Wearable monitor with electrochemical multi-sensor

Abstract

Traditionally, the risk or progression of health conditions such as acute kidney injury (AKI) or congenital heart failure (CHF) is evaluated based on laboratory tests. While being worn by a patient, a patient monitor having a plurality of working electrodes continuously monitors a plurality of analytes in interstitial tissue of a patient. The patient monitor further including one or more external sensors for monitoring levels of one or more physiological parameters of the patient. In this way, by continuously monitoring a plurality of internal and / or external physiological parameters, the patient monitor can promote early detection of health conditions such as existing or progressing CRM conditions, AKI, and / or CHF without laboratory tests.

Description

Attorney Docket No. A0014277W001WEARABLE MONITOR WITH ELECTROCHEMICAL MULTI-SENSORCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 765,424, filed February 28, 2025, and U.S. Provisional Patent Application Serial No. 63 / 909,759, filed November 1, 2025the entire content of which is incorporated herein by reference.FIELD

[0002] The disclosure is generally related to electrochemical sensors for medical applications including metabolic monitoring of patients.BACKGROUND

[0003] Many health conditions require blood samples for monitoring, diagnosing, and / or treating patients. For example, the risk or progression of health conditions such as acute kidney injury (AKI), cardiovascular-renal-metabolic (CRM) conditions (e.g., type-2 diabetes (T2D), cardiovascular diseases (CVD), chronic kidney disease (CKD)) or congenital heart failure (CHF) are generally evaluated based on blood tests. AKI (also known as acute renal failure) is characterized by a relatively sudden decline in kidney function, such as over a few hours or a few days. The kidneys are important organs that are responsible not only for filtering toxins and excess water from the blood but for producing enzymes (e.g., renin) and hormones (e.g., erythropoietin), which help regulate a range of bodily functions, such as blood pressure, fluid and electrolyte balance, and red blood cell production. CRM conditions, as the name suggests, are disorders in which an acute or chronic dysfunction in one system (e.g., heart or kidneys) induces an acute or chronic dysfunction in the other (e.g., kidneys or heart, respectively). CHF is typically caused by structural heart defects present at birth, but the onset of symptoms (e.g., edema, fatigue, shortness of breath, rapid or irregular heartbeat, and the like) may occur over time and / or may not initially be recognized as indicative of CHF. Unfortunately, unless a patient has been admitted to a hospital, these conditions are only monitored periodically, e.g., when a patient visits a healthcare facility or laboratory and submits a blood sample.Attorney Docket No. A0014277W001Continuous monitoring of a patient’s blood would enable these and other health conditions to be identified and addressed earlier, promoting better outcomes for patients.SUMMARY

[0004] This disclosure generally relates to a monitor having a plurality of sensors configured to detect a plurality of physiological parameters of a patient. For example, the monitor may include a combination of one or more implantable (internal) sensors and one or more external sensors. The one or more implantable sensors may include one or more flex sensors (or flex circuits) configured for insertion into the interstitial fluid layer (or interstitial tissue) of a patient’s skin to detect internal parameters, such as body temperature and / or interstitial analyte levels of multiple analytes, such as glucose, creatinine, oxygen, and potassium. A housing of the monitor may include one or more external sensors, such as a movement sensor (e.g., accelerometer, gyroscope, inertial measurement unit (IMU)), a temperature sensor (e.g., thermistor, digital IC sensor), and / or an oxygen sensor (e.g., pulse oximeter or optical oxygen sensor) for externally measuring one or more parameters (e.g., external parameters), such as oxygen saturation, respiratory rate, heart rate, pulse rate, physical activity or inactivity, and body temperature. The monitor may also be in communication with a point of care (POC) system and / or a laboratory testing facility. In this way, periodic measurement of additional analytes (e.g., using blood testing) can be used in conjunction with the continuous measurement of analytes by the monitor for more robust diagnostics, confirmation of monitor measurements, and / or calibration purposes.

[0005] With respect to the implantable sensors, each flex sensor may be configured with one or more electrodes and / or a temperature sensor (e.g., thermistor, digital IC sensor). For example, each flex sensor may include one or more of a working electrode, a counter electrode and / or a reference electrode. In some aspects, the one or more flex sensors may include at least two working electrodes; in other aspects, the one or more flex sensors may include at least three working electrodes; in still other aspects, the one or more flex sensors may include at least four working electrodes. Each working electrode is configured to interact with an analyte within the interstitial fluid layer (or interstitial tissue) and generate an electrical signal indicative of an analyte level (e.g., analyteAttorney Docket No. A0014277W001concentration). For example, a first working electrode may be configured to detect a creatinine level, a second working electrode may be configured to detect a glucose level, a third working electrode may be configured to detect a potassium ion level, and a fourth working electrode may be configured to detect an oxygen level. Additionally or alternatively, the one or more flex sensors may include at least one working electrode and a temperature sensor (e.g., thermistor, digital IC sensor); in other aspects, the one or more flex sensors may include at least two working electrodes and a temperature sensor; in still other aspects, the one or more flex sensors may include at least three working electrodes and a temperature sensor.

[0006] In practice, the one or more flex sensors of the monitor are encased in a large-gauge (small diameter) retractable needle, which is inserted through the patient’s skin and into the interstitial space. As described above, the housing of the monitor may include one or more external sensors, such as a movement sensor (e.g., accelerometer, gyroscope, inertial measurement unit (IMU)), a temperature sensor (e.g., thermistor, digital integrated circuit (IC) sensor), and / or an oxygen sensor (e.g., pulse oximeter or optical oxygen sensor). The housing of the monitor is affixed to an exterior surface of the patient’s skin and can be worn for several days or longer, during which time the monitor can be configured to continuously detect both external parameters and the levels of multiple analytes within the interstitial fluid layer (or interstitial tissue). In this way, a patient can be monitored in any location for the risk or progression of various health conditions that ordinarily require laboratory blood tests, such as acute kidney injury (AKI), cardiovascular-renal-metabolic (CRM) conditions, or congenital heart failure (CHF), as well as more generalized prophylactic patient health monitoring.

[0007] In an aspect, a wearable monitor configured to determine a health condition of a patient is provided. The wearable monitor includes a plurality of internal sensors configured to be positioned within interstitial fluid of the patient. The plurality of internal sensors includes at least one flex circuit, including a first working electrode responsive to a first analyte concentration over time, a second working electrode responsive to a second analyte concentration over time, and a third working electrode responsive to a third analyte concentration over time. The wearable monitor further including at least one external sensor configured to sense at least one external parameter value of the patient over time. The health condition of the patient being determined at a first time based on oneAttorney Docket No. A0014277W001or more of the at least one external parameter value, the first analyte concentration, the second analyte concentration, or the third analyte concentration at the first time.

[0008] In another aspect, a wearable monitor is provided. The wearable monitor including one or more flex sensors configured to be positioned within interstitial tissue of a patient. The one or more flex sensors including a plurality of working electrodes, including a first working electrode responsive to a first analyte concentration over time, a second working electrode responsive to a second analyte concentration over time, a third working electrode responsive to a third analyte concentration over time, and a fourth working electrode responsive to a fourth analyte concentration over time, where at least two of the plurality of working electrodes are positioned on the same flex sensor of the one or more flex sensors.

[0009] In another aspect, a method of determining a health condition of a patient using a wearable monitor having at least one internal sensor positioned in interstitial tissue of the patient and at least one external sensor positioned in the wearable monitor is provided. The method includes interacting, at a first working electrode of the at least one internal sensor, with a first analyte in the interstitial tissue over time, and interacting, at a second working electrode of the at least one internal sensor, with a second analyte in the interstitial tissue over time. Additionally, the method includes generating, by the first working electrode, a first electrical signal proportional to a first analyte concentration in the interstitial tissue over time, and generating, by the second working electrode, a second electrical signal proportional to a second analyte concentration in the interstitial tissue over time. The method further including converting, by a processor, the first electrical signal to a first analyte level in the interstitial tissue over time and the second electrical signal to a second analyte level in the interstitial tissue over time. The method also includes receiving, by the processor from the at least one external sensor, a third electrical signal corresponding to an external parameter value of the patient over time. Additionally, the method includes determining, at a first time, the health condition of the patient based on the external parameter value, the first analyte level, and the second analyte level at the first time.

[0010] The details of one or more aspects of the disclosure are set forth in the accompanying drawings and the description below. Other features, objects, andAttorney Docket No. A0014277W001advantages of the techniques described in this disclosure will be apparent from the description and drawings, and from the claims.BRIEF DESCRIPTION OF DRAWINGS

[0011] Non-limiting and non-exhaustive examples are described with reference to the following Figures.

[0012] FIGS. 1A-1F are conceptual diagrams illustrating an example system including an analyte monitor and example flex sensors configured to measure multiple analyte levels in an interstitial fluid layer of a patient’s skin, in accordance with one or more examples described herein.

[0013] FIGS. 2A-2B are schematic diagrams illustrating examples of one or more flex sensors of an analyte monitor, in accordance with aspects described herein.

[0014] FIGS. 3A-3F are schematic diagrams illustrating further examples of one or more flex sensors of an analyte monitor, in accordance with aspects described herein.

[0015] FIGS. 4A-4E are schematic diagrams illustrating further examples of one or more flex sensors of an analyte monitor, in accordance with aspects described herein.

[0016] FIGS. 5A-5G are schematic diagrams illustrating further examples of one or more flex sensors of an analyte monitor, in accordance with aspects described herein.

[0017] FIG. 6 is a schematic diagram illustrating an example amperometric sensor flex, in accordance with aspects described herein.

[0018] FIGS. 7A-7B are schematic diagrams of example potassium potentiometric sensor flexes, in accordance with aspects described herein.

[0019] FIG. 8 is a block diagram illustrating an example electronics system, in accordance with aspects described herein.

[0020] FIG. 9 is a flowchart illustrating an example method for determining an analyte level in interstitial tissue of a patient, in accordance with aspects described herein.

[0021] FIG. 10 is a graph illustrating an example of in vitro operation of a monitor designed to electrochemically track glucose, potassium, and creatinine levels, in accordance with aspects described herein.Attorney Docket No. A0014277W001DETAILED DESCRIPTION

[0022] This disclosure generally relates to a monitor having multiple sensors configured to detect a plurality of physiological parameters of a patient. For example, the monitor may include a combination of one or more implantable (internal) sensors and one or more external sensors. The one or more implantable sensors may include one or more flex sensors (or flex circuits) configured for insertion into the interstitial fluid layer (or interstitial tissue) of a patient’s skin to detect internal body temperature and / or serum analyte levels of multiple analytes, such as glucose, creatinine, oxygen, and potassium. A housing of the monitor may include one or more external sensors, such as a movement sensor (e.g., accelerometer, gyroscope, IMU), a temperature sensor (e.g., thermistor, digital IC sensor), and / or an oxygen sensor (e.g., pulse oximeter or optical oxygen sensor) for externally measuring one or more parameters, such as oxygen saturation, respiratory rate, heart rate, pulse rate, physical activity or inactivity, and body temperature. The individual sensors described herein can be calibrated in the factory or at the point of use by a user at defined intervals. The monitor may also include a combination of factory and point of use calibrated sensors with defined calibration intervals unique to each sensor.

[0023] With reference to the implantable sensors, a flex sensor is a circuit built on a flexible substrate that includes one or more of a working electrode, a temperature sensor, a counter electrode and / or a reference electrode. For example, a flex sensor may be constructed in accordance with thin film mask techniques to form elongated thin film conductors embedded or encased between layers of a selected insulative material such as a polyimide film. Each working electrode of a flex sensor may be configured to detect an analyte, which may be the same as or different than analytes detected by other working electrodes. In some aspects, the monitor may include one or more flex sensors configured with at least two working electrodes; in other aspects, the one or more flex sensors may be configured with at least three working electrodes; and in still other aspects, the one or more flex sensors may be configured with more than three working electrodes. In addition to one or more working electrodes, a flex sensor may additionally include a temperature sensor (e.g., thermistor, digital IC sensor), as described above.Attorney Docket No. A0014277W001

[0024] To detect an analyte, a working electrode may comprise or be coated with a substance that causes, facilitates, or participates in an electrochemical interaction with an analyte. In some examples, the substance may be an enzyme (or enzymes); in other examples, the substance may be an oxidative or reductive chemical or compound. In still other examples, a working electrode may facilitate a charge separation and corresponding electrical potential proportional to a concentration of an ionic analyte. As described above, each working electrode is configured to interact with an analyte in the interstitial fluid layer to generate an electrical signal indicative of an analyte level (e.g., concentration). For example, the monitor may include one or more processors for executing one or more algorithms to convert electrical signals generated by each working electrode into corresponding analyte levels. Analyte levels of each analyte may be recorded by the monitor over time to identify changes and / or rates of change in the analyte levels. In aspects, a first working electrode may be configured to detect a creatinine level, a second working electrode may be configured to detect a glucose level, a third working electrode may be configured to detect a potassium ion level, and a fourth working electrode may be configured to detect an oxygen level within the interstitial fluid layer of a patient.

[0025] In practice, the one or more flex sensors of the monitor are encased in a large-gauge (small diameter) retractable needle. In aspects, the needle is inserted through the patient’s skin and into the interstitial space and then retracted, leaving the one or more flex sensors in the patient’s interstitial fluid layer. A housing of the monitor is affixed to an exterior surface of the patient’s skin and can be worn for several days or longer, during which time the monitor is configured to continuously detect one or more physiological parameters, including the levels of multiple analytes within the interstitial fluid layer. In aspects, the monitor may be configured to detect physiological parameters that are indicative of one or more health conditions. For example, interstitial glucose levels may be indicative of a risk and / or progression of diabetes and, combined with serum creatinine and / or serum potassium levels, interstitial glucose levels may be indicative of a risk and / or progression of AKI. Moreover, high serum potassium levels (hyperkalemia) may be indicative of heart conditions and / or CHF progression. Additionally, a patient’s blood oxygen level, heart rate, and / or respiration rate may be indicative of cardiovascular function. An increase in body temperature may be a sign of infection or inflammation, whereas a decrease in body temperature, particularly when taken at the skin of extremities,Attorney Docket No. A0014277W001may indicate low blood perfusion or circulation. Continuous monitoring of all or many of these physiological parameters is important for ongoing care of diabetic patients, cardiac patients, renal patients, and cross-over CRM patients. Moreover, continuous monitoring of these parameters may be particularly important during certain treatments for heart, lung and / or kidney disease, including dialysis (which involves filtering out water and toxins from the blood when the kidneys are not functioning properly) and / or extracorporeal membrane oxygenation (ECMO) (which is a type of artificial life support that adds oxygen and filters out carbon dioxide from the blood when the heart and / or lungs are not functioning properly).

[0026] In this way, by configuring the monitor to for internal and external detection of multiple physiological parameters, including heart rate, respiratory rate, internal or external body temperature, physical activity, SpCh and / or multiple serum analytes (e.g., oxygen, glucose, creatinine, and / or potassium), a patient can be monitored for the risk and / or progression of AKI, CRM conditions (e.g., type-2 diabetes (T2D), cardiovascular diseases (CVD), chronic kidney disease (CKD)) and / or CHF, which would ordinarily require laboratory blood tests.

[0027] Creatine is a naturally occurring compound in muscle cells that is involved in energy production; and creatinine is a waste product resulting from the breakdown of creatine that is excreted by the muscle cells. Ordinarily, creatinine is filtered out of the blood and released in urine by the kidneys. Serum creatinine (Scr) is a biomarker used to measure glomerular filtration rate (GFR), which is indicative of kidney function. High levels of serum creatinine may indicate renal impairment or even failure. Serum creatinine is often monitored in CHF patients to detect a decline in kidney function. Additionally, serum creatinine is an important criterion for detecting and diagnosing AKI. However, since serum creatinine is a lagging indicator of AKI, it is beneficial to identify changes in creatinine levels as they arise. Accordingly, occasional blood tests that measure Scr may be insufficient for early detection of AKI.

[0028] Managing glucose levels is important for metabolic stability. High levels of glucose (hyperglycemia) can lead to complications like infection and poor wound healing, while low levels of glucose (hypoglycemia) can cause neurological damage. In aspects, blood glucose levels are indicative of kidney function. Under normal conditions, theAttorney Docket No. A0014277W001kidneys function to reabsorb glucose. Thus, hyperglycemia - particularly in non-diabetic patients - can be indicative of abnormal kidney function and / or AKI. Moreover, elevated glucose levels can damage blood vessels, exacerbating the symptoms and progression of CHF as a common complication of kidney dysfunction. In fact, for patients admitted to the hospital with high baseline glucose, the risk of AKI and mortality may be almost double. In contrast, a subsequent decline in glucose level can be indicative of kidney improvement or Acute Kidney Recovery (AKR). In combination with creatinine monitoring, continuously monitoring fluctuations in blood glucose levels would be beneficial in detecting reduced kidney function associated with AKI and / or an onset or progression of CHF.

[0029] Potassium (e.g., in the form of potassium ion, K+) is essential for maintaining proper heart and muscle function and is another measurable biomarker that exhibits changes in interstitial concentration as kidney function deteriorates during AKI onset. As noted above, normally functioning kidneys maintain electrolyte balance within the body. For example, the hormone aldosterone acts on the kidneys to promote sodium (Na+) and water reabsorption in exchange for potassium (K+) secretion at the distal renal tubules. As kidney function declines, the Na+ / K+ ion exchange may be disrupted, altering the balance of electrolytes. In addition to being correlated with AKI, abnormal potassium levels may be indicative of a progression in CHF. Moreover, many medications used to manage CHF may cause hypokalemia (low K+) or hyperkalemia (high K+), both of which can lead to cardiac arrhythmias or even death. Indeed, high serum potassium levels, such as levels greater than or equal to 5.50 mmol / L, are associated with AKI and a significantly increased short- and long-term risk of death.

[0030] Oxygen is an essential analyte for cellular metabolism and energy production. Blood oxygen level (or oxygen saturation) is indicative of a patient’s respiratory and / or cardiovascular health. In aspects, blood oxygen reflects how well oxygen is being transported from the lungs and delivered through the vasculature by the heart to the tissues and organs throughout the body. Efficient delivery of oxygen to the tissues is evidenced by various measures of blood oxygenation, for example, partial pressure of O2 in arterial blood (Path) from about 90 mmHg to about 100 mmHg, capillary O2 from about 40 mmHg to 50 mmHg, and mitochondrial O2 from about 1 mmHg to 10 mmHg. The oxygen sensors described herein may be designed to measure O2 within interstitial tissue at aAttorney Docket No. A0014277W001range between about 0 mmHg to about 100 mmHg, with normal values in a range from about 30 mmHg to about 40 mmHg, and low values in a range below about 30 mmHg. Low oxygen levels (e.g., hypoxemia) may signify lung disorders that impair gas exchange in the lungs (e.g., COPD, pneumonia, asthma, sleep apnea) and / or cardiac disorders that impede transport of oxygen to the tissues (e.g., CHF, CVD). Additionally, blood oxygen may be used as an internal standard or background electrode to improve accuracy of creatinine and / or glucose sensors, which may become less accurate in low O2 environments.

[0031] In aspects, physical activity is linked to better cardiovascular health and can influence kidney function. A motion sensor, such as an accelerometer, an IMU or a gyroscope, can track a patient’s physical movement and / or activity level. Patients equipped with wearable technology that includes a motion sensor may be more engaged in their own care, which can lead to better adherence to prescribed activities and lifestyle changes that support heart, metabolic, and kidney health. When placed around the chest or stomach of a patient, a motion sensor can be used to determine heart rate and / or respiratory rate. For example, a motion sensor can capture the expansion and contraction of a patient’s chest during breathing. By detecting the frequency of the expansion and contraction, a respiratory rate for the patient can be determined. Using ballistocardiography (BCG), a motion sensor can detect the small movements or vibrations caused by heartbeats, which can be translated into a heart rate of the patient. Changes in heart rate, especially when correlated with fluctuations in creatinine, potassium, and glucose, could serve as an early warning system for complications. For instance, tachycardia (elevated heart rate) alongside rising creatinine might signal worsening kidney function. Additionally, data collected from a motion sensor can also enable fall detection, movement (or non-movement) alerts, and / or weakness detection (e.g., when a patient stands up or is mobile). By correlating activity level with fluctuations in creatinine, potassium, glucose, and / or oxygen, healthcare providers can tailor interventions to the individual needs of a patient. For instance, adjustments in medication, diet, or physical therapy can be made based on real-time activity data. Data from the motion sensor, for example, can inform clinicians regarding whether changes in the monitored analytes are changing due to a decline in heart, lung, and / or kidney function, or due to changes inAttorney Docket No. A0014277W001patient activity levels (e.g., improved health may result in increased activity which may cause transient analyte depletion).

[0032] Heat is a byproduct of normal cellular respiration and metabolism. To maintain a stable internal environment, the body implements various processes, such as sweating and vasodilation, to transport heat via the blood and release the heat from the skin.Accordingly, body temperature is a at reflects the body’s ability to maintain a stable internal environment and is indicative of patient health. For example, physical activity, infection and / or inflammation can result in a higher body temperature. Cardiovascular diseases can reduce the efficiency of the body’s thermoregulation by impairing blood circulation and / or blood perfusion, which can cause uneven heat distribution within the body (e.g., lower body temperature at extremities and / or the skin), put additional strain on the heart to maintain homeostasis, and reduce kidney function. Accordingly, measuring body temperature offers another data point that enables clinicians to detect or monitor cardiovascular and / or renal diseases while potentially distinguishing other conditions such as infection and / or inflammation.

[0033] As should be appreciated, the monitor described herein enables continuous internal and external monitoring of multiple physiological parameters, including serum analytes that would otherwise require laboratory testing. By continuously monitoring physiological parameters that are indicative of one or more health conditions, the risk and / or progression of such health conditions can be better managed, leading to better patient outcomes. For example, continuous monitoring of serum creatinine, glucose, oxygen and / or potassium, as well as physical activity and body temperature, enables earlier detection and / or progression supervision of acute health conditions such as AKI and / or CHF. Early detection of AKI is particularly important as the progression from AKI onset to death can occur over a few days. Additionally, continuous monitoring of these physiological parameters enables better management of existing and / or progressive health conditions, such as CRM conditions (e.g., type-2 diabetes (T2D), cardiovascular diseases (CVD), and chronic kidney disease (CKD)).

[0034] FIGS. 1A-1F are conceptual diagrams illustrating an example system 100 including a monitor 102 configured to measure multiple physiological parameters and / orAttorney Docket No. A0014277W001serum analyte levels of a patient, in accordance with one or more examples described herein.

[0035] As illustrated by FIG. 1 A, monitor 102 includes housing 104, adhesive layer 106, and needle 108. Housing 104 encases an electronics system 110 and is mounted by adhesive layer 106 onto an exterior surface of skin 112 of patient 114. As further described with reference to FIG. 8, electronics system 110 may include one or more computing components, including at least one micro-processing unit (MCU) 171 and memory 172; and, in some examples, electronics system 110 may include one or more sensors 177, such as a motion sensor 179 (e.g., accelerometer, IMU, or gyroscope), a temperature sensor 181 (e.g., thermistor, digital integrated circuit (IC), resistance-temperature-detector (RTD), or thermocouple), and / or an oxygen sensor 183 (e.g., pulse oximeter or optical oxygen sensor).

[0036] As indicated above, one or more sensors 177 may be incorporated into the housing 104 of monitor 102. When incorporated, motion sensor 179 may include an accelerometer, an IMU, and / or a gyroscope, for example. An accelerometer detects changes in velocity (acceleration) along one or more axes (X, Y, Z) based on changes in capacitance or resistance, which is then converted to an electrical signal. In aspects, an accelerometer can detect linear motion in X, Y, Z directions (e.g., up / down, left / right, forward / backward), static acceleration (e.g., using gravity for tilt sensing), and dynamic acceleration (e.g., vibrations). A gyroscope detects rotational movement around one or more axes (X, Y, Z) by sensing shifts in a vibration pattern of a vibrating structure. The vibration shift is then converted into angular velocity to detect rotational motion (e.g., turning, spinning, tilting) and orientation changes (e.g., within three-dimensional (3D) space). An IMU uses a combination of sensors, including accelerometer(s), gyroscope(s), and in some examples magnetometer(s), to measure the specific force, angular rate, and in some examples magnetic field, of a body. While examples are described with reference to an accelerometer, either type of motion sensor may be incorporated into the monitor and methods described herein.

[0037] When incorporated into the housing 104 of monitor 102, temperature sensor 181 may be a thermistor, a digital integrated circuit (IC), a resistance-temperature-detector (RTD), or a thermocouple. A thermistor is a low-cost, temperature-sensitive resistor thatAttorney Docket No. A0014277W001generates a two-wire ohms measurement that can be calibrated to temperature. The resistance of a thermistor changes significantly with small changes in temperature, enabling high sensitivity and fast detection of body temperature at a low cost. In aspects, for a negative temperature coefficient (NTC) thermistor, resistance decreases as temperature increases. While thermistors operate across a limited temperature range, they work well within the range of human body temperature. However, the resistance response of a thermistor is non-linear and requires calibration. Additionally, thermistors require a current source and are relatively fragile. A thermocouple consists of two different metals that are joined together at one end. When heated, a thermocouple generates a voltage proportional to a temperature difference between the junction and a reference point. While thermocouples are sturdy, inexpensive, and self-powered, they have a non-linear response requiring a reference point. Additionally, thermocouples are not as accurate within the low-temperature range of body temperature. An analog IC solid-state sensor provides an output as a voltage or current that is proportional to temperature without additional circuitry. Digital IC sensors (also called terminal IC sensors or temperature IC sensors) provide accurate and stable body temperature output processed through an integral A-D converter that is ready for input into digital control and monitoring systems. While digital IC sensors are relatively inexpensive and do not require linearization or other circuitry, digital IC sensors require a power supply and response time can be slow. An RTD sensor uses a pure metal (e.g., Pt) characterized by a resistance that increases linearly with temperature. RTD sensors generate a highly accurate and stable body temperature measurement and are often used in medical equipment. However, RTD sensors are expensive and self-heating, require a current source, and can have lower response times. In aspects described herein, thermistors and digital IC sensors may be preferable to thermocouples and RTD sensors.

[0038] When incorporated into the housing 104 of monitor 102, oxygen sensor 181 may be a pulse oximeter or an optical oxygen sensor, for example. A pulse oximeter is a non-invasive sensor that measures blood oxygen (or oxygen saturation, SpCh) using a photoemitter and one or more photodetectors. The photoemitter emits light through skin, tissue, and blood at two different wavelengths, red and infrared. In aspects, oxygenated hemoglobin in the blood absorbs more infrared light and less red light, whereas deoxygenated hemoglobin in the blood absorbs more red light and less infrared light. TheAttorney Docket No. A0014277W001one or more photodetectors measure how much of each wavelength passes through the tissue and blood without being absorbed, which enables the device to determine how much of each wavelength was absorbed by the tissue and blood. Based on the measurements, the pulse oximeter calculates a ratio between absorbed red light and absorbed infrared light, which correlates with a percentage of oxygenated hemoglobin in the blood. Additionally, a pulse oximeter can detect pulsatile blood flow by isolating pulsating arterial blood from other non-pulsatile tissues and venous blood. In this way, the pulse oximeter can determine a pulse rate of the patient, generally in beats-per-minute (BPM), and determine the oxygen saturation based on arterial blood. An optical oxygen sensor is a non-invasive sensor that utilizes luminescence quenching to determine oxygen concentration based on a fluorescent dye delivered to the blood of a patient. In particular, an optical reader of the optical oxygen sensor emits blue or red light to excite the dye, which then emits light. Oxygen in the blood “quenches” the light emitted by the dye by reducing its intensity, for example. The optical oxygen sensor then calculates the oxygen concentration of the blood based on the change in intensity of the light emitted by the dye.

[0039] Needle 108, which includes one or more flex sensors 116 (see FIGS. 1B-1C), extends distally from housing 104 into skin 112. In aspects, needle 108 is retractable following insertion of the one or more flex sensors 116, which are configured to remain in the interstitial fluid layer 122.

[0040] Skin 112 includes multiple layers, including an epidermal layer 118, which is positioned above a dermal layer 120, which is positioned above an interstitial fluid layer 122. In aspects, interstitial fluid layer 122 may include interstitial tissue and interstitial fluid (collectively referred to herein as “interstitial tissue”). In some examples, dermal layer 120 may comprise at least a portion of the interstitial fluid layer 122. In addition to fluid, which includes primarily water, the interstitial fluid layer 122 includes, for example, blood cells 124 and analytes 126. In some aspects, analytes 126 may include glucose, creatinine, oxygen, and / or potassium. One or more blood vessels 128 (which exchange fluids, analytes 126, blood cells 124, waste products, and the like, with the interstitial fluid layer 122) may be located within or below the interstitial fluid layer 122 and / or the dermal layer 120.Attorney Docket No. A0014277W001

[0041] When monitor 102 is mounted on an exterior surface of skin 112, the one or more flex sensors 116 within needle 108 may be positioned subcutaneously within the interstitial fluid layer 122 and configured to measure interstitial analyte levels of multiple analytes 126, including one or more of glucose, creatinine, oxygen, and / or potassium. In some aspects, an interstitial analyte level may correspond to a concentration of an analyte 126 within the interstitial fluid layer 122; in other aspects, an interstitial analyte level may correspond to another designation or measure of an analyte quantity within the interstitial fluid layer 122.

[0042] In aspects, monitor 102 may be mounted on skin 112 of patient 114 for a period of time, such as an hour, a plurality of hours, a day, a plurality of days, a week, a plurality of weeks, or any subset, combination or extension thereof. In this way, monitor 102 may be configured to periodically or continuously monitor a plurality of physiological parameters over the period of time, enabling early detection of abnormal physiological parameters, which can minimize delays in detecting a risk and / or progression of one or more health conditions.

[0043] FIG. IB illustrates a first example of a first bisectional view of needle 108 from a first lateral perspective (e.g., first side of needle 108), and a second bisectional view of needle 108 from a second lateral perspective (e.g., second side of needle 108). As shown, a first flex sensor 116A is visible in the first bisectional view and a second flex sensor 116B is visible in the second bisectional view. In examples, the first flex sensor 116A may be loaded back-to-back with the second flex sensor 116B within a single needle 108. In further examples, first flex sensor 116A is adhered back-to-back with second sensor 116B within needle 108. In still further examples, one or more electrodes may be formed on a first side of a flexible substrate and one or more electrodes may be formed on a second side of the flexible substrate, thereby configuring a single flex sensor 116 with a plurality of electrodes on each side. As should be appreciated, within the constraints of needle 108, any configuration of electrodes on the one or more flex sensors 116A-B is contemplated herein. As mentioned above, needle 108 is configured for delivering the one or more flex sensors 116 into the interstitial fluid layer 122. Following insertion, needle 108 may be retracted into monitor 102 or otherwise removed from the insertion site.Attorney Docket No. A0014277W001

[0044] As described further herein, each of the one or more flex sensors 116A-116B may include one or more of a working electrode (e.g., WE 134, WE 136, WE 142), one or more counter electrodes (e.g., CE 140), and / or one or more reference electrodes (e.g., RE 138). In general, a working electrode is configured to interact with an analyte 126 and generate an electrical signal proportional to a level or concentration of the analyte 126 in the interstitial fluid layer 122. A counter electrode is configured to complete a circuit with one or more working electrodes to enable electrical signals to flow and be measured. For example, a counter electrode may include any suitable material compatible with an electrical circuit, such as one or more metals including carbon, platinum, palladium, gold, silver, copper, titanium, iridium and alloys thereof. In some examples, the one or more flex sensors 116A-B do not include a counter electrode, which may alternatively be positioned on an exterior surface of skin 112 or within monitor 102 or otherwise electrically coupled with the one or more working electrodes and the electrical circuitry of electronics system 110.

[0045] A reference electrode is configured to maintain a known and stable baseline electrical signal against which electrical signal(s) generated by one or more working electrodes can be measured. In aspects, an electrical signal generated by a working electrode may be in the form of a voltage (e.g., a difference in electrical potential between two points), a current (e.g., a measure of a rate at which charge flows through a circuit), or an impedance (e.g., a measure of a resistance to current flow in a circuit). The relationship between the electrical signal and an analyte level may be represented by a formula or algorithm stored by electronics system 110. By processing the electrical signal according to the algorithm, the electronics system 110 converts the electrical signal into a corresponding analyte level, which can be evaluated to determine a risk and / or progression of a health condition of patient 114.

[0046] FIG. 1C illustrates a second example of a first bisectional view of needle 108 from a first lateral perspective (e.g., first side of needle 108), and a second bisectional view of needle 108 from a second lateral perspective (e.g., second side of needle 108). As shown, a third flex sensor 116C is visible in the first bisectional view and a fourth flex sensor 116D is visible in the second bisectional view. Similar to FIG. IB, the third flex sensor 116C may be loaded back-to-back with the fourth flex sensor 116D within a single needle 108. In further examples, third flex sensor 116C is adhered back-to-back withAttorney Docket No. A0014277W001fourth flex sensor 116D within needle 108. In still further examples, one or more electrodes may be formed on a first side of a flexible substrate and one or more electrodes may be formed on a second side of the flexible substrate, thereby configuring a single flex sensor 116 with a plurality of electrodes on each side. As should be appreciated, within the constraints of needle 108, any configuration of electrodes and / or a temperature sensor on one or more flex sensors 116C-116D is contemplated herein. As mentioned above, needle 108 is configured for delivering the one or more flex sensors 116C-116D into the interstitial fluid layer 122. Following insertion, needle 108 may be retracted into monitor 102 or otherwise removed from the insertion site.

[0047] As described further herein, each of the one or more flex sensors 116C-D may include one or more of a working electrode (e.g., WE 134, WE 136, WE 142, WE 148), one or more counter electrodes (e.g., CE 140), one or more reference electrodes (e.g., RE 138A-B), and / or a temperature sensor 152 (TS 152). In some examples, the temperature sensor may include multiple electrodes. In some examples, the one or more flex sensors 116C-D do not include a counter electrode, which may alternatively be positioned on an exterior surface of skin 112, within monitor 102, or otherwise electrically coupled with the one or more working electrodes and the electrical circuitry of electronics system 110. In further examples, the one or more flex sensors 116C-116D do not include a temperature sensor, which may alternatively be positioned on an exterior surface of skin 112, within monitor 102, or otherwise electrically coupled with the one or more working electrodes and the electrical circuitry of electronics system 110.

[0048] FIG. ID illustrates a first design of a flex sensor layout, including a fifth flex sensor 116E. Fifth flex sensor 116E includes a first design of general electrodes 146A (e.g., configured for general sensor operation), which are electrically coupled with an electronics system of a monitor (e.g., electronic system 110 of monitor 102). Fifth flex sensor 116E further includes a first design of electrical circuitry 144 A, which includes a plurality of conductive paths (or wires) coupled to the general electrodes 146 A. Further, the fifth flex sensor 116E includes a first design of sensor electrodes 130A, including one or more working electrodes, counter electrodes, and / or reference electrodes. In aspects, each sensor electrode 130A is electrically coupled by one of the conductive paths of the electrical circuitry 144Ato one of the general electrodes 146A. As detailed above, each general electrode 146A is in electrical communication with the electronics system of aAttorney Docket No. A0014277W001monitor. As illustrated, the first design of general electrodes 146 A includes “n” general electrodes, one for each sensor electrode 130A.

[0049] FIG. IE illustrates a second design of a flex sensor layout, including a sixth flex sensor 116F. Sixth flex sensor 116F includes a second design of general electrodes 146B (e.g., configured for general sensor operation), which are electrically coupled with an electronics system of a monitor (e.g., electronic system 110 of monitor 102). Sixth flex sensor 116F further includes a second design of electrical circuitry 144B, which includes a plurality of conductive paths (or wires) coupled to the general electrodes 146B. Further, the sixth flex sensor 116F includes a second design of sensor electrodes 130B, including one or more working electrodes, counter electrodes, and / or reference electrodes. In aspects, each sensor electrode 130B is electrically coupled by one of the conductive paths of the electrical circuitry 144B to one of the general electrodes 146B. As detailed above, each general electrode 146B is in electrical communication with the electronics system of a monitor. As illustrated, the second design of general electrodes 146B includes “n” general electrodes, one for each sensor electrode 13 OB.

[0050] FIG. IF illustrates a third design of a flex sensor layout, including a seventh flex sensor 116G. Seventh flex sensor 116G includes a third design of general electrodes 146C (e.g., configured for general sensor operation), which are electrically coupled with an electronics system of a monitor (e.g., electronic system 110 of monitor 102). Seventh flex sensor 116G further includes a third design of electrical circuitry 144C, which includes a plurality of conductive paths (or wires) coupled to the general electrodes 146C. Further, the seventh flex sensor 116G includes a third design of sensor electrodes 130C, including one or more working electrodes, counter electrodes, and / or reference electrodes. In aspects, each sensor electrode 130C is electrically coupled by one of the conductive paths of the electrical circuitry 144C to one of the general electrodes 146C. As detailed above, each general electrode 146C is in electrical communication with the electronics system of a monitor.

[0051] As illustrated by FIGS. 1D-1F, various designs of flex sensors are contemplated herein. However, the illustrated designs are not so limited. Rather, any flex design satisfying manufacturing requirements, biocompatibility standards, and interstitialfluid stability may be appropriate for use herein. In aspects, the various flex sensor designsAttorney Docket No. A0014277W001may comprise different flex geometries, electrode geometries, connector pad geometries (e.g., electrical circuitry configuration), substrates, coatings, and the like. Although electrode layouts are described herein with reference primarily to the third flex design of FIG. IF, other designs either now known or developed in the future may be suitable for use with the electrode layouts described herein.

[0052] FIGS. 2A-2B are schematic diagrams illustrating examples of one or more flex sensors 216A-216D of a monitor 202. As should be appreciated, description of the components of the monitor 102 and / or the one or more flex sensors 116A-116D of FIGS.1 A-1C may be applicable to the subsequent FIGS. 2A-5G, which are illustrated and described below. Moreover, description of the components of the monitor 202 and / or the one or more flex sensors 216A-216D may be applicable to previous FIGS. 1 A-1C, as illustrated and described above. As illustrated by FIGS. 2A-2B, analyte monitor 202 (e.g., the same as or similar to monitor 102 of FIG. 1A) may include one or more flex sensors 216A-216D (e.g., the same as or similar to the one or more flex sensors 116A-116D of FIGS. 1B-1C).

[0053] In aspects, flex sensors 216A-216D are circuits built on one or more flexible substrates that includes one or more working electrodes, counter electrodes and / or reference electrodes. In aspects, when the monitor 202 is mounted on an exterior skin surface of a patient, a needle 208 (e.g., needle 108 of FIG. 1 A) encasing the one or more flex sensors 216A-216D is configured to extend distally through the skin and into an interstitial fluid layer (or interstitial tissue). The interstitial fluid layer is below the top layers of a patient’s skin but above adjacent layers of tissue. Similar to needle 108, needle 208 is configured for delivering the one or more flex sensors 216A-216D into the interstitial fluid layer of the patient. Following insertion, needle 208 may be retracted into monitor 202 or otherwise removed from the insertion site.

[0054] To deliver and / or maintain the one or more flex sensors 216A-216D within the interstitial fluid layer and prevent penetration into the underlying tissue, a length of the needle 208 and / or the one or more flex sensors 216A-D may be limited. For example, the length may be limited to about two millimeters (2 mm) to about 4 mm. “About,” as used herein, encompasses values within 10%, 20%, or 30% percent of a stated value. Moreover, a size of the needle 208 (e.g., diameter and / or length) may be limited to prevent patientAttorney Docket No. A0014277W001discomfort during insertion. As a result, a number of flex sensors 216A-D and a number of electrodes on each flex sensor may be limited by the diameter and / or length of the needle 208.

[0055] As illustrated by FIG. 2 A, the one or more flex sensors 216A-216B include a first flex sensor 216A and a second flex sensor 216B. The first flex sensor 216A includes a first proximal end 230A and a first distal end 232A, and the second flex sensor 216B includes a second proximal end 23 OB and a second distal end 232B. In aspects, prior to insertion into a patient’s skin, the first proximal end 230A of the first flex sensor 216A and the second proximal end 23 OB of the second flex sensor 216B are positioned proximally with respect to monitor 202 within needle 208. In additional aspects, the first distal end 232A of the first flex sensor 216A and the second distal end 232B of the second flex sensor 216B are positioned distal to monitor 202 within needle 208. In this way, when monitor 202 is mounted and needle 208 penetrates a patient’s skin, the first distal end 232A of the first flex sensor 216A and the second distal end 232B of the second flex sensor 216B may be delivered into the interstitial fluid layer of the patient.

[0056] Positioned at first distal end 232A of first flex sensor 216A are a plurality of electrodes (e.g., three electrodes). First flex sensor 216A includes two working electrodes and a reference electrode. The working electrodes include a creatinine working electrode (WEc) 234 (configured to detect a creatinine level in the interstitial fluid layer of the patient) and a glucose working electrode (WEg) 236 (configured to detect a glucose level in the interstitial fluid layer of the patient). In some examples, WEc 234 and WEg 236 are amperometric enzymatic sensors that incorporate enzyme layers to facilitate electrochemical interactions with an analyte (e.g., an analyte 126 of FIG. 1A). To regulate diffusion of the analyte (e.g., creatinine and / or glucose) into the enzyme layer, a limiting membrane may be applied to an exterior surface of amperometric enzyme sensors, such as WEc 234 and WEg 236. By positioning WEc 234 and WEg 236 on the same flex sensor 216A, the limiting membrane can be applied during the same manufacturing step to both electrodes, thereby simplifying manufacturing of the first flex sensor 216A.

[0057] In the illustrated example, WEc 234 is positioned proximal to WEg 236 along first flex sensor 216A; however, in other examples, WEc 234 may be positioned distal to WEg 236 along first flex sensor 216A. In some cases, WEc 234 may be less sensitive toAttorney Docket No. A0014277W001creatinine than WEg 236 is to glucose. By positioning WEc 234 proximal to WEg 236, a length of a conductive path may be minimized between WEc 234 and an electronics system 210 of monitor 202 (e.g., the same or similar as electronics system 800 of FIG. 8), thereby minimizing resistance and potentially improving detection of electrical signals generated by WEc 234. Moreover, by increasing a size (e.g., thickness, width, surface roughness and / or length) of WEc 234, the available surface area and / or volume of WEc 234 for reacting with creatinine is increased, thereby increasing the sensitivity of WEc 234 to creatinine.

[0058] Further, at first distal end 232A, the first flex sensor 216A includes a reference electrode (RE) 238 configured to maintain a known and stable baseline electrical signal against which electrical signal(s) generated by WEc 234, WEg 236, and / or a potassium working electrode (WEp) 242 of second flex sensor 216B (described further below) can be measured. As shown, RE 238 is positioned between WEc 234 and WEg 236 at first distal end 232A; however, in other examples, RE 238 may be positioned distally with respect to both WEc 234 and WEg 236 or proximally with respect to both WEc 234 and WEg 236 at first distal end 232A. As distance increases between a reference electrode and a working electrode, resistance also increases. Since signal noise is proportional to resistance, locating RE 238 between WEc 234 and WEg 236 may minimize noise associated with electrical signals generated by one or both of WEc 234 and WEg 236.

[0059] With respect to the second flex sensor 216B, the second distal end 232B includes two electrodes, a counter electrode (CEg / c) 240 (which is configured to complete circuits with WEc 234 and WEg 236) and a potassium working electrode (WEp) 242 (which is configured to detect a level of potassium ion in the interstitial fluid layer of the patient). In some aspects, WEp 242 is a potentiometric sensor, which is an electrochemical sensor that creates an electrical potential (e.g., voltage) with respect to another electrode based on a concentration of an analyte ion (e.g., potassium ion, K+) in a solution (e.g., interstitial fluid layer). In the illustrated example, CEg / c 240 is positioned proximal to WEp 242 along the second flex sensor 216B; however, in other examples, CEg / c 240 may be positioned distal to WEp 242 along the second flex sensor 216B.

[0060] As described above, a counter electrode is configured to complete a circuit with one or more working electrodes by participating in or facilitating a complementary (orAttorney Docket No. A0014277W001reverse) reaction, thereby enabling electrical signal(s) to flow from the one or more working electrodes and be measured. However, if the counter electrode is unable to efficiently facilitate the counter reaction, e.g., due to byproduct buildup, surface saturation, etc., the counter electrode may interfere with the electrical signal(s) generated by the one or more working electrodes. To minimize such interference, CEg / c 240 may have a greater surface area than the cumulative surface area of WEc 234 and WEg 236. In aspects, the surface area of CEg / c 240 may be increased two-dimensionally or three-dimensionally. For example, surface area may be increased two-dimensionally by increasing the width and / or length of CEg / c 240, and surface area may be increased three-dimensionally by increasing a roughness or undulation on the surface of CEg / c 240. For example, to increase roughness, CEg / c 240 may be formed of electroplated platinum, or screen-printed platinum or carbon. Based on factors associated with a particular system, the surface area of CEg / c 240 may be equal to or greater than the cumulative surface area of WEc 234 and WEg 236.

[0061] As further illustrated, first flex sensor 216A includes first electrical circuitry 244A, which includes a first plurality of conductive paths (or wires) between the three sensor electrodes (e.g., WEc 234, WEg 236, and RE 238) and first general electrodes 246A (e.g., configured for general sensor operation) associated with electronics system 210 of monitor 202. Each electrode may be associated with one of the plurality of conductive paths, whereby the electrode is electrically coupled with an analog front end (AFE) of the electronics system 210 (see FIG. 8). As shown, since first flex sensor 216A has three sensor electrodes, first electrical circuitry 244A includes three conductive paths (or wires) coupling the three sensor electrodes to the first general electrodes 246A and electronics system 210. Similarly, second flex sensor 216B includes second electrical circuitry 244B, which includes a second plurality of conductive paths (or wires) between the sensor electrodes (e.g., CEg / c 240 and WEp 242) and second general electrodes 246B associated with the electronics system 210. Since second flex sensor 216B has two sensor electrodes, second electrical circuitry 244B includes two conductive paths (or wires) coupling the three sensor electrodes to the second general electrodes 246B.

[0062] In aspects, prior to insertion into a patient’s skin, first flex sensor 216A may be loaded back-to-back with second flex sensor 216B within needle 208. For example, a first substrate layer of first flex sensor 216A may be aligned against a second substrate layer ofAttorney Docket No. A0014277W001second flex sensor 216B within needle 208. In this way, first electrical circuitry 244 A of first flex sensor 216A may be aligned against second electrical circuitry 244B of the second flex sensor 216B within needle 208. In some cases, the first substrate layer of first flex sensor 216A may be adhered (e.g., with an adhesive) to the second substrate layer of second sensor 216B and loaded into needle 208. In other cases, one or more first electrodes (e.g., electrodes WEc 234, WEg 236, and RE 238) may be formed on a first side of a flexible substrate and one or more second electrodes (e.g., CEg / c 240 and WEp 242) may be formed on a second side of the flexible substrate. In this way, both sides of a single flex sensor may include a plurality of electrodes (e.g., WEc 234, WEg 236, RE 238, CEg / c 240, and WEp 242). As should be appreciated, within the constraints of needle 208, the one or more flex sensors 216 may be loaded in any suitable configuration. By implementing a plurality of working electrodes on one or more flex sensors 216A-B, monitor 202 is configured to detect interstitial analyte levels of multiple analytes (e.g., creatinine, glucose, and potassium). In this way, while being worn by a patient, the monitor 202 is configured to continuously monitor for certain health conditions, such as AKI and CHF, without requiring laboratory testing.

[0063] As shown in FIG. 2B, the one or more flex sensors 216A, 216C include first flex sensor 216A (e.g., the same as flex sensor 216A of FIG. 2 A) and a second flex sensor 216C. The first flex sensor 216A of FIG. 2B is configured with three electrodes in the same positions as those of the first flex sensor 216A of FIG. 2 A, including a creatinine working electrode (WEc) 234, a glucose working electrode (WEg) 236, and a first reference electrode (RE) 238 A. However, the third flex sensor 216C of FIG. 2B may be different from the second flex sensor 216B of FIG. 2A. In this example, third distal end 232C of third flex sensor 216C includes two electrodes: a potassium working electrode (WEp) 242 and a second reference electrode (RE) 238B. That is, in this example, third flex sensor 216C is not configured with a counter electrode. In this case, a counter electrode may be positioned in an alternative location, for example, at or within monitor 202, associated with needle 208, or at any other suitable location (not shown) for completing circuits with working electrode WEc 234 and / or WEg 236 of the first flex sensor 216A.

[0064] As in FIG. 2A, WEp 242 may be a potentiometric sensor configured to detect a level of potassium ion in the interstitial fluid layer of the patient. To determine an accurate electrical signal corresponding to K+ concentration, a particularly stable and reliableAttorney Docket No. A0014277W001baseline electrical signal may be beneficial. As illustrated by FIG. 2B, since resistance increases with increased distance between a reference electrode and a working electrode, and signal noise is proportional to resistance, it may be beneficial to position a second reference electrode (e.g., RE 238B) in close proximity to WEp 242. Additionally, as illustrated by FIG. 2B, a size (e.g., thickness, width and / or length) of second reference electrode RE 238B may be greater than a size of first reference electrode RE 238 A. In aspects, a reference electrode with increased dimensions may enhance potential stability due to a larger electrode surface area, which reduces resistance and minimizes external noise interference. Additionally, a larger reference electrode volume may increase the lifetime of the reference electrode, ensuring a stable baseline electrical potential over time. However, increasing the electrode's thickness, rather than its area, may increase resistance and noise, although potentially extending the electrode's operational lifetime.

[0065] In aspects, the second reference electrode (e.g., RE 238B) is implemented specifically for the potassium sensor (e.g., WEp 242), ensuring comprehensive isolation of the potassium sensor circuitry from that of other sensors within the device. This configuration achieves galvanic separation, thereby optimizing the signal-to-noise ratio for the potassium sensor. In further aspects, a third reference electrode (not shown) may be employed for the creatinine sensor (e.g., WEc 234), if necessary, to prevent any interference between the glucose and creatinine sensors. It is envisaged that, if desired, any working electrode (WE) within the system could be paired with its own dedicated reference electrode. As shown, RE 238B is in a proximal position with respect to WEp 242 along the third flex sensor 216C; however, in other examples, RE 238B may be positioned distal to WEp 242 along the third flex sensor 216C.

[0066] As with first and second flex sensors 216A-B, third flex sensor 216C includes third electrical circuitry 244C, which includes a third plurality of conductive paths (or wires) between the two sensor electrodes (e.g., RE 238B and WEp 242) and third general electrodes 246C, which are electrically coupled to or included in the electronics system 210. Since third flex sensor 216C has two sensor electrodes, third electrical circuitry 244C includes two conductive paths (or wires).

[0067] As described with reference to FIG. 2A, prior to insertion into the patient’s skin, first flex sensor 216A may be loaded back-to-back with third flex sensor 216C withinAttorney Docket No. A0014277W001needle 208. In some cases, a first substrate layer of first flex sensor 216A may be adhered (e.g., with an adhesive) to a third substrate layer of third sensor 216B and loaded into needle 208. In other cases, one or more first electrodes (e.g., electrodes WEc 234, RE 238A, and WEg 236) may be formed on a first side of a flexible substrate and one or more second electrodes (e.g., RE 238B and WEp 242) may be formed on a second side of the flexible substrate. In this way, both sides of a single flex sensor may include a plurality of electrodes (e.g., WEc 234, WEg 236, RE 238A-238B, and WEp 242. As should be appreciated, within the constraints of needle 208, the one or more flex sensors 216A, 216C may be loaded in any suitable configuration. By implementing a plurality of working electrodes on one or more flex sensors 216A, 216C, monitor 202 is configured to detect interstitial analyte levels of multiple analytes (e.g., creatinine, glucose, and potassium). In this way, while being worn by a patient, monitor 202 is configured to continuously monitor for certain health conditions, such as AKI and CHF, without laboratory testing.

[0068] FIGS. 3A-3F are schematic diagrams illustrating further examples of one or more flex sensors 316A-F of a monitor 302. As should be appreciated, description of the components of the monitors 102, 202 and / or the one or more flex sensors 116A-116D, 216A-216D of FIGS. 1 A-1C, 2A-2B above may be applicable to the subsequent FIGS. 3 A-5G, which are illustrated and described below. Moreover, description of the components of the monitor 302 and / or the one or more flex sensors 316A-316F may be applicable to the previous FIGS. 1 A-1C, 2A-2B, as illustrated and described above.

[0069] As shown in FIG. 3 A, the one or more flex sensors include a first flex sensor 316A and a second flex sensor 316B. The first flex sensor 316A (e.g., the same or similar as first flex sensor 216A of FIGS. 2A-2B) includes a first proximal end 330A and a first distal end 332A, and the second flex sensor 316B includes a second proximal end 330B and a second distal end 332B. Similar to FIGS. 2A-2B, FIG. 3 A illustrates first flex sensor 316A having three electrodes, including a creatinine working electrode (WEc) 334 (configured to detect a creatinine level in the interstitial fluid layer of the patient), a glucose working electrode (WEg) 336 (configured to detect a glucose level in the interstitial fluid layer of the patient), and a first reference electrode (RE) 338 A (configured to maintain a known and stable baseline electrical signal against which electrical signal(s) generated by WEc 334 and / or WEg 336 can be measured). As further illustrated, first flex sensor 316A includes first electrical circuitry 344A, which includes three conductive pathsAttorney Docket No. A0014277W001(or wires) coupling the three sensor electrodes (e.g., WEc 334, WEg 336, and first RE 338A) with first general electrodes 346A associated with electronics system 310 of monitor 302.

[0070] In the illustrated example of first flex sensor 316A, WEc 334 is larger than WEg 336 and is positioned proximal to WEg 336; however, in other examples, WEc 334 may be the same or similar size as WEg 336 and / or may be positioned distal to WEg 336. As shown, the first RE 338A is positioned between WEc 334 and WEg 336; however, in other examples, the first RE 338Amay be positioned distal to both WEc 334 and WEg 336 or proximal to both WEc 334 and WEg 336. In some examples, WEc 334 and WEg 336 are amperometric enzymatic sensors that incorporate enzyme layers to facilitate electrochemical interactions with an analyte (e.g., creatinine and / or glucose).

[0071] The second flex sensor 316B of FIG. 3A includes three electrodes: a counter electrode (CEg / c 340) (configured to complete circuits with WEc 334 and WEg 336), a potassium working electrode (WEp 342) (configured to detect a potassium ion level in the interstitial tissue), and a second reference electrode (RE) 338B (configured to maintain a known and stable potential against which a potential of WEp 342 can be measured). In the illustrated example, CEg / c 340 is larger than WEp 342 and the second RE 338B; moreover, CEg / c 340 is positioned proximal to WEp 342 and second RE 338B along second flex sensor 316B; however, in other examples, CEg / c 340 may be the same size or smaller than WEp 342 and / or second RE 338B and may be positioned distal to WEp 342 and / or second RE 338B along second flex sensor 316B. As further illustrated, the second flex sensor 316B includes second electrical circuitry 344B, which includes three conductive paths (or wires) coupling the three sensor electrodes (e.g., CEg / c 340, second RE 338B, and WEp 342) with second general electrodes 346B associated with the electronics system 310 of the monitor 302.

[0072] As noted above, a size of needle 308 (e.g., diameter and / or length) and size of the one or more flex sensors 316A-B (e.g., thickness, width, and / or length) may be limited so as to extend into but not beyond the interstitial fluid layer and / or to promote patient comfort. Accordingly, configuring second flex sensor 316B with three electrodes, rather than the two electrodes of second flex sensor 216B of FIG. 2 A and third flex sensor 216C of FIG. 2B, may result in altering a size of one or more electrodes. For example, counterAttorney Docket No. A0014277W001electrode (CEg / c) 340, which is configured to complete circuits with WEc 334 and WEg 336, may be of a different size (e.g., different width and / or length) than counter electrode (CEg / c) 240 of FIG. 2 A. As illustrated, CEg / c 340 is larger than CEg / c 240 of FIG. 2 A; however, in other examples, CEg / c 340 may be the same size or smaller than CEg / c 240 of FIG. 2 A. In aspects, the limitations of the size of the needle 308 are balanced against the need of the counter electrode CEg / c 340 to have adequate surface area to efficiently facilitate the counter reaction without interfering with the electrical signal(s) generated by the one or more working electrodes. As with CEg / c 240, to minimize such interference, CEg / c 340 may have a greater surface area than the cumulative surface area of WEc 334 and WEg 336. For example, the surface area of CEg / c 340 may be increased two-dimensionally or three-dimensionally, as described above.

[0073] Additionally, potassium working electrode (WEp) 342, which is configured to detect a level of potassium ion in the interstitial fluid layer of the patient, may be of a different size (e.g., different width and / or length) than potassium working electrode (WEp) 242 of FIGS. 2A-2B. As illustrated, WEp 342 is smaller than WEp 242; however, in other examples, WEp 342 may be the same size or larger than WEp 242. As illustrated by FIG.3 A, CEg / c 340 is in a proximal position with respect to WEp 342 along the second flex sensor 316B; however, in other examples, CEg / c 340 may be positioned distal to WEp 342 along the second flex sensor 316B.

[0074] Further, unlike second flex sensor 216B of FIG. 2 A, second flex sensor 316B of FIG. 3 A includes a second reference electrode (RE) 338B. In this example, second RE 338B is configured to maintain a known and stable potential against which a potential of WEp 342 can be measured. As described above, WEp 342 may be a potentiometric sensor, which is an electrochemical sensor that generates an electrical potential (e.g., voltage) based on a concentration of an analyte (e.g., potassium ion, K+) in a solution (e.g., interstitial fluid layer). To determine an accurate electrical signal corresponding to K+ concentration, a particularly stable and reliable baseline electrical signal may be beneficial. Since resistance increases with increased distance between a reference electrode and a working electrode, and signal noise is proportional to resistance, it may be beneficial to position a reference electrode (e.g., second RE 338B) in close proximity to WEp 342. In one example, second RE 338B may be positioned between CEg / c 340 and WEp 342 (shown); in another example, second RE 338B may be positioned distal to WEpAttorney Docket No. A0014277W001342 (not shown). By incorporating second RE 338B, noise may be minimized with respect to electrical signal(s) (e.g., voltage) generated by WEp 342. Additionally or alternatively, second RE 338B can be used as a ‘noise cancellation’ electrode or ‘working background’ electrode rather than an additional reference electrode, e.g., as an alternate method to minimize electrical and / or chemical noise.

[0075] Similar to FIG. 3 A, FIG. 3B illustrates the first flex sensor 316A and the second flex sensor 316B. The first flex sensor 316A includes the creatinine working electrode (WEc) 334, the glucose working electrode (WEg) 336, and the first reference electrode (RE) 338A. The first flex sensor 316A includes first electrical circuitry 344A, which includes the three conductive paths (or wires) coupling the three sensor electrodes (e.g., WEc 334, WEg 336, and first RE 338A) with the first general electrodes 346A associated with the electronics system 310 of the monitor 302. The second flex sensor 316B includes the counter electrode (CEg / c) 340, the potassium working electrode (WEp) 342, and the second reference electrode (RE) 338B. Similarly, the second flex sensor 316B includes second electrical circuitry 344B, which includes the three conductive paths (or wires) coupling the three sensor electrodes (e.g., CEg / c 340, second RE 338B, and WEp 342) with the second general electrodes 346B associated with the electronics system 310 of the monitor 302.

[0076] However, unlike FIG. 3 A, the monitor 302 of FIG. 3B incorporates one or more external sensors 377, including at least one of a motion sensor 379, a temperature sensor 381, and / or an oxygen sensor 383. Motion sensor 379, such as an accelerometer, an IMU or a gyroscope, can track a patient’s physical movement and / or activity level.Additionally, as described above, the motion sensor 379 can be used to determine heart rate and / or respiratory rate. Data collected from the motion sensor 379 can also enable fall detection, movement (or non-movement) alerts, and / or weakness detection (e.g., when a patient stands up or is mobile).

[0077] The temperature sensor 381 may be a thermistor, a digital integrated circuit (IC), a resistance-temperature-detector (RTD), or a thermocouple, for example. In aspects, temperature sensor 381 may preferably be a thermistor or a digital IC sensor. As described above, measuring external body temperature can enable clinicians to better understand the health condition of a patient. For example, physical activity, infection and / or inflammationAttorney Docket No. A0014277W001can result in a higher body temperature. Cardiovascular diseases can impair blood circulation and / or blood perfusion, which can cause uneven heat distribution within the body, such as lower body temperature at the extremities and / or the skin.

[0078] The oxygen sensor 383 may be a pulse oximeter or an optical oxygen sensor, for example. A pulse oximeter is a non-invasive sensor that measures red and infrared light absorption to determine oxygen saturation (SpCh). An optical oxygen sensor is a non-invasive sensor that utilizes luminescence quenching to determine oxygen concentration. Oxygen is an essential analyte for cellular metabolism and oxygen saturation is a measure indicative of a patient’s respiratory and / or cardiovascular health. Additionally, blood oxygen may be used as an internal standard or background electrode to improve accuracy of creatinine and / or glucose sensors, which may become less accurate in low O2 environments.

[0079] Similar to FIGS. 3 A-3B, FIG. 3C illustrates the second flex sensor 316B, which includes the counter electrode (CEg / c) 340, the potassium working electrode (WEp) 342, and a single reference electrode (RE) 338. As further illustrated by FIG. 3C, the second flex sensor 316B includes second electrical circuitry 344B, which includes three conductive paths (or wires) coupling the three sensor electrodes (CEg / c 340, RE 338, and WEp 342) with the second general electrodes 346B associated with the electronics system 310 of monitor 302.

[0080] Unlike FIGS. 3 A-3B, FIG. 3C illustrates a third flex sensor 316C. The third flex sensor 316C includes the creatinine working electrode (WEc) 334 and the glucose working electrode (WEg) 336. However, rather than a reference electrode, the third flex sensor 316C includes an oxygen working electrode (WEo) 348. As further illustrated by FIG. 3C, the third flex sensor 316C includes third electrical circuitry 344C, which includes three conductive paths (or wires) coupling the three sensor electrodes (WEc 334, WEg 336, WEo 348) with third general electrodes 346C associated with the electronics system 310 of monitor 302.

[0081] With further reference to the third flex sensor 316C, WEc 334 and WEg 336 are amperometric enzymatic sensors that incorporate enzyme layers to facilitate electrochemical interactions with an analyte (e.g., creatinine and / or glucose). The oxygen working electrode WEo 348 may be a “Clark-style” oxygen sensor or may include at leastAttorney Docket No. A0014277W001a portion of a pulse oximeter, for example. A Clark-style oxygen sensor is an electrochemical sensor that measures a concentration of dissolved oxygen in an electrolyte solution, such as the interstitial tissue of a patient. In this case, WEo 348 may include a cathode, an anode (or reference electrode), and a gas permeable membrane. WEo 348 may be formed of platinum (Pt) or, in some examples, may be screen printed silver (Ag) or carbon (C). The cathode functions to reduce oxygen (O2) and consume electrons and hydrogen (H+) to result in water according to the following formula:Reaction 1.

[0082] The anode (or reference) of WEo 348 may be formed of silver / silver chloride (Ag / AgCl), which is oxidized to release electrons according to the following formula:4 Ag + 4 Cl -> 4 AgCl + 4 e , Reaction 2.

[0083] The electron change due to the reduction reaction is correlated to the oxygen concentration in the interstitial tissue of the patient.

[0084] Alternatively, WEo 348 may include at least a portion of a pulse oximeter. As described above, a pulse oximeter operates to determine oxygen saturation by emitting red and infrared light into the skin, tissue, and blood. In this case, the monitor 302 may include the photoemitter and WEo 348 may include the photodetector, which measures the amount of red and infrared light that passes through the skin, tissue, and blood without being absorbed and enables the monitor 302 to determine oxygen saturation.

[0085] In some aspects, the single RE 338 may act as a reference for multiple electrodes of the second flex sensor 316B and / or the third flex sensor 316C. Alternatively, RE 338 may be configured as a reference for a single electrode on either the second flex sensor 316B or the third flex sensor 316C. That is, RE 338 may be configured to maintain a known and stable baseline electrical signal against which electrical signals generated by WEc 334 and / or WEg 336, and / or WEo 348 and / or WEp 342 may be measured.Alternatively, additional reference electrodes may be incorporated within monitor 302 or otherwise.

[0086] In further aspects, the monitor 302 of FIG. 3C incorporates one or more external sensors 377, including a motion sensor 379, a temperature sensor 381 and,Attorney Docket No. A0014277W001optionally, at least a portion of an oxygen sensor 383. As described above, the motion sensor 379 can be an accelerometer, an IMU or a gyroscope, which can be used to determine heart rate and / or respiratory rate, as well as fall detection, movement (or nonmovement) alerts, and / or weakness detection. Temperature sensor 381 may preferably be a thermistor or a digital IC sensor for detecting external body temperature of the patient. Optionally, when WEo 348 includes a photodetector, oxygen sensor 383 may be incorporated into monitor 302 and may include a photoemitter of a pulse oximeter, for example, for projecting red and infrared light into the tissue and blood.

[0087] Similar to FIGS. 3 A-3C, FIG. 3D illustrates the second flex sensor 316B, which includes the counter electrode (CEg / c) 340, the potassium working electrode (WEp) 342, and the single reference electrode (RE) 338. As further illustrated by FIG. 3D, the second flex sensor 316B includes second electrical circuitry 344B, which includes three conductive paths (or wires) coupling the three sensor electrodes (CEg / c 340, RE 338, and WEp 342) with the second general electrodes 346B associated with the electronics system 310 of monitor 302.

[0088] However, unlike FIGS. 3A and 3B, FIG. 3D illustrates a fourth flex sensor 316D. The fourth flex sensor 316D includes the creatinine working electrode (WEc) 334 and the glucose working electrode (WEg) 336. However, rather than a reference electrode, the fourth flex sensor 316D includes a temperature sensor (TS) 352. As further illustrated by FIG. 3D, the fourth flex sensor 316D includes fourth electrical circuitry 344D, which includes three conductive paths (or wires) coupling the three sensor electrodes (WEc 334, WEg 336, and TS 352) with fourth general electrodes 346D associated with the electronics system 310 of monitor 302.

[0089] With reference to the fourth flex sensor 316D, WEc 434 and WEg 436 may be amperometric enzymatic sensors that incorporate enzyme layers to facilitate electrochemical interactions with an analyte (e.g., creatinine and / or glucose). The TS 352 may be a thermistor or a thermocouple, for example. In aspects, a thermistor (or a thermocouple) requires measuring a change in resistance. The change in resistance may be measured between two electrodes (e.g., two thermistors or one thermistor and a reference electrode), or the change in resistance may be measured by a single thermistor formed of chromium(IV) silicide (or chromium monosilicide) (CrSi). For the single-electrodeAttorney Docket No. A0014277W001resistance measurement, the resistance of Cr-Si changes with temperature in a very reproducible and scalable way that can be measured by the single electrode. For the two-electrode resistance measurement, the two electrodes can be located on either flex sensor, as space allows, and resistance can be measured between the two electrodes. In the two-electrode configuration, both of the electrodes can be thermistor electrodes or one of the electrodes can be a thermistor electrode and the other electrode can be a reference electrode or other shared electrode on the flex sensor.

[0090] As described above, a thermistor is a temperature-sensitive resistor in which resistance changes significantly with small changes in temperature, enabling a high sensitivity temperature measure. In aspects, for a negative temperature coefficient (NTC) thermistor, resistance decreases as temperature increases. By incorporating TS 352 on the fourth flex sensor 316D, a very accurate, localized internal body temperature may be obtained. As described above, physical activity, infection and / or inflammation can result in a higher body temperature. Cardiovascular diseases can impair blood circulation and / or blood perfusion, which can cause uneven heat distribution within the body, such as lower body temperature at the extremities and / or the skin. Accordingly, measuring internal body temperature offers another data point that enables clinicians to detect or monitor cardiovascular and / or renal diseases while potentially distinguishing other conditions such as infection and / or inflammation.

[0091] In some aspects, the single RE 338 may act as a reference for multiple electrodes of the second flex sensor 316B and / or the fourth flex sensor 316D.Alternatively, RE 338 may be configured as a reference for a single electrode (e.g., TS 352) on either the second flex sensor 316B or the fourth flex sensor 316D. That is, RE 338 may be configured to maintain a known and stable baseline electrical signal against which electrical signals generated by WEc 334 and / or WEg 336 and / or WEp 342 may be measured. Alternatively, additional reference electrodes may be incorporated within monitor 302 or otherwise.

[0092] In further aspects, the monitor 302 of FIG. 3D incorporates one or more external sensors 377, including one or more of a motion sensor 379 and / or an oxygen sensor 383. As described above, the motion sensor 379 can be an accelerometer, an IMU or a gyroscope, which can be used to determine heart rate and / or respiratory rate, as wellAttorney Docket No. A0014277W001as fall detection, movement (or non-movement) alerts, and / or weakness detection. The oxygen sensor 383 may be a pulse oximeter or an optical oxygen sensor, for example. A pulse oximeter determines oxygen saturation by measuring the amount of red and infrared light that passes through the skin, tissue, and blood without being absorbed. An optical oxygen sensor is a non-invasive sensor that utilizes luminescence quenching to determine oxygen concentration.

[0093] Similar to FIGS. 3 A-3B, FIG. 3E illustrates the first flex sensor 316A, which is configured with three electrodes, including the creatinine working electrode (WEc) 334, the glucose working electrode (WEg) 336, and a reference electrode (RE) 338. As further illustrated by FIG. 3E, the first flex sensor 316A includes first electrical circuitry 344A, which includes three conductive paths (or wires) coupling the three sensor electrodes (WEc 334, WEg 336, and RE 338) with the first general electrodes 346A associated with the electronics system 310 of monitor 302.

[0094] Unlike FIGS. 3 A-3B, FIG. 3E illustrates a fifth flex sensor 316E. The fifth flex sensor 316E includes the counter electrode (CEg / c) 340 and the potassium working electrode (WEp) 342. However, rather than a reference electrode, the fifth flex sensor 316E includes an oxygen working electrode (WEo) 348. As further illustrated by FIG. 3E, the fifth flex sensor 316E includes fifth electrical circuitry 344E, which includes three conductive paths (or wires) coupling the three sensor electrodes (CEg / c 340, WEp 342, WEo 348) with fifth general electrodes 346E associated with the electronics system 310 of monitor 302.

[0095] In aspects of the fifth flex sensor 316E, the potassium WEp 342 may be a potentiometric sensor that facilitates a charge separation and corresponding electrical potential proportional to a concentration of potassium ion in the interstitial fluid layer. The oxygen working electrode WEo 348 may be the same as or similar to WEo 348 of FIG. 3C, for example, a “Clark-style” oxygen sensor or at least a portion of a pulse oximeter. As noted above, a Clark-style oxygen sensor is an electrochemical sensor configured to measure a concentration of dissolved oxygen in the interstitial tissue of a patient. In this case, WEo 348 may include a cathode, an anode (or reference electrode), and a gas permeable membrane. The cathode of WEo 348 functions to reduce oxygen (O2) and consume electrons and hydrogen (H+) to result in water; and the anode of WEo 348Attorney Docket No. A0014277W001functions to oxidize AgCl to release electrons. The electron change due to the reduction reaction is correlated with the oxygen concentration in the interstitial tissue of the patient. Alternatively, WEo 348 may include at least a portion of a pulse oximeter. As described above, a pulse oximeter operates to determine oxygen saturation by emitting red and infrared light into the skin, tissue, and blood. In this case, the monitor 302 may include the photoemitter and WEo 348 may include the photodetector, which measures the amount of red and infrared light that passes through the skin, tissue, and blood without being absorbed and enables the monitor 302 to determine oxygen saturation.

[0096] In some aspects, the single RE 338 may act as a reference for multiple electrodes of the first flex sensor 316A and / or the fifth flex sensor 316E. Alternatively, RE 338 may be configured as a reference for a single electrode on either the first flex sensor 316A or the fifth flex sensor 316E. That is, RE 338 may be configured to maintain a known and stable baseline electrical signal against which electrical signals generated by WEc 334 and / or WEg 336 and / or WEp 342 and / or WEo 348 may be measured.Alternatively, additional reference electrodes may be incorporated within monitor 302 or otherwise.

[0097] In further aspects, the monitor 302 of FIG. 3E incorporates one or more external sensors 377, including one or more of a motion sensor 379, a temperature sensor 381 and, optionally, at least a portion of an oxygen sensor 383. As described above, the motion sensor 379 can be an accelerometer, an IMU or a gyroscope, which can be used to determine heart rate and / or respiratory rate, as well as enable fall detection, movement (or non-movement) alerts, and / or weakness detection. Temperature sensor 381 may preferably be a thermistor or a digital IC sensor for detecting external body temperature of the patient. Optionally, when WEo 348 includes a photodetector, oxygen sensor 383 may be incorporated into monitor 302 and may include a photoemitter of a pulse oximeter, for example, for projecting red and infrared light into the tissue and blood.

[0098] Similar to FIGS. 3 A-3B, FIG. 3F illustrates the first flex sensor 316A having three electrodes, including the creatinine working electrode (WEc) 334, the glucose working electrode (WEg) 336, and a reference electrode (RE) 338. As further illustrated by FIG. 3F, the first flex sensor 316A includes first electrical circuitry 344A, which includes three conductive paths (or wires) coupling the three sensor electrodes (WEc 334,Attorney Docket No. A0014277W001WEg 336, and RE 338) with the first general electrodes 346A associated with the electronics system 310 of the monitor 302.

[0099] Unlike FIGS. 3A-3B, FIG. 3F illustrates a sixth flex sensor 316F. The sixth flex sensor 316F includes the counter electrode (CEg / c) 340 and the potassium working electrode (WEp) 342. However, rather than a reference electrode, the sixth flex sensor 316F includes a temperature sensor (TS) 352. As further illustrated by FIG. 3F, the sixth flex sensor 316F includes sixth electrical circuitry 344F, which includes three conductive paths (or wires) coupling the three sensor electrodes (CEg / c 340, WEp 342, TS 352) with sixth general electrodes 346F associated with the electronics system 310 of the monitor 302.

[0100] In aspects of the sixth flex sensor 316F, the potassium WEp 342 may be a potentiometric sensor that facilitates a charge separation and corresponding electrical potential proportional to a concentration of potassium ion in the interstitial tissue layer. The TS 352 may be the same as or similar to TS 352 of FIG. 3D, e.g., a thermistor. As described above, a thermistor is a temperature-sensitive resistor in which resistance changes significantly with small changes in temperature, enabling high sensitivity to body temperature. By incorporating TS 352 on the sixth flex sensor 316F, a very accurate, localized internal body temperature may be obtained. As indicated above, measuring internal body temperature offers another data point that enables clinicians to detect or monitor cardiovascular and / or renal diseases while potentially distinguishing other conditions such as infection and / or inflammation.

[0101] In some aspects, the single RE 338 may act as a reference for multiple electrodes of the first flex sensor 316A and / or the sixth flex sensor 316F. Alternatively, RE 338 may be configured as a reference for a single electrode on either the first flex sensor 316A or the sixth flex sensor 316F. That is, RE 338 may be configured to maintain a known and stable baseline electrical signal against which electrical signals generated by WEc 334 and / or WEg 336 and / or WEp 342 may be measured. Alternatively, additional reference electrodes may be incorporated within monitor 302 or otherwise.

[0102] In further aspects, the monitor 302 of FIG. 3F incorporates one or more external sensors 377, including one or more of a motion sensor 379 and / or an oxygen sensor 383. As described above, the motion sensor 379 can be an accelerometer, an IMUAttorney Docket No. A0014277W001or a gyroscope, which can be used to determine heart rate and / or respiratory rate, as well as fall detection, movement (or non-movement) alerts, and / or weakness detection. The oxygen sensor 383 may be a pulse oximeter or an optical oxygen sensor, for example. A pulse oximeter determines oxygen saturation by measuring the amount of red and infrared light that passes through the skin, tissue, and blood without being absorbed. An optical oxygen sensor is a non-invasive sensor that utilizes luminescence quenching to determine oxygen concentration.

[0103] As should be appreciated, by implementing a plurality of working electrodes on one or more flex sensors 316A-316F, monitor 302 of FIGS. 3A-3F is configured to detect interstitial analyte levels of multiple analytes (e.g., creatinine, glucose, oxygen, and potassium). Moreover, by implementing one or more external sensors 377, monitor 302 is further configured to detect additional physiological parameters, including respiratory rate, heart rate, oxygen saturation, pulse rate, and external body temperature. In this way, while being worn by a patient, the monitor 302 enables earlier detection and / or progression supervision of acute health conditions such as AKI and / or CHF, as well as better management of existing and / or progressive health conditions, such as CRM conditions (e.g., type-2 diabetes (T2D), cardiovascular diseases (CVD), chronic kidney disease (CKD)), without laboratory testing.

[0104] FIGS. 4A-4E are schematic diagrams illustrating further examples of one or more flex sensors 416A-416H of a monitor 402. As should be appreciated, description of the components of the monitors 102, 202, 302 and / or the one or more flex sensors 116A-116D, 216A-216D, 316A-316F of FIGS. 1A-1C, 2A-2B, 3A-3F above may be applicable to the subsequent FIGS. 4A-5G, which are illustrated and described below. Moreover, description of the components of the monitor 402 and / or the one or more flex sensors 416A-416H may be applicable to the previous FIGS. 1 A-1C, 2A-2B, 3A-3F, as illustrated and described above.

[0105] As shown in FIG. 4A, the one or more flex sensors include a first flex sensor 416A and a second flex sensor 416B. Unlike FIGS. 2A-3F, FIG. 4 A illustrates the first flex sensor 416A having four electrodes, including a creatinine working electrode (WEc) 434, a glucose working electrode (WEg) 436, an oxygen working electrode (WEo) 448, and a first reference electrode (RE) 438 A. As further illustrated by FIG. 4 A, the first flex sensorAttorney Docket No. A0014277W001416A includes first electrical circuitry 444 A, which includes four conductive paths (or wires) coupling the four sensor electrodes (WEc 434, WEg 436, WEo 448, and first RE 438 A) with first general electrodes 446A associated with the electronics system 410 of the monitor 402.

[0106] With reference to the first flex sensor 416A, WEc 434 is larger than WEg 436, which is larger than the WEo 448 and the first RE 438 A. Additionally, the WEc 434 is the proximal-most electrode, first RE 438 A is positioned distally adjacent to WEc 434, WEo 448 is positioned distally adjacent to first RE 438A, and WEg 436 is positioned distally adjacent the WEo 448 in the distal-most position. However, as should be appreciated, the four electrodes of first flex sensor 416A may be of any size or position relative to one another for optimized sensing within the constraints of the first flex sensor 416A.

[0107] In aspects of first flex sensor 416A, WEc 434 and WEg 436 are amperometric enzymatic sensors that incorporate enzyme layers to facilitate electrochemical interactions with an analyte (e.g., creatinine and / or glucose). The first RE 438A is configured to maintain a known and stable baseline electrical signal against which electrical signals generated by WEc 434 and / or WEg 436 can be measured. The oxygen working electrode WEo 448 may be a “Clark-style” oxygen sensor, which is an electrochemical sensor configured to measure a concentration of dissolved oxygen in the interstitial tissue of a patient. Alternatively, WEo 448 may include a photodetector portion of a pulse oximeter, which measures the amount of red and infrared light that passes through the skin, tissue, and blood without being absorbed.

[0108] As shown, the second flex sensor 416B of FIG. 4A also includes four electrodes: a counter electrode (CEg / c) 440, a potassium working electrode (WEp) 442, a temperature sensor (TS) 452, and a second reference electrode (RE) 438B. As further illustrated by FIG. 4 A, the second flex sensor 416B includes second electrical circuitry 444B, which includes four conductive paths (or wires) coupling the four sensor electrodes (CEg / c 440, WEp 442, TS 452, and second RE 438B) with second general electrodes 446B associated with the electronics system 410 of the monitor 402.

[0109] In the illustrated example of the second flex sensor 416B, CEg / c 440 is larger than WEp 442, which is larger than TS 452 and the second RE 438B. Additionally, the CEg / c 440 is the proximal -most electrode, TS 452 is positioned distally adjacent to CEg / cAttorney Docket No. A0014277W001440, second RE 438B is positioned distally adjacent to TS 452, and WEp 442 is positioned distally adjacent the second RE 438B in the distal-most position. In this orientation, when the first flex sensor 416A and the second flex sensor 416B are aligned back-to-back within needle 408, the first RE 438 A and the second RE 438B may be offset from one another. However, as should be appreciated, the four electrodes of the second flex sensor 416B may be of any size or position relative to one another for optimized sensing within the constraints of the second flex sensor 416B.

[0110] With further reference to the second flex sensor 416B, the counter electrode CEc / g 440 is configured to complete circuits with WEg 436 and WEc 434 of first flex sensor 416A. The potassium WEp 442 may be a potentiometric sensor that facilitates a charge separation and corresponding electrical potential proportional to a concentration of potassium ion in the interstitial fluid layer. The second RE 438B is configured to maintain a known and stable baseline electrical signal against which electrical signals generated by WEp 442 can be measured. The TS 452 may be a thermistor, which is a temperaturesensitive resistor in which resistance changes significantly with small changes in temperature, enabling high sensitivity detection of internal body temperature.[OHl] In further aspects, the monitor 402 of FIG. 4 A incorporates one or more external sensors 477, including one or more of a motion sensor 379 and, optionally, at least a portion of an oxygen sensor 383. As described above, the motion sensor 379 can be an accelerometer, an IMU or a gyroscope, which can be used to determine heart rate and / or respiratory rate, as well as fall detection, movement (or non-movement) alerts, and / or weakness detection. Optionally, when WEo 448 includes a photodetector, oxygen sensor 483 may be incorporated into monitor 402 and may include a photoemitter of a pulse oximeter, for example, for projecting red and infrared light into the tissue and blood.

[0112] FIG. 4B illustrates a third flex sensor 416C and a fourth flex sensor 416D. Similar to FIG. 4 A, the third flex sensor 416C and the fourth flex sensor 416D are configured with four electrodes. Further, similar to the first flex sensor 416A, the third flex sensor 416C includes the creatinine working electrode (WEc) 434, the glucose working electrode (WEg) 436, and the first reference electrode (RE) 438 A. However, rather than an oxygen working electrode, the third flex sensor 416C includes temperature sensor (TS) 452. Moreover, similar to the second flex sensor 416B, the fourth flex sensor 416DAttorney Docket No. A0014277W001includes the counter electrode (CEg / c) 440, the potassium working electrode (WEp) 342, and the second reference electrode (RE) 438B. However, rather than a temperature sensor, the fourth flex sensor 416D includes oxygen working electrode (WEo) 448.

[0113] As further illustrated by FIG. 4B, the third flex sensor 416C includes third electrical circuitry 444C, which includes four conductive paths (or wires) coupling the four sensor electrodes (e.g., WEc 434, WEg 436, TS 452, and first RE 438A) with third general electrodes 446C associated with the electronics system 410 of monitor 402.Similarly, the fourth flex sensor 416D includes fourth electrical circuitry 444D, which includes four conductive paths (or wires) coupling the four sensor electrodes (CEg / c 440, WEp 442, WEo 448, and second RE 438B) with fourth general electrodes 446D associated with the electronics system 410 of the monitor 402.

[0114] In aspects of third flex sensor 416C, WEc 434 and WEg 436 are amperometric enzymatic sensors that incorporate enzyme layers to facilitate electrochemical interactions with an analyte (e.g., creatinine and / or glucose). The first RE 438A is configured to maintain a known and stable baseline electrical signal against which electrical signals generated by WEc 434 and / or WEg 436 can be measured. TS 452 may be a thermistor, which is a temperature-sensitive resistor in which resistance changes significantly with small changes in temperature, enabling high sensitivity detection of internal body temperature.

[0115] In aspects of the fourth flex sensor 416D, the counter electrode CEc / g 440 is configured to complete circuits with WEg 436 and WEc 434 of third flex sensor 416C. The potassium working electrode WEp 442 may be a potentiometric sensor that facilitates a charge separation and corresponding electrical potential proportional to a concentration of potassium ion in the interstitial fluid layer. The second RE 438B is configured to maintain a known and stable baseline electrical signal against which electrical signals generated by WEp 442 can be measured. The oxygen working electrode WEo 448 may be a “Clark-style” oxygen sensor, which is an electrochemical sensor configured to measure a concentration of dissolved oxygen in the interstitial tissue of a patient. Alternatively, WEo 448 may include a photodetector portion of a pulse oximeter, which measures the amount of red and infrared light that passes through the skin, tissue, and blood without being absorbed.Attorney Docket No. A0014277W001

[0116] In further aspects, the monitor 402 of FIG. 4B incorporates one or more external sensors 477, including a motion sensor 479 and, optionally, at least a portion of an oxygen sensor 483. In aspects, the motion sensor 479 can be an accelerometer, an IMU or a gyroscope, which can be used to determine heart rate and / or respiratory rate, as well as fall detection, movement (or non-movement) alerts, and / or weakness detection.Optionally, when WEo 448 includes a photodetector, oxygen sensor 483 may be incorporated into monitor 402 and may include a photoemitter of a pulse oximeter, for example, for projecting red and infrared light into the tissue and blood.

[0117] Similar to FIG. 4B, FIG. 4C illustrates the fourth flex sensor 416D. As illustrated, the fourth flex sensor 416D includes the counter electrode (CEg / c) 440, the potassium working electrode (WEp) 442, the oxygen working electrode WEo 448, and a reference electrode (RE) 438. The fourth flex sensor 416D includes the fourth electrical circuitry 444D, which includes four conductive paths (or wires) coupling the four sensor electrodes (CEg / c 440, WEp 442, WEo 448, and RE 438) with the fourth general electrodes 446D associated with the electronics system 410 of the monitor 402.

[0118] Unlike FIG. 4B, FIG. 4C illustrates a fifth flex sensor 416E. The fifth flex sensor 416E is similar to the fourth flex sensor 316D of FIG. 3D. In particular, rather than four electrodes, the fifth flex sensor 416E is configured with three electrodes, including the creatinine working electrode (WEc) 434, the glucose working electrode (WEg) 436, and the temperature sensor (TS) 452. As further illustrated, the fifth flex sensor 416E includes fifth electrical circuitry 444E, which includes three conductive paths (or wires) coupling the three sensor electrodes (WEc 434, WEg 436, and TS 452) with fifth general electrodes 446E associated with the electronics system 410 of monitor 402.

[0119] In some aspects, the single RE 438 may act as a reference for multiple electrodes of the fourth flex sensor 416D and / or the fifth flex sensor 416F. Alternatively, RE 438 may be configured as a reference for a single electrode on either the fourth flex sensor 416D or the fifth flex sensor 416F. That is, RE 438 may be configured to maintain a known and stable baseline electrical signal against which electrical signals generated by WEc 434 and / or WEg 436 and / or WEp 442 and / or WEo 448 may be measured.Alternatively, additional reference electrodes may be incorporated within monitor 402 or otherwise.Attorney Docket No. A0014277W001

[0120] Similar to FIGS. 4A-4B, the monitor 402 of FIG. 4C incorporates one or more external sensors 477, including a motion sensor 479 and, optionally, at least a portion of an oxygen sensor 483. In aspects, the motion sensor 479 can be an accelerometer, an IMU or a gyroscope, which can be used to determine heart rate and / or respiratory rate, as well as fall detection, movement (or non-movement) alerts, and / or weakness detection.Optionally, when WEo 448 includes a photodetector, oxygen sensor 483 may be incorporated into monitor 402 and may include a photoemitter of a pulse oximeter, for example, for projecting red and infrared light into the tissue and blood.

[0121] Similar to FIG. 4B, FIG. 4D illustrates the third flex sensor 416C, which includes the creatinine working electrode (WEc) 434, the glucose working electrode (WEg) 436, the temperature sensor (TS) 452, and a reference electrode (RE) 438. The third flex sensor 416C further includes third electrical circuitry 444C, which includes four conductive paths (or wires) coupling the four sensor electrodes (e.g., WEc 434, WEg 436, TS 452, and RE 438) with third general electrodes 446C associated with the electronics system 410 of monitor 402.

[0122] Unlike FIG. 4B, FIG. 4D illustrates a sixth flex sensor 416F. The sixth flex sensor 416F is similar to the fifth flex sensor 316E of FIG. 3E. In particular, rather than four electrodes, the sixth flex sensor 416F is configured with three electrodes, including the counter electrode (CEg / c) 440, the oxygen working electrode (WEo) 448, and the potassium working electrode (WEp) 442. As further illustrated by FIG. 4D, the sixth flex sensor 416F includes sixth electrical circuitry 444F, which includes three conductive paths (or wires) coupling the three sensor electrodes (CEg / c 440, WEp 442, and WEo 448) with sixth general electrodes 446F associated with the electronics system 410 of monitor 402.

[0123] In some aspects, the single RE 438 may act as a reference for multiple electrodes of the third flex sensor 416C and / or the sixth flex sensor 416F. Alternatively, RE 438 may be configured as a reference for a single electrode on either the third flex sensor 416C or the sixth flex sensor 416F. That is, RE 438 may be configured to maintain a known and stable baseline electrical signal against which electrical signals generated by WEc 434 and / or WEg 436 and / or WEp 442 and / or WEo 448 may be measured.Alternatively, additional reference electrodes may be incorporated within monitor 402 or otherwise.Attorney Docket No. A0014277W001

[0124] Similar to FIGS. 4A-4C, the monitor 402 of FIG. 4D incorporates one or more external sensors 477, including a motion sensor 479 and, optionally, at least a portion of an oxygen sensor 483. In aspects, the motion sensor 479 can be an accelerometer, an IMU or a gyroscope, which can be used to determine heart rate and / or respiratory rate, as well as fall detection, movement (or non-movement) alerts, and / or weakness detection.Optionally, when WEo 448 includes a photodetector, oxygen sensor 483 may be incorporated into monitor 402 and may include a photoemitter of a pulse oximeter, for example, for projecting red and infrared light into the tissue and blood.

[0125] FIG. 4E illustrates a seventh flex sensor 416G and an eighth flex sensor 416H. Similar to the first flex sensor 416A of FIG. 4A, the seventh flex sensor 416G is configured with four electrodes, including the creatinine working electrode (WEc) 434, the glucose working electrode (WEg) 436, and the oxygen working electrode (WEo) 448. However, rather than the first reference electrode (RE) 438 A, the seventh flex sensor 416G includes a temperature sensor (TS) 452. As further illustrated, the seventh flex sensor 416G includes seventh electrical circuitry 444G, which includes four conductive paths (or wires) coupling the four sensor electrodes (WEc 434, WEg 436, WEo 448, and TS 452) with seventh general electrodes 446F associated with the electronics system 410 of monitor 402.

[0126] With reference to the seventh flex sensor 416G, the WEc 434 and WEg 436 may be amperometric enzymatic sensors, which incorporate enzyme layers to facilitate electrochemical interactions with an analyte (e.g., creatinine and / or glucose). The oxygen working electrode WEo 448 may be a “Clark-style” oxygen sensor, which is an electrochemical sensor configured to measure a concentration of dissolved oxygen in the interstitial tissue of a patient, or may include a photodetector portion of a pulse oximeter, which measures the amount of red and infrared light that passes through the skin, tissue, and blood without being absorbed. TS 452 may be a thermistor, which is a temperaturesensitive resistor providing high sensitivity detection of internal body temperature.

[0127] The eighth flex sensor 416H is similar to the second flex sensor 316B of FIGS.3 A-C, including the counter electrode (CEg / c) 440, the potassium working electrode (WEp) 442, and a reference electrode (RE) 438. The eighth flex sensor 416H includes eighth electrical circuitry 444H having three conductive paths (or wires) coupling the threeAttorney Docket No. A0014277W001sensor electrodes (CEg / c 440, WEp 442, and RE 438) with the eighth general electrodes 446F associated with the electronics system 410 of the monitor 402.

[0128] In some aspects, the single RE 438 may act as a reference for multiple electrodes of the seventh flex sensor 416G and / or the eighth flex sensor 416H.Alternatively, RE 438 may be configured as a reference for a single electrode on either the seventh flex sensor 416G or the eighth flex sensor 416H. That is, RE 438 may be configured to maintain a known and stable baseline electrical signal against which electrical signals generated by WEc 434 and / or WEg 436 and / or WEp 442 and / or WEo 448 may be measured. Alternatively, additional reference electrodes may be incorporated within monitor 402 or otherwise.

[0129] In further aspects, the monitor 402 of FIG. 4E incorporates one or more external sensors 477, including a motion sensor 479 and, optionally, at least a portion of an oxygen sensor 483. In aspects, the motion sensor 479 can be an accelerometer, an IMU or a gyroscope, which can be used to determine heart rate and / or respiratory rate, as well as fall detection, movement (or non-movement) alerts, and / or weakness detection.Optionally, when WEo 448 includes a photodetector, oxygen sensor 483 may be incorporated into monitor 402 and may include a photoemitter of a pulse oximeter, for example, for projecting red and infrared light into the tissue and blood.

[0130] As should be appreciated, by implementing a plurality of working electrodes on one or more flex sensors 416A-416H, the monitor 402 of FIGS. 4A-4E is configured to detect interstitial analyte levels of multiple analytes (e.g., creatinine, glucose, oxygen, and potassium). Moreover, by implementing one or more external sensors 477, the monitor 402 is further configured to detect additional physiological parameters, including respiratory rate, heart rate, oxygen saturation, pulse rate, and external body temperature. In this way, while being worn by a patient, the monitor 402 enables earlier detection and / or progression supervision of acute health conditions such as AKI and / or CHF, as well as better management of existing and / or progressive health conditions, such as CRM conditions (e.g., type-2 diabetes (T2D), cardiovascular diseases (CVD), chronic kidney disease (CKD)), without laboratory testing.

[0131] FIGS. 5A-5G are schematic diagrams illustrating further examples of one or more flex sensors 516A-516G of a monitor 502. As should be appreciated, description ofAttorney Docket No. A0014277W001the components of the monitors 102, 202, 302, 402 and / or the one or more flex sensors 116A-116D, 216A-216D, 316A-316F, 416A-416H of FIGS. 1A-1C, 2A-2B, 3A-3F, 4A-4E above may be applicable to the subsequent FIGS. 5A-5G, which are illustrated and described below. Moreover, description of the components of the monitor 502 and / or the one or more flex sensors 516A-516G may be applicable to the previous FIGS. 1A-1C, 2A-2B, 3A-3F, 4A-4E, as illustrated and described above.

[0132] As shown in FIG. 5 A, the one or more flex sensors 516 include a first flex sensor 516Aand second flex sensor 516B. The first flex sensor 516Ahas seven electrodes, including three working electrodes, three counter electrodes and a reference electrode. The working electrodes include three glucose working electrodes (WEg) 534A-C (configured to detect a glucose level in the interstitial fluid layer of the patient), three counter electrodes (CEg / c) 540A-C (configured to complete circuits with WEg 536A-C and a creatinine working electrode WEc 534 of second flex sensor 516B), and a first reference electrode (RE) 538 A (configured to maintain a known and stable baseline electrical signal against which electrical signals generated by WEg 536A-C can be measured). As illustrated, first flex sensor 516A includes first electrical circuitry 544 A, which includes seven conductive paths (or wires) coupling the seven sensor electrodes (e.g., WEg 536A-C, CEg / c 540A-C, and first RE 538 A) with first general electrodes 546A associated with electronics system 510 of monitor 502.

[0133] In the illustrated example, each of CEg / c 540A-C are larger than each of WEg 536A-C. However, in other examples, CEg / c 540A-C may be the same or similar size or smaller than WEg 536A-C; and in still other examples, one or more of CEg / c 540A-C may be the same size, smaller, or larger than one or more of WEg 536A-C. As further illustrated in this example, each of CEg / c 540A-C may be smaller than the counter electrodes described above (e.g., CEg / c 240, CEg / c 340, and CEg / c 440). In contrast, a combined size of CEg / c 540A-C may be larger than at least one of CEg / c 240, CEg / c 340, and / or CEg / c 440. As discussed above, a counter electrode is configured to complete a circuit with one or more working electrodes by participating in or facilitating a complementary (or reverse) reaction, thereby enabling electrical signal(s) to flow from the one or more working electrodes and be measured. However, if the counter electrode is unable to efficiently facilitate the counter reaction, e.g., due to byproduct buildup, surface saturation, etc., the counter electrode may interfere with the electrical signal(s) generatedAttorney Docket No. A0014277W001by the one or more working electrodes. To minimize such interference, CEg / c 540A-C may have a greater surface area than the cumulative surface area of WEg 536A-C and WEc 534. In aspects, the cumulative surface area of CEg / c 540A-C may be increased two-dimensionally or three-dimensionally, as described above.

[0134] Additionally, in this example, CEg / c 540A-C are interleaved with WEg 536A-C, that is, each of CEg / c 540A-C is positioned proximal to one of WEg 536A-C along first flex sensor 416A. For example, CEg / c 540Ais positioned proximal to WEg 536A, which is positioned proximal to CEg / c 540B, which is positioned proximal to WEg 536B, which is positioned proximal to CEg / c 540C, which is positioned proximal to WEg 536C. In some aspects, a smaller working electrode may respond more quickly to changes and achieve lower detection limits for trace analytes (e.g., glucose) than a larger working electrode; moreover, the smaller surface area of a smaller working electrode may reduce a signal-to-noise ratio. By interleaving a counter electrode with each working electrode, polarization may be reduced by distributing current more evenly across the multiple working electrodes. However, due to the smaller individual surface area and increasing distance, multiple smaller counter electrodes spread across first distal end 532Amay be disadvantageous to a creatinine working electrode having a proximal position along second distal end 532B of second flex sensor 516B. Accordingly, the multiple CEg / c 540A-C may be positioned in any suitable configuration with respect to one another, the multiple WEg 536A-C, and the WEc 534. In examples, WEc 534 and WEg 536A-C are amperometric enzymatic sensors that incorporate enzyme layers to facilitate electrochemical interactions with an analyte (e.g., an analyte 126 of FIG. 1A).

[0135] The second flex sensor 516B of FIG. 5 A includes three electrodes: a creatinine working electrode (WEc) 534, a potassium working electrode (WEp) 542 and a second reference electrode (RE) 538B. The second flex sensor 516B includes second electrical circuitry 544B, which is configured with three conductive paths (or wires) coupling the three electrodes (e.g., WEc 534, RE 538B and WEp 542) with second general electrodes 546B associated with the electronics system 510.

[0136] In aspects, WEp 542 may be a potentiometric sensor, which is an electrochemical sensor that generates an electrical potential (e.g., voltage) based on a concentration of analyte (e.g., potassium ion, K+) in the interstitial fluid layer. In order toAttorney Docket No. A0014277W001determine an accurate electrical signal corresponding to K+ concentration, a particularly stable and reliable baseline electrical signal may be beneficial. Since resistance increases with increased distance between a reference electrode and a working electrode, and signal noise is proportional to resistance, it may be beneficial to position second RE 538B in close proximity to WEp 542. As shown, second RE 538B is positioned between WEc 534 and WEp 542 along the second flex sensor 516B; however, in other examples, second RE 538B may be configured in any suitable position along the second flex sensor 516B.

[0137] Similar to FIG. 5 A, FIG. 5B illustrates the first flex sensor 516A and the second flex sensor 516B. The first flex sensor 516A includes the three glucose working electrodes (WEg) 534A-C, the three counter electrodes (CEg / c) 540A-C, and the first reference electrode (RE) 538 A. As illustrated, first flex sensor 516A further includes first electrical circuitry 544A, which is configured with seven conductive paths (or wires) coupling the seven sensor electrodes (e.g., WEg 536A-C, CEg / c 540A-C, and first RE 538 A) with the first general electrodes 546A associated with electronics system 510 of monitor 502. The second flex sensor 516B includes the creatinine working electrode (WEc) 534, the potassium working electrode (WEp) 542 and the second reference electrode (RE) 538B. The second flex sensor 516B further includes second electrical circuitry 544B, which is configured with three conductive paths (or wires) coupling the three electrodes (e.g., WEc 534, second RE 538B and WEp 542) with the second general electrodes 546B associated with the electronics system 510.

[0138] However, unlike FIG. 5 A, the monitor 502 of FIG. 5B incorporates one or more external sensors 577, including at least one of a motion sensor 579, a temperature sensor 581, and / or an oxygen sensor 583. Motion sensor 579, such as an accelerometer, an IMU or a gyroscope, can track a patient’s physical movement and / or activity level.Additionally, as described above, the motion sensor 579 can be used to determine heart rate and / or respiratory rate, as well as fall detection, movement (or non-movement) alerts, and / or weakness detection.

[0139] The temperature sensor 581 may be a thermistor, a digital temperature integrated circuit (IC), a resistance-temperature-detector (RTD), an infrared (IR) thermometer, or a thermocouple, for example. In aspects, temperature sensor 581 may preferably be a thermistor or a digital temperature IC sensor. As described above,Attorney Docket No. A0014277W001measuring external body temperature can enable clinicians to better understand the health condition of a patient. For example, physical activity, infection and / or inflammation can result in a higher body temperature. Cardiovascular diseases can impair blood circulation and / or blood perfusion, which can cause uneven heat distribution within the body, such as lower body temperature at the extremities and / or the skin.

[0140] The oxygen sensor 583 may be a pulse oximeter or an optical oxygen sensor, for example, which are non-invasive sensors that measure oxygen saturation (SpCh) or oxygen concentration. Oxygen is an essential analyte for cellular metabolism and oxygen saturation is a measure indicative of a patient’s respiratory and / or cardiovascular health. Additionally, blood oxygen may be used as an internal standard or background electrode to improve accuracy of creatinine and / or glucose sensors, which may become less accurate in low O2 environments.

[0141] Similar to FIGS. 5A-5B, FIG. 5C illustrates the first flex sensor 516A, which includes the three glucose working electrodes (WEg) 534A-C, the three counter electrodes (CEg / c) 540A-C, and a single reference electrode (RE) 538. As illustrated, first flex sensor 516A further includes first electrical circuitry 544A, which is configured with seven conductive paths (or wires) coupling the seven sensor electrodes (e.g., WEg 536A-C, CEg / c 540A-C, and RE 538) with the first general electrodes 546A associated with electronics system 510 of monitor 502.

[0142] Unlike FIGS. 5A-5B, FIG. 5C illustrates a third flex sensor 516C. Similar to the second flex sensor 516B, the third flex sensor 516C includes the creatinine working electrode (WEc) 534 and the potassium working electrode (WEp) 542. However, rather than the second RE 538B, the third flex sensor 516C includes an oxygen working electrode (WEo) 548. The WEo 548 may be a “Clark-style” oxygen sensor, which is an electrochemical sensor configured to measure a concentration of dissolved oxygen in the interstitial tissue of a patient. Alternatively, WEo 548 may include a photodetector portion of a pulse oximeter, which measures the amount of red and infrared light that passes through the skin, tissue, and blood without being absorbed. As further illustrated, the third flex sensor 516C includes third electrical circuitry 544C, which is configured with three conductive paths (or wires) coupling the three electrodes (e.g., WEc 534, WEo 548, andAttorney Docket No. A0014277W001WEp 542) with the third general electrodes 546C associated with the electronics system 510.

[0143] In further aspects, the monitor 502 of FIG. 5C incorporates one or more external sensors 577, including one or more of the motion sensor 579, the temperature sensor 581 and, optionally, at least a portion of the oxygen sensor 583. As described above, the motion sensor 579 can be an accelerometer, an IMU or a gyroscope, which can be used to determine heart rate and / or respiratory rate, as well as enable fall detection, movement (or non-movement) alerts, and / or weakness detection. Temperature sensor 581 may preferably be a thermistor or a digital temperature IC sensor for detecting external body temperature of the patient. Optionally, when WEo 548 includes a photodetector, oxygen sensor 583 may be incorporated into monitor 502 and may include a photoemitter of a pulse oximeter, for example, for projecting red and infrared light into the tissue and blood.

[0144] Similar to FIGS. 5A-5C, FIG. 5D illustrates the first flex sensor 516A, which includes the three glucose working electrodes (WEg) 534A-C, the three counter electrodes (CEg / c) 540A-C, and reference electrode (RE) 538. As illustrated, first flex sensor 516A further includes first electrical circuitry 544A, which is configured with seven conductive paths (or wires) coupling the seven sensor electrodes (e.g., WEg 536A-C, CEg / c 540A-C, and RE 538) with the first general electrodes 546A associated with electronics system 510 of monitor 502.

[0145] Unlike FIGS. 5A-5C, FIG. 5D illustrates a fourth flex sensor 516D. Similar to the second flex sensor 516B, the fourth flex sensor 516D includes the creatinine working electrode (WEc) 534 and the potassium working electrode (WEp) 542. However, rather than the second RE 538B, the fourth flex sensor 516D includes a temperature sensor (TS) 552. TS 552 may be a thermistor, which is a temperature-sensitive resistor in which resistance changes significantly with small changes in temperature, enabling high sensitivity detection of internal body temperature. As further illustrated, the fourth flex sensor 516D includes fourth electrical circuitry 544D, which is configured with three conductive paths (or wires) coupling the three electrodes (e.g., WEc 534, TS 552, and WEp 542) with the fourth general electrodes 546D associated with the electronics system 510.Attorney Docket No. A0014277W001

[0146] In further aspects, the monitor 502 of FIG. 5D incorporates one or more external sensors 577, including one or more of the motion sensor 579 and the oxygen sensor 583. As described above, the motion sensor 579 can be an accelerometer, an IMU or a gyroscope, which can be used to determine heart rate and / or respiratory rate, as well as enable fall detection, movement (or non-movement) alerts, and / or weakness detection. The oxygen sensor 583 may be a pulse oximeter or an optical oxygen sensor, for example. A pulse oximeter is a non-invasive sensor that measures oxygen saturation (SpCh) by measuring the amount of red and infrared light that passes through the skin, tissue, and blood without being absorbed. An optical oxygen sensor is a non-invasive sensor that utilizes luminescence quenching to determine oxygen concentration.

[0147] Similar to FIGS. 5A-5D, FIG. 5E illustrates the first flex sensor 516A, which includes the three glucose working electrodes (WEg) 534A-C, the three counter electrodes (CEg / c) 540A-C, and reference electrode (RE) 538. As illustrated, first flex sensor 516A further includes first electrical circuitry 544A, which is configured with seven conductive paths (or wires) coupling the seven sensor electrodes (e.g., WEg 536A-C, CEg / c 540A-C, and RE 538) with the first general electrodes 546A associated with electronics system 510 of monitor 502.

[0148] Unlike FIGS. 5A-5D, FIG. 5E illustrates a fifth flex sensor 516E. The fifth flex sensor 516E is configured with four electrodes, including the creatinine working electrode (WEc) 534, the potassium working electrode (WEp) 542, the oxygen working electrode (WEo) 548, and the temperature sensor (TS) 552. As further illustrated, the fifth flex sensor 516E includes fifth electrical circuitry 544E, which includes four conductive paths (or wires) coupling the four sensor electrodes (WEc 534, WEp 542, WEo 548, and TS 552) with fifth general electrodes 546E associated with the electronics system 510 of monitor 502.

[0149] In further aspects, the monitor 502 of FIG. 5E incorporates one or more external sensors 577, including one or more of the motion sensor 579 and, optionally, at least a portion of the oxygen sensor 583. As described above, the motion sensor 579 can be an accelerometer, an IMU or a gyroscope, which can be used to determine heart rate and / or respiratory rate, as well as enable fall detection, movement (or non-movement) alerts, and / or weakness detection. Optionally, when WEo 548 includes a photodetector,Attorney Docket No. A0014277W001oxygen sensor 583 may be incorporated into monitor 502 and may include a photoemitter of a pulse oximeter, for example, for projecting red and infrared light into the tissue and blood.

[0150] Similar to FIGS. 5A-5E, FIG. 5F illustrates the first flex sensor 516A, which includes the three glucose working electrodes (WEg) 534A-C, the three counter electrodes (CEg / c) 540A-C, and the first reference electrode (RE) 538 A. As illustrated, first flex sensor 516A further includes first electrical circuitry 544 A, which is configured with seven conductive paths (or wires) coupling the seven sensor electrodes (e.g., WEg 536A-C, CEg / c 540A-C, and first RE 538 A) with the first general electrodes 546A associated with electronics system 510 of monitor 502.

[0151] Unlike FIGS. 5A-5D, FIG. 5F illustrates a sixth flex sensor 516F. The sixth flex sensor 516F is configured with four electrodes, including the creatinine working electrode (WEc) 534, the potassium working electrode (WEp) 542, the temperature sensor (TS) 552, and a second reference electrode (RE) 538B. As further illustrated, the sixth flex sensor 516F includes sixth electrical circuitry 544F, which includes four conductive paths (or wires) coupling the four sensor electrodes (WEc 534, WEp 542, TS 552, and second RE 538B) with sixth general electrodes 546F associated with the electronics system 510 of monitor 502.

[0152] In further aspects, the monitor 502 of FIG. 5F incorporates one or more external sensors 577, including one or more of the motion sensor 579 and the oxygen sensor 583. As described above, the motion sensor 579 can be an accelerometer, an IMU or a gyroscope, which can be used to determine heart rate and / or respiratory rate, as well as enable fall detection, movement (or non-movement) alerts, and / or weakness detection. The oxygen sensor 583 may be a pulse oximeter or an optical oxygen sensor, for example. A pulse oximeter is a non-invasive sensor that measures oxygen saturation (SpCh) by measuring the amount of red and infrared light that passes through the skin, tissue, and blood without being absorbed. An optical oxygen sensor is a non-invasive sensor that utilizes luminescence quenching to determine oxygen concentration.

[0153] Similar to FIGS. 5A-5F, FIG. 5G illustrates the first flex sensor 516A, which includes the three glucose working electrodes (WEg) 534A-C, the three counter electrodes (CEg / c) 540A-C, and the first reference electrode (RE) 538 A. As illustrated, first flexAttorney Docket No. A0014277W001sensor 516A further includes first electrical circuitry 544 A, which is configured with seven conductive paths (or wires) coupling the seven sensor electrodes (e.g., WEg 536A-C, CEg / c 540A-C, and first RE 538 A) with the first general electrodes 546A associated with electronics system 510 of monitor 502.

[0154] Unlike FIGS. 5A-5F, FIG. 5G illustrates a seventh flex sensor 516G. The seventh flex sensor 516G is configured with four electrodes, including the creatinine working electrode (WEc) 534, the potassium working electrode (WEp) 542, the oxygen working electrode (WEo) 548, and the second reference electrode (RE) 538B. As further illustrated, the seventh flex sensor 516G includes seventh electrical circuitry 544G, which includes four conductive paths (or wires) coupling the four sensor electrodes (WEc 534, WEp 542, WEo 548, and second RE 538B) with seventh general electrodes 546G associated with the electronics system 510 of monitor 502.

[0155] In further aspects, the monitor 502 of FIG. 5E incorporates one or more external sensors 577, including one or more of the motion sensor 579, the temperature sensor 581 and, optionally, at least a portion of the oxygen sensor 583. As described above, the motion sensor 579 can be an accelerometer, an IMU or a gyroscope, which can be used to determine heart rate and / or respiratory rate, as well as enable fall detection, movement (or non-movement) alerts, and / or weakness detection. Temperature sensor 581 may preferably be a thermistor or a digital temperature IC sensor for detecting external body temperature of the patient. Optionally, when WEo 548 includes a photodetector, oxygen sensor 583 may be incorporated into monitor 502 and may include a photoemitter of a pulse oximeter, for example, for projecting red and infrared light into the tissue and blood.

[0156] As should be appreciated, by implementing a plurality of working electrodes on one or more flex sensors 516A-516G, the monitor 502 of FIGS. 5A-5G is configured to detect interstitial analyte levels of multiple analytes (e.g., creatinine, glucose, oxygen, and potassium). Moreover, by implementing one or more external sensors 577, the monitor 502 is further configured to detect additional physiological parameters, including respiratory rate, heart rate, oxygen saturation, pulse rate, and external body temperature. In this way, while the monitor 502 is being worn by a patient, the monitor 502 enables earlier detection and / or progression supervision of acute health conditions such as AKI and / orAttorney Docket No. A0014277W001CHF, as well as better management of existing and / or progressive health conditions, such as CRM conditions (e.g., type-2 diabetes (T2D), cardiovascular diseases (CVD), chronic kidney disease (CKD)), without laboratory testing.

[0157] FIG. 6 is a schematic diagram illustrating an example amperometric sensor flex 600, in accordance with one or more examples described herein.

[0158] In aspects, amperometric sensor flex 600 may correspond to a creatinine working electrode (e.g., WEc 634) or a glucose working electrode (not shown) of flex sensor 616 (e.g., the same as or similar to flex sensors 116A-B, 216A, 316A, 416A, 516A-B). As described above, flex sensor 616 may be delivered into interstitial tissue 622 of a patient via a needle 608 of an interstitial analyte monitor 602. As described above, flex sensor 616 may include an electrical circuit formed on a flexible substrate 650, such as sapphire, polyimide, silicon, or the like. In some examples, a conductive adhesion layer (e.g., titanium, Ti) may be formed between the flexible substrate 650 and a conductive metal layer 654 (e.g., trace gold, Au); in other examples, conductive metal layer 654 may be formed of multiple layers (e.g., including gold and titanium, TiAu) and / or otherwise exhibit adhesive properties. In further examples, an insulation layer 656 may be formed on the metal layer 654. In aspects, the insulation layer 656 may be polyimide and include one or more openings or holes exposing the underlying metal layer 654 (e.g., formed using a mask technique during application or using etching or other technique after application). In this way, an electrode embedded in an opening in insulation layer 656 is configured to contact metal layer 654.

[0159] As shown, amperometric sensor flex 600 further includes an electrode layer 658 in contact with metal layer 654. Over the electrode layer 658 is an enzyme layer 660, which is overlaid by a limiting membrane 662. In aspects, electrode layer 658 may be formed of a conductive metal that resists corrosion, such as platinum (Pt), gold (Au), or rhodium (Rh). The limiting membrane 662 may be designed to regulate an amount of analyte 626 that diffuses from a testing fluid (e.g., interstitial tissue 622) into the enzyme layer 660, thereby ensuring that an analyte concentration in the enzyme layer 660 corresponds to the analyte concentration in the interstitial tissue of the patient. In additional or alternative aspects, the limiting membrane 662 may be configured to slow an immune response by the patient and / or improve electrode stability while implanted. InAttorney Docket No. A0014277W001aspects, the limiting membrane may be formed of one or a combination or copolymer of the following: polyethyleneimine (PEI), polyurethane (PU), poly(ethylene glycol) (PEG), cellulose acetate, polyhydroxyethylmethacrylate (pHEMA), or a physical perforated membrane of any material, such as carbon, ceramic, ablated metals, or polymers. In additional or alternative aspects, limiting membrane 662 may be a hydrogel such as poly(vinyl alcohol), poly(methylmethacrylate), phosphoryl choline-containing zwitterionic polymers.

[0160] The enzyme layer 660 may include a suspension of one or more enzymes 664 for reacting with one or more analytes 626 (e.g., creatinine or glucose, respectively). For example, when amperometric sensor flex 600 is configured to detect a creatinine level in the interstitial tissue 622, the one or more enzymes 664 may include one or more of creatinine amidohydrolase, creatine amidinohydrolase, sarcosine oxidase, and / or creatinine iminohydrolase. In aspects, an enzyme load in the enzyme layer 660 may be optimized such that it is not too low (e.g., which may inhibit sensor sensitivity and / or responsiveness due to a shortage of available enzymes 664) and not too high (e.g., which may interfere with diffusion of the analyte 626 into the enzyme layer 660). In some aspects, an enzyme load of enzymes 664 in the enzyme layer 660 of a creatinine sensor may be optimized between about two times (2x) a baseline enzyme load to about three times (3x) the baseline enzyme load. In this example, chemical reactions 678A-C facilitated by the enzymes 664 are illustrated in FIG. 6. The hydrogen peroxide released from chemical reaction 678C reacts with the surface of electrode layer 658 according to chemical reaction 680. As shown by FIG. 6, two electrons are released for each molecule of creatinine that reacts, and the electrons are conducted via metal layer 654 to electronics system 610. In aspects, the number of electrons released via reaction 680 is proportional to the analyte level (e.g., concentration) of creatinine in the interstitial tissue 622.

[0161] In contrast, when amperometric sensor flex 600 is configured to detect a glucose level in the interstitial tissue 622, the enzymes 664 may include one or more of glucose oxidase and / or glucose dehydrogenase (not shown). In this case, the chemical reaction facilitated in enzyme layer 660 to detect the glucose level, for example, may be as follows:Attorney Docket No. A0014277W001Glucose OxidaseGlucose + O2- > Gluconic acid + H2O2, Reaction 1.

[0162] The hydrogen peroxide released from the chemical reactions occurring in the enzyme layer 660 may react with the surface of electrode layer 658 according to the following reaction:H2O2— > O2+ 2H++ 2e’, Reaction 2.

[0163] As with the creatinine sensor, two electrons are released by Reaction 2. The electrons released from electrode layer 658 are conducted via the metal layer 654 to an electronics system 610 of monitor 602. In this example (not shown), the number of electrons released via Equation 2 is proportional to the analyte level (e.g., concentration) of glucose in the interstitial tissue 622.

[0164] As should be appreciated, components of amperometric sensor flex 600 are described for purposes of example and explanation and should not be considered limiting or exclusive. That is, described components may be removed, additional components may be included, and / or alternative components may be substituted without departing from the disclosure provided herein.

[0165] FIGS. 7A-7B are schematic diagrams of example potassium potentiometric sensors, in accordance with one or more examples described herein. FIG. 7A is a schematic diagram of an example potentiometric sensor flex 700 A, including potassium working electrode (WEp) 742A (e.g., the same as or similar to WEp 242, 342, 442, and / or 542), which is configured to detect a level of an analyte 726 (e.g., potassium ion, K+) in a solution (e.g., interstitial tissue 722). In some examples, a reference electrode (not shown) may be included on potentiometric sensor flex 700A. In general, a reference electrode is configured to maintain a known and stable baseline electrical signal against which electrical signal(s) generated by WEp 742A.

[0166] As illustrated, potentiometric sensor flex 700A includes flexible substrate 750 (e.g., polyimide) overlaid by a conductive metal layer 754 (e.g., trace gold, Au). In some examples, a conductive adhesion layer (e.g., titanium, Ti) may be formed between the flexible substrate layer 750 and the conductive metal layer 754; in other examples,Attorney Docket No. A0014277W001conductive metal layer 754 may itself be formed of multiple layers (e.g., including titanium and gold, TiAu) or otherwise exhibit adhesive properties. In aspects, flexible insulation layer 756 (e.g., polyimide) may be applied over the conductive metal layer 754. In addition to flexibility, flexible insulation layer 756 may include insulative properties and be applied using a film mask or other application technique, for example, to create openings or holes for exposing portions of the underlying conductive metal layer 754.

[0167] In some examples, WEp 742Amay include a solid-contact electrode 757 that is coated with an ion-selective membrane (ISM) 759 and embedded in flexible insulation layer 756 at one or more exposed portions, thereby enabling WEp 742Ato contact conductive metal layer 754. In other examples, WEp 742Amay be an integrated circuit (IC) embedded in flexible insulation layer 756 at one or more exposed portions, thereby enabling WEp 742Ato contact conductive metal layer 754. As illustrated by FIG. 7A, ISM 759 is applied as an overlay on an upper surface of flexible insulation layer 756; however, in other examples, ISM 759 may be fully recessed (not shown) or partially recessed into flexible insulation layer 756 (see, e.g., FIG. 7B). In aspects, conventional ion-selective potassium electrodes include an inner filling solution (e.g., a potassium chloride, KC1, solution) and an inner conducting reference (e.g., comprising silver, Ag, or silver chloride, AgCl). In contrast, the solid-contact electrode 757 described herein may be formed of: a conducting polymer (e.g., poly(aniline), poly(2,3-dihydrothieno-l,4-dioxin)-poly(styrenesulfonate), and poly(pyrrole), and any derivatives thereof); a high surface area conductive carbon material (e.g., a carbon powder or paste); and / or carbon nanotubes (CNT) or vertically aligned carbon nanotubes (VCNT), for example. Alternatively, when WEp 742Ais an IC, WEp 742Amay comprise one or more transistors, resistors, and / or capacitors connected via miniaturized metal circuitry and embedded in the flexible insulation layer 756 in contact with conductive metal layer 754. In either example, the need for an inner filling solution is eliminated, thereby facilitating better production scaling of WEp 742A and eliminating risks, such as filling solution leaking into the interstitial tissue of a patient.

[0168] As described above, when WEp 742A includes solid-contact electrode 757, which contacts conductive metal layer 754 along a bottom surface and is overlayed with an ion-selective membrane (ISM) 759 along a top surface. ISM 759 may be a membrane infused with one or more ionophores and / or ionic sites, for example. In aspects, anAttorney Docket No. A0014277W001ionophore is configured to interact with a particular ion (e.g., K+) in the ISM 759. For example, when a K+-selective electrode is in contact with a sample (e.g., interstitial tissue 722) containing an analyte 726 (e.g., K+), the ionophore preferentially extracts a small amount of the analyte 726 from the interstitial tissue 722 into the ISM 759, without extracting its counter ion (e.g., chloride, Cl-), resulting in formation of a charge separation layer and a corresponding electrical potential (often referred to as a phase boundary potential) at an interstitial tissue / ISM interface 778A(e.g., first interface). In aspects, the interstitial tissue / ISM interface 778Amay comprise an upper surface of the ISM membrane 759 in contact with the interstitial tissue 722 and may further comprise at least a portion (or layer) of the ISM membrane 759 adjacent the upper surface. A change in the K+ concentration in the interstitial tissue 722 produces a change in the phase boundary potential at the interstitial tissue / ISM interface 778A, which causes the electrical potential (e.g. voltage) of electrode WEp 742Ato change. The potential of the electrode is proportional to the concentration of the target analyte 726 (e.g., K+) in the interstitial tissue 722, and can therefore be used to determine the concentration of the analyte 726 (e.g., K+) in the interstitial tissue 722.

[0169] An ionic site may be a salt wherein one component is a hydrophobic anion (e.g., tetrakis(4-chlorophenyl)borate) and another component is a hydrophilic cation (e.g., K+). The hydrophobic anion has poor solubility in the sample phase (e.g., interstitial tissue 722), but the cation has high solubility. Alternatively, an ionic site may include an anion covalently attached to the polymer ISM 759 whereas the cation (e.g., K+) is not attached. In this case, the cation is free to exchange with cations in the sample (e.g., interstitial tissue 722). In aspects, the role of the ionic sites is to prevent coextraction of K+ and any counterions (e.g., C1-) into the ISM 759.

[0170] In examples, the solid-contact electrode 757 facilitates ion-to-electron transduction either by double-layer capacitance (e.g., when comprising a high surface area conductive carbon material, CNT, or VCNT) or a redox reaction (e.g., when comprising conducting polymers), resulting in a stable phase boundary potential at an ISM / solid-contact interface 778B (e.g., second interface). In aspects, the ISM / solid-contact interface 778B may be defined at a boundary of a lower surface of the ISM 759 in contact with the top surface of the solid-contact electrode 757 and may further comprise at least a portion (or layer) of the solid-contact electrode 757 adjacent the top surface of solid-contactAttorney Docket No. A0014277W001electrode 757 and / or at least a portion (or layer) of the ISM 759 adjacent the lower surface of ISM 759. This ensures that only the phase boundary potential at the interstitial tissue / ISM interface 778A(e.g., first interface) changes during sensor operation. In further examples, the solid-contact electrode 757 also conducts the electrical signal to conductive metal layer 754, which in turn conducts the electrical signal to an electronics system (e.g., electronics system 800 of FIG. 8) of a patient monitor (e.g., monitor 102 of FIG. 1 A).

[0171] In still further aspects, the ISM 759 may be deposited across electrodes of a field-effect transistor (FET) (or an ion-selective field-effect transistor, ISFET), embedded in a flex sensor. In this example, the FET gate may be covered by an insulating layer before the ISM 759 is deposited. When K+ interacts with the ISM 759 the surface potential at the interface changes, altering the electric field at an electrode and thus voltage across the channel. The resulting change in voltage is proportional to the concentration of K+ in the ISM 759, which is proportional to the concentration of K+ in the interstitial tissue. In some examples, integrated circuits associated with operation of the FET are imbedded in the flex sensor.

[0172] Voltametric methods may also be applied to the K+ electrode (e.g., WEp 742A-B) configurations described herein to determine the K+ concentration using two or three electrode cell configurations (e.g., including a reference electrode and / or a counter electrode). In one example, a potential sweep is applied to the ion-selective electrode relative to the reference electrode by cyclic voltammetry or square wave voltammetry. In some examples, the counter electrode for the creatinine and glucose sensors could also be used for the K+ sensor (e.g., WEp 742A-B) or a dedicated counter electrode could be used. In cyclic voltammetry, a linear potential sweep is applied to the K+ ion-selective electrode (e.g., WEp 742A-B) from a starting potential El to a final potential E2 relative to the reference electrode, followed by reversal of the potential sweep from E2 to El. This causes the K+ ion to be transferred from the sample (e.g., interstitial tissue 722) into the ion-selective membrane (ISM) 759 or transfer of the K+ ion from the ISM 759 into the sample (depending on the direction of the potential sweep). As the K+ concentration in the ISM 759 occurs, a redox reaction at the solid contact (e.g., in the case of conducting polymers) occurs, resulting in a current passing through the ion-selective electrode (e.g., WEp 742A-B) that can be measured. In some embodiments, the potential at which the maximum current flow (corresponding to ion K+ ion transfer into or out of the ISM 759)Attorney Docket No. A0014277W001occurs can be used to determine the K+ concentration in the sample (e.g., the potential change is proportional to the K+ concentration in the interstitial tissue 722).

[0173] In another example, ion transfer stripping voltammetry can be used. In this method, an initial potential (El) is applied to the K+-selective electrode (e.g., WEp 742A-B) relative to a reference electrode for a specific time period (tl). Then, a potential sweep (e.g., linear sweep voltammetry, differential pulse voltammetry) can be applied to the ion-selective electrode (e.g., WEp 742A-B) to drive the K+ ions from the ISM 759 (ion stripping step). The current or total charge measured during the stripping step can be used to determine the K+ concentration in the sample (e.g., current or charge are proportional to K+ concentration in the interstitial tissue 722).

[0174] In another example, electrochemical impedance spectroscopy (EIS) could be used. In this method, the ISM 759 is deposited over two interdigitated electrodes. The impedance at discrete frequencies or over a range of frequencies between the two electrodes is measured and correlated to K+ concentration in the interstitial tissue 722. When EIS is used the ISM 759 may contain ionophores and ionic sites.

[0175] Similar to FIG. 7A, FIG. 7B is a schematic diagram of an example potentiometric sensor flex 700B, including potassium working electrode (WEp) 742B (e.g., the same as or similar to WEp 242, 342, 442, 542, and / or 742A), which is configured to detect a potassium ion (K+) level in a solution (e.g., interstitial tissue 722). In some examples, a reference electrode (not shown) may be included on potentiometric sensor flex 700B. In general, a reference electrode is configured to maintain a known and stable baseline electrical signal against which electrical signal(s) generated by WEp 742B. As with FIG. 7A, potentiometric sensor flex 700B includes flexible substrate 750 (e.g., polyimide) overlaid by a conductive metal layer 754 (e.g., trace gold, Au). In some examples, a conductive adhesion layer (e.g., titanium, Ti) may be formed between the flexible substrate layer 750 and the conductive metal layer 754; in other examples, conductive metal layer 754 may itself be formed of multiple layers (e.g., including titanium and gold, TiAu) or otherwise exhibit adhesive properties. As with FIG. 7A, flexible insulation layer 756 (e.g., polyimide) is applied over the conductive metal layer 754 using a film mask or other application technique, for example, and may include insulative properties.Attomey Docket No. A0014277W001

[0176] As with WEp 742A, WEp 742B may include a solid-contact electrode 757 that is coated with an ion-selective membrane (ISM) 759 embedded in flexible insulation layer 756 at one or more exposed portions, thereby enabling WEp 742B to contact conductive metal layer 754. As illustrated by FIG. 7B, ISM 759 is partially recessed into flexible insulation layer 756; however, in other examples, ISM 759 may be fully recessed (not shown) or applied as an overlay on an upper surface of flexible insulation layer 756 (see, e.g., FIG. 7A). Solid-contact electrode 757 may include a conducting polymer (e.g., poly(aniline), poly(2,3-dihydrothieno-l,4-dioxin)-poly(styrenesulfonate), and poly(pyrrole), and any derivatives thereof) or a high surface area conductive carbon material (e.g., carbon powder, nanotubes or paste) to facilitate ion-to-electron transduction. As described above, ISM 759 may be a membrane infused with ionophores and / or ionic sites, for example.

[0177] As illustrated by FIG. 7B, WEp 742B may also include a permeable membrane 763 overlaying ISM 759. In aspects, permeable membrane 763 may be configured to regulate a type of analyte 726 (e.g., K+) that is diffusible from interstitial tissue 722 to the ISM 759. In this way, permeable membrane 763 limits large molecules (e.g., proteins), cells, and other chemicals in the interstitial tissue 722 from reaching the ISM 759, thereby ensuring that a target analyte concentration (e.g., K+ concentration) at the permeable membrane / ISM interface 778C (e.g., third interface) corresponds to the analyte concentration in the interstitial tissue 722 of the patient. In aspects, the permeable membrane / ISM interface 778C may be defined at a boundary of a lower surface of the permeable membrane 763 in contact with an upper surface of the ISM 759 and may further comprise at least a portion (or layer) of the ISM 759 adjacent the upper surface and / or at least a portion (or layer) of the permeable membrane 763 adjacent the lower surface.

[0178] In additional or alternative aspects, the permeable membrane 763 may be configured to slow an immune response by the patient and / or improve electrode stability while implanted. In aspects, the permeable membrane 763 may be formed of one or a combination or copolymer of the following: polyethyleneimine (PEI), polyurethane (PU), polyethylene glycol) (PEG), cellulose acetate, polyhydroxyethylmethacrylate (pHEMA), or a physical perforated membrane of any material, such as carbon, ceramic, ablated metals, or polymers. In additional or alternative aspects, permeable membrane 763 may be a hydrogel such as poly(vinyl alcohol), poly(methylmethacrylate), phosphoryl choline-Attorney Docket No. A0014277W001containing zwitterionic polymers. In aspects, permeable membrane 763 may be the same as or different from limiting membrane 662.

[0179] As should be appreciated, components of potentiometric sensor flexes 700A-700B are described for purposes of example and explanation and should not be considered limiting or exclusive. That is, described components may be removed, additional components may be included, and / or alternative components may be substituted without departing from the disclosure provided herein.

[0180] FIG. 8 is a block diagram illustrating an example electronics system 800, in accordance with one or more examples described herein. Electronics system 800 includes an analog frontend (AFE) 866, a power supply component 867, a computing component 868, and a transmission component 869. In aspects, AFE 866 may comprise or be communicatively coupled to a plurality of channels 870 for independently receiving electrical signals from multiple working electrodes (WEs), counter electrodes (CEs), and / or reference electrodes (REs) associated with the one or more flex sensors (see FIGS.2-5). In some examples, the plurality of channels 870 may include twelve (12) channels, with four (4) WE channels, four (4) CE channels, and four (4) RE channels; in other examples, the plurality of channels 870 may include nine (9) channels, with three (3) WE channels, three (3) CE channels, and three (3) RE channels; in still other examples, the plurality of channels 870 may include fifteen (15) channels, with five (5) WE channels, five (5) CE channels, and five (5) RE channels. As should be appreciated, the plurality of channels 870 may include any suitable number and / or configuration of channels so as enable AFE 866 to receive independent electrical signals from electrodes associated with the one or more flex sensors.

[0181] In further aspects, AFE 866 may be responsible for conditioning the electrical signals received from the one or more flex sensors. For example, AFE 866 may include or be associated with amplifiers, filters, analog-to-digital converters (ADC), and / or other electronic circuitry for enhancing quality of and / or performing processing on the electrical signals. For example, AFE 866 may filter the electrical signals to remove noise, may boost weak electrical signals, may prepare the electrical signals for analog-to-digital conversion, and / or may perform analog-to-digital conversion of the electrical signals.Attorney Docket No. A0014277W001

[0182] In some aspects, power supply component 867 may include one or more batteries. Different battery technologies may be utilized, such as lithium-based chemistries, alkaline batteries, nickel metal hydride, or the like, and different numbers of batteries may be used. Electronics system 800 provides power to electrodes via power supply component 867, e.g., via a suitable electrical interface coupling electronics system 800 to electrical circuitry (e.g., electrical circuitry 244 of FIG. 2A, et seq.). Alternatively, power supply component 867 may be another type of power storage device suited for a small interstitial monitor.

[0183] Computing component 868 may include one or more microcontrollers (MCU) 871 (e.g., including at least one processor 876), memory 872, sensors 877 and, in some cases, removable memory 873 (e.g., a micro secure digital (SD) card), in examples. In some aspects, MCU 871 may be a processor, digital signal processors (DSPs), application specific integrated circuits (ASICs), field programmable gate arrays (FPGAs), or any other equivalent integrated or discrete logic circuitry. In other examples, MCU 871 may include processor 876. In some examples MCU 871 may be configured to cause a specific voltage or current to be output from power supply 867 to one or more flex sensors, which each include one or more electrodes such as working electrodes, counter electrodes, and / or reference electrodes, for example.

[0184] In aspects, sensor(s) 877 may include one or more external sensors for measuring one or more physiological parameters. For example, sensors 877 may include a motion sensor, such as an accelerometer, an IMU or a gyroscope, that can track a patient’s physical movement and / or activity level. Additionally, the motion sensor can be used to determine heart rate and / or respiratory rate, as well as fall detection, movement (or nonmovement) alerts, and / or weakness detection. Sensors 877 may further include a temperature sensor, which may be a thermistor, a digital temperature integrated circuit (IC), a resistance-temperature-detector (RTD), or a thermocouple, for example. In aspects, measuring external body temperature can enable clinicians to better understand the health condition of a patient. Sensors 877 may further include an oxygen sensor, which may be a pulse oximeter or an optical oxygen sensor, for example. A pulse oximeter is a non-invasive sensor that measures red and infrared light absorption to determine oxygen saturation (SpCh) of a patient’s blood. An optical oxygen sensor is a non-invasive sensor that utilizes luminescence quenching to determine oxygen concentration. Blood oxygenAttorney Docket No. A0014277W001can also be used as an internal standard or background electrode to improve accuracy of creatinine and / or glucose sensors, which may become less accurate in low O2 environments.

[0185] Memory 872 may be any type of memory device and may be configured to store measurements produced by processor 876, reference values for computing baselines, formulas or algorithms for converting electrical signals to analyte levels (where different formulas and / or algorithms may be stored for each analyte being tested), and / or other data used and / or produced by processor 876 and / or MCU 871. In some examples, memory 872 may further store software and / or firmware that is executable by processor 876 and / or MCU 871. In some examples, SD card 873 may backup data stored by memory 872 and / or SD card 873 may store data (e.g., processor 876 outputs) for removal and transfer to another computing device or system.

[0186] In general, processor 876 may be configured to receive a current, voltage, and / or impedance from each working electrode (e.g., WEc, WEg, WEo, WEp) of the flex sensors. As described above, each working electrode generates an electrical signal indicative of a level (e.g. a concentration) of an analyte being measured. In some cases, the working electrodes may measure the same analyte; in other examples, the working electrodes may measure different analytes. For example, a first working electrode (e.g., WEc) may generate an electrical signal indicative of a creatinine level, where the electrical signal may be a current (e.g., iSig) or a voltage measured at the first working electrode. Similarly, a second working electrode (WEg) may generate an electrical signal indicative of a glucose level, where the electrical signal may be a current (e.g., iSig) or a voltage measured at the second working electrode. In further examples, a third working electrode (WEp) may generate an electrical signal indicative of a potassium level, where the electrical signal may be a voltage measured at the third working electrode. In still further examples, a fourth working electrode (WEo) may generate an electrical signal indicative of an oxygen level, where the electrical signal may be a current (e.g., iSig) or a voltage measured at the fourth working electrode.

[0187] For example, processor 876 may receive each electrical signal (e.g., a measured current, voltage, and / or impedance) after the electrical signal is measured at each working electrode (e.g., first, second, third, or fourth working electrodes above). Upon receipt of anAttorney Docket No. A0014277W001electrical signal, processor 876 may calibrate the electrical signal utilizing one or more reference values, which are based on a known analyte quantity, e.g., a zero-analyte measurement to determine a baseline electrical signal. In some examples, reference values may be specific to the analyte being tested and may be stored, e.g., in a reference memory of memory 872 and / or SD Card 873, and retrieved by processor 876. Based on the received electrical signal and the reference values, processor 876 may determine an analyte measurement, such as an analyte level or analyte concentration in an interstitial fluid layer of a patient. In aspects, one or more algorithms or formulas may be processed by processor 876 to convert the received electrical signal into an analyte level.

[0188] Processor 876 may store the analyte measurements in memory 872 and / or SD card 873. Additionally, processor 876 and / or MCU 871 may send the analyte measurements to transmission component 869, which may be associated with a display (not shown) and / or one or more communication protocols, such as Bluetooth low energy (BLT) technologies 874, near-field communication (NFC / RFID) extensions 875, or any other suitable transmission protocol or standard.

[0189] FIG. 9 is a flowchart illustrating an example method 900 for determining a health condition of a patient using a wearable monitor having at least one internal sensor positioned in interstitial tissue of the patient and at least one external sensor positioned on or in the wearable monitor. The health condition of the patient may be based on one or more analyte levels in the interstitial tissue of the patient and / or one or more external parameter values measured by the at least one external sensor, in accordance with one or more examples described herein. One or more of the operations of FIG. 9 may be performed using monitor 102 of FIG. 1 A, monitor 202 of FIG. 2, monitor 302 of FIG. 3, monitor 402 of FIG. 4, monitor 502 of FIG. 5, amperometric sensor flex 600, potentiometric sensor flexes 700A-700B of FIGS. 7A-7B, and / or electronics system 800 of FIG. 8. However, the disclosed monitors and sensors may be used to perform other techniques, and the illustrated technique may be performed with other devices. The illustrated technique is described with concurrent reference to electronics system 800 of FIG. 8.

[0190] In aspects of the method 900, a power supply component (e.g., power supply component 867 of FIG. 8) of an analyte monitor (e.g., monitor 102 of FIG. 1A) mayAttorney Docket No. A0014277W001generate a reference voltage (e.g., VSET) between one or more working electrodes (e.g., a creatine working electrode and / or a glucose working electrode) and a counter electrode. In some aspects, the power supply component may generate a reference voltage between the one or more working electrodes and a reference electrode. In further aspects, the one or more working electrodes, the counter electrode, and / or the reference electrode are configured on one or more flex sensors (e.g., flex sensors 216A-C, 316A-F, 416A-E, 516A-G) and positioned in an interstitial fluid layer (e.g., interstitial fluid layer 122 of FIG. 1 A) of a patient. In aspects, the one or more working electrodes may be amperometric sensors (e.g., amperometric sensor flex 600), potentiometric sensors (e.g., potentiometric sensor flexes 700A-700B), or Clark-style oxygen sensors.

[0191] At operation 902, a first working electrode of at least one internal sensor may interact with a first analyte in the interstitial fluid layer of the patient. In aspects, the first working electrode may be an amperometric sensor, which comprises one or more enzymes configured to facilitate chemical reactions with the first analyte (e.g., creatinine or glucose). In at least some aspects, the first working electrode may interact with the first analyte substantially continuously, for example, over a period of time in which the first working electrode is positioned within the interstitial tissue of the patient.

[0192] At operation 904, a second working electrode of the at least one internal sensor may interact with a second analyte (e.g., K+ or O2) in the interstitial fluid layer of the patient. In aspects, the second working electrode may be a potentiometric sensor, which is configured to facilitate a charge separation or electric potential responsive to a second analyte (e.g., potassium). Alternatively, the second sensor may be a Clark-style oxygen sensor, which is configured to facilitate a redox reaction resulting in a detectable electron change that correlates with the oxygen concentration in the interstitial tissue of the patient. In at least some aspects, the second working electrode may interact with the second analyte substantially continuously, for example, over a period of time in which the second working electrode is positioned within the interstitial tissue of the patient.

[0193] At operation 906, the first working electrode may generate a first electrical signal proportional to a first analyte concentration of the first analyte consumed by the chemical reactions. In aspects, one or more products of the chemical reactions may react with an electrode layer (e.g., electrode layer 658 of FIG. 6) of the first working electrodeAttorney Docket No. A0014277W001to generate the first electrical signal. Since the one or more products output by the chemical reactions are limited by the first analyte concentration, the magnitude or strength of the generated first electrical signal is proportional to the first analyte concentration (e.g., glucose or creatinine). In aspects, the first working electrode may substantially continuously generate first electrical signals while the first working electrode is positioned in the interstitial fluid layer of a patient, e.g., over the period of time that the first working electrode is interacting with the first analyte, and subject to any latencies in conducting the first electrical signals between the first working electrode and the wearable monitor. In this way, changes in the first analyte concentration may be substantially continuously monitored.

[0194] At operation 908, the second working electrode may generate a second electrical signal proportional to a second analyte concentration of the second analyte in the interstitial tissue. For example, when the second working electrode is a Clark-style oxygen sensor, a detectable electron change resulting from the redox reaction correlates with an oxygen concentration in the interstitial tissue of the patient. In contrast, when the second working electrode is a potentiometric sensor, an ion-selective membrane (e.g., ISM 759 of FIGS. 7A-7B) may interact with the second analyte (e.g., K+) to extract it from the interstitial fluid layer into the ISM at the interstitial tissue / ISM interface (e.g., interstitial tissue / ISM interface 778A), without extracting the analyte’s counterion (e.g., C1-), thereby causing a phase boundary potential at the interstitial tissue / ISM interface to develop. In this way, the second electrical signal (e.g., voltage) that is generated is proportional to a potassium concentration in the interstitial fluid layer. In aspects, the second working electrode may substantially continuously generate second electrical signals while the second working electrode is positioned in the interstitial fluid layer of a patient, e.g., over the period of time that the second working electrode is interacting with the second analyte, and subject to any latencies in conducting the second electrical signals between the second working electrode and the wearable monitor. In this way, changes in the second analyte concentration may be substantially continuously monitored.

[0195] At operation 910, a processor (e.g., processor 876) may convert the first electrical signal into a first analyte level. For example, the processor may execute a first formula to convert the first electrical signal to the first analyte level. In aspects, the first formula may represent a first relationship between the first electrical signal and the firstAttorney Docket No. A0014277W001analyte level. In aspects, the first relationship may be a direct relationship such that a greater magnitude or strength of the first electrical signal may correspond to a higher first analyte level and a lower magnitude or strength of the first electrical signal may correspond to a lower first analyte level. In aspects, the processor may substantially continuously convert the first electrical signals into first analyte levels over time, e.g., over the period of time that the first working electrode is interacting with the first analyte, and subject to any processing latencies in converting the first electrical signals into the first analyte levels over time. In this way, changes in the first analyte levels may be substantially continuously monitored.

[0196] At operation 912, the processor may convert the second electrical signal into a second analyte level. For example, the processor may execute a second formula to convert the second electrical signal to the second analyte level. In aspects, the second formula may represent a second relationship between the second electrical signal and the second analyte level. In aspects, the second relationship may be a direct relationship such that a greater second electrical signal may correspond to a higher second analyte level and a lower magnitude or strength of the second electrical signal may correspond to a lower second analyte level. In aspects, the processor may substantially continuously convert the second electrical signals into second analyte levels over time, e.g., over the period of time that the second working electrode is interacting with the second analyte, and subject to any processing latencies in converting the second electrical signals into the second analyte levels over time. In this way, changes in the second analyte levels may be substantially continuously monitored.

[0197] At operation 914, the processor may receive a third electrical signal corresponding to an external parameter value of the patient from the at least one external sensor. For example, the third electrical signal may be received from a motion sensor, such as an accelerometer, an IMU or a gyroscope, and may correspond to a respiratory rate or a heart rate of the patient. Alternatively, the third electrical signal may be received from a temperature sensor, such as a thermistor or a digital temperature IC sensor, and may correspond to an external body temperature of the patient. Alternatively still, the third electrical signal may be received from an oxygen sensor, such as a pulse oximeter or an optical oxygen sensor, and may correspond to an oxygen saturation or oxygen concentration of the patient.Attorney Docket No. A0014277W001

[0198] At operation 916, at a first time, based on one or more of the first analyte level, the second analyte level, and / or the external parameter value, a health condition of the patient may be determined at the first time. For example, high serum creatinine levels (e.g., above 150 pmol / L), high serum glucose levels (e.g., above 170 mg / dL), high serum potassium levels (e.g., >5.50 mmol / L), and / or low ISF oxygen levels (e.g., less than about 30 mmHg) may be indicative of one or more acute conditions, such as AKI, and / or a progression of one or more existing conditions (e.g., CRM conditions, cardiovascular disease (CVD), chronic kidney disease (CKD) or CHF) at the first time.

[0199] At operation 918, at a second time, based on a change in at least one of the first analyte level, the second analyte level, and / or the external parameter value, the health condition of the patient may be determined at the second time. For example, one or more of a glucose level, a creatinine level, an oxygen level, and / or a potassium level may change at the second time. Moreover, a body temperature, a heart rate, or a respiratory rate of the patient may change at the second time. For example, at the second time, a high serum creatinine level (e.g., above 150 pmol / L), a high serum glucose level (e.g., above 170 mg / dL), a high serum potassium level (e.g., >5.50 mmol / L), and / or a low ISF oxygen level (e.g., less than about 30 mmHg) may be indicative of one or more acute conditions, such as AKI, and / or a progression of one or more existing conditions (e.g., CRM conditions, cardiovascular disease (CVD), chronic kidney disease (CKD) or CHF).

[0200] As should be appreciated, operations 902-918 of FIG. 9 are not so limited and may be performed in a different order, some or all of operations 902-918 may be performed at the same or different times, and additional operations may be performed with operations 902-918. For example, each flex sensor of the one or more flex sensors may comprise one or more working electrodes, including two or more working electrodes, three or more working electrodes, and so on, without departing from the present disclosure.EXPERIMENTAL EXAMPLES

[0201] A series of tests were performed to validate the use of a monitor that includes one or more flex sensors, where each flex sensor may include a plurality of electrodes, such as working electrodes, counter electrodes, and / or reference electrodes.Attorney Docket No. A0014277W001

[0202] FIG. 10 is a graph 1000 illustrating an example in vitro operation of a monitor (e.g., monitor 102 of FIG. 1) designed to electrochemically track glucose, potassium, and creatinine levels with the electrode layout described in FIG. 5.

[0203] A test solution of phosphate-buffered saline (PBS) at room temperature was prepared. The flex sensors (e.g., flex sensors 516A and 516B) of the monitor were introduced to the text solution at an initial time, and then analytes (e.g., analytes 126 of FIG. 1) were added in a stepwise and staggered fashion. Each analyte was tested through a normal physiological range and into an abnormal physiological range associated with AKI. In aspects, the normal physiological range for creatinine in blood is from about 50 pmol / L to about 80 pmol / L for adult females and 57 pmol / L to about 93 pmol / L for adult males, the normal physiological range for potassium in blood is from about 3.4 mmol / L to about 4.8 mmol / L, and the normal physiological range for fasting blood glucose is from about 67 mg / dL to about 93 mg / dL.

[0204] Turning to the graph, the left axis shows a voltage count in arbitrary units (AU) seen at the potassium sensor in response to changes in potassium, and the right axis shows a current count in arbitrary units (AU) seen at the glucose and creatinine sensors in response to respective changes in glucose and creatinine. Data was smoothed using a 20-point moving average (potassium and creatinine) and 10-point moving average (glucose) to eliminate erroneous electrical noise spikes.

[0205] In the illustrated example, creatinine was increased in the test solution in a stepwise fashion over a first period of about 4000 seconds (s). For example, at a first time (e.g., C-Tl) (e.g., about 8000 s), a first bolus of creatinine was delivered; at a second time (C-T2) (e.g., about 10000 s), a second bolus of creatinine was delivered; and at a third time (C-T3) (e.g., about 12000 s), a third bolus of creatinine was delivered. In aspects, the amount of creatinine delivered in each of the first, second, and third boluses was the same or different. As illustrated by FIG. 10, the creatinine sensor measured a current count (AU) over the same period (e.g., C-Tl to C-T3). In proportion to the concentration of creatinine in the test solution after each bolus, at about time C-Tl, the monitor measured a current count of about 5 AU; at about time C-T2, the monitor measured a current count of about 10 AU; and at about time C-T3, the monitor measured a current count of about 15 AU.Attorney Docket No. A0014277W001

[0206] Similarly, potassium was increased in the test solution in a stepwise fashion over a second period of about 5000 s, the second period being after the first period. That is, in this example, potassium was increased in the test solution after creatinine was increased; however, in other examples, the increase in potassium could be performed prior to the increase in creatinine or concurrently with the increase in creatinine. As illustrated, at a first time (e.g., P-Tl) (e.g., about 12000 s) a first bolus of potassium was delivered; at a second time (P-T2) (e.g., about 13000 s), a second bolus of potassium was delivered; at a third time (P-T3) (e.g., about 14000 s), a third bolus of potassium was delivered; and at a fourth time (P-T4) (e.g., about 17000 s), a fourth bolus of potassium was delivered. In aspects, the amount of potassium delivered in each of the first, second, third, and fourth boluses was the same or different. In this example, the potassium sensor measured a voltage count in arbitrary units (AU) over the same period (e.g., P-Tl to P-T4). In proportion to the concentration of potassium in the test solution after each bolus, at about time P-Tl, the monitor measured a voltage count of about 215 AU; at about time P-T2, the monitor measured a voltage count of about 220 AU; at about time P-T3, the monitor measured a voltage count of about 223 AU; and at about time P-T4, the monitor measured a voltage count of about 230 AU.

[0207] Following the increase of the creatinine and the potassium, glucose was increased in the test solution in a stepwise fashion over a third period of about 4000 s, the third period being after the first period and the second period. That is, in this example, glucose was increased in the test solution after creatinine and potassium were increased; however, in other examples, the increase in glucose could be performed prior to the increase in creatinine and / or potassium or concurrently with the increase in creatinine and / or potassium. As illustrated, at a first time (e.g., G-Tl) (e.g., about 18000 s), a first bolus of glucose was delivered; at a second time (G-T2) (e.g., about 19000 s), a second bolus of glucose was delivered; and at a third time (G-T3) (e.g., about 21000 s), a third bolus of glucose was delivered. In aspects, the amount of glucose delivered in each of the first, second, and third boluses of glucose was the same or different. In this example, the glucose sensor measured a current count in arbitrary units (AU) over the same period (e.g., G-Tl to G-T3). In proportion to the concentration of glucose in the test solution after each bolus, at about time G-Tl, the monitor measured a current count of about 6 AU; at aboutAttorney Docket No. A0014277W001time G-T2, the monitor measured a current count of about 11 AU; and at about time G-T3, the monitor measured a current count of about 16 AU.

[0208] In sum, as illustrated by FIG. 10, one or more sensors of the multi-electrode configuration described in FIG. 5 exhibited independent operation and responsiveness to a particular analyte.

[0209] The following describes aspects of the disclosure herein, provided as a plurality of clauses that may be used alone or in combination.

[0210] Clause 1 : A wearable monitor configured to determine a health condition of a patient, comprising: a plurality of internal sensors configured to be positioned within interstitial fluid of the patient, the plurality of internal sensors including at least one flex circuit, comprising: a first working electrode responsive to a first analyte concentration over time; a second working electrode responsive to a second analyte concentration over time; and a third working electrode responsive to a third analyte concentration over time; and at least one external sensor configured to sense at least one external parameter value of the patient over time, wherein the health condition of the patient is determined at a first time based on one or more of the at least one external parameter value, the first analyte concentration, the second analyte concentration, or the third analyte concentration at the first time.

[0211] Clause 2: The wearable monitor of clause 1, wherein the health condition of the patient is determined at a second time based on at least one change in at least one of the external parameter value, the first analyte concentration, the second analyte concentration, or the third analyte concentration at the second time.

[0212] Clause 3 : The wearable monitor of any one of clauses 1 or 2, wherein the at least one external sensor is configured to determine the at least one external parameter value substantially continuously over time.

[0213] Clause 4: The wearable monitor of any one of clauses 1-3, wherein at least one of the plurality of internal sensors is configured to determine at least one of the first analyte concentration, the second analyte concentration, or the third analyte concentration substantially continuously over time.Attorney Docket No. A0014277W001

[0214] Clause 5: The wearable monitor of any one of clauses 1-4, the at least one flex circuit further comprising a fourth working electrode responsive to a fourth analyte concentration over time.

[0215] Clause 6: The wearable monitor of any one of clauses 1-5, the at least one flex circuit comprising a first flex circuit and a second flex circuit.

[0216] Clause 7: The wearable monitor of any one of clauses 1-6, wherein the wearable monitor is mounted on an exterior skin surface of the patient.

[0217] Clause 8: The wearable monitor of any one of clauses 1-7, wherein the first working electrode is responsive to a creatinine concentration over time, the second working electrode is responsive to a glucose concentration over time, and the third working electrode is responsive to a potassium concentration over time.

[0218] Clause 9: The wearable monitor of clause 5, wherein the fourth working electrode is responsive to an oxygen concentration over time.

[0219] Clause 10: The wearable monitor of any one of clauses 1-9, wherein the at least one external sensor is at least one of a temperature sensor, an oxygen sensor, or a motion sensor.

[0220] Clause 11 : A wearable monitor comprising one or more flex sensors configured to be positioned within interstitial tissue of a patient, the one or more flex sensors including a plurality of working electrodes, comprising: a first working electrode responsive to a first analyte concentration over time; a second working electrode responsive to a second analyte concentration over time; a third working electrode responsive to a third analyte concentration over time; and a fourth working electrode responsive to a fourth analyte concentration over time; and wherein at least two of the plurality of working electrodes are positioned on the same flex sensor of the one or more flex sensors.

[0221] Clause 12: The wearable monitor of clause 11, wherein a health condition of the patient is determined at a first time based on at least one of the first analyte concentration, the second analyte concentration, the third analyte concentration, or the fourth analyte concentration at the first time.Attorney Docket No. A0014277W001

[0222] Clause 13: The wearable monitor of clause 12, wherein the health condition of the patient is determined at a second time based on at least one change in at least one of the first analyte concentration, the second analyte concentration, the third analyte concentration, or the fourth analyte concentration at the second time.

[0223] Clause 14: The wearable monitor of any one of clauses 11-13, wherein the first working electrode is responsive to a creatinine concentration over time and the second working electrode is responsive to a glucose concentration over time.

[0224] Clause 15: The wearable monitor of any one of clauses 11-14, wherein the third working electrode is responsive to a potassium concentration over time and the fourth working electrode is responsive to an oxygen concentration over time.

[0225] Clause 16: The wearable monitor of any one of clauses 11-15, the one or more flex sensors further comprising a thermistor responsive to changes in temperature of the interstitial tissue over time.

[0226] Clause 17: The wearable monitor of any one of clauses 11-16, further comprising: one or more external sensors, each external sensor configured to measure an external parameter value of the patient over time.

[0227] Clause 18: The wearable monitor of clause 17, the one or more external sensors comprising one or more of a temperature sensor, a motion sensor, or an oxygen sensor.

[0228] Clause 19: A method of determining a health condition of a patient using a wearable monitor having at least one internal sensor positioned in interstitial tissue of the patient and at least one external sensor positioned in the wearable monitor, comprising: interacting, at a first working electrode of the at least one internal sensor, with a first analyte in the interstitial tissue over time; interacting, at a second working electrode of the at least one internal sensor, with a second analyte in the interstitial tissue over time; generating, by the first working electrode, a first electrical signal proportional to a first analyte concentration in the interstitial tissue over time; generating, by the second working electrode, a second electrical signal proportional to a second analyte concentration in the interstitial tissue over time; converting, by a processor, the first electrical signal to a first analyte level in the interstitial tissue over time and the second electrical signal to a second analyte level in the interstitial tissue over time; receiving, by the processor from the atAttorney Docket No. A0014277W001least one external sensor, a third electrical signal corresponding to an external parameter value of the patient over time; and determining, at a first time, the health condition of the patient based on the external parameter value, the first analyte level, and the second analyte level at the first time.

[0229] Clause 20: The method of clause 19, further comprising: determining, at a second time, the health condition of the patient based on at least one change in at least one of the external parameter value, the first analyte level, or the second analyte level at the second time.

[0230] The techniques described in this disclosure may also be embodied or encoded in a computer-readable medium, such as a computer-readable storage medium, containing instructions. Instructions embedded or encoded in a computer-readable medium may cause a programmable processor, or other processor, to perform the method, e.g., when the instructions are executed. Computer-readable media may include non-transitory computer-readable storage media and transient communication media. Computer readable storage media, which is tangible and non-transitory, may include random access memory (RAM), read only memory (ROM), programmable read only memory (PROM), erasable programmable read only memory (EPROM), electronically erasable programmable read only memory (EEPROM), flash memory, a hard disk, a CD-ROM, a floppy disk, a cassette, magnetic media, optical media, or other computer-readable storage media. It should be understood that the term “computer-readable storage media” refers to physical storage media, and not signals, carrier waves, or other transient media.

[0231] Such hardware, software, and firmware may be implemented within the same device or within separate devices to support the various operations and functions described in this disclosure. In addition, any of the described units, modules or components may be implemented together or separately as discrete but interoperable logic devices. Depiction of different features as modules or units is intended to highlight different functional aspects and does not necessarily imply that such modules or units must be realized by separate hardware or software components. Rather, functionality associated with one or more modules or units may be performed by separate hardware or software components, or integrated within common or separate hardware or software components.Attorney Docket No. A0014277W001

[0232] Various examples have been described. These and other examples are within the scope of the following claims.

Claims

1. Attorney Docket No. A0014277W001CLAIMSWhat is claimed is:

1. A wearable monitor (102) configured to determine a health condition of a patient, comprising:a plurality of internal sensors (116A-116G) configured to be positioned within interstitial fluid of the patient, the plurality of internal sensors including at least one flex circuit, comprising:a first working electrode (134, 136, 142, 148) responsive to a first analyte (126) concentration over time;a second working electrode (134, 136, 142, 148) responsive to a second analyte (126) concentration overtime; anda third working electrode (134, 136, 142, 148) responsive to a third analyte (126) concentration overtime; andat least one external sensor (179, 181, 183) configured to sense at least one external parameter value of the patient over time,wherein the health condition of the patient is determined at a first time based on one or more of the at least one external parameter value, the first analyte concentration, the second analyte concentration, or the third analyte concentration at the first time.

2. The wearable monitor of claim 1, wherein the health condition of the patient is determined at a second time based on at least one change in at least one of the external parameter value, the first analyte concentration, the second analyte concentration, or the third analyte concentration at the second time.

3. The wearable monitor of any one of claims 1 or 2, wherein the at least one external sensor is configured to determine the at least one external parameter value substantially continuously over time.Attorney Docket No. A0014277W0014. The wearable monitor of any one of claims 1-3, wherein at least one of the plurality of internal sensors is configured to determine at least one of the first analyte concentration, the second analyte concentration, or the third analyte concentration substantially continuously over time.

5. The wearable monitor of any one of claims 1-4, the at least one flex circuit further comprising a fourth working electrode responsive to a fourth analyte concentration over time.

6. The wearable monitor of any one of claims 1-5, the at least one flex circuit comprising a first flex circuit and a second flex circuit.

7. The wearable monitor of any one of claims 1-6, wherein the wearable monitor is mounted on an exterior skin surface of the patient.

8. The wearable monitor of any one of claims 1-7, wherein the first working electrode is responsive to a creatinine concentration over time, the second working electrode is responsive to a glucose concentration over time, and the third working electrode is responsive to a potassium concentration over time.

9. The wearable monitor of claim 5, wherein the fourth working electrode is responsive to an oxygen concentration over time.

10. The wearable monitor of any one of claims 1-9, wherein the at least one external sensor is at least one of a temperature sensor, an oxygen sensor, or a motion sensor.

11. A method of determining a health condition of a patient using a wearable monitor (102) having at least one internal sensor (116A-116G) positioned in interstitial tissue of the patient and at least one external sensor (179, 181, 183) positioned in the wearable monitor, comprising:interacting (902), at a first working electrode (134, 136, 142, 148) of the at least one internal sensor, with a first analyte (126) in the interstitial tissue over time;Attorney Docket No. A0014277W001interacting (904), at a second working electrode (134, 136, 142, 148) of the at least one internal sensor, with a second analyte (126) in the interstitial tissue over time;generating (906), by the first working electrode, a first electrical signal proportional to a first analyte concentration in the interstitial tissue over time;generating (908), by the second working electrode, a second electrical signal proportional to a second analyte concentration in the interstitial tissue over time;converting (910, 912), by a processor (876), the first electrical signal to a first analyte level in the interstitial tissue over time and the second electrical signal to a second analyte level in the interstitial tissue over time;receiving (914), by the processor from the at least one external sensor, a third electrical signal corresponding to an external parameter value of the patient over time; and determining (916), at a first time, the health condition of the patient based on the external parameter value, the first analyte level, and the second analyte level at the first time.

12. The method of claim 11, further comprising:determining (918), at a second time, the health condition of the patient based on at least one change in at least one of the external parameter value, the first analyte level, or the second analyte level at the second time.

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