redox potential is above the redox potential of the first test substance-sensitive active region and is proportional to the concentration of the first test substance in the fluid, obtaining a second signal whose redox potential is above the redox potential of the second test substance-sensitive active region and is proportional to the concentration of the second test substance in the fluid, obtaining a third signal whose redox potential is above the redox potential of the third test substance-sensitive active region and is proportional to the concentration of the third test substance in the fluid, obtaining a fourth signal whose redox potential is above the redox potential of the third test substance-sensitive active region and is proportional to the concentration of the fourth test substance in the fluid, and correlating the first signal, second signal, third signal, and fourth signal with the concentrations of the first test substance, second test substance, third test substance, and fourth test substance in the fluid, respectively. With respect to the potentials applied to the first, second, third, and fourth electrodes, the same potential may be applied to all electrodes, different potentials may be applied to different electrodes, or the same potential may be applied to some electrodes and different potentials to others.

[0104] In some embodiments, the detected test substances include, but are not limited to, glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactic acid.

[0105] In some embodiments, the test substance sensor may further comprise a first film that is permeable to a first test substance and covers a first test substance-sensitive active region, and a second film that is permeable to a second test substance and covers a second test substance-sensitive active region. The films may have the same composition or different compositions. In a sensor device having multiple sensitive active regions, the sensor may include as many different films as there are different sensitive active regions.

[0106] In some embodiments, the reference material layer within the sensor tail may contain Ag and AgCl. The reference material layer may be placed on the counter electrode or the reference electrode. In some embodiments, each of the first and second test substance-sensitive active regions comprises an electron transfer agent covalently bonded to the polymer in each of the first and second test substance-sensitive active regions. Alternatively, the first test substance-sensitive active region further comprises a first electron transfer agent, a first polymer, and an enzyme system comprising a plurality of enzymes capable of working together to facilitate the detection of the first test substance, and the second test substance-sensitive active region further comprises a second electron transfer agent, a second polymer, and an enzyme system comprising a plurality of enzymes capable of working together to facilitate the detection of the second test substance.

[0107] In embodiments that include a subsensor sharing a counter electrode and reference electrode on another sensor rather than having the counter electrode and reference electrode on the tail of the embedded sensor, the sensor system may include an analog front-end circuit that receives data on the substance being tested from all working electrodes of the subsensor in addition to the working electrodes of the sensor on which the counter electrode and reference electrode are located. For example, if the primary sensor has two working electrodes and a counter electrode and reference electrode, and the subsensor has four working electrodes (without a counter electrode and reference electrode), the analog front-end circuit may receive data from the first and second working electrodes of the first (primary) sensor, and the first, second, third, and fourth working electrodes of the second (sub) sensor. The analog front-end circuit may be installed within the housing of the primary sensor or within the housing of the subsensor.

[0108] In some embodiments, the signal may be correlated to the corresponding concentration of the test substance by referring to a reference table or calibration curve. A reference table of the test substance may be added by analyzing multiple samples with known test substance concentrations and recording the sensor response at each concentration. Similarly, a calibration curve of the test substance may be determined by plotting the test substance sensor response against the test substance concentration and determining an appropriate calibration function over the calibration range (e.g., by regression, specifically by linear regression).

[0109] The processor determines which sensor sensitivity value in the reference table is closest to the value measured for a sample with an unknown concentration of the test substance, and then reports the concentration of the test substance based on that. In some embodiments or other embodiments, if the sensor sensitivity value for a sample with an unknown concentration of the test substance falls between two values ​​recorded in the reference table, the processor may estimate the concentration of the test substance by interpolating between the two values ​​in the reference table. The interpolation may assume a linear change in concentration between the two values ​​recorded in the reference table. Interpolation may be employed if the sensor sensitivity differs from a given value in the reference table by a significant amount, such as 10% or more.

[0110] Similarly, according to some or other various embodiments, the processor may input a sensor-sensitive value for a sample having an unknown concentration of the test substance into a corresponding calibration function. The processor may then report the concentration of the test substance based on this.

[0111] The sensor tail may further comprise an additional working electrode having a test substance-sensitive active region positioned thereon, the test substance-sensitive active region may include a second electron transfer agent, a third polymer, and an enzyme covalently bonded to the third polymer. Thus, the method may further include applying a potential to the additional working electrode, obtaining an additional signal above the redox potential of each test substance-sensitive active region and proportional to the concentration of the test substance in the fluid, and correlating the additional signal with the concentration of the test substance in the fluid.

[0112] In a more specific embodiment, to provide sufficient separation to independently generate a signal from the first active region, the redox potential associated with the first test substance-sensitive active region may be at least about 100 mV, or at least about 150 mV, or at least about 200 mV, from the redox potential of the second test substance-sensitive active region. The difference in redox potentials may result from incorporating different electron transfer agents within the active regions. Similarly, to provide sufficient separation to independently generate a signal from the first active region, the redox potential associated with each of the third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth test substance-sensitive active regions may be at least about 100 mV, or at least about 150 mV, or at least about 200 mV, from any of the other redox potentials.

[0113] The method may further include applying a potential to a first working electrode and a potential to a second working electrode; obtaining a first signal having a redox potential above the first test substance-sensitive activity region and proportional to the concentration of the first test substance in the fluid; obtaining a second signal having a redox potential above the glucose-sensitive activity region and proportional to the concentration of the second test substance in the fluid; and correlating the first signal with the concentration of the first test substance in the fluid and correlating the second signal with the concentration of the second test substance in the fluid.

[0114] In a more specific embodiment, signals from different working electrodes may be measured at different times. For example, if two working electrodes are present, the potential may be applied alternately to the first and second working electrodes. In another specific embodiment, the first and second signals may be measured simultaneously through the first and second channels, in which case the potential may be applied to both electrodes simultaneously. In other cases, the signals associated with each active region may be correlated to the concentration of the respective test substance in a manner similar to that described above, using a reference table and calibration function.

[0115] Figures 8A–D show exemplary plots of the test substance sensor response to changes in glucose and ketone concentrations. As shown in Figures 8C and 8D, the test substance sensor showed a linear response to both test substances across the tested concentration range. As shown in Figure 8A, the sensor response was rapid for both test substances and remained stable at a given test substance concentration. Figures 9A–D show exemplary plots of the test substance sensor response to changes in glucose and lactate concentrations. As shown in Figures 9C and 9D, the test substance sensor showed a linear response to both test substances across the tested concentration range. As shown in Figure 9A, the sensor response was rapid for both test substances and remained stable at a given test substance concentration. Typical compositions of the active sites and membranes for glucose, ketone, and lactate can be found in U.S. Patent Application No. 16 / 774,835 (U.S. Publication No. 2020 / 0237275; Reference No. 13548USO1) and U.S. Patent Application No. 16 / 259,157 (U.S. Publication No. 2019 / 0320947; Reference No. 13335USO1), which are incorporated in their entirety by reference for all purposes.

[0116] The embodiments described herein are described and extended in the following paragraphs without explicit reference to the figures. In many embodiments, a test substance sensor is described. The test substance sensor includes a first working electrode, a second working electrode in which the first and second working electrodes are separated by a substrate, a reference electrode, a counter electrode, a layer of reference material, a first test substance-sensitive active region disposed on the surface of the first working electrode, and a second test substance-sensitive active region disposed on the surface of the second working electrode.

[0117] In some embodiments, the test substance sensor also includes a first film that is permeable to the first test substance and covers a first test substance-sensitive active region, and a second film that is permeable to the second test substance and covers a second test substance-sensitive active region. In some embodiments, the first film covers both the first and second test substance-sensitive active regions.

[0118] In some embodiments, each of the first test substance-sensitive active region and the second test substance-sensitive active region comprises an electron transfer agent covalently bonded to the polymer in each of the first test substance-sensitive active region and the second test substance-sensitive active region.

[0119] In some embodiments, the first test substance-sensitive active region further comprises a first electron transfer agent, a first polymer, and an enzyme system comprising a plurality of enzymes capable of working together to facilitate the detection of the first test substance.

[0120] In some embodiments, the second test substance-sensitive active region further comprises a second electron transfer agent, a second polymer, and an enzyme system comprising a plurality of enzymes capable of working together to facilitate the detection of the second test substance.

[0121] In some embodiments, the reference material layer includes Ag and AgCl. In some embodiments, a layer of reference material is placed on top of the counter electrode or the reference electrode.

[0122] In some embodiments, the first test substance is selected from the group consisting of glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactic acid. In some embodiments, the second test substance is selected from the group consisting of glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactic acid.

[0123] In some embodiments, the implantable sensor tail is configured to be inserted into tissue. In some embodiments, the first and second films have different compositions from each other.

[0124] In some embodiments, the first and second films have the same composition. In some embodiments, the first working electrode is isolated from the counter electrode or reference electrode by a dielectric layer.

[0125] In some embodiments, the second working electrode is isolated from the counter electrode or reference electrode by a dielectric layer. In some embodiments, the substance sensor further includes a first dielectric layer and a second dielectric layer disposed on a reference electrode and a counter electrode.

[0126] In many embodiments, a method is described. The method is a step of exposing a substance sensor to a fluid containing at least a first substance and a second substance, wherein the substance sensor comprises an embedded sensor tail having a first working electrode, a second working electrode, a reference electrode, a counter electrode, a layer of reference material, a first substance-sensitive active region disposed on the surface of the first working electrode, and a second substance-sensitive active region disposed on the surface of the second working electrode, and the first and second working electrodes are separated by a substrate. The method includes the steps of: applying an electric potential to a first working electrode and a second working electrode; obtaining a first signal having an oxidation-reduction potential above that of the first substance-sensitive active region and proportional to the concentration of the first substance in the fluid; obtaining a second signal having an oxidation-reduction potential above that of the second substance-sensitive active region and proportional to the concentration of the second substance in the fluid; and correlating the first signal with the concentration of the first substance in the liquid and correlating the second signal with the concentration of the second substance in the liquid.

[0127] In some embodiments, the embedded sensor tail further comprises a first film that is permeable to the first test substance and covers a first test substance-sensitive active region, and a second film that is permeable to the second test substance and covers a second test substance-sensitive active region.

[0128] In some embodiments, each of the first test substance-sensitive active region and the second test substance-sensitive active region comprises an electron transfer agent covalently bonded to the polymer in each of the first test substance-sensitive active region and the second test substance-sensitive active region.

[0129] In some embodiments, the first test substance-sensitive active region further comprises a first electron transfer agent, a first polymer, and an enzyme system comprising a plurality of enzymes capable of working together to facilitate the detection of the first test substance.

[0130] In some embodiments, the second test substance-sensitive active region further comprises a second electron transfer agent, a second polymer, and an enzyme system comprising a plurality of enzymes capable of working together to facilitate the detection of the second test substance.

[0131] In some embodiments, the reference material layer includes Ag and AgCl. In some embodiments, a layer of reference material is placed on top of the counter electrode or the reference electrode.

[0132] In some embodiments, the first test substance is selected from the group consisting of glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactic acid. In some embodiments, the second test substance is selected from the group consisting of glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactic acid.

[0133] In some embodiments, the implantable sensor tail is configured to be inserted into tissue. In some embodiments, the first and second membranes have different compositions. In some embodiments, the first and second membranes have the same composition.

[0134] In some embodiments, the first working electrode is isolated from the counter electrode or reference electrode by a dielectric layer. In some embodiments, the second working electrode is isolated from the counter electrode or reference electrode by a dielectric layer.

[0135] In some embodiments, the substance sensor further includes a first dielectric layer and a second dielectric layer disposed on a reference electrode and a counter electrode. In some embodiments, the fluid is a biological fluid, and the substance sensor is exposed to the biological fluid in vivo.

[0136] In some embodiments, the first signal and the second signal are measured at different times. In some embodiments, the first signal and the second signal are measured simultaneously.

[0137] In some embodiments, the first signal and the second signal are acquired simultaneously through the first channel and the second channel. In many embodiments, a test substance sensor is described. The test substance sensor includes an embedded sensor tail comprising a first working electrode, a second working electrode electrically insulated from the first working electrode, a first test substance-sensitive active region located on the surface of the first working electrode, and a second test substance-sensitive active region located on the surface of the second working electrode.

[0138] In some embodiments, the test substance sensor further includes a first film that is permeable to the first test substance and covers a first test substance-sensitive active region. In some embodiments, the test substance sensor further includes a second film that is permeable to the second test substance and covers a second test substance-sensitive active region.

[0139] In some embodiments, the first working electrode and the second working electrode are separated by a substrate. In some embodiments, the first working electrode and the second working electrode are separated by a dielectric layer.

[0140] In some embodiments, a third working electrode and a third substance-sensitive active region disposed on the surface of the third working electrode. In some embodiments, the substance sensor further includes a third working electrode and a third substance-sensitive active region located on the surface of the third working electrode. In some embodiments, the substance sensor further includes a fourth working electrode and a fourth substance-sensitive active region located on the surface of the fourth working electrode.

[0141] In some embodiments, each of the first test substance-sensitive active region and the second test substance-sensitive active region comprises an electron transfer agent that is covalently bonded to the polymer in each of the first test substance-sensitive active region and the second test substance-sensitive active region, respectively.

[0142] In some embodiments, the test substance sensor further includes a first test substance-sensitive active region comprising a first electron transfer agent, a first polymer, and an enzyme system comprising a plurality of enzymes capable of working together to facilitate the detection of the first test substance.

[0143] In some embodiments, the test substance sensor further includes a second test substance-sensitive active region comprising a second electron transfer agent, a second polymer, and an enzyme system comprising a plurality of enzymes capable of working together to facilitate the detection of the second test substance.

[0144] In some embodiments, the first test substance is selected from the group consisting of glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactic acid. In some embodiments, the second test substance is selected from the group consisting of glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactic acid.

[0145] In some embodiments, the implantable sensor tail is configured to be inserted into tissue. In some embodiments, the substance sensor does not include a counter electrode and a reference electrode.

[0146] In some embodiments, the substance sensor is configured to be electrically coupled to an additional substance sensor comprising a counter electrode and a reference electrode. In many embodiments, a method is described. The method is a step of exposing a test substance sensor system to a fluid containing at least a first test substance and a second test substance, wherein the test substance sensor system comprises a first test substance sensor and a second test substance sensor, the first test substance sensor comprising an embedded sensor tail comprising a reference electrode and a counter electrode, the second test substance sensor comprising an embedded sensor tail comprising a first working electrode, a second working electrode, a first test substance-sensitive active region disposed on the surface of the first working electrode, and a second test substance-sensitive active region disposed on the surface of the second working electrode, and the second test substance sensor comprising a counter electrode The method includes the steps of: exposing a test substance sensor system that does not include a reference electrode; applying a potential to a first test substance sensor and a second test substance sensor; obtaining a first signal which is above the redox potential of the first test substance-sensitive active region and is proportional to the concentration of the first test substance in the fluid; obtaining a second signal which is above the redox potential of the second test substance-sensitive active region and is proportional to the concentration of the second test substance in the fluid; and correlating the first signal with the concentration of the first test substance in the liquid and correlating the second signal with the concentration of the second test substance in the liquid.

[0147] In some embodiments, the first substance sensor further includes at least one working electrode and at least one substance-sensitive region disposed on the surface of the working electrode. In some embodiments, each of the first test substance-sensitive active region and the second test substance-sensitive active region comprises an electron transfer agent covalently bonded to the polymer in each of the first test substance-sensitive active region and the second test substance-sensitive active region.

[0148] In some embodiments, the second test substance sensor further includes a first test substance-sensitive active region comprising a first electron transfer agent, a first polymer, and an enzyme system comprising a plurality of enzymes capable of working together to facilitate the detection of the first test substance.

[0149] In some embodiments, the second test substance sensor further includes a second test substance-sensitive active region comprising a second electron transfer agent, a second polymer, and an enzyme system comprising a plurality of enzymes capable of working together to facilitate the detection of the second test substance.

[0150] In some embodiments, the first test substance is selected from the group consisting of glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactic acid. In some embodiments, the second test substance is selected from the group consisting of glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactic acid.

[0151] In some embodiments, the implantable sensor tails of the first and second sensors are configured to be inserted into the tissue. In some embodiments, the fluid is a biological fluid, and the substance sensor is exposed to the biological fluid in vivo.

[0152] In some embodiments, the first signal and the second signal are measured at different times. In some embodiments, the first signal and the second signal are measured simultaneously.

[0153] In some embodiments, the first signal and the second signal are acquired simultaneously through the first channel and the second channel. In some embodiments, the second test substance sensor further includes a third working electrode, the third working electrode further comprises a third test substance-sensitive active region comprising a third electron transfer agent, a third polymer, and an enzyme system comprising a plurality of enzymes capable of working together to facilitate the detection of the third test substance. In some embodiments, the second test substance sensor further comprises a fourth working electrode, the fourth working electrode further comprises a fourth test substance-sensitive active region comprising a fourth electron transfer agent, a fourth polymer, and an enzyme system comprising a plurality of enzymes capable of working together to facilitate the detection of the third test substance.

[0154] In some embodiments, the method further includes the steps of: applying a potential to a third working electrode, a fourth working electrode, and a first sensor; obtaining a third signal which is above the redox potential of the third test substance-sensitive active region and is proportional to the concentration of the third test substance in the fluid; obtaining a fourth signal which is above the redox potential of the fourth test substance-sensitive active region and is proportional to the concentration of the fourth test substance in the fluid; and correlating the third signal with the concentration of the third test substance in the liquid and correlating the fourth signal with the concentration of the fourth test substance in the liquid.

[0155] In many embodiments, an on-body device used in a substance monitoring system is described. The on-body device may comprise a housing and a first sensor and a second sensor disposed within the housing, wherein the first sensor comprises an embedded sensor tail having a first working electrode, a second working electrode, a shared reference electrode, and a shared counter electrode, and the second sensor comprises an embedded sensor tail having a first working electrode and a second working electrode, and the second sensor does not include a counter electrode and a reference electrode.

[0156] In some embodiments, the first sensor further comprises a first test substance-sensitive active region located on the surface of a first working electrode of the first sensor, and a second test substance-sensitive active region located on the surface of a second working electrode of the first sensor. In some embodiments, each of the first test substance-sensitive active region and the second test substance-sensitive active region further comprises an electron transfer agent covalently bonded to the polymer in each of the first and second test substance-sensitive active regions. In some embodiments, the first test substance is selected from the group consisting of glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactic acid. In some embodiments, the second test substance is selected from the group consisting of glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactic acid. In some embodiments, the first sensor further comprises a first film that is permeable to a first test substance and covers a first test substance-sensitive active region, and a second film that is permeable to a second test substance and covers a second test substance-sensitive active region.

[0157] In some embodiments, the second sensor further comprises a third test substance-sensitive active region located on the surface of the first working electrode of the second sensor, and a fourth test substance-sensitive active region located on the surface of the second working electrode of the second sensor. In some embodiments, each of the third and fourth test substance-sensitive active regions further comprises an electron transfer agent covalently bonded to the polymer in each of the third and fourth test substance-sensitive active regions. In some embodiments, the third test substance is selected from the group consisting of glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactic acid. In some embodiments, the fourth test substance is selected from the group consisting of glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactic acid. In some embodiments, the second sensor further comprises a third membrane that is permeable to the third test substance and covers a third test substance-sensitive active region, and a fourth membrane that is permeable to the fourth test substance and covers a fourth test substance-sensitive active region.

[0158] In some embodiments, the implantable sensor tails of the first and second sensors are configured to be inserted into the tissue. In some embodiments, the second sensor further comprises a third working electrode and a fourth working electrode. In some embodiments, the second sensor further comprises a fifth test substance-sensitive active region located on the surface of the third working electrode of the second sensor, and a sixth test substance-sensitive active region located on the surface of the fourth working electrode of the second sensor. In some embodiments, each of the fifth test substance-sensitive active region and the sixth test substance-sensitive active region further comprises an electron transfer agent covalently bonded to the polymer in each of the fifth test substance-sensitive active region and the sixth test substance-sensitive active region. In some embodiments, the fifth test substance is selected from the group consisting of glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactic acid. In some embodiments, the sixth test substance is selected from the group consisting of glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactic acid.

[0159] In some embodiments, the device further includes an analog front-end circuit located within a housing, which receives data on the substance being tested from the first and second working electrodes of the first sensor and the first and second working electrodes of the second sensor. In some embodiments, the first and second working electrodes of the second sensor are connected to the analog front-end circuit by circuit wires. In some embodiments, the first and second working electrodes of the second sensor are connected to the analog front-end circuit by flexible circuit connections.

[0160] In some embodiments, the device further includes an analog front-end circuit located within a housing, which receives data on the substance being tested from the first and second working electrodes of the first sensor, and the first, second, third, and fourth working electrodes of the second sensor. In some embodiments, the first, second, third, and fourth working electrodes of the second sensor are connected to the analog front-end circuit by circuit wires. In some embodiments, the first, second, third, and fourth working electrodes of the second sensor are connected to the analog front-end circuit by flexible circuit connections.

[0161] In many embodiments, a method is described. The method is a step of exposing a test substance sensor system to a fluid containing at least a first test substance, a second test substance, a third test substance and a fourth test substance, wherein the test substance sensor system comprises a first sensor and a second sensor, the first sensor comprising an embedded sensor tail comprising a first working electrode, a second working electrode, a shared reference electrode and a shared counter electrode, the second sensor comprising an embedded sensor tail comprising a first working electrode and a second working electrode, the second sensor not comprising a counter electrode and a reference electrode, each of the first working electrode and the second working electrode of the first sensor comprising a first test substance-sensitive active region and a second test substance-sensitive active region, each of the first working electrode and the second working electrode of the second sensor comprising a third test substance-sensitive active region and a fourth test substance-sensitive active region, and the first sensor and The method includes the steps of: applying a potential to the first working electrode and the second working electrode of the second sensor; obtaining a first signal which is above the redox potential of the first test substance-sensitive active region and is proportional to the concentration of the first test substance in the fluid; obtaining a second signal which is above the redox potential of the second test substance-sensitive active region and is proportional to the concentration of the second test substance in the fluid; obtaining a third signal which is above the redox potential of the third test substance-sensitive active region and is proportional to the concentration of the third test substance in the fluid; obtaining a fourth signal which is above the redox potential of the third test substance-sensitive active region and is proportional to the concentration of the fourth test substance in the fluid; and correlating the first signal, second signal, third signal, and fourth signal with the concentrations of the first test substance, second test substance, third test substance, and fourth test substance in the fluid, respectively.

[0162] In some embodiments, each of the first, second, third, and fourth test substance-sensitive active regions comprises an electron transfer agent covalently bonded to the polymer in each of the first, second, third, and fourth active regions, respectively.

[0163] In some embodiments, the first test substance is selected from the group consisting of glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactic acid. In some embodiments, the second test substance is selected from the group consisting of glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactic acid.

[0164] In some embodiments, the third test substance is selected from the group consisting of glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactic acid. In some embodiments, the fourth test substance is selected from the group consisting of glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactic acid.

[0165] In some embodiments, the implantable sensor tails of the first and second sensors are configured to be inserted into the tissue. In some embodiments, at least a portion of the embedded sensor tail of the first sensor further comprises a first film deposited on a first test substance-sensitive active region and a second film deposited on a second test substance-sensitive active region.

[0166] In some embodiments, at least a portion of the embedded sensor tail of the second sensor further comprises a third film deposited on a third substance-sensitive active region and a fourth film deposited on a fourth substance-sensitive active region.

[0167] In some embodiments, the first working electrode of the first sensor is isolated from the counter electrode or reference electrode by a dielectric layer. In some embodiments, the second working electrode of the first sensor is isolated from the counter electrode or reference electrode by a dielectric layer.

[0168] In some embodiments, the substance sensor system further includes a first dielectric layer and a second dielectric layer disposed on a reference electrode and a counter electrode. In some embodiments, the fluid is a biological fluid, and the substance sensor is exposed to the biological fluid in vivo.

[0169] In some embodiments, the first signal, second signal, third signal, and fourth signal are measured at different times from each other. In some embodiments, the first signal, second signal, third signal, and fourth signal are measured simultaneously.

[0170] In some embodiments, the first signal, second signal, third signal, and fourth signal are acquired simultaneously through different channels. In some embodiments, the fluid includes a fifth test substance and a sixth test substance, and the embedded sensor tail of the second sensor further comprises a third working electrode and a fourth working electrode, each of the third and fourth working electrodes of the second sensor comprising a fifth test substance-sensitive active region and a sixth test substance-sensitive active region, respectively.

[0171] In some embodiments, the method further includes the steps of: applying a potential to the third and fourth working electrodes of a second sensor; obtaining a fifth signal which is above the redox potential of the fifth substance-sensitive active region and is proportional to the concentration of the fifth substance in the fluid; obtaining a second signal which is above the redox potential of the sixth substance-sensitive active region and is proportional to the concentration of the sixth substance in the fluid; and correlating the fifth signal and the sixth signal with the concentrations of the fifth substance and the sixth substance in the fluid, respectively.

[0172] In some embodiments, the first sensor and the second sensor are located within the same housing. In some embodiments, the first sensor is located in a first housing, and the second sensor is located in a second housing. In some embodiments, the substance sensor system further comprises an analog front-end circuit located in the first housing, which receives substance data from the first and second working electrodes of the first sensor and the first and second working electrodes of the second sensor.

[0173] In some embodiments, the substance sensor system further comprises an analog front-end circuit located within a first housing, the analog front-end circuit receiving substance data from the first and second working electrodes of the first sensor, and the first, second, third, and fourth working electrodes of the second sensor.

[0174] In some embodiments, the test substance sensor system further comprises a third sensor, the third sensor comprising an embedded sensor tail comprising a first working electrode and a second working electrode, and the third sensor does not include a counter electrode and a reference electrode. In some embodiments, the third sensor is located within a third housing. In some embodiments, the fluid comprises a seventh test substance and an eighth test substance, and the embedded sensor tail of the third sensor further comprises a first working electrode and a second working electrode, each of the first and second working electrodes of the third sensor comprising a seventh test substance-sensitive active region and an eighth test substance-sensitive active region, respectively. In some embodiments, the method further includes the steps of: applying a potential to the first working electrode and the second working electrode of the third sensor; obtaining a seventh signal which is above the redox potential of the seventh substance-sensitive active region and is proportional to the concentration of the seventh substance in the fluid; obtaining an eighth signal which is above the redox potential of the eighth substance-sensitive active region and is proportional to the concentration of the eighth substance in the fluid; and correlating the seventh signal and the eighth signal with the concentrations of the seventh substance and the eighth substance in the fluid, respectively.

[0175] In some embodiments, the fluid contains a ninth substance and a tenth substance, and the embedded sensor tail of the third sensor further comprises a third working electrode and a fourth working electrode, each of the third and fourth working electrodes of the third sensor comprising a ninth substance-sensitive active region and a tenth substance-sensitive active region, respectively. In some embodiments, the method further comprises the steps of applying a potential to the third and fourth working electrodes of the third sensor, obtaining a ninth signal which is greater than or equal to the redox potential of the ninth substance-sensitive active region and is proportional to the concentration of the ninth substance in the fluid, obtaining a tenth signal which is greater than or equal to the redox potential of the tenth substance-sensitive active region and is proportional to the concentration of the eighth substance in the fluid, and correlating the ninth and tenth signals with the concentrations of the ninth and tenth substance in the fluid, respectively.

[0176] In some embodiments, on-body devices used in a substance monitoring system are described. The device includes a first housing and a first sensor located within the first housing, the first sensor having an embedded sensor tail comprising a first working electrode, a second working electrode, a reference electrode, and a counter electrode; and a second housing and a second sensor located within the second housing, the second sensor having an embedded sensor tail comprising a first working electrode and a second working electrode, but without a counter electrode and a reference electrode.

[0177] In some embodiments, the apparatus also includes an adhesive layer, and the first and second housings are arranged on the adhesive layer. In some embodiments, the first sensor further comprises a first test substance-sensitive active region located on the surface of the first working electrode of the first sensor, and a second test substance-sensitive active region located on the surface of the second working electrode of the first sensor. In some embodiments, each of the first test substance-sensitive active region and the second test substance-sensitive active region further comprises an electron transfer agent covalently bonded to the polymer in each of the first and second test substance-sensitive active regions. In some embodiments, the first test substance is selected from the group consisting of glucose, β-hydroxybutyric acid, uric acid, ketones, creatinine, ethanol, and lactic acid. In some embodiments, the second test substance is selected from the group consisting of glucose, β-hydroxybutyric acid, uric acid, ketones, creatinine, ethanol, and lactic acid. In some embodiments, the second sensor further comprises a third test substance-sensitive active region located on the surface of the first working electrode of the second sensor, and a fourth test substance-sensitive active region located on the surface of the second working electrode of the second sensor. In some embodiments, each of the third and fourth test substance-sensitive active regions further comprises an electron transfer agent covalently bonded to the polymer in each of the third and fourth test substance-sensitive active regions. In some embodiments, the third test substance is selected from the group consisting of glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactic acid. In some embodiments, the fourth test substance is selected from the group consisting of glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactic acid.

[0178] In some embodiments, the implantable sensor tails of the first and second sensors are configured to be inserted into the tissue. In some embodiments, the second sensor further comprises a third working electrode and a fourth working electrode. In some embodiments, the second sensor further comprises a fifth test substance-sensitive active region located on the surface of the third working electrode of the second sensor, and a sixth test substance-sensitive active region located on the surface of the fourth working electrode of the second sensor. In some embodiments, each of the fifth test substance-sensitive active region and the sixth test substance-sensitive active region further comprises an electron transfer agent covalently bonded to the polymer in each of the fifth test substance-sensitive active region and the sixth test substance-sensitive active region. In some embodiments, the fifth test substance is selected from the group consisting of glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactic acid. In some embodiments, the sixth test substance is selected from the group consisting of glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactic acid.

[0179] In some embodiments, the test substance system further includes an analog front-end circuit located within a first housing, which receives test substance data from the first and second working electrodes of the first sensor and the first and second working electrodes of the second sensor. In some embodiments, the first and second working electrodes of the second sensor are connected to the analog front-end circuit by circuit wires. In some embodiments, the first and second working electrodes of the second sensor are connected to the analog front-end circuit by flexible circuit connections.

[0180] In some embodiments, the test substance system further includes an analog front-end circuit located within a housing, which receives test substance data from the first and second working electrodes of the first sensor, and the first, second, third, and fourth working electrodes of the second sensor. In some embodiments, the first, second, third, and fourth working electrodes of the second sensor are connected to the analog front-end circuit by circuit wires. In some embodiments, the first, second, third, and fourth working electrodes of the second sensor are connected to the analog front-end circuit by flexible circuit connections.

[0181] In some embodiments, the test substance system further includes a third housing disposed on an adhesive layer, and a third sensor disposed within the second housing, wherein the third sensor comprises an embedded sensor tail having a first working electrode and a second working electrode, and the third sensor does not include a counter electrode and a reference electrode. In some embodiments, the third sensor further includes a seventh test substance-sensitive active region disposed on the surface of the first working electrode of the third sensor, and an eighth test substance-sensitive active region disposed on the surface of the second working electrode of the third sensor. In some embodiments, each of the seventh test substance-sensitive active region and the eighth test substance-sensitive active region further comprises an electron transfer agent covalently bonded to the polymer in each of the seventh test substance-sensitive active region and the eighth test substance-sensitive active region. In some embodiments, the seventh test substance is selected from the group consisting of glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactic acid. In some embodiments, the eighth test substance is selected from the group consisting of glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactic acid.

[0182] In some embodiments, the test substance system further includes an analog front-end circuit located within a first housing, which receives test substance data from a first working electrode and a second working electrode of a third sensor. In some embodiments, the first and second working electrodes of the third sensor are connected to the analog front-end circuit by circuit wires. In some embodiments, the first and second working electrodes of the third sensor are connected to the analog front-end circuit by flexible circuit connections.

[0183] In some embodiments, the embedded sensor tail of the third sensor further comprises a third working electrode and a fourth working electrode, a ninth test substance-sensitive active region disposed on the surface of the third working electrode of the third sensor, and a tenth test substance-sensitive active region disposed on the surface of the fourth working electrode of the third sensor. In some embodiments, each of the ninth test substance-sensitive active region and the tenth test substance-sensitive active region further comprises an electron transfer agent covalently bonded to the polymer in each of the ninth test substance-sensitive active region and the tenth test substance-sensitive active region. In some embodiments, the ninth test substance is selected from the group consisting of glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactic acid. In some embodiments, the tenth test substance is selected from the group consisting of glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactic acid. In some embodiments, the test substance system also includes an analog front-end circuit located within a first housing, which receives test substance data from the third and fourth working electrodes of a third sensor. In some embodiments, the third and fourth working electrodes of the third sensor are connected to the analog front-end circuit by circuit wires. In some embodiments, the third and fourth working electrodes of the third sensor are connected to the analog front-end circuit by flexible circuit connections.

[0184] In many embodiments, a test substance sensor is described. The test substance sensor includes a substrate having a first side and a second side, a first working electrode mounted on the substrate, a second working electrode mounted on the substrate, a first test substance-sensitive active region located on the surface of the first working electrode, and a second test substance-sensitive active region located on the surface of the second working electrode, wherein the first test substance-sensitive active region is located closer to the distal end of the substrate than the second test substance-sensitive active region, and the distance between the proximal end of the first test substance-sensitive active region and the distal end of the second test substance-sensitive active region is at least about 0.2 mm.

[0185] In some embodiments, the first working electrode and the second working electrode are separated by an insulating layer or a dielectric layer. In some embodiments, the first working electrode is installed on the first side of the substrate, and the second working electrode is installed on the second side of the substrate.

[0186] In some embodiments, the first working electrode and the second working electrode are mounted on the first side of the substrate. In some embodiments, the distance between the proximal end of the first test substance-sensitive active region and the distal end of the second test substance-sensitive active region is between approximately 0.4 and approximately 1.1 mm.

[0187] In some embodiments, the test substance sensor further includes a first film that is permeable to a first test substance and covers a first test substance-sensitive active region, and a second film that is permeable to a second test substance and covers both the first test substance-sensitive active region and the second test substance-sensitive active region. In some embodiments, the first and second films have different compositions. In some embodiments, the first and second films have the same composition.

[0188] In some embodiments, each of the first test substance-sensitive active region and the second test substance-sensitive active region comprises an electron transfer agent covalently bonded to the polymer in each of the first test substance-sensitive active region and the second test substance-sensitive active region.

[0189] In some embodiments, the first test substance-sensitive active region further comprises a first electron transfer agent, a first polymer, and an enzyme system comprising a plurality of enzymes capable of working together to facilitate the detection of the first test substance.

[0190] In some embodiments, the second test substance-sensitive active region further comprises a second electron transfer agent, a second polymer, and an enzyme system comprising a plurality of enzymes capable of working together to facilitate the detection of the second test substance.

[0191] In some embodiments, the substance sensor further includes a reference electrode and a counter electrode. In some embodiments, the substance sensor further includes a layer of reference material on the surface of the reference electrode. In some embodiments, the reference material includes Ag and AgCl.

[0192] In some embodiments, the first test substance is selected from the group consisting of glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactic acid. In some embodiments, the first test substance is a ketone or β-hydroxybutyrate.

[0193] In some embodiments, the second test substance is selected from the group consisting of glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactic acid. In some embodiments, the second test substance is glucose.

[0194] In some embodiments, the implantable sensor tail is configured to be inserted into tissue. In some embodiments, the distal portion of the implanted sensor tail has a maximum thickness between approximately 0.25 mm and approximately 0.4 mm.

[0195] In many embodiments, a method is described. The method is a step of exposing a test substance sensor to a fluid containing at least a first test substance and a second test substance, wherein the test substance sensor comprises an embedded sensor tail having a substrate having a first side and a second side, a first working electrode placed on the first side of the substrate, a second working electrode placed on the first side of the substrate, a first test substance-sensitive active region disposed on the surface of the first working electrode, and a second test substance-sensitive active region disposed on the surface of the second working electrode, wherein the first test substance-sensitive active region is located closer to the distal end of the substrate than the second test substance-sensitive active region, and the proximal end of the first test substance-sensitive active region and the second test substance The method includes the steps of: exposing a test substance sensor to which the distance to the distal end of the material-sensitive active region is at least about 0.2 mm; applying a potential to a first working electrode and a second working electrode; obtaining a first signal which is above the redox potential of the first test substance-sensitive active region and is proportional to the concentration of the first test substance in the fluid; obtaining a second signal which is above the redox potential of the second test substance-sensitive active region and is proportional to the concentration of the second test substance in the fluid; and correlating the first signal with the concentration of the first test substance in the fluid and correlating the second signal with the concentration of the second test substance in the fluid.

[0196] In some embodiments, the first working electrode and the second working electrode are separated by an insulating layer. In some embodiments, the embedded sensor tail further comprises a first film that is permeable to the first test substance and covers the first test substance-sensitive active region, and a second film that is permeable to the second test substance and covers the first test substance-sensitive active region and the second test substance-sensitive active region.

[0197] In some embodiments, each of the first test substance-sensitive active region and the second test substance-sensitive active region comprises an electron transfer agent covalently bonded to the polymer in each of the first test substance-sensitive active region and the second test substance-sensitive active region.

[0198] In some embodiments, the first test substance-sensitive active region further comprises a first electron transfer agent, a first polymer, and an enzyme system comprising a plurality of enzymes capable of working together to facilitate the detection of the first test substance.

[0199] In some embodiments, the second test substance-sensitive active region further comprises a second electron transfer agent, a second polymer, and an enzyme system comprising a plurality of enzymes capable of working together to facilitate the detection of the second test substance.

[0200] In some embodiments, the first test substance is selected from the group consisting of glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactic acid. In some embodiments, the first test substance is a ketone or β-hydroxybutyrate.

[0201] In some embodiments, the second test substance is selected from the group consisting of glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactic acid. In some embodiments, the second test substance is glucose.

[0202] In some embodiments, the first and second films have different compositions from each other. In some embodiments, the first working electrode is separated from the second working electrode by a dielectric layer.

[0203] In some embodiments, the fluid is a biological fluid, and the substance sensor is exposed to the biological fluid in vivo. In some embodiments, the first signal and the second signal are measured at different times.

[0204] In some embodiments, the first signal and the second signal are measured simultaneously. In some embodiments, the first signal and the second signal are acquired simultaneously through the first channel and the second channel.

[0205] In some embodiments, the distal portion of the implanted sensor tail has a maximum thickness between approximately 0.25 mm and approximately 0.4 mm. In many embodiments, a test substance sensor is described. The test substance sensor includes an embedded sensor tail comprising a substrate having a first side and a second side, a first working electrode positioned on and in contact with the first side of the substrate, a first test substance-sensitive active region positioned on the surface of the first working electrode, a second working electrode positioned on and in contact with the first side of the substrate, a second test substance-sensitive active region positioned on the surface of the second working electrode, a counter electrode, and a reference electrode, wherein the first test substance-sensitive active region is positioned closer to the distal end of the substrate than the second test substance-sensitive active region.

[0206] In some embodiments, the distance between the proximal end of the first test substance-sensitive active region and the distal end of the second test substance-sensitive active region is between approximately 0.4 mm and approximately 1.1 mm. In some embodiments, the first working electrode and the second working electrode are not separated from the first side of the substrate by a dielectric layer.

[0207] In some embodiments, the counter electrode and the reference electrode are positioned on and in contact with the first side of the substrate. In some embodiments, the counter electrode and the reference electrode are not separated from the first side of the substrate by a dielectric layer.

[0208] In some embodiments, the counter electrode and the reference electrode are mounted on and in contact with the second side of the substrate. In some embodiments, the test substance sensor further includes a first film that is permeable to the first test substance and covers a first test substance-sensitive active region, and a second film that is permeable to the second test substance and covers both the first test substance-sensitive active region and the second test substance-sensitive active region.

[0209] In some embodiments, each of the first test substance-sensitive active region and the second test substance-sensitive active region comprises an electron transfer agent covalently bonded to the polymer in each of the first test substance-sensitive active region and the second test substance-sensitive active region.

[0210] In some embodiments, the first test substance-sensitive active region further comprises a first electron transfer agent, a first polymer, and an enzyme system comprising a plurality of enzymes capable of working together to facilitate the detection of the first test substance.

[0211] In some embodiments, the second test substance-sensitive active region further comprises a second electron transfer agent, a second polymer, and an enzyme system comprising a plurality of enzymes capable of working together to facilitate the detection of the second test substance.

[0212] In some embodiments, the distal portion of the implanted sensor tail has a maximum thickness between approximately 0.25 mm and approximately 0.4 mm. In many embodiments, a method is described. The method is a step of exposing a test substance sensor to a fluid containing at least a first test substance and a second test substance, wherein the test substance sensor comprises an embedded sensor tail comprising a substrate having a first side and a second side, a first working electrode placed on and in contact with the first side of the substrate, a first test substance-sensitive active region disposed on the surface of the first working electrode, a second working electrode placed on and in contact with the first side of the substrate, a second test substance-sensitive active region disposed on the surface of the second working electrode, a counter electrode, and a reference electrode, wherein the first test substance-sensitive active region is located near the second test substance-sensitive active region The method includes the steps of: exposing a sensor for a substance to be tested, which is installed near the distal end of the substrate; applying a potential to a first working electrode and a second working electrode; acquiring a first signal which is above the redox potential of the first substance-sensitive active region and is proportional to the concentration of the first substance to be tested in the fluid; acquiring a second signal which is above the redox potential of the second substance-sensitive active region and is proportional to the concentration of the second substance to be tested in the fluid; and correlating the first signal with the concentration of the first substance to be tested in the fluid and correlating the second signal with the concentration of the second substance to be tested in the fluid.

[0213] In some embodiments, the distance between the proximal end of the first test substance-sensitive active region and the distal end of the second test substance-sensitive active region is between approximately 0.4 mm and approximately 1.1 mm. In some embodiments, the first working electrode and the second working electrode are not separated from the first side of the substrate by a dielectric layer.

[0214] In some embodiments, the counter electrode and the reference electrode are positioned on and in contact with the first side of the substrate. In some embodiments, the counter electrode and the reference electrode are not separated from the first side of the substrate by a dielectric layer.

[0215] In some embodiments, the counter electrode and the reference electrode are mounted on and in contact with the second side of the substrate. In some embodiments, the test substance system further includes a first membrane that is permeable to the first test substance and covers the first test substance-sensitive active region, and a second membrane that is permeable to the second test substance and covers the first test substance-sensitive active region and the second test substance-sensitive active region.

[0216] In some embodiments, each of the first test substance-sensitive active region and the second test substance-sensitive active region comprises an electron transfer agent covalently bonded to the polymer in each of the first test substance-sensitive active region and the second test substance-sensitive active region.

[0217] In some embodiments, the first test substance-sensitive active region further comprises a first electron transfer agent, a first polymer, and an enzyme system comprising a plurality of enzymes capable of working together to facilitate the detection of the first test substance.

[0218] In some embodiments, the second test substance-sensitive active region further comprises a second electron transfer agent, a second polymer, and an enzyme system comprising a plurality of enzymes capable of working together to facilitate the detection of the second test substance.

[0219] In some embodiments, the fluid is a biological fluid, and the substance sensor is exposed to the biological fluid in vivo. In some embodiments, the first signal and the second signal are measured at different times.

[0220] In some embodiments, the first signal and the second signal are measured simultaneously. In some embodiments, the first signal and the second signal are acquired simultaneously through the first channel and the second channel.

[0221] In some embodiments, the first test substance is selected from the group consisting of glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactate. In some embodiments, the first test substance is β-hydroxybutyrate or ketone. In some embodiments, the second test substance is selected from the group consisting of glucose, β-hydroxybutyrate, uric acid, ketones, creatinine, ethanol, and lactate. In some embodiments, the second test substance is glucose.

[0222] In some embodiments, the distal portion of the implanted sensor tail has a maximum thickness between approximately 0.25 mm and approximately 0.4 mm. Unless otherwise indicated, all numbers representing quantities, etc., in this specification and related claims should be understood in all cases as being modified by the term “approximately.” Therefore, unless otherwise indicated, the numerical parameters expressed in the following specification and appended claims are approximations that may be modified depending on the desired characteristics to be obtained by embodiments of the present invention. Since there is no intention to limit the application of the doctrine of equivalents to the claims, each numerical parameter should be interpreted by applying ordinary rounding, taking into account at least significant figures.

[0223] One or more exemplary embodiments, including a variety of features, are described herein. For clarity, not all features of physical implementation are described or shown in this application. In developing physical embodiments, including embodiments of the present invention, many implementation-specific decisions must be made, such as compliance with system-related constraints, business-related constraints, government-related constraints, and other constraints, which vary depending on the implementation and time, in order to achieve the developer's goals. The developer's efforts may require considerable time, but nevertheless, such efforts are routine work for those skilled in the art who are interested in this disclosure.

[0224] Although various systems, tools, and methods are described herein using the term “comprising” various components or processes, systems, tools, and methods may also “consist essentially of” or “consist of” various components and processes.

[0225] When used herein, the term "and" or "or" preceding a set of items separates any of the items. The phrase "of)" modifies the list as a whole rather than each element (i.e., each item) of the list. The phrase "at least one" can mean at least one of any one of the items, and / or at least one of any combination of the items, and / or at least one of each of the items. For example, each of the phrases "at least one of A, B, and C" or "at least one of A, B, or C" can mean A only, B only, or C only, and / or any combination of A, B, and C, and / or at least one of each of A, B, and C.

[0226] Accordingly, the disclosed systems, tools, and methods are well adapted to achieve not only the objectives and benefits mentioned, but also those specific to them. The teachings of this disclosure can be modified and implemented in different but equivalent ways, which will be obvious to those skilled in the art who have an interest in the teachings herein, so the specific embodiments disclosed above are merely illustrative. Furthermore, no limitation is intended to the structural or design details shown herein other than those described in the following claims. Accordingly, it is obvious that the specific exemplary embodiments disclosed above may be changed, combined, or modified, and all such variations will be considered within the scope of this disclosure. The systems, tools, and methods disclosed exemplary herein can be adequately implemented even without any elements not specifically disclosed herein and / or any optional elements disclosed herein. While the systems, tools, and methods are described using the terms “comprising,” “containing,” or “including” various components or processes, the systems, tools, and methods may also “consist essentially of” or “consist of” various components and processes. All numerical values ​​and ranges disclosed herein may be modified to some extent. Whenever numerical ranges with lower and upper limits are disclosed, any encompassing ranges within any numerical value and range are also clearly disclosed. In particular, any range of values ​​disclosed herein (in the form of "about a to about b," or equivalently, "about a to b," or equivalently, "about a to b") should be understood to define any numerical value and range that is encompassed within a broader range of values. Furthermore, terms used in the claims have their plain and ordinary meanings unless explicitly defined by the patentee. In addition, the indefinite articles "a" or "an" used in the claims are defined herein to mean one or more of the elements into which they are introduced.If there is any inconsistency in the use of a word or term in this specification and in one or more patents or other documents incorporated herein by reference, the definition consistent herein should be adopted.

Claims

1. First working electrode and The second working electrode and A ketone-sensitive active region disposed on the surface of the first working electrode, comprising an enzyme system including at least two enzymes that facilitate the detection of nicotinamide adenine dinucleotide (NAD) and ketones, A glucose-sensitive active region disposed on the surface of the second working electrode, comprising a glucose-sensitive enzyme, A first membrane directly disposed on the ketone-sensitive active region, A second membrane disposed on the first membrane and the glucose-sensitive active region, An electrochemical analyte sensor for continuous in vivo detection of glucose and ketones, comprising: In order to separately control the flow of the test substance in the ketone-sensitive active region and the glucose-sensitive active region, the first membrane and the second membrane have different permeability values. The ketone-sensitive active region is located closer to the distal end of the sensor than the glucose-sensitive active region. The distance between the ketone-sensitive active region and the glucose-sensitive active region is 0.4 mm to 1.1 mm in the sensor.

2. The sensor according to claim 1, wherein the ketone-sensitive active region comprises a first polymer and a first electron transfer agent covalently bonded to the first polymer.

3. The sensor according to claim 1, wherein the glucose-sensitive active region comprises a second polymer and a second electron transfer agent covalently bonded to the second polymer.

4. The sensor according to claim 1, wherein the first film and the second film have different compositions.

5. The sensor according to claim 1, wherein the distal end of the sensor has a maximum thickness of about 0.2 mm to about 0.4 mm.

6. The sensor according to claim 1, wherein the first membrane comprises polyvinylpyridine.

7. The sensor according to claim 1, wherein the second membrane comprises polyvinylpyridine-co-styrene.

8. The sensor according to claim 1, further comprising a substrate, wherein the first working electrode and the second working electrode are disposed on the substrate.

9. The sensor according to claim 8, wherein the distance between the ketone-sensitive active region and the glucose-sensitive active region is the distance along the length of the substrate between the proximal end of the ketone-sensitive active region and the distal end of the glucose-sensitive active region.

10. The sensor according to claim 2, wherein one or more of the at least two enzymes are covalently bonded to the first polymer.

11. The sensor according to claim 2, wherein each of the at least two enzymes is covalently bonded to the first polymer.

12. The sensor according to claim 2, wherein the enzyme system comprises hydroxybutyrate dehydrogenase (HBDH) and diaphorase.

13. The sensor according to claim 12, wherein the hydroxybutyrate dehydrogenase and diaphorase are covalently bonded to the first polymer.

14. The sensor according to claim 1, wherein the ketone-sensitive active region further comprises albumin.

15. The sensor according to claim 1, wherein the first membrane is selectively positioned to cover the ketone-sensitive active region with respect to the glucose-sensitive active region.

16. Exposing the test substance sensor according to claim 1 to a fluid containing at least glucose and ketones, Applying a first potential to the first working electrode and applying a second potential to the second working electrode, To obtain a first signal having a redox potential above the ketone-sensitive active region, and the first signal being proportional to the ketone concentration in the fluid, To obtain a second signal having a redox potential above the glucose-sensitive active region, and which is proportional to the glucose concentration in the fluid, A method comprising correlating the first signal with the ketone concentration in the fluid and correlating the second signal with the glucose concentration in the fluid.

17. The method according to claim 16, wherein the first signal and the second signal are measured at different times.

18. The method according to claim 16, wherein the first signal and the second signal are measured simultaneously.

19. The method according to claim 16, wherein the fluid is interstitial fluid.

20. Sensor electronics and, A sensor according to any one of claims 1 to 15, which acquires a first signal indicating ketone concentration and a second signal indicating glucose concentration, and transmits the first signal and the second signal to the sensor electronics, A sensor control device equipped with the following features.

21. The sensor control device according to claim 20, wherein the sensor electronics are configured to correlate the first signal with the ketone concentration.

22. The sensor control device according to claim 20 or 21, wherein the sensor electronics are configured to correlate the second signal with the glucose concentration.

23. (i) Sensor electronics and, (ii) A sensor according to any one of claims 1 to 15, which acquires a first signal indicating ketone concentration and a second signal indicating glucose concentration, and transmits the first signal and the second signal to the sensor electronics, A glucose and ketone sensing system comprising, A glucose and ketone sensing system comprising sensor electronics configured to (a) correlate the first signal acquired by the sensor with the ketone concentration, (b) correlate the second signal acquired by the sensor with the glucose concentration, and (c) transmit the ketone concentration and the glucose concentration to a reading device for display.

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